Progress in Cardiovascular Diseases - eHealth Initiative · 2017-10-17 · diseases (CVD), the...

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Progress inCardiovascularDiseases

Vol. 60, No. 2September/October

2017

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2016Impact Factor

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Update on ContemporaryManagement of Heart Failure

Hector O. Ventura, MDand Ileana L. Piña, MD, MPH

Guest Editors

Carl J. Lavie, MDEditor-in-Chief

Christopher J. White, MDand Hector O. Ventura, MD

Editors

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CardiovascularDiseases

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169 Comprehensive Heart Failure Management Hector O. Ventura and Ileana L. Piña

171 Is an Admission for Decompensated Heart Failure Inevitable? Alexander J. Blood , Ariane M. Fraiche , and Zubin J. Eapen

178 Approach to Acute Heart Failure in the Emergency Department Benton R. Hunter, Jennifer Martindale, Osama Abdel-Hafez,and Peter S. Pang

187 Pharmacologic Therapy for Heart Failure With Reduced Ejection Fraction: Closing the Gap Between Clinical Guidelines and Practice J. Barr Biglane, Miriam F. Becnel, Hector O. Ventura, and Selim R. Krim

198 Late In-Hospital Management of Patients Hospitalized With AcuteHeart Failure Nicole B. Cyrille and Snehal R. Patel

205 Changing our Approach to Stage D Heart Failure Miriam Becnel, Hector O. Ventura, and Selim R. Krim

215 Palliative Care in Heart Failure: What Triggers Specialist Consultation? Mitchell A. Psotka , Kanako Y. McKee , Albert Y. Liu , Giovanni Elia ,and Teresa De Marco

226 Heart Failure With Myocardial Recovery - The Patient Whose Heart Failure Has Improved: What Next? Petra Nijst, Pieter Martens, and Wilfried Mullens

237 A Blueprint for the Post Discharge Clinic Visit After an Admission for Heart Failure Aaron Soufer, Ralph J. Riello, Nihar R. Desai, Jeffrey M. Testani,and Tariq Ahmad

249 Heart Failure Transitions of Care: A Pharmacist-Led Post-DischargePilot Experience Sherry K. Milfred-LaForest , Julie A. Gee, Adam M. Pugacz, Ileana L. Piña, Danielle M. Hoover, Robert C. Wenzell, Aubrey Felton, Eric Guttenberg, and Jose Ortiz

259 Implementation of a Patient Navigator Program to Reduce 30-day Heart Failure Readmission Rate Katherine E. Di Palo , Khusbu Patel , Manaf Assafin , and Ileana L. Piña

Special Article

267 A Review of Cardiac Rehabilitation Delivery Around the World Ella Pesah, Marta Supervia, Karam Turk-Adawi, and Sherry L. Grace

Editor’s Commentary

281 From Heart Failure to Journal Metrics-Making Progress in Cardiovascular Diseases Carl J. Lavie

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For details on the contents of any issue of Progress in Cardiovascular Diseases, or to order a copy, please visit www.onlinepcd.com.

Vol. 60, No. 2 September/October 2017

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Ross Arena, PhD, PT, FAHAUniversity of Illinois Chicago

Chicago, ILSripal Bangalore, MDNew York University

New York, NYAnthony N. DeMaria, MD, MACCUniversity of California San Diego

San Diego, CAJames J. DiNicolantonio, PharmD

Mid-America Heart InstituteKansas City, MO

Bernard J. Gersh, MB, ChB, DPhilMayo Clinic

Rochester, MN

Henry Greenberg, MDSt. Luke’s-Roosevelt Hospital Center

New York, NYFranz H. Messerli, MD

St. Luke’s-Roosevelt Hospital CenterNew York, NY

Richard V. Milani, MD, FACCJohn Ochsner Heart and Vascular InstituteOchsner Clinical School–The University of

Queensland School of MedicineNew Orleans, LA

Daniel P. Morin, MD, MPH, FACC, FHRSJohn Ochsner Heart and Vascular InstituteOchsner Clinical School–The University of

Queensland School of MedicineNew Orleans, LA

James H. O’Keefe, MD, FACCMid-America Heart Institute

Kansas City, MO

Former EditorsHenry Greenberg, MD

Michael Lesch, MDEdmund Sonnenblick, MD

Charles Friedberg, MD, Founding Editor

Editor-in-ChiefCarl J. Lavie, MD, FACC

John Ochsner Heart and Vascular InstituteOchsner Clinical School–The University of Queensland School of Medicine

New Orleans, LA

EditorsChristopher J. White, MD, FACC

John Ochsner Heart and Vascular InstituteOchsner Clinical School–The University of Queensland School of Medicine

New Orleans, LA

Hector O. Ventura, MD, FACCJohn Ochsner Heart and Vascular Institute

Ochsner Clinical School–The University of Queensland School of MedicineNew Orleans, LA

Editorial Board

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Editorial

Comprehensive Heart Failure Management

Scope of heart failure Current progress in CVD (PCVD) issue

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Epidemiology

Heart failure (HF) is a major public health problem in thUnited States (US) and across the world.1–3 It is estimated thathere are 5.7 million adults in the US living with HF and thathere are 1 million hospitalizations for HF yearly.3 Despitedecline in mortality and morbidity from most cardiovasculadiseases (CVD), the prevalence of HF has increaseworldwide,4,5 whereas the incidence has plateaued.6 Thubetween 1994 and 2003, the prevalence of HF in a US Medicarpopulation increased from 90 to 121 per 1000 subjects.7 ThAmerican Heart Association estimates that the prevalence oHF will increase by 46% from 2012 to 2030, which amounts tomillion people older than 18 years old with a HF diagnosisWith the increase in incidence and prevalence, projected cosincreases are highly significant.

Hospitalizations

Index hospitalizations and readmissions remain as majoissues in CVD, particularly affecting older patients. ThCenters of Medicare and Medicaid Services recognize thathe older adults with HF are also bringing a minimum of 4–comorbidities in each hospitalization.3,8 Furthermore, thnatural history of HF is characterized by clinical exacerbationthat contribute to a need for hospitalizations. Multiplhospitalizations place a burden on patients, health carsystems, and society. It has been reported that hospitadischarges for HF has increased by 155% during the las20 years,6 and the health care costs exceed 30.7 billion dollarannually and will increase to 69.7 billion dollars in 2030.4,9 It irecognized that some hospital readmissions for patients witHF are unavoidable, but many can be prevented.10,11 Factorthat are associated with readmission rates for HF includshorter length of stay and multiple emergency room (ERvisits within 6 months of hospitalization. An alarming statistic is that once patients are hospitalized, each admissiocontributes to an increase in mortality.9,10

0033-0620/© 2017 Elsevier Inc. All rights reserved.

Because of the complexity of this syndrome as noted above,is paramount to compile a comprehensive analysis of patientwith HF and their associated problems.

In this current issue of PCVD, leaders in the field of Hdiscuss several aspects of the management of these patientsfrom ER to chronic care, including treatment of acute, chronicand advanced HF, as well as patients who achieved myocardial recovery. Palliative care and transitions of care in order treduce hospitalizations and to improve quality of life of thespatients are also discussed.

It has been said, that “Planning is bringing the futurinto the present so that you can do something about it nowWe sincerely hope that this HF issue of PCVD will guidclinicians to make evidence based choices for their patientsHowever, where no evidence is available, hopefully this issuhelps to at least apply fundamental knowledge and wisdomto their care.

R E F E R E N C E S

1. Hall MJ, Levant S, DeFrances CJ. Hospitalization for congestivheart failure: United States, 2000–2010. NCHS data brief, no108. Hyattsville, MD: National Center for Health Statistics;2012.

2. Enciso JS, Greenberg B. Evolving issues in heart failuremanagement. Prog Cardiovasc Dis. 2016;58:365-366.

3. Ventura HO, Silver MA. Observations and reflections on theburden of hospitalizations for heart failure. Mayo Clin Proc.2017;92:175-178.

4. Mozzafarian D, Benjamin EJ, Go AS, et al, on behalf of theAmerican Heart Association Statistics Committee and StrokStatistics Subcommittee. Heart disease and stroke statis-tics—2016 update: a report from the American Heart Associ-ation. Circulation. 2016;133:e38-e360.

5. Heidenreich PA, Albert NM, Allen LA, et al, on behalf of theAmerican Heart Association Advocacy CoordinatingCommittee, Council on Arteriosclerosis, Thrombosis andVascular Biology, Council on Cardiovascular Radiology and

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170 P R O G R E S S I N C A R D I O V A S C U L A R D I S E A S E S 6 0 ( 2 0 1 7 ) 1 6 9 – 1 7 0

Intervention, Council on Clinical Cardiology, Council onEpidemiology and Prevention, Stroke Council. Forecastingthe impact of heart failure in the United States: a policystatement from the American Heart Association. Circ HearFail. 2013;6:606-619.

6. Roger VL, Weston SA, Redfield MM, et al. Trends in heartfailure incidence and survival in a community-based population. JAMA. 2004;292(3):344-350.

7. Curtis LH, Whellan DJ, Hammill BG, et al. Arch Intern Med.2008;168(4):418-2.

8. Roger VL. The changing landscape of heart failure hospitali-zations. JACC. 2013;61:1268-1270.

9. Heidenreich PA, Trogdon JG, Khavjou OA, et al. Forecastingthe future of cardiovascular disease in the United States: apolicy statement from the American Heart Association.Circulation. 2011;123:933-944.

10. Baker H, Oliver-McNeil S, Deng L, Hummel S. Regionalhospital collaboration and outcomes in Medicare heart failurpatients: see you in 7. JACC Heart Fail. 2015;3:765-773.

11. Ziaeian B, Fonarow GC. The prevention of hospitalreadmissions in heart failure. Prog Cardiovasc Dis. 2016;58:379-385.

Hector O. Ventura, MDJohn Ochsner Heart and Vascular Institute, Ochsner Clinical Scho

The University of Queensland School of Medicine, Australi

Ileana L. Piña, MD, MPAlbert Einstein College of Medicine and Montefiore Heart and Vascula

Center, Bronx, NY, United State

⁎Corresponding author at: Ochsner Clinic Foundatio1514 Jefferson Highway, New Orleans, LA 70121, United State

E-mail address: [email protected]

© 2017 Published by Elsevier In

http://dx.doi.org/10.1016/j.pcad.2017.08.001



ScienceDirect


Is an Admission for Decompensated Heart Failure
Inevitable?
Alexander J. Blood, Ariane M. Fraiche, Zubin J. Eapen⁎

Department of Medicine, Duke University Medical Center, Durham, NC, United States

A R T I C L E I N F O

Statement of Conflict of Interest: See pDisclosures: Alexander J Blood, MD - n

⁎ Corresponding author at: Duke ClinicalE-mail address: [email protected]

http://dx.doi.org/10.1016/j.pcad.2017.07.000033-0620/© 2017 Elsevier Inc. All rights re

A B S T R A C T

,
Keywords: esFn-e
.

Given the high prevalence of heart failure (HF) and the profound impact on morbidmortality, and health care costs, strategies to improve outcomes and reduce cost havbecome progressively more attractive. Reducing HF hospitalizations as a study outcome hagained traction in recent years. The basic hypothesis of these investigations is that Hhospitalizations are preventable and harmful. This article examines advancements ipharmacotherapy, medical devices, and health care delivery techniques targeting reductions in HF hospitalizations and evaluates the role and implications of hospitalization in thnatural history of HF.

© 2017 Elsevier Inc. All rights reserved

Heart failureHospitalizationsReadmissionTransitions of careTelehealthAlternativePayment models

Contents

22344555

Factors leading to HF hospitalization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17HF hospitalization as an outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Transitions of care and alternative venues for HF care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Financial considerations of HF readmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Advancements in payment and reimbursement models focusing on HF . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Turning back to a key question: Hospitalization, morbidity, or mortality? . . . . . . . . . . . . . . . . . . . . . . . . . . 17Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

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The population affected and health care impact of heart failur(HF) are striking with estimates of roughly 5.7 million adults ithe United States (US) living with HF and 1 million hospitalizations for HF in 2000 and in 2010.1 The American HeaAssociation (AHA) projects that the prevalence of HF wiincrease by 46% from 2012 to 2030, which amounts to 8 millio

age 175.one. Ariane M Fraiche, MDResearch Institute, PO B

(Z.J. Eapen).

3served.

people older than 18 years old with a HF diagnosis.2 The healtcare costs related to HF exceed 30.7 billion dollars annuallywhich is estimated to increase by 127% to 69.7 billion dollars i2030.3,4 As a major driver of hospitalizations and health cardollars, HF has become a critical area for health care reformContemporary objectives for reform include reducing hospita

– none. Zubin J Eapen, MD, MHS - none.ox 17969, Durham, NC 27715, United States.

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Abbreviations and Acronyms

ACEI = Angiotensin convertingenzyme inhibitor

AHA = American HeartAssociation

APM = Alternative paymentmodels

BB = Beta blocker

CMS = Centers for Medicare &Medicaid Services

CRT = Cardiac-resynchronizationtherapy

CV = Cardiovascular

EF = Ejection fraction

ERR = Excess Readmission Ratios

GWTG = Get with the guidelines

HF = Heart failure

HRRP = Hospital ReadmissionReduction Program

HTN = Hypertension

ICD = Implantable cardioverter –defibrillator

IPPS = Inpatient Prospective Pay-ment System

NYHA = New York HeartAssociation

US = United States


izations, decreasinduration of inpatientreatment and limitinhospital readmissionsStudies have showthat hospitalization foHF leads to additionahospitalizations and predicts higher mortalityThus, there has beentremendous amount oeffort directed at reducing hospitalizations witthe inherent assumptioof these efforts is thasomeHFhospitalizationare preventable and noinevitable.Thisarticleexamines the preventablnature of HF hospitalzations and outlineinnovations in diseasmonitoring and treatment, care deliverand transitions of carthat target reductionin HF hospitalizations

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Factors leading tHF hospitalization

Understanding thpathophysiology, justification, etiology anprecipitants for de

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compensated HF admission is integHF hospitalizations are inevitable. Instigated by precipitantsuch as increased cardiac demands, acute coronary syndromeand dietary or medication non-compliance, preexisting poocardiac output is stressed by increasing preload and afterloadThis decrease in cardiovascular (CV) function causes fluid taccumulate within the vascular space, and decreased oncotipressure forces extravasation of this fluid into the interstitiaspace. As body weight increases secondary to the excess fluidphysical activity decreases, and along with it, passive mechanisms for the reabsorption of interstitial fluid. As the fluiaccumulates further, the pulmonary system reserves are slowlreduced contributing to dyspnea on exertion that progresses torthopnea, paroxysmal dyspnea, and finally, shortness of breatat rest. At its most extreme, a HF exacerbation can lead trespiratory failure due to pulmonary edema, cardiac failure fromoverwhelmed circulatory demands or death.6 Small changes ithe clinical status of heart failure patients tip the delicate balancbetween safe home and more intensive monitoring and management in an inpatient clinical setting. In this patient population, hospitalizations have been shown to beget morhospitalizations and this increased burden of hospitalizationhas been associated with mortality.7

The 2013 American College of Cardiology/AHA HearFailure Guideline emphasizes the importance of differentiating de novo hospitalizations for HF from acute worsening ochronic stable HF.3 For the purposes of this article, the authoraddress the challenges surrounding the latter. Commoprecipitants for decompensated chronic HF leading to hosptalization include but are not limited to the following: dietarindiscretion (sodium and/or fluid restriction), medicationoncompliance, coronary ischemia, uncontrolled hypertension (HTN), infection, arrhythmia and endocrine abnormalties being among the most common.8–10 Fonarow, Abrahamand Albert investigated the frequency of these triggers amonpatients admitted for HF exacerbation by analyzing a randomsample of the Organized Program to Initiate LifesavinTreatment in Hospitalized Patients with Heart Failur(OPTIMIZE-HF) registry which included 48,612 patients hosptalized for HF at 259 sites in the US.8 The most commoetiologies for decompensated HF admission of the 61.3% opatients with precipitant identified included two or morfactors in most patients (19.2%), respiratory infection (15.3%coronary ischemia (14.7%), arrhythmia (13.5%), uncontrolleHTN (10.7%) and medication and dietary nonadherence (8.9%and 5.2%, respectively).7–9 Recently, Wu et al. reviewed aadmissions for HF at a tertiary hospital in a 12-month perioincluding 482 patients, and interestingly, the most commotrigger that precipitated hospitalization in this cohort wasuboptimal medication adherence.11 Contrary to the findingof Wu et al., of the identified causes for HF hospitalization ithe OPTIMIZE-HF cohort, sub-optimal medication adherenchad one of the weakest associations with HF hospitalizationMoreover, Farmer et al. conducted interviews with clinicianHF patients and caretakers to determine qualitative contributors to hospitalization for HF. Issues with communicatioboth between providers and patients and system-level factorwere identified as significant determinants of wellness ipatients with HF. Lack of patient education of the diseasprocess and effects of medical therapy, mental healtdisorders and direct costs to patients were barriers tpreventing hospitalizations.12 This diversity of identifiabltriggers for HF hospitalization among these studies highlightthat it is challenging to identify targets ripe for intervention treduce HF hospitalizations and suggests that controlling fofactors leading to decompensation when there are severasimultaneously is a difficult goal.

HF hospitalization as an outcome

Because hospitalizations are associated with increased healtcare costs and worse patient outcomes in the natural historof HF, reducing hospitalizations is typically included asprimary or secondary outcome in investigations of novel Htherapies.13 For example, an analysis from the Systolic Hearfailure treatment with the If inhibitor ivabradine Trial (SHIFTshows that patients with an index hospitalization for worsening HF have a 3.5 fold increased risk of mortality a18 months.14 Yet, research has also shown that althougthey incur financial penalties, 30-day readmissions do nocorrelate with mortality.15 Repeated hospitalizations for HF

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however, has been shown to predict mortality in a HF patienpopulation.16 In the evaluation and management of patientwho have HF, new medications, telemonitoring, electrophysiologic and advanced HF therapeutic devices allow for thtreatment of these patients in ways not imagined before nowThe objectives for new treatments in HF have historicallbeen mortality, but in recent years, reducing hospitalizatiohas gained emphasis. Reviewing how hospitalization habeen addressed in several landmark heart failure trialshowcases that numerous HF hospitalizations may bprevented with optimal management.

The cornerstones of pharmacotherapy in HF have reducenot only mortality but also HF hospitalizations. For examplethe investigators of the Survival And Ventricular Enlargemen(SAVE) trial studied the role of the angiotensin-convertingenzyme inhibitor (ACEI) captopril in improving outcomes ipatients with left ventricular dysfunction—defined as aejection fraction (EF) <40%—after myocardial infarction. ThACEI reduced hospitalizations to 14% of the study populatioversus 17% of patients receiving placebo therapy (RR 0.78, 95%CI 0.63–0.96, P = 0.019). Moreover, the results revealed thapatients who were hospitalized had higher mortality regardless of study versus control population with 47% mortality ipopulation admitted for HF versus 18% not hospitalized for H(RR 6.4, 95% CI 5.3–7.8, P < 0.001).17 The RandomizeAldactone Evaluation Study (RALES) trial included patientwith EF ≤ 35%, New York Heart Association (NYHA) Class IHF documented in the last six months (III or IV at time oenrollment), and receiving treatment with loop diuretics anACEIs. Secondary outcome results revealed a significanreduction in hospitalization for CV causes when comparinthe aldosterone receptor blocker spironolactone to placebo b30% (RR 0.70; 95% CI 0.59–0.82; P < 0.001).18

Concerning beta blocker (BB) therapy, combined outcomethat encompass hospitalizations are featured and showstatistically significant improvement with BB therapy in thmajor landmark trials such as Metoprolol CR/XL RandomizeIntervention Trial in Congestive Heart Failure (MERIT- HF) anCarvedilol Post-Infarct Survival Control in LV Dysfunctio(CAPRICORN).19,20 Cardiac Insufficiency Bisopolol Study(CIBIS-II) revealed a statistically significant reduction iall-cause hospital admissions and HF hospitalizations by 6%for each.21 Using propensity-matched cohort observationadata, Bhatia et al. respond to the concern that the negativinotropic effect when initiating BB therapy would lead tincreased 30-day all-cause readmission rates.22 Contradictorto this concern, the initiation of BB therapy was noassociated with higher 30-day all-cause readmission—aimportant conclusion affecting the 30-day readmission targets for health cost reduction reform.

It is now commonplace for large phase 3 trials to use thcomposite end point of CV mortality and HF-related hospitaization to evaluate HF medications. Novel medical therapiefor HF also focus on readmissions as a target outcomeAngiotensin-neprilysin inhibition (Entresto) has been showto reduce CV and all-cause mortality and drive dramatireductions in hospitalizations for HF as compared to ACEI12.8% in the study group versus 15.6% in the enalapril grou(HR 0.79; 95% CI 0.71–0.89, P < 0.001).23 Moreover, th

composite outcome, CV death or hospitalization for worsening HF in the SHIFT trial was heavily influenced by hospitaizations for decompensated HF–16% in the ivabradine grouversus 21% in the placebo group (HR 0.74, 0.66–0.83P < 0.0001), although ivabradine failed to show mortalitreduction.14

Regarding device therapy in HF patients showing reductionin HF hospitalizations, in Biventricular versus Right VentriculaPacing in Heart Failure (BLOCK HF), patients with NYHA ClassII, III HF and high degree atrioventricular block, who underwenbiventricular pacing had a reduced risk of HF hospitalizatio(HR 0.70, 95% CI 0.52–0.93, posterior probability of HR <0.9922).24 Also, the Resynchronization-Defibrillator for Ambulatory Heart Failure Trial (RAFT) investigators featured deatfrom any cause or HF hospitalization as the primary outcome.2

1798 patientswith an EF < 30%, NYHAClass II or III HF, andQRinterval ≥ 120 milliseconds or paced QRS duration ≥200 millseconds were randomized to implantable cardioverterdefibrillator (ICD) or cardiac-resynchronization therapy (CRTin addition to ICD. The investigators showed a reduction in thprimary outcome (33.2% of ICD plus CRT patients versus 40.3%in ICD alone patients (HR 0.75, 95% CI 0.62–0.91) and reductioin HF hospitalizations alone with a hazard ratio of 0.68 (95% C0.53–0.83, P < 0.001).

These examples highlight several innovations in medicaand device therapy that have shown to reduce HF hospitalizations. Yet, these advancements in medical and device therapdo not target some of the most common culprits of Hdecompensation as described previously such as poor diemedication non-compliance and respiratory infections. Strategies to improve transitions of care can complement medicaand device therapies as a means to reducing rehospitalizationamong HF patients.

Transitions of care and alternative venues for Hcare

Regarding transitions of care after HF hospitalization, conclusions from theOPTIMIZE-HF andGetWith theGuidelines-HearFailure (GWTG-HF) registries suggest that higher rates opost-discharge clinic follow-up within 7 days is associatewith decreased 30-day readmission rates for hospitals.2

Determining how to coordinate outpatient care after inpatienhospitalization offers opportunities for quality improvemenprojects in this key transitional period. Examples of interventions to reach this endpoint include a French study whicshowed that a more aggressive outpatient managemenapproach with regularly scheduled appointments and higheoutpatient diuretic doseswas associatedwith fewer unforeseeappointments and fewer hospitalizations.27 Al-Damluji et apropose that communication elements conveyed to primarcare providers such as including more elements in dischargdocumentation such as principal diagnosis, problem lismedication list, transferring physician name and contacinformation, cognitive status of the patient, test results anpending test results were associated with a lower risk oreadmission, further emphasizing the key role of outpatienmanagement to reduce hospitalization.28

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To complement evidence-basedmedications and devicesthere is a myriad of alternative venues in which a HF patienmay be able to receive care. Whellan et al. establishedprecedent for studying a comprehensive outpatient diseasmanagement approach to optimizing HF treatment. Thidisease management program for patients with HF was ablto improve the percentage of patients on optimal medicatherapy and decrease hospitalization, all while reducincosts.29 For example, the use and dose of BB therapincreased after enrollment in the disease managemenprogram, which utilized protocols to optimize medicamanagement, frequent visits and telephone encounterwith the HF team based on severity of illness and robuspatient education materials. Moreover, the median rate ohospitalizations per patient-year decreased from 1.5 hospitalizations per patient-year to 0 for patients enrolled in thprogram (P < 0.01). Contemporary care model exampleinclude the Duke Same Day Access clinic and the Brighamand Women's Hospital's Ambulatory Cardiac, Triage, Intervention, and Education (ACTIVE) Unit, which provide alternatives to the emergency room for patients needing acutevaluation and management for worsening Hsymptoms.30,31 During the first three years of operation othe Duke Same Day Access Clinic, the hospital saw aabsolute 10.2% reduction in 30-day HF re-admissions.3

Similarly, an analysis of 60 chronic HF patients treated ithe Brigham and Women's Hospital's ACTIVE Unit supportthe effectiveness of protocoled intravenous diuretics tincrease urinary output, achieve weight loss and avoihospitalization.31 In addition to improving access to carand extending the arm of clinical care, alternative clinicavenues potentially allow hospitals to avoid the penaltieassociated with hospital readmissions.

In terms of telehealth strategies to reduce hospitalizations related to HF, the data is mixed. A large meta-analysiof 41 peer-reviewed, randomized controlled trials showedpositive impact of a wide range of telehealth methods oHF-related hospitalizations, but the conclusions are limiteby the diversity of interventions, size and quality oresults.32,33 CardioMEMS Heart Sensor Allows Monitoring oPressure to Improve Outcomes in NYHA Class III HearFailure Patients (CHAMPION)—a single-blinded, multicenterandomized controlled trial with 550 patients—included Hhospitalizations as a primary outcome.34 The 37% decrease ithe rate of HF hospitalizations in the treatment grousuggests that implantable hemodynamic monitoring devicehave a role in reducing HF-related hospitalizations. On thother hand, a recent meta-analysis and systematic reviewincluding telemonitoring as an intervention to reducreadmissions in HF patients did not show a statisticallsignificant benefit on all-cause 30-day readmission nor 3 o6-month all-cause readmission.35 Diverse and conflictinevidence has hampered efforts to enact telehealth strategiesyet future research encompassing telehealth strategies intalternative payment models and readmission reductioprograms may play a role in high value HF care.32 Thescreative avenues for HF management are further instruments to prevent hospitalizations for high risk patients thafocus on known triggers for decompensation.

Financial considerations of HF readmission

Health care reform that targets reducing hospitalizations igeneral harvests significant interest in HF hospitalizationJencks et al. found that HF was the most common condition aindex discharge for patients in the Medicare Fee-for-ServicProgram readmitted within 30 days with a 26.9% readmissiorate, and HF was also the most frequent reason for readmissiofor patients discharged with HF as condition at index dischargand for all patients readmitted within 30 days.36 Centers foMedicare & Medicaid Services (CMS) started to publicize 30-dareadmission rates for patients hospitalized and discharged witpneumonia, myocardial infarction and HF in 2009.37 This publireporting beganwith the aimof increasing transparency, but threporting itself has not been shown to reduce 30-day readmission rates.38 The Inpatient Prospective Payment System (IPPSdelivers payments for Medicare beneficiaries who are hospitaized, and since 2012, the IPPS has been used to limit Medicarreimbursements for hospitals with higher than predictereadmission rates.39 A study analyzing the effect of the HospitaReadmission Reduction Program (HRRP) found that 73% ohospitals in 2014 received penalties for rehospitalizationFurther analysis of the penalties revealed that HF had strongeExcess Readmission Ratios (ERR) than other conditions and hathe strongest correlation with the scale of the penalty.40 In thHRRP CMS defines the ERR as a calculation of a hospitalreadmission rate compared to the national average readmissiorate for similar peer hospitals taking care of patientswith similademographic and comorbid conditions.41 Medicare data from2009 to 2012 estimates the median risk-standardized 30-dareadmission rate for HF as 23.0%.42 Whether HF hospitalizatioor all-cause hospitalization is the ideal outcome is a pertinenquestion. All-cause re-hospitalization, currently the focus ofinancial penalties, occurswithmuch greater frequency than Hreadmission and captures not only the financial but also thpatient-centric aspect of this outcome.43 In the context of thHRRP, an analysis of Medicare data showed that hospitalsubject to penalty had greater reductions in readmission ratewhen compared with hospitals not at risk for the penalty.44

Advancements in payment and reimbursemenmodels focusing on HF

The Medicare Access and CHIP Reauthorization Act of 201(MACRA)was passedwith the aim to transition from traditionafee-for-service payment structure to value-based care (PubliLaw: 114–10). MACRA establishes the Quality Payment Programwith two options for Medicare providers to design value-basepayment reform including the Merit-based Incentive PaymenSystem and alternative payment models (APMs). Througeither of these payment pathways, physicians will receivreimbursements for Medicare patients through measurementrelated to four core domains—quality activities, clinical improvement activities, advancing care information performancand cost.45 Examples of APMs include bundled payments for Hhospitalizations, which fall under APMs built on the feefor-service architecture with risk and gainsharing an

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population-based payments for heart failure care.32,46,47 Thadvent of APMs inHF offer opportunities for quality-driven carthat encompasses the previously mentioned strategies such atelemonitoring and alternative outpatientmanagement effort

Within theAPM frameworks, resourceswill likely shift awafrom a reactive approach to management to a proactivapproach to managing these patients outside of the hospitaProviding the appropriate level of monitoring and therapy fopatients at different stages of their illness will likely be criticato reduce hospitalizations. With increasing application otechnological advancements using health metrics and montoring, predictivemodels to identify HF patients who are at risof developing adverse events such as hospitalization and deatare improving, and there are increasing opportunities to guidresource allotment efficiency.48 The goal of these reform effortimprove prevention and reduce costs. The hope is that Hhospitalization may be prevented in many if not most cases.

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Turning back to a key question: Hospitalizationmorbidity, or mortality?

The knowledge that hospitalization as an event in the naturahistory of HF portends a poor prognosis has been discussedand diverse approaches to preventing hospitalizations habeen shown to be effective in this assessment. However, sompopulations have higher risks of hospitalizations offeringpotential confounder when assuming hospitalization portends mortality and when determining the inevitability ohospitalization.

Studies have demonstrated that race, ethnicity and socioeconomic states affect hospitalization outcomes in HF patientVivo et al. elucidate several noteworthy differences ireadmissions and mortality based on race and ethnicity of Hpatients using the GWTG-HF registry coupled with Medicardata.49 A critical finding of this study including 47,149 Medicarpatients over age 65 is that even though black and Hispanipatients were more likely to be admitted at 30-day and 1-yeafollow-up intervals than white patients, mortality was lower ithe black and Hispanic population at the same follow-uintervals. When socioeconomic status, patient clinical characteristics and hospital-related variables were added to thmultivariable model, the mortality outcome differences amonrace/ethnicities remained the same, but the groups becammore similar regarding readmissions. Black patients still hahigher 1-year readmission rates. Similarly, median householincome has been shown to be inversely associated with 30-damortality (OR 0.97, 95% CI 0.95–1.00, P = 0.032).50 These conclusions highlight an important concept: HF hospitalizations arnot associated with higher mortality in all patient populationAs evidence-based methods shift to focus on hospitalizatiooutcomes as described above, mortality-based managemenand therapeutics are still relevant.

Hospitalization is now featured in many HF trials. As thprevalence of HF continue to increase, the 1 million hearfailure hospitalizations in 2000 and 2010 has remainestable.3 Interventions aimed at reducing hospitalizationmay have contributed to reducing the inevitability of Hhospitalization in many cases. But, the natural history o

heart failure is one of gradual decline punctuated by acutexacerbations, which in part may be due to non-preventablevents. Considering ongoing advances in the developmendesign and implementation of new HF care, it is importanthat mortality is not overlooked in favor of hospitalizatioreduction. Innovation in medical therapies, devices anhealth care delivery will likely continue to improve accesand adeptness of monitoring and management for HF witthe added benefit of aiming to reduce hospitalizationsHowever, while many of these punctuations are preventabland manageable outside of the walls of the hospital, such atools and systems to ensure medication and dietary complance, medications to reduce the incidence of coronarischemia and paroxysms of HTN, these culprits are often noreversible or available within the outpatient setting. Thespatients are often at risk for rapid and non-reversible clinicadecompensation that is not amenable to outpatient management. While we will continue to improve our ability tmonitor and prevent HF hospitalizations that are not inevitable, high risk patients will likely continue to experiencdecompensation that will require inevitable hospitalization.

Conflict of interest

None.

R E F E R E N C E S

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2. Heidenreich PA, Albert NM, Allen LA, et al. Forecasting theimpact of heart failure in the United States: a policy statemenfrom the American Heart Association. Circ Heart Fail. 2013;6:606-619.

3. Mozzafarian D, Benjamin EJ, Go AS, et al, on behalf of theAmerican Heart Association Statistics Committee and StrokStatistics Subcommittee. Heart disease and stroke statis-tics—2016 update: a report from the American Heart Associ-ation. Circulation. 2016;133:e38-e360.

4. Heidenreich PA, Trogdon JG, Khavjou OA, et al. Forecastingthe future of cardiovascular disease in the United States: apolicy statement from the American Heart Association.Circulation. 2011;123:933-944.

5. Solomon SD, Dobson J, Pocock S, et al. Influence of nonfatalhospitalization for heart failure on subsequent mortality inpatient with chronic heart failure. Circulation. 2007;116:1482-1487.

6. Lilly LS. Heart Failure: Pathophysiology of Heart Disease: ACollaborative Project of Medical Students and Faculty (Ed 5). WolterKluwer/Lippincott Williams & Wilkins: Baltimore, MD. 2011.

7. Fonarow GC, AbrahamWT, Albert NM, et al. Factors identifieas precipitating hospital admissions for heart failure andclinical outcomes: findings from OPTIMIZE-HF. Arch InternMed. 2008;168:847-854.

8. Fonarow GC, Abraham WT, Albert NM, et al. Organizedprogram to initiate lifesaving treatment in hospitalizedpatients with heart failure (OPTIMIZE-HF): rationale anddesign. Am Heart J. 2004;148:43-51.

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14. Swedberg K, Komajda M, Bohm M, et al. Ivabradine andoutcomes in chronic heart failure (SHIFT): a randomisedplacebo-controlled study. Lancet. 2010;375:875-885.

15. Krumholz HM, Lin Z, Keenan PS, et al. Relationship betweenhospital readmission and mortality rates for patients hospi-talized with acute myocardial infarction, heart failure, orpneumonia. JAMA. 2013;309:587-593.

16. Setoguchi S, Stevenson LW, Schneeweiss S. Repeated hospi-talizations predict mortality in the community populationwith heart failure. Am Heart J. 2007;154(2):260-266.

17. The SAVE investigators. Effect of captopril on mortality andmorbidity in patients with left ventricular dysfunction aftermyocardial infarction. Results of the survival and ventriculaenlargement trials. N Engl J Med. 1992;327:669-677.

18. Pitt B, Zannad F, RemmeWJ, et al. The effect of spironolactonon morbidity and mortality in patients with severe heartfailure. N Engl J Med. 1999;341:709-717.

19. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol onsurvival in severe chronic heart failure. N Engl J Med. 2001;3441651-1658.

20. MERIT-HF Study Group. Effect of metoprolol CR/XL in chroniheart failure: metoprolol CR/XL randomised intervention triain congestive heart failure (MERIT- HF). Lancet. 1999;353:2001-2007.

21. CIBIS-II Investigators and Committees. The cardiac insuffi-ciency Bisoprolol study II (CIBIS-II): a randomised trial. Lance1999;353:9-13.

22. Bhatia V, Bajal NS, Sanam K, et al. Beta-blocker use and30-day all-cause readmission in medicare beneficiaries withsystolic heart failure. Am J Med. 2015;128:715-772.

23. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysiinhibition versus enalapril in heart failure. N Engl J Med.2014;371(11):993-1004.

24. Curtis AB, Worley SJ, Adamson PB, et al. Biventricular versusright ventricular pacing in heart failure patients with atrio-ventricular block. N Engl J Med. 2013;368:1585-1593.

25. Tang ASL,Wells GA, Talajic M. Cardiac-resynchronization therapfor mild-to-moderate therapy. N Engl J Med. 2010;363:2385-2395.

26. Hernandez AF, Greiner MA, Fonarow GC, et al. Relationshipbetween early physician follow-up and 30-day readmissionamong Medicare beneficiaries hospitalized for heart failure.JAMA. 2010;303:1716-1722.

27. Duflos CM, Solecki K, Papinaud L, et al. The intensity ofprimary care for heart failure patients: a determinant ofreadmissions? The CarPaths study: a French region-wideanalysis. PLoS One. 2016;11:e0163268.

28. Salim Al-Damluji M, Dzara K, Hodshon B, et al. Association odischarge summary quality with readmission risk for patienthospitalized with heart failure exacerbation. Circ CardiovascQual Outcomes. 2015;8:109-111.

29. Whellan DJ, Gaulden L, Gattis WA, et al. The benefit ofimplementing a heart failure disease management programArch Intern Med. 2001;161:2223-2228.

30. DeVore AD, Allen LA, Eapen ZJ. Thinking outside the box:treating acute heart failure outside the hospital to improvecare and reduce admissions. J Card Fail. 2015;21:667-673.

31. Buckley LF, Carter DM, Matta L, et al. Intravenous diuretictherapy for the management of heart failure and volumeoverload in a multidisciplinary outpatient unit. J Am CollCardiol Heart Fail. 2016;4:1-8.

32. Fraiche AM, Eapen EJ, McClellan MB. Moving beyond the walof the clinic: opportunities and challenges to the future oftelehealth in heart failure. J Am Coll Cardiol Heart Fail. 2017. [piS2213-1779(16)30677-1].

33. Feltner C, Jones CD, Cene CW, et al. Transitional careinterventions to prevent readmission for persons with heartfailure. Ann Intern Med. 2014;160:774-784.

34. Abraham WT, Adamson PB, Bourge RC, et al. Wireless pulmo-nary artery haemodynamicmonitoring in chronic heart failura randomised controlled trial. Lancet. 2011;377:658-666.

35. Inglis SC, Clark RA, Dierckx R, et al. Structure telephonesupport or non-invasive telemonitoring for patients withheart failure. Cochrane Database Syst Rev. 2015;10:CD007228.

36. Jencks SF, Williams MV, Coleman EA. Rehospitalizationsamong patients in the Medicare fee-for-service program. NEngl J Med. 2009;360:1418-1428.

37. Hall MJ, Levant S, DeFrances CJ. Hospitalization for congestiveheart failure: United States, 2000–2010. NCHS data brief, no 10Hyattsville, MD: National Center for Health Statistics; 2012.

38. DeVore AD, Hammill BG, Hardy NC, et al. Has public reportinof hospital readmission rates affected patient outcomes? J AmColl Cardiol. 2016;67:963-972.

39. Centers for Medicare & Medicaid Services. Acute InpatientPPS. Available at: https://www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/AcuteInpatientPPS/index.html?redirect=/AcuteInpatientPPS. [Accessed: 26 March 2017

40. Vidic JT, Chibnall JT, Hauptman PJ. Heart failure is a majorcontributor to hospital readmission penalties. J Card Fail.2015;21:134-137.

41. Centers for Medicare & Medicaid Services. Readmissionsreduction program. Available at: https://www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/AcuteInpatientPPS/Readmissions-Reduction-Program.html.[Accessed: 17 February 2017].

42. Mozaffarian D, Bengamin EJ, Go AS, et al. Heart disease andstroke statistics—2015 update: a report from the AmericanHeart Association. Circulation. 2015;131:e29-322.

43. Blecker S, Paul M, Taksler G, Ogedegbe G, Katz S. Heart failureassociated hospitalizations in the United States. J Am CollCardiol. 2013;61:1259-1267.

44. Desai NR, Ross JS, Kwon JY, et al. Association betweenhospital penalty status under the hospital readmissionreduction program and readmission rates for target andnontarget conditions. JAMA. 2016;316:2647-2656.

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46. Alternative Payment Model Framework and Progress Trackin(APM FPT) Work Group. Alternative payment model (APM)framework: final white paper. Available at: https://hcp-lan.org/workproducts/apm-whitepaper-total.pdf 2016. [Accessed17 February 2017].

47. Department of Health and Human Services. CMS fact sheet:better care. Smarter spending. Healthier people: paying pro-viders for value, not volume. Centers for Medicare & MedicaidServices. January 2015. Available at: https://www.cms.gov/

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48. Triptoliti EE, Papadopoulos TG, Karanasiou GS, et al. Heartfailure: diagnosis, severity estimation and prediction ofadverse events through machine learning techniques. CompuStruct Biotechnol J. 2016;15:26-47.

49. Vivo RP, Krim SR, Liang L, et al. Short-and long-termrehospitalization and mortality for heart failure in 4racial/ethnic populations. J Am Heart Assoc. 2014;16:e001134.

50. Eapen ZJ, McCoy LA, Fonarow GC, et al. Utility of socioeco-nomic status in predicting 30-day outcomes after heart failurhospitalization. Circ Heart Fail. 2015;8:473-480.



ScienceDirect


Approach to Acute Heart Failure in the
Emergency Department
Benton R. Huntera, Jennifer Martindaleb, Osama Abdel-Hafeza, Peter S. Pangc,⁎, 1

aIndiana University School of Medicine, Indianapolis, IN, United StatesbSUNY Downstate, Brooklyn, NY, United StatescIndiana University School of Medicine, Indianapolis EMS, Indianapolis, IN, United States


Statement of Conflict of Interest: see p⁎ Corresponding author at: Department

46202, United States.E-mail address: [email protected] (P.S. Pang

1 Peter Pang is or has been in the lastRelypsa and Research Support: Roche, Nov


A B S T R A C T

r,s,

Keywords:Heart failure

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Acute heart failure (AHF) patients rarely present complaining of ‘acute heart failure.’ Rathethey initially present to the emergency department (ED) with a myriad of chief complaintsymptoms, and physical exam findings. Such heterogeneity prompts an initially broadifferential diagnosis; securing the correct diagnosis can be challenging. Although AHFmabe the ultimate diagnosis, the precipitant of decompensation must also be sought anaddressed. For those AHF patients who present in respiratory or circulatory failure requirinimmediate stabilization, treatment begins even while the diagnosis is uncertain.The initial diagnostic workup consists of a thorough history and exam (with a particulafocus on the cause of decompensation), an EKG, chest X-ray, laboratory testing, anpoint-of-care ultrasonography performed by a qualified clinician or technologist. Wrecommend initial treatment be guided by presenting phenotype. Hypertensivpatients, particularly those in severe distress and markedly elevated blood pressurshould be treated aggressively with vasodilators, most commonly nitroglycerinNormotensive patients generally require significant diuresis with intravenous loodiuretics. A small minority of patients present with hypotension or circulatory collapsThese patients are the most difficult to manage and require careful assessment of intraand extra-vascular volume status. After stabilization, diagnosis, and management, mosED patients with AHF in the United States (US) are admitted. While thisunderstandable, it may be unnecessary. Ongoing research to improve diagnosis, initiatreatment, risk stratification, and disposition may help ease the tremendous publhealth burden of AHF.


Acute heart failureDecompensated heart failureEmergency department

age 184.of Emergency Medicine, Fifth Third Office Bldg, 720 Eskenazi Ave, 3rd Floor, Indianapolis, IN

).one year a Consultant for: BMS, Novartis, Trevena, scPharmaceuticals, Roche Diagnostics,artis, AHA, NIH, PCORI, AHRQ.

served.


ACC/AHA = American College ofCardiology/AmericanHeart Association

ACEI = ace inhibitor

ACS = acute coronary syndrome

AHF = acute heart failure

ASCEND-HF = Acute Study ofClinical Effectiveness ofNesiritide in DecompensatedHeart Failure

BNP = brain natriuretic peptide

BP = blood pressure

ED = emergency department

EF = ejection fraction

EKG = electrocardiogram

ESC = European Societyof Cardiology

HF = heart failure

ICU = intensive care unit

IV = intravenous

IVC = inferior vena cava

IVC-CI = inferior vena cavacollapsibility index

LOS = length of stay

NIPPV = non-invasive positivepressure ventilation

NTG = nitroglycerin

SBP = systolic blood pressure

STEMI = ST-elevationmyocardial infarction

US = United States


Contents

9911112223344

Stabilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Initial diagnosis and assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Initial management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18Initial classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18Initial therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18The hypotensive AHF patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18Inotropes and vasopressors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18The hypertensive patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18The normotensive patient (SBP 100–140 mmHg) . . . . . . . . . . . . . . . . . . 18Disposition and outcomes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18Statement of conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . 18References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

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Diagnosis andmanagement begins in themergencydepartmen(ED) for the vast majority of patients hospitaized with acute heafailure (AHF). Unfortunately, the evidencbase for ED management is limited.1,2 Thlack of evidence, combined with the heterogeneity of the AHpatient population, results in tremendouvariability in clinicapractice. The potentiaimpact of ED management is significant, adiagnostic delay osub-optimal treatmenmay have significandownstream consequences. Perhaps thcostliest ED manage

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ment decision is deciding who dohospitalization, the most expensive resource in healthcare.3

As epidemiology and pathophysiology of AHF are covereelsewhere, this review focuses on initial ED management.

Stabilization

Occasionally, patients with possible AHF present in extremior near respiratory failure. In these instances, the diagnostiwork up and management occur in parallel. Importantly, thprecipitating cause of the patient's dramatic presentatiomust be simultaneously identified and treated. Arrhythmiainfection, and acute coronary syndromes are just a fewpotential precipitants. The classical teaching of ensurin“Airway, Breathing, and Circulation” first is worth reiterating

Obtunded patients with severe respiratory failure wilikely require endotracheal intubation and mechanicaventilation.5 For patients with respiratory distress who arawake and cooperative, early initiation of non-invasivpositive pressure ventilation (NIPPV) significantly decreasemortality and need for intubation.6 NIPPV can be instituteeven if the diagnosis of AHF is in doubt, as evidence suggestbenefit even inundifferentiated severedyspnea.7 The increaseintra-thoracic pressure from NIPPV may decrease bloopressure (BP), but this is uncommon clinically and more likelwith endotracheal intubation. Once the patient has beestabilized, the focus turns to diagnosis.

Initial diagnosis and assessment

Fortunately, most AHF patients do not present in extremisEstablishing the diagnosis is the sine qua non ofmedicine, buis not always easy. It is worth noting the myriad of differenpatient complaints: Fatigue, dizziness, shortness of breathchest pain, weakness, exercise intolerance, swelling, anweight gain are all symptoms prompting consideration oAHF as the cause.

The clinical presentation of AHF varies widely, ranginfrommildly worsening heart failure, de novo or new onset HFto overt cardiogenic shock, to hypertensive flash pulmonaredema. Despite the high prevalence of AHF in the EDsetting, misdiagnosis occurs in 14–29% of patients.8–1

Heterogeneous pathophysiology and phenotypic expressionvaried underlying causes and precipitants, and substantiaco-morbid burden underlie the challenges of diagnosing thisyndrome. Nevertheless, timely and accurate diagnosis of AHis critical to preventing delays in treatment, which have beeassociated with increased risk of inpatientmortality and longelength of stay (LOS).12–14

Unfortunately, no single historical variable, symptomphysical exam finding, biomarker, or imaging modality isensitive enough to sufficiently exclude the diagnosis of AHFDyspnea is the most common symptom prompting patientwith AHF to seek care, 15 and is most often due to vascula

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congestion. Discriminating AHF from other causes odyspnea, however, remains challenging, especially for thospatients without a preexisting diagnosis of heart failure (HFand those with comorbidities, such as chronic obstructivpulmonary disease. Symptoms classically associated with HFsuch as orthopnea and paroxysmal nocturnal dyspnea arreported by only half of patients with AHF and are <75%specific for the diagnosis.16 The physical exam finding witthe highest likelihood ratio (LR+) is an S3 gallop (LR+ 4.[95%CI 2.7–5.9]), but the absence of this finding has minimaeffect on changing the pre-test probability of AHF (LR− 0.9[95%CI 0.89–0.95]).16 Jugular venous distension and thhepatojugular reflex are more specific, but are insensitivand dependent on the examiner. Despite knowledge thacongestion is the primary underlying cause of patient signand symptoms, measuring congestion with a high degree ointra and interobserver reliability remains challenging.17,18

Natriuretic peptides are the most useful biomarkers foexcluding the diagnosis of AHF.19 Cutoff points of 100 pg/mand 300 pg/mL for brain natriuretic peptide (BNP) anN-terminal (NT)-proBNP, respectively, substantially reducthe post-test probability of AHF (LR− 0.1) in patients presenting tthe ED with dyspnea.16 Very high BNP values are modestlhelpful in ruling in AHF, but intermediate values (100–800 pg/mfor BNP) lack diagnostic specificity. Likelihood ratios associatewith even the most elevated NT-proBNP values only modestlfavor the diagnosis of AHF.16 The specificity of these biomarkerabove proposed cutoff points are limited by renal dysfunctioand advanced age.19 Other conditions to consider in patientwith modestly elevated BNP values are acute respiratordistress syndrome,20 pulmonary embolism,21,22 pulmonarhypertension,23 and valvular heart disease.24 While natriuretipeptides provide additive diagnostic value beyond clinical anhistorical variables,25–27 several studies have failed to demonstrate differences in patient-centered clinical outcomes beyonhospital LOS28,29 with the addition of diagnostic BNP testing.

In addition to a basic metabolic profile and complete bloocount, troponin testing should be considered in AHF patientsOccasionally, troponin testing may uncover occult acutcoronary syndrome (ACS), an important precipitant oAHF.30,31 Importantly, an elevated troponin does not rule iACS, asmany AHF patients may have troponin release.32 Witthe recent approval in the US of higher sensitivity assays,greater proportion of AHF patients will likely be identifiewith “abnormal” troponin values.33 Troponins also adprognostic information,30 but should not be considereddiagnostic test to rule in or out AHF. However, highesensitivity assays may demonstrate troponin release as aintegral part of the AHF syndrome; one recent study demonstrated 98% of AHF patients have measurable troponin, wit81% above the 99th percentile.34 Both BNP and troponin arrecommended in guidelines for the assessment anrisk-stratification of the AHF patient.35,36

Given the limitations of laboratory testing in isolationimaging plays a significant role in the diagnostic approach tAHF. The chest radiograph is considered a key component othe diagnostic workup. Chest radiography can identifvascular engorgement, hilar redistribution, interstitial edemaand alveolar edema as well as alternative causes of dyspnea.3

While highly specific for AHF, these radiographic findings arpoorly sensitive.25,38,39 One series found that cardiomegalalone had moderate sensitivity (79%) and specificity (80%).25

Lung ultrasound has emerged as a useful point-of-care toofor identifying pulmonary edema and diagnosing AHF.40,4

Sonographic detection of pulmonary edema is based on thidentification of vertical artifacts called B-lines, which arthought to result from the reverberation of sound waves off ofluid-filled pulmonary interstitium. When distributed diffusely in the proper clinical setting, B-lines represent cardiogenipulmonary edema. A positive lung ultrasound study, defineas two or more bilateral thoracic zones with ≥3 B-lines, hagood discriminatory value with a LR+ of 7.4 (95% CI 4.2–12.8A negative lung ultrasound study substantially lowers thprobability of AHF (LR− 0.16 [95% CI 0.05–0.51]).16 The extent opulmonary edema can also be semi-quantitatively measureby the sum of the number of B-lines with high inter-ratereliability.42–44 B-line severity has been shown to correlatwith other measures of pulmonary congestion45 and with thseverity of AHF.46,47 The ESC HF guidelines now include lunultrasound as a recommended diagnostic test to confirmpulmonary congestion.37

Point-of-care ultrasound -determined estimates of intravascular volume and right atrial pressures can be made bmeasuring the diameter of the inferior vena cava (IVC) anpercentage change in IVC diameter during the respiratorcycle. An IVC diameter that fails to substantially decreaswith inspiration is considered to have a low collapsibilit(or caval) index (IVC-CI), reflecting volume overload and higRAP. The diagnostic performance of different cutoff valuefor IVC collapsibility index, ranging from 20%–50% havbeen tested in dyspneic patients presenting to the ED.48–5

Sensitivities of 80% or greater were achieved in studies thaused an IVC-CI cutoff of 33% or greater.49–51 Specificitieassociated with these cut-offs ranged from 81%–87%Alternative causes of a plethoric IVC include tricuspiregurgitation, pulmonary embolism, pulmonary hypertension, and right ventricular infarction.

Echocardiography is integral to the diagnostic workup oHF. While formal echocardiography is rarely available rapidlin the ED, focused cardiac ultrasound in the hands of traineemergency physicians can be used as a point-of-care tool tassess global systolic dysfunction. Qualitative visual estimations of reduced versus normal ejection fraction (EF) can bmade by assessing the inward movement of the interventricular septum and inferior wall of the left ventricle durinsystole and by observing the degree of excursion of thanterior leaflet of the mitral valve toward the interventriculaseptum during diastole. These qualitative assessmentcorrelate with more formal, quantitative echocardiographimeasures of EF.52,53 Reduced EF identified by emergencphysicians using focused cardiac ultrasound discriminateAHF from other causes of dyspnea with sensitivities ranginfrom 77 to 83% and specificities ranging from 74 to 90%.48,54,5

However, sonographic assessments of dyspneic patientlimited to this single variable would fail to identify Hpatients with preserved EF. Identification of a restrictivpattern of diastolic filling using pulsed Doppler analysis omitral inflow as a surrogate measure of elevated fillin

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pressures assists in the diagnosis of AHF (LR+ 8.3 [95%CI 4.016.9]).54 Acquisition and interpretation of mitral inflow antissue Doppler data are currently beyond the scope of Ephysicians who lack formal fellowship training. Diagnostiapproaches that integrate lung, cardiac, and IVC assessmentincrease the specificity of diagnosing AHF in the ED beyonclinical gestalt, biomarkers, and lung ultrasound alone.48,50,5

Further research is needed to help delineate the role ofocused cardiac ultrasound in the workup of AHF and howdifferent sonographic assessments can be incorporated intdiagnostic algorithms. Importantly, point of care US does noreplace formal echocardiography.56

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Initial management

Once the diagnosis is made, presenting phenotype and causof exacerbation guides initial treatment. As mentioneearlier, first assuring respiratory and hemodynamic stabilitis paramount (see Table 1 for goals of EDmanagement). Whiladdressing the patient's respiratory status, the precipitant oAHF should be sought and treated. For example, rapid atriafibrillation (AF), ACS, pulmonary embolism, underlying infection or dietary indiscretion can all trigger AHF.57 Often thprecipitant is unclear or challenging to identify. Complicatinmatters, co-morbid conditions may cloud the picture or adchallenges to management. A classic example is the patienwith both chronic obstructive pulmonary disease and AHFwheezing may be bronchial or ‘cardiac wheezing’, and onexacerbation may incite the other. While simultaneoutreatment frequently occurs clinically, untoward effect(such as inciting AF with beta agonists) may be detrimental.

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Initial classification

As an initial guide, we recommend grouping patients witsuspectedAHFby systolic BP (SBP).58,59 As evidencedby registrieSBP is often high (>140 mm Hg) at the time of presentation.60Wrecommend using cutpoints of >140 mm Hg, 100–140 mm Hand <100 mm Hg to guide initial selection of pharmacolog

Table 1

Goals of ED management (although written sequentially,steps may occur simultaneously)

1. Ensure stability of Airway, Breathing, and Circulation orresuscitate immediately

2. Identify and treat any other potential life threats (i.e. STEMI,dysrhythmias)

3. Ensure diagnosis of AHF and begin treatment.4. Identify the precipitant of AHF and modify treatment if necessary.5. Consider the potential contribution of other co-morbid conditions

and whether they require urgent treatment6. Re-evaluate patient to ensure improvement in symptoms,

hemodynamics, and clinical impression7. Risk-stratify patient8. Disposition planning (admission, observation, discharge)

therapy.58,59 While there is considerable overlap, simple categorization aids the busy clinician. As such, it is reasonable tassume the predominant pathophysiologic derangement inpatient based onpresenting SBP. Notably, not all patients presenwith total volume overload; the prototypical example is the flaspulmonary edema patient.61–63 Such patients have also beedescribed as ‘vascular failure’ or ‘volume redistributionpatients.64–66 These patients most commonly present witelevated SBP. Of note, the latest ESC HF guidelines also suppordividingpatients basedon ‘cardiac’ (fluid overloadpredominatesvs. ‘vascular’ (hypertension predominates) phenotypes.1

Initial therapy

At the present time, no AHF therapy receives a Level I, Class Arecommendation from guidelines,1,2 highlighting the lack orobust evidence from randomized studies. Therapies usetoday are largely the same as those employed 4 decades ag(Table 2). Rotating tourniquets and phlebotomy are no longeused; whether this represents a major advance is debatableImportantly, lack of high quality evidence from robusrandomized controlled trials does not equate with ineffectivenesin achieving symptom relief, hemodynamic improvement, andecongestion; all important targets of therapies.

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The hypotensive AHF patient

Shock due solely to worsening HF rarely occurs relative tother types of AHF.15 Given its relatively uncommon presentation combined with the complexity of these patientsunderlying pathophysiology, precipitant, cardiac structurefunction, and resultant hemodynamic status, managemencan be challenging. Patients with advanced HF may presenwith alarmingly low SBP. This may, in fact, reflect theibaseline SBP. Even when resuscitating shock, a commomistake is attempting to normalize SBP and HR to values seein those with baseline normal cardiac structure and functionHowever, for patients with severely reduced EF, a ‘normal’ SBmay be unattainable, and tachycardia may be the kecontributor to cardiac output.

For patients with low SBP, administering a fluid bolus inearly a reflexive action. But in the setting of hypoperfusiosecondary to heart failure rather than hypovolemia, this ma

Table 2 – Therapeutic options for the early treatment ofAHF – a historical perspective.

197467 2017

Sit the patient upright Sit the patient uprightOxygen OxygenPositive pressure ventilation Positive pressure ventilationMorphine MorphineDiuretics DiureticsIntra-aortic balloon pump Intra-aortic balloon pumpPhlebotomy InotropesRotating tourniquets Vasodilators/nesiritide

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result in worsening pulmonary edema. On the other handinfection and overdiuresis are common precipitants that marespond quite well to fluid. At the bedside, assessing volumstatus is challenging, especially in patients with advanced HFAs noted above, ultrasound may be useful, but response tinitial treatment will often be the best guide to subsequenmanagement. Although rarely applied in the ED setting due tconcerns of precipitating circulatory failure, AHF patientwith low SBP who are congested may require decongestivtherapies. Optimizing volume status through diuresis anvasodilation may lead to significant clinical improvement. Isome refractory cases, inotropes and vasopressors are requireto augment cardiac output and blood pressure.

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Inotropes and vasopressors

Table 3 shows commonly used inotropes and vasopressorsAlthough inotropes and vasodilators improve hemodynamics, to date, none are associated with better clinical outcomesIn fact, available inotropes have been associated with harmthough the evidence base is small and inconsistent.68–71 Iterms of vasopressors, there is a paucity of robust data tstrongly recommend one vasopressor over another. Subgrouanalysis from a large randomized trial found increasemortality in patients with cardiogenic shock who werrandomized to dopamine compared with those randomizeto norepinephrine.72

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The hypertensive patient

Approximately half of patients admitted with AHF presenwith hypertension (SBP ≥ 140 mm Hg).15,60 In general, thespatients tend to be older, have preserved EF,60 and presenwith a more acute onset of symptoms, often <24 h. Pulmonary edema in such patients is more likely to be caused bvascular redistribution than by hypervolemia. As suchvasodilators are the mainstay of treatment.

Of the guideline-recommended vasodilator options [nitroglycerin (NTG), nitroprusside, or nesiritide], we recommenNTG as first line.73 Clinicians and nurses are familiar witNTG; it can be administered rapidly via sublingual anintravenous routes, and it's inexpensive. Bolus doses of u

Table 3

Initial dose Infusion

Dobutamine 2–3 ucg/kg/min 2–20 ucg/kMilrinone 0.375–0.75Levosimendan 0.05–0.2 μgDopamine 2–5 ucg/kg/min 2–50 ucg/kNorepinephrine 0.2–1.0 ucgNitroglycerin 5–20 ucg/min (rapidly titrate to effect) 5–200 ucg/Nitroprusside 5–10 mcg/min 0.25 ucg/kgNesiritide 0.01 ucg/kgACE-I (enalaprilat) 1.25–5 mg IV bolus q6 h NA

a Consider bolus dosing.

to 2–3 mg are well tolerated and effective, thougmany clinicians are reluctant to give such large doses.74,7

Anecdotally, NTG as an IV drip is often withheld due to threquirement for an intensive care unit (ICU) bed. However, thrapid onset/offset of NTG makes it an ideal titratable drug tinitiate before transitioning to topical NTG or alternativtherapies.

Nitroprusside and nesiritide are alternatives to NTG. Awith NTG, neither nitroprusside nor nesiritide has beeshown to decrease mortality or morbidity in AHF.76 Howeveboth are effective vasodilators, with nitroprusside being thmore potent. While NTG predominantly acts on the venoucirculation until at higher doses, nitroprusside acts rapidly oboth the arterial and venous circulation. It may precipitousllower BP; thus careful monitoring is required. Nesiritide is onof the most well studied vasodilators in terms of largrandomized controlled trials. After initial concerns regardinsafety, a large randomized, controlled trial (ASCEND-HF; n7141) found no relative benefit or harm associated witnesiritide in terms of mortality, hospital readmission, odyspnea.77 It may be a reasonable option if a vasodilator idesired but ICU beds are unavailable.

Despite the lack of compelling evidence supporting acutangiotensin converting enzyme inhibitor (ACEI) use in the EDthese agents are sufficiently used in the setting of AHF to bmentioned in the American College of EmergencPhysicians.78 A common misperception: the benefit of ACEin chronic HF with reduced EF extends to the acute settingLack of evidence does not equal a bad therapy; onlthat sufficiently powered, well-designed trials have not yebeen performed.

Morphine's historic use in AHF continues todayRetrospective observational data suggests an increased risof death in patients treated with morphine for AHF.79 Asoffers no defined benefit, we recommend against routinmorphine use in AHF.

The normotensive patient (SBP 100–140 mm Hg)

AHF patients presenting with SBP ranging from 100 t140 mm Hg rarely arrive to the ED in extremis.60 Thprototypical patient reports an indolent course over days oeven weeks, and may report significant weight gain

range Recommendation class (evidence level)

g/min IIB (Level B)ucg/kg/mina IIB (Level B)/kg/mina Not available in USg/min IIB (Level B)/kg/minmin (rapidly titrate to effect) IIB (Level A)/min–10 ucg/kg/min IIB (Level A)/mina IIB (Level A)

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Decongestion with intravenous (IV) loop diuretics is thprimary therapy. Bolus or continuous infusion diuretiadministration makes no difference.80 A randomized triacomparing IV doses of the patient's standard oral dose tlarger IV doses (2.5 times the standard oral dose) found thalarger doses resulted in more diuresis and marginally bettedyspnea over the first 72 h, but also increased the likelihood ocreatinine elevation.80 In addition to diuretic therapy, low-dosvasodilators should be considered in normotensive patients.

A Hospitalist's Perspective in Brief:

From the hospitalist perspective, whether so many AHpatients warrant admission is debatable.81 Neverthelesat the present time, most AHF patients are hospitalizedThus, it is worth highlighting the different clinical framework between hospitalists and ED physicians for thmanagement of AHF. While risking overgeneralization, Ephysicians work with limited data in a fast-paced environment where rapid disposition and ensured access to shorterm follow-up are paramount. Thorough diagnostic evaluation of cardiac structure, function, and AHF etiology arsecondary objectives for ED physicians. Hospitalists tend texpect greater diagnostic clarity and institute managemenplans that address comorbid conditions and the long-termconsequences of cardiac remodeling.

In regards to clinical management, the use of diuretics ioften a major point of contention between hospitalists anED physicians. IV loop diuretics are the cornerstone of acuttherapy for AHF patients. Nearly 90% of patients hospitaized with AHF receive IV loop diuretics in the82,15 ACC/AH(American College of Cardiology/American Heart Association) and ESC guidelines, though large randomized controlled trials have yet to be performed (and it is doubtful theever will be). Given the absence of other therapies to readildecongest patients, why IV diuretics are withheld ounderdosed appears perplexing. Although retrospectivstudies suggest harm associated with early aggressive Iloop diuretic use, no prospective evidence supports thhypothesis.83,84 Withholding IV diuretics in the ED may bperceived by the inpatient teams as delaying patient care.

If diuretics are given in the ED, they are ofteunderdosed. By their very mechanism of action,85 loodiuretics must be secreted via active transport in thproximal tubules of the kidney. Rather than minimizdoses, especially in patients with impaired renal functionhigher doses are required to reach the dose-responsthreshold.85

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Disposition and outcomes

Contrary to commonly held belief, most patients whvisit the ED are sent home; only 9.3% of the annual 13million ED visits in the US result in hospitalization. Howevenearly all ED patients with AHF are hospitalized. From 2006 t2011, the annual US hospitalization rate for AHF patients ithe ED has consistently been around 85%.86 Given financia

penalties tied to excess re-hospitalization, this admission ratwarrants scrutiny.

Administrative data analyses suggest up to 50% of patientwith AHF could be discharged or observed briefly anreleased.87 AHF is a progressive illness and the short-termprognosis following hospitalization is unacceptably poor. Thimakes the concept of a low-risk AHF patient difficult for themergency physician to embrace. Yet within the spectrum orisk, some are lower than others. Identifying patients safe tbe sent home from the ED remains challenging, as thmajority of risk-stratification work in AHF focuses on defininand characterizing high risk in-patients, making extrapolation to the ED setting challenging.88 While some risinstruments, such as the AHF Index, EMHRG, STRATIFY, othe Ottawa Heart Failure Index are promising,89–91 none havgained widespread acceptance, either due to the need fofurther validation, differences in patient populations, olimited information on outcomes for discharged patientidentified as lower risk.92 Identifying patients low enough risfor safe discharge from the ED remains a key focus for research

The absence of high risk features (i.e. low BP, high BNlevels, worsening renal function, elevated troponin, anhyponatremia) does not equal no risk,88,93,94 but it doeequate to lower risk. In the future, absence of myocardiainjury by high sensitivity troponin assays may help identiflow risk patients.33 As risk-stratification improves, approprate selection of patients for treatment in observation oshort-stay units in AHF may become easier.95,96 These unitmay provide more time to risk stratify patients, gaugresponse to therapy, provide education, engage case management and social work as needed, reconcile medicationsand facilitate close follow up. These tasks are often challenging to complete during a brief ED stay. Furthermore, given threluctance to discharge lower-risk AHF patients from the EDthe use of observation medicine as a ‘bridge’ may be morclinically feasible and acceptable to ED physicians.3,93

For higher risk patients, hospitalization may offer benefto improve symptoms, optimize volume status, and ensurinitiation of guideline directed chronic medical therapy. AHpharmacologic therapies, on their own, have not been proveto affect post-discharge outcomes.2 However, hospitalizatiomay help higher risk patients achieve symptomatic relieeuvolemia/complete decongestion, andmedical optimizationPatients with new onset or de novo HF should also badmitted, as potentially reversible or modifiable causes mabe identified. These patients will also need education abouself-managing their new chronic illness. Overall howeveindiscriminate admission is unlikely to translate intpatient-centered benefit or justifiable cost. As mentionepreviously, identifying who can be safely observed odischarged from the ED remains an unmet need.

Conclusion

The ED management of AHF centers around diagnosisstabilization, identification of the precipitant of AHF, initiatreatment, and risk-stratification. We recommend initial EDtreatment be guided by presenting phenotype but treatmen

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largely centers around diuretics and vasodilators. Althougcurrently available therapies improve symptoms, none definitively improve outcomes. Identification of life saving therapies for the early treatment of AHF remains an unmet needthough whether a short-term treatment can influence longeterm post-discharge outcomes remains unclear. As US EDcontinue to admit nearly all AHF patients, identifyinappropriate low-risk patients for discharge and closfollow-up would result in tremendous value to the healtcare system.

ses

Statement of conflict of interest

Benton Hunter has no conflicts of interest.Osama Abdel Hafez has no conflicts of interest.Jennifer Martindale has no conflicts of interest.

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35. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelinefor the diagnosis and treatment of acute and chronic heartfailure 2012: the task force for the Diagnosis and Treatment oAcute and Chronic Heart Failure 2012 of the European Societof Cardiology. Developed in collaboration with the HeartFailure Association (HFA) of the ESC. Eur J Heart Fail. 2012;14(8803-869.

36. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHAguideline for the management of heart failure: a report of thAmerican College of Cardiology Foundation/American HeartAssociation Task Force on Practice Guidelines. J Am CollCardiol. 2013;62(16):e147-239.

37. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelinefor the diagnosis and treatment of acute and chronic heartfailure: the task force for the diagnosis and treatment of acutand chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of theHeart Failure Association (HFA) of the ESC. Eur J Heart Fail.2016;18(8):891-975.

38. Martinez-Rumayor AA, Vazquez J, Rehman SU, Januzzi JL.Relative value of amino-terminal pro-B-type natriuretic peptide testing and radiographic standards for the diagnosticevaluation of heart failure in acutely dyspneic subjects.Biomarkers. 2010;15(2):175-182.

39. Collins SP, Lindsell CJ, Storrow AB, Abraham WT. Prevalenceof negative chest radiography results in the emergencydepartment patient with decompensated heart failure. AnnEmerg Med. 2006;47(1):13-18.

40. Martindale JL. Diagnosing acute heart failure in the emer-gency department. Acad Emerg Med. 2016.

41. Gargani L, Pang PS, Frassi F, et al. Persistent pulmonarycongestion before discharge predicts rehospitalization inheart failure: a lung ultrasound study. Cardiovasc Ultrasound.2015;13:40.

42. Jambrik Z, Monti S, Coppola V, et al. Usefulness of ultrasounlung comets as a nonradiologic sign of extravascular lungwater. Am J Cardiol. 2004;93(10):1265-1270.

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46. Agricola E, Bove T, Oppizzi M, et al. “Ultrasound comet-tailimages”: a marker of pulmonary edema: a comparative studwith wedge pressure and extravascular lung water. Chest.2005;127(5):1690-1695.

47. Frassi F, Gargani L, Gligorova S, Ciampi Q, Mottola G, Picano EClinical and echocardiographic determinants of ultrasoundlung comets. Eur J Echocardiogr. 2007;8(6):474-479.

48. Anderson KL, Jenq KY, Fields JM, Panebianco NL, Dean AJ.Diagnosing heart failure among acutely dyspneic patientswith cardiac, inferior vena cava, and lung ultrasonography.Am J Emerg Med. 2013;31(8):1208-1214.

49. Gil Martinez P, Mesado Martinez D, Curbelo Garcia J,Cadinanos Loidi J. Amino-terminal pro-B-type natriureticpeptide, inferior vena cava ultrasound, and biolectricalimpedance analysis for the diagnosis of acute decompensateCHF. Am J Emerg Med. 2016;34(9):1817-1822.

50. Kajimoto K, Madeen K, Nakayama T, Tsudo H, Kuroda T, AbT. Rapid evaluation by lung-cardiac-inferior vena cava (LCI)integrated ultrasound for differentiating heart failure frompulmonary disease as the cause of acute dyspnea in theemergency setting. Cardiovasc Ultrasound. 2012;10(1):49.

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52. Unluer EE, Karagoz A, Akoglu H, Bayata S. Visual estimation obedside echocardiographic ejection fraction by emergencyphysicians. West J Emerg Med. 2014;15(2):221-226.

53. Gudmundsson P, Rydberg E, Winter R, Willenheimer R.Visually estimated left ventricular ejection fraction by echo-cardiography is closely correlated with formal quantitativemethods. Int J Cardiol. 2005;101(2):209-212.

54. Nazerian P, Vanni S, Zanobetti M, et al. Diagnostic accuracy oemergency Doppler echocardiography for identification ofacute left ventricular heart failure in patients with acutedyspnea: comparison with Boston criteria and N-terminalprohormone brain natriuretic peptide. Acad Emerg Med.2010;17(1):18-26.

55. Russell FM, Ehrman RR, Cosby K, et al. Diagnosing acute hearfailure in patients with undifferentiated dyspnea: a lung andcardiac ultrasound (LuCUS) protocol. Acad Emerg Med.2015;22(2):182-191.

56. Gullett J, Donnelly JP, Sinert R, et al. Interobserver agreemenin the evaluation of B-lines using bedside ultrasound. J CritCare. 2015;30(6):1395-1399.

57. Tsuyuki RT, McKelvie RS, Arnold JM, et al. Acute precipitantof congestive heart failure exacerbations. Arch Intern Med.2001;161(19):2337-2342.

58. Collins S, StorrowAB, Kirk JD, Pang PS, Diercks DB, GheorghiadM. Beyond pulmonary edema: diagnostic, risk stratification,and treatment challenges of acute heart failuremanagement ithe emergency department. Ann Emerg Med. 2008;51(1):45-57.

59. Pang PS, Collins SP, Miro O, et al. The role of the emergencydepartment in the management of acute heart failure: aninternational perspective on education and research. EurHeart J Acute Cardiovasc Care. 2015.

60. Gheorghiade M, Abraham WT, Albert NM, et al. Systolic bloopressure at admission, clinical characteristics, and outcomein patients hospitalized with acute heart failure. JAMA.2006;296(18):2217-2226.

61. Miller WL. Fluid volume overload and congestion in heartfailure: time to reconsider pathophysiology and how volumeis assessed. Circ Heart Fail. 2016;9(8):e002922.

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62. Miller WL, Mullan BP. Volume overload profiles in patientswith preserved and reduced ejection fraction chronic heartfailure: are there differences? A pilot study. JACC Heart Fail.2016;4(6):453-459.

63. Miller WL, Mullan BP. Understanding the heterogeneity involume overload and fluid distribution in decompensatedheart failure is key to optimal volume management: role forblood volume quantitation. JACC Heart Fail. 2014;2(3):298-305

64. Fallick C, Sobotka PA, Dunlap ME. Sympathetically mediatedchanges in capacitance: redistribution of the venous reservoiras a cause of decompensation. Circ Heart Fail. 2011;4(5):669-675

65. Cotter G, Felker GM, Adams KF, Milo-Cotter O, O'Connor CMThe pathophysiology of acute heart failure–is it all about fluiaccumulation? Am Heart J. 2008;155(1):9-18.

66. Cotter G, Metra M, Milo-Cotter O, Dittrich HC, Gheorghiade MFluid overload in acute heart failure–re-distribution and othemechanisms beyond fluid accumulation. Eur J Heart Fail.2008;10(2):165-169.

67. Ramirez A, Abelmann WH. Cardiac decompensation. N EnglMed. 1974;290:499-501.

68. Tacon CL, McCaffrey J, Delaney A. Dobutamine for patientswith severe heart failure: a systematic review andmeta-analysis of randomised controlled trials. Intensive CareMed. 2012;38(3):359-367.

69. Chen HH, Anstrom KJ, Givertz MM, et al. Low-dose dopaminor low-dose nesiritide in acute heart failure with renaldysfunction: the ROSE acute heart failure randomized trial.JAMA. 2013;310(23):2533-2543.

70. Giamouzis G, Butler J, Starling RC, et al. Impact of dopamineinfusion on renal function in hospitalized heart failurepatients: results of the Dopamine in Acute DecompensatedHeart Failure (DAD-HF) Trial. J Card Fail. 2010;16(12):922-930.

71. Felker GM, Benza RL, Chandler AB, et al. Heart failure etiologand response to milrinone in decompensated heart failure:results from the OPTIME-CHF study. J Am Coll Cardiol.2003;41(6):997-1003.

72. De Backer D, Biston P, Devriendt J, et al. Comparison ofdopamine and norepinephrine in the treatment of shock. NEngl J Med. 2010;362(9):779-789.

73. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHAguideline for the management of heart failure: executivesummary: a report of the American College of cardiologyfoundation/American heart association task force on practicguidelines. Circulation. 2013.

74. Cotter G, Metzkor E, Kaluski E, et al. Randomised trial ofhigh-dose isosorbide dinitrate plus low-dose furosemide versuhigh-dose furosemide plus low-dose isosorbide dinitrate insevere pulmonary oedema. Lancet. 1998;351(9100):389-393.

75. Levy P, Compton S, Welch R, et al. Treatment of severedecompensated heart failure with high-dose intravenousnitroglycerin: a feasibility and outcome analysis. Ann EmergMed. 2007;50(2):144-152.

76. Carlson MD, Eckman PM. Review of vasodilators in acutedecompensated heart failure: the old and the new. J Card Fai2013;19(7):478-493.

77. Huffman KM, Pieper CF, Hall KS, St Clair EW, Kraus WE.Self-efficacy for exercise, more than disease-related factors, iassociated with objectively assessed exercise time andsedentary behaviour in rheumatoid arthritis. Scand JRheumatol. 2015;44(2):106-110.

78. Silvers SM, Howell JM, Kosowsky JM, Rokos IC, Jagoda AS,American College of Emergency P. Clinical policy: criticalissues in the evaluation and management of adult patients

presenting to the emergency department with acute heartfailure syndromes. Ann Emerg Med. 2007;49(5):627-669.

79. Peacock WF, Hollander JE, Diercks DB, Lopatin M, Fonarow GEmerman CL. Morphine and outcomes in acute decompen-sated heart failure: an ADHERE analysis. Emerg Med J.2008;25(4):205-209.

80. Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patientwith acute decompensated heart failure. N Engl J Med.2011;364(9):797-805.

81. Chang AM, Rising KL. Cardiovascular admissions,readmissions, and transitions of care. Curr Emerg Hosp MedRep. 2014;2(1):45-51.

82. Peacock WF, Costanzo MR, De Marco T, et al. Impact ofintravenous loop diuretics on outcomes of patients hospitalized with acute decompensated heart failure: insights fromthe ADHERE registry. Cardiology. 2009;113(1):12-19.

83. Felker GM, O'Connor CM, Braunwald E. Heart failure clinicalresearch network I. Loop diuretics in acute decompensatedheart failure: necessary? Evil? A necessary evil? Circ Heart Fa2009;2(1):56-62.

84. Hasselblad V, Gattis Stough W, Shah MR, et al. Relationbetween dose of loop diuretics and outcomes in a heart failurpopulation: results of the ESCAPE trial. Eur J Heart Fail.2007;9(10):1064-1069.

85. Oh SW, Han SY. Loop diuretics in clinical practice. ElectrolyteBlood Press. 2015;13(1):17-21.

86. Storrow A, Jenkins C, Self WH, et al. The burden of acute heafailure on US emergency departments. J Am Coll Cardiol HearFail. 2014.

87. Graff L, Orledge J, Radford MJ, Wang Y, Petrillo M, Maag R.Correlation of the Agency for Health Care Policy and Researccongestive heart failure admission guideline with mortalitypeer review organization voluntary hospital associationinitiative to decrease events (PROVIDE) for congestive heartfailure. Ann Emerg Med. 1999;34(4 Pt 1):429-437.

88. Collins SP, Storrow AB. Acute heart failure risk stratificationcan we define low risk? Heart Fail Clin. 2009;5(1):75-83. [vii].

89. Lee DS, Stitt A, Austin PC, et al. Prediction of heart failuremortality in emergent care: a cohort study. Ann Intern Med.2012;156(11):767-775. [W-261, W-262].

90. Collins SP, Jenkins CA, Harrell Jr FE, et al. Identification ofemergency department patients with acute heart failure atlow risk for 30-day adverse events: the STRATIFY decisiontool. JACC Heart Fail. 2015;3(10):737-747.

91. Stiell IG, Perry JJ, Clement CM, et al. Prospective and explicitclinical validation of the Ottawa heart failure risk scale, withand without use of quantitative NT-proBNP. Acad Emerg Med2017;24(3):316-327.

92. Hsieh M, Auble TE, Yealy DM. Validation of the acute heartfailure index. Ann Emerg Med. 2008;51(1):37-44.

93. Pang PS, Jesse R, Collins SP, Maisel A. Patients with acute heafailure in the emergency department: do they all need to beadmitted? J Card Fail. 2012;18(12):900-903.

94. Donlan SM, Quattromani E, Pang PS, Gheorghiade M. Therapfor acute heart failure syndromes. Curr Cardiol Rep. 2009;11(3192-201.

95. Ross MA, Aurora T, Graff L, et al. State of the art: emergencydepartment observation units. Crit Pathw Cardiol. 2012;11(3):128-138.

96. Schrager J, Wheatley M, Georgiopoulou V, et al. Favorable beutilization and readmission rates for emergency departmenobservation unit heart failure patients. Acad Emerg Med.2013;20(6):554-561.



ScienceDirect


Pharmacologic Therapy for Heart Failure With
Reduced Ejection Fraction: Closing the Gap BetweenClinical Guidelines and Practice
,

J. Barr Biglanea, b, 1, Miriam F. Becnela, b, 1, Hector O. Venturaa, b, c, Selim R. Krima, b, c,⁎aDivision of Cardiology, John Ochsner Heart and Vascular Institute, New Orleans, LA, United StatesbSection of Cardiomyopathy & Heart Transplantation, John Ochsner Heart and Vascular Institute, Ochsner Clinic Foundation, New OrleansLA, United StatescThe University of Queensland School of Medicine, Ochsner Clinical School, New Orleans, LA, United States


n

Statement of conflict of interest: see pa⁎ Address reprint requests to Selim R. Kri

Institute, Ochsner Clinic Foundation, 1514E-mail address: [email protected]

1 Dr. J. Barr Biglane and Miriam Becnel c


A B S T R A C T

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Keywords:Heart failure with reduced ejectio

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Despite the great progress made in the management of heart failure (HF) with reduceejection fraction (HFrEF), its prevalence continues to rise owing to an aging population anan epidemic of hypertension, obesity and coronary artery disease. For decades, angiotensiconverting enzyme inhibitors and beta blockers have been the mainstay of HFrEF therapyThe recent addition of sacubitril/valsartan and ivabradine to the HF armamentarium hathe potential to transform our therapeutic approach to HFrEF, while simultaneously raisinsome questions and uncertainties on their applicability. In this paper, we review thpathophysiology of HFrEF, discuss already established and novel evidenced-basepharmacologic therapies available for these patients. We also share some therapeutistrategies aimed to optimize HF therapy in specific undertreated patient populationincluding the elderly and patients with chronic kidney disease, while offering insight ohow to tailor therapy in the “real-world.”


fractionGuideline directed medical therapyManagementOutcomes

Contents

990

889

ACEI therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18ARB therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18BB therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18SNS and RAAS systems: two key HF therapeutic targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18The good: HF therapy that improves survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

ge 196.m, MD, Section of Cardiomyopathy & Heart Transplantation, John Ochsner Heart and VascularJefferson Highway, New Orleans, LA 70121, United States.(S.R. Krim).ontributed equally to the article.

6served.

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ACEI = angiotensin convertingenzyme inhibitors

ACCF = American College of Car-diology Foundation


A-HeFT = African-AmericanHeart Failure Trial

ANP = atrial natriuretic peptide

ARB = angiotensin receptorblocker

ARNI = angiotensin-receptorneprilysin inhibitors

BB = beta blockers

BMP = beats per minute

BNP = brain natriuretic peptide

BP = blood pressure

CHARM = Candesartan in HeartFailure Assessment of Reductionin Mortality and Morbidity

CIBIS = Cardiac InsufficiencyBisoprolol Study

CIBIS-ELD = Cardiac Insufficien-cy Bisoprolol Study in Elderly

CKD = chronic kidney disease

CONSENSUS = CooperativeNorth Scandinavian EnalaprilSurvival Study

CNP = C-natriuretic peptide

COPERNICUS = Carvedilol Pro-spective Randomized Cumula-tive Survival Study Group

COR = class of recommendation

CV = cardiovascular

DOSE = Diuretic OptimizationStrategies Evaluation

EMPHASIS-HF = Eplerenone inMild Patients Hospitalization andSurvival Study in Heart Failure

FDA = Food and DrugAdministration

GDMT = guideline-directed med-ical therapy

HF = Heart Failure

HFN-LIFE = Entresto TM In Ad-vanced Heart Failure

3

34

4

566


Aldosterone antagonist therapy . . . . . . . . . . . . . . . . . . . . . 19Hydralazine and isosorbide dinitrate therapy . . . . . . . . . . . . . . 19

Diuretic therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Digoxin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Ivabradine therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Angiotensin receptor-neprilyin inhibitor therapy . . . . . . . . . . . . 19

Drug selection, initiation and titration . . . . . . . . . . . . . . . . . . 19Patients with CKD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19The elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Incorporating sacubitril/valsartan into clinical practice . . . . . . . . . 19

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

The bad: HF therapy for symptom relief . . . . . . . . . . . . . . . . . . . . . . 19

The ugly: inotropic therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19The new kids on the HF block . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Misconceptions, uncertainties and opportunities to optimize GDMT . . . . . . . 19

Conclusion and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . 19Financial disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

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Introduction

In the United State(US), 200,000 new caseof heart failure (HF) ardiagnosed each yeawith a total populatioexceeding 6 millionThis population is onlexpected to grow iview of our aging population and improvintherapies.1,2,3 Whildata regarding the successful treatment of Hwith preserved ejectiofraction (HFpEF) arlacking, great progreshas been made in thpharmacologic therapof HF with reduceejection fraction (HFrEFGuideline-directed medical therapy (GDMT) haled to significant improvement in both survival and reduction ohospitalization of HFrEpatients.4,5 For decadeangiotensin convertinenzyme inhibitors (ACEand beta blockers (BBhave been the mainstay of HFrEF therapyThese agents targeboth the sympathetinervous system (SNS

and renin-angiotensin-aldosterone system (RAAS), two majoneurohormonal pathways that play a crucial role in thpathogenesis of HF.4,5 In the focused update of the HF guidelinepublished collaboratively by the American College of Cardiolog(ACC), the American Heart Association (AHA) and Heart FailurSociety of America (HFSA), two new drug classes were addeafter their approval by the Food and Drug Administratio(FDA)—ivabradine andsacubitril/valsartan.4,5,6,7 The addition othese new agents has the potential to transform the way wapproach medical therapy in HFrEF, while simultaneouslraising questions and uncertainties on their applicability. Thiarticle aims to review the pathophysiology of HFrEF, the majoHFrEF randomized controlled trials (RCT), in addition tdiscussing established and novel evidenced-based pharmacologic therapies available for these patients. We also discussome therapeutic strategies aimed to optimize HF therapy ispecific undertreated patient populations including the elderland patients with chronic kidney disease (CKD), while alsoffering insight on how to tailor therapy in the “real-world”.

SNS and RAAS systems: two key HF therapeutitargets

The SNS, RAAS, vasopressin pathway, and the natriuretipeptides (NP) system have been identified as the kepathophysiological mechanisms leading to the onset anprogression of HFrEF.7 Naturally, these pathways have beethe quintessential targets of current HF therapy.

Chronic stimulation of the SNS leads to desensitization andown-regulation of the beta-1 receptors in both the myocardiumand baroreceptors. Over time, this results in a decreased ability othemyocardiumto respondtoelevatedcatecholamine levels.Hearate variability and baroreceptor dysfunction have consistentlbeen observed in chronic HF patients.8 Studies have demonstratethat excessive sympathetic activation is associated with cardiamyocyte apoptosis, hypertrophy, andmyocardial necrosis.9

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HFrEF = heart failure with re-duced ejection fraction

HFSA = Heart Failure Society ofAmerica

LCZ696 = sacubitril-valsartan

LV = Left ventricle or leftventricular

LVEF = Left ventricular ejectionfraction

LOE = level of evidence

MERIT-HF = Metoprolol CR/XLRandomized Intervention Trialin Congestive Heart Failure

NP = Natriuretic peptides

NSR = normal sinus rhythm


PARADIGM-HF = ProspectiveComparison of ARNI with ACEI toDetermine Impact on GlobalMortality and Morbidity in HeartFailure

PIONEER = ComParIson OfSacubitril/valsartaN VersusEnalapril on Effect on ntpRo-bnpin Patients Stabilized From anAcute Heart Failure Episode

QoL = Quality of Life

RAAS =renin-angiotensin-aldosteronesystem

RADIANCE = Randomized As-sessment of Digoxin on Inhibi-tors of the AngiotensinConverting Enzyme

RALES = Randomized AldactoneEvaluation Study

RCT = randomized controlledtrial

SENIORS = Study of the Effects ofNebivolol Intervention on Out-comes and Rehospitalization inSeniors

SHIFT = Systolic Heart FailureTreatment with the If inhibitorIvabradine tria

SNS = sympathetic nervoussystem

SOLVD = Studies of Left Ventric-ular Dysfunction


One downstream efect of ongoing sympathetic stimulation ithe ensuing chroniover- activation of thRAAS cascade. RAAstimulation leads to increased concentrationof renin, angiotensin Ialdosterone and vasopressin. The circulatioof additional renin triggers the production oangiotensin II. Angiotensin II, one of the mosvasoactive peptides, contributes to LV remodeing and may lead to thendothelial dysfunctioobserved in HF.8

NP have becomenew target for future Htherapies. Vasoactive peptides such as NP, bradyknin, and adrenomedulliare degraded by the enzymeneprilysin.3Theneurohormonal overactivatiothat occurs in HF can boffset by the inhibition oneprilysin, as increaselevels of these vasoactivpeptides help to preventhe long-term deleterioueffects of sodium retention, vasoconstriction, anmaladaptive remodelingThemostrecentlyapprovedrug and the angiotensinreceptor neprilysin inhibito(ARNI) focuses on thaforementioned pathway. Fig. 1 summarizethe targets in the RAAand SNS pathways wittheir respective therapeutic interventions.

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The good: HFtherapy thatimproves survival

Evidence-based medcine obtained througRCTs has remainethe catalyst in drivinthe development an

progress made in HF therapy. From the early vasodilatotrials10–13 to the most recent ARNI study,7 each trial has beea stepping stone for the next. Themajor pharmacologic HFrEtrials are outlined in Table 1.

ACEI therapy

ACEI have been a mainstay of treatment for many years givetheir mortality and morbidity reducing abilities in the HFrEpopulation. With an ACC/AHA class of recommendatio(COR) I and level of evidence (LOE) A recommendation, theare sure to remain a pillar in HFrEF therapy.3–5 Multiple largand multicenter RCT have shown these therapies to improvfunctional capacity and symptoms, decrease hospitalizationsand most importantly reduce mortality in both ischemic annon-ischemic cardiomyopathy.12,13 The first ACEI trial witfavorable results was the Cooperative North ScandinaviaEnalapril Survival Study (CONSENSUS), which studied theffects of enalapril vs. placebo in patients with New YorHeart Association (NYHA) class IV HF.12 The enalapril armexhibited a 40% relative risk reduction in mortality, improvement in NYHA classification, reduction in heart size, andecreased medication requirements when compared to thplacebo arm.12 Following the results of the CONSENSUS triayielded the Studies of Left Ventricular Dysfunction (SOLVDtreatment trial,13 which aimed to further explore the rolof ACE-inhibition in NYHA class II and III patientsSOLVD-treatment reinforced the survival benefit and reductioin hospitalizations in these patients with less severe HF.1

Starting and target doses forACEI is further described inTable 2

ARB therapy

Following the success of the CONSENSUS12 and SOLVD13 trialprompted the hypothesis that additional inhibition of thRAAS pathway at a different level could be beneficial ichronic HF. The Valsartan HF Trial (Val-HeFT)14 tested thaddition of valsartan versus placebo in NYHA class II-Ipatients who were already receiving background medicatherapy which included ACEI in most patients and iapproximately one-third, BBs.14 Although no survival benefwas found in the valsartan arm, improvement in NYHA classquality of life (QoL) and ejection fraction (EF) was seen whecompared to the placebo arm, as well as a reduction ihospitalizations. In the post hoc observation of adversevents, the group receiving combination therapy of valsartanan ACEI and a BB carried a statistically significant negativeffect on mortality. In contrast, patients receiving onlvalsartan had a reduction in mortality risk. It should bnoted that the patients who were not on a background ACEwere not deemed “intolerant” but the therapy was chosen bthe referring physician.14

The Candesartan in HF Assessment of Reduction iMortality and Morbidity Trial (CHARM)15 compared the usof candesartan versus placebo in addition to standard therapwith ACEI, BB, and aldosterone antagonists. In comparison tthe findings of Val-HeFT, CHARM found a significant reduction of all-cause mortality, cardiovascular (CV) death and Hhospitalizations in the candesartan arm. Interestingly an

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US = United States

Val-HeFT = Valsartan Heart Fail-ure Trial

V-HeFT = Vasodilator in HeartFailure Trial


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unlike Val-HeFT, concomitant ACEI use dinot negate the beneficiaeffects of candesartan.1

ARBs are a reasonablalternative for thospatients intolerant o

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ACE as they antagonize the angioavoiding kinase inhibition. In turn, this results in a loweincidence of cough and angioedema.3

BB therapy

SNS activation is one of the many pathophysiologic abnormalities that leads to chronic HF.8 Sympathetic antagonisthave been studied and proven to reduce morbidity anmortality in HF.16,17 In this regard, several trials havelucidated the beneficial effects of BB, the first being thCardiac Insufficiency Bisoprolol Study (CIBIS II).16 CIBISaimed to show that bisoprolol, when compared to placeboreduced morbidity and mortality in HF. With a significanmortality and morbidity benefit when compared to placebothe trial was stopped early. Interestingly, while mortalitbenefit was seen in non-ischemic patients, the greatest effecin CIBIS-II was seen in ischemic cardiomyopathy patientwith NYHA class III symptoms.16

The U.S. HF Study Group17 compared carvedilol to placebin patients with chronic HF, primarily NYHA II and III, anwas ultimately stopped early given the significant morbiditand survival benefits seen in the treatment group, althougnot powered to test mortality directly. Several years later, thCarvedilol Prospective Randomized Cumulative Survival StudGroup (COPERNICUS) trial18 reaffirmed these benefits inmoderatesevere HF.

1 – RAAS and SNS targets

Finally, the Metoprolol CR/XL Randomized InterventioTrial in congestive HF (MERIT-HF)19 was a RCT which studieNYHA class II-IV patients assigned either to placebo ometoprolol CR/XL, with a primary endpoint of all-causmortality. MERIT-HF reduced all-cause mortality and hosptalizations for worsening HF, while simultaneously improvinNYHA class and QoL.19

As evidenced in the previously mentioned RCTs, metoprolol succinate controlled release/extended release (CR/XLcarvedilol, and bisoprolol are the only approved BB to use iHFrEF. The use of one of these three agents carries a COR I LOA recommendation and should be initiated in all patientwith chronic HFrEF.3–5 Patients who are not taking thesspecific BBs, but qualify for HFrEF diagnosis should bchanged to one of the three discussed above.

Aldosterone antagonist therapy

Aldosterone plays a considerable role in the pathophysiologof HF and RAAS pathway.8 The use of an aldosterone inhibitowas first highlighted in the Randomized Aldactone EvaluatioStudy (RALES).20 Patients with NYHA III-IV symptoms werrandomized to receive spironolactone, an aldosterone antagonist, or placebo in addition to an ACEI and loop diuretic.2

The trial was discontinued early due to a 30% reduction in thrisk of death in the spironolactone group. In addition tmortality benefits, it showed morbidity benefits througsymptom improvement and NYHA class regression.20 Onote, 10% ofmale patientswhowere treatedwith spironolactonreported gynecomastia or breast pain, a side effect attributed tthe nonselective properties of spironolactone that allow thdrug to bind to progesterone and androgen receptors.20

Following RALES the Eplerenone in Mild Patients Hospitaization and Survival Study in HF (EMPHASIS-HF),21 enrolle

for therapeutic interventions.

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Table 1 –Major pharmacologic HFrEF trials.

Clinical TrialAcronym Year

TrialPopulationCharacteristics

HF BackgroundTherapy (>50%) Intervention Comparator

Mortality/MorbidityFindings

MortalityReduction

V-HeFT I10 1986 Mild tomoderate HFLVEF < 45%

Digoxin, diuretics HydralazineIsosorbidedinitrate ORPrazosin

Placebo ↓ in mortality↑ improvement in LV function inhydralazine/isosorbide dinitrategroup

38%

CONSENSUS12 1987 NYHA IV HFIncreasedheart size

Diuretics,spironolactone,digitalis

Enalapril Placebo ↓ in mortality↓ NYHA class, heart size andmedication requirements

27%

SOLVD-Treatment13 1991 NYHA II, IIILVEF ≤ 35%

Digoxin, diuretics Enalapril Placebo ↓ in mortality↓ in hospitalizations

16%

V-HeFT II11 1991 NYHA II,IV Digoxin, diuretics Hydralazineisosorbidedinitrate

Enalapril ↓ in mortalityenalapril group at 2 years↔ hospitalizations betweengroups

N/A

US Carvedilol HFStudy17

1996 NYHA II, III, IVLVEF ≤ 35%

ACEI, digoxin,diuretics

Carvedilol Placebo ↓ in mortality hospitalizations 65%

CIBIS II16 1999 NYHA III, IVLVEF < 35%


Bisoprolol Placebo ↓ in mortality and hospitalizationsin bisoprolol group

34%

MERIT-HF19 1999 NYHA II, III, IVLVEF < 40%

ACEI, diuretics Metoprolol XL Placebo ↓ in mortality andhospitalizations↑ functional class and QOL inmetoprolol group

39%

RALES20 1999 NYHA III–IVLVEF ≤ 35%


Spironolactone Placebo ↓ in mortality↑ NYHA class and QOL

30%

COPERNICUS18 2001 NYHA IVLVEF < 25%

ACEI/ARB, digoxin,diuretics

Carvedilol Placebo ↓ in mortality andhospitalizations

35%

Val-HeFT14 2001 NYHA II, III, IVLVEF < 40%Increased heartsize


Valsartan Placebo ↔ all-cause mortality↓ hospitalizations↑ NYHA class, QOL

N/A

CHARM15 2004 NYHA II, III, I VLVEF ≤ 40%

ACEI, BB, digoxin,digoxin

Candesartan Placebo ↓ in mortalityReduction inmortality andhospitalizations

33%

A-HeFT22 2004 NYHA III, IVAA patientsIncreasedheart size

ACEI, BB, dgoxin,diuretics

Hydralazine/isosorbidedinitrate

Placebo ↓ in mortality andhospitalizations

43%

SHIFT6 2010 NYHA II, III, IVLVEF ≤35%Resting HR≥70 bpm inNSR

ACEI, aldosteroneantagonist, BB,diuretics

Ivabradine Placebo ↓ hospitalizations N/A

EMPHASIS-HF21 2011 NYHA IILVEF ≤ 35%

ACEI, BB, diuretics Eplerenone Placebo ↓ in mortality andhospitalizations

37%

PARADIGM-HF7 2014 NYHA II, III, IVLVEF ≤ 35%

Aldosteroneantagonist, BB,diuretics

LCZ696(sacuibitril/valsartan)

Enalapril ↓ in mortality andhospitalizations↑QOL in LCZ696 group

16%

Abbreviations: HFrEF, heart failure with reduced ejection fraction; HF, heart failure; V-HeFT: Vasodilator in Heart Failure Trial; LV, Left ventricleor left ventricular; LVEF, left ventricular ejection fraction; CONSENSUS, Cooperative North Scandinavian Enalapril Survival Study; NYHA, NewYork Heart Association; SOLVD, Studies of Left Ventricular Dysfunction; US, United States; ACEI, angiotensin-converting-enzyme inhibitors;CIBIS, Cardiac Insufficiency Bisoprolol Study; MERIT-HF, Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure; QOL,quality of life; RALES, Randomized Aldactone Evaluation Study; COPERNICUS, Carvedilol Prospective Randomized Cumulative Survival StudyGroup; ARB, angiotensin receptor blockers; Val-HeFT, Valsartan Heart Failure Trial; CHARM, Candesartan in Heart Failure Assessment ofReduction in Mortality and Morbidity; BB, beta blockers; A-HeFT, African-American Heart Failure Trial; SHIFT, Systolic Heart Failure Treatmentwith the If inhibitor Ivabradine trial; HR, heart rate; EMPHASIS-HF, Eplerenone in Mild Patients Hospitalization and Survival Study in HeartFailure; PARADIGM-HF: Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure.


NYHA class II HFrEF patients with an EF of 35% or less anwere randomized to receive eplerenone vs. placebo. Eplerenonwas found to reduce all-cause morbidity and reduce hospitaizations when added to standard HF therapy.21 Given tha

eplerenone is more selective to the aldosterone receptor thaspironolactone, gynecomastia was quite rare and observed i<1% of trial participants. Hyperkalemia was the most commoadverse event noted in the treatment arm of the trial.21

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Table 2 – Currently available pharmacotherapy for HFrEF.

Drug Starting Dose Maximum Daily DoseMean Dose Achieved inClinical Trials COR LOE

If channel inhibitorIvabradine 5 mg QD 7.5 mg BID 6.4 mg BID (at 28 days)

6.5 mg BID (at 1 year)II B-R

ARNI I B-RSacubitril/Valsartan 49/51 mg BID (therapy may

be initiated at 24/26 mg BID)97/103 mg BID 375 mg QD; target dose: 24/26 mg,

49/51 mg OR 97/103 mg BIDACE I ACaptopril 6.25 mg TID 50 mg TID 122.7 mg QDEnalapril 2.5 mg BID 10–20 mg BID 16.6 mg QDFosinopril 5–10 mg QD 40 mg QD N/ALisinopril 2.5–5 mg QD 20–40 mg QD 32.5–35 mg QDRamipril 1.25–2.5 mg QD 10 mg QD N/ATrandolapril 1 mg QD 4 mg QD N/APerindopril 2 mg QD 8–16 mg QD N/AQuinapril 5 mg BID 20 mg BID N/AARBCandesartan 4–8 mg QD 32 mg QD 24 mg QDLosartan 25–50 mg QD 50–150 QD 129 mg QDValsartan 20–40 mg BID 160 mg BID 254 mg QD

BBBisoprolol 1.25 QD 10 mg QD 8.6 mg QDCarvedilol 3.125 mg BID 50 mg BID 37 mg QDCarvedilol CR 10 mg QD 80 mg QD N/AMetoprolol Succinate 12.5–25 mg QD 200 mg QD 159 mg QDAldosterone antagonists I ASpironolactone 12.5–25 mg QD 25 mg QD or BID 26 mg QDEplerenone 25 mg QD 50 mg QD 42.6 mg QDHydralazine and isosorbide Dinitrate I AFixed dose combination 37.5 mg hydralazine/

20 mg isosorbidedinitrate TID

5 mg hydralazine/40 mgisosorbide dinitrate TID

~175 mg hydralazine/90 mgisosorbidedinitrate QD

Hydralazine and isosorbide Hydralazine: 25 to 50 mg,TID or QID and isosorbidedinitrate: 20 to 30 mgTID or QID

Hydralazine: 300 mg daily individed doses and isosorbidedinitrate 120 mg daily individed doses

N/A

Abbreviations: GDMT, guideline directed medical therapy; HFrEF, heart failure with reduced ejection fraction; mg, milligram; ARNI, angiotensinreceptor-neprilysin inhibitor; QD, every day; BID, twice daily; ACE, angiotensin-converting-enzyme inhibitor; TID, three times daily; ARB,angiotensin receptor blocker; BB, beta blocker; CR, controlled release; QID, four times daily.


Candidates for aldosterone receptor antagonist therapinclude those with NYHA class II-IV HF with an LVEF of <35%who are already receiving background therapy with a BB anACEI.3–5 This ACC/AHA COR I LOE A recommendatiospecifies that in order to deem a NYHA class II HF patientcandidate for aldosterone antagonists they should have beeeither hospitalized for a CV condition or have elevated plasmNP levels. Additionally, patients with an LVEF of 40% or lesfollowing an acute myocardial infarction, who develop Hsymptoms or have diabetes mellitus should be initiated on aaldosterone antagonist.3–5

Hydralazine and isosorbide dinitrate therapy

The potential therapeutic benefit in HFrEF patients witcombination hydralazine and isosorbide dinitrate was firsexplored in the Vasodilator-HF Trial (V-HeFT I).10 In this triapatients with chronic HF already taking digoxin and diuretic

were randomized to either placebo, prazosin, or hydralazine pluisosorbide dinitrate therapy. This trial aimed to evaluate ifmortality benefit existed with use of these vasodilator therapieThe group treatedwith both hydralazine and isosorbide dinitratshowed a statistically significant mortality reduction at twyears, in addition to an improvement in LV function.10

The approval of ACEI use in HFrEF coincided closely in timto V-HeFT I prompting V-HeFT II.11 This trial compareenalapril to hydralazine plus isosorbide dinitrate, and founthat the ACEI had a more favorable effect on mortality thathe vasodilator combination.11 Upon retrospective analysis othe V-HEFT I and II trials, it was noted that African-Americanwere more likely to respond to the combination of hydraazine and isosorbide dinitrate, whereas enalapril only provided a mortality reduction in their Caucasian counterparts. Thiinteresting observation was theorized to be related to a lowebioavailability of nitric oxide and a more active RAAS withithe black subgroup.10,11

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Table 3 – Properties of commonly used diuretics in HFrEF.

Agent Potency Oral:IV Duration of effect Bioavailabilty Half life

Furosemide 1x 2:1 6–8 h 10–100% 2Bumetanide 40x 1:1 4–6 h 80–100% 1–1.5Torsemide (not available IV) 2x 1:1 6–16 h 80–100% 3.5

Abbreviations: x, times; IV, intravenous; h, hours.


These striking discoveries prompted further investigation bmeansof theAfrican-AmericanHFTrial (A-HeFT)22which targeteblacks with NYHA III and IV symptoms and dilated LVs. Thlandmark studypublished in 2004 confirmed theprevious findingthat the addition of a fixed-dose combination of isosorbiddinitrate and hydralazine to standard HF therapy in this population was associated with a significant reduction in all-causmortality and hospitalizations while also improving QoL.22

Two major recommendations were generated through thgains of these trials. The first endorses the use of combinatiohydralazine and isosorbide dinitrate to reduce morbidity anmortality in NYHA III and IV African American patients witHF who are already receiving ACEI and BB therapy. Thsecond advises that the same therapy may be useful ireducing mortality and morbidity in this same cohort who arunable to tolerate an ACEI or ARB.3–5

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The bad: HF therapy for symptom relief

Diuretic therapy

Diuretic therapy has maintained a seat at the table in thmanagement of HF therapy through its symptom relieproperties. Bearing in mind that it holds no mortality benefidiuretics are mainly used for symptom relief in patients whpresent with acute decompensated HF and fluid retention.2

These agents should be used in conjunction with GDMT.Furosemide, bumetanide, and torsemide are three loo

diuretics that are commonly used in clinical practice (Table 3).2

Furosemide is the most widely used due to low cost, longevityand provider familiarity. Nonetheless, both bumetanide antorsemide have better bioavailability and as a result are morefficacious in some situations.25 In cases of refractory volumretention, thiazide diuretics may be used in conjunction to loodiuretics.24–27 A noteworthy study to consider when managindiuretic therapy is the Diuretic Optimization Strategies Evaluation (DOSE) trial28 which showed no difference in outcomebetween continuous infusion versus bolus dosing of furosemidin patients hospitalized for HF. In addition, there was nobserved difference in the safety and efficacy of bolus injectionin comparison to continuous infusions of loop diuretics. However, the higher dose resulted in better diuresis.28

Digoxin

Heralded as the oldest known CV drug, digoxin acts bincreasing contractility through inhibition of the Na+K + ATPase in the myocardium.29 Though not effective areducing mortality, this medication has been shown t

decrease hospitalizations and improve functional class.30,3

Current guidelines recommend to consider digoxin for Hpatients who remain symptomatic despite the use of mortaity reducing GDMT.4,5 Another utility of digoxin in the HFrEpopulation is in patients with atrial fibrillation in whom a ratcontrol strategy is preferred, and may be considered for thospatients unable to tolerate a BB or who remain inadequatelrate controlled on maximum doses of BB.4,5

Owing to a narrow therapeutic range, careful consideration should be given to the side effects and potential toxicitof digoxin prior to initiation. In light of this, digoxin use hasignificantly decreased, particularly in the era of safer anmore proven HFrEF therapies such as BB, ACE and ARNIsFindings from the Randomized Assessment of Digoxin oInhibitors of theANgiotensinConverting Enzyme (RADIANCE)3

and Prospective Randomized Study of Ventricular Failure anthe Efficacy of Digoxin (PROVED)33 trials suggest thatwithdrawal of digoxin in patients with HFrEF can result in worseninclinical symptoms, thuswerecommendcautionwhendiscontinuintherapy.

The ugly: inotropic therapy

Despite their often controversial presence on the HF scenecontinuous inotrope therapymaintains an important role infew circumstances.34 The twomost commonly used inotropein HFrEF are dobutamine, a beta-agonist, and milrinone,phosphodiesterase-3 inhibitor.34 The net effect of both othese inotropes on the myocardium is amplified calciuminflux resulting in increased LV contraction. Both agents havthe potential to cause peripheral vasodilation and hypotension, but is often more pronounced with milrinone. Iaddition, providers should be aware of their arrhythmogeninature.34

Data has shown that routine use of these agents foacute decompensated HF without low-output or shock ofor long-term treatment of HFrEF increases mortality.3

Accordingly, current ACC/AHA guidelines urge against thipractice.4 Clinical scenarios that inotropes may be appropriate is in the setting of cardiogenic shock where inotropecan serve as a bridge-to-decision or as a palliative therapyWhen employed as a bridge, the goal should be clearldefined, whether that includes initiation and uptitration oGDMT, addition of cardiac-resynchronization therapy, oadvanced HF therapies such as mechanical circulatorsupport and cardiac transplantation. As a final resort, anin the absence of candidacy for advanced HF therapiespalliative inotropes may be used for symptomatic relieduring end of life care.4

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The new kids on the HF block

Ivabradine therapy

Ivabradine was approved for use in the US in 2015 and isselective inhibitor of the If current in the sinoatrial node. Thprimary therapeutic effect is heart rate reduction and iexclusive of any other effects on the heart or vascular systemThemajor publication driving drug approval in the USwas thSystolic HF treatment with the If inhibitor ivabradine Tria(SHIFT) trial.6 This European-based study aimed to assess thbenefit of heart rate reduction with ivabradine in moderate tsevere HF patients, with the vast majority of the enrolleefalling into NYHA class II and III. The composite primarendpoint of CV death or hospital admission for worsening Hshowed a relative risk reduction of 18%, but was driven by threduction in HF hospitalizations.6

Ivabradine carries a class IIa LOE B-R recommendation ithe most recent ACCF/AHA/HFSA guidelines,5 and is indicated to reduce hospitalizations in NYHA II and III patients witsymptomatic HFrEF who are receiving GDMT, but mosimportantly a BB at a maximum tolerated dose.5 Thespatients should have a heart rate >70 beats per minut(bpm) at rest and be in normal sinus rhythm (NSR). Thadoption of this drug has been slow in the US and more datis needed to evaluate its full benefit in our HFrEF patienpopulation.

Angiotensin receptor-neprilyin inhibitor therapy

The newest agent on the market has the potential to brinnew enthusiasm to the treatment of HFrEF. The ProspectivComparison of ARNI with ACEI to Determine Impact on GlobaMortality and Morbidity in Heart Failure trial (PARADIGM-HF)sought to test the hypothesis that the addition of neurohormonal inhibition to RAAS inhibition via the ARB mechanismmay be superior to ACEI alone. This double-blind triacompared a twice daily combination form of the ARvalsartan and the neprilysin-inhibitor sacubitril, otherwisknown as LCZ696, to twice daily enalapril (10 mg twice dailyin NYHA class II-IV HF patients. The impressive 20% reductioin the endpoint of CV deaths or hospitalizations for HF ithose treated with LCZ696 lead to early trial termination.3

The reduction in mortality and HF hospitalizations observed in this trial prompted the focused update of the ACCAHA HF guidelines.5 The COR I LOE B-R recommendation callfor replacement with ARNI in NYHA class II and III patientwho are tolerating therapy with an ACEI or ARB to furthereduce mortality.5

In regard to the side effect profile, the results were versimilar between the two drugs with the exception of a slightlhigher rate of non-life threatening angioedema and hypotension in the LCZ696 group. It is important to note that an ACEshould not be co-administered with an ARNI and that,already taking an ACEI, patients are recommended to discontinue the ACE-inhibitor at least 36 h prior to starting sacubitrivalsartan.3,5 More clinical trial data is warranted for additionarecommendations including its use in hospitalized patients.

Misconceptions, uncertainties and opportunities toptimize GDMT

Drug selection, initiation and titration

Step-wise initiation and titration of GDMT to efficacious doseas seen in RCTs is imperative to obtain any and all morbiditand mortality benefits in HF patients. Regardless of symptomseverity, ACEI therapy remains first-line therapy followed bBB therapy.3–5 We recommend starting at low doses wituptitration and frequent clinical assessment during thaperiod. Following ACEI initiation, serum creatinine anpotassium levels should be assessed within 1 to 2 weeks.

As previously mentioned, and unlike ACEIs, the benefitobtained with BB therapy are not a class effect, therefore onlmetoprolol succinate, carvedilol or bisoprolol should be usein HFrEF.3–5 Early initiation of BB therapy is imperative anprescribers need not wait until target doses of ACEI arachieved prior to adding it.36,37 This strategy has led to greateimprovement in symptoms and reduction in the risk of deatwhen compared to delayed use of BBs until maximal dose ACis reached.36,37 It is acceptable to discontinue BB therapy ithe setting of marked hypoperfusion. Moreover, amonpatients admitted for new onset HF, initiation of BB befordischarge has been shown to increase adherence anlikelihood to achieve target doses and is recommended ithe Guidelines.38

When changing from one BB to another, current datsuggest starting the new agent at an equivalent dose witclose monitoring of clinical status and adverse events. Durinthe up-titration period, the risk of hypotension can be avoideby administering the BB and the ACEI at different times oday. In addition, BB should be titrated to maximally toleratedose regardless of target heart rate as recent data suggestethat titration of BB doses may provide a greater benefit thareduction of heart rate in well treated HFrEF patients.3,39

Patients with CKD

The use of ACEI and aldosterone antagonists in patients witCKD continues to be a conundrum in clinical practice. Datregarding the use of these agents within this populatioremain scarce, as most HF trials exclude patients witsignificant renal dysfunction. Hence the conventional wisdomhas been to avoid the use of these therapies entirely in patientwith impaired renal function. Guidelines recommend the use othese agents with caution in patients with advanced renaimpairment and with clear directions in regard to creatininand potassium levels that would preclude the use of thesagents.4,5 Despite the aforementioned, we believe these agentand underused, are potentially safe, and should be used (witcaution) as they have the ability to benefit this population.

The element of renal dysfunction that exists in a largmajority of HF patients is quite indicative of the strugglclinicians face in the complexities of the cardio-renal relationship. The increased prevalence of CKD in the HFrEpopulation highlights that ACEI and aldosterone antagonisuse may be beneficial in improving renal perfusion an

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decreasing congestion through their systemic vasodilatorproperties as well as providing renal protection. It is important to note that patients with CKD stages 1–3 have beeincluded in landmark HF clinical trials and data suggessurvival benefit when used in this patient population.40 Iaddition a recent study41 suggested a strong associatiobetween ACEI use and survival in HFrEF patients with severrenal impairment, whichmay be indicative that ACEI usemabe associated with an even higher absolute mortality reduction in this population.41

The elderly

Elderly patients now represent the largest group of HFrEpatients and paradoxically, limited data exists on the efficacof GDMT in this population due to their under-representatioand frequent exclusion from large clinical trials.1 Withouquestion, age related physiological changes and drug metabolism in the elderly put them at higher risk for adversevents.42 Moreover, comorbid conditions such as renal anliver impairment further complicate the elderly's response tdrugs and increase their risk for adverse events such ahypotension and bradycardia. Despite the scarcity of data ithe elderly, there are two noteworthy trials. The Study of thEffects of Nebivolol Intervention on Outcomes and Rehosptalization in Seniors with Heart Failure (SENIORS)43 includeover 2000 patients over the age of 70 who were randomized treceive either nebivolol or placebo. Treatment with this agenwas found to be statistically significant in decreased all-causmortality and CV hospitalization. Strengths of the triainclude the exclusive focus on the older cohort of HF patientand an extensive follow-up of 21 months.43 Limitations ithis trial primarily include the use of nebivolol, a BB that doenot carry a HFrEF indication, and the presence of HFpEpatients due to laxity in the inclusion criteria. Neverthelesthe study offered some valuable lessons with regard ttolerability and response to therapy in the elderly.43 ThCIBIS in Elderly (CIBIS-ELD)44 was another large study thafocused on drug specific side effects. This multicentedouble-blind superiority trial of bisoprolol versus carvediloincluded 883 elderly HF patients with both HFpEF and HFrEFAlthough tolerability was low, no differences between thegroups were seen in the primary end point as defined breaching and maintaining guideline-recommended targedoses after 12 weeks of therapy.44 Intriguingly, adverse eventvaried among the two drugs in the trial. While bradycardiwas more common in the bisoprolol group, pulmonaradverse events were more likely to occur with carvediloDespite the above-mentioned studies,many important questionremain unanswered on the efficacy and safety of HF GDMT ithe elderly.44 Large clinical trials and data from nationaregistries are essential to close this knowledge gap.

Incorporating sacubitril/valsartan into clinical practice

With a 20% reduction in CV mortality,3 there is no doubt thasacubitril/valsartan is by far themost efficacious HFrEF therapdeveloped in the last decade supplanting both ACEI and ARtherapies. Despite this, there has been a very slow adoption o

this novel drug in the HF community. Cost may be a factor ithe slow implementation of this ANRI into clinical practicethough other concerns exist and have been raised from expertin the field as well as community providers. One of thosconcerns includes a middle dose of enalapril compared tohigher equivalent dose of valsartan. Often times translatinclinical trial results and implementing them to daily practiccan be challenging. The reality is patients tend to be older acompared to clinical trials, and frequently possess comorbidties that would be otherwise exclude them from clinical trialsAn important limiting factor in prescribing this therapy is lowBP. In the PARADIGM-HF study,3 roughly 1/5 of patients werexcluded in the run-in phase due to hypotension in either thsacubitril/valsartan or enalapril group.3 For this reason, wrecommend caution when using this agent in the elderly, ipatients with borderline-low BP, or in the advanced Hpopulation. We urge clinicians to use the “start low and titratslow” approach as it is likely the safest method to avoid sucevents. Identifying the patient population thatwill benefitmosfrom this drug can also be arduous. The majority of patientenrolled in PARADIGM-HF were stable patients with NYHAclass II patients, which leaves uncertainty in the efficacy ansafety of this drug in sicker patients. In a recent study,45 84% oHFrEF patients in the US were projected to be good candidatefor ARNI therapy highlighting the clear opportunity to expanthe use of this drug in patients who would benefit the most.4

Two additional clinical trials are underway: ComParIson OSacubitril/valsartaN Versus Enalapril on Effect on ntpRo-bnp iPatients Stabilized From an Acute Heart Failure Episod(PIONEER-HF) study and the EntrestoTM In Advanced HearFailure HFN-LIFE trial. The PIONEER study will be exploring thsafety and efficacy of in-hospital initiation of ARNI therapy anits potential role among patients hospitalized for acutdecompensated HF. The LIFE trial will focus on the utility oARNI therapy in patients with advanced HF.

Conclusion and future directions

The journey to efficacious pharmacologic therapy in HFrEhas been far from fleeting. Beginning with the V-HeFT trial1

in 1986 which set the stage by introducing vasodilator therapin the HF arena, and ending most recently with thPARADIGM-HF trial,3 major milestones have been met alonthe way. For decades, ACEI, BB, aldosterone antagonists ancombined therapy with hydralazine- isosorbide dinitrate havbeen the mainstay therapies for HFrEF. With the most recenfocused updates to the ACC/AHA Guidelines for the management of HF,5 several new pharmacologic interventions are nowavailable and may provide superior survival benefits icomparison to established agents. One fundamentatake-away message is that provider familiarity with propepatient selection, initiation, maintenance, and adverse eventrelated to thedifferent drug classes is of theutmost importanceContinued collection of data through clinical trials and registries related to this chronic illness is key in ensuring progressivtreatment options with a special focus on previouslunderstudied populations in the literature. It is only througthis undertaking that we can begin to remedy the HF epidemic

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Financial disclosures

The authors have no financial or proprietary interest in thsubject matter of this article.

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7. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysiinhibition versus enalapril in heart failure. N Engl J Med.2014;371:993-1004.

8. Jackson G, Gibbs CR, Davies MK, Lip GYH. ABC of heart failurePathophysiology. 2000;320:167.

9. Mann DL, Kent RL, Parsons B, Cooper G. Adrenergic effects othe biology of the adult mammalian cardiocyte. Circulation.1992;85(2):790-804.

10. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilatortherapy on mortality in chronic congestive heart failure.Results of a Veterans Administration Cooperative Study. NEngl J Med. 1986;314:1547-1552.

11. Cohn JN, Johnson G, Ziesche S, et al. A comparison ofenalapril with hydralazine-isosorbide dinitrate in the treat-ment of chronic congestive heart failure. N Engl J Med.1991;325:303-310.

12. The CONSENSUS Trial Study Group, ed. Effects of enalapril onmortality in severe congestive heart failure. Results of the Cooper-ative North Scandinavian Enalapril Survival Study (CONSENSUS).Engl J Med. 1987;316:1429-1435.

13. The SOLVD Investigators, ed. Effect of enalapril on survival inpatients with reduced left ventricular ejection fractions and congestive heart failure.N Engl J Med. 1991;325:293-302.

14. Cohn JN, Tognoni G. Valsartan heart failure trial investigatorA randomized trial of the angiotensin-receptor blockervalsartan in chronic heart failure. N Engl J Med. 2001;345(23):1667-1675.

15. Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartain patients with chronic heart failure and reducedleft-ventricular systolic function intolerant toangiotensin-converting enzyme inhibitors: theCHARM-alternative trial. Lancet. 2003;362:772-776.

16. CIBIS Investigators and Committees. A randomized trial ofbeta-blockade in heart failure. The Cardiac InsufficiencyBisoprolol Study (CIBIS). Circulation. 1994;90:1765-1773.

17. Packer M, Bristow MR, Cohn JN, et al. The effect of carvediloon morbidity and mortality in patients with chronic heartfailure: U.S. Carvedilol Heart Failure Study Group. N Engl J Med1996;334:1349-1355.

18. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol onsurvival in severe chronic heart failure. N Engl J Med. 2001;3441651-1658.

19. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/Xrandomised intervention trial in congestive heart failure(MERIT-HF).Lancet. 1999;353:2001-2007.

20. Pitt B, Zannad F, RemmeWJ, et al. The effect of spironolactonon morbidity and mortality in patients with severe heartfailure. Randomized Aldactone Evaluation Study Investiga-tors. N Engl J Med. 1999;341(10):709-717.

21. Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patientwith systolic heart failure and mild symptoms. N Engl J Med2011;364:11-21.

22. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbiddinitrate and hydralazine in blacks with heart failure. N EnglMed. 2004;351(20):2049-2057.

23. Wilson JR, Reichek N, Dunkman WB, Goldberg S. Effect ofdiuresis on the performance of the failing left ventricle inman. Am J Med. 1981;70(2):234-239.

24. Buggey J, Mentz RJ, Pitt B, et al. A reappraisal of loop diureticchoice in heart failure patients. Am Heart J. 2015;169(3):323-333

25. Murray MD, Deer MM, Ferguson JA, et al. Open-label ran-domized trial of torsemide compared with furosemide ther-apy for patients with heart failure. Am J Med. 2001;111(7):513

26. Casu G, Merella P. Diuretic therapy in heart failure—currentapproaches. Eur Cardiol Rev. 2015;10(1):42-47.

27. Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patientwith acute decompensated heart failure. N Engl J Med.2011;364(9):797-805.

28. Allen LA, Turer AT, Dewald T, Stough WG, Cotter G, O'ConnoCM. Continuous versus bolus dosing of furosemide forpatients hospitalized for heart failure. Am J Cardiol.2010;105(12):1794-1797.

29. Vivo RP, Krim SR, Perez J, Inklab M, Tenner Jr T, Hodgson J.Digoxin: current use and approach to toxicity. Am J Med Sci.2008;336(5):423-428.

30. The Captopril-Digoxin Multicenter Research Group. Comparative effects of therapy with captopril and digoxin in patientwith mild to moderate heart failure. JAMA. 1988;259:539-544

31. The Digitalis Investigation Group. The effect of digoxin onmortality and morbidity in patients with heart failure. N EnglMed. 1997;336:525-533.

32. Packer M, Gheorghiade M, Young JB, et al. Withdrawal ofdigoxin from patients with chronic heart failure treated withangiotensin-converting-enzyme inhibitors. RADIANCE StudyN Engl J Med. 1993;329(1):1-7.

33. Uretsky BF, Young JB, Shahidi FE, Yellen LG, Harrison MC, JollMK. Randomized study assessing the effect of digoxin

e

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e.

n

-

c

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-e

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l


withdrawal in patients with mild to moderate chroniccongestive heart failure: results of the PROVED trial. PROVEDInvestigative Group. J Am Coll Cardiol. 1993;22(4):955-962.

34. Abraham WT, Adams KF, Fonarow GC, et al. In-hospitalmortality in patients with acute decompensated heart failurrequiring intravenous vasoactive medications: an analysisfrom the Acute Decompensated Heart Failure NationalRegistry (ADHERE). J Am Coll Cardiol. 2005;46(1):57.

35. Cuffe MS, Califf RM, Adams Jr KF, et al. Short-term intravenousmilrinone for acute exacerbation of chronic heart failure: arandomized controlled trial. JAMA. 2002;287(12):1541.

36. Remme WJ, Riegger G, Hildebrandt P, et al. The benefits ofearly combination treatment of carvedilol and anACEinhibitor in mild heart failure and left ventricular systoldysfunction. The carvedilol and ACE-inhibitor remodellingmild heart failure evaluation trial (CARMEN). Cardiovasc DrugTher. 2004;18:57-66.

37. Sliwa K, Norton GR, Kone N, et al. Impact of initiatingcarvedilol before angiotensin converting enzyme inhibitortherapy on cardiac function in newly diagnosed heart failurJ Am Coll Cardiol. 2004;44:1825-1830.

38. GattisWA, O'Connor CM, GallupDS, et al. Pre-discharge initiatioof carvedilol in patients hospitalized for decompensated heartfailure: results of the IMPACT-HF (initiation management pre-discharge process for assessment of carvedilol therapy in heartfailure) trial. J Am Coll Cardiol. 2004;43:1534-1541.

39. Fiuzat M, Wojdyla D, Pina I, et al. Heart rate orbeta-blocker dose? Association with outcomes in

ambulatory heart failure patients with systolic dysfunction: results from the HF-ACTION trial. JACC Heart Fail.2016;4(2):109-115.

40. Damman K, Tang WH, Felker GM, et al. Currentevidence on treatment of patients with chronic systoliheart failure and renal insufficiency: practical consid-erations from published data. J Am Coll Cardiol.2014;63(9):853-871.

41. Edner M, Benson L, Dahlström U, Lund LH. Associationbetween renin-angiotensin system antagonist use and mor-tality in heart failure with severe renal insufficiency: aprospective propensity score-matched cohort study. Eur HeaJ. 2015;36(34):2318-2326.

42. Lazzarini V, Mentz RJ, Fiuzat M, et al. Heart failure in elderlypatients: distinctive features and unresolved issues. Eur JHeart Fail. 2013;15(7):717-723.

43. Flather MD, Shibata MC, Coats AJ, et al. Randomized trial todetermine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failur(SENIORS). Eur Heart J. 2005;26:215-225.

44. Dungen HD, Apostolovic S, Inkrot S, et al. Titration to targedose of bisoprolol vs. carvedilol in elderly patients withheart failure: the CIBIS-ELD trial. Eur J Heart Fail. 2011;13:670-680.

45. Fonarow GC, Hernandez AF, Solomon SD, Yancy CW. Potentiamortality reduction with optimal implementation of angio-tensin receptor neprilysin inhibitor therapy in heart failure.JAMA Cardiol. 2016;1(6):714-717.



ScienceDirect


Late In-Hospital Management of Patients Hospitalized
with Acute Heart Failure
Nicole B. Cyrille, Snehal R. Patel⁎

Department of Medicine, Division of Cardiology, Montefiore Medical Center-Albert Einstein College of Medicine, Bronx, NY


Statement of Conflict of Interest: see pDrs. Patel and Cyrille have no disclosur

⁎ Address reprint requests to Snehal R Pat7th floor, Bronx, N.Y. 10467.



A B S T R A C T

d
Keywords: tedetd
.

Acute Heart Failure (AHF) hospitalization presents a significant financial burden anportends a poor prognosis following discharge. As such, there has been significanemphasis on the late inpatient management of patients hospitalized with AHF to ensursuccessful transition to the outpatient setting and to reduce overall readmission anmortality rates. Thorough discharge planning and a multidisciplinary team approach aressential and as outlined in this review should focus on four key elements: the assessmenof patients' readiness for discharge, optimization of goal directed medical therapy anappropriate device therapy, patient education and transition to the outpatient care.


Acute heart failurePatient educationDischargeLate managementTransition

Contents

99011222333

Assessing readiness for discharge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Body weight changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Hemoconcentration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Goal directed medical therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Device therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Patient education . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Transition to outpatient care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Statement of conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

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Acute heart failure (HF; AHF) accounts for about 1 millioadmissions annually in the United States (US).1 In 2012, Hexpenditure totaled approximately $30.7 billion and is est

age XX.es to report.el MD, Montefiore-Einstei

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mated to increase to $69.7 billion by 2030.2 Hospitalization foAHF is the major contributor to total HF expenditure anaccounts for up to 69%.3 In addition, the prognosis followin

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ACC = American College ofCardiology

ACEI = Angiotensin-Converting En-zyme Inhibitor

ADHERE = Acute DecompensatedHeart Failure Registry

AHA = American Heart Association

AHF = Acute Heart Failure

ARB = Angiotensin II ReceptorBlocker

ASCEND-HF = Acute Study of ClinicalEffectiveness of Nesiritide in De-compensated Heart Failure

BB = Beta Blocker

BNP = Brain Type Natriuretic Peptide

CardioMEMS =CardioMicroelectromechanicalsystem

CHAMPION =CardioMicroelectromechanical sys-tem (CardioMEMS) Heart Sensor Al-lows Monitoring of Pressures toImprove Outcomes in New YorkHeart Association Class III HeartFailure Patients trial

COMET = Carvedilol Or MetoprololEuropean Trial

CRT = Chronic ResynchronizationTherapy

CV = Cardiovascular

EVEREST = Efficacy of VasopressinAntagonism in Heart Failure Out-come Study with Tolvaptan trial

GAL-3 = Galectin-3

GDMT = Goal Directed MedicalTherapy

HF = Heart Failure

ICD = Implantable CardioverterDefibrillator

IMPACT-HF = Initiation Manage-ment Predischarge Process for As-sessment of Carvedilol Therapy forHeart Failure

INTERMACS = Interagency Registryof Mechanically Assisted CirculatorySupport

LV = Left Ventricular


AHF hospitalzation remainpoorwithhospitamortality ranginfrom 4% to 7%post-discharge60 to 90 daymotality as high a7%–11%, and onyear mortality ahigh as 36%.4 Readmission rateare also a signifcant burden wit≥50% patientreadmitted tthe hospitawithin 6 monthof discharge.5 Aanalysis of 200to 2009 Medicarclaims-baseddata showed tha24.8% of patientadmittedwithHwere readmittewithin 30 daywith 35.2% othosereadmissions foHF.6 Furthermore, a 200study found thain patients witstage D HF, onl32% were alivand had nobeen readmitteat one year aftedischarge foAHF.7 Reductioin readmissiorates particularlin an effort treduce cost habeen a majofocus in pay foperformance intiatives resultinin the US Centefor MedicareMedicaid Services requirinpublic reportinof all-cause readmission rateafter HF hospitaization and thimplementation

of financial penalties for hospitals with the highest readmissiorates during the first 30 days after discharge.5,8 While there habeen a significant emphasis on post-discharge follow-up treduce readmissions, it is also well established that appropriatpre-discharge care affects outcomes. Therefore, ensuring that Hpatients areoptimizedprior todischargeanddevelopingeffectivstrategies for transition to the outpatient care are of paramounimportance and are the focus of this review. In particular, wewiemphasize the keymanagement issues that should be addressein the late stages of the hospitalization. (Fig 1).

Assessing readiness for discharge

It is well established that the goal of all AHF hospitalizationis to achieve maximal decongestion.9 What is unclear is howbest to determine when this goal has been met and patientcan be transitioned to the outpatient setting. In fact, studiehave shown that a large proportion of patients are dischargewith unresolved symptoms and this may be a majocontributor to high readmission rates.10–12 For instanceamong the 363 hospitalized patients enrolled in the InitiatioManagement Predischarge Process for Assessment of Carvedilol Therapy for Heart Failure (IMPACT-HF) trial, approxmately 60% of patients were discharged with continuinsymptoms of dyspnea or fatigue. At 60 days after dischargeapproximately 45% of these patients experienced worseninHF and 25% required rehospitalization.11 For this reasonsurrogate markers to assess a patient's readiness for discharge are important.

Body weight changes

A decrease in admission body weight is often used assurrogate measure for adequate diuresis. In the Acute Decompensated Heart Failure (ADHERE) registry, among 105,35patients discharged from AHF hospitalization, 52% reportethat they were asymptomatic, 37% were improved (but stisymptomatic), <1% were unchanged, and <1% were worseOverall one-third had lost only 0–5 lbs in weight on dischargand 16% had actually gained weight.12 More recently, amon4172 AHF patients enrolled in the Acute Study of ClinicaEffectiveness of Nesiritide in Decompensated Heart Failur(ASCEND-HF) trial the median change in body weight durinhospitalizationwas −1.0 kg (interquartile range: −2.1 to 0.0 kg) a24 h and −2.3 kg (interquartile range: −5.0 to −0.7 kg) bdischarge/day 10. After risk adjustment, increasing bodyweighduring hospitalization was associated with a 16% increase pekg in the likelihood of 30-day mortality or HF readmission fopatients showing weight loss ≤1 kg or weight gain durinhospitalization (OR per kg increase 1.16, 95% CI: 1.09 to 1.27p < 0.001). Therefore, the simple but often overlookedmetric oreliable daily weights can help guide therapy and assesreadiness for discharge. After achievement of pre-admissio“dry” weight, patients should ideally be transitioned to oradiuretic therapy during the hospital stay to ensure its effectiveness. A period of 24 h of observation in the hospital aftetransition to an oral regimen may be required but is oftedifficult due to external pressures to reduce length of stay. I

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•Timely communication with

outpatient provider

•Follow up within 7-14 days

•Follow up in heart failure clin

•Assess Body Weight chang

•Check Biomarkers including

NT-proBNP, BNP, Galectin

•Hemoconcentration

Fig 1 – Late management of patients hospEnzyme inhibitor, ARB = Angiotensin II RCardioMEMS = CardioMicroelectromechaCardioverter Defibrillator, ProBNP = N-ter

LVAD = Left Ventricular AssistDevice

LVEF = Left ventricular EjectionFraction

NT-proBNP = N-terminalproBrain-type Natriuretic Peptide

OPTIMIZE-HF = Organized Programto Initiate Lifesaving Treatment inHospitalized Patients with HeartFailure registry

PROTECT = Pro-BNP Outpatient Tai-lored CHF Therapy Study

SURVIVE = Survival of Patients withAcute Heart Failure in Need of Intra-venous Inotropic Support trial

US = United States


the case thatpatient remainwith congestivsymptoms aftetransition fromIV to oral regmen, diureticshould be increased and new“dry” weightestablished.13

Biomarkers

Several biomarkers including Brain-typnatriuretic peptide (BNPN-terminal

nin I and galectin-
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proBNP (NT-proBNP), high sensitivity tropo(Gal-3) have been studied for their prognostic value in AHF anmay be useful in assessing readiness for discharge.14–19 Thnatriuretic peptides, BNP and NT-proBNP are the best studieand are produced by myocardial stretch. In 1999, one of thearliest studies by Yu et al. showed that in a small prospectivcohort of 91 patients admittedwith AHF, plasma BNP levelswersignificantly higher in patients who died of a cardiovascular (CVcause within 12 months (P < 0.0001) or at 1-month (P < 0.001after recruitment. By Kaplan–Meier estimated life-table curvespatients with above median plasma ANP or BNP levels hasignificantly higher 1-year mortality (42.5% vs. 11.6%, botP < 0.005) and by multivariate Cox proportional hazard regression analysis, the plasma BNP level was the most importanprognostic factor predicting mortality (chi2 = 18.3, P < 0.0001).2

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Assess for

Adequate

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Transition to

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italized for acute heeceptor Blocker, BBnical system, CRT =minal proBrain-type

More recently in OPTIMIZE-HF, among 7039 patients, media(25th, 75th) admission and discharge BNPs were 832 pg/mL (4511660) and 534 pg/mL (281, 1111) respectively. The 1-yearmortalitand 1-year mortality or rehospitalization rates were 35.2% an79.4%. In this study the discharge BNP was the most importanfor predicting 1-year mortality (HR 1.34; 95% CI 1.28–1.40) an1-year death or rehospitalization (HR 1.15; 95% CI 1.12–1.18Comparedwith a clinical variables onlymodel, thedischargeBNmodel improved risk reclassification and discrimination ipredicting each outcome (1-year mortality: NRI 5.5%, P < 0.0001IDI 0.023, P < 0.0001; 1-year mortality or rehospitalization: NR4.2%, P < 0.0001; IDI 0.010, P < 0.0001).19 NT-proBNP has a sloweclearance from plasma compared to BNP and shows a correspondingly greater rise in disease which may make it a bettemarker for prognostication. In 2003, O′Brien et al. measureNT-proBNP at admission in 96 patients hospitalized with AHF. Ia subset of 34 patients, NT-proBNP was also measured prior tdischarge. Onmultivariate analysis of the clinical and serologicapredictors of a combined primary endpoint of death or H(hospitalization or as an outpatient), admission plasmNT-proBNP was not predictive (OR 1.84 [0.75–4.51], P = 0.185However, in the 34 patients for whom both admission anpre-discharge NT-proBNP was available, only pre-dischargplasma NT-proBNP (OR 15.30 [95% CI: 1.4–168.9], P = 0.026) waindependently predictive of the composite endpoint. The areunder the receiver–operator-characteristic curve (AUC ROC) fopre-discharge NT-proBNP was superior to that for admissioNT-proBNP for prediction of death or HF (AUC ROC 0.87 cf. 0.70for death (0.79 cf. 0.66), left ventricular (LV) failure hospitalizatio(0.78 cf. 0.70) or HF as an outpatient (0.71 cf. 0.61).21 A ≥30%reduction in natriuretic peptide levels may be used in assessinadequate decongestion prior to discharge based on an analysis othe Survival of Patients with Acute Heart Failure in Need oIntravenous Inotropic Support (SURVIVE) trial. The associatiobetween changes in BNP levels and all-cause mortality wa

•Activity Level

•Appropriate Diet

•Avoidance of triggers

•Discharge Medication List

•Vaccinations

•Ensure patients are on

maximally tolerated doses of

BB, ACEi, ARB,

mineralocorticoids, and

neprilysin inhibitors

•Assess need for ICD/CRT

•Consider CardioMEMS

Optimize

GDMT and

Assess for

Devices

Patient

Education

art failure. Abbreviations: ACEi = Angiotensin Converting= Beta Blocker, BNP = Brain-type natriuretic peptide,Chronic Resynchronization Therapy, ICD = implantableNatriuretic Peptide.

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assessed among 1038 patients admitted with AHF and randomized to levosimendan or dobutamine. A patient was classified aa “responder” if the follow-upBNP levelwas > or =30% lower thabaseline BNP. Responders at days 1, 3, and 5 had lower all-causmortality compared to nonresponders (p < or = 0.001), witday-5 levels showing superior discriminating value. Short-term(31-day) all-cause mortality risk reduction was 67% in day-5 BNresponders compared with nonresponders, whereas long-term(180-day) risk reduction was 47%.22

Galectin-3 (Gal-3) is a novel biomarker believed to bassociated with cardiac macrophage activation of fibroblastfibrosis, and ventricular remodeling. The addition of Gal-3 tdischarge BNP has been shown to provide significantlimproved prediction of 60-day readmission. In additionGal-3 alone was found to be a significant predictor of 60-dareadmission in patients with preserved LV ejection fractio(LVEF; AUC 0.85, p < 0.001). The net reclassification improvement was 55.2 (p = 0.037). Using multivariate analysis, foevery 100 pg/L BNP increase, the probability of readmissioincreased by approximately 10%, and for every 1-ng/ml Gal-increase, the probability further increased 8%. Obtaining botbiomarkers at discharge may thus provide additive information in determining likelihood of readmission.18 Gal-3 is nowavailable in a number of commercial laboratories and in thprocess of being added to many hospital laboratories.

Hemoconcentration

Achievement of hemoconcentration may also be used assurrogate marker of adequate decongestion with restoration oeuvolemia leading to a rise in hemoglobin levels. This has beeshown to be related to favorable outcomes including a lower risofmortality andHF rehospitalization.23 In 1684 patients assigneto the placebo arm of the Efficacy of Vasopressin Antagonism iHeart FailureOutcomeStudywith Tolvaptan (EVEREST) trial, 26%of patients hadevidence ofhemoconcentration (i.e., ≥3%absolutincrease in hematocrit). Patients with greater increases ihematocrit tended to have better baseline renal functionHemoconcentration correlated with greater risk of in-hospitaworsening renal function, but renal parameters generallreturned to baseline within 4 weeks post-discharge. Patientwith hemoconcentration were less likely to have clinicacongestion at discharge, and experienced greater in-hospitadecreases in body weight and natriuretic peptide levels. Afteadjustment for baseline clinical risk factors, every 5% increase oin-hospital hematocrit change was associated with a decreaserisk of all-cause death [hazard ratio (HR) 0.81, 95% confidencinterval (CI) 0.70–0.95]. Hematocrit change was also associatewith decreased CV mortality or HF hospitalization at ≤100 daypost-randomization (HR 0.73, 95% CI 0.71–0.76).23 Ter Mateeet al. analyzed diuretic response (defined as weight change pe40 mg of furosemide on day 4 after admission) anhemoconcentration (change in hemoglobin at discharge or da7) to predict the risk of HF and CV rehospitalization 60 days aftehospitalization for AHF among patients enrolled in the Pro-BNOutpatient Tailored CHF Therapy Study (PROTECT) and furthevalidated their findings in EVEREST. The median diuretiresponse was −0.36 [−0.77 to −0.13] kg/40 mg furosemid(PROTECT) and −0.30 [−0.79 to −0.03] kg/40 mg furosemid

(EVEREST). The median hemoconcentration was 0.20 [−0.50 t0.26] g/dL (PROTECT) and 0.20 [−0.40 to 0.90] (EVEREST), with 58%of patients in PROTECT and 56% of patients in EVERESdisplaying a rise in hemoglobin by day 7 or discharge. Patientwho displayed both favorable diuretic response (< median kg/4mg furosemide) and hemoconcentration had a markedly lowerisk of rehospitalization for HF in PROTECT (multivariable HR0.41; 95% CI, 0.24 to 0.70; P < 0.001) compared with all othepatients. This finding was also validated in EVEREST (multivariable HR, 0.52; 95% CI, 0.33 to 0.82; P = 0.004).24

Goal directed medical therapy

The presentation of AHF is dependent on the volume anperfusion status of the patient. Patients may be congeste(wet) or not congested (dry), adequately perfused (warm) opoorly perfused (cold).25 Irrespective of tailored therapywhich may include diuretics, vasodilators and inotropesefforts should be made to ensure optimal goal directemedical therapy (GDMT) on discharge. Angiotensiconverting enzyme inhibitors (ACEIs), angiotensin receptoblockers (ARBs), neprilysin inhibitors and aldosterone antagonists should be continued whenever possible. Thoughyperkalemia, acute kidney injury and oliguria may requirtemporary discontinuation of these drugs, they should brestarted cautiously in the inpatient setting. Continuation oACEIs or ARBs and beta blockers (BBs) for most patients is wetolerated and results in better outcomes.25–29 The datregarding BB use are particularly strong and discontinuing oreducing BB therapy should be considered only in patienthospitalized after recent initiation or increase in BB therapythose with marked volume overload or those in a low outpustate. Among 752 patients enrolled in the 2003 Carvedilol OMetoprolol European Trial (COMET), 61 patients (8%) had Btreatment withdrawn, 162 (22%) had a dose reduction and 52(70%) were maintained on the same dose. The risk of deatwas higher in patients who discontinued BB therapy or thoswho had their dose reduced with 1 and 2 year cumulativmortality rates of 28.7% and 44.6% for patients whose BB wawithdrawn, 37.4% and 51.4% for those with a reduced dosag(NS) and 19.1% and 32.5% for those maintained on the samdose (HR, 1.59; 95%CI, 1.28–1.98; p < 0.001, compared to thothers).28 Similar findings were also found on review of thOrganized Program to Initiate Lifesaving Treatment in Hosptalized Patients with Heart Failure registry (OPTIMIZE-HF) iwhich pre-specified 60- to 90-day outcomes at 91 academiand community hospitals throughout the US were analyzedAmong 2373 patients, of which 1350 (56.9%) were receivinBBs before admission and continued on therapy, 632 (26.6%were newly started, 79 (3.3%) had their therapy withdrawnand 303 (12.8%) were eligible but not treated. In this cohorcontinuation of BBs was associated with a significantly lowerisk and propensity adjusted post-discharge death (HR: 0.6095% CI: 0.37 to 0.99, p = 0.044) and death or rehospitalizatio(OR: 0.69; 95% CI: 0.52 to 0.92, p = 0.012) comparedwith no BBsIn contrast, withdrawal of BBs was associated withsubstantially higher adjusted risk for mortality comparewith those continued on BBs (HR: 2.3; 95% CI: 1.2 to 4.6, p

te-ee

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0.013), but with similar risk as HF patients eligible but notreated with BBs.27 Patients taking digoxin should also bcontinued on therapy unless contraindicated since withdrawal may lead to worsening HF.30 Lastly, oral therapies should buptitrated to maximally tolerated doses prior to dischargwhenever feasible.25

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Device therapies

Given the increased risk of fatal ventricular tachyarrhythmiaappropriate patients may be evaluated for implantablcardioverter-defibrillator (ICD) or chronic resychronizatiotherapy (CRT) prior to transition to the outpatient care. ICDmay be placed as secondary prevention in patients who havhad sustained ventricular tachycardia, ventricular fibrillationunexplained syncope, or cardiac arrest or prophylactically iselect groups of patients who have been on GDMT forminimum of 3 to 6 months.25,31–33 CRT has also been proveto have numerous benefits in HF patients including reductions in rehospitalization and all-cause mortality and iadvised for patients who meet criteria.34–36 Prior to dischargeeligible patients may be considered for outpatient monitorinwith a CardioMicroelectromechanical system (CardioMEMSSt Jude Medical, Inc., Atlanta, GA), which allows pulmonarartery (PA) pressure guided-HF management using a wirelesimplantable hemodynamic monitoring system. ThCardioMicroelectromechanical system (CardioMEMS) HearSensor Allows Monitoring of Pressures to Improve Outcomein New York Heart Association Class III Heart Failure Patient(CHAMPION) trials have shown that implementation oCardioMEMS results in a significant reduction in HF hospitaization rates and a greater reduction in PA pressures, mordays alive and outside of the hospital for HF, and aimprovement in quality of life when compared witguideline-directed standard of care HF managemenalone.37,38 Moreover, based on the cost-effectiveness thresholds followed by the American College of Cardiology/Amercan Heart Association (ACC/AHA) guidelines, with a thresholof <$50,000 indicating highly cost-effective and >$150,000 nocost-effective per quality-adjusted life-years (QALYsgained,39 the CardioMEMS has been shown to bcost-effective compared to usual care in populations similato the CHAMPION if the trial effectiveness is sustainedCardioMEMS reduced lifetime hospitalizations (2.18 vs. 3.12increasing quality-adjusted life-years (QALYs) (2.74 vs. 2.46with increased costs ($176,648 vs. $156,569) yielding a cost o$71,462 per QALY gained and $48,054 per life-year gained. Thdevice was more cost-effective in those with preserved LVEcompared to patients with reduced LVEF ($47,768 vs $82,30per QALY gained respectively).40 Finally, appropriate patientmay be evaluated for implantation of a left ventricular assisdevice (LVAD) which has been shown to improve survival anquality of life in select patients particularly those with NYHAClass IV.41,42 The Interagency Registry of MechanicallAssisted Circulatory Support (INTERMACS) has developeclinical profiles to allow for optimal selection of patients foLVADs. Over the past 5 years, there has been a shift such thathe majorities of patients being implanted are INTERMAC

profiles 3 and 4 and thus include those who have beestabilized but are inotrope dependent or those who requiretemporary circulatory support during hospitalization.43

Patient education

Patient education remains one of the most crucial components of discharge planning. Patients and their familieshould receive verbal and written discharge instructions iaddition to educational material. Thorough discharge planning is associated with improved patient outcomes. Eacpatient should have a clear understanding of their recommended activity level, diet, discharge medications, follow-uappointment, weight monitoring, and what to do if anrecurrent signs and symptoms of decompensation.4

Restricting sodium intake to <2 g/d or fluid intake to <2 L/or <1–1.5 L/d should be underscored when applicable.deemed safe patients should be encouraged to performmoderate exercise for 30 min at least 5 days/week. Modifiabltriggers should be addressed prior to transition to thoutpatient setting. Excessive sodium and water intakemedication non-adherence, the use of over the countedrugs such as non-steroidal anti-inflammatory drugs anpseudoephedrine, excessive alcohol intake and illicit drug usmay all precipitate AHF.25,45 Counseling on smoking cessation, limiting alcohol consumption, and avoidance of precipitating over-the counter medications should be performed. Apatients should be offered influenza and pneumococcavaccines prior to discharge when appropriate.11 Studies havshown that introduction of nurse educator-delivered teachinsessions at the time of hospital discharge may result iimproved clinical outcomes, increased self-care and treatment adherence, and reduced cost of care in addition tolower risk of rehospitalization or death.46,47 The incorporatioof a pharmacist in discharge counseling has also been showto be beneficial in reducing 30 day mortality and HF-relatereadmissions.11

Transition to outpatient care

Any new diagnostic information or changes in medicationduring the hospital stay should be communicated clearly anin a timely manner to outpatient clinicians to ensure a propetransition to the outpatient setting. For individual practtioners with heavy patient loads, this is often difficult anneeds to be addressed at the institutional level. As mentioneprior, patients and their families should have a cleaunderstanding of what to expect when they leave the hospitaand there should be follow-up plans for any outstanding testEarly outpatient follow-up has been associated with a lowerisk of subsequent rehospitalization. A follow-up visit withi7 to 14 days and/or a telephone follow-up within 3 days ohospital discharge are reasonable goals.48 Follow up ispecialized HF clinics reduces hospitalization, improvemedication adherence, increases titration efficacy of goadirected medical therapy and has also been shown to reduc90 day all-cause mortality.11

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Conclusion

Thorough discharge planning is essential to the late management of patients hospitalized with AHF. Several markers mabe utilized in assessing patients' readiness for discharge anpredicting poor outcomes such as hospital readmission anmortality. A multidisciplinary approach is beneficial ifacilitating a smooth transition to the outpatient settinwith early follow-up allowing for improved success.

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None of the authors have any conflicts of interests witregard to this publication.

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16. Reny JL, Millot O, Vanderecamer T, et al. AdmissionNT-proBNP levels, renal insufficiency and age as predictors omortality in elderly patients hospitalized for acute dyspnea.Eur J Intern Med. 2009;20(1):14-19.

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21. O'Brien RJ, Squire IB, Demme B, et al. Pre-discharge, but notadmission, levels of NT-proBNP predict adverse prognosisfollowing acute LVF. Eur J Heart Fail. 2003;5(4):499-506.

22. Cohen-Solal A, Logeart D, Huang B, et al. Lowered B-typenatriuretic peptide in response to levosimendan or dobuta-mine treatment is associated with improved survival inpatients with severe acutely decompensated heart failure. JAm Coll Cardiol. 2009;53(25):2343-2348.

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26. Hammond DA, Smith MN, Lee KC, et al. Acute decompensateheart failure. J Intensive Care Med. 2016.

27. Fonarow GC, Abraham WT, Albert NM, et al. Influence ofbeta-blocker continuation or withdrawal on outcomes inpatients hospitalized with heart failure: findings from theOPTIMIZE-HF program. J Am Coll Cardiol. 2008;52(3):190-199.

28. Metra M, Torp-Pedersen C, Cleland JG, et al. Shouldbeta-blocker therapy be reduced or withdrawn after anepisode of decompensated heart failure? Results fromCOMET. Eur J Heart Fail. 2007;9(9):901-909.

29. Butler J, Young JB, Abraham WT, et al. Beta-blocker use andoutcomes among hospitalized heart failure patients. J Am CoCardiol. 2006;47(12):2462-2469.

30. Packer M, Gheorghiade M, Young JB, et al. Withdrawal ofdigoxin from patients with chronic heart failure treated withangiotensin-converting-enzyme inhibitors. RADIANCE studyN Engl J Med. 1993;329(1):1-7.

31. Moss AJ, Hall WJ, CannomDS, et al. Improved survival with aimplanted defibrillator in patients with coronary disease athigh risk for ventricular arrhythmia. Multicenter automaticdefibrillator implantation trial investigators. N Engl J Med.1996;335(26):1933-1940.

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33. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or animplantable cardioverter-defibrillator for congestive heartfailure. N Engl J Med. 2005;352(3):225-237.

34. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiaresynchronization on morbidity and mortality in heartfailure. N Engl J Med. 2005;352(15):1539-1549.

35. Bristow MR, Saxon LA, Boehmer J, et al.Cardiac-resynchronization therapy with or without an im-plantable defibrillator in advanced chronic heart failure. NEngl J Med. 2004;350(21):2140-2150.

36. Abraham WT, Fisher WG, Smith AL, et al. Cardiacresynchronization in chronic heart failure. N Engl J Med.2002;346(24):1845-1853.

37. Abraham WT, Adamson PB, Bourge RC, et al. Wireless pulmo-nary artery haemodynamicmonitoring in chronic heart failurea randomised controlled trial. Lancet. 2011;377(9766):658-666.

38. AbrahamWT, Stevenson LW, Bourge RC, et al. Sustained efficacof pulmonary artery pressure to guide adjustment of chronicheart failure therapy: complete follow-up results from theCHAMPION randomised trial. Lancet. 2016;387(10017):453-461.

39. Anderson JL, Heidenreich PA, Barnett PG, et al. ACC/AHAstatement on cost/value methodology in clinical practiceguidelines and performance measures: a report of theAmerican College of Cardiology/American Heart AssociationTask Force on Performance Measures and Task Force onPractice Guidelines. J Am Coll Cardiol. 2014;63(21):2304-2322.

40. Sandhu AT, Goldhaber-Fiebert JD, Owens DK, et al.Cost-effectiveness of implantable pulmonary artery pressur

monitoring in chronic heart failure. JACC Heart Fail. 2016;4(5368-375.

41. Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term use of aleft ventricular assist device for end-stage heart failure. N EnJ Med. 2001;345(20):1435-1443.

42. Slaughter MS, Rogers JG, Milano CA, et al. Advanced heartfailure treated with continuous-flow left ventricular assistdevice. N Engl J Med. 2009;361(23):2241-2251.

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44. Bonow RO, Bennett S, Casey Jr DE, et al. ACC/AHA clinicalperformance measures for adults with chronic heart failure:report of the American College of Cardiology/American HeaAssociation Task Force on Performance Measures (WritingCommittee to Develop Heart Failure Clinical PerformanceMeasures) endorsed by the Heart Failure Society of America.Am Coll Cardiol. 2005;46(6):1144-1178.

45. Arcand J, Ivanov J, Sasson A, et al. A high-sodium diet isassociated with acute decompensated heart failure in ambulatory heart failure patients: a prospective follow-up study.Am J Clin Nutr. 2011;93(2):332-337.

46. Koelling TM, Johnson ML, Cody RJ, et al. Discharge educationimproves clinical outcomes in patients with chronic heartfailure. Circulation. 2005;111(2):179-185.

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ScienceDirect


Changing our Approach to Stage D Heart Failure

,

Miriam F. Becnela, b, Hector O. Venturaa, b, c, Selim R. Krima, b, c,⁎aDivision of Cardiology, John Ochsner Heart and Vascular Institute, New Orleans, LA, United StatesbSection of Cardiomyopathy&Heart Transplantation, JohnOchsner Heart and Vascular Institute, Ochsner Clinic Foundation, 1514 JeffersonHighwayNew Orleans, LA 70121, United StatescThe University of Queensland School of Medicine, Ochsner Clinical School, New Orleans, LA, United States


Financial disclosures: The authors hav⁎ Corresponding author at: Section of Ca

Clinic Foundation, 1514 Jefferson HighwayE-mail addresses: miriam.becnel@ochsn


A B S T R A C T

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Despite the tremendous progress made in themanagement of heart failure (HF), many patients reacadvancedstages.ThispaperaimstopresentapracticalapproachtothestageDHFpatientwhoisnolongeresponding to optimalmedical therapy.We discuss all available therapies for this patient population.Walsooffer some importantcaveatswith regard to identification, riskstratification, evaluationandtreatmenincludingearlypatient referral to a centerwithanadvancedHFprogram.Given thechanging landscapeoheart transplantation and an impending change in the allocation system, we also intend to engagediscussionontheneedforaparadigmshift towards leftventricularassistdevicetherapy inthispopulation


Left ventricular assist deviceMechanical circulatory supportHeart transplantation

Contents

667778880002223

Early recognition and referral of the stage D HF patient. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Risk stratification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Clinical risk scores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Cardiopulmonary exercise testing (CPX) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Hemodynamic assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Available therapies for stage D HF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Heart transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Durable left ventricular assist devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Inotrope therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21End of life care and palliative therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Mechanical circulatory support for the cardiogenic shock patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Current heart allocation system and its limitations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Newly proposed heart allocation system and its implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Durable MCS: What the future holds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

e no financial or proprietary interest in the subject matter of this article.rdiomyopathy & Heart Transplantation, John Ochsner Heart and Vascular Institute, Ochsner, New Orleans, LA 70121, United States.er.org (M.F. Becnel), [email protected] (H.O. Ventura), [email protected] (S.R. Krim).

3served.

33


ACC = American Collegeof Cardiology


BP = blood pressure

BTT = bridge to transplant

CO = cardiac output

CO2 = carbon dioxide

CPX = cardiopulmonaryexercise testing

DT = destination therapy

ECMO = extracorporealmembranous oxygenation

HF = heart failure

HFSS = HF Survival Score

HT = heart transplantation

IABP = intra-aortic balloon pump

ICD = implantablecardioverter-defibrillator

INTERMACS = InteragencyRegistry for MechanicallyAssisted Circulatory Support

LBM = lean body mass

LVAD = left ventricularassist device

MCS = mechanical circulatorysupport

NYHA = New YorkHeart Association

OMT = optimal medical therapy

RER = respiratory exchange ratio

RHC = right heart catheterization

SHFM = Seattle HF Model

TAH = total artificial heart

UNOS = United Network ofOrgan Sharing

US = United States

VE = minute ventilation

VO2 = ventilator oxygen uptake


Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

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With a worldwidpopulation exceedin26 million individualsHF constitutes a significant burden othe healthcare systemNearly 6 million HF patients reside in the UnitedStates (US)withovermillion patients beinadmitted on a yearlbasis.1,2Owing toagrowingandagingpopulationmore patients arreaching advancestages of HF despite tremendous progress iavailable therapies.3 Historically,heart transplantation (HT) was the onloption for stage D HFWith limited donor supply and a rising neewithin this populationmechanical circulatorsupport (MCS) in thform of the left ventricular assist device (LVADhas emerged as a viabladvanced therapy ancontinues to maturthrough innovation aninvention. LVADs arrapidly becoming standard of care within thfield. These devices arbeing implanted eitheas a bridge to transplantation (BTT), destinatiotherapy (DT), or in somcases cardiac recoveryUnfortunately not all patients with advanced Hwill be candidates for thaforementioned surgicaoptions, and other treatment options includpalliative inotropes anhospice care.

ents reach end-stage H
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Clinical recognition of when patican be difficult, but identifying patients who need advanceHF therapies is often more challenging. Early patient referrato a center with an advanced HF program is imperative t

ensure proper identification, risk stratification, evaluatioand treatment. This paper aims to present a practicaapproach to the stage D HF patient. Given the changinlandscape of transplantation and an impending change in thallocation system, we also intend to engage a discussioon the need for a paradigm shift towards LVAD therapy ithis population.

Early recognition and referral of the stage DHF patien

Timely detection of patient progression from stage C to stagD HF is crucial in relation to treatment. While there are somvariations in how different organizations define advanced HFis it universally accepted that all patients with end-stage Hhave become refractory to optimal medical therapy (OMT).should also be noted that to deem a patient truly refractory tguideline-directed OMT, any other etiologies that may explaitheir symptomatic decline should be explored.5,6 This tell-talsign should signal immediate referral to an expert HT cente

Monitoring patients closely for signs and symptoms suggestive of stage D HF is vital to ensure early detection and prompreferral. Frequent hospitalizations, low or declining bloopressure (BP), inability to tolerate HF therapy, hyponatremiafrequent implantable cardioverter-defibrillator (ICD) shocks, oincreasing arrhythmia burden are examples of red flags thashould the heighten suspicion of end-stage HF (Table 1).6 Iaddition, end-organ damage in the form of worsening creatnine or bilirubin may be indicative of a low-output state anshould never be ignored. Any patient with New York HearAssociation (NYHA) functional class IIIb or IV symptomAmerican College of Cardiology (ACC) and American HearAssociation (AHA) stage D HF, or even individuals with as littlas 1 hospitalization for HF in the last 12 months should breferred for evaluation by an advanced HF cardiologist.6

Although the current classification of patients with NYHClass IV symptoms does not accurately define patient clinicarisk profile there are other profiling systems that can be usefor risk stratification, such as the Interagency Registry foMechanically Assisted Circulatory Support (INTERMACS)The INTERMACS profiles (Table 2) are useful in determinincandidacy and optimal timing when considering the use otemporary MCS, durable LVADs, or HT. Some patients mabenefit initially from durable MCS, whereas others marequire temporary MCS as a bridge to decision, candidacy, orecovery.4

Risk stratification

Patients referred for advanced HF treatment options typicallundergo initial risk stratification prior to a full evaluationThis essential step in the process helps to select patients wh

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Table 1 – Signs and symptoms of Stage D HF. Adaptedfrom ACC/AHA guidelines6

Triggers for Advanced HF Referral

Frequent (≥2) hospitalizations or ED visits for HF in the past yearIntolerance to ACE inhibitors due to hypotension and/orworsening renal functionWeight loss without other cause (e.g. cardiac cachexia)Intolerance to beta blockers due to worsening HF or hypotensionFrequent systolic blood pressure < 90 mm HgPersistent dyspnea with dressing or bathing requiring restProgressive deterioration in renal function(e.g. rise in BUN and creatinine)Progressive decline in serum sodium, usually to <133 mEq/LFrequent ICD shocks

Abbreviations: HF, heart failure; ED, emergency department; ACE,angiotensin converting enzyme; BUN, blood urea nitrogen; ICD,implantable cardioverter-defibrillator.


warrant and will benefit from these therapies. Risstratification includes the use of clinical risk scoreobjective functional tests such as cardiopulmonary exercistesting, and right heart catheterization to assess patienthemodynamics.

Clinical risk scores

Risk stratification of patients with HF is crucial for propeprognostication and recognition of patients who need moradvanced therapies. Risk scores typically include patiencharacteristics, clinical signs and laboratory tests. Twclinical risk scores are used commonly in practice whestratifying HF patients. The HF Survival Score (HFSS) usesparameters and was validated among HF patients who werreferred for HT.8,9 The Seattle HF Model (SHFM) includes20-variable model that combines clinical, laboratory antherapeutic data.10,11 Although both models are useful iclinical practice, only the HFSS was derived and validated ipatients referred for HT, and therefore should be used instea

Table 2 – INTERMACS classification.

INTERMACS Profiles

Profile 1 Critical cardiogenic shock defines a patientin which a patient has life threatening hyp

Profile 2 Progressive decline defines a patient who hon inotropic support but continues to exhib

Profile 3 Stable but inotrope dependent defines a paof intravenous inotropes however cannot b

Profile 4 Resting symptoms defines a patient who ishas symptoms of congestion at rest or with

Profile 5 Exertion intolerant defines a patient who isand essentially housebound

Profile 6 Exertion limited also defines a patient whowith ADL however who becomes quickly sy

Profile 7 Advanced NYHA class 3 defines a patient wand no recent episode of acute decompens

Abbreviations: INTERMACS, Interagency Registry for Mechanically AssisHeart Association.

of the SHFM in the advanced HF population. It should bnoted that the SHFM tends to overestimate survival in thstage D HF population as it originated from ambulatorpatient data.10,11

Cardiopulmonary exercise testing (CPX)

Despite not being available in all centers, cardiopulmonarexercise testing (CPX) is a key test in assessing patients foadvanced HF therapies.12 Two important CPX variables arusually used for risk stratification and prognosis—peaventilator oxygen uptake (VO2) andminute ventilation/carbodioxide production (VE/VCO2) slope. Peak VO2 has been showto be a strong predictor of mortality among HF patientevaluated for HT.13 A reduced maximal oxygen consumptiopeak VO2 of <12 mL/kg/min (or <14 mL/kg/min for patientusing beta blockers) signifies advanced HF stage and warrantevaluation for HT. A low peak VO2 should always binterpreted in the context of adequate effort which is defineas a respiratory exchange ratio (RER) > 1.1.12 Owing tsignificant variability in body composition in our HF population, correcting peak VO2 for lean body mass (LBM) seems tbe a better discriminator of outcome than traditionallreported total weight adjusted values. In this regard, a peaVO2 corrected for LBM cutoff of 19 mL/kg/min has shown tbe a superior discriminator of major cardiac events (deatand/or urgent HT) than the total weight-adjusted figure o14 mL/kg/min in patients with stage D HF.12 The VE/VCOslope is another important variable andwhen abnormal (VE/VCOslope > 34) it provides additional and independent prognostiinformation. Evaluation of the VE/VCO2 slope in conjunction witpeak VO2 is recommended to optimize prognostication in patientwith HF.14–16

Hemodynamic assessment

Right heart catheterization (RHC) is considered the golstandard in evaluating hemodynamics, particularly the cardiac index and pulmonary pressures, when determining thneed for HT. A cardiac index value of <2.5 L/min/m2 i

who is “crashing and burning”,otension and rapidly escalating inotropic pressor supportas been demonstrated “dependent”it signs of clinical deteriorationtient who is clinically stable on mild moderate dosese weaned off inotropesat home on oral therapy but frequentlyregular activity. So called “frequent flyer”comfortable at rest and with ADL but unable to engage in any activity,

is comfortable at rest without evidence of fluid overload at rest ormptomatic with any other activity. So called “walking wounded”ho is clinically stable with an acceptable level of comfortable activity,ation

ted Circulatory Support; ADL, activities of daily living; NYHA, New York

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Table 3 – Current indications and contraindications of cardiac tranplantations.

Indications for Cardiac Transplantation

Cardiogenic shock requiring either continuous intravenous inotropic support or MCS with an intraaorticballoon pump counterpulsation device or MCSPersistent NYHA class IV congestive HF symptoms refractory to maximal medical therapy (LVEF < 20%; peak VO2 < 12 mL/kg/1/min)Intractable or severe anginal symptoms in patients with coronary artery disease not amenable to percutaneous or surgical revascularizationIntractable life-threatening arrhythmias unresponsive to medical therapy, catheter ablation,and/or implantation of implantable cardioverter-defibrillatorEnd-stage congenital HF with no evidence of pulmonary hypertension

Absolute Contraindications to Cardiac Transplantation

Irreversible/fixed pulmonary hypertension with PVR > 3 woods unitsClinically severe symptomatic cerebrovascular diseaseSevere extra-cardiac amyloid organ dysfunctionActive substance abuseCandidates with a history of primary central nervous system lymphoma and visceral Kaposi sarcomaAcute or fulminant HBV/HCV infectionChronic HBV/HCV with clinical, radiologic or biochemical signs of cirrhosis, portal hypertension, or hepatocellular carcinomaSevere, irreversible multisystemic disease process

Relative Contraindications to Cardiac Transplantation

Age > 70 years of ageObesity with BMI of >35 kg/m2

Irreversible renal dysfunction (eGFR < 30 mL/min/1.73 m2) for heart transplant alonePeripheral vascular disease that may limit rehabilitation and is not amenable to revascularizationDiabetes with end organ damage other than non-proliferative retinopathy or persistent poor glycemic control(HbA1C > 7.5% or 58 mmol/mol) despite optimal effortRecent substance abuseNeoplasm (requires individualized assessment)Infection (requires individualized assessment)Insufficient social support to achieve compliant care in the outpatient settingSevere cognitive-behavioral disabilities or dementia(e.g., self-injurious behavior, inability to ever understand and cooperate with medical care)Inability to comply with drug therapy on multiple occasionsActive tobacco smoking

Abbreviations: MCS, mechanical circulatory support; NYHA, New York Heart Association; HF, heart failure; LVEF, left ventricular ejectionfraction; VO

2, ventilator oxygen uptake; PVR, pulmonary vascular resistance; HBV, hepatitis b virus; HCV, hepatitis C virus; BMI, body mass

index; eGFR, estimated glomerular filtration rate; HbA1C, hemoglobin A1C.


suggestiveof advanceddisease. Theuseof RHC iskey indiagnostievaluation of pulmonary vascular resistance considering thatprecludes HT if found to be elevated and irreversible.17

With regard to LVAD implantation, important hemodynamiparameters identified as strong markers of post-operativright HF, including right atrial pressure > 15 mmHg, righatrial pressure to pulmonary capillary wedge pressurratio > 0.63, and right ventricular stroke work inde≤0.25 mm Hg × l/m2.18,19

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Available therapies for stage D HF

Heart transplantation

For the last 4 decades, HT has been the panacea for stage D HFWith improved immunosuppressive therapies in addition to 1and 5-year post-HT survival, HT will likely remain the golstandard treatment for this critically ill patient population.2

Only 2500 HTs are performed annually in the US, and owing tomeager donor pool this is unlikely to change. As a result, manpatients die on the heart transplant list while they wait forfavorable donor.

Consideration should be made for HT if OMT ancardiac resynchronization therapy as recommended bcurrent ACC/AHA guidelines have failed to improve patiensymptoms and slow disease progression.5 Assessing for anreversible or surgically amenable cardiac conditions shoulbe addressed before HT or MCS are considered. Tablesummarizes eligibility criteria for HT. By the same token,thorough assessment of conditions that may preclude Hshould be explored. Examples of absolute and relativcontraindications to HT are listed in Table 3.21,22

Durable left ventricular assist devices

The use of MCS grew and quickly became a viable option fostage D HF patients (Table 4) after revealing prolongesurvival with the first pulsatile LVAD, the HeartMate XV

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Table 4 – Indications and contraindications of Lvad therapy.

Indications for LVAD Therapy

As a bridge to transplantation strategy in patients who are in cardiogenic shock and too sick to wait or who havetemporary contraindications for transplantAs a permanent therapy so called “destination therapy” for patients considered ineligible for cardiac transplantationAs a bridge to myocardial recovery such as in patients acute myocarditis where recovery is expectedAs bridge-to-decision or “bridge-to-bridge” is used for those patients who present with severe shock or followingcardiac arrest and are supported with a temporary support VAD to see if they become candidates for a long-term support device

Contraindications to LVAD Therapy

Potentially reversible cause of heart failureRecent or evolving strokeNeurological deficits impairing the ability to manage deviceCoexisting terminal condition (e.g., metastatic cancer, cirrhosis)Abdominal aortic aneurysm > 5 cmSymptomatic right heart failureActive systemic infection or major chronic risk for infectionSevere pulmonary dysfunction (e.g., FEV1 < 1 L)Current or impending renal or hepatic failureMultisystem organ failureHeparin-induced thrombocytopeniaSignificant underlying psychiatric illness or lack of social support

Abbreviations: LVAD, left ventricular assist device; VAD, ventricular assist device; FEV1, forced expiratory volume.


(Abbott Laboratories, formerly Thoratec Corporation, AbboPark, IL), in the pivotal 2001 REMATCH trial.23 This device waapproved in 1994 for BTT and in 2003 for DT.24 Unfortunatelythe associated adverse event profile and large pump size leto limited durability with device life averaging only 18 t30 months. Consequently, pulsatile pumps gave rise to thnext generation of continuous-flow LVADs, which include thaxial-flow HeartMate II (Abbott Laboratories, Abbott Park, ILand the centrifugal-flow HVAD (HeartWare Inc., Framingham

Fig. 1 – Proposed algorithm for advancedheart failure therapies. ⌘

HFpEF with refractory Angina), *LVAD complications: pump throm

MA).25 The HeartMate II is approved for BTT and DT, whereathe HVAD is only approved for BTT at present.25–27 Thcentrifugal-flow HeartMate 3 (Abbott Laboratories, AbbotPark, IL) is the newest device under investigation in the Uand is seeking both BTT and DT indications. Additional BToptions include the total artificial heart (TAH) or biventriculaventricular assist devices (Bi-VAD), which are usually onlindicated in a select population with biventricular failure orefractory ventricular arrhythmias (Fig. 1). With 1- and 2-yea

Infiltrative cardiomyopathies (e.g. cardiac amyloidosis, Sarcoidosis,bosis, pumpmalfunction, pump stop, driveline infection.

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survival rates of 80% and 70% respectively, the LVADpopulation is expected to grow exponentially over the cominyears.25,26

Inotrope therapy

Positive inotropic agents are frequently used in the setting oacute decompensated HF when evidence of pulmonarcongestion and signs of hypoperfusion are present.2

Milrinone and dobutamine are themost widely used inotropiagents in the US.29 Dobutamine, a β-adrenergic agonist, irecommended for treatment of patients with low cardiaoutput (CO) and reduced BP. Concomitant use of β-blockerwith dobutamine is not recommended as it may attenuate thbenefit of both agents. Milrinone, a phosphodiesterasinhibitor, is sometimes preferred over dobutamine in thsetting of significantly elevated systemic and pulmonarvascular resistance, low CO and hypoperfusion symptoms.3

While inotropes have been shown to improve both symptomand hemodynamics, concerns have been raised with the use othese agents on a long-term continuous basis for patients witrefractory HF declined for definitive therapy (HT or MCS).31,3

Therefore, long-term continuous or intermittent inotropinfusions should only be recommended as a bridge to decision

End of life care and palliative therapy

Patients with advanced HF unresponsive to OMT who do noqualify for either HT or MCS should be offered palliativmeasures. After exhausting all standard of care optionshospice should be offered to patients with NYHA class Isymptoms with less than a 6-month life expectancy.33–3

These services can be performed at home, in the hospital, oat a specialized hospice center, which can generally providoral medications and focus on symptom managemenCertain hospice programs may provide complex treatmentssuch as intravenous inotropes or continuous positive airwa

Fig. 2 – MCS as a bridge therapy for the cardiogenic shock patiSarcoidosis, small ventricles).

pressure ventilation.33,34 It is only with continued engagement of the clinician and meticulous management of fluistatus that quality of life can be fully maximized in hospiccare. A noteworthy topic specific to end-of-life within thipatient population is ICD deactivation. While this may makfor a difficult discussion, thoughtfully counseling patients odeactivation is an essential step for these terminal patients aICD discharges only exacerbate pain and anxiety.38

Mechanical circulatory support for the cardiogenishock patient

Many patients are too sick upon presentation to undergo Hor durable LVADs. In this regard, temporary MCS may be useas a bridge to more definitive therapy (e.g., bridge to durablLVAD or BTT). INTERMACS profile 1 patients are considere“critical cardiogenic shock” or “crashing and burning” anhave held a consistent 15% stake in the total number opatient's receiving durable LVADs from 2008 to 2014.7,39,4

INTERMACS 2 patients are patients with “progressive declineon inotropic therapy, and accounted for 38% of total implantover the same 6-year time frame.7,40 Given the overainstability of profile 1 and the foreseeable deterioration iprofile 2 patients, temporizing measures are often pursuedWith the aim of reversing end-organ damage, temporary MCalso allows care teams time to explore whether a mordefinitive therapy can be accomplished. In this case, the usof temporary MCS has been coined “bridge to decision”. Whilit is still unclear whether reversal of end-organ damage anstabilization via temporary MCS decreases perioperative risand mortality, there is widespread acceptance and use othese devices. Patient and device selection varies amoncenters, but ideally should be based on expertise and trainingwhile also being individually tailored to the patient's hemodynamic and structural profile. Ease of implant differbetween devices and method (percutaneous versus surgica

ent. *Infiltrative cardiomyopathies (e.g. cardiac amyloidosis,

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Table 5 – Currently available temporary MCS devices in the US.

Device Blood Flow Support Type Inflow Outflow Access Type Access Approach

Counterpulsation IABP 0.5–1 L/min LV N/A N/A Percutaneous Axillary or femoral arteryMicroaxial Impella 2.5 2.5 L/min LV LV AA Percutaneous Axillary or femoral artery

Impella CP 3.5 L/min LV LV AA PercutaneousImpella 5.0 5 L/min LV LV AA Surgical Axillary,

femoral or subclavianartery cut-down

Impella RP 4.4 L/min RV IVC PA Percutaneous Femoral VeinCentrifugal Tandemheart 5 L/min LV LA FA Percutaneous Transeptal catheterization of

left atrium via femoral veinRV IVC PA Percutaneous Internal jugular vein

Centrimag 9.9 L/min LV LA/LV AA Surgical Median sternotomyRV RA/RV PA

VA-ECMO Complete CV bypass IJV/FV FA, SCA, CA Peripheral Internal jugular vein, femoral veinRA/IVC AA Surgical (Central) Median sternotomy

Abbreviations: IABP, intraaortic balloon pump; LV, left ventricle; RV, right ventricle; AA, ascending aorta; IVC, inferior vena cava; PA, pulmonaryartery; FA, femoral artery; RA, right atrium; LA, left atrium; VA, venoarterial; ECMO, extracorporeal membrane oxygenation; CV, cardiovascular;IJV, internal jugular vein; FV, femoral vein; SC, subclavian atery; CA, carotid artery.


determines location of implant (cardiac catheterizatiolaboratory or operating room). Optimal timing betweetemporary device implant and crossover to durable MCS hanot been well defined. Additional data including protocoland algorithms are needed to guide providers in selecting th

Table 6 – New Heart Allocation System.

Adapted from Meyer et al.43

Tiers Criteria

Tier 1 ECMOContinuous MechaniNon-dischargeable (sMCS with life-threate

Tier 2 Intra-aortic balloon pVentricular tachycarMCS with device maTotal artificial heartDischargeable BiVADAcute circulatory sup

Tier 3 Dischargeable LVADMultiple inotropes orMCS with device infeMCS with hemolysisMCS with pump throMCS with right heartMCS with mucosal bMCS with aortic insu

Tier 4 Stable LVAD candidaInotropes without heDiagnosis of congeniDiagnosis of ischemiDiagnosis of hypertrDiagnosis of restrictiDiagnosis of amyloidRetransplant

Tier 5 Combined organ tranTier 6 All remaining activeTier 7 Inactive/not transpla

Abbreviations: ECMO, extracorporeal membrane oxygenation; VAD, vbiventricular assist device; RVAD, right ventricular assist device; LVAD

most appropriate device for suitable patients at the rightime. Contraindications vary between devices and ouproposed algorithm is intended to help guide the selectioof support in the cardiogenic shock patient based on theiprofile (Fig. 2). Table 5 highlights temporary counterpulsation

cal ventilationurgically implanted) VADning ventricular arrhythmiaumpdia/ventricular fibrillation, mechanical support not requiredlfunction/mechanical failure

or RVADportfor up to 30 dayssingle high-dose inotropes with continuous hemodynamic monitoringction

mbosisfailure

leedingfficiencytes not using 30 day discretionary periodmodynamic monitoringtal heart diseasec heart disease with intractable anginaophic cardiomyopathyve cardiomyopathyosis

splantscandidatesntable

entricular assist device; MCS, mechanical circulatory support; BiVAD,, left ventricular assist device.

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microaxial and centrifugal pumps currently available for usin the US.

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Current heart allocation system and its limitation

Established over a decade ago, the current three-tiered hearallocation system has led to tremendous decrease in the ratof waiting list mortality and improvement in post-Hsurvival.20,22 Based on the severity of medical conditions, thUnited Network of Organ Sharing (UNOS) assigns a status tall patients listed for HT.41,42 Those with an expected survivaof <1 month are listed 1A, the highest waitlist status. Thigravely ill cohort includes those patients either on high doseof inotropic drugs, receiving mechanical ventilation or requiring MCS who meet appropriate criteria (e.g., LVAD 30-datime, temporary LVAD, RVAD, BiVADs, durable devices witcomplications). The next listing tier is status 1B and iassigned to patients who are stable on lower-dose inotropitherapy or durable mechanical support, and can be inpatienor outpatient. Status 2, the third tier, are stable ambulatorpatients who are not on inotropic drugs.41,42

Despite improvement in outcomes after the implementation of the 3-tier system, there are several limitations tharemain. For each status within a geographic zone, hearts arallocated to candidates in order of decreasing time spent athat status in addition to blood type-matching. One majodrawback of the current system is the lack of clinicadifferentiation between waitlisted status 1A and 1candidates.43 In addition, the rising number of patients listestatus 1A and 1B has become a concern and is primarilattributed due to the increased use of durable MCS.44 This haled experts in the field to question the appropriate designation status of stable LVAD patients.43 This becomes particularly relevant as recent data has denoted the low risk oadverse events in stable LVAD patients.45 These events ardefined as death or waitlist removal for being too ill ttransplant when compared to other status 1A patients (e.gdual inotropes, paracorporeal VADs, congenital heart disease). It is important to note when a LVAD patient developsdevice-related complication that satisfies criteria for 1Alisting, they instantly carry a higher waiting list mortality.4

Consequentially, the continued expansion of LVAD therapy aBTT will undoubtedly contribute to an increased number opatients listed UNOS status 1A secondary to device malfunction, thrombosis, and infection. In turn, the present long-termHT outcomes could be negatively impacted.

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Newly proposed heart allocation system andits implications

In response to the conundrum of the present-day allocatiostructure, the UNOS heart subcommittee has proposed a new6-tier system which aims to 1) improve utilization of thlimited supply of donor hearts by modifying geographidistribution and improve overall access to HT; 2) reducwaiting list mortality by prioritizing sicker patients anundeserved groups (congenital heart disease, restrictiv

cardiomyopathies) without compromising post-HT survivaand 3) decrease the use of exceptions by better accommodating all candidates within the system. The new allocatiosystem is summarized in Table 6.42,43

In a nutshell, the sickest patients under the new systemare given top priority in tier 1, including those patientreceiving mechanical ventilation and extracorporeal membranous oxygenation (tier 1), and stable LVAD patients winow fall in tier 4—much lower when compared to the curren3-tier system. In view of the recent data revealing lowmortality rates among stable LVAD patients, our belief ithat these changes will lead to better utilization of availabldonor hearts and allow sicker patients to receive HT in aexpedited fashion. On the other hand, we feel that tierpatients with LVAD complications such as pump thrombosior right HF are at a much higher risk for adverse events andeath, and as a result should be given a higher priorityFurthermore, we believe that those patients sick enough tnecessitate a higher level of temporary MCS (e.g., ImpellaTandemHeart, CentriMag) should certainly be assigned tohigher tier than those only requiring intra-aortic balloopump support. We also have serious concerns abouassigning patients bridged with extracorporeal membranouoxygenation (ECMO) to tier 1 knowing the potential increasin post-HT mortality given their critically ill nature. Lastly, wworry that this newly proposed system may not solve thprevious issue of other disadvantaged groups such acongenital heart disease and restrictive cardiomyopathies.

Durable MCS: What the future holds

With the upcoming changes in organ allocation, advancement in durable LVAD technology and management wibecome more important than ever. With nearly half of LVAimplants performed as destination therapy, continued amelioration of durable devices is imperative to prolong survivaon support. Bleeding, infection and device thrombosis armajor sources of morbidity and mortality in the present dapopulation.40 Reduction in the frequency of these adversevents should remain a major driver in the development obetter device therapy.

Tunneled drivelines are a major source of infection and arcurrently used in all durable LVADs. The driveline exits througthe skin to connect to an external power source, thusmakingprone to mechanical complications. Infection risk is likely to bsubstantially reduced by way of driveline elimination. A fullimplantable system would also allow patients to submerse iwater which would increase patient quality of life.

Frequent hospital admissions for LVAD patients withsubtherapeutic international normalized ratio is anotheimportant issue. Not only do these unnecessary hospitalizations impact their quality of life, but they also drive thcost-effectiveness of this therapy down. Many centers havadopted strategies for outpatient bridging of anticoagulatiowith low-molecular weight heparin (e.g., enoxaparin). Validation of the safety and efficacy of such strategies in addition tprotocols designed for use in this population need to be testeat a multicenter level in the ambulatory setting.46

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Integration of hemodynamic monitoring capabilities witLVAD technology could provide a whole new level of care tthese patients. Especially true for the centrifugal type-pumps (e.gHVAD,HeartMate3), bothhypo-andhyper-volemic conditionscatrigger LVAD alarms and often the culprit driving the conditiondifficult to ascertain. Adding this type of feature to the nexgeneration device would complement the existent resources ievaluation and management of these patients. Ideally, this datwould be remotely accessibly, which has the potential to decreashospital readmissions and cost if providers were able to triage anmanage patients without necessitating inpatient evaluation.

The most recent device under investigation employs newmagnetic levitationandartificial pulse technology in anattempt tmimic native cardiac contractility in hopes of reducing bleedinand thrombosis complications.47 The future of durable LVADremains promising, and it is only through experience and refinintechnology that patient survival will continue to improve.

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Conclusion

In light of improvement in LVAD outcomes and the continuelimited organ supply we propose a paradigm shift in thmanagement of advanced stage D HF patients. First anforemost, we believe that all patients with refractory Hshould be promptly referred and evaluated for durable LVADSecond, only patients deemed to not be candidates for LVAtherapy or those who develop complications post-VAimplant (e.g., gastrointestinal bleeding, driveline infectionpump thrombosis, RV failure) should be offered HT. Thiapproach, albeit controversial, may reduce the currennumber of patients listed as a status 1A or 1B for HT.would also allow for sicker and traditionally disadvantagepopulations (congenital heart disease, infiltrative cardiomyopathies, refractory arrhythmias) to get transplanted intimely fashion. Third, although the new allocation systemaims to reduce waiting list mortality by prioritizing sickepatients, we have significant concerns with regard to post-Houtcomes in patients receiving ECMO as a BTT given the lacof data in this population. Despite the impressive survivabenefit provided by LVAD therapy, the unacceptably higshort-and long-term adverse event profile remains a kehindrance. In conclusion, more research is crucial annecessary to better understand and subsequently reducthese events in order to make this technology a viablepermanent and cost-effective alternative to HT.

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47. Heatley G, Sood P, Goldstein D, et al. Clinical trial design andrationale of the Multicenter Study of MagLev Technology inPatients Undergoing Mechanical Circulatory Support Therapwith HeartMate 3 (MOMENTUM 3) investigational deviceexemption clinical study protocol. J Heart Lung Transpl.2016;35(4):528-536.



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Palliative Care in Heart Failure: What Triggers
Specialist Consultation?
Mitchell A. Psotkaa, Kanako Y. McKeeb, Albert Y. Liuc, Giovanni Eliab, Teresa De Marcoa,⁎aDivision of Cardiology, University of California San Francisco, San Francisco, CAbPalliative Care Program, University of California San Francisco, San Francisco, CAcDepartment of Medicine, University of California San Francisco, San Francisco, CA


Statement of Conflict of Interest: see p⁎ Address reprint requests to Teresa De

CA, 94143-0124, USA.E-mail address: [email protected]


A B S T R A C T

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Heart failure (HF) continues to cause substantial death and suffering despite the availabilitof numerous medical, surgical, and technological therapeutic advancements. Aspatient-centered holistic discipline focused on improving quality of life and decreasinanguish, palliative care (PC) has a crucial role in the care of HF patients that has beeacknowledged by multiple international guidelines. PC can be provided by all members othe HF care team, including but not limited to practitioners with specialty PC trainingUnfortunately, despite recommendations to routinely include PC techniques and providerin the care of HF patients, use of general PC strategies as well as expert PC consultation ilimited by a dearth of evidence-based interventions in the HF population and knowledge ato when to initiate these interventions, uncertainty regarding patient desires, prognosiand the respective roles of each member of the care team, and a general shortage ospecialist PC providers. This review seeks to provide guidance as to when to employ thlimited resource of specialist PC practitioners, in combination with services from othemembers of the care team, to best tend to HF patients as their disease progresses aneventually overcomes.


Palliative careTriggerConsultation

Contents

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Palliative care defined. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Palliative care needs of heart failure patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Communication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Preparedness planning. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Psychosocial and spiritual support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Symptom management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Evidence supporting palliative care interventions for heart failure patients . . . . . . . . . . . . . . . . . . . . . . . . . 22When to involve specialized palliative care consultants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

age 222.Marco, University of California, San Francisco, 505 Parnassus Avenue, 1174-M, San Francisco,

sf.edu (T. De Marco).

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Fig 1 – Trajectory of Heart Failure SyTrajectory of heart failure symptomstability, eventually leading to constransplantation versus transition toworsening quality of life or diseasethe initial heart failure diagnosis, co


HF = Heart Failure

HT = Heart Transplantation

ICD = ImplantableCardioverter-Defibrillator

KCCQ = Kansas City Cardiomy-opathy Questionnaire

LVAD = Left Ventricular AssistDevice


PC = Palliative Care

QoL = Quality of Life

US = United States


Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22Statement of conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . 22References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

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Heart failure (HF) is a deadly cardiac syndrome commonlmanifest by shortness of breath, fatigue, pain and fluiaccumulation.1,2 It is a worldwide epidemic with risininternational prevalence including more than 5.7 milliopatients in the United States (US). It occurs more frequentlwith increasing age and accumulating comorbidities. Despitdiverse underlying etiologies, affected patients experiencetypical progressive decline in function punctuated by unpredictable acute exacerbations from which there is only partiarecovery (Fig 1).3 The high burden of HF morbidity in thifragile population has spurred development of multipl

mptoms, Clinical Care, ans and disease progressionideration for advanced thehospice when symptomsprogression can trigger spnsideration for advanced

complicated medical and surgical therapies including implantable cardiac devices to improve survival and quality olife (QoL).4 Despite these advancements, HFmortality remainhigh at close to 50% at 5 years, and hospital readmission ifrequent at over 50% by one year.1,5 In addition, HF therapiesuccessful at preventing mortality can prolong the length otime patients experience serious illness and comorbiditiesuch that they spendmore time confronting their symptoms

Because of the burden of HF on families and care systemand the medical complexities of HF management includinthe intricate interplay of patient, family, and caregivedecision making, involvement of palliative care (PC) speciaists who excel in these domains is imperative.6–9 PC iprovided contemporaneously by these specialized multidiscplinary teams and other HF practitioners, limited by locaavailability, primary provider expertise and desire, anpatient inclination. PC intervention strives for adequatsymptom management in addition to treating the underlyinpathophysiology, counseling and support during sharedecision making including the transitions through advancetherapy options, ascertaining the goals and values of patientand families, and changing the focus of care when the timarrives for end of life discussions. These goals are recommended by international HF guidelines and the United StateCenters for Medicare & Medicaid services.10,11 This article wi

d Potential Triggers for Specialist Palliative Care Involvement.over time with typical exacerbations and periods of relativerapies including mechanical circulatory support and heartbecome sufficiently severe. Throughout the clinical course,ecialist palliative care consultation, including but not limited totherapies, and transition to hospice care. (Adapted from27).

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describe common sources of suffering and stress experienceby HF patients and caregivers, present the knowledge barrierthat currently exist to providing effective PC services trelieve these discomforts, and provide a framework to uswhen considering involving PC specialists in themanagemenof a HF patient.

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Palliative care defined

PC focuses on improving patients' and their families' QoLspecifically their psychological, physical, and spiritual welbeing, during life-threatening illness and death by usingpatient-centered multidisciplinary approach. Although thexact interventions supplied depend on the details of thpatient experience, prognosis, and resource availability, PC isphilosophy of care in addition to a specific holistic skill set thais part of a multidimensional practice to relieve pain andiscomfort. PC assists patients and families to define their goaand values and plan care so that medical decision-makinresults in treatment that is alignedwith their uniqueneeds. It icomplementary to all other medical therapies. The WorlHealth Organization purposefully states that PC is “applicablearly in the course of illness, in conjunction with othetherapies that are intended to prolong life.”12 PC is thus ideallintegrated into the network of all HF care and should be applieby all involved health care providers across a range of settingincluding hospitals, outpatient clinics, long-term care facilitieand patients' homes, by a wide variety of health care workerPC is also useful to patients of any age and at any stage ofserious illness – from the moment of diagnosis through cure odeath – and should be implemented concurrently with aggressive, disease-modifying, or curative treatments aimed aprolonging life.

Unfortunately, the common misconception equating Pwith end-of-life care or hospice endures in both patients anproviders. Structured qualitative interviews with physiciannurse practitioners, and physician assistants from cardiologyprimary care and palliative care fields demonstrated thathese providers had limited knowledge regarding how PC cacomplement curative therapies, why PC is valuable tpatients and care teams, and even what PC entails.13 Hospicis a specific subset of PC reserved for patients withlife-limiting illness and with a prognosis of 6 months or lesto live who wish to focus primarily on QoL and avoid repeatehospitalizations. However, involvement of PC principles aninterventions is not limited to the end-of-life, and is usefuthroughout care because patients who receive early Pconcurrent with disease-modifying treatments have bettesymptom control, improved satisfaction, more focused goals ocare, and overall better QoL without accelerated mortality.14 Pintends neither to hasten nor postpone death, and may everesult in longer survival, as evidenced by early PC providefor patients diagnosed with metastatic non-small cell luncancer.15

PC can be explained in part by the services thatincorporates. In general, effective PC interventions fall intohandful of broad domains encompassing communicationpreparedness planning, psychosocial and spiritual suppor

and direct symptom management. Appropriate communication topics include patient prognosis, uncertainty surrounding the expected disease trajectory, anticipated benefits andrawbacks of potential treatments, elicitation of patient ancaregiver goals and values, and facilitation of shared decisionmaking. Preparedness planning includes choices arounreturning for hospitalization, surrogate decision makingresuscitation orders, coping with the unpredictability of thdisease course including the possibility of both sudden anprolonged death, and the consideration of end-of-life optionsPsychosocial and spiritual stressors lead to substantiaanxiety and depression that should be addressed throughouthe disease process. Direct symptommanagement consists ointerventions such as opiates for pain or psychiatric medications for depression and anxiety; however, much of thsymptom management in the context of HF is provided bcardiologists and other members of the primary care teamuntil symptoms are refractory.

Specialized PC is that subset of PC ideally provided bytransdisciplinary team of expertly-trained specialty physcians, nurses, social workers, chaplains, pharmacists, anothers who work alongside a patient's typical healthcarpractitioners to provide additional comprehensive and integrated symptom management. It involves experience ancultured communication skills above the PC principlepracticed by other physicians and healthcare providers – foexample, by a patient's primary care physician or cardiologisSpecialized palliative care consultation is commonly requested by the primary patient care team and often only exists aselect secondary and tertiary medical centers worldwidemaking it a limited commodity.16 Because specialized Pproviders are a relatively scarce resource in many circumstances, their use may be best restricted to specific high-ristimes when PC needs are most likely to remain uncovered oincompletely addressed (Fig 1, Table 1).

Palliative care needs of heart failure patients

PC interventions have a vital role in HF disease managemenbecause HF is both deadly and prone to cause suffering worsthan many malignant cancers.17,18 It is a progressivelsymptomatic disease with baseline deficits in QoL ansymptomatic status associated with more severe worseninover time.19,20 Symptom exacerbations lead to expensivhospitalizations and increased care needs that eventuallrequire full time care or lead to death.21

Despite these data, PC remains an underused tool in thcare of both ambulatory and hospitalized HF patients fromboth large and small medical systems.22 While a Britisprimary care database showed that 48% of patients witcancer who died in 2009 were recognized as needing palliativservices, only 7% of similarly deceased HF patients werentered onto the same palliative register.23 Of 40 stage D Hpatients that died over a 2 year period at one academic centeless than half received any specialist PC consultation or evehospice services.24 Of 4474 hospitalized Veterans Affairpatients with severe HF followed from 2007 to 2013, onl7.6% were seen by a specialist PC provider within one year o

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Table 1 – Common indications for specialist palliative care consultation in heart failure.

New Diagnosis of Heart Failure

First hospitalization or intensive care unit admission for heart failureFrequent admissions for heart failure (>1 within several months)Functional or cognitive decline, loss of independence, complex care requirementsSubstantial worsening of prognosis or progressing diseaseSubstantial worsening or difficulty in controlling physical or psychological symptoms from heart failureSignificant worsening of a comorbidity (new renal replacement therapy, oxygen requirement)Perceived emotional, spiritual, or relational distress to patient, family or surrogateNegative response to the ‘surprise’ question: would you be surprised if the patient died within 1 year?Deliberation of:high risk procedures (cardiac surgery, thoracic surgery)implantable cardiac devices (pacemaker, implantable cardioverter defibrillator)advanced heart failure therapies (outpatient inotropic infusion, left ventricular assist device, cardiac transplantation)feeding tube placement, tracheostomy, initiation of renal replacement therapy

Any need for mechanical circulatory supportAborted cardiac arrestUnclear patient goals-of-care or their documentationDisagreements, uncertainty, or ethical concerns (among patient, staff, or family) concerning treatment decisions or resuscitation preferences.Request for palliative care of hospice services or previous hospice enrollment


hospitalization even though 51.2% died within that same timperiod.25 Finally, of 37,270 severe HF patients included inlarge US database of 360 hospitals representing 26 health carinstitutions, only 9.6% were seen by specialist PC within onyear, with only mild improvement in usage between 200(5.7%) and 2014 (13.4%).26

The epidemiology of PC use is similar with HF patientbeing evaluated for advanced HF therapies; if utilized at alproviders have historically waited until late in the diseasprocess to enlist specialist PC services to aid in patient care. Ithe case of destination therapy left ventricular assist device(LVAD), only 15% of patients in one single-center study werenrolled in hospice care at the time of death, and less thahalf had seen a PC provider within one month precedindeath.27 Close to 80% of these LVAD patients died in thhospital, despite most HF patients preferring to die at homeand data from the oncologic literature demonstrating thapatients who die in a hospital (and their caregivers) experence worse QoL compared to those at home with hospice.2

Part of this discrepancy may be due to the differencebetween HF patients and the oncology patients manhospices were designed to support: management of LVADand inotropes is expensive and complicated, and may not bsupported by hospice agencies. However, in the case oimplantable cardioverter defibrillators (ICD) deactivations aa single center, an inexpensive and straightforward intervention, the median time from PC introduction to death wasdays, with only half of those discussions leading to specialtPC referral.29

Communication

Clear and effective communication between patients anhealthcare providers is essential to the provision of highquality care. Patients and families want open, honest, timelyand accurate information about their chronic or terminadiseases; however, communication about prognoses and carpreferences are uncommon.30,31 Multiple qualitative studieof New York Heart Association (NYHA) class 3 HF patient

have demonstrated similar findings, specifically that Hpatients desire to know their prognosis from their physiciawhile they have robust cognitive function, usually at the timof diagnosis, and such a discussion should include the rangof potential prognostic possibilities.32,33 Nevertheless, thisame study showed how patients want these truths balancewith hope for improved quality and quantity of life. Patientand caregivers typically use this information to elaborattheir care goals, as in two studies that asked patients tchoose between two potential futures: shorter survival timwith improved QoL versus longer survival at current QoLThese revealed that patients have strong but polarizepreferences and that these desires are malleable over timdepending on the symptom burden and prognosis.34,3

Additionally, patients and their caregivers often disagrewith respect to potential health care decisions. In 10patient-caregiver pairs from two centers, 47% were incongruent, and incongruent pairs reported greater psychosociadistress.36

Unfortunately, HF patients and caregivers frequentlremain unaware of the severity of their illness and thuunable to formulate their own goals of care. When effectivcommunication does not take place, patients may not realizthat HF is a progressive and life-limiting syndrome. A moderstudy of 51 stage D HF patients who died within one yeaasked them to describe their disease and where they sawthemselves one year in the future: only 14% believed HF waterminal.37 Similarly, of experienced caregivers for patientwith stage D HF with mean 10 years duration of caregivingonly 67% realized that HF was terminal.24

In contrast to the linear and predictable health decline oterminal cancer, prognosticating outcomes in HF is difficuand uncertain, further impeding effective communication.1

As stated above, patients poorly estimate their own mortalitand suffering, and HF progresses differently from cancer antypical aging with regards to the patient experience anrapidity of decline. When compared with the Seattle HearFailure Model, patients from a single center predicted a mea40% longer life-expectancy; patients who were younger o

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who had more severe disease generated particularly divergenestimates.38 This may be because model predictions, and thuthe likely influential factors leading to death, make use omarkers of disease severity not understood by patients wheenvisioning their own survival.38 Nonetheless, despite reasonable c-statistics at the population level, none of themultitude orisk models permeating the HF literature reliably predictwhether an individual patient will die, with sensitivities lesthan 5% for 1-year mortality.39 Thus, there is confusion durinthe progression of HF regarding the overall prognosis, the timinof life-changing decompensations requiring hospitalizationsudden cardiac death, shocks if ICDs are implanted, candidacfor advanced therapies including LVADs and heart transplantation (HT), and appropriate timing for hospice referral.

Shared decision making is an extension of appropriatcommunication. It relies on eloquent description of thmedical situation in a manner than can be appropriateldigested by patients and caregivers with varied educationabackgrounds and medical literacy, as well as elicitation opreferences from patients and their support networks regarding their desires during their HF therapy. Specific patient aimto be addressed include not only end-of-life requests, but alsdecisions surrounding increasingly risky but high rewartherapies including LVADs and HT. For instance, despitemedian survival of 14 months following destination therapLVAD implantation, the inpatient mortality for the surgerapproaches 11%.27 Structured interviews with LVAD canddates, patients, and caregivers showed that many particpants made decisions about the LVAD quickly and reflexivelymost felt there was no real choice because the alternative wadeath, and more than half were admitted to the hospitawhen the potential for LVAD was first expressed to them anthus depended principally on clinicians to decide for them.4

The relatively late introduction of patients to the concept oreceiving an LVAD limited their ability tomentally process thidea, ask reasonable questions, and actively participate in thdecision. In contrast, interviews with candidates who initialldeclined LVAD placement reveal that decision-making, whiloften initially reflexive, is malleable over time as symptomworsen and QoL declines, highlighting the need for earliediscussions and perhaps decision aids to assist in thiprocess.41,42 Thus, shared decision-making relies on appropriate baseline communication of the clinical situation anfurther develops the care plan by empowering the patient tincorporate their own individualized care preferences.

Preparedness planning

Preparedness planning encompasses education regardingwide array of potential future events that HF patients ancaregivers should anticipate. While not specific to the Hdisease process, the universal goals are to assist patients tcommunicate their wishes to their families and friendincluding advanced directives and resuscitation orders. Areported earlier, patients prefer to know their prognosithroughout the HF disease course as best as it can bdescribed. Unfortunately, in a community-based cohort oover 600 HF patients, only 41% had an advance directive iplace to document their end-of-life preferences or appoin

surrogate decision makers.43 Other critical issues include thdeactivation of implanted cardiac devices around the end olife, including ICDs and LVADs, which can be ethically anemotionally difficult.44 HF patients implicitly and explicitlweigh the trade-off between improved QoL and decreasesurvival time to make decisions about resuscitation preferences; however, they can only assess the situation if approprately informed.45 The United States Centers for Medicare &Medicaid Services acknowledged these issues by requiring Pinvolvement in LVAD preparedness counseling.10

There are numerous additional end-of-life choices relevant tHF patients that have not been historically well-discussed. Onexample is location or setting of death. While 46% of cancepatients in a Dutch registry died at home, the same was true foonly 21%ofHFpatients; of the remainingHFpatients, 28%died ia hospital, 26% in a skilled nursing facility, and 22% in a carhome.21 Identification and conversation regardingdeath athomas an end-of-life goal may help to resolve these differences, apatients in one US cohort spent a median of 28% of their finamonth of life in the hospital.20 The opportunity to deactivatimplanted cardiovascular devices serves as another primexample of how HF patients may be better informed of themedical options. Despite guideline recommendations, no onfroma single-center retrospective case review of 44 patientswitan ICD who died over a 12-month period was informed of thpossibility of device deactivation prior to implantation; furthermore, only 23 (52%) had an end-of-life discussion prior to deatand only 16 (36%) had their ICD deactivated prior to death.29,46 Ia separate investigation, telephone interviews with 278 ICDpatients demonstrated that 86% had never considered or beeknowingly counseled whether to alter their ICD settings if thewere unlikely to survive, though 95% agreed that they shoulhave the opportunity to decide.44 Willingness to deactivate aICD varies greatly by patient, with reported prevalence ranginfrom12–79%,making conversations on this topic crucial to actinin concordance with patient desires.47

Finally, there are largely inevitable implications of the Hdisease process that must also be anticipated. Chief amonthem are the financial implications of HF care, which aroften overlooked but can be devastating to patients anfamilies. In one observational cohort of patients within thlast week of life, 13% had a family member who had quwork, 16% of families had lost at least one large source oincome, and 23% had lost most or all of their family savingdue to the patient's illness.20 These financial matters arparticularly relevant for advanced therapies, both in patienqualification and for their survival afterwards.48

Psychosocial and spiritual support

The burdens of HF extend beyond the physical domain anencompass all aspects of patient life. HF patients experiencadjustment reactions to progressive losses that lead tgrowing anxiety and depression. When compared with othecommon cardiovascular conditions including myocardiainfarction and coronary artery bypass grafted patients, Hpatients have the highest prevalence of clinical depressio(occurring in two-thirds of patients), and the highest level oanxiety.49 Physical symptoms and loss of function caus

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Table 2 –Management strategies for heart failure symptoms unresponsive to optimal standard therapies.

Symptom Potential Interventions

Constipation Senna (1st line, 2–10 tab/day), Polyethylene glycol or Lactulose (2nd line), avoid docusate (no benefit)Cough Address reversible causes (gastroesophageal reflux, pulmonary or laryngeal infection)

Menthol lozenges, Benzonatate, Guaifenesin, OpioidsConsider exchanging ACE-inhibitor for ARB

Depression/Anxiety Screen for and treat physical and existential distress, cognitive behavioral therapyAntidepressant (SSRI, mirtazapine – also improves appetite and nausea), cautious Benzodiazepines, avoid TCAs/SNRIs

Dry Mouth Consider changing culprit medications: anticholinergics, sympatholytics, opioids, benzodiazepinesSalivary gland stimulation (sugarless gum or candy)Saliva substitutes (ice chips, mucin-based artificial saliva products)Optimal oral hygiene, acid avoidance

Dyspnea Address reversible causes (pleural effusion, pulmonary edema, infection, bronchoconstriction, anxiety)Physical therapy, rehabilitation, mindfulness trainingEnvironmental interventions (fans for air circulation, hospital bed for head elevation)Opioids (i.e. Morphine 2.5–5 mg orally q4h as needed or similar, titrated to effect)

Fatigue Address reversible causes (hypothyroidism, depression, sleep disordered breathing, anemia)Physical therapy, rehabilitation, exercise trainingConsider decreased beta-blocker dosing

Nausea/Vomiting Address reversible causes (medication effect, hepatic/gastrointestinal edema, renal failure)Ondansetron or Metoclopramide or low-dose Haloperidol (all can prolong QTc), Benzodiazepines

Pain Physical therapy, rehabilitation, acupuncture, mindfulness training, cognitive behavioral therapySpinal cord stimulation, transcutaneous nerve stimulationAcetaminophen (1st line), Opioids (2nd line), Gabapentin (if neuropathic pain), avoid NSAIDs/TCAs

Abbreviations: ACE = angiotensin converting enzyme; ARB = angiotensin receptor blocker; NSAID = non-steroidal anti-inflammatory drug;SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant.


significant life disruption, loss of roles, and social isolationwhich in turn engender spiritual distress, loss of stabilizinsense of peace, purpose, meaning, and connections to othersThese declines in social, psychological, and spiritual statucorrelate with physical deterioration.50 Additional emotionachallenges occur in the setting of the financial stress due tlost ability to work and the high costs of HF treatmenincluding advanced therapies, hospitalizations, and caregivingUnfortunately, HF patient caregivers report substantial dissatisfaction overall with the current level of emotional supporprovidedby themedical establishment, likely becauseof a relativlackof screening for theseunder-recognizednon-physical sourceof distress and rare referrals to specialists for their treatment.51

Symptom management

Distressing symptoms may arise from HF and its treatmentor from coexisting comorbidities. Although HF patientcommonly experience shortness of breath, fatigue, pain anedema, this syndrome can elicit diverse symptomatologincluding nausea, excessive thirst, concentration and memory deficits, weakness, anxiety, and depression.2 As thdisease progresses, multifactorial pain increases, dyspnebecomes more severe, and depression worsens. Symptompreceding death from progressive pump failure are oftesevere. HF patients experience an average of 9–12 symptomeach, with half of patients reporting high symptom-relatedistress.52,53 Singular symptoms may derive from diverscauses. While 48% of HF patients report pain, most inon-cardiac and may represent neurologic, musculoskeletaor psychiatric illnesses including depression, each of whicmay need separate treatment.54 As with cancer, the higsymptom burden may also include emotional, spiritual an

caregiver strain. Each symptom can adversely affect patienwell-being and health-related QoL, while improvement isymptoms is associated with better survival and functionastatus. However, when compared to cancer, HF patients tento have greater unresolved dyspnea relative to other symptoms of chronic illness, which may be best treated wittherapies targeted at the underlying disease process such adiuretics and vasodilators, or advanced therapies such aLVAD and cardiac transplant, until those modalities are nlonger effective.55 Thus while PC practitioners may haverole in ameliorating some of the symptom distress iadvanced and refractory HF, the central symptom of dyspnetypically remains the domain of the other physicians anteam members involved until late in HF progression.common symptoms are unresponsive to or incompletelattenuated by maximally tolerated HF therapies, alternativsymptom management strategies can be utilized (Table 2).

Evidence supporting palliative care interventionfor heart failure patients

Because of the complexity of the multidisciplinary carprovided to HF patients and the relative paucity of datastudied PC interventions have been diverse and unstandardized, leaving HF teams without clear guidance on how timplement PC services. Part of this confusion likely also derivefromuncertainty aroundhowpatients and families plan care ichronic disease and HF. While assorted PC interventions havvariably been associatedwith decreasedmedical costs, reducehospitalizations and pain, improved QoL and survival, as weas better patient satisfaction in multiple populations includincancer patients, the best interventions in HF patients remai

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undefined and understudied.56,57 Although it is hypothesizethat combining structured PC techniques with diseasemodifying HF therapy should improve QoL and perhaptraditional clinical outcomes including hospital admissionand survival, this has not been well-proven. Many guidelinerecommended approaches have been extrapolated from thoncologic literature, but few randomized controlled trials exisin the HF realm and many have significant caveats limitintheir interpretation or reproducibility.

Many of the randomized trials of PC interventions thahave been performed with HF patients have either utilizeadditional disease-modifying components, sowing doubregarding which aspect of the trial caused a change in thoutcome, or failed to meet their primary outcome measureFor instance a multidisciplinary intervention in 282 acute Hpatients included nurse directed education, diet changesocial work consultation, and intensive follow up with homvisits.58 Although the treatment group had numerically fewehospitalizations, improved QoL, and lower costs of care, thcausality is unknown. The Swedish Palliative Advanced HomCare and Heart Failure Care (PREFER) trial randomized 7patients to a multidisciplinary team intervention withperson-centered home care component and found no clincally significant change in the Kansas City CardiomyopathQuestionnaire (KCCQ) summary scores.59 There was a suggestion of QoL improvement from less robust scorinmethods and from changes in KCCQ sub-scores; however,remains uncertain whether these were clinically significanimprovements or due to the intervention, and which components of the intervention were responsible for any productivchanges. The Patient-Centered Disease Management (PCDMmulticenter trial randomized 392 HF patients to multidiscplinary care including nurses, cardiologists, psychiatristhome telemonitoring, and screening with treatment odepression.60 There was no significant improvement betweetreatments groups in the KCCQ summary score, and thougthere were numerically fewer deaths in the treatment armthe trial was not powered for this outcome.

Some more simply developed trials have demonstratebenefit for PC involvement in HF care, while others have faileto support typical interventions. A single center trial of 23patients with acute HF randomized to inpatient specialist Pconsultation or standard care demonstrated clinically anstatistically significant improvement in QoL after one montas measured by the Minnesota Living with Heart FailurQuestionnaire.61 In contrast, despite the demonstrated association between clinical depression andworse outcomes in Hpatients, sizeable randomized controlled trials of the antidepressants escitalopram and sertraline for 12–24 weeks demonstrated no reduction in depression and no benefits in Hmorbidity or mortality.62,63 Rather, cognitive behavior therapadministered by experienced therapists for 6 months atsingle institution to NYHA class 1 through 3 HF patients witclinical depression effectively improved depression scoreand clinically significantly increased QoL, as measured by thKCCQ.64

Systematic reviews and meta-analyses have sometimeshown improvements in HF QoL, rehospitalizations, andmortaity from PC interventions, but they have also demonstrate

considerable heterogeneity in design and outcome quantification. One meta-analysis of the association between PC interventions and outcomes for patients and their caregivers, from botthe oncologic and HF literature, found statistically and clinicallsignificant benefits for patient QoL.65 The 14 included HF trialrepresented 32.5% of the meta-analysis. Notably, there was nassociation between PC use and survival, and due to thsubstantial inter-trial heterogeneity, the evidence for all thassociations was weak. A separate systematic review of 1prospective and retrospective interventions in HF patients, onleight of which solely included HF patients with only five of theight randomized and controlled, found general improvementin QoL and patient satisfaction with PC. However, meta-analysiwas limited to only three small studies to showa42% relative risreduction in risk of hospitalization.56 The limited ability tanalyze the data again occurred due to substantial interventioand location heterogeneity, including by social workers, nursesand physicians in inpatients, outpatients, home-based, anhospice settings.66 The services provided were equally varied, awere the outcomes studied, and overall only 18% of randomizecontrolled trials investigating PC from 2001 through 2015 utilizeHF patients.66

Two recently completed randomized clinical trials maadd to the PC HF milieu, but results remain tentative. ThPalliative Care in Heart Failure (PAL-HF) trial randomized 15HF patients at increased risk to a multi-dimensional intervention focused on physical symptoms, psychosocial anspiritual well-being, and advanced care planning provided ba nurse practitioner.67 The treatment group demonstratedsubstantial and clinically significant increase in QoL over 2weeks, with no change in mortality. The Social Worker-AidePalliative Care Intervention in High Risk Patients with HearFailure (SWAP-HF) trial randomized 50 hospitalized Hpatients to a social worker instituted intervention focuseon documentation of advanced care preferences.68 Thtreatment arm increased the proportion of medical chartwith recorded advanced care preferences from 33% to 65%over 6 months, with improved alignment of care goalbetween patients and physicians from 26% to 94%. Thesstudies may serve as pilots for larger multi-site trials thopefully establish feasible and effective PC interventions ithe HF population. As this nascent field grows more robusthemethods for providing PCmay becomemore codified witclearer delineation of which services to dispense and how tprovide them.

When to involve specializedpalliative care consultant

There exists no certain unique time to involve specialist Pproviders in the care of a HF patient, as the decision dependon the clinical setting, the availability of such specialists, thexpertise of the currently involved management team, anthe specific characteristics of the interaction between thpatient, their providers, and their caregivers. Part of thdearth of experimental evidence for specific PC interventionin HF includes the timing of specialist PC consultation, anthe uncertainty regarding a patient's clinical trajectory makeit difficult to determine when to offer PC services. Thus, whil

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sensible guidelines can be postulated, it is ultimately thresponsibility of HF and PC providers to identify, test, anprove utility of interventions and their appropriate timingNevertheless, it is well-accepted that specialty PC consultation is being initiated too late in the HF disease process. Inretrospective chart review from one academic center betwee2006 and 2011, the median time from specialist PC consultation to death was 21 days, leaving little time to accomplismany of the tasks set forth in the preceding discussion.69 Thiis in spite of data from the oncologic literature that earlier Pconsultation is associated with better outcomes and decreased costs.70

The local absence of specialty PC resources may constraiutilizing these specialist consultations. For instance, althougavailability of inpatient PC services has grown substantiallfrom 15% of hospitals over 50 beds in 2001 to 67% of the samhospitals in 2014, there exists considerable regional variabiliteven within the United States. In some areas of the countrinpatient PC consultation is only present in 42% of similarlsized hospitals.71 Thus, inherent in deciding when to consuPC is to understand the local presence of these services anproviders.

Because QoL decreases and symptoms persist throughouthe duration of the HF disease process, PC is theorized tideally be integrated into the multidisciplinary holistic care oHF patients throughout their illness, although robust Hclinical trial data to support this assertion is lacking. Thability to achieve this integration depends on each provider'skillset and comfort with PC approaches and techniques, anof course the availability of specialized PC resources. Nevertheless, the current shortage of specialist PC practitionermay force members of the primary HF care team into thirole.16 Although there is no clear agreement by patients oproviders on which parts of the management team, includinthe cardiologists, primary care doctors, and PC specialistsshould be responsible for advanced care directives anpreparedness planning in HF, there is clear onus to providthese resources as part of appropriate patient-centered care.4

If the involved care team requires assistance completinnecessary PC tasks described in the above manuscript, thespecialist PC help should be enlisted.

PC must be adaptive to the needs of the patient in theicurrent situation, which requires frequent reassessmengiven the unpredictability of the disease, the complexity othe management options, and the rational tendency fopatients to re-evaluate their preferences as the clinicasituation changes.44,45,72 Without systematic consultatiowith PC specialists there are common opportunities fopalliation that reliably occur despite the overall unreliabilitof disease progression.13 These periods of elevated risk founaddressed PC needs include: the first diagnosis of symptomatic or stage C HF, which should be considered akin tofirst diagnosis of life-threatening cancer; before implantatioof an ICD; during a time of repeated HF hospitalizations oother worsening symptoms; upon consideration of advanceHF therapies including LVAD or HT; and when there appearto be no further life-sustaining therapy to be offered and thpatient has arrived at the end-of-life with potential transitioto hospice care (Table 1).73 Treating these moments a

objective ‘triggers’ to initiate an expert PC consultation cadecrease the uncertainty and improve confidence around threferral process; however, the specific events may differ bcommunity and ideally should be agreed upon by local carteams and their associated specialist PC providers.

In order to ease the referral process to specialty Pproviders in the above situations, the common understandinof PC should embrace the many levels of support that a Pconsultation can offer from diagnosis through death.74 Thpalliative care referral process should not worry patients nopractitioners that hope for improvement in the underlyindisease is being abandoned. Rather, the goal is to helpatients and families live as well as possible for as long apossible by integrating supportive care and coping strategiewith ongoing medical and surgical care. At the end of lifepatients and providers should be reassured that after accounting for the decline in clinical status, advancing age, ancompounding comorbidity, transition to a do-not-resuscitatorder does not appear to independently worsen the risk odeath.72

Conclusions

Even though substantial work remains to be done before thpotential benefits of specialty PC for HF patients are realizedcurrently available data suggest that utilizing specialist Pproviders may be helpful to improve symptoms and QoL fothese ill and complicated individuals. HF patients have manneeds that a PC provider can assist the medical team imeeting, including issues surrounding communication oprognosis and expectations, preparing for medical and sociadecisions unforeseen by patients, buttressing both the patientand caregivers in times of high stress and emotional fatigueand at times assisting in managing the cornucopia of symptoms that coalesce with worsening HF. However, maninteractions with patients that theoretically fall under thumbrella of PC are typically already provided by HF practtioners but are not labeled ‘PC.’ Thus, the appropriate time focardiologists and other members of the care team to reach outo specialized PC providers is best tailored to the expertise ancomfort of the team members involved, particularly given threlative shortage of highly-trained PC consultants. Evolvinexpert guidelines along with additional PC training for medicapractitioners throughout their educationmayhelp them to leathese challenging conversations. At the same time, systematiincorporation of PC conversations and interventions throughout the HF patient journey may improve shared decisionmaking and assist patients in achieving their desired outcomeIn themeantime, typical triggers for calling specialist PC can bused as guidelines to help patients and caregivers achieve thehealth care goals during management of chronic HF and easprogression to worsening symptoms, potential advanced therapies, and eventual death.


There is no conflict of interest of any of the listed authors.

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ScienceDirect


Heart failure with Myocardial Recovery - The Patient
Whose Heart Failure Has Improved: What Next?
Petra Nijsta, b, Pieter Martensa, b, Wilfried Mullensa, c,⁎aDepartment of Cardiology, Ziekenhuis Oost-Limburg, Genk, BelgiumbDoctoral School for Medicine and Life Sciences, Hasselt University, Diepenbeek, BelgiumcBiomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium


n

Statement of Conflict of Interest: see⁎ Address reprint requests to Wilfried M

Genk, Belgium.E-mail address: wilfried.mullens@zol.


A B S T R A C T

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Keywords:Heart failure with recovered ejectio

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In an important number of heart failure (HF) patients substantial or complete myocardiarecovery occurs. In the strictest sense, myocardial recovery is a return to both normastructure and function of the heart. HF patients with myocardial recovery or recovereejection fraction (EF; HFrecEF) are a distinct population of HF patients with differenunderlying etiologies, demographics, comorbidities, response to therapies and outcomecompared to HF patients with persistent reduced (HFrEF) or preserved ejection fractio(HFpEF). Improvement of left ventricular EF has been systematically linked to improvequality of life, lower rehospitalization rates and mortality. However, mortality anmorbidity in HFrecEF patients remain higher than in the normal population. Alsopersistent abnormalities in biomarker and gene expression profiles in these patientlends weight to the hypothesis that pathological processes are ongoing. Currently, therremains a lack of data to guide the management of HFrecEF patients. This review widiscuss specific characteristics, pathophysiology, clinical implications and future needs foHFrecEF.


fractionMyocardial recoveryReverse remodeling

Contents

77889991

889990

Myocardial recovery and definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22Myocardial processes associated with reverse remodeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22Improved EF or cured HF? Phenotype versus genotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22Prevalence, predictors and prognosis of myocardial recovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22The contribution of different therapies to LVEF improvement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Neurohumoral blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22Cardiac resynchronization therapy (CRT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22VADs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

222222222223

page 232.ullens, MD, PhD, Department of Cardiology, Ziekenhuis Oost-Limburg, Schiepse Bos 6, 3600

be (W. Mullens).

served.

111122220


AAs = aldosterone receptorantagonists

ACEI = angiotensin convertingenzyme inhibitor

ARB = angiotensin receptorblocker

BB = beta blocker

CRT = cardiac resynchronizationtherapy


HF = heart failure

HFmrEF = heart failure with midrange ejection fraction

HFrEF = heart failure with re-duced ejection fraction

HFpEF = heart failure with pre-served ejection fraction

HFrecEF = heart failure with re-covered ejection fraction

LV = left ventricular

LVEF = left ventricular ejectionfraction

ICD = intracardiac cardioverterdefibrillator

NTproBNP = N-terminal of theprohormone of Brain NatriureticPeptide


001122222


Revascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23Life style. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

Current literature on management strategies of patients with HFrecEF . . . . . . 23Pharmocotherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23Cardiac device therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

Clinical implications and management of patients with myocardial recovery . . 23Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23Statement of Conflict of Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . 23References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

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Four to five decadeago, heart failure (HFwas a deadly diseaswith few options tstabilize the diseasprocess, let alone improvor cure HF. However, duto the success of neurohumoral blockers animplantable devices, Hhas become treatableOnly a minority of patients will rapidly decline despite therapy tend-stageHFwarrantinheart transplantation omechanical circulatorsupport. In contrast, inlarge part of HF patientstabilization and ofteimprovement of symptoms and cardiac dysfunction is possiblMoreover, in an impotant number of Hpatients substantial o

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complete myocardial recovery occurthis number of HF patients will further increase in the futureThese patients differ from HF patients with persistent reduceejection fraction (EF; HFrEF) as well as preserved EF (HFpEF) iunderlying mechanisms of cardiac dysfunction, comorbiditieand prognosis. In this review we will discuss specific characteristics, pathophysiological and clinical implications anfuture needs for HF patients with myocardial recovery.

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Myocardial recovery and definitions

The main terminology used to describe HF is historical anbased on clinical signs and symptoms as well as measurements of left ventricular (LV) EF (LVEF) (Table 1). Three distinccategories are defined: those with normal LVEF (considered a≥50%; HF with preserved EF (HFpEF)), those with HFrEF (<40%and recently, patients with an EF of 40–49% defined as HF witmid range ejection fraction (HFmrEF) or in the 2013 Americaguidelines defined as “HFpEF, improved” (41–49%).2,3 Howeve

this group is probably a heterogeneous population consisting opatients with mild systolic HF and patients with improveHFrEF.3 It is well recognized that EF is dynamic over time wit39% of HFpEF patients progressing to an LVEF < 50% and 39% oHFrEFpatients progressing to an LVEF ≥ 50%at somepoint aftediagnosis over a mean 5-year follow up (Fig 1).4

Reverse remodeling, the opposite of (negative or maladaptive) remodeling, is the process associated with a decrease iLV volume and mass leading to a (more) normal ellipticashape of the LV which can occur spontaneously or due tmedical or device therapy.5 In the strictest sense, myocardiarecovery is a return to both normal structure and normafunction of the heart.6 Due to the absence of a strict definitioof patients with improved or recovered EF (HFrecEF) therremains to be heterogeneity regarding the cut-off value foLVEF (≥40% to ≥50%) in the literature. However, a correcdifferentiation between HFrEF, HFpEF, HFmrEF and HFrecEF iimportant. All these patient categories often have differenunderlying etiologies, demographics, comorbidities, responsto therapies and outcomes; which is crucial information fothe patient as well as the treating physician. Moreovecorrect definitions are necessary to stimulate researcwhich can lead to the development of successful individuaized management strategies in HF.

Myocardial processes associated with reversremodeling

The progression of HF is associated with LV remodelingwhich manifests as gradual increases in LV end-diastolic anend-systolic volumes, wall thinning, and a change in chambegeometry to a more spherical, less elongated shape. Thiprocess is usually associated with a progressive decline iLVEF. Different triggers can lead to a decline in LVEF and thprocess of remodeling (Fig 2). The process is influenced bhemodynamic load, neurohumoral activation and othefactors. Due to continuous maladaptive remodeling, myocardial dysfunction is usually a progressive condition. Icontrast, the biology of myocardial recovery is not weunderstood. It is likely a spectrum of improvement wit(partial) reversal of biological processes which occur in thfailing heart. These may be categorized into those that occuin cardiac myocyte versus changes within the extracellulamatrix of the myocardium (Fig 2).5 During the process oreverse remodeling several studies showed that change

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Table 1 – Overview of definitions of heart failure.

Acronym Criteria LVEF Cut-off

DefinitionAdopted byCurrentGuidelines

Heart failure with reducedejection fraction(synonym: systolic HF)

HFrEF Symptoms and signs of HF+ LVEF ≤ 40%

- LVEF < 40%79

- LVEF ≤ 40%80ACCF/AHAESC

Heart failure with preservedejection fraction(synonym: diastolic HF, Heartfailure with normalejection fraction)

HFpEF

HFNEF

Symptoms and signs of HF+ LVEF ≥ 50%+ elevated levels of natriuretic peptides+ at least one of the following 1) relevantstructural heart disease (left ventricularhypertrophy or left atrial enlargement)2) diastolic dysfunction

LVEF ≥ 50%79,80 ACCF/AHA + ESC

Heart failure with mid rangeejection fraction

Heart failure with preservedejection fraction,borderline80

HFmrEF

HFpEF borderline

Symptoms and signs of HF+ LVEF 40–49%+ elevated levels of natriuretic peptides+ at least one of the following 1) relevantstructural heart disease (left ventricularhypertrophy or left atrial enlargement)2) diastolic dysfunction

LVEF 40–49%79

LVEF 41–49%80

ESC

ACCF/AHA

Heart failure with recoveredejection fraction

(synonym: HF with improvedejection fraction)

HFrecEF

HFpEFImproved80

Recovery is a substantial or completeimprovement of left ventricularsystolic function79

- Previous LVEF<40%but currentlyLVEF ≥ 40%80or

- PreviousLVEF < 40%butcurrentlyLVEF ≥ 50%

ACCF/AHA

The acronyms in bold are used throughout the manuscript.


within cardiac myocytes, extracellular matrix but also genetiand proteomic alterations (partly) reverses.5 Recovery ostructure and function probably occurs easier in hearts witfewer pre-existing myocyte and extracellular matriderangements.7 Perhaps the purest example is a Takotsubcardiomyopathy, in which an acute stressor leads to severregional LV dysfunction with return to normal LV structurand function once the insult resolves.8

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Improved EF or cured HF? Phenotype versugenotype

Observational studies suggest that improved hearts, evethose with normal LVEF (“phenotype”), are not truly normadespite parallel improvements at organ, tissue, and cellulalevel (“genotype”). As such, HFrecEF patients have higher thanormal levels of brain natriuretic protein (BNP), Troponinsoluble fms-like tyrosine kinase receptor and uric acidalthough significantly lower than patients with HFrEF anHFpEF.9 Furthermore, subtle LV systolic changes such aglobal longitudinal strain often remain decreased despiterecovery in LVEF.10 This suggests the ongoing of abnormalties in the salt and water homeostasis and abnormal myocytbiology in at least a subset of patients.9 Moreover, studieusing microarrays to profile myocardial gene expressio

revealed that the reverse-remodeled heart is different fromnormal or non-failing heart.11,12

Prevalence, predictors and prognosis of myocardiarecovery

Improvement of LVEF has been increasingly observed in a varietof clinical settings over the past 10–15 years. In some etiologies oHF such as acute lymphocytic myocarditis, peripartum cardiomyopathy, some forms of toxic cardiomyopathies (e.g. ethanol oanthracyclines), tachycardia or hyperthyroidism associated cardiomyopathies; recovery and normalization of LV structure anfunctioncanoccur spontaneously inup to40-50%ofpatients.13–1

HFwithmyocardial recovery (definedas a previous LVEF < 40 bu≥40% at the time of study inclusion) was relatively prevalent insingle tertiary HF clinic setting.17 Within a sample of 358 Hpatients, 56were defined as HFpEF, 181 as HFrEF and 121 (34%) aHFrecEF. Another report on chronic HF patients identified 10% aHFrecEF, however in this study HFrecEF was defined asLVEF ≥ 50% and previously <50%.9

Patients with myocardial recovery are typically youngethan patients with HFpEF and HFrEF, and have a loweprevalence of comorbidities such as hypertension, diabeteand atrial fibrillation.17 Nonischemic origin of HF and no priomyocardial infarction were associated with improvement i

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Fig 1 – Heart failure definitions based on left ventricularejection fraction and evolution over time. Abbreviations: EF:ejection fraction; HFmrEF: heart failure with mid rangeejection fraction; HFpEF: heart failure with preserved ejectionfraction; HFrEF: heart failure with reduced ejection fraction;HFrecEF: heart failure with recovered ejection fraction.


LVEF in the large IMPROVE-HF cohort, a finding that supportthe experience of many HF physicians.18 Also, myocardiarecovery is more likely in patients with a shorter duration anless myocardial fibrosis.19,43

Improvement of LVEF has been systematically linked timproved quality of life and lower rehospitalization rates anmortality, regardless of how it is achieved.20 HFrecEF patienthave often milder symptoms, with patients mainly functioning in New York Heart Association (NYHA) class I or II.1

All-cause mortality, the need for cardiac transplantation omechanical circulatory supports are lower in patients witHFrecEF (LVEF ≥ 50%) when compared to HFrEF and HFpE(HR for HFrEF compared to HF recovered 4.1 (2.4–6.8); HR foHFpEF compared to HF recovered 2.3 (1.2–4.5)). Howevepatients with myocardial recovery still experienced a signiicant number of hospitalizations for HF, with approximatel50% of this group being hospitalized by 6 years hintintowards ongoing subclinical alterations driving residual Hmorbidity.9

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The contribution of different therapies to LVEimprovement

Renin-angiotensin-aldosterone inhibitors, beta-blockers (BBscardiac resynchronization therapy (CRT) and ventricular assisdevices (VADs) have the potential to achieve reverse remodeing and to date, every therapy with mortality benefits (excepfor a cardioverter defibrillator) in HFrEF is capable of inducinreverse remodeling.15 Moreover, reverse remodeling strategiewhether medical or device-based therapies, seem to exhibitdose-response relationship.21 Indeed, the higher the intake oneurohumoral blockers or effective biventricular pacing, thhigher the chance of recovery. However, not every patienexposed to these therapies achieves myocardial recovery anreverse remodeling is not always durable.

Neurohumoral blockers

Optimal medical therapy appears to be a key component oachieving myocardial recovery. In the IMPROVE-HF (Registrto improve the Use of Evidence-Based Heart Failure Therapiein the Outpatient Setting) study, a large observational cohorof outpatients enrolled in a performance measure intervention, almost one-third of patients experienced meaningfurecovery of myocardial function with nearly doubling of LVE(from 25% to 46%).18 Beta-blockers are the medical therapmost strongly linked to reverse remodeling. In the magnetiresonance imaging substudy of the MERIT-HF trial, treatmenwith metoprolol for 6 months significantly increased LVEF ban average of 28%.22 Animal and human studies havrevealed that sustained beta-blocker treatment improvecardiac myocyte contractility, contractile reserve and calciumhandling in myopathic hearts.23–27 Several trials demonstrated early and sustained effects on LVEF and LV dimensionafter initiation of angiotensin-converting-enzyme inhibitor(ACE-Is) or angiotensin receptor blockers (ARBs).28,29 Additionally, even when aldosterone receptor antagonists (AAs) aradded to background therapy with ARB/ACEi and BBs, significant beneficial effects on LV volume and function occur.30–3

Limited data regarding the reverse remodeling responsfollowing Sacubitril/valsartan exists as the PARADIGM-HF triadid not collect follow-up echocardiography data. However, inrat model of myocardial infarction (MI), 4 weeks of therapwith Sacubitril/valsartan resulted in significant improvemenof LVEF and reduction of LV end diastolic diameter. Undoubtedly, data regarding the effect of reverse remodeling ansacubitril/valsartan will arise in the future.27

Table 2 summarizes the effect of different pharmacotherapies on LVEF in large randomized trials.

Cardiac resynchronization therapy (CRT)

Among HFrecEF patients, a very intriguing group are thoswith improved LVEF after CRT. Indeed, patients eligible foCRT had persistent LVEF ≤ 35% despite maximally tolerateneurohumoral blockers. Yet, systolic function often improveafter implantation of a CRT. The average increase in LVEF ithe large CRT trials (MIRACLE-ICD, CARE-HF, REVERSE anMADIT-CRT) ranged from +2 to +11% (Table 2).34–38 Substantiaregression of myocardial dilatation and improvement oejection fraction is likely the effect of resynchronizatiowhich initiates a cascade of positive effects such as improvecontractility and filling of the ventricles, reduction of mitraregurgitation, decreased sympathetic nerve activity, anreduction of LV wall stress.39,40 Moreover, dog-models oCRT actually indicate that CRT is capable of targeting thmolecular underpinnings of progressive LV remodelinghereby inducing reverse remodeling on a cellular level. CRhas been shown to improve calcium, sodium and potassiumchannel function, hereby improving calcium cycling anabbreviating action potential duration, with the latter assocated with a lower pro-arrhythmogenic risk. Furthermore, CRinduces mitochondrial genome expression hereby improvinmyocardial substrate utilization and decreasing apoptotisignaling.41–45

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Fig 2 – Factors involved in the process of remodeling and reverse remodeling. The changes that occur in the biology of thefailing cardiac myocyte include 1) cell hypertrophy 2) changes in excitation-contraction coupling leading to alteration in thecontractile properties of the myocyte 3) progressive loss of myofilaments 4) beta-adrenergic desensitization 5) abnormalmyocardial energetics secondary to mitochondrial abnormalities and altered substrate metabolism and 6) progressive lossand/or disarray of the cytoskeleton. Changes within the ECM constitute the second important myocardial adaptation thatoccurs during cardiac remodeling and include changes in collagen content, the relative contents of different collagen subtypes,collagen cross-linking, and connections between cells and the extracellular matrix via integrins.5


VADs

Since hemodynamic overload is regarded as one of the mosprominent stimuli for maladaptive remodeling, VADs are aeffective mean to induce reverse remodeling.46 It has beedemonstrated that the powerful mechanical unloading of thLV offered by VADs, accompanied by increments in dosages oHFmedication which can then be tolerated by the HF patientscan be a major contribution towards the process of myocardial recovery during mechanical support.47,48 A number oreports have demonstrated the effect of VAD therapy ocellular and subcellular reverse remodeling. One prominenfeature of reverse remodeling in VAD-supported hearts iregression of myocyte hypertrophy and cell lengths and thiwas associated with echocardiographically documented reduction in LV dimensions and LV mass.49,50 FurthermoreLVADs are capable of enhancing long chain acylcarnitines usin the failing heart, which is indicative of a recoverinmyocardial metabolism.51 However, this improvement onlallows for successful explanation of the LV-VAD in 1–2% opatients.52–54

Revascularization

There is extensive clinical trial-based evidence supporting thpotential for reverse remodeling in patients with chronic H

who have received surgical interventions.21 Significant improvement in systolic function in the days and weeks aftemyocardial infarction, as well as the potential for recoverafter revascularization for patients with myocardial stunninor hibernation is observed.55,56 Both medical and catheterbased revascularization techniques have been associatewith significant rates of reverse remodeling following acutmyocardial ischemia in patients with chronic ischemiheart disease.57–59 More viable myocardial segments indcate a greater likelihood of improved LV function followinrevascularization.60

Life style

Relatively high rates of myocardial recovery and improveLVEF have also been associated with the discontinuation oethanol. One of the largest series indicated a >50% rate omyocardial recovery following cessation of ethanol use and6-fold better survival with abstinence compared with ongoinheavy ethanol use.61 Additionally, long-term moderate exercise training has been shown to induce reverse remodeling ipatients with stable chronic HF.62

Additionally, there are indications that several other (lesor more experimental) therapies can influence LV remodelinsuch as mitral clipping, intravenous iron substitution, kidnetransplantation, etc.63–66

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Table 2 – Average change in LVEF in response to HeartFailure therapies compared to placebo

Intervention

Change inLVEF(95% CI)

Mean WeeksFollow up(range)

Beta Blockers- Bisoprolol81 12.0 (4.4 to 19.6) 52- Carvedilol82–103 6.9 (5.8 to 8.0) 30 (13–52)- Metoprolol104–107 4.5 (1.8 to 7.1) 26 (24–26)

ACE-inhibitors/ARB- Captopril108–112 3.3 (0.3 to 6.4) 37 (12–52)- Enalapril28,113–117 3.7 (1.5 to 5.9) 24 (4–52)- Valsartan29 1.3 (0.7 to 1.9) 78- Candesartan118 4.0 (0.5 to 7.5) 26

Aldosterone receptorantagonist31–33

3.0 (1.9 to 4.1) 26 (8–52)

Cardiac resynchronizationtherapy (CRT)119–122

2.7 (1.9 to 3.5) 21 (6–26)

- MIRACLE-ICD35 2.1- CARE-HF35 6.9- REVERSE36,37 3.8- MADIT CRT38 11- CONTAK CD121 5.1- PATH CHF123 24


Current literature on management strategies opatients with HFrecEF

There remains to be a lack of prospective data to guide thmanagement of patients with improved LVEF or myocardiarecovery. There is a paucity of evidence on treatmenstrategies for patients with an LVEF in the grey zone of 4050% (HFmrEF) or full recovery (LVEF ≥ 50%).

Pharmocotherapy

The persistent abnormalities in biomarker profile in thespatients lend weight to the hypothesis that HF pharmacotherapy should be continued.67 However, there are nprospective data to support this approach and data olong-term use of neurohormonal medications in HF recoverepatients are lacking. Only small studies studied the effects owithdrawal of medication in stable HF patients with recovered LVEF.68 Swedberg et al. withdrew BBs from 15 patientwhose HF had improved (mean LVEF 46 ± 3%).69 Echocardiography demonstrated an overall reduction in LVEF from 46 ±3% to 35 ± 3% (p < 0.01) after a mean of 72 days followinbeta-blocker withdrawal. Clinical features of HF recurred inof the 15, with 1 sudden death. In a retrospective cohort studof 42 patients with dilated cardiomyopathy and improveLVEF (LVEF ≥ 40%), medication cessation was the only identfied predictor of recurrence.70 A retrospective cohort study o85 patients with LVEF recovery > 45% evaluated outcomafter LV recovery with no changes in baseline medicapharmacotherapy.71 Thirty-three patients (39%) developedrecurrence of LV systolic dysfunction. When divided by thpresence or absence of recurrence of systolic dysfunctionboth groups had comparable ACEIs/ARBs but a trend towardlower BBs and AAs. Therefore, in the absence of more robusprospective data, these studies suggest potential benefit ocontinuation of standard guideline recommended HF medcations in patients with HF and myocardial recovery.

Cardiac device therapy

Discontinuation of biventricular pacing in patients witimproved or even normalized LVEF is contraindicated. Onstudy in patients with mean LVEF 40 ± 15% showed thadiscontinuation of CRT during 4 weeks resulted in a rapid anprogressive decline in LVEF (after 1 week 33 ± 14% and afterweeks 30 ± 12%) and increases in LV dimensions.72 Regardinthe indication for CRT implantation, a large gap in evidencexists in patients with an LVEF of 35–50%. One small pilostudy looked at the effects of CRT in patients with only mildlreduced LVEF beyond the current indications for CRT (n = 15LVEF 40 ± 2%).73 Biventricular pacing resulted in significanincrease in LVEF and decrease in dyssynchrony. Patientreported a significant reduction in NYHA class, however,this results in an improvement of mortality and hospitalization rates is unclear. The MIRACLE EF (clinicaltrials.goidentifier: NCT01735916) and MADIT-ASIA (ClinicalTrials.govIdentifier NCT01872234) trials were designed to addrespatients with HFmrEF, but both trials have been halted du

to difficulties with enrolment. Therefore, up until now, fonew implantation of cardiac devices current guidelineshould be followed and these exclude HFmrEF with lefbundle branch block patients as well as patients witcomplete myocardial recovery if there is no additional pacinindication.

Patients with complete myocardial recovery after CRT ara specific subset of HFrecEF patients since these patients onldemonstrated full recovery after CRT and not under optimamedical therapy. Currently a randomized prospective cohorstudy is investigating if neurohumoral blockers can safely bwithdrawn in CRT patients with fully recovered hearfunction (clinical trial.gov identifier NCT02200822).

Additionally, many HF patients with implantablcardioverter-defibrillator (ICD) have an improved LVEF at thmoment of battery change and therefore do not fulfianymore guideline criteria for an ICD. In one study amon91 patients undergoing ICD generator exchange, 25 had LVEimprovement of at least 10% greater than 35%. The incidencof appropriate ICD shocks was the same between individualwith or without recovery.74 In a cohort of 231 Veterans affairpatients, 26% no longer met guideline indications for ICDtherapy at the time of generator exchange.75 Subjects withouongoing ICD indication received a smaller number of appropriate ICD therapies than patients with indications (2.8 v10.7% annually, p < 0.001), but again, appropriate shocks werdelivered in HF patients with myocardial recovery. Othestudies report similar observations.75,76,77 However, onlysubstudy of the MADIT-CRT trial investigated the prevalencof arrhythmias in HF patients with myocardial recovery to aLVEF ≥ 50%. The investigators observed that only one ventricular arrhythmia event among 55 subjects occurred antherefore suggested that these patients could be considerefor downgrade from CRT-defibrillator to CRT-pacemaker athe time of battery depletion, if the device was placed i

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primary prevention and ventricular arrhythmias have nobeen detected during the life-span of the device.78

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Clinical implications and management of patientwith myocardial recovery

Many patients with HFrEF have some degree of myocardiarecovery or improvement in LVEF. In our daily clinicapractice, we will encounter more and more patients witHFrecEF. Although prognosis of these patients is better thaHFrEF and HFpEF patients, outcome is not normal anperiodic follow up with echocardiographic assessment of Lfunction remains necessary.67 Until prospective data iavailable, pharmacotherapy and device therapy as for HFrEpatients should be continued/applied. Should there bereason to withdraw medication following recovery of function, periodic screening of LV function remains necessary tensure stability of cardiac function. In case of batterdepletion of a ICD, a limited amount of evidence suggestthat in patients with a LVEF ≥ 50% a downgrade is justifiedno prior arrhythmias have been detected.

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Conclusions

Future research should focus at identifying the best diagnostic and treatment strategies. A one-size-fits-all approach fodrug development andmanagement strategies in HF patientswhere patients with persistent reduced LVEF and myocardiarecovery (HFrecEF) are combined, should be replaced bindividualized strategies. Therefore, prospective randomizestudies looking at the potential of therapy withdrawal otherapy selection and specific (laboratory or imaging) biomarkers of recovery are urgently warranted.

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Statement of Conflict of Interest


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R E F E R E N C E S

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ScienceDirect


A Blueprint for the Post Discharge Clinic Visit after an
Admission for Heart Failure
,

Aaron Soufer, Ralph J. Riello, Nihar R. Desai, Jeffrey M. Testani, Tariq Ahmad⁎

Section of Cardiovascular Medicine, Department of Internal Medicine, Yale New Haven Hospital, Yale University School of MedicineNew Haven, CT, United States


Funding sources: This manuscript was⁎ Correspondence to: Tariq Ahmad, MD, M

New Haven, CT 06520, United States.E-mail address: [email protected] (T

http://dx.doi.org/10.1016/j.pcad.2017.08.000033-0620/© 2017 Published by Elsevier In

A B S T R A C T

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The immense symptom burden and healthcare expenditure associated with heart failur(HF) has resulted in hospital systems, insurance companies, and federal agencies playinclose attention to systems of care delivery. In particular, there has been a large extent ofocus on decreasing the frequency of HF readmissions through the development of hospitaquality measures and the expansion of post discharge services to improve transitions ocare from the inpatient to the outpatient setting. The post discharge clinic visit (PDV) servean important role in this process as it acts as a fulcrum for the multi-disciplinary serviceavailable to HF patients, as well as an opportunity to fill any gaps that might have occurrein evidence based care of the patient. The objective of this review is to provide a blueprinfor the PDV that will allow clinicians to construct the key elements of the PDV inpatient-centered fashion that is firmly rooted in the guidelines.

© 2017 Published by Elsevier In

Decompensated heart failureChronic careClinic management

Contents

8899112244566

Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23The Post Discharge Visit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23Preparing for the PDV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23History and physical examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23Comorbidities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24Laboratory tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24Medication reconciliation and optimization of GDMT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24Defibrillators/pacemakers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24Coronary artery and valvular disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24Lifestyle modification and self-care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24Consideration of advanced therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24End of life care. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

funded internally by the Yale University Section of Cardiovascular Medicine, New Haven, CT.PH, Section of Cardiovascular Medicine, Yale School of Medicine, 135 College Street, Suite 230,

. Ahmad).

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Abbreviations and Acronym

ACE-I = Angiotensin ConvertingEnzyme Inhibitors

ARNI = Angiotensin ReceptorNeprilysin Inhibitor

CMS = Centers for Medicare andMedicaid Services

CRT = cardiacresynchronization therapy

GDMT = guideline directedmedical therapy

HCS = health care system

HF = heart failure

ICD = implantablecardioverter defibrillator

LVEF = Left VentricularEjection Fraction

LOS = length of stay

PDV = Post Discharge Visit

SGLT-2 = sodium-glucosecotransporter-2 inhibitors


Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24Statement of conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . 24References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

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Background

As would be readily apparent tomostwhoreathis review, heart failur(HF) is a health carissue of enormous proportions, both in termof patient suffering, ancosts to the health carsystem (HCS).1 The syndrome we call HF is aamalgam of several disease states, with somcommonalities that include dysregulation iseveral key moleculapathways that lead timpairments in thbody's ability to fulfiit's own metabolic de

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mandsandmaintain euvolemia.2 This lea physiologic “tipping point” with ease, and being hospitalized foissues such as worsening renal function and volume overloadThese are relatively frequent, with published data putting 30 dareadmission rates at 26% –42%,dependingonnumerousmodifiabland fixed risk factors.3 Due to their enormous impact on the HCSthemetric ofHF readmissions is publicly reportedby theCenters foMedicare andMedicaid Services (CMS) and included in the HospitaReadmission Reduction Program, which financially penalizes hospitals for excess readmissions, closelymeasured by entities such aHCSandtheCMS.4–6Severalprogramshavebeenpiloted todecreasreadmission rates, with one key intervention being thpost-discharge follow up visit (PDV).7,8

The PDV is a key point in the transition of care from thinpatient to the outpatient setting and serves as a fulcrum fokey multi-disciplinary services available to HF patients. Thivisit is not only a time slot for patients to be medicalloptimized, but serves as an opportunity to frame a diseasstate within the context of an individual patient, and trecalibrate goals of patient care aimed towards alleviation osymptoms, reduction in risk of readmissions, and thimprovement of quality of life (QoL) and outcomes. Howeveas shown in Fig. 1, much can go wrong in the post dischargperiod for the HF patient, who is particularly susceptible tfailed opportunities in management due to complexity of thsyndrome. The goal of this review is to serve as guide fophysicians and advanced practice providers to construct the keelements of the PDV in a targeted―and importantlpatient-centered fashion―by reviewing the currently recommended best practices for this vulnerable patient populationTo utilize our blueprint in the clinical setting, we have als

created a PDV checklist that can be printed and used to streamlinthe appointment (Fig. 2).

The Post Discharge Visit

Both theU.S. and European guidelines recommend close followuafter discharge, with a 2-week period considered ideal.10,11 Thesrecommendations are based on observational data includinglandmark 2010 study byHernandez and colleagues demonstratinthat participation in early discharge follow up programs for Hpatients can lead to reductions in30 day readmission rates.8 Thesstudies have also noted several issues with the immediatpost-discharge care ofHFpatients, including substantial variationin the timing of follow-up, infrequent involvement by a cardiologist, lack of familiarity with what occurred during the hospitalization, and inadequate involvement of transition care teamsFurthermore, even when appropriate follow up visits are performed, several key interventions that might improve outcomemight be overlooked. This has led to the realization thatsomewhat protocolized approach to the post discharge HF patienmight be necessary.7

Whereas the structure of PDV can vary between medicacenters, depending on the resources available, we believe thathe following key components should be considered:

• Evaluation by a cardiologist, or an advanced practice provideunder thesupervisionofacardiologist (ideally, aHFcardiologist• Evaluation by a pharmacist

• Thorough physical examination, with vital signs, bloopressure (BP) measurement, weight, jugular venous pressure assessment, and evaluation for edema.

• Measurement of laboratories including basic metabolipanel, hepatic function testing, and brain natriuretipeptide (BNP) levels.

• Medication education, reconciliation, and uptitrate/adguideline recommended medical therapies as tolerated.

• Review need for device therapies [e.g. implantablcardioverter-defibrillator(ICD)/cardiacresynchronization therapy (CRT)].

• Individualized HF disease education emphasizing selmaintenance, self-monitoring, and self-management.

• Coordination of outpatient health care resources (e.gsocial work and home health aides).

• Assessment of need for advanced therapies and goals ocare discussion.

With the caveat that HF is a heterogenous syndrome, aneach patient's needs are likely to be unique, we believe thatuniversal protocol as we present in Fig. 2 can serve asblueprint for personalized care, and for the purposes oreducing errors or oversights.

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Preparing for the PDV

As is the case for any clinic encounter, providers should preparprior to the PDV by reviewing the patient's cardiovascular angeneralmedical history, with special attention paid to the hospitacourse and discharge summary. Although this is the routine for apatients discharged from the hospital for any medical conditionthe evaluation of a HF patient ought not to miss key questions:

• Is this a new diagnosis of HF or an exacerbation ofknown condition?

• Does thepatient have preserved or reduced systolic function• What work up has been performed to investigate thetiology of the patient's cardiomyopathy?

• What precipitated the patient's HF exacerbation? Havthese precipitating factors been addressed?

• Was the patient discharged on an appropriate medicaregimen? Are follow up laboratories needed to monitothe safety of these treatments?

• Was the hospital course complicated (i.e., requirement foinotropes, worsening kidney function, extended length ostay (LOS), inability to completely decongest the patient)

Ideally these questions can be answered by review ohistorical records, but communication with the discharginprovider might be helpful if this information is not at hand

Fig. 1 – Prominent factors impeding trans

Answering these key questions prior to the visit allows thprovider to anticipate the needs of each individual patienand helps to avoid redundancy in diagnostic workup antherapeutic interventions.

History and physical examination

When evaluating a patient after discharge, the symptoms thainitially prompted hospitalization should be explored, and thprovider should verify that these symptoms have subsidedTypical symptoms of HF exacerbation include dyspneaorthopnea, paroxysmal nocturnal dyspnea (PND), loweextremity edema, and weight gain.12 Every office physicaexam should also include assessment of vital signs includinweight, and orthostatic vital signs when appropriate. Thcardiovascular response to the Valsalvamaneuver is a simpleinexpensive, and highly specific bedside test for estimation ovolume status and detection of left ventricular (LV) systolidysfunction in patients with HF. With the blood pressure cufinflated 15 mm Hg over the systolic pressure, the patient iasked to perform a Valsalva maneuver. A normal response iwhen Korotkoff sounds are audible only at the onset ostraining and at release. In patients with HF and volumoverload, Korotkoff sounds can be heard throughout thValsalva maneuver (the square wave response). I

ition of care in chronic heart failure care.3

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Fig. 2 – Printable Yale heart failure discharge follow-up checklist.


compensated HF the pattern results in a lack of reappearancof the sounds after release (the absent overshoot responseOther key physical exam maneuvers to assess volume statuinclude estimation of jugular venous pressure (JVP) througneck vein inspection and the abdominojugular reflux test.1

The third heart sound (or gallop rhythm) is commonly presenwith tachycardia and volume overload and signifies severhemodynamic compromise and elevated left-sided filling pressures. It is important to remember that signs of pulmonarcongestion such as rales and pulmonary edema may be lackinin patients with chronic HF and elevated pulmonary capillarwedge pressure. Supplemental exam items include generaappearance, cardiac auscultation to evaluate for murmurs, Sand pericardial friction rubs, and evaluation for abdominal ascitesWeight loss isoftenneglectedasacauseofHF, but it canbepresendue to cardiac cachexia. Lastly, if the etiology of the HF remain

unclear, an exam focused on clues as to the underlying causshould be undertaken (e.g. amyloid).

It is widely accepted that the history and physical exam playcentral role in evaluating the stability of patients and gauging thappropriateness for diuretics and neurohormonal titration. Wshould, however, be cognizant of the limitations of this approacfor clinical decisionmaking.13 Several definitive studies have showthat physical exam findings lack profoundly in sensitivity anspecificity for the purpose of intravascular volume status appraisathe sine qua non for management of patients with HF.14,1

Furthermore, even right heart catheterization based hemodynamimeasurements— mistakenly considered a test for assessment ovolume—use intra-cardiac chamber pressures as a surrogate fointravascular volume, a relationship that has repeatedly beedemonstrated to be weak, and may partly explain the results othe ESCAPE trial that failed to show the benefit of titration t

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hemodynamic goals.14,16,17 As a result, management for patientwith volume overload remains heterogeneous and a sizeablpercentage of patients are inadequately treated.18 It is expectethat in the future, improveddiagnosticswill help cliniciansmeasurvolume status in amanner that is precise and accurate. Until thenweshould interpretexamfindings incontextofcomprehensivedaton the individual patient, rather than standalone information.

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Comorbidities

The PDV serves as an opportunity to identify conditions that aroften associated with HF, such as sleep apnea, hypertensionhyperlipidemia, and anemia. Table 1 highlights key comorbiconditions that shouldbeconsideredwhile caring for theHFpatienand interventions performed with a clear understanding of thcutting-edgedataon their efficacy, as theseare constantly changinFor example, while it is reasonable to refer HF patients for a formasleepstudy toestablishadiagnosisof sleepapneaand todistinguisbetween a central and obstructive process, data from randomizecontrolled trials in regards to the most appropriate treatment fosleep apnea in HF have recently cast uncertainty on acceptewisdom, and positive pressure ventilation might not be universallhelpful.19 Other examples include recent findings of intravenouiron replacement being efficacious in HF, but not the per os formand the new sodium-glucose cotransporter-2 inhibitors (SGLT-2)―novel diabetic therapies ― having a potential role in improving Hrelated outcomes in diabetics.20–22

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Laboratory tests

Laboratory studies provide a key role in the transition of carfrom the inpatient to the outpatient setting. Most often thi

Table 1 – Therapeutic implications of comorbid conditions du

Comorbidcondition

Treatment implications

Angina • Consider nitrates, and ivabradine• Referral for assessment and treatment of ischemic

Dyslipidemia • No data for initiation of statins• Continue if already on statin

Hypertension • Avoid non-dihydropyridine CCB and alpha blockadBP control if on max evidence based therapy.

• ACE-I/ARB/ARNI/beta-blocker/MRA are first line inCOPD • Can interfere with the diagnostic processSleep apnea • Diagnose CSA versus OSA

• Refer to sleep specialist for treatmentDiabetes • Consider metformin, SGLT2 inhibitors

• Avoid glitazonesRenaldysfunction

• Can limit use of ACE-I/ARB/ARNI/AA• Worsens prognosis from HF• Co-management with nephrologist

Cancer • Consider potential cardiotoxicity of cancer therapi• Serial ECG, imaging, and biomarkers of myocardia

Anemia • Intravenous ferric carboxymaltose for iron deficienArthritis • Avoid NSAIDs and COX-2 inhibitors

CCB = calcium channel blocker; BP = blood pressure; ARNI = angiotensSodium-glucose co-transporter 2; NSAID = Nonsteroidal Anti-inflamm

includes a simple “metabolic panel or chem 7” to follow up orenal function and electrolytes when patients are continueon diuretics post discharge, but initial workups should bmore thorough, as shown in Table 2. Electrolytes should bchecked and replenished in these patients, with specifiattention paid to potassium. If patients are on daily diureticsthen standing electrolyte repletion can be considered depending on serum electrolyte levels and medication interactions with potassium sparing agents. Electrolytes should alsbe checked if patients are started on angiotensin convertinenzyme inhibitors (ACEI), angiotensin receptor blockers (ARBangiotensin-neprilysin inhibitor (ARNIs) or mineralocorticoiantagonists prior to discharge, as these agents can affecserum potassium concentration and creatinine. Underlyindisorders that can cause an exacerbation of HF, and aramenable to monitoring via laboratory testing should bordered during the PDV (Table 2).

Circulating biomarkers, specifically BNP levels, are centrato the diagnosis and prognostication of HF patients in botthe inpatient and outpatient settings.2 Either (BNP)or itprecursor N-Terminal (NT)-pro BNP are readily measurablat laboratories within most HCS. During the clinic visitesting of natriuretic peptides―either BNP or NTproBNP―arrecommended by the American College of Cardiology(ACCAmerican Heart Association(AHA) for (a) Support of clinicadecision making regarding the diagnosis of HF, especially ithe setting of clinical uncertainty, (b) For establishing prognosis or disease severity in chronic HF, and (c) To achievoptimal dosing of guideline directed medical therapy (GDMTin select clinically euvolemic patients followed inwell-structured disease management program.23 The toline results of GUIDE-IT were recently published and showeno significant difference in outcomes with NT-proBNP guidetherapy versus usual care. However, the results do no

ring the follow up visit.

heart disease

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definitively address the question the trial sought to address athere were no significant differences in biomarker levelbetween patients randomized to either strategy.24 Other2

biomarkers of injury (troponin) and fibrosis (serum ST2galectin-3) can be considered to further fine-tune risstratification.26

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Imaging

All relevant imaging studies from the inpatient admissioshould be reviewed including electrocardiograms (ECGechocardiograms, chest radiography, cardiac catheterizatiodata, and nuclear imaging. The role of obtaining new imaginstudies during the post discharge follow up is useful in seleccircumstances. If there was no ECG obtained during hospitaization and the patient has a new diagnosis of heart failurethen an ECG should be obtained during the post dischargfollow up (Table 2). A follow up ECG should be obtained at thPDV if there was a notable rhythm disturbance or myocardiainfarction during the index hospitalization, or if the patienhas any new cardiac complaints in the office. In general, chesradiography should be reviewed from the index hospitalization. Further chest imaging is not necessary unless a patient'symptoms have worsened and there is suspicion of worsening pulmonary edema, or if there were persistent signs ovolume overload on chest radiography prior to discharge, ana repeat study would help to evaluate for stability oimprovement of these findings. Transthoracic echocardiography (TTE) should have been obtained for any new diagnosis oHF during the index hospitalization. If a TTE was noperformed while in the hospital for a new diagnosis of HFthen one should be obtained in the post discharge follow uvisit to assess LV ejection fraction (LVEF), LV wall thicknessLV size, wall motion, right ventricular function, pulmonarpressures, and valvular function. Alternatively, especially ithe absence of prior imaging, cardiac magnetic resonancimaging (MRI) can provide superior temporal and contrasresolution, and can serve as an alternate, especially in caseof newly diagnosed cardiomyopathy of unclear etiology.there is lingering suspicion for ischemic heart disease, stresimaging using TTE, Positron emission tomography (PETsingle photon emission computed tomography (SPECT), ocardiac MRI should be pursued, depending on patient ancenter specific characteristics. Nonetheless, in cases of higpre-test probability for ischemic heart disease, it is reasonablto proceed with coronary angiography.10

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Medication reconciliation andoptimization ofGDMT

Adverse drug reactions are a commoncomplicationof preventablmedication errors that increase hospital admission rates anprolonged LOS.27 PatientswithHF,who are likely to be onmultiplmedications, and are susceptible to frequent transitions of careare especially prone to these errors, and may be discharged oinappropriate therapies. In order to prevent this, the JoinCommission incorporated new requirements for safe transition

of care for HF in 2011, updated comprehensive medicatiomanagement performance standards in 2017, and endorsenational patient safety goals to maintain and communicataccurate patient medication information across continuumof care.28 The initial post discharge encounter is thereforegreat opportunity to optimize HF medication management ialignment with regulatory quality of care benchmarks anevidence-based treatment recommendations (Table 3). Performinpatient-centered medication reconciliation, as a component omedication therapymanagement, entails a thoroughevaluationoexisting andpreviousmedication regimens at each care transitionPrudentmedication adjustment tomitigate prescribing errors anassessment of medication compliance is central to thorougreconciliation. The appropriateness of new medication regimechanges should be corroborated with hospital discharge summaries and the latest expert consensus disease state managemenguidelines; this is especially the case in HF with reduced LVEFwhere the pharmacologic armamentarium is broad (Fig. 3). Thasaid, even strong, high quality level of evidence recommendationneed to be weighed against individualized patient characteristicFor example, if prescription drug insurance copayments exceepatients' ability to pay, for example, following recent guidelinupdates to switch from an ACEI or ARB to an ARNI may requirreconsideration.29

Beyond appropriate agent selection and monitoring, optmization of medication dosing is also a critical component oearly discharge HF management, an opportunity that ifrequently missed in clinical practice.30 This is a point of keimportance, as familiarity with guideline-recommended target treatment doses and reasonable up-titration schedules icrucial for HF patients to derive maximal morbidity anmortality benefit (Table 3).31

The PDV also enables a reassessment of fluid status ansubsequent adjustment of loop diuretics when indicatedEscalating loop diuretic doses, switching to more potent obetter absorbed diuretics, and adjunctive use of thiazide-likdiuretics may be necessary to maintain adequate decongestion in the early discharge period, particularly if diuretiresistance or poor dietary compliance has occurred oncoutside of the hospital environment. Recognizing thespatients during the early post-discharge period may prevenan avoidable hospital readmission. Referral to an ambulatorintravenous diuretic infusion clinic rather than hospitalization may also be warranted for patients with worsening HF.3

Patient and caregiver education is also essential to thpost-acute care encounter. Teaching common adverse drueffects, proper administration schedules, and self-care technique can improve patient engagement and regimecompliance.33 Improving adherence to HF medications antherapeutic patient education performed by trained pharmacists can decrease hospital readmission rates and reducmortality.34,35 Studies have supported the premise thapharmacists' delivery of tailored, health-literacy sensitivcounseling and medication reconciliation services can hava meaningful impact on healthcare outcomes in HF.1

Specifically, clinical pharmacists as part of an outpatient Hclinic can perform medication reconciliation, perform therapeutic drug monitoring for agents like digoxin, screen foclinically significant drug-drug interactions, and educat

Table 2 – Clinical Implications of Laboratory Abnormalities and Electrocardiogram Findings in HF Patients.

Abnormality Causes Clinical implications

Renal/kidney impairment(creatinine >150 μmol/L/1.7 mg/dL,eGFR <60 mL/min/1.73 m2)

Renal diseaseRenal congestionACE-I/ARB/MRADehydrationNSAIDs and other nephrotoxic drugs

Calculate eGFRCheck potassiumand BUNConsider reducingdiuretic dose if dehydrated,but if renal congestion morediuresis may helpReview drug therapyIf renal function worsenedsignificantly near RAASinitiation/titration,consider discontinuationor dose reduction

Anemia(<13 g/dL/8.8 mmol/L in men,<12 g/dL/7.4 mmol/L in women)

Chronic HF, hemodilution,iron loss or poor utilization,renal failure, chronic disease, malignancy

Diagnostic work-upConsider treatment

Hyponatremia (<135 mmol/L) Chronic HF, hemodilution, AVP release,diuretics (especially thiazides) and other drugs

Consider water restriction,adjusting diuretic dosageVasopressin antagonist(no good outcome data)Review drug therapy

Hypokalemia (<3.5 mmol/L) Diuretics, secondary hyperaldosteronism Risk of arrhythmiaConsider ACE inhibitor/ARB,MRA, potassium supplements

Hyperkalemia (>5.5 mmol/L) Renal failure, potassium supplement,renin–angiotensin–aldosterone system blockers

Stop potassiumsupplements/potassium-sparingdiureticConsider potassium binding resinReduce dose of/stopACE inhibitor/ARB, MRAAssess renal function and urine pHRisk of bradycardia andserious arrhythmias

Hyperglycemia (>6.5 mmol/L/117 mg/dL) Diabetes, insulin resistance Evaluate hydration,treat glucose intoleranceSGLT-I

Hyperuricemia (>500 μmol/L/8.4 mg/dL) Diuretic treatment, gout, malignancy AllopurinolReduce diuretic doseSGLT-I

Albumin low (<30 g/L) Poor nutrition, renal loss Diagnostic work-upDiuresis

Elevated bilirubin Liver dysfunctionLiver congestionDrug toxicity

Diagnostic work-upLiver congestionReview drug therapy

Elevated troponins Myocyte necrosisProlonged ischemia,severe HF, myocarditis, sepsis, renal failure

Evaluate pattern of increase(mild increases common in severe HF)Perfusion/viability studiesCoronary angiographyEvaluation for revascularization

Elevated creatine kinase Inherited and acquired myopathies (including myositis) Consider genetic cardiomyopathy(laminopathy, desminopathy,dystrophinopathy),muscular dystrophiesStatin use

Abnormal thyroid tests Hyper−/hypothyroidismAmiodarone

Treat thyroid abnormalityReconsider amiodarone use

Urine analysis Proteinuria, glycosuria, bacteria Diagnostic work-upRule out infection, diabetes

International normalized ratio > 3.5 Anticoagulant overdoseLiver congestion/diseaseDrug interactions

Review anticoagulant doseAssess liver functionReview drug therapy

(continued on next page)


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Table 2 (continued)

Abnormality Causes Clinical implications

CRP >10 mg/L, neutrophilic leukocytosis Infection, inflammation Diagnostic work-upSinus tachycardia Decompensated HF, anemia,

fever, hyperthyroidismClinical assessmentLaboratory investigation

Sinus bradycardia Beta-blockade, digoxin, ivabradine,verapamil, diltiazemAntiarrhythmicsHypothyroidismSick sinus syndrome

Review drug therapyLaboratory investigation

Atrial tachycardia/flutter/fibrillation Hyperthyroidism, infection,mitral valve diseaseDecompensated HF, infarction

Slow AV conduction,anticoagulation,pharmacological cardioversion,electrical cardioversion,catheter ablation

Ventricular arrhythmias Ischemia, infarction, cardiomyopathy,myocarditis, hypokalemia, hypomagnesemiaDigitalis overdose

Laboratory investigationExercise test,perfusion/viability studies,coronary angiography,electrophysiology testing, ICD

LV hypertrophy Hypertension, aortic valve disease,hypertrophic cardiomyopathy

Echocardiography/CMR

Low QRS voltage Obesity, emphysema,pericardial effusion, amyloidosis

Echocardiography/CMR,chest x-ray, for amyloidosisconsider further testing(CMR, 99mTc-DPD scan)andendomyocardial biopsy

QRS duration ≥120 ms andLBBB morphology

Electrical and mechanical dyssynchrony EchocardiographyCRT-P, CRT-D

ACE, angiotensin-converting enzyme; ARB angiotensin-receptor blocker; AV, atrioventricular; BUN, blood urea nitrogen; CMR, cardiac magneticresonance; CRP, C-reactive protein; CRT-P, cardiac resynchronization therapy with pacemaker; CRT-D, cardiac resynchronization therapy withdefibrillator; eGFR, estimated glomerular filtration rate; ICD, implantable cardioverter defibrillator; LBBB, left bundle branch block; MRA,mineralocorticoid receptor antagonist; NSAIDs, nonsteroidal anti-inflammatory drugs; RAAS, renin-angiotensin-aldosterone system; SGLT-2,Sodium-glucose co-transporter 2.52


patients about their medications. Furthermore, they cafacilitate prior authorization requirements for third partpayers and navigate prescription cost savings programs.

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Defibrillators/pacemakers

It is important to be mindful of the candidacy for ICD and/oCRT in HF patients. The post discharge follow up visits is aopportunity to determine appropriateness of these therapieon an individual patient basis. Patients with reduceLVEF < 35% are at high risk for sudden cardiac death, andis crucial to consider the risks and benefits of ICD therapy aprimary prevention in these patients. If the index hospitalzation was in the setting of myocardial infarction with newlidentified LVEF < 35%, then repeat evaluation of LVEF shoulbe performed after 40 days while on of GDMT, and afte3 months in patients with non-ischemic cardiomyopathy.the LVEF remains <35% after this interval, ICD therapy shoulbe considered in patients with New York Heart Associatio(NYHA) class II-III symptoms and survival predicted to b>1 year. Wearable external cardiac defibrillators can bconsidered in high risk patients in the interim period betweeinitial and follow up evaluation of LVEF, but their cost to th

patient should be considered prior to prescription.36 Addtionally, CRT is another consideration in patients with NYHclass II, III or ambulatory IV HF, LVEF < 35% and left bundlbranch morphology QRS complex with duration ≥150 ms.3

We recommend that practitioners download the GuidelinClinical App (https://www.acc.org/tools-and-practice-suppormobile-resources/features/guideline-clinical-app), as it cagreatly streamline the evaluation of an individual patientcandidacy for devices and other therapies.

Coronary artery and valvular disease

In patients with ischemic cardiomyopathy, revascularizatiocan be considered in select circumstances, including patientwith both preserved or reduced LVEF with continued anginwhile on optimal anti-anginal therapy. Additionally, revascularization should be considered in patients with obstructivcoronary artery disease and reduced LVEF, although targetinintervention to regions of viable myocardium remains controversial in light of the STICH trial results.38 The extent ovalvular disease should also be considered in patients witworsening HF. Whereas it is beyond the scope of the currenreview, repair or replacement of the mitral and aortic valve

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Table 3 – Guideline-directed medical therapy dosing for heart failure.

Starting dose Mean daily dose achieved in clinical trials Target dose

ACEICaptopril 6.25 mg TID 122.7 mg 50 mg TIDEnalapril 2.5 mg BID 16.6 mg 10–20 mg BIDLisinopril 2.5–5 mg QD 32.5–35 mg 20–40 mg QDRamipril 1.25–2.5 mg QD 7.7 mga 10 mg QDTrandolapril 0.5–1 mg QD 2.5 mgb 4 mg QD

ARBCandesartan 4–8 mg QD 24 mg 32 mg QDLosartan 50 mg QD 129 mg 150 mg QDValsartan 40 mg BID 254 mg 160 mg BID

ARNISacubitril/valsartan 24/26–49/51 mg BID 375 mg 97/103 mg BID

Beta-blockersBisoprolol 1.25 mg QD 8.6 mg 10 mg QDCarvedilol 3.125 mg BID 37 mg 25 mg BIDMetoprolol succinate 12.5–25 mg QD 159 mg 200 mg QDNebivolol 1.25 mg QD 7.7 mg 10 mg QD

MCREplerenone 25 mg QD 42.6 mg 50 mg QDSpironolactone 12.5–25 mg QD 26 mg 50 mg QD

VasodilatorsHydralazine/isosorbide dinitrate 20/37.5 mg TID 175 mg/90 mg 40/75 mg TID

If channel inhibitorIvabradine 2.5–5 mg BID 13 mg 7.5 mg BID

ACEI: angiotensin converting enzyme inhibitor, ARB: angiotensin receptor blocker, ARNI: angiotensin receptor-neprilysin inhibitor, MCR:mineralocorticoid receptor antagonists.a 77% of patients tolerated ramipril 5 mg BID in the HOPE trial.b 62% of patients tolerated trandolapril 4 mg QD in the TRACE trial.


depends on etiology, symptoms, and patient specific condtions; decisions should be made with current guidelines imind that discuss the nuances of clinical decision making igreat detail.39 Of note, remarkable strides in transcathetevalvular interventions are likely to change the landscape othese interventions at a rapid pace.

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Lifestyle modification and self-care

Although hospitalization poses a burden to patients and oftemarks progression of disease, it also provides an educationaopportunity that can potentially empower patients to maknecessary lifestyle modifications.40 Indeed, patient educationviewed by the ACC and AHA as a necessary aspect of propetransitions of care in HF patients. Thismay take the form of face tface education led by providers, nurses or pharmacists, but can alstake the form of flyers, videos and postings to web basedmaterial

Topics of lifestyle modifications in HF are broad, bugenerally focus in on recommendations regarding lifestylmodification including physical activity and diet. In the casof exercise, recommendations for HF patients have evolvefrom bedrest to supervised graduated exercise programs. Baseon the positive results from Heart Failure: a Controlled TriaInvestigating Outcomes of Exercise Training (HF-ACTION) tharandomized >2300 HF patients with reduced LVEF patients t

usual care versus exercise training, the ACC/AHA/EuropeaSocietyofCardiologyguidelineshave thehighest recommendatioof regular aerobic exercise in patients with HF to improvfunctional capacity and symptoms and to reduce the risk of Hhospitalization. Therefore, patients with HF with reduced LVEshould be referred to cardiac rehabilitation programs during thPost Discharge Visit.41–43

The accepted wisdom about dietary restrictions in Hlargely revolves around avoidance of salt. Despite beinrooted in outdated data and shaky clinical evidence,remains a class IIa recommendation by the AHA and ACCInformation to the contrary is emerging: recent data showethat in elderly adults, self-reported sodium restricted dietdid not affect mortality, incidence of cardiovascular diseasor HF.44 In HF patients admitted with acutely decompensateHF, aggressive sodium and fluid restriction was not associated with any change in weight loss or readmission withi30 days, but was accompanied by increased thirst.45 Furthermore, a sodium restricted diet of <2500 mg per day in Hpatients with NYHA class II–III symptoms was associatewith higher rate of hospitalization over 36 months.46 Givethe lack of definitive data from a clinical trial, for now it ireasonable to discuss sodium intake with patients anconsider moderation of sodium intake to <3 g per day ipatients with stage C and D heart failure, based on thenational average of 4 g sodium intake per day.47

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Fig. 3 – Guideline recommendations for patients with HF with reduced ejection fraction, adapted from the ESC guidelines.10


Even with teaching from and contact with healthcarprofessionals, active involvement of patients in the management of their disease is important in ensuring goooutcomes.48,49 Three different components make up patienself-care: maintenance, monitoring, and management. Maintenance involves adherence to medication and lifestylchanges, while monitoring of the signs and symptoms of HFSelf-care management means responding appropriately tany changes in symptoms—for example, by increasing thdose of medications prescribed for use as needed.

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Consideration of advanced therapies

A subset of patients with HF will continue to have symptomand rapid disease progression despite being on maximalltolerated GDMT, and may even need down titration oneurohormonal blockade.50 These patients are referred to ahaving stage D HF and their treatment options are limited t

advanced treatment strategies, such as mechanical circulatorsupport (LV Assist Device), continuous inotropic infusioncardiac transplantation, and hospice. Objective evidence oend stage HF should be sought in patients suspected to neeadvanced therapies via right heart catheterization or cardiopulmonary exercise testing.

End of life care

HF remains a chronic disease without a cure for the cleamajority of patients. Thus, it is imperative for caregivers tdiscuss goals of care and continued focus on improvement othe QoL for patients. This was highlighted by results ofrecent landmark study―Palliative Care in Heart Failur[PAL-HF]―showing that an interdisciplinary palliative carintervention in advanced HF patients consistently led tgreater benefits in QoL, anxiety, depression, and spirituawell-being compared with usual care alone.51 Effort

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should also be made to have honest discussions about thrisks and benefits of aggressive medical therapies, especiallin circumstances of advanced illness. There will be a time ithe disease course of many chronic HF patients wheretransition to hospice will be reasonable. However, despite thdire prognosis from HF, and data showing its significanbenefit to the patient, referral to palliative care for thespatients remains rare. Therefore, we recommend thasome discussion related to palliative care be considereduring the PDV.

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Conclusion

The PDV for the HF patient is a key opportunity to make surthat the highest level of quality and evidence based care idelivered. It can serve as the basis for gauging stability of thpatient, filling in any gaps in treatment, and considerinadditional care. Furthermore, it can be a good time to engagin discussions around goals of care. When executed well,can ensure that this vulnerable population gets the bescare possible.

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Dr. Ahmad reports receiving research funding from the HearFailure Society of America and serves as a consultant foNovartis and Amgen; Drs. Riello and Soufer report no relevandisclosures. Dr. Desai is supported by grant K12 HS023000-0from the Agency for Healthcare Research and Qualityreceives research support from Johnson & Johnson througYale University; and receives funding from CMS. Dr. Testanconsults for Boehringer Ingelheim and his research is supporteby NIH 2017 K23 HL and NIH 2017 R01 HL.

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17. Gelman S. Venous function and central venous pressure: aphysiologic story. Anesthesiology. 2008;108:735-748.

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22. Lewis GD, Malhotra R, Hernandez AF, et al. Effect of oral ironrepletion on exercise capacity in patients with heart failurewith reduced ejection fraction and iron deficiency: theIRONOUT HF randomized clinical trial. JAMA. 2017;317:1958-1966.

23. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSAfocused update of the 2013 ACCF/AHA guideline for theManagement of Heart Failure: a report of the AmericanCollege of Cardiology/American Heart Association Task Forcon Clinical Practice Guidelines and the Heart Failure Society oAmerica. Circulation. 2017.

24. Felker GM, Ahmad T, Anstrom KJ, et al. Rationale and designof the GUIDE-IT study: guiding evidence based therapy usinbiomarker intensified treatment in heart failure. JACC HeartFail. 2014;2:457-465.

25. Felker GM, Anstrom KJ, Adams KF, et al. Effect of natriureticpeptide-guided therapy on hospitalization or cardiovascularmortality in high-risk patients with heart failure and reduceejection fraction: a randomized clinical trial. JAMA. 2017 Aug22;318(8):713-720.

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26. Ahmad T, Fiuzat M, Neely B, et al. Biomarkers of myocardialstress and fibrosis as predictors of mode of death in patientwith chronic heart failure. JACC Heart Fail. 2014;2:260-268.

27. LaPointe NM, Jollis JG. Medication errors in hospitalizedcardiovascular patients. Arch Intern Med. 2003;163:1461-1466.

28. Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSAfocused update on new pharmacological therapy for heartfailure: an update of the 2013 ACCF/AHA Guideline for theManagement of Heart Failure: a report of the AmericanCollege of Cardiology/American Heart Association Task Forcon Clinical Practice Guidelines and the Heart Failure Society oAmerica. J Am Coll Cardiol. 2016;68:1476-1488.

29. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSAfocused update of the 2013 ACCF/AHA Guideline for theManagement of Heart Failure: a report of the AmericanCollege of Cardiology/American Heart Association Task Forcon Clinical Practice Guidelines and the Heart Failure Society oAmerica. J Card Fail. 2017.

30. Yancy CW, Fonarow GC, Albert NM, et al. Adherence toguideline-recommended adjunctive heart failure therapiesamong outpatient cardiology practices (findings fromIMPROVE HF). Am J Cardiol. 2010;105:255-260.

31. Chin KL, Skiba M, Tonkin A, et al. The treatment gap inpatients with chronic systolic heart failure: a systematicreview of evidence-based prescribing in practice. Heart FailRev. 2016;21:675-697.

32. Zsilinszka R, Mentz RJ, DeVore AD, Eapen ZJ, Pang PS,Hernandez AF. Acute heart failure: alternatives to hospitali-zation. JACC Heart Fail. 2017;5:329-336.

33. Ha Dinh TT, Bonner A, Clark R, Ramsbotham J, Hines S. Theeffectiveness of the teach-back method on adherence andself-management in health education for people with chronidisease: a systematic review. JBI Database System Rev ImplemenRep. 2016;14:210-247.

34. Milfred-Laforest SK, Chow SL, Didomenico RJ, et al. Clinicalpharmacy services in heart failure: an opinion paper from thHeart Failure Society of America and American College ofClinical Pharmacy Cardiology Practice and Research NetworkJ Card Fail. 2013;19:354-369.

35. Komajda M, Lapuerta P, Hermans N, et al. Adherence toguidelines is a predictor of outcome in chronic heart failurethe MAHLER survey. Eur Heart J. 2005;26:1653-1659.

36. Piccini Sr JP, Allen LA, Kudenchuk PJ, et al. Wearablecardioverter-defibrillator therapy for the prevention of sud-den cardiac death: a science advisory from the AmericanHeart Association. Circulation. 2016;133:1715-1727.

37. Epstein AE, Dimarco JP, Ellenbogen KA, et al. ACC/AHA/HRS2008 guidelines for device-based therapy of cardiac rhythmabnormalities: executive summary. Heart Rhythm. 2008;5:934-955.

38. Velazquez EJ, Lee KL, Jones RH, et al. Coronary-artery bypasssurgery in patients with ischemic cardiomyopathy. N Engl JMed. 2016;374:1511-1520.

39. Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ACCfocused update of the 2014 AHA/ACC guideline for theManagement of Patients with Valvular Heart Disease: a repoof the American College of Cardiology/American HeartAssociation Task Force on Clinical Practice Guidelines. J AmColl Cardiol. 2017;70:252-289.

40. Ahmad T, Testani JM. Physical activity prevents obesity andheart failure: nowwhat are we going to do about it? JACC HeaFail. 2017;5:385-387.

41. O'Connor CM, Whellan DJ, Lee KL, et al. Efficacy and safety oexercise training in patients with chronic heart failure:HF-ACTION randomized controlled trial. JAMA. 2009;301:1439-1450.

42. Piepoli MF, Binno S, Corra U, et al. ExtraHF survey: the firstEuropean survey on implementation of exercise training inheart failure patients. Eur J Heart Fail. 2015;17:631-638.

43. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSAfocused update of the 2013 ACCF/AHA Guideline for theManagement of Heart Failure: a report of the AmericanCollege of Cardiology/American Heart Association Task Forcon Clinical Practice Guidelines and the Heart Failure Society oAmerica. J Am Coll Cardiol. 2017.

44. Kalogeropoulos AP, Georgiopoulou VV, Murphy RA, et al.Dietary sodium content, mortality, and risk for cardiovasculaevents in older adults: the health, aging, and body composi-tion (health ABC) study. JAMA Intern Med. 2015;175:410-419.

45. Aliti GB, Rabelo ER, Clausell N, Rohde LE, Biolo A,Beck-da-Silva L. Aggressive fluid and sodium restriction inacute decompensated heart failure: a randomized clinicaltrial. JAMA Intern Med. 2013;173:1058-1064.

46. Doukky R, Avery E, Mangla A, et al. Impact of dietary sodiumrestriction on heart failure outcomes. JACC Heart Fail. 2016;4:24-35.

47. Yancy CW. The uncertainty of sodium restriction in heartfailure: we can do better than this. JACC Heart Fail. 2016;4:39-4

48. Riegel B, Moser DK, Anker SD, et al. State of the science:promoting self-care in persons with heart failure: a scientifistatement from the American Heart Association. Circulation.2009;120:1141-1163.

49. Cowie MR, Anker SD, Cleland JGF, et al. Improving care forpatients with acute heart failure: before, during and afterhospitalization. ESC Heart Fail. 2014;1:110-145.

50. Russell SD, Miller LW, Pagani FD. Advanced heart failure: acall to action. Congest Heart Fail. 2008;14:316-321.

51. Rogers JG, Patel CB, Mentz RJ, et al. Palliative care in heartfailure: the PAL-HF randomized, controlled clinical trial. J AmColl Cardiol. 2017;70:331-341.

52. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelinefor the diagnosis and treatment of acute and chronic heartfailure 2012: the Task Force for the Diagnosis and Treatmenof Acute and Chronic Heart Failure 2012 of the EuropeanSociety of Cardiology. Developed in collaboration with theHeart Failure Association (HFA) of the ESC. Eur Heart J. 2012;331787-1847.



ScienceDirect


Heart Failure Transitions of Care: A Pharmacist-Led
Post-Discharge Pilot Experience
Sherry K. Milfred-LaForesta,⁎, Julie A. Geeb, Adam M. Pugaczc, Ileana L. Piñad,Danielle M. Hoovere, Robert C. Wenzella, Aubrey Feltona, Eric Guttenberga, Jose Ortizb, f

aDepartment of Pharmacy, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH, United StatesbDivision of Cardiology, Department of Medicine, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH, United StatescNational Institutes of Health Clinical Center, Pharmacy Department, Bethesda, MD, United StatesdAlbert Einstein College of Medicine, Division of Cardiology, Montefiore-Einstein Medical Center, Bronx, NY, United StateseDepartment of Medicine, VA Ann Arbor Healthcare System, Ann Arbor, MI, United StatesfCase Western Reserve University School of Medicine, Cleveland, OH, United States


Grant and industry financial support: N⁎ Correspondence to: Sherry K. Milfred-L

Center, 10701 East Blvd, Cleveland, OH 441E-mail address: [email protected]

http://dx.doi.org/10.1016/j.pcad.2017.08.000033-0620/Published by Elsevier Inc.

A B S T R A C T

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Objective To perform a pilot evaluation of a pharmacist-led, multidisciplinary transitionacare clinic for heart failure (HF) patients.BackgroundTransitions of care in HF should include: medication reconciliationmultidisciplinary care, early post-discharge follow-up, and prompt intervention on Hsigns and symptoms. We hypothesized that combining these elements with optimization omedications would impact outcomes.Methods In the SERIOUS HF Medication Reconciliation Transitional Care Clinic (HF MRTCCpatients were seen by a clinical pharmacist trained in HF. The pharmacist performemedication reconciliation, a basic physical exam, and a HF symptom history. Medicationwere adjusted by the clinical pharmacist or medical provider. Data were retrospectivelcollected for a quality improvement evaluation of this novel clinic on medicatiodiscrepancies, medications optimized, and 30-day readmissions. Descriptive statistics anpaired t-tests were used for medication doses.Results All patients (n = 135) had a diagnosis of HF, 59% were recently discharged. Thmean time from discharge to the clinic appointment was 10 ± 6 days, and the 30 daall-cause readmission rate was 9%. Medication discrepancies were detected in 53% opatients. Medications were optimized in 70%, most frequently beta blockers, ace inhibitorand diuretics. In patients with an ejection fraction ≤40%, significantly higher doses of betblockers and ace inhibitors were prescribed after the clinic visit.Conclusion The HF MRTCC identified and corrected numerous medication discrepancieup-titrated medications, and was associated with a 30-day readmission rate of 9%. Thesencouraging pilot results are hypothesis-generating and warrant further controlled trials.

Published by Elsevier In

TransitionMedication reconciliation

one.aForest, PharmD, BCPS, Department of Pharmacy, 119(w), Louis Stokes Cleveland VA Medical08, United States.(S.K. Milfred-LaForest).

5



ACE = angiotensin convertingenzyme

ADHF = acute decompensatedheart failure


CMR = comprehensive medica-tion reconciliation

CMS = Centers for Medicare andMedicaid

ED = emergency department


EMR = electronic medical record

GDMT = guideline-directed med-ical therapy

GWTG = Get With the Guidelines

H2H = Hospital to Home

HF = heart failure

HF MRTCC = Heart Failure Med-ication Reconciliation Transi-tional Care Clinic

HFSA = Heart Failure Society ofAmerica

HFpEF = heart failure with apreserved ejection fraction

HFrEF = heart failure with areduced ejection fraction

MRA = mineralocorticoid recep-tor antagonists

VA = Veterans Affairs


Contents

011234446677777

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Clinic description . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25Methods for clinic assessment . . . . . . . . . . . . . . . . . . . . . . . . . . 25Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Comprehensive medication reconciliation . . . . . . . . . . . . . . . . . . . 25Clinic structure and transitional care . . . . . . . . . . . . . . . . . . . . . . 25Role of the pharmacist . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25Authors' industry relationships . . . . . . . . . . . . . . . . . . . . . . . . . . . 25Statement of conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . 25Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

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Table 1 – Recommended components of a transitionalcare program.

• Medication reconciliation• Very early telephone contact (within 24–72 h)• Early office follow-up within 7–14 days of discharge• Clinical assessment (weight, volume status, functional status,

symptoms)• Patient education on symptom recognition and chronic self-care

behaviors

Introduction

Heart failure (HF) continues to burden thCenters for Medicarand Medicaid (CMSbudget. HF hospitalzations for American>65 years old armore prevalent thaany other medicacondition.1,2 Due tthe aging populatioand high incidencethe total costs of Hare projected to be 7billion by 2030.1 Noonly is HF the mosprevalent diagnosifor hospitalizations oMedicare recipient

potentially preventabl

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• Communication of patient health record with the patient andpost-discharge providers

• Integrated interdisciplinary collaboration and coordination• Framework that ensures education is initiated during

hospitalization and continues during initial community caresetting

• Screen patients for features that confer a higher risk for pooroutcomes (e.g. cognitive impairment, non-English speaking,long travel time to healthcare appointments)

• Ensure that health care providers are adequately trained toprovide HF education

• Allot adequate time to deliver complex HF interventions andassess patient/caregiver response

• Use health informatics to assist in program sustainability withpatient and provider-centric tools

Adapted from: American Heart Association, Inc.12

but also the highest diagnosis for30 day readmissions.3 Reducing readmission rates by 2%potentially saves more than $100 million a year for the U.Shealth care system.4

Medication discrepancies are found in 50–60% of apatients who are discharged from the hospital.5 The JoinCommission National Patient Safety Goals recommend medication reconciliation at all transitions of care.6 System leveand patient-related factors are equally prevalent causes fopost-dischargemedication discrepancies. Unintentional medication errors account for 30–50% of discrepancies, anpost-discharge medication discrepancies are associated wita higher risk of readmission.7 A best practices model has beedeveloped for discharge counseling in patients with HF thadescribes optimal processes for comprehensive medicatioreconciliation (CMR) to overcome these barriers.8

After discharge for acute decompensated heart failur(ADHF), patients exhibit variable levels of improvement anself-management skills to maintain symptomatic stabilityThese factors, coupled with a high incidence of medicatioerrors, demonstrate why early and effective post-dischargfollow up has become a strategic intervention impactinreadmission rates.9 In an observational study by Hernandeet al.10 of 225 hospitals (>30,000 hospitalized patientsparticipating in Get With the Guidelines (GWTG), the hosptals with the lowest percentage of patients who hafollow-up within 7 days had a significantly higher 30-dareadmission rate. The Hospital to Home (H2H) initiative, le

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Table 2 – Primary elements of the SERIOUS HF MedicationReconciliation Transitional Care Clinic (HF MRTCC).

Abbreviations: HF—heart failure; ADHF—acute decompensatedheart failure; GDMT—guideline-directed medical therapy;EMR—electronic medical record.


by the American College of Cardiology (ACC) and the Institutfor Healthcare Improvement, was an initiative to reduccardiovascular-related hospital readmissions and improvtransitional care for individuals hospitalized with cardiovascular disease. Early discharge follow-up, medication reconciliation, and patient recognition of worsening HF symptomwere the targets of this initiative.11 The American HearAssociation (AHA)/ACC recently published a scientific statement on transitions in care in HF.12 The recommendecomponents of a transitional care program are detailed iTable 1. Despite these transitional care guidelines, there is nconsistent literature on how to develop and execute a transtional care clinic. To address early post-discharge follow-ucare in a HF population, we developed an innovativpharmacist-led, multidisciplinary, post-discharge medicatioreconciliation clinic that encompasses guideline recommendations as well as transitional care.

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Methods

Clinic description

The SERIOUS HF Medication Reconciliation Transitional CarClinic (HF MRTCC) was a collaborative effort between thdepartments of pharmacy, cardiology, and the VeteranAffairs (VA) Quality Scholars Program. It was designed assingle visit to combine pharmacist CMR with focused Htransitional care. The primary elements of the clinic ardetailed in Table 2. Evaluation of early data determined thaone of the crucial aspects of the program was CMR with thpatient and their bottles performed by a pharmacist.13 The HMRTCC visit was an in-person, 60 min appointment. Reviewof symptoms and CMR were performed by staff pharmacistssupervised by a clinical pharmacist specializing in HF. Apharmacists attended a HF continuing education programcreated by the clinical pharmacists and a HF nurse practtioner. Based on the patient's reported symptoms, vital signsand weight fluctuation since discharge, the pharmacisrequested further assessment and physical exam by a nurspractitioner or physician. The patient received HF educatioand tools to aid in adherence. For those patients unable tattend clinic, a phone interview was performed. If concerninsymptoms were identified during the call, the case wareviewed with the medical provider, and appropriatfollow-up was arranged.

Upon review of HF discharges from the Cleveland VAMedical Center, patients were contacted to schedule aappointment in the HF MRTCC with a goal follow-up withi7 days of discharge. Patients could also be referred by thdischarging medical team, inpatient clinical pharmacistsoutpatient primary care, or cardiology providers. Patientnot recently hospitalized could be referred for clinical Hdeterioration, medication non-adherence, assessment ofpatient's medication use system or additional focused medication education.

A model was developed (SERIOUS model) to standardizthe method for CMR, optimization, and communication witthe patient and his/her other health care providers (Fig 1).1

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Fig 1 – SERIOUS model for medication reconciliation.Adapted from: Hoover et al. Presented at Institute for Healthcare Improvement 20thAnnual National Forum on Quality Improvement in Healthcare. Nashville, TN, 2008.13


Patients were instructed to bring all medication bottles, andpill organizer if used, to the visit. Each visit included CMusing open-ended questions and a discussion of the patient'system for home medication use. Medical records, refipatterns, and contents of the bottles were all assessedReview of symptoms using a standardized approach, vitasigns, laboratory values, and recent clinical tests werreviewed and discussed with the clinical pharmacist and/omedical provider. The clinical pharmacists operated underscope of practice agreement that allowed for titration of Hmedications (beta-blockers, angiotensin converting enzym(ACE) inhibitors, mineralocorticoid receptor antagonist(MRAs), diuretics, etc.).14,15 An individualized plan wadeveloped accounting for symptoms, findings during CMRbarriers identified, and collaborative input from the clinicapharmacist and providers.

Methods for clinic assessment

A retrospective quality assurance analysis was performefor patients seen at least once in the HF MRTCC betweeMarch 2008 and December 2009. Inclusion criteria wereage > 18 years and a primary or secondary diagnosis of HFPatients seen more than once during the evaluation periohad each visit reviewed separately. Exclusion criteria weredischarge to a long term care facility/nursing home, ohospice service, no active medications, or <30 days folowing clinic visit to time of chart abstraction. The projecwas reviewed by the hospital's IRB and determined to bequality improvement initiative and, therefore, exempfrom review. All data were obtained from medical anpharmacy records through the VA electronic medicarecord (EMR). Demographic data, dates of clinic visi

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Table 3 – Baseline characteristics.

All Patients(n = 135)

HFrEF (EF ≤ 40%)(n = 71)

Post-ADHFHospitalization (n = 80)

Age (mean ± sd) 69 ± 11 65 ± 11 69 ± 11Age ≥ 80 years n, (%) 21 (16%) 5 (7%) 13 (16%)

GenderMale (%) 99% 100% 99%Female (%) 1% 0% 1%

EthnicityCaucasian 31% 30% 35%African American 65% 65% 64%Declined to answer 4% 5% 1%

ComorbiditiesIschemic Heart Disease (%) 48% 61% 53%Hypertension (%) 94% 93% 95%Atrial fibrillation (%) 30% 28% 38%History of cerebrovascular accident (%) 16% 13% 16%Diabetes (%) 53% 44% 50%Chronic Obstructive Pulmonary Disease (%) 39% 35% 34%Obstructive Sleep Apnea (%) 24% 21% 23%Chronic Kidney Disease, Stage IV or V (%) 7% 3% 4%

Estimated Glomerular Filtration Rate (mean ± sd) 62 ± 23 67 ± 21 63 ± 22EF > 40% (n, %) 61 (46%) n/a 37 (46%)EF ≤ 40% (n, %) 71 (54%) 71 (100%) 43 (54%)Ischemic etiology of HF n/a 44% n/aChronic Resynchronization Therapy (% of those with EF ≤ 40%) n/a 6% n/aImplantable Cardiac Defibrillator (% of those with EF ≤ 40%) n/a 28% n/a

Mortality within 30 days of clinic visit 3 (2.2%) 2 (2.8%) 3 (3.7%)Baseline medicationsACE inhibitor (%) 65% 68% 69%mean daily dosea 34 ± 23 mg 30 ± 20 mg 35 ± 23 mgBeta-blocker (%) 94% 97% 96%mean daily doseb 152 ± 110 mg 152 ± 109 mg 132 ± 98 mgAngiotensin receptor blockers (%) 32% 38% 30%Loop diuretic (%) 74% 75% 71%mean daily dose c 60 ± 45 mg 60 ± 48 mg 62 ± 46 mgSpironolactone (%) 31% 42% 33%mean daily dose 29 ± 30 mg 27 ± 32 mg 30 ± 35 mgHydralazine (%) 33% 38% 33%mean daily dose 151 ± 111 mg 144 ± 106 mg 144 ± 111 mgNitrate (%) 50% 58% 53%

Abbreviations: HFrEF—heart failure with reduced ejection fraction; ADHF—acute decompensated heart failure.Dosages not provided for angiotensin receptor blockers or nitrates as multiple formulations used.a Lisinopril equivalents.b Metoprolol equivalents.c Furosemide equivalents.


discharge from admission prior to, and admission following the clinic visit were recorded (if applicable). All-causand HF admissions and mortality within 30 days of thclinic visit were identified. HF with a reduced ejectiofraction (HFrEF) was defined as a left ventricular ejectiofraction (EF) ≤ 40%. HF with a preserved EF (HFpEF) included patients with an EF > 40%.

Medication discrepancies from the prescribed medicatioregimen were collected and categorized as duplicate medications or discrepancies between the patient's reported regimeand the current prescribed list. To compare across druclasses, equivalent doses of the most common agent in thcohort were used: ACE inhibitors were converted to lisinoprequivalents, beta-blockers were converted to metoproloequivalents, and loop diuretics were converted to furosemid

equivalents.16 All patients receiving an MRA during the studperiod were prescribed spironolactone. All other medicationwere recorded without conversion. Patients who were sent tthe emergency department (ED) or admitted to the hospitadirectly from the clinic were counted as having no adjustments. Interventions and tools to aid in adherence werdocumented in the EMR.

Statistical analysis

Descriptive statistics were used for demographic variables ameans and standard deviations. Comparisons were madbetween the doses prescribed prior to and following the clinivisit using Student's paired t-tests with significance recordeas an alpha of 0.05.

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Results

On the day prior to the visit, a telephone call remindepatients to bring their medications. Patients (n = 135) withprimary or secondary diagnosis of HF (54% HFrEF, 46% HFpEFwere seen in the HF MRTCC. Table 3 depicts the baselincharacteristics and medications. Eighty patients (59%) werseen following a hospitalization for ADHF; 19 (14%) were seefollowing a hospitalization for a primary diagnosis other thaHF; 11 (8%) were referred following an ED visit for HF. Twentseven (20%) were referred by primary care or cardiologproviders. Most patients were seen in the clinic only oncehowever 7% were seen more than once primarily due thaving multiple ED or hospital admissions during th21 month evaluation period. Face to face encounters occurrein 91%, while 9% had a telephone interview due to travebarriers. Of those who attended clinic, 95% brought medication bottles or pill boxes as instructed. Mortality withi30 days of the clinic visit was 2.2% (n = 3) in the entire cohor

Among the 59% of patients who were seen followinghospitalization for ADHF, 54% had HFrEF. The mean timfrom discharge to the clinic appointment was 10 ± 6 daysand the 30 day all-cause readmission rate was 9%. Threadmitting diagnosis was ADHF for all but one of thespatients. Mean time to readmission was 16 ± 6 days (range 522 days). In 2007, prior to implementation of the HF MRTCC athe Cleveland VA Medical Center, the 30 day readmission ratwas 19%.

Medication discrepancies were identified in 53% opatients. This was consistent across those who had bee

l-r,Table 4 – Intensity of non-pharmacologic interventions

for patients seen face-to-face in the HF MedicationReconciliation Transitional Care Clinic (HF MRTCC) (n =123).

Patients ReceivingIntervention (%)

Patient assessmentSymptom assessment (by staffpharmacist and clinical pharmacist)

100%

Additional clinical assessment(by nurse practitioner or physician)

57%

Patient educationComprehensive medicationreconciliation (CMR)

100%

Medication education and/orregimen simplification a

48%

Daily weight monitoring, low sodiumdiet, or HF signs and symptoms

28%

Self-management tools issuedPill boxes 13%Pill boxes filled during clinic visit 8%Blood pressure cuffs 6%Scales 6%

a Regimen simplification: elimination of obsolete, duplicative, orunnecessary medications, consolidation of medication dosingtimes, creating a medication schedule chart.

recently hospitalized, and those with HFpEF or HFrEF. Fothose who had been recently hospitalized, 77% hamedication reconciliation and counseling performed bypharmacist before discharge. The mean number of discrepancies per patient was 3 (range 0–12) with 33% having errorof omission, 19% having errors of commission, and 7% takinduplicate medications. Polypharmacy was common in thipopulation with the mean number of oral, injectable, aninhaled medications of 15 ± 5, (range 4–27)/patient. Over 95%of patients had at least 8 active medications at the clinic visiand 19% had ≥20 medications. In addition to regimesimplification, other non-pharmacologic interventions ardetailed in Table 4.

Seventy percent of the entire cohort had medicationoptimized (Fig 2). Mean number of medications optimized pepatient was 1.5 (range 0–7). Medication optimization involvecorrecting or altering the current prescription for discrepancies identified, however medications were also adjustebased on clinical presentation. Details of medication titratiocan be found in Fig 2 and Table 5. For the entire cohorbeta-blockers, followed by diuretics and ACE inhibitors werthe most commonly optimized medications. Among the 7patients with HFrEF, 77% had medications optimized at thclinic visit. Beta-blockers and ACE inhibitors were the mosfrequently optimized medications, and MRAs were adjustemore frequently in this group than in the entire cohorBeta-blocker doses were significantly higher in the entircohort (152 ± 110 mg/day vs 162 ± 106 mg/day, p = 0.004) anamong patients with HFrEF (152 ± 109 mg/day vs 165 ±108 mg/day, p = 0.005) after the clinic visit. Patients witHFrEF had higher mean ACE inhibitor doses (30 ± 20 mg/davs 31 ± 19, p = 0.044), with a trend toward a higher hydraazine dose after the clinic visit (Table 5). Angiotensin receptoblockers (ARBs) were prescribed in 38% of patients with HFrEFhowever doses were adjusted in only two patients.

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Discussion

Our model of a pharmacist-led, multidisciplinary postdischarge transitional care clinic facilitated detection omedication discrepancies and increased the prevalence oguideline-directed medical therapy (GDMT), resulting in30 day readmission rate of 9% for those who attendedAppropriate up-titration of GDMT and assessment of clinicastability were performed by clinic staff. Patients and caregivers received counseling on self-management skills. ThEMR allowed communication with other providers. The cliniwas modeled after the recommendations made by the AHAGWTG and the ACC's H2H program.8,9,11

Comprehensive medication reconciliation

Medication reconciliation traditionally includes a review opertinent medications, identifying discrepancies, correctinthem according to the prescribed list, and issuing the patiena clean and verified list. The SERIOUS Medication Reconciliation model combined CMR and optimization, patiensafety, and guideline-based HF care in a standardize

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Fig 2 –Medications Optimized. Medications optimized during clinic visit as categorized by drug class. Represented as the entirecohort in part a, and for those patients with HFrEF (EF ≤ 40%) in part b. HFrEF—heart failurewith reduced ejection fraction; ACEi/ARB—angiotensin converting enzyme inhibitors or angiotensin receptor blockers; BB—beta-blockers; MRA—mineralocorticoidreceptor antagonists; other CV—other cardiovascular medications; EF—left ventricular ejection fraction.


multidisciplinary approach.13 Direct assessment of thpatient's medication system allowed for prompt intervention on errors. This model encourages collaboration anprovides a mechanism for other providers to gain additiona

Table 5 –Medication dosages before and after clinic visit.

All pa(N =

Pre-Visit

Angiotensin converting enzyme inhibitor a (mg/day) 34 ± 23Beta-blocker b (mg/day) 152 ± 110Loop diuretics c (mg/day) 60 ± 45Spironolactone (mg/day) 29 ± 30Hydralazine (mg/day) 151 ± 111

a Lisinopril equivalents.b Metoprolol equivalents.c Furosemide equivalents.

insight into their patients' medication use behaviors anproper dosing.

Accurate post-discharge CMR with direct review omedication bottles was a pivotal element in the design o

tients135)

P Value HFrEF (EF ≤ 40%)(N = 71)

P Value

Post-Visit Pre-Visit Post-Visit

34 ± 22 1.0 30 ± 20 31 ± 19 0.044162 ± 106 0.004 152 ± 109 165 ± 108 0.00559 ± 50 0.547 60 ± 48 62 ± 59 0.56331 ± 30 0.183 27 ± 32 29 ± 31 0.326

167 ± 111 0.0130 144 ± 106 157 ± 102 0.055

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this clinic. Numerous studies have described medicatioreconciliation at discharge,17–20 and in the outpatiensetting.21–27 Post-discharge medication discrepancies arhighly prevalent, with at least one medication discrepancidentified in >50% of discharged patients.22,28,29 Direct visuaization of the patient's system and medication supplies aroften limited to interventions performed in home carsettings. One study compared the medication discrepancdetection rate between a face-to-face in-home encounteversus a verbal report of medication use, and found discrepancies that had been undetected on a telephone interview i62% of patients.22 The frequency of medication discrepanciefound in the HFMRTCCwas 53%, similar to prior reports usindirect review of medication bottles. The SERIOUS model wadeveloped to promote a standardized approach to the CMprocess, meeting all components of The Joint Commission'National Patient Safety Goal6 and with the addition o“optimization” of medication therapy. The HF MRTCC madclinically appropriate adjustments of GDMT and diuretics ithe early post-discharge period. ACE inhibitor anbeta-blocker doses were significantly higher in patients witHFrEF following the clinic visit.

Clinic structure and transitional care

Transitional care interventions have been shown to improvshort and long term outcomes in a variety of settings.30,31 Thiclinic model can be easily adapted to meet the recommendations for a transitional care clinic appointment following a Hhospitalization and/or ED visit.12,32 This clinic model iappealing to Accountable Care Organizations who seestrategies to decrease acute care utilization and improvoutcomes.

The HF MRTCC was not intended to replace longitudinaHF or primary care relationships, rather it was meant to servas a single clinic visit augmenting longitudinal care. The HMRTCC clinic pilot experience integrated interdisciplinarcollaboration, allotted time to deliver complex HF interventions, and assess patient/caregiver response. These arimportant components of a transitional care program areferenced in Table 1. The EMR was also utilized asmechanism for communication and coordination usingtemplated clinic note that informed providers assuming thnext level of care.

Role of the pharmacist

The role of a pharmacist in HF care has been expanded in thpast several years to include direct patient care. The existinliterature demonstrates conflicting results on the impact oclinical pharmacy services in HF. Several studies have showa decrease in HF hospitalizations and mortality followininterventions including a clinical pharmacist which focuseon medication optimization of GDMT, CMR and medicatioeducation. These interventions have been demonstrated ilongitudinal clinics over several visits,33,34 and in singltransitional post-discharge home care visits.25,27 Other studies have shown neutral effects of pharmacist interventionsThe majority of these studies have not been multidisciplinar

in nature.21,23,35 Most studies did not describe how thpharmacists acted upon discrepancies after performing medication reconciliation other than notifying the provider, nodid they attempt to titrate GDMT. Adequate training opharmacists providing interventions is important. In previoustudies some pharmacists were not clinical pharmacists buwere community pharmacists, and may not have haadequate training or access to HF providers.21,23 These studieare further limited by patient selection, including onlpatients with HFrEF,23 or “low risk” patients who had nobeen recently hospitalized.35 Outcomes evaluated in somstudies were unlikely to be impacted by a single pharmacisvisit.21,35 The endpoints evaluated in the HF MRTCC piloprogram are clinically relevant and were impacted by a singlclinic visit. Approximately 45% of patients hospitalized for Hat our institution have HFpEF. Including them in transitionacare is important, even though GDMT is limited in thipopulation.

Multidisciplinary interventions targeting patients durinperiods of clinical instability are more likely to producebeneficial effect on readmission.12 Our pilot program imultidisciplinary, allowing pharmacists to focus on medication management but not to the exclusion of other importanaspects of HF management, including clinical assessment ba HF trained medical provider. Furthermore, guideline recommendations for HF are fulfilled by the staff pharmacistperforming medication reconciliation, recognizing worseninof HF symptoms, providing patient education, and facilitatincare coordination. The clinical pharmacists have scopes opractice which allow prescribing and titration of HF medications, and ordering and evaluation of appropriate laboratortests. The HF MRTCC team became the patient's surrogatpoint of contact until they were seen at the next episode ocare.

We recognize that the multidisciplinary nature of the cliniwas critical to the observed outcomes. More than half of thpatients in this cohort were also seen by a HF nurspractitioner or a physician during the HF MRTCC visiThe results of our pilot experience are more consistent witthe results of previously described multidisciplinary interventions27,33 versus other pharmacist-led interventions.21,3

The Heart Failure Society of America (HFSA) and AmericaCollege of Clinical Pharmacy Cardiology Practice and ResearcNetwork published a joint opinion paper regarding the role ofpharmacist on a HF team which highlighted appropriatclinical activities and training for pharmacists in thesroles.36 The ACC published a health policy statement on throle of cardiovascular team-based care and advanced practicproviders, including advanced practice nurses, physiciaassistants, and clinical pharmacists.37 The results of our piloexperience suggest that a scope of practice for the clinicapharmacist is essential in this setting and enables practice oall HF team members at the highest level, improving efficiencand broadening the scope of HF care.

There are limitations to this analysis. It was designed asquality improvement project to evaluate the impact of a newclinical service (the HF MRTCC), and therefore wanon-randomized and did not have a pre-defined controgroup. Patients with a very large medication burden or wit

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a prior history of medication non-adherence may have beemore likely to be referred while others may have chosen noto attend at all. Given that a proportion of patients whreceive a scheduled follow-up appointment fail to attendpatients who did attend the clinic appointment may havbeen subject to some degree of bias. We also had no way treport on or control for patients who did not attend the cliniappointment, and therefore the results presented are reflective of patients who were able to attend at least onfollow-up appointment.

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Conclusion

The SERIOUS HF MRTCC was developed as a pharmacistled, multidisciplinary transitional care clinic. This modeaimed to improve HF care and “bridge the gap” betweehospitalization and routine outpatient care by providinearly post-discharge follow-up, CMR with GDMT optimization, prompt medical intervention, and appropriate transtional care. It offers a framework that can easily be adapted bHF care providers to meet organizational goals and achievenhanced patient-centered outcomes. Numerous medicatiodiscrepancies were identified and corrected, GDMT doses werhigher at the end of the clinic visit, and patients who attendethe clinic had a 30-day all-cause readmission rate of 9%. ThAHA/ACC's Transitional Care in HF Scientific Statement highlights the diverse formats of transitional care interventionand calls for additional research to evaluate componentswhicmay be most beneficial. These encouraging pilot results arhypothesis-generating and warrant further controlled trials tevaluate clinically important endpoints such as health carutilization, medication titration, medication adherence, anpatient self-management skills. A collaborative multidisciplinary team approach where clinical pharmacists are utilized aalternative providers offers a future care delivery option for Hpatients.

.

-

Authors' industry relationships

Sherry Milfred-LaForest—NoneJulie Gee—NoneAdam Pugacz—NoneIleana Pina—NoneDanielle Hoover—NoneRobert Wenzell—NoneAubrey Felton—NoneEric Guttenberg—NoneJose Ortiz—None

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There is no conflict of interest of any of the listeauthors.

Acknowledgements

The authors gratefully acknowledge the following peoplwho provided invaluable input into the design, data collection, and daily operation of the clinic; and without whomthis report would not have been possible: David Aron, MDJulio Barcena, MD, Patrick Bugaj, PharmD, Arielle CalvilloPharmD, Jon Folstad, PharmD, Matthew Kubiak, PharmDGeoffrey Mospan, PharmD, Catherine Ortiz, PharmD, SharoSabatka, RPh, William Salem, PharmD, Kimberley SchaubPhD, Stephanie Sodders, PharmD, and Diana WalickPharmD.

R E F E R E N C E S

1. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and strokstatistics—2013 update: a report from the American HeartAssociation. Circulation. 2013;127:e6-e245.

2. Heidenreich PA, Albert NM, Allen LA, et al. Forecasting theimpact of heart failure in the United States: a policy statemenfrom the American Heart Association. Circ Heart Fail. 2013;6:606-619.

3. Medicare Payment Advisory Commission. Report to Congressa Path to Bundled Payment Around a Hospitallization[Washington DC]. 2008.

4. Bradley EH, Curry L, Horwitz LI, et al. Hospital strategiesassociated with 30-day readmission rates for patientswith heart failure. Circ Cardiovasc Qual Outcomes. 2013;6:444-450.

5. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHAguideline for the management of heart failure: executivesummary: a report of the American College of CardiologyFoundation/American Heart Association task force onpractice guidelines. Circulation. 2013;128:1810-1852.

6. The Joint Commission. Hospital: 2015 National Patient SafetGoals. Available at:The Joint Commission, http://www.jointcommission.org/standards_information/npsgs.aspx2015, Accessed date: 15 August 2015.

7. Coleman EA, Smith JD, Raha D, Min SJ. Posthospital medica-tion discrepancies: prevalence and contributing factors. ArchIntern Med. 2005;165:1842-1847.

8. Wiggins BS, Rodgers JE, DiDomenico RJ, Cook AM, Page II RLDischarge counseling for patients with heart failure ormyocardial infarction: a best practices model developed bymembers of the American College of Clinical Pharmacy'scardiology practice and research network based on thehospital to home (H2H) initiative. Pharmacotherapy. 2013;33:558-580.

9. American Heart Association. Get with the guidelines heartfailure. Available at:, http://www.heart.org/HEARTORG/HealthcareResearch/GetWithTheGuidelinesHFStroke/GetWithTheGuidelinesHeartFailureHomePage/Get-With-TheGuidelines-Heart-Failure-Home-Page_UCM_306087_SubHomePage.jsp 2015, Accessed date: 7May 2015.

10. Hernandez AF, Greiner MA, Fonarow GC, et al. Relationshipbetween early physician follow-up and 30-day readmissionamong Medicare beneficiaries hospitalized for heart failure.JAMA. 2010;303:1716-1722.

11. American College of Cardiology, Institute for HealtcareImprovement. Hospital to home (H2H). Available at:AmericaCollege of Cardiology, http://cvquality.acc.org/Initiatives/H2Haspx 2014, Accessed date: 18 July 2014.

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12. Albert NM, Barnason S, Deswal A, et al. Transitions of care iheart failure: a scientific statement from the American HearAssociation. Circ Heart Fail. 2015;8:384-409.

13. Hoover D, Schaub K, Gee J, et al. Getting SERIOUS aboutmedication reconciliation: a model for improving the qualityof the medication reconciliation process. Presented at Insti-tute for Healthcare Improvement 20th Annual NationalForum on Quality Improvement in Healthcare; 2008.[Nashville, TN].

14. Dunn SP, Birtcher KK, Beavers CJ, et al. The role of the clinicapharmacist in the care of patients with cardiovasculardisease. J Am Coll Cardiol. 2015;66:2129-2139.

15. Gilbertson S, Yoder S, Lee MP. Improving Patient and HealthSystem Outcomes Through Advanced Pharmacy Practice; a Report tthe US Surgeon General. Washington DC: US Public Health Service2011.

16. Pina IL, Bruckman D, Lance C, et al. Quality improvement inheart failure: a randomized educational intervention tochange provider behavior. Congest Heart Fail. 2012;18:245-253

17. Kripalani S, Roumie CL, Dalal AK, et al. Effect of a pharmacisintervention on clinically important medication errors afterhospital discharge: a randomized trial. Ann Intern Med.2012;157:1-10.

18. Murphy EM, Oxencis CJ, Klauck JA, Meyer DA, Zimmerman JMMedication reconciliation at an academic medical center:implementation of a comprehensive program from admissioto discharge. Am J Health Syst Pharm. 2009;66:2126-2131.

19. Pal A, Babbott S, Wilkinson ST. Can the targeted use of adischarge pharmacist significantly decrease 30-dayreadmissions? Hosp Pharm. 2013;48:380-388.

20. Sarangarm P, London MS, Snowden SS, et al. Impact ofpharmacist discharge medication therapy counseling anddisease state education: pharmacist assisting at routinemedical discharge (project PhARMD). Am J Med Qual. 2013;28292-300.

21. Barker A, Barlis P, Berlowitz D, Page K, Jackson B, Lim WK.Pharmacist directed home medication reviews in patientswith chronic heart failure: a randomised clinical trial. Int JCardiol. 2012;159:139-143.

22. Costa LL, Poe SS, Lee MC. Challenges in posthospital care:nurses as coaches for medication management. J Nurs CareQual. 2011;26:243-251.

23. Holland R, Brooksby I, Lenaghan E, et al. Effectiveness of visitfrom community pharmacists for patients with heart failureHeartMed randomised controlled trial. BMJ. 2007;334:1098-1105.

24. Pherson EC, Shermock KM, Efird LE, et al. Development andimplementation of a postdischarge home-based medicationmanagement service. Am J Health Syst Pharm. 2014;71:1576-1583.

25. Roughead EE, Barratt JD, Ramsay E, et al. The effectiveness ocollaborative medicine reviews in delaying time to nexthospitalization for patients with heart failure in the practice

setting: results of a cohort study. Circ Heart Fail. 2009;2:424-428.

26. Sanchez GM, Douglass MA, Mancuso MA. Revisiting projectre-engineered discharge (RED): the impact of a pharmacisttelephone intervention on hospital readmission rates.Pharmacotherapy. 2015;35:805-812.

27. Stewart S, Pearson S, Horowitz JD. Effects of a home-basedintervention among patients with congestive heart failuredischarged from acute hospital care. Arch Intern Med. 1998;1581067-1072.

28. Kilcup M, Schultz D, Carlson J, Wilson B. Postdischargepharmacist medication reconciliation: impact on readmissiorates and financial savings. J Am Pharm Assoc (2003). 2013;5378-84.

29. Ziaeian B, Araujo KL, Van Ness PH, Horwitz LI. Medicationreconciliation accuracy and patient understanding ofintended medication changes on hospital discharge. J GenIntern Med. 2012;27:1513-1520.

30. Feltner C, Jones CD, Cene CW, et al. Transitional careinterventions to prevent readmissions for persons with heafailure: a systematic review and meta-analysis. Ann InternMed. 2014;160:774-784.

31. Kansagara D, Chiovaro JC, Kagen D, et al. So many options,where do we start? An overview of the care transitionsliterature. J Hosp Med. 2016;7:221-230.

32. Centers for Medicare and Medcaid Services. Transitional carmanagement services. Available at:, http://www.cms.gov/Outreach-and-Education/Medicare-Learning-Network-MLN/MLNProducts/MLN-Publications-Items/ICN908628.html 2014Accessed date: 18 July 2014.

33. Gattis WA, Hasselblad V,Whellan DJ, O'Connor CM. Reductioin heart failure events by the addition of a clinical pharmacisto the heart failure management team: results of thepharmacist in heart failure assessment recommendation anmonitoring (PHARM) study. Arch Intern Med. 1999;159:1939-1945.

34. Jackevicius CA, de Leon NK, Lu L, Chang DS, Warner AL, ModFV. Impact of a multidisciplinary heart failurepost-hospitalization program on heart failure readmissionrates. Ann Pharmacother. 2015;49:1189-1196.

35. Lowrie R, Mair FS, Greenlaw N, et al. Pharmacist interven-tion in primary care to improve outcomes in patients withleft ventricular systolic dysfunction. Eur Heart J. 2012;33:314-324.

36. Milfred-Laforest SK, Chow SL, Didomenico RJ, et al. Clinicalpharmacy services in heart failure: an opinion paper from thHeart Failure Society of America and American College ofClinical Pharmacy Cardiology Practice and Research NetworkJ Card Fail. 2013;19:354-369.

37. Brush Jr JE, Handberg EM, Biga C, et al. 2015 ACC health policstatement on cardiovascular team-based care and the role oadvanced practice providers. J Am Coll Cardiol. 2015;65:2118-2136.



ScienceDirect


Implementation of a Patient Navigator Program to
Reduce 30-day Heart Failure Readmission Rate
Katherine E. Di Paloa,⁎, Khusbu Patelb, Manaf Assafina, Ileana L. Piñac

aMontefiore Medical Center, Bronx, NY, United StatesbSt. John's University Queens, NY, United StatescAlbert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, United States


Statement of conflict of interest: see paFrom: Montefiore Medical Center, BronSupported in part by: American College

⁎ Corresponding author at: Montefiore MStates.



A B S T R A C T

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With increasing awareness to provide personalized care our institution applied thAmerican College of Cardiology (ACC) Patient Navigator Program to identify hospitalizeheart failure (HF) patients and improve transitions and outcomes. Utilizing a NavigatoTeam (NT) composed of a nurse and clinical pharmacist, we delivered evidenced-baseinterventions and hypothesized this approach would improve identification of Hinpatients and reduce the 30-day all-cause readmission rate. Patients were followed fromadmission to discharge and received at least one intervention, tailored to the patienthealth literacy and social needs. The 30-day all-cause readmission rate was 17.6% for thPatient Navigator Program and 25.6% for the medical center. Compared to the medicacenter there was a statistically significant increase in education and follow-up. For patientwho received specific NT interventions of education and follow-up the readmission ratwas 10.3% and 6.1% respectively. Hospital programs can easily embed a NT into existininitiatives to further reduce the readmission rate.


30-Day readmissionsPharmacistNurse

Contents

011122233

Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

Patient navigator program . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26Navigator team pilot . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

Statistical methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

Identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26Education and follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26Biomarker monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

ge 265.x, NY.of Cardiology Patient Navigator Program.edical Center, 1825 Eastchester Road, Cardiology Administration, Bronx, NY 10461, United

(K.E. Di Palo).

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ARB = Angiotensin-II receptorblocker


ACE inhibitor =Angiotensin-converting enzymeinhibitor

ADHF = Acute decompensatedheart failure

BB = Beta-blocker

CMS = Centers for Medicare andMedicaid Services

EF = Ejection fraction

GDMT = Guideline-directedmedical therapy

HF = Heart failure

HFpEF = Heart failure with pre-served ejection fraction

HFrEF = Heart failure with re-duced ejection fraction

HRRP = Hospital ReadmissionsReduction Program

MRA = Mineralocorticoid recep-tor antagonist

NT = Navigator Team

NT-proBNP = N-terminalpro-brain natriuretic peptide



Guideline-directed medical therapy . . . . . . . . . . . . . . . . . . . 26Readmissions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26Statement of conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . 26References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

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Background

Heart failure (HF) ione of the leadincauses of hospital admissions. Data repeatedly show thaeach hospitalizatioincreases mortality a6 months and a1 year.1–2 In the United States, the cosburden of HF is estmated to be 30.7 billiodollars annually.3 Thicost can be potentiallcurtailed as hospitareadmissions occuin approximatelyin 4 patients withi30 days.4 While somreadmissions are unavoidable due to barriers in care oconcomitant diseasstates, there are a proportion of patientwith preventablcauses.5 Health car

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factors attributed to readmissions istay and multiple emergency department visits withi6 months of hospitalization.6–7 The Hospital ReadmissionReduction Program (HRRP), which financially penalizes hospitasystems for Medicare fee-for-service patients readmitted i30 days for HF or other select diseases, is one of the federainitiatives to address this issue and has raised hospitalsawareness of the readmissions quandary. Programs may varin the type of interventions included to reduce HF readmissionsbut the most common outcome measured for HF teams ihospital readmission rates. Since multiple interventions aroften implemented at the same timewith confounding variablesthe composite endpoint of readmissions may impede thidentification of specific interventions that are significant.

Results from currently implemented hospital programshow varying effects on readmission rates. One study foun<1.4% of hospitals reaching a 20% reduction rate in 30-dareadmissions.8 Nevertheless, identifying interventions thacan slow the current hospital HF readmission rate is in thbest interest of healthcare institutions. Strategies used b

health care institutions to curb unplanned readmissioninclude early identification of patients with HF, improvincoordination of care between the care team and education fopatients and caregivers.9–10 Stratification of patients withigh risk of readmissions can be performed through the use oa 30-day readmission calculator released by the Center foOutcome Research and Evaluation (CORE). Items included othe risk calculator include demographics, presentation ainitial hospitalization, medical history, physical exam andiagnostic labs at admission.11

In addition to the risk calculator, an objective marker thais correlated with HF risk is the N-terminal pro-brainatriuretic peptide (NT-proBNP) laboratory test in whichhigh risk of adverse outcomes is seen with levels abov900 pg/mL.12 A single NT-proBNP reading is a prognostimarker for adverse outcomes; however, additional NT-proBNtesting is also warranted as a trend allows for the identificatioof clinically significant change in health status.13 Knowledge othe increase in NT-proBNP levels can facilitate beneficiatreatment modifications. Despite services provided during thhospitalizations, changes in health status post discharge obarriers to following a plan are among causes that can lead toreadmission. Current evidence identifies drug regimens thaprevent HF complications and reduce disease progression yesuboptimal dosing, especially with angiotensin-convertinenzyme inhibitors (ACE inhibitor), angiotensin II receptoblockers (ARB), beta-blockers (BB) and mineralocorticoid receptor antagonists (MRA), are still identified as issues that impacpatient outcomes.14–15 Furthermore, medication nonadherencis a well-studied factor that leads to readmissions and aincrease in morbidity and mortality.16–19 In conjunction witpharmacotherapy, modifications in diet and exercise have alsbeen areas of targeted interventions.20–22 Discharges planninwith a timely follow-up with telephone calls, home visits ooutpatient providers are needed to provide continuity of care.2

Moreover, follow-up within 7–14 days of a hospitalization hashown to lower readmission rates.24–25

Albert Einstein, the namesake of Montefiore MedicaCenter's College of Medicine, highlighted the importance t“learn from yesterday, live for today and hope for tomorrowHF as a syndrome, embodies the learning that has occurrefrom yesterday, the challenge today of Centers for Medicarand Medicaid Services (CMS) penalties for high readmissiorates and hope for tomorrow to lower this marker of pooquality. As our institution strives to reduce its readmissiorates for HF a simple and fundamental question needed to banswered before looking to future directions. A readmissionreduction program could not be definitively and accuratelimplemented if patients with the diagnosis of HF could not b

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Table 1 – American College of Cardiology Patient Navigator Program Metrics.

Domain Metric

Outcome 30-day CMS risk stratified readmission rate30-day unadjusted readmission rate

Satisfaction % of patients who reported patient/provider communication was “always good”% of patients who reported an understanding of their medications during or after hospitalization% of patients who reported an understanding of their signs and symptoms during or after hospitalization

Process % of patients with documentation that LV function was evaluated% of patients with an EF <40% prescribed an ACE inhibitor or ARB at discharge% of patients with an EF <40% prescribed a guideline beta-blocker a at discharge% of patients with documented medication reconciliation performed on admission and discharge% of patients that were provided with specific education and documentation on their self-care plan% of patients with 7-day follow-up appointment documented on discharge summary% of patients receiving community resources for health care services

Abbreviations: ACE inhibitor, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CMS, Centers for Medicare andMedicaid Services; EF, ejection fraction.a Defined as metoprolol succinate, bisoprolol or carvedilol per ACCF/AHA Heart Failure Guidelines.


identified. Hospital Administration and Division of Cardiologasked the question: Can we accurately identify HF patientwhile they are hospitalized? The answer is critical. Identifcation of a HF admission is essential to prevent a Hreadmission. The primary objective of our study was tmanually identify patients admitted with a primary diagnosiof HF in real time. Secondary objectives included optimizinHF treatment based on American College of Cardiology (ACCFoundation/American Heart Association (AHA) Guideline fothe Management of HF, educating patients on diet, exercisand medication, detecting barriers contributing to readmissionand improving access to follow-up care post discharge. Thhypotheses were that by studying the processes used to identifHF patients, examining current practices and implementininterventions the goal of reduction in readmission rates coulbe reached.

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Methods

Patient navigator program

The ACC launched the Patient Navigator Program in 2013 tapply a team-based approach for keeping patients at homand healthy after hospital discharge for HF and acutmyocardial infarction (AMI). A total of 35 hospitals werselected from across the country to participate in this first oits kind cardiology initiative that applied evidence-baseprocesses to avoid readmissions. The design and implementation of the Patient Navigator Program for each of thparticipating hospitals was determined at the site level. Ouinstitution elected for a nurse and clinical pharmacist tcompose the Navigator Team (NT), as there is robust evidencwith these particular disciplines demonstrating a positivimpact on HF outcomes.26–28 A heart failure specialist waavailable to the NT for guidance and served as a liaison to thinpatient cardiology and HF services. While other institutionutilized care managers, physicians, nutritionists and physicatherapists for their NTs, our pharmacist and nurse teamdynamic was unique among participating hospitals.

Quarterly data was submitted from Q1 2015 to Q4 201using ACC's National Cardiovascular Data Registry (NCDRACTION Registry-Get With The Guidelines (GWTG). Datmeasures were broken up into 5 domains: outcomes, patiensatisfaction, patient quality of life, efficiency and processExamples of HFmeasures specific to each domain are listed iTable 1. Data was collected through a retrospective charreview of 30 patients discharged with a diagnosis of AMI an30 patients discharged with a diagnosis of HF for a total of 6patients per quarter. Resources available to participatinhospitals included digital scales and pedometers. Quarterlsite visits were conducted by the ACC, as well as communitwebinars and conference calls, to discuss challenges anshare best practices.

Navigator team pilot

In alignment with the goals of the institution and the PatienNavigator Program, a pilot was initiated by HF leadership anadministration on a cardiac telemetry unit that historicallhad the highest number of heart failure admissions withithe institution and an annual readmission rate above 25%Data were collected from June to December 2015. The Nprimarily implemented the pilot with support from thinterdisciplinary team (IDT) composed Care TransitionClinical Coordinators (CTCCs), staff nurses, physician assistants, cardiologists, social workers, nurse managers annutritionists. During daily IDT rounds the NT screenepatients with particular attention to new admissions. Enrolment into the pilot was based on specific clinical criteria useto diagnose acute decompensated HF (ADHF) and includeelevated NT-proBNP defined as >900 pg/mL, presence of Hon imaging such as a chest X-ray or echocardiogramadmitting symptoms of dyspnea or edema and treatmenwith an intravenous or oral diuretic. The process of the NT idescribed in Fig. 1. After identification and enrollment, thnurse and pharmacist completed an intake assessment anclinical workup. The intake assessment was a predictivmodel for readmission which focused on acuity, individuabarriers and access to follow-up. The clinical workucontained past medical history, admission medicatio

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Admission

•RN: intake assessment•PharmD: clinical workup

Inpatient

•RN: NT-proBNP monitoring•PharmD: GDMT recommendations•RN/PharmD: patient education

Discharge

•RN: post discharge appointments•PharmD: medication counseling

Fig. 1 – Abbreviations: GDMT, Guideline-directed MedicalTherapy; RN, registered nurse; PharmD, clinical pharmacist.


reconciliation, daily labs, 30-day readmission risk using CORcalculator and recommendations for guideline-directed medical therapy (GDMT) optimization. HF severity was assesseby New York Heart Association (NYHA) criteria. The Npresented new admissions to the HF consult team whcould provide expert assistance on further identification anmanagement.

Providers were encouraged to order NT-proBNP, a biomarker that is a strong predictor for prognosis in ADHFHowever, standard of practice on the unit did not includroutine monitoring. Under direction of the HF consult teamthe Navigator nurse independently ordered NT-proBNP analerted providers of the results.

The NT focused on providing HF education and obtaining14-day follow-up appointment prior to discharge. BaselinPatient Navigator Program data revealed that these two areaneeded the most improvement. Deficits in these areas arexamined by CMS and signal lack of quality care. As per thPatient Navigator Program process measure, education needed to be documented as HF specific within the medical recordEducation was conducted by both the Navigator nurse anpharmacist in multiple sessions throughout the hospitalization for a total of at least 60 min. Education was standardizedtailored to the patient's health literacy and numeracy andocumented in the electronic medical record. The primarteaching resource was an internal booklet created by thHeart Failure Program entitled Living with Heart Failure anincluded 6 core components: disease state pathogenesissigns and symptoms, weight monitoring, diet, exercise anmedication therapy with focus on adherence. These topicwere also available as videos on demand in English anSpanish. Auxiliary resources such as scales, pedometers, piboxes, weight logs, wallet cards, NT-proBNP logs and shopping lists were distributed by the NT based on patient needFamily members and caregivers were encouraged to particpate in education sessions with the patient.

Efforts to obtain a follow-up appointment within 14 daywere led by the nurse. The discharge appointment timelindiffered from the Patient Navigator Program's process measurof appointment scheduled within 7 days of discharge. Internadata demonstrated that prior to pilot initiation approximatel50% of patients were discharged with no scheduled appointment. Preferences to office location and coordination otransportation were discussed with the patient and family.

Previous data from the GWTG-HF registry demonstratepoor adherence to GDMT among patients with heart failurwith reduced ejection fraction (HFrEF) at our institutionAdditionally, process measures from the Patient NavigatoProgram included percent of patients with an ejection fractio(EF) <40% that were prescribed an ACE inhibitor or ARB or aevidence based BB at discharge. To improve GDMT prescribinpatterns, pharmacotherapy notes were written by the pharmacist for patients with frequent admissions or suboptimatherapy. Recommendations for the treatment of chronic Hincluded personalized therapy, dose targets and monitorinparameters as well as references to pertinent literature tsupport suggestions. Dischargemedication reconciliation waperformed by the pharmacist and a final medication list waprepared highlighting prescription changes such as druinitiation, dose titration or discontinuation. A personalizemedication schedule with administration times to improvadherence, optimize therapy and minimize side effects waalso provided. Finally, the pharmacist and patient discussedplan to obtain new medications post discharge. Prescriptioprocurement was arranged for bedside delivery prior tdischarge forpatientswithadocumentedhistoryofnonadherencor upon patient request.

Statistical methods

Descriptive analyses were performed; categorical variablewere described by frequencies and percentages and continuous variables were described by means and standard deviations. Interventions with dichotomous outcomes wersummarized in 2 × 2 tables and analyzed using a χ2 tesReadmission rates associated with specific interventionwere compared to aggregate medical center data collecteannually using a one-sample t-test. We assumed a p-value o<0.05 to be significant.

Results

Identification

The NT enrolled 120 patients during the pilot study period.HF admission was defined by post discharge coding usinDiagnosis Related Groups (DRGs) 291, 292 and 293. ThesDRGs contained ICD-10 codes that correlated to a principal oindex diagnosis of HF. Of the 120 patients enrolled, 5admissions were confirmed as HF. The remaining 69 admissions identified by the NT were classified as history of HF anexcluded from further analysis. The total number of primar

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Fig. 2 – Abbreviations: HF, heart failure; NT, Navigator Team.


HF admissions on the telemetry unit during the piloenrollment period was 94. The NT identified and enrolled 5of these encounters and the accuracy of pilot identificatiowas 54.3%. The 43 primary HF admissions during the studperiod that were not identified by the NT during inpatienhospitalization, but confirmed post discharge as primary Hby coding, served as a control for analysis (Fig. 2).

Patient demographics of the 94 primary HF admissions arillustrated in Table 2. Baseline characteristics, such as age angender, were similar among NT and control groups. NYHfunctional class was also similar within the two groups; thmajority of patients were class III. However, there wasstatistically significant difference in average length of staand average EF. The NT group had a longer length of sta(6.3 days vs. 3.7 days) and lower EF (36.5% vs. 46.3%). Thmajority of NT patients had HFrEF (68.6%) while the majoritof control patients had heart failure with preserved ejectiofraction (HFpEF) (51.2%).

Education and follow-up

Results for specific NT interventions are described in Table 3There was a statistically significant difference in HF specifieducation (p = 0.0002); documented education increased b59.0% among the NT group. There were 29 patients (56.8%that received education by the NT compared to 10 patient(23.3%) that received education by the telemetry nurses. Therwas also a statistically significant increase in schedule14-day follow-up among the NT group (p = 0.0044). Posdischarge appointments, with either a cardiologist or primarcare provider, were scheduled within 14 days for 35 patient(68.6%) in the NT group. Conversely, post discharge appoinments for the control group were scheduled within 14 dayfor 17 patients (39.5%). Of the scheduled appointmentNavigator patients were more likely to follow-up withcardiologist (56.8%) than the control group (18.6%). Thutilization of a NT in the discharge process resulted in53.2% decrease in the number of patients discharged withoua scheduled post discharge follow-up visit.

Biomarker monitoring

NT-proBNP was routinely ordered on admission by providerin the emergency department or on the telemetry unit fo

both Navigator and control groups. Within the Navigatogroup at least one repeat measurement was attempted prioto discharge and was ordered exclusively by the NT nurseRepeat orders for the control group were ordered by physiciaassistants or attending providers. There was a statisticallsignificant increase in the rate of repeat measurement amonthe NT group (p = 0.0002); 55.8% of patients in the NT grouhad at least one repeat NT-proBNP compared to 22.0% opatients in the control group. Repeat measurement irecommended during hospitalization and evidence suggestthat a reduction of 30% during admission for ADHF appears thave a favorable prognosis for readmission or cardiovascula(CV) death.29–31 There were more patients in the Navigatogroup that had a 30% or greater reduction in NT-proBNPHowever, this was likely due to the larger sample size opatients who received repeat measurements. NT-proBNmonitoring by the NT nurse did not affect treatmenstrategies as this was determined by the care team.

Guideline-directed medical therapy

Eligibility for GDMT was determined by the clinical pharmacist using the 2013 ACCF/AHA HF guidelines. HFpEF patientwere excluded from the analysis. Patients were also excludeif they had a documented contraindication to an ACinhibitor, ARB or BB, such as hyperkalemia, restrictive lundisease or acute kidney injury at time of discharge. Of theligible HFrEF patients in the NT group, 85.2% received an ACinhibitor or an ARB at discharge and 90.9% received a BB adischarge compared to 68.4% and 75.0% of eligible contropatients. This trended towards statistical significant (p = 0.17p = 0.12). The addition of a clinical pharmacist to the IDresulted in a 24.6% increase in the number of ACE inhibitor oARB prescriptions and a 17.5% increase in the number of Bprescriptions.

Readmissions

Using the CMS definition of a 30-day readmission, there wer18 all-cause readmissions among patients discharged fromthe unit during the study period. Among the NT group of 5patients there were 9 readmissions. The 30-day all-causreadmission rate for the Navigator group was 17.6%. Amonthe control group of 43 patients there were 9 readmissions

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Table 2 – Baseline demographics and characteristics.

Pilot μ (sd) Control μ (sd) p-Value

Age, years 69.7 (12.7) 67.9 (11.2) 0.48Gender, n (%)Female 22 (43.1) 19 (44.2)Male 29 (56.9) 24 (55.8) 0.92

Ejection fraction, % 36.5 (14.6) 46.3 (16.3) 0.003Length of stay, days 6.29 (5.8) 3.67 (2.9) 0.002NYHA class, n (%)I 0 0II 5 (9.8) 3 (7.0)III 40 (78.4) 37 (86.1)IV 6 (11.7) 3 (6.9)

HFrEF (≤40) 35 (68.6) 20 (46.5) 0.02HFpEF (≥50) 14 (27.5) 22 (51.2) 0.02HFmrEF (41–49) 2 (3.9) 1 (2.3)

Abbreviations: HFrEF, heart failure with reduced ejection fraction;HFmrEF, heart failure with mid-range ejection fraction; HFpEF,heart failure with preserved ejection fraction; NYHA, New YorkHeart Association.


The 30-day all-cause readmission rate for the control grouwas 20.9%. During the study period the 30-day all-causreadmission rate for the medical center was 25.6%. ThPatient Navigator Program resulted in a 15.8% decrease ithe rate of unplanned readmission for HF patients whecompared to the readmission rate of the control group and31.3% decrease when compared to the medical centeThough readmission penalty is indiscriminate of readmissiocause, patients in the NT group were less likely to breadmitted for HF. Of the 9 readmissions in the Navigatogroup only 2 were readmitted for HF (22.2%) compared toreadmissions for HF among the control group (66.6%) whictrended towards statistical significance (p = 0.15). There isstrong correlation between NT interventions of education anfollow-up to readmission rate summarized in Table 4. Amonpatients who received education by the NT (n = 29) threadmission rate was 10.3% and among patients who receive

Table 3 – Summary of evidence-based interventionsprovided by Navigator team.

Intervention Patient NavigatorProgram

Control p-value

Education, % 56.8 23.3 0.000214 day follow-up, % 68.6 39.5 0.0044NT-proBNPmonitoring, %Admission 82.3 95.1 0.243Repeat 58.8 22.0 0.0002

HFrEF GDMT, %ACE inhibitor/ARBat discharge

85.2 68.4 0.17

Beta-blocker a atdischarge

90.9 75.0 0.12

Abbreviations: ACE inhibitor, angiotensin-converting enzymeinhibitor; ARB, angiotensin II receptor blocker; HFrEF, HeartFailure with Reduced Ejection Fraction.a Defined as metoprolol succinate, bisoprolol or carvedilol perACCF/AHA Heart Failure Guidelines.

post discharge follow-up arranged by the NT (n = 35) threadmission rate was 6.1%. Patients who received botinterventions of education and follow-up (n = 21) hadreadmission rate of 4.8%.

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Discussion

Our institution's incentive to reduce readmission rates wanot only financial as it relates to penalties imposed by CMbut in alliance with its mission to advance the health of thcommunities it serves and to practice by evidence-baseguidelines and ultimately improve outcomes. Prior to thimplementation of the Patient Navigator Program and NT aour institution there was no active, real-time effort to identifpatients admitted for ADHF. Utilizing the designated Nincreased cognizance of patients admitted with HF. Howeveidentification accuracy was lower than expected. The predominant reason for not identifying an admitted patient wita primary HF diagnosis was inadequate documentation by thattending physician in the patient's electronic medical recordOther contributing factors included short length of staycompeting diagnoses such as atrial fibrillation, pulmonarhypertension, end-stage renal disease and chronic obstructive pulmonary disease and weekend or holiday admissionThe NT enrolled 69 patients who were actively treated foADHF but were not coded as an index HF admission antherefore not appropriate for readmission analysis based oCMS rules. Among this group, the final coding trends includeother cardiac diagnoses and surgical procedures. Thougthese chronic HF patients inherently benefited from Ninterventions, it may have diluted efforts and contributed tmissed acute index admissions.

However, the accurate identification of a HF admissioultimately led to care coordination and enhanced teachinand learning for high risk patients. The impact of nurses anpharmacists as part of an interdisciplinary team oreadmissions has been extensively described in literatureNurses have historically been the most common team leadeand have had multiple roles within a team including carcoordination, case management and serving as liaisons fopatients. The role of the pharmacist in this setting hainvolved identification of unnecessary medications anclinically significant drug interactions, drug monitoringmedication reconciliation and medication adherence education. The makeup of the health professions involved onmultidisciplinary team may vary especially when there aroverlapping scopes, which may consequentially impact th

Table 4 – Comparison of readmission rates by intervention

Readmission rat

Medical Center 25.6%Telemetry Unit 20.9%Patient Navigator Program 17.6%Education intervention 10.3%Follow-up intervention 6.1%Education & follow-up interventions 4.8%

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specific roles of each team member. Therefore, specializetraining inHFmay bemore important thanprovider credentialwhen HF care transitions are involved. Implementing the Nwithin the existing IDT created a platform for routine discussion of ADHF admissions during daily rounds and allowed fogreater awareness.

Before the Patient Navigator Program, clinical pathwayfor ADHF management were not standardized and varied bprovider team. Prior to deployment of the NT, the primareducators on the unit were telemetry nurses. Pharmacistwere not involved in direct patient care activities. Educatioprovided by telemetry nurses was not standardized and dinot specify the amount of time spent with a patient ocaregiver. The majority of documented counseling pointwere on diuretic use or low sodium diet. Guidelines for posdischarge appointments at our institution's outpatient cardology and primary care clinics mandated follow-up withi30 days as opposed to 7 to 14 days. The NT focused odecreasing variance among evidence-based interventionThe resulting standardization of clinical care, education anfollow-updecreased the 30-day readmission rate among theNgroup. The control group and Medical Center had a highereadmission rate because evidence-based interventions sucharoutine biomarker monitoring, adherence to GDMT, HF specifieducation and expedited post discharge follow-up were nostandards of practice. Patients were not routinely identifiedcauses for decompensation were not discussed and strategieto prevent readmission were not addressed prior to discharge

Most importantly, the provision of services by the NT watailored to meet patients' needs and overall risk of adversoutcomes. Greater success occurred when the patient waincluded as a member of the team. Methods to customize thdischarge plan to literacy and social needs increased motivation and adherence. Involving family members and caregiverin post discharge planning and HF management discussionimproved disease state awareness. Effective teaching occurred over several sessions to increase attention anretention. Overall a patient and patient-family-centereapproach proved critical to prevent readmissions. Efforts treduce HF readmissions require a high level of vigilance ancommitment from a designated team. Our study encouragecontinuity of care and allowed team members to collaborateHowever, the role of each team member should be clearldefined. From time of admission to hospital unit to dischargwe recommend the following:

• Identify HF as primary diagnosis early during hospitalzation through daily team discussion

• Confirm HF diagnosis by provider documentation imedical record

• Initiate standardized education in small daily sessionand engage family members or caregivers

• Utilize teach-back method to ensure patient recall• Accurately reconcile medications on admission• Consult heart failure team for readmitted patients anescalate high risk patients to NT or specialized HF educator

• Initiate and/or optimize guideline-directed medical therapy during hospitalization

• Repeat NT-proBNP prior to discharge

• Accurately reconcile medications at discharge and highlight changes in regimen with patient

• Obtain follow-up appointment prior to discharge within 714 days and discuss with patient to ensure transportation

There are several limitations of our study. First, the samplsize was small and the study period was during summer anfall. Seasonal trends in HF hospitalizations demonstratincreased admissions and mortality during winter monthsThe study was conducted on a cardiac telemetry unit whichad an IDT composed of health care professionals witextensive HF experience. Results may not be easily reproducible on a non-cardiac telemetry unit with hospitalists anhouse staff. Because interventions were not blinded orandomized the control group inherently benefited fromfocused readmissions reductions efforts on the unit despitnot being identified or enrolled into the pilot.

Conclusion

The results of our study demonstrated that a diligent effort tidentify hospitalized HF patients led to evidence-baseinterventions that improved patient outcomes and ultimatelreduced the 30-day readmission rate. A designated NT ofnurse and clinical pharmacist allowed for effective deliverand a patient-centered approach.

HRRPs can easily embed a NT into existing initiatives tfurther reduce the readmission rate.



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2. Setoguchi Soko, Stevenson Lynne Warner, SchneeweissSebastian. Repeated hospitalizations predict mortality in thecommunity population with heart failure. Am Heart J.2007;154(2):260-266.

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7. Albert NM, Barnason S, Deswal A, et al. Transitions of care iheart failure: scientific statement from the American HeartAssociation. Circ Heart Fail. 2015;8:384-409.

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8. Bergethon KE, Ju C, Adam MS, et al. Trends in 30-dayreadmission rates for patients hospitalized with heart failurefindings from the get with the guidelines-heart failureregistry. Circ Heart Fail. 2016;9(6), e002594.

9. JackB,BickmoreAT.The re-engineeredhospitaldischargeprogramto decrease rehospitalization. Cardiol Manage. 2011;16:12-17.

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12. ZileMR, Clagget BL, PrescottMF, et al. Prognostic implications ochanges in N-terminal pro-B-type Natriuretic peptide in pa-tients with heart failure. J Am Coll Cardiol. 2016;68:2425-2436.

13. Yancy CW, Jessup M, Bozkurt B, et al. Circulation. 2013; 2013ACCF/AHA guideline for the management of heart failure: areport of the American College of CardiologyFoundation/American Heart Association task force on prac-tice guidelines. J Am Coll Cardiol. 2013;62(16):e147-239.

14. Yancy CW, Jessup M, Bozkurt B, et al. ACC/AHA/HFSA focuseupdate on new pharmacological therapy for heart failure: anupdate of the 2013 ACCF/AHA guideline for the Managemenof Heart Failure. J Am Coll Cardiol. 2016;134:e282-e293.

15. Fonarow GC, Albert NM, Curtis AB, et al. Improvingevidence-based Care for heart failure in outpatient cardiologpractices (IMPROVE HF). Circulation. 2010;122:585-596.

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17. Riegel B, Dickson VV. A qualitative secondary data analysis ointentional and unintentional medication nonadherence inadults with chronic heart failure. Heart Lung. 2016;45:468-474

18. Molloy GJ, O'Carroll RE, Witham MD, et al. Interventions toenhance adherence to medications in patients with heartfailure. Circ Heart Fail. 2012;5:126-133.

19. Ho MP, Bryson CL, Rumsfeld JS. Medication adherence: itsimportance in cardiovascular outcomes. Circulation. 2009;1193028-3035.

20. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline olifestyle Manangement to reduce cardiovascular risk. A repor

of the American College of Cardiology/American HeartAssociation task force on practice guidelines. JACC.2013;65(25):2960-2984.

21. Larsson SC, Tektonidis TG, Gigante B, et al. Health lifestyleand risk of heart failure: results from 2 prospective cohortstudies. Circ Heart Fail. 2016;9, e002855.

22. Djousse L, Driver JA, Gaziano JM, et al. Relation betweenmodifiable lifestyle factors and lifetime risk of heart failure.JAMA. 2009;302(4):394-400.

23. Coleman EA, Parry C, Chalmers S, Min SJ. The care transitionintervention: results of a randomized controlled trial. ArchIntern Med. 2006;166:1822-1828.

24. Jackson C, Shahsahebi M, Wedlake T, et al. Timeliness ofoutpatient follow-up: an evidence-based approach forplanning after hospital discharge. Ann Fam Med. 2015;13:115-122.

25. McAlister FA, Youngson E, Kaul P, et al. Early follow-up afteheart failure exacerbation: the importance of continuity. CirHeart Fail. 2016;9, e003194.

26. Coen Jennifer, Curry Kimberly. Improving heart failureoutcomes. Crit Care Nurs Q. 2016;39(4):335-344.

27. Davis Estella M, Packard Kathleen A, Jackevicius Cynthia A.The pharmacist role in predicting and improving medicationadherence in heart failure patients. J Manag Care Pharm.2014;20(7):741-755.

28. Milfred-LaForest S, Chow SL, DiDomenico EJ, et al.Clinical pharmacy services in heart failure: an opinionpaper from the heart failure Society of American andAmerican College of clinical pharmacy cardiology prac-tice and research network. Pharmacotherapy. 2013;33(5):529-548.

29. Januzzi JJ, Troughton R. Serial Natriuretic peptide measure-ments are useful in heart failure management. Circulation.2013;127:500-508.

30. Bayés-Genís A, Lopez L, Zapico E, et al. NT-ProBNP reductionpercentage during admission for acutely decompensatedheart failure predicts long-term cardiovascular mortality.J Card Fail. 2005;11(5):S3-S8.

31. Verdiani V, Ognibene A, Rutili MS, et al. NT-ProBNP reductiopercentage during hospital stay predicts long-term mortalitand readmission in heart failure patients. J Cardiovasc Med(Hagerstown). 2008;9(7):694-699.



ScienceDirect


Special Article

A Review of Cardiac Rehabilitation Delivery Around
the World
Ella Pesaha, Marta Superviab, c, Karam Turk-Adawid, Sherry L. Gracea, e,⁎aSchool of Kinesiology and Health Science, York University, CanadabCardiovascular Rehabilitation Program, Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USAcMiguel Servet Hospital, Zaragoza, SpaindDepartment of Public Health, Qatar University, Al-Doha, QatareCardiovascular Prevention and Rehabilitation Program, University Health Network, University of Toronto, Canada


Statement of Conflict of Interest: see p⁎ Corresponding author at: School of Kin

IP3, Canada.E-mail address: [email protected] (S.L. Gr


A B S T R A C T

ye

Keywords:Cardiac rehabilitation

eae.rits..

Herein, 28 publications describing cardiac rehabilitation (CR) delivery in 50 of the 113 countries globallsuspected todeliver it are reviewed, to characterize thenatureof services.Government fundingwas thmain source ofCR reimbursement inmost countries (73%),withprivate andpatient funding in about¼of cases.Myocardial infarctionpatientsandthosehaving revascularizationwerecommonlyserved.Thmain professions delivering CR were physicians, nurses, and physiotherapists. Programs offeredmedian of 20 sessions, although this varied. Most programs offered the core components of exercistraining, patient education and nutrition counselling. Alternative models were not commonly offeredLack of human and/or financial resources as well as space constraints were reported as the majobarriers todelivery.Overall,CRdeliveryhasbeencharacterized in less thanhalfof thecountrieswhereis offered. Thenature of servicesdelivered is fairly consistentwithmajorCRguidelines andstatement


Global healthSecondary prevention

Contents

889945556

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

CR delivery in East Asia and the Pacific. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26CR delivery in Europe and Central Asia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27CR delivery in Latin America and the Caribbean . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27CR delivery in the Middle East and North Africa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27CR delivery in North America . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27CR delivery in South Asia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

age 278.esiology and Health Science, Bethune 368, York University, 4700 Keele Street, Toronto, ON M3J

ace).

7served.

6888

Abbreviations and Acronym

AS = administrative support

CABG = coronary artery bypassgraft

CB = community-based

CR = cardiac rehabilitation

CPR = cardiopulmonaryresuscitation

CVD = cardiovascular disease

ECG = electrocardiogram

EQ = equipment

ET = exercise training

FR = financial resources

HB = home-based

HF = heart failure

HR = human resources

IA = initial assessment

IB = internet-based

IHD = ischemic heart disease

LMIC = low- and middle-incomecountry

MI = myocardial infarction

NC = nutrition counseling

NZ = New Zealand

PAW = patient awareness

PCI = percutaneous coronaryintervention

PE = patient education

PR = patient referral

RF = risk factor management

SC = smoking cessation

SM = stress management and/orpsychosocial support/counselling

TI = transportation issues

UAE = United Arab Emirates

VAD = ventricular assist device


Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27Statement of conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . 27Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

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Introduction

By 2030, it is expecte84 million individualwill be diagnosed witcardiovascular diseas(CVD).1 Moreover, it iamong the leadincauses of disabilitaround the world, ancontributes to 10% odisability-adjusted lifyears lost world-wideWith improved survival (ihigh-income countries3

clearly there is a greaneed for secondary prevention,suchas isofferein cardiac rehabilitatio(CR) programs.

Manymeta-analysedemonstrate that participation in CR is associated with improvequality of life, as weas decreased morbiditand mortality.4–7 CR ialso cost-effective.8 Accordingly, it is a classlevel A recommendation in clinical practicguidelines for CVDpatients.9,10

The International,11,1

British13 and Canadian14,1

Associations forCardiovascular Prevention anRehabilitation,AmericaAssociation of Cardiovascular and PulmonarRehabilitation,16AustraliaCardiovascular Healtand RehabilitatioAssociation,17 and thEuropean Associatio

thers,19 have establishe
Rhri-e
-hen

of Preventive Cardiology,18 among oguidelines to ensure consistent provision and quality of Cdelivery in order to achieve the greatest population healtbenefits. They all outline the nature of patients indicated foservices, and make recommendations regarding the compostion of a multi-disciplinary CR team. They also establish th

core components such as initial assessment, structured exercise training, nutrition counseling, patient education, risk factomanagement and psychosocial support.

Recently a review of all CR guidelines was undertakenwhich compared recommendations across countries.20 Whilsome consistencies were noted, much variation was identfied, raising questions about the nature of CR servicedelivered around the globe. There have been few reviews othe nature of CR services on a global scale.21,22 However therhave been a considerable number of studies reporting onational or regional surveys of CR programs.23–26 To ouknowledge these have never been reviewed, with an eye tunderstanding how CR services conform to practice guidelines in different regions of the world. This is important aresults of some of these national surveys have shown thaservices may not meet minimum standards.27 Therefore, thobjectives of this narrative review were to identify thesstudies, to summarize and evaluate what is known about thnature of CR services, namely: funding sources, type annumber of patients served, staff composition, number osessions recommended, components delivered, alternativmodel offerings, and barriers to delivery, by country anregion of the world.

Methods

Studies reporting results of surveys assessing delivery and/ocomponents of comprehensive phase II CR programs onnational or regional level were sought for this narrativreview. Sources were identified by searching MEDLINEPubMed and Scopus. Examples of search terms included“cardiac rehabilitation”, “components”, “characteristics“survey”, “status” and “inventory”. Articles were also identfied by consulting with experts in the field, as well ahand-searching reference lists of CR reviews.

CR characteristics of interest primarily included: capacitand resources, reimbursement sources (i.e., governmensocial security, private insurance), staff composition (i.enurses, cardiologists, physiotherapists), patient diagnoseaccepted into CR programs (i.e. myocardial infarction, percutaneous coronary intervention, angina), dose (programduration × session frequency), core components delivere(i.e. physical training, patient education, dietary counselingalternative model delivery and barriers. All studies reportinresults of surveys describing at least one of these characteristics in the English language were included. Studies witEnglish-language abstracts, where the full publications wernot available in English, were described but not included idata synthesis.

eeedt

eehdsan

Fig 1 – World Map depicting countries where surveys of cardiac rehabilitation programs have been undertaken.


Studies were classified by world regions according to thWorld Bank classification (i.e. East Asia and Pacific, Europand Central Asia, Latin America and the Caribbean, MiddlEast and North Africa, North America, South Asia anSub-Saharan Africa).28 Data was extracted in tabular formaand summarized qualitatively.

03oesg1.).gll6tdnnfene

nRee.

R]srt

dynsnde),gd

essrss-1

Results

A total of 35 publications were included, describing CR in 5(25%) of the 203 countries of the world, or (44%) of the 11countries (manuscript in preparation) where CR is known tbe offered. Forty-two were high-income countries,28 with thremaining from middle-income countries. Multiple studiewere identified in the United Kingdom, Europe (includinPortugal), as well as North and South/Latin America. Figdisplays the countries with CR where a study was identified

An additional 10 citations were identified (total = 45There were 4 English-language abstracts identified describinCR in Chile, Italy, Hong Kong and Mexico,29–33 but the fupublications were not available in English. There were alsopapers identified describing CR but they did not reporprimary data (Germany, Hong Kong, Singapore, Switzerlanand Thailand34–39). These publications were summarized ithe text only. Two non-English publications were found iJapan and Spain40,41 that were excluded. Finally, an issue oProgress in Cardiovascular Diseases was comprised of narrativreviews on CR delivery in Canada, United States, Brazil, LatiAmerica, India and Japan.42–47 What primary data could bgleaned from these sources were summarized in the text.

A summary of findings from included studies is shown iTable 1, except those with a specific focus on an aspect of Cdelivery (e.g., ventricular assist device patients [VAD]; thesare described in text only). No studies were identified in thfollowing regions: Sub-Saharan Africa and South Asia

Thirteen (57%) of the included studies were published sinc2010, and hence can be considered fairly current. Thresponse rate across all studies is reported in the Table, witsummary statistics for all major elements for each region anoverall shown at the bottom. The total number of programidentified by country ranged from a minimum of 124 tomaximum of 1000,48 with a median of 65. Results not showin the table are summarized below.

CR delivery in East Asia and the Pacific

There have been 6 studies in this region, reporting on Cservices in Australia, China, Japan and New Zealand (4 [11%of 38 countries; 1 [4%] of 23 low and middle-income countrie[LMICs]). There were also two descriptive studies found foGermany and Switzerland,36,39 and therefore these were noincluded in Table 1 but are described below.

First, a survey conducted in Australia and New Zealan(NZ)49 aimed to describe the prevalence of cardiopulmonarresuscitation (CPR) training for patients and their families iCR programs (and hence is not shown in Table 1). Surveywere completed by 253 (47%) phase II programs; 206 (46%) iAustralia and 45 (52%) in New Zealand. Findings indicateCPR training was only available in 74 (30%) CR programs. Thtraining was delivered by nurses (82%), physiotherapists (8%and exercise physiologists (4%). Major barriers to CPR traininin CR were lack of resources (50%), awareness (34%) antime (11%).

Two national surveys were conducted in Australia. Thfirst aimed to describe the status of CR in Australia.50 Findingindicated that the mean exercise session duration wa55 min. In addition to those shown in Table 1, othehealthcare professionals on the teams were pharmacist(69%), occupational therapists (61%) and social worker(52%). Psychological counselling (86%), and medication education (86%) were also offered inmost programs. The second5

Tab

le1–Su

mm

aryof

findings

–resu

ltsfrom

national/reg

ional

survey

sof

CRpr

ogram

s,N

=28

.

Res

ults

Cou

ntry

(yea

rof

publication)

Num

bero

fresp

onde

nts/

numbe

rof

CRcenters

(respo

nse

rate

%)

Reim

bursem

ent

Source

§,‡

Patie

ntdiag

noses

accepted

‡

(%of

prog

rams)

Patie

nts

Served

§

perprog

ram

orcoun

try

peryear

Staff

compo

sitio

n‡

(%of

prog

rams)

Dos

e§

(wee

ks×

freq

uency

/wee

k)

Core

compo

nents

deliv

ered

‡

(%of

prog

rams)

Alte

rnate

mod

els

(%ye

s)

Barriers

‡

(%of

prog

rams)

East

Asiaan

dth

ePa

cific

Australia

50

(201

6)22

5/30

5(74%

)Pu

blic

(68%

)Private(13%

)Pa

tien

t(14%

)

MI(10

0%)

CABG

(100

%)

PCI(10

0%)

250

Nurses

(88%

)Dietitian

s(82%

)Ph

ysiotherap

ists

(77%

)

11(7

×1.6)

ET(100

%)

PE(98%

)NC(88%

)

CB(18%

)HB(15%

)-

China5

3

(201

6)10

/--

PCI(10

0%)

HF(100

%)

MI(92

%)

-Ph

ysicians(100

%)

Nurses

(85%

)Dietitian

s(46%

)

-IA

(100

%)

PE(100

%)

NC(100

%)

-Interest

inCR

(58%

)HR(58%

)PA

W(50%

)Japa

n55

(200

7)52

/-Pu

blic

(100

%)

-4,89

6-

--

HR(77%

)EQ

(41%

)Ach

ieving

facilit

ystan

dard

s(31%

)New

Zea

land5

2

(201

6)34

/46

(74%

)-

--

-6(6

×1)

ET(100

%)

RF(100

%)

NC(100

%)

CB(62%

)HB(12%

)-

Reg

ional

summary:

mea

n(m

edian)

74%

(74%

)Pu

blic;8

4%(84%

)PC

I:10

0%(100

%)

MI:96

%(96%

)~

Nurses

:87

%(87%

)Dietitian

s:64

%(64%

)

8.6(8.6)

(6.5

[6.5]×

1.3

[1.3])

ET:1

00%

(100

%)

NC:9

6%(100

%)

PE:9

9%(99%

)

CB:

40%

(40%

)HB:

14%

(14%

)HR:6

8%(68%

)

Euro

pean

dCen

tral

Asia

Euro

pe58

(200

2)-

13co

untries

252/44

3(57%

)-

--

Phys

ioth

erap

ists

(90%

)¶

Nurses

(87%

)¶

Cardiolog

ists

(82%

)¶

-(8.4×[-])

ET(95%

)¶

NC(90%

)¶

SC(70%

)¶

--

Euro

pe23

(201

0)-

28co

untries

28/39⁎

(72%

)Pu

blic

(89%

)Private(39%

)CABG

(86%

)MI(82

%)

Valve

(60%

)

--

-(9×[-])

-HB(28%

)-

United

Kingd

om66

(199

8)26

3/27

3(96%

)-

--

Nurses

(89%

)Ph

ysioth

erap

ists

(85%

)Dietitian

s(84%

)

--

--

Englan

d&

Wales

25

(199

7)22

/25⁎⁎

(88%

)Pu

blic

(56%

)-

166

3,81

3Nurses

(100

%)¶

Phys

ioth

erap

ists

(88%

)¶

Phys

icians(16%

)¶

11(7

×1.5)

ET(100

%)

PE(100

%)

SM(96%

)

CB(4%)

HB(4%)

-


publication)

numbe

rof

CRcenters

(respo

nse

rate

%)

acce

pted

‡

(%of

prog

rams)

perprog

ram

orcoun

try

peryear

(%of

prog

rams)

freq

uenc

y/wee

k)de

livered

‡

(%of

prog

rams)

(%ye

s)prog

rams)

Den

mark6

0

(200

5)44

/--

MI(10

0%)

IHD

(81%

)HF(75%

)

-Ph

ysioth

erap

ists

(100

%)

Dietitian

s(89%

)

-NC(89%

)ET

(77%

)SM

(71%

)

--

Englan

d26

(200

6)28

/28⁎⁎

(100

%)

-MI(10

0%)

CABG

(100

%)

-Nurses(100

%)

Phys

iotherap

ists

(90%

)Dietitians

(90%

)

14(7

×2)

ET(100

%)

PE(100

%)

SM(100

%)

HB(36%

)CB(21%

)-

Irelan

d67

(200

1)21

/-(81%

)Pa

tien

ts(14%

)-

-Coo

rdinator

s,Nurses

,Dietitian

s14

(8×1.7)

ET,P

E,SM

-PR

N.Ireland6

8

(199

7)8/9

(89%

)-

MI(10

0%)

CABG

(88%

)HF(13%

)

--

6(6

×1)

--

-

Italy6

1

(200

8)51

/65

(78%

)Pu

blic

(99%

)-

-Ph

ysicians(100

%)

Nurses

(90%

)Ph

ysioth

erap

ists

(84%

)

-(12.5×[-])

-HB(10%

)-

Portuga

l62

(200

7)12

/12

(100

%)

Public

(51%

)Pa

tien

ts(-)

--

Cardiolog

ists

(100

%)

Nutritionists

(92%

)Ph

ysioth

erap

ists

(85%

)

--

--

Portuga

l63

(201

0)14

/14

(100

%)

Public

(82%

)Pa

tien

t(8%)

--

Cardiolog

ists

(100

%)

Phys

ioth

erap

ists

(88%

)Nutritionists

(81%

)

-ET

(100

%)

RF(75%

SM(25%

)

--

Portuga

l64

(201

6)19

/19

(100

%)

Public

(90%

)Pa

tien

t(5%)

-1,92

7Cardiolog

ists

(100

%)

Nutritionists

(87%

)Ph

ysioth

erap

ists

(87%

)

25(10×2.5)

ET(100

%)

RF(96%

)NC(96%

)

--

Scotland6

9

(199

6)69

/69

(100

%)

Public

(50%

)MI(96

%)

PCI(81

%)

Angina(70%

)

4,98

0-

--

-Res

ources

(46%

)

Spain65

(200

3)11

/12

(92%

)-

MI(10

0%)

PCI(10

0%)

CABG

(91%

)

639

Phys

ioth

erap

ists

(100

%)

Nurses

(100

%)

Cardiolog

ists

(82%

)

30(10×3)

PE(100

%)

ET(73%

)SM

(55%

)

-AS(73%

)PA

W(55%

)Res

ources

(55%

)Su

mmary:

mea

n(m

edian)

89%

(96%

)Pu

blic:7

4%(82%

)MI:96

%(100

%)

CABG

:91%

(90%

)PC

I:91

%(91%

)

402(402

)3,57

3(3,573

)Nurses:94

%(94%

)Ph

ysiotherap

ists:9

0%(88%

)Ph

ysicians

:83%

(100

%)

17(14)

(9[9]×

2[2])

PE10

0%(100

%)

ET92

%(100

%)

SM70

%(71%

)

HB:

19%

(19%

)CB:

12%

(12%

)~

LatinAmericaan

dth

eCaribbe

anLa

tinAmerica

andthe

Caribb

ean7

0

(2009)-9

coun

tries

33/-

Public

(48%

)Private(24%

)Pa

tien

ts(-)

MI(10

0%)

PCI(97

%)

CABG

(97%

)

-Ca

rdiologists(100

%)

Physiotherap

ists

(94%

)Dietitians

(91%

)

33(13×2.5)

-CB(48%

)HR(41%

)FR

(33%

)Sp

ace(13.0%

)

SouthAmerica7

1

(201

3)-9

coun

tries

107/-

Mixed

(46%

)Private(19%

)Pa

tien

t(18%

)

MI(10

0%)

PCI(99

%)

CABG

(97%

)

180

Cardiologists(85%

)Nutritio

nists(72%

)Ph

ysiotherap

ists

(72%

)

-ET

(97%

)RF(96%

)NC(91%

)

-FR

(13%

)TI(13

.0%)

Spac

e(6%)

(con

tinue

don

next

page)


Tab

le1(con

tinue

d)

Res

ults

Cou

ntry

(yea

rof

publication)

Num

bero

fresp

onde

nts/

numbe

rof

CRcenters

(respo

nse

rate

%)

Reim

bursem

ent

Source

§,‡

Patie

ntdiag

noses

accepted

‡

(%of

prog

rams)

Patie

nts

Served

§

perprog

ram

orcoun

try

peryear

Staff

compo

sitio

n‡

(%of

prog

rams)

Dos

e§

(wee

ks×

freq

uenc

y/wee

k)

Core

compo

nents

deliv

ered

‡

(%of

prog

rams)

Alte

rnate

mod

els

(%ye

s)

Barriers

‡

(%of

prog

rams)

Mex

ico7

2

(201

6)24

/24

(100

%)

-IH

D(100

%)

PCI(10

0%)

HF(92%

)

-Ph

ysicians

(100

%)

Adm

inistrative

assistan

ts(100

%)

Physiotherap

ists

(83%

)

-ET

(100

%)

NC(90%

)SM

(80%

)

HB(37.5%

)FR

(83%

)HR(67%

)EQ

(46%

)

Summarymea

n(m

edian)

~Private:

21%

(21%

)MI:10

0%(100

%)

PCI:99

%(99%

)CABG

:97%

(97%

)

~Ph

ysicians:

95%

(100

%)

Dietitian

s:81

%(81%

)

~ET

:98%

(98%

)NC:9

0%(90%

)~

HR:5

4%(54%

)FR

:58%

(58%

)Sp

ace:

9%(9%)

MiddleEa

stan

dNor

thAfrica

ArabCo

untries2

4

(201

5)-4

coun

tries

5/8

(63%

)Pu

blic

(40%

)Private(40%

)-

224

Nurses

(60%

)Cardiolog

ists

(40%

)Ph

ysioth

erap

ists

(20%

)

25(11×2.3)

PE(100

%)

IA(80%

)ET

(80%

)

Not

offered

PR(60%

)Sp

ace(50%

)HR(50%

)

Nor

thAmerica

Can

ada2

4

(201

5)39

/128

(31%

)Pu

blic

(100

%)

Patien

ts(34%

)-

512

Nurses(56%

)Ex

ercise

specialists

(38%

)Ph

ysiotherap

ists

(35%

)

41(18×2.3)

PE(100

%)

NC(100

%)

ET(100

%)

CB(28%

)HB(3%)

FR(62%

)HR

(34%

)Sp

ace

(22%

)Ontario,C

anad

a74

(201

2)38

/45

(84%

)-

--

-44

(22×2)

PE(97%

)ET

(97%

)RF(92%

)

HB(68%

)IB

(11%

)-

United

States

48

(201

3)13

7/10

00(14%

)-

-12

919

,689

Nurses(38%

)Ex

ercise

specialists

(28%

)Re

spiratorytherap

ists

(10%

)

-PE

(100

%)

--

United

States

76

(201

4)28

1/82

3(34%

)-

-16

541

,525

--

--

-

New

Yor

k,UnitedStates

77

(199

0)

16/24

(67%

)Pa

tien

ts(-)

--

Exercise

specialists

(90%

)Ph

ysicians

(69%

)Ph

ysiotherap

ists

(25%

)

-ET

(100

%)

PE(55%

)RF(45%

)

--

Nor

thCarolina,

UnitedStates

78

(200

6)

61/77

(79%

)-

--

Nurses(97%

)Ex

ercise

specialists

(87%

)Dietitians

(84%

)

-SM

(100

%)

NC(100

%)

ET(97%

)

--

Ohio,UnitedStates

79

(201

2)94

/142

(66%

)-

--

Exercise

specialis

ts(73%

)ET

(97%

)NC(97%

)SC

(88%

)

--

Summarymea

n(m

edian)

41%

(32%

)~

~26

9(165

)30

,607

(30,60

7)Nurses

;70%

(73%

)Ex

ercise

specialists:

42(42)

(20[20]

×2[2])

ET:9

8%(97%

)HB:

35%

(35%

)~


fte2y-te

s1nnnrslr

es),yR,)).nte

RtRl-ye

f),ndnee

6efdtsse-n

Re

publication)

numbe

rof

CRcenters

(respo

nse

rate

%)

accepted

‡

(%of

prog

rams)

perprog

ram

orcoun

try

peryear

(%of

prog

rams)

freq

uenc

y/wee

k)de

livered

‡

(%of

prog

rams)

(%ye

s)prog

rams)

57%

(56%

)Ph

ysiotherap

ists:

30(30)

PE:8

8%(99%

)NC:9

9%(100

%)

Ove

rallsu

mmary

mea

n(m

edian)

76%

(79%

)Pu

blic:7

3%(75%

)Private:

27%

(24%

)Pa

tien

t:26

%(26%

)

MI:97

%(100

%)

PCI:97

%(100

%)

CABG

:94%

(97%

)

283(202

)12

,805

(4,938

)Ph

ysicians

:84%

(100

%)

Nurses;81

%(88%

)Ph

ysiotherap

ists

89%

(85%

)

22(20)

(10[9]×2[2])

ET:9

5%(99%

)PE

:95%

(100

%)

NC:9

5%(96%

)

CB:

30%

(24%

);HB:

24%

(15%

)HR:5

3%(52%

)FR

:47%

(46)

Spac

e:23

%(17%

)

(-)A

rticle

didnot

repo

rt.

~Unab

leto

compu

te.

CABG

=co

ronar

yar

tery

bypas

sgr

aft;

HF=Hea

rtfa

ilure

;IH

D=isch

emic

hea

rtdisea

se;MI=m

yoca

rdialin

farc

tion

;PC

I=per

cuta

neo

us

coro

nar

yin

terv

ention

;VAD

=ve

ntricular

assist

dev

ice.

CB=co

mmunity-ba

sed;

HB=hom

e-ba

sed;

IB=intern

et-bas

ed(orother

form

oftech

nolog

y).

IA=initialas

sessmen

t;ET

=ex

ercise

training;

RF=risk

factor

man

agem

ent(w

hich

inso

meinstan

cesmay

include

smok

ing);PE

=Pa

tien

ted

uca

tion

;NC

=nutrition

counse

ling;

SC=sm

oking

cessation;S

M=stress

man

agem

entan

d/or

psyc

hos

ocials

upp

ort/co

unse

lling.

AS=ad

ministrativesu

ppor

t;EQ

=eq

uipmen

t;FR

=finan

cial

reso

urces

;HR=human

reso

urces

;PAW

=pa

tien

taw

aren

ess;

PR=pa

tien

treferral;T

I=tran

spor

tation

issu

es.

‡Only

thetop3repo

rted

arelis

ted.

§Ifon

lyarange

was

prov

ided

,themidpo

intof

range

sis

repo

rted

;ifmultiple

range

srepo

rted

,theon

ewithth

ehighes

tpe

rcen

tage

was

repo

rted

.⁎numbe

rof

countries(1

survey

was

fille

dou

tpe

rco

untry).

⁎⁎Only

sub-sa

mpleof

entire

popu

lation

survey

ed.

¶Valueba

sedon

appr

oxim

ationfrom

figu

re.A

uth

orco

ntacted

torequ

estac

tual

values

,butnoresp

onse

.


study aimed to describe screening and assessment opsychosocial risk factors in CR programs (and hence was noshown in Table 1). Surveys were completed by 165 (49%) phasII programs. Of these, 157 (95%) screened at entry and 13(80%) screened at exit. Patient screening was undertaken bnurses (98%), physiotherapists (46%), and exercise physiologists (15%). Major barriers to screening included insufficienstaff time (44%), lack of funding (24%), lack of administrativsupport (24%), and lack of space (21%).

In the survey conducted in New Zealand,52 findingindicated that 50% of programs had a session frequency ofsession per week. In addition to the core components showin Table 1, stress management (94%), smoking cessatio(79%), and weight management (59%) were also included imost CR programs. The survey also assessed support fospecial populations (i.e. Maori and Pacific peoples). Resultshowed that 56% of programs provided a specific culturaprovider or liaison, but 29% of programs offered no support fothese patients.

In the survey in China,53 findings indicated programs weronly available in 8% of hospitals. In addition to providershown in Table 1, CR teams included clinical educators (31%exercise physiologists (15%), and psychologists (15%). Dietarcounseling and smoking cessation were also offered in all Cprograms. In addition to themajor diagnoses shown in Table 1most programs also accepted patients with pacemakers (92%and post-coronary artery bypass graft surgery (CABG; 69%Major barriers to establishing CR (specified in this paper iaddition to those to delivering CR) were mainly lack of interes(58%), human resources (58%), awareness (50%), and spac(47%).

An English-language abstract33 and study34 describing Cin Hong Kong specifically were also identified. The abstracoutlined a survey that was completed by 9 phase II Cprograms. Results showed that all CR teams include cardioogists, nurses and physiotherapists. The descriptive studoutlined phase II CR components that included exercistraining, relaxation therapy, and risk factor management.

There were 4 publications in Japan, based on surveys ohospitals (including designated cardiology training centresregarding their delivery of CR. In the survey conducted i199954 76 hospital directors were contacted and 46 responde(61%). Results indicated that 21% of MI patients participated iCR. In the 2007 survey,55 findings indicated CR programs weronly available in 5% of hospitals. Only 6% of facilities werapproved for CR. Assuming all patients transferred fromphase I CR, phase II programs served an estimated 4,89patients. Barriers to implementing CR other than thosreported in Table 1 included lack of space (23%), and 12% ohospitals believed CR was not necessary. A seconpublication56 based on the 2007 survey55 analyzed patiensafety in CR. Findings indicated the rate of adverse events wa12 events/383, 096 patient hours. The final publication57 wabased on a 2009 national survey40 and aimed to examine thCR referral process in Japan. Findings indicated that outpatient CR was implemented in 18% of hospitals, which was aincrease from the previous assessment.

In addition, there was a narrative review44 comparing Cstatus between the 2004 survey (described above) and th

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2009 survey (published in Japanese).40 This reported thapublic health insurance covers only 70% of CR costs fopatients under 70 years old and 90% for patients over 70 yearold. In terms of CR implementation, rates doubled from 9% t21%, however CR was still only offered in 325 (4%) of 8,24hospitals. On average, patients have a longer hospital stawhich can explain the in-patient nature of CR in Japan. Amajor barrier cited was patient referral; there is no system oreferral in Japan, and if the patient has not been treated infacility that offers CR they will not participate in any CR at alFinally, another national survey was conducted in 201(personal communication, Yoichi Goto, October 24, 2016); thresults of this survey are greatly awaited.

In the paper describing CR in Singapore35, 3 phase II Cprograms were identified. All programs included exercistraining and patient education. Phase II programs fromcenters were described in detail. Program durations wereand 12 weeks respectively, with a session frequency ofsessions/week. Both centers included nurses and physiotherapists as part of the CR team. The main center acceptepatients with myocardial infarction(MI), CABG, percutaneoucoronary intervention (PCI), heart transplant, angina, hearfailure and valvular disease.

In the paper describing the status of CR in Thailand,38 5 Cprograms were identified (phase was not specified). Thesprograms included exercise and lifestylemodification. The barrierto patient participation in CR listed were time constraintstransportation, and lack of a caregiver to take them to sessions.

CR delivery in Europe and Central Asia

There have been 15 studies in this region, covering CR in thfollowing 32 countries: Austria, Belarus, Belgium, CroatiaCyprus, Czech Republic, Denmark, England, Finland, FranceGermany, Greece, Hungary, Iceland, Ireland, Italy, LithuaniaLuxembourg, the Netherlands, Norway, Northern IrelandPoland, Portugal, Romania, Russia, Serbia, Slovak RepublicScotland, Spain, Sweden, Switzerland, and Wales (54% of 5European/Central Asian countries; 4 [19%] of 21 regionaLMICs). One English language abstract in Italy31 anddescriptive study in Switzerland36 were also identified. Onote, 3 (23.1%) of these studies noted phase II CR servicebeing provided in a residential setting.

Three regional surveys were conducted in Europe. In the firssurvey,58 findings indicated that most programs offered 20–2exercise sessions (40%). In addition to those shown inTable 1othehealthcare professionals on the teams were dietitians, psychologists and social workers. Another core component that was alsoffered inmany phase II programs was smoking cessation.

The second of these studies23 was completed by respondents each describing CR delivery in their entire countryTwenty-four (86%) of these countries were high-incomeResults showed that majority of CR programs had a duratioranging between 6–12 weeks. As well as the major diagnosepresented in Table 1, CR programs also accepted patients witheart transplants (46%). Finally, many countries offereresidential phase II programs; 3 (11%) countries offered onlsuch programs, and 18 (64%) offered them in addition to othemodels.

The third and final European survey59 aimed to describthe characteristics of programs for VAD patients specificall(and hence is not shown in Table 1). Surveys were completeby 32 phase II programs in VAD centers in 26 countrieResults specified the duration of out-patient CR programs tbe between 4 and 12 weeks. CR teams were composed ophysiotherapists (73%), psychologists (51%), nurses (49%specialized cardiologists (49%) and dietitians (47%). Thexercise component of many programs included exercistraining (84%), respiratory muscle training (55%), and resistance training (49%). Alternative models were offered, mostlhome-based (9%).

The survey in Denmark60 was completed by 44 phase II Cprograms. CR teams were also composed of nurses anphysicians. The core component that was also offered imany programs was smoking cessation (71%).

Two surveys were conducted in Italy. In the first,61 iaddition to those shown in Table 1, other healthcarprofessionals on CR teams were psychologists (74%) andietitians (62%). Sixty-eight percent of phase II programwere residential. The mean length of stay for these programwas 18.5 days. Results of the second survey31 were reported ian English-language abstract. The survey was completed b102 phase II programs. Over 75% of programs were headed ba cardiologist. In terms of alternative models, 8% offeretele-rehab and 5% offered home-based CR.

Three surveys were conducted in Portugal. In the first,62 iaddition to those noted in Table 1, CR teams also includephysiatrists (61%), and psychologists (61%). In the second,6

findings indicated that in addition to the healthcare providershown in Table 1, again physiatrists (75%) and psychologist(62%) were also included as part of the CR team. In the mosrecent survey,64 again physiatrists (74%) and psychologist(61%) were also included as part of the CR team. The corcomponents that were also offered in most programs werdietary counseling (96%), and smoking cessation (96%).

In the survey conducted in Spain,65 in addition to thosshown in Table 1, occupational therapy (9%) was offered apart of the CR program. In addition to the major diagnoseaccepted shown in Table 1, patients with valvular surger(73%) and with heart failure (64%) were also included. Barrierto CR creation (not delivery as shown in the Table) includelack of support from administration (72.7%), lack of patieninformation/patient skepticism (54.5%), and lack of stainterest (45.5%).

Finally, for Europe, 2 descriptive studies were also identfied. In the Swiss paper,36 57 phase II CR programs weridentified. CR teams were composed of cardiologists, physiotherapists, nurses, dietitians, psychologists, occupationatherapists and social workers. In the German paper,3

coverage for phase II CR by government for all MI patientand following CABG and valvular surgeries was describedPhase II programs were delivered in inpatient and outpatiensettings, where both are 3 weeks long and are delivered bymultidisciplinary team including physicians, nurses, exercisspecialists, physiotherapists and nutritionists.

Six surveys were conducted in the United Kingdom. In thfirst survey66 which was conducted throughout the 4 countries, findings indicated that, in addition to the top

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healthcare professions shown in Table 1, CR teams alsincluded occupational therapists (40%) and physicians (39%In the second survey25 conducted in England and Walefindings indicated the mean exercise session duration wa55 min. There were 7 major public funding bodies reportewhich reimbursed CR services, but for 7 (28%) programfunding source was unknown. In addition to the healthcarprofessionals shown in Table 1, CR teams also includedietitians (8%), psychologists (4%) and exercise physiologist(4%). Counselling (40%) was also offered as a component of Cprograms.

In the survey conducted in England only,26 results showethat the mean exercise session duration was 60 minutes. Iaddition to those shown in Table 1, other healthcarprofessionals on the teams were pharmacists, occupationatherapists and psychologists.

In the survey conducted in Ireland only,67 results showethat 21 of 53 (40%) hospitals had a CR program (of which 1were in the Republic of Ireland, with the remainder iNorthern Ireland). Other healthcare professionals deliverinCR were physiotherapists and ECG technicians. Other components offered included smoking cessation, medicatioadvice as well as sexual and vocational counselling. Iaddition, the study in Northern Ireland68 showed that fewcenters (13%) accepted patients with valvular disease, hearfailure, angina, or PCI.

Finally, for the United Kingdom, a survey was conducted iScotland.69 Findings indicated programs were only availablin 7% of hospitals. As well as the major diagnoses accepted iCR programs shown in Table 1, patients suffering from hearfailure (35%) were also accepted. Another major barrier tpatient participation identified was transportation issue(49%).

CR delivery in Latin America and the Caribbean

As shown in Table 1, there have been 3 studies in this regionrepresenting CR in the following 11 countries: ArgentinaBrazil, Chile, Colombia, Costa Rica, Ecuador, Mexico, Paraguay, Peru, Uruguay and Venezuela (11 [26%] of 42 countries;[35%] of 26 LMICs in the region). One English-languagabstract was identified from Chile.29

In the survey conducted in Latin America and thCaribbean,70 in addition to those shown in Table 1, CR teamwere also composed of nurses (52%), psychologists (48%), ansocial workers (33%). As well as the major diagnoses acceptein CR programs shown in Table 1, patients with valvulaconditions (82%), heart failure (73%) and heart transplant(21%) were also accepted.

In the survey in South America,71 in addition to thhealthcare providers listed in Table 1, many CR teams alsincluded psychologists (53%), nurses (50%), and sport physcians (32%). Psychological counseling (68%) and smokincessation (59%) were also provided as core components imost programs. As well as themajor diagnoses accepted in Cprograms shown in Table 1, patients with heart failure (97%and valvular disease (95%) were also accepted. Notably, thmain perceived barrier to CR participation was lack of patienreferral (70%).

Two surveys were conducted in Mexico. In the first,7

findings revealed CR teams were also composed of nurse(79%), nutritionists (79%) and psychologists/psychiatrist(71%). In addition to those shown in Table 1, programs alsaccepted patients with CABG (87%) and valvular disease (83%Other barriers to CR cited included lack of space (42%), andreduction in operating centers (38%).

An English-language abstract was identified from a surveconducted in Chile.29,73 The survey was completed by 7 (87%phase II programs. Findings indicated that CR teams wermainly composed of cardiologists, nurses, physiotherapistand nutritionists. All programs included initial assessmenphysical activity counseling, and dietary counseling. Thmajor barrier reported was a lack of patient referral.

There have been 2 narrative reviews in Latin America.43,4

The review in Latin America43 showed that the source of Cfunding across this region was highly variable. Onlycountries offered 100% coverage through the national healtsystem, while patients paid for most programs out-of-pockeCore components commonly available included exercistraining, risk factor management, and patient educationMajor barriers described included poor physician referradistance to CR center, lack of finances and lack of trainepersonnel.

Finally, the narrative review in Brazil47 indicated that thduration of Phase II CR was between 3 and 6 months, witmany programs allowing patients to stay longer. Exercissessions were typically offered 3 times/week for 55 min. Mosprograms were comprised of an interdisciplinary teamincluding physicians, physical educators, physiotherapistspsychologists and nutritionists. The major barrier to Caccess was funding, as CR is more available to patients witthe means to pay or who have insurance. Another barrier wathat CR was mainly located in large urban centers.

CR delivery in the Middle East and North Africa

As shown in Table 1, there has been 1 study in this region,2

reporting on CR services in Bahrain, Egypt, Qatar and thUnited Arab Emirates (4 [19%] of 21 countries; 1 [8%] of 1LMICs in the region). The survey was completed by 5 (62%phase II CR programs. Results indicated that, along with thosshown in Table 1, CR teams included social workers (20%), anexercise specialists (20%). Nutrition counselling (80%) anprescription or titration of secondary prevention medication(80%) were also offered in most CR programs. The majobarriers (reported on a 5-point scale, with higher scoreindicating greater barriers) also included lack of financiaresources (3.6) and equipment (3.6).

CR delivery in North America

As shown in Table 1, there have been 7 studies in this regionfrom Canada, its province of Ontario, and the United Statesincluding in the states of New York, North Carolina and Ohi(2 [67%] of 3 countries; all high-income). In the nationaCanadian study,24 alongside those presented in Table 1, Cteams also included kinesiologists (35%) and dietitians (12%All programs also offered nutrition counselling (100%) an

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physical activity counselling (100%) as core components of thprogram. Major barriers (again reported on the same 5-poinscale as per above) also included patient referral (3.2), and lacof equipment (2.7). In the provincial survey,74 results showethat in addition to those shown in Table 1, 68% of programalso offered psychosocial services. There were also 2 narrativreviews published describing CR status in Canada.42,75

The two surveys conducted in the United States and thesurveys conducted in the individual states of New York, NortCarolina, and Ohio are shown in Table 1.48,76–79 Finally,narrative review describing CR in the United States45 listelack of patient referral and distance to CR programs as majobarriers to CR participation.

CR delivery in South Asia

A narrative review was published describing CR in India.4

The publication showed that there are less than 50 programin the entire country. Programs are delivered by physiotherapists, physicians, dietitians and nurses. Alongside exercistraining, many programs in India include yoga as componenof CR. The major barriers to CR were distance from the Ccenter and lack of transportation.

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Discussion

Through this review, the nature of CR services in less thahalf of countries offering CR around the globe was characterized. This first-ever such study sheds light on variation iquality and nature of CR globally. Clearly evidence-basepractices should be applied consistently globally, but tailorinto local health systems and patient needs is requiredArguably many of the recommendations in CR guidelines arconsensus rather than evidence-based however. Regardlessthe results herein for the first time characterize how CR idelivered in relation to established standards.13,14,18,27

Most programswere funded publicly (73%of studies reportinfunding source). This is positive, considering previous researchas shown that more sessions are funded where programs arfunded publicly.80 Regionally, in Europe and Central Asia CR wamore commonly reimbursed through a national health servicewhile in the rest of the world private systems may play a morimportant role (e.g., United States, Middle East and North AfricaWhile this review shed light on CR reimbursement and variatioin these sources,more information regarding CRdelivery costs tthe healthcare system and to patients would be informative.

Where reported, MI was the diagnosis most frequentlyaccepted in Europe and Central Asia, compared to PCI iEastern Asia and Pacific, as well as Latin America and thCaribbean. Clearly, there is excellent evidence supporting thbenefits of CR for acute coronary syndrome and associaterevascularization. There is now growing evidence supportinthe benefits of CR for arrhythmia patients,81,82 those witvalve disorders,83 and heart failure.84–86 With regard to thformer, atrial fibrillation was not mentioned as an indicatioin any study (this could be due to recency of evidencregarding the benefits of exercise in this population), howeverhythm devices were stated as an indication in man

European countries (i.e., Austria, Belarus, Belgium, CroatiaCyprus, Czech Republic, Denmark, England, Finland, FranceGermany, Hungary, Iceland, Ireland, Italy, Lithuania, Luxembourg, the Netherlands, Norway, Northern Ireland, PolandPortugal, Romania, Russia, Serbia, Slovak Republic, ScotlandSpain, Sweden, Switzerland, Wales) and also Mexico foexample. Valve disorders/procedures were also recognizeindications in many European (Austria, Belarus, BelgiumCroatia, Cyprus, Czech Republic, Denmark, England, FinlandFrance, Germany, Hungary, Iceland, Ireland, Italy, LithuaniaLuxembourg, the Netherlands, Norway, Northern IrelandPoland, Portugal, Romania, Russia, Serbia, Slovak RepubliScotland, Spain, Sweden, Switzerland, Wales, Singapore, anSpain) as well as South American (Argentina, Brazil, ChileColombia, Costa Rica, Ecuador, Mexico, Paraguay, Peru, UruguayVenezuela) countries. A very similar list of countries alsaccepted HF patients. Thus, it seems CR programs have thcapacity and expertise to adapt to new evidence, and accordinglchange their policies regarding patient indications for admission

In the 7 (30%) studies reporting capacity, the number opatients served per program ranged from 129 to 639, withmedian of 202. This appeared higher in Europe than NortAmerica. The impact of patient volume on CR care qualitappears irrelevant based on early work on this question fromthe United Kingdom,87 but research has suggested highevolume acute cardiac care centres have better outcomes thalower-volume ones.88 The number of patients served pecountry was also reported in some instances, and datconfirmed the gross under-capacity established in othework.89

When comparing by region, considerable comparability iCR staff composition was observed. In almost all studies (n21, 72%), programs were delivered by a multidisciplinarteam. The most common types of healthcare providers werphysicians, nurses and physiotherapists. While there is nonecessarily an evidence base to support recommendationthat CR programs be staffed by an inter-professional teamthis certainly supports competent delivery of all recommended core components needed to optimize secondary prevention. Contrary to some (but not all20) guidelinrecommendations15,16,18 that CR be directed by physicianhowever, these providers were only among the top threemosfrequent personnel in the Middle East and North Africa, LatiAmerica and the Caribbean, Europe as well Central Asia (bunot in East Asia, the Pacific, and North America). Alsinterestingly, in some regions physiotherapists were a maipart of the team (n = 17 of 21 papers reporting staff composition, e.g., Australia, England, Scotland, Northern IrelandWales, Denmark, Italy, Portugal, Spain, Mexico, BahrainEgypt, Qatar, UAE and Canada; e.g.,24,50,61,66), whereas iothers, exercise specialists were more common (i.e., exercisphysiologists, kinesiologists; n = 7 of 21 papers reporting stacomposition; North America, China and the Middle Ease.g.,24,48). Whether this is a function of availability of traininprograms and hence staff to hire, reimbursement policies ithe healthcare system, costs to programs, or other factors iunknown, as is the impact for patient outcomes (althougthere is no basis on which to assume different outcomewould be observed).

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There is no evidence to our knowledge on which to basclinical practice recommendations regarding number of Csessions, or dose, to prescribe. A previous review of clinicapractice guidelines revealed broad variability in recommendations internationally,20 as did a review of primary studieby our group.90 The range of sessions prescribed spannefrom a minimum of 16.5 ± 2.1 sessions in France, tomaximum of 142.0 ± 112.4 sessions in Spain. Herein, dos(both program duration and session frequency) was onlreported in 12 (41%) studies, and ranged from 6 (New Zealandto 44 (Canada), with a median of 20. The variability ipostulated to be based on reimbursement policies. Clearlyevidence is needed to demarcate minimumdose of CR needeto significantly improve patient quality and quantity of lifewith consideration of case-mix,91 so quality of care icountries/regions not meeting this minimum can bimproved.

With regard to core components delivered, exercistraining was the most consistently offered one overall, bualso in the regions of Europe and Latin America; this ilaudable given that the greatest improvements in prognosiare explained by improvements in cardiorespiratory fitnesachieved through physical activity.92–95 Clearly great effortare needed to increase CR penetration in healthcare systemacross the globe, given these are highly cost-effectivstrategies.96–99 The next most commonly-offered componenwas patient education, which was delivered particularly oftein North America, as well as the Middle East and North AfricaDietary counseling was particularly common in Eastern Asiand Pacific, which is reflected in the high prevalence odietitians on their CR teams in this region. Overall resultsuggest most programs globally offer the main core components, however clearly the results herein are only generalizable to the primarily high-income countries represente(Fig 1).

Due to the challenges of delivering supervised CR in thclinical setting to all patients in need, alternative models sucas home-based and community-based programs have beedeveloped, which arguably may have broader reach. They aralso shown to be efficacious.100–103 The offering of alternativmodels was first reported in a 1997 publication from Englanand Wales.25 The degree of implementation of these alternative models is shown to be incredibly low globally througthis review. Where reported, home-based CR was offered bymedian of 15% of programs, community-based CR by 24% oprograms, and internet or other technologically-based CR b11% of programs. In the Middle East and North Africa, CR inot available outside a clinical center.24 Further research othe comprehensiveness and nature of alternative models ineeded to understand whether CR standards are being met inon-supervised settings. In addition, we must apply toolfrom implementation science to ensure these alternativmodels are available to patients who cannot access, or fowhom there is no space, at a supervised program (anarguably even those who only prefer to undertake Cindependently, so CR is patient-centered).

On a related note, through this review it was identified thaphase II CR is offered in residential settings in the followincountries: Austria, Belarus, Croatia, Czech Republic, Finland

France, Germany, Hungary, Iceland, Italy, Lithuania, thNetherlands, Romania, Russia, Serbia, and Spain. Again, it isuspected that this is a function of historic practice anreimbursement policies rather than evidence. To our knowedge, the effect on care quality, patient satisfaction anoutcomes as well as long-term maintenance of heart-healtbehaviors has not been established; this represents aimportant area for future study.

The most commonly-reported barrier to CR deliveraround the globe was lack of resources. This was the mosconsistent finding across all studies. It continues to bbaffling that a Class I, Level A recommendation in applicablclinical practice guidelines around the globe9,10,104 iunder-resourced, when compared to other similarly-graderecommendations for the same indications. The cardiacommunity (including societies, foundations, and governments) must continue to advocate for CR reimbursement.8

Indeed, the International Council of Cardiovascular Prevention and Rehabilitation has recently developed and collateresources to achieve this aim (see: http://globalcardiacrehabcom/advocacy/). On a final note, lack of referral was alsnoted as a significant barrier in many studies.

Through this review, several areas where further researcis urgently needed have been identified. First, there is littlinformation on the nature of CR in the following regionswhich also have among the highest burdens of CVD: East Asiathe Pacific, the Middle East, North Africa, Sub-Saharan Africand South Asia (Fig 1). Specifically, in East Asia and the Pacifithere are 38 countries, of which we perceive 15 have CRhowever services are only characterized in 4 of thescountries. There are 21 countries in the Middle East anNorth Africa, of which we perceive 12 have CR, and serviceare only characterized in 4. In Sub-Saharan Africa there are 4countries, of which we perceive 7 have CR, and services havnever been characterized. Similarly, South Asia includescountries, of which we perceive 5 have CR, yet CR has alsnever been characterized there. Second, while number ocenters and center capacity was reported in many of thpapers, given that this was not reported consistently, thnumber of countries not represented, the low response ratesand that capacity was not juxtaposed against CVD burdenfirm conclusions regarding CR availability and capacitshould not be drawn from this work. More comprehensivebut gross, information on this is reported elsewhere.21,89 Morinformation on CR density globally is needed. Finally, the wathe constructs under investigation in this study were measured was not consistent across studies, and therefore somcaution in interpreting the comparisons made across studieherein is warranted. Administering a standardized anvalidated set of survey items in all countries would addresthis limitation. Our group is currently performing this.

Caution is warranted in interpreting these results. Firsthe search was not systematic and only English-languagpublications were included, so some studies might have beemissed, along with grey literature. Second, in many casesrespondents' estimates of characteristics and delivery of Cprograms were reported, and hence values should binterpreted with caution. Finally, generalizability is limitein several ways. Surveys of CR programs have only bee

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undertaken in half of the countries where it is suspected to boffered. Moreover, better-resourced countries (and perhapeven programs) are represented in the surveys (Fig 1), anthus this characterization of CR services likely reflecthigher-quality care than is the norm. As a final point, thresponse rate was low in some studies (n = 3, 16%<40%),24,48,76 and not reported in many others (n = 621%),53,55,60,67,70,71 and hence caution is warranted in generaizing results from those studies in particular.

In conclusion, while the CVD burden and associated deatrates are increasing, and CR is recognized as one of the mosbeneficial and cost-effective mitigation strategies, information about the nature and quality of CR services is onlavailable for about half of countries globally where it ibelieved to be offered. This review has demonstrated that Cis most often reimbursed by public sources, imost-commonly offered to MI patients with revascularization, with the average program serving ~200 such patients, ba multi-disciplinary team most-frequently comprised ophysicians, nurses and physiotherapists. Most programdeliver the major core components, most-commonly exercistraining, patient education and nutrition counselling, overmedian of 20 sessions (2 sessions/week over 9 weeks). Aconsequent observation from the review is the lack of Cdensity, due to lack of human and financial resources as weas space, consistent with previous reviews, but has also fothe first time quantified the dearth of delivery of CR ialternate settings globally. This represents an importanmeans to increase reach of CR. Documentation of CR delivervariation can be used to support meeting of minimumstandards by all countries.

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All authors declare that there are no conflicts of interest.

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Acknowledgments

This work was supported by aminor research grant from YorUniversity's Faculty of Health. We also acknowledge thcollaboration of Ms. Maureen Pakosh, BA, MISt, InformatioSpecialist with University Health Network for assistance witthe literature search.

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55. Goto Y, Saito M, Iwasaka T, et al. Poor implementation ofcardiac rehabilitation despite broad dissemination of coro-nary interventions for acute myocardial infarction in Japana nationwide survey. Circ J. 2007;71(2):173-179.

56. Saito M, Ueshima K, Saito M, et al. Safety of exercise-basedcardiac rehabilitation and exercise testing for cardiac patientin Japan: a nationwide survey. Circ J. 2014;78(7):1646-1653.

57. Arakawa T, Kumasaka L, Nakanishi M, et al. Regional clinicaalliance path and cardiac rehabilitation after hospital dis-charge for acute myocardial infarction patients in Japan —nationwide survey. Circ J. 2016;80(8):1750-1755.

58. Vanhees L, McGee HM, Dugmore LD, et al. A representativestudy of cardiac rehabilitation activities in European unionmember states: the Carinex survey. J Cardpulm Rehabil.2002;22(4):264-272.

59. Ben Gal T, Piepoli MF, Corr U, et al. Exercise programs forLVAD supported patients: a snapshot from the ESC affiliatecountries. Int J Cardiol. 2015;201:215-219.

60. Zwisler A, Traeden UI, Videbaek J, et al. Cardiac rehabilita-tion services in Denmark: still room for expansion. Scand JPublic Health. 2005;33(5):376-383.

61. Tramarin R, Ambrosetti M, De Feo S, et al. The Italian surveon cardiac rehabilitation-2008 (ISYDE-2008). Part 3. Nationaavailability and organization of cardiac rehabilitation facilities. Monaldi Arch Chest Dis. 2008;70(4):175-205.

62. Teixeira M, Sampaio F, Brizida L, et al. Reabilitação Cardíacem Portugal - evolução entre 1998 e 2004. Rev Port Cardiol.2007;27(9):815-825.

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66. Lewin RJ, Ingleton R, Newens AJ, et al. Adherence to cardiarehabilitation guidelines: a survey of rehabilitationprogrammes in the United Kingdom. BMJ. 1998;316(7141):1354-1355.

67. McGee HM, Hevey D, Horgan JH, et al. Cardiac rehabilitationservice provision in Ireland: the Irish Association of CardiaRehabilitation survey. Ir J Med Sci. 2001;170(3):159-162.

68. Bradley JM, Wallace ES, McCoy PM, et al. A survey of exercisbased cardiac rehabilitation services in Northern Ireland.Ulster Med J. 1997;66(2):100-106.

69. Campbell NC, Grimshaw JM, Rawles JM, et al. Cardiacrehabilitation in Scotland: is current provision satisfactory?Public Health Med. 1996;18(4):478-480.

70. Korenfeld Y, Mendoza-Bastidas C, Saavedra L, et al. Currenstatus of cardiac rehabilitation in Latin America and theCaribbean. Am Heart J. 2009;158(3):480-487.

71. Cortes-Bergoderi M, Lopez-Jimenez F, Herdy AH, et al.Availability and characteristics of cardiovascular rehabilitation programs in South America. J Cardiopulm Rehabil Prev.2013;33(1):33-41.

72. Ilarraza-lomelí H, García-saldivia M, Rojano-castillo J, et al.National registry of cardiac rehabilitation programs inMexico II (RENAPREC II). Arch Cardiol Mex. 2016;27:27.

73. Santibáñez C. Situación actual de la rehabilitación cardiacaen Chile. Rev Méd. 2012:561-568.

74. Polyzotis PA, Tan Y, Prior PL, Oh P, Fair T, Grace SL. Cardiacrehabilitation services in Ontario. J Cardiovasc Med.2012;13(11):727-734.

75. Grace SL, Turk-Adawi K, Pio CS, et al. Ensuring cardiacrehabilitation access for the majority of those in need: a cato action for Canada. Can J Cardiol. 2016;32(10):S358-S364.

76. Pack QR, Squires RW, Lopez-Jimenez F, et al. The current anpotential capacity for cardiac rehabilitation utilization in thUnited States. J Cardiopulm Rehabil Prev. 2014;34(5):318-326.

77. Gutin B, Prince L, Stein R. Survey of cardiac rehabilitationcenters in New York City. J Community Health. 1990;15(4):227-238.

78. Evenson KR, Johnson A, Aytur SA. Five-year changes inNorth Carolina outpatient cardiac rehabilitation. J CardpulmRehabil. 2006;26(6):366-376.

79. Zullo MD, Jackson LW, Whalen CC, et al. Evaluation of therecommended core components of cardiac rehabilitationpractice: an opportunity for quality improvement. JCardiopulm Rehabil Prev. 2012;32(1):32-40.

80. Babu AS, Lopez-Jimenez F, Thomas RJ, et al. Advocacy foroutpatient cardiac rehabilitation globally. BMC Health ServRes. 2016;16(1):471.

81. Giacomantonio NB, Bredin SSD, Foulds HJ, et al. A systematicreview of the health benefits of exercise rehabilitation in personliving with atrial fibrillation. Can J Cardiol. 2013;29(4):483-491.

82. Warburton DER, Nicol CW, Bredin SSD. Health benefits ofphysical activity: the evidence. Can Med Assoc J. 2006;174(6)801-809.

83. Sibilitz KI, Berg SK, Tang LH, et al. Exercise-based cardiacrehabilitation for adults after heart valve surgery (Review)exercise-based cardiac rehabilitation for adults after heartvalve surgery. Cochrane Database Syst Rev. 2016(3).

84. Taylor RS, Sagar VA, Davies EJ, et al. Exercise-basedrehabilitation for heart failure (review) exercise-based rehabilitation for heart failure. Cochrane Database Syst Rev. 2014(4

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88. Halm E, Lee C, Chassin M. Is volume related to outcome inhealth care? A systematic review and methodologic critiquof the literature. Ann Intern Med. 2002;137(6):511-520.

89. Turk-Adawi K, Sarrafzadegan N, Grace SL. Global availabilitof cardiac rehabilitation. Nat Rev Cardiol. 2014;11(10):586-596

90. Santiago de Araujo Pio C, Marzolini S, Pakosh M, Grace S.Dose of cardiac rehabilitation across the globe. Toronto GeRes Inst Res Day; 2016.

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95. Myers J, Mcauley P, Lavie CJ, et al. Physical activity andcardiorespiratory fitness as major markers of cardiovascularisk: their independent and interwoven importance to healtstatus. Prog Cardiovasc Dis. 2014;57(4):306-314.

96. Arena R, Harrington RA, Després J-P. A message frommodern-day healthcare to physical activity and fitness:welcome home! Prog Cardiovasc Dis. 2015;57:293-295.

97. Carlson SA, Fulton JE, Pratt M, Yang Z, Adams EK. Inadequatphysical activity and health care expenditures in the UniteStates. Prog Cardiovasc Dis. 2014;57(4):315-323.

98. Pratt M, Perez LG, Goenka S, et al. Can population levels ofphysical activity be increased? global evidence and experi-ence. Prog Cardiovasc Dis. 2014;57(4):356-367.

99. Sallis R, Franklin B, Joy L, et al. Strategies for promotingphysical activity in clinical practice. Prog Cardiovasc Dis.2014;57(4):375-386.

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ScienceDirect


Editor’s Commentary

From Heart Failure to Journal Metrics-Making
Progress in Cardiovascular Diseases
In this issue of Progress inTable 1 – Progress in Cardiovascular Diseases Journal

),i-,ean-h6h–6

'sd

Rankings.

Year Impact Factor Rank of CV Journals

2016 8.177 9/1262015 4.635 21/1242014 2.418 55/1232013 2.443 57/1252012 4.0 28/1222011 4.931 18/117

CV = Cardiovascular.

0033-0620/© 2017 Elsevier

Cardiovascular Diseases (PCVDmy good friend and PCVD Assocate Editor, Hector Ventura, MDalong with a major name in thfield of heart failure (HF), IleanPiña, MD, have put together aexcellent issue on the contemporary management of patients witsevere HF. Our first issue of 201was also devoted to HF,1 witseveral highly cited papers.2

Hopefully Dr. Ventura and Piñaome amajor one to help patients an

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Table 2 – Top 25 cardiovascular journals impact factorratings for 2016.

JournalImpactFactor

1. Journal of the American College of Cardiology 19.8962. European Heart Journal 19.6513. Circulation 19.3094. Nature Reviews Cardiology 14.2995. Circulation Research 13.9656. JACC-Cardiovascular Imaging 10.1897. JACC-Cardiovascular Interventions 8.8418. JACC-Heart Failure 8.4939. Progress in Cardiovascular Diseases 8.17710. Circulation-Cardiovascular Interventions 7.19811. Journal of Heart And Lung Transplantation 7.11412. European Journal of Heart Failure 6.96813. Journal of the American Society of

Echocardiography6.852

14. Circulation-Cardiovascular Imaging 6.80315. Circulation-Heart Failure 6.37216. International Journal of Cardiology 6.18917. Heart 6.05918. European Heart Journal – Cardiovascular Imaging 5.9919. Cardiovascular Research 5.87820. Journal of Molecular and Cellular Cardiology 5.6821. Journal of Cardiovascular Magnetic Resonance 5.60122. Circulation – Arrhythmia and

Electrophysiology5.41

23. Basic Research in Cardiology 5.30624. Eurointervention 5.16525. Trends in Cardiovascular Medicine 4.964

current HF issue will becscientists in the field of advanced HF.

As advances are being rapidlymade in the field ofHF, our PCVJournal is also making major advances in Journal Metrics. Whentook over as Editor in Chief (EIC) of PCVD in January 2014, our firstwo Impact Factors (IFs) were both 2.4. However, as mentionepreviously,7,8 our very first January 2014 issue on obesity and th“obesity paradox” produced some of our highest rated papers iPCVD history, largely leading to my first IF in 2015, based on th2013 papers before I was EIC andmy 2014 papers, increasing from2.4 and ranked 55th ofmajor cardiovascular (CV) journals to 4.63which gaveus a ranking of 21st amongmajor CV journals.Wealshad many highly ranked papers in 2015, particularly from ouJanuary 2015 Physical Activity Issue9–15 and Atrial FibrillatioIssue,16–22whichhavebeenwell-cited, helping to increaseour 201IF to 8.177, now ranking us 9th of all CV Journals (Tables 1 and 2)

There is another Journal Metric that we are also closelfollowing, which is the Elsevier Cite Score. Unlike the 2-year Iwhich generally follows two years' worth of papers (e.g. the 201IF represents papers published in 2014 and 2015 that are cited i2016, although there is also a 5-year IF that is also available, bunot generally as popular), the Elsevier Cite Score follows paperfor three years (e.g. the 2016 Cite Score represents all paperpublished in 2013, 2014 and 2015 that were cited in 2016.) Unlikthe IF, which typically counts all reviews and original investigations but doesnot count commentaries, editorials or letters to theditor, the Cite Score counts all of these papers in thdenominator, which is a disadvantage for journals that havmany commentaries and editorials, since these are generally nocited as often as reviews and original papers. Although our #

Inc. All rights reserved.

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Table 3 – Top 25 of 328 cardiovascular journals byElsevier – 2016 cite score.

Rank Source Title Cite Score Percentile

1. Circulation 8.41 99th2. Circulation Research 8.14 99th3. Journal of the American College of

Cardiology7.96 99th

4. European Heart Journal 7.42 98th5. Progress in Cardiovascular Diseases 5.96 98th6. Circulation: Heart Failure 5.69 98th7. Journal of Cardiovascular Magnetic

Resonance5.42 98th

8. European Journal of Heart Failure 5.38 97th9. Translational Stroke Research 5.31 97th10. Arteriosclerosis, Thrombosis,

and Vascular Biology5.28 97th

11. Stroke 4.94 96th12. JACC: Heart Failure 4.83 96th13. Journal of Cerebral Blood

Flow and Metabolism4.78 96th

14. Cardiovascular Research 4.73 95th15. Journal of Heart and Lung

Transplantation4.72 95th

16. Journal of Molecular and CellularCardiology

4.69 95th

17. Basic Research in Cardiology 4.68 94th18. Cardiovascular Diabetology 4.38 94th19a. Circulation: Cardiovascular Imaging 4.36 94th19b. JACC: Cardiovascular Imaging 4.36 94th21. JACC: Cardiovascular Interventions 4.35 93rd22. Circulation: Cardiovascular

Interventions4.32 93rd

23. Journal of the American Society ofEchocardiography

4.31 93rd

24. Journal of Stroke 4.08 92nd25. Journal of Clinical Lipidology 4.04 92nd


ranking of 126 CV Journals for the 2016 IF is quite impressive, ouElsevier Cite Score rank of #5 of 328 CV Journals is even morimpressive (Table 3).

Going forward, I do not think that our 2016 paperswill be citeas highly as our 2014 ones were, although we have a number o2016 obesity papers,4,23 sugar/carbohydrate toxicity ones,24,25 anseveral from our November/December 2016 HypertensioIssue,26–30 which should do quite well. Still, I suspect that ou2017 IF will not be as high as the 2016 one, but still will be quitsolid. Regarding the Cite Score, since our 2016 papers should bcited much more than our 2013 ones were, I suspect that thiscore, which still counts our highly cited 2014 papers for onmore year,may be even better in 2017 than in 2016. Neverthelesswe have a number of terrific issues in 2017, especially lasmonth's Exercise Issue and including the current HF Issue, soam very optimistic that the general trend for the PCVD JournaMetricswill be continuingupward formanyyears to come,whicis good news for our Readership, Scientists and authors.

.

e

R E F E R E N C E S


2. Hsiao R, Greenberg B. Contemporary treatment of acute heafailure. Prog Cardiovasc Dis. 2016;58:367-378.


4. Lavie CJ, Sharma A, Alpert MA, et al. Update on obesity and obesitparadox in heart failure. Prog Cardiovasc Dis. 2016;58:393-400.

5. DiNicolantonio JJ, Chatterjee S, O'Keefe JH. Dietary saltrestriction in heart failure: where is the evidence? ProgCardiovasc Dis. 2016;58:401-406.

6. Ghashghaei R, Yousefzai R, Adler E. Palliative care in heartfailure. Prog Cardiovasc Dis. 2016;58:455-460.

7. Lavie CJ. Analyzing 2015 impact factors: special editor'scommentary. Prog Cardiovasc Dis. 2016;58:323.

8. Lavie CJ. Special editor's page: two years as editor-in-chief.Prog Cardiovasc Dis. 2016;58:461-462.

9. Arena R, Despres J-PA. Message from modern-day health carto physical activity and fitness: welcome home. ProgCardiovasc Dis. 2015;57:293-295.

10. Myers J, McAuley P, Lavie CJ, et al. Physical activity andcardiorespiratory fitness as major markers of cardiovascularisk: their independent and interwoven importance to healtstatus. Prog Cardiovasc Dis. 2015;57:306-314.

11. DeFina LF, Haskell WL, Willis BL, et al. Physical activity versucardiorespiratory fitness: two (partly) distinct components ocardiovascular health? Prog Cardiovasc Dis. 2015;57:324-329.

12. Carlson SA, Fulton JE, Pratt M, Yang Z, Adams EK. Inadequatphysical activity and health care expenditures in the UnitedStates. Prog Cardiovasc Dis. 2015;57:315-323.

13. Pratt M, Perez LG, Goenka S, et al. Can population levels ofphysical activity be increased? Global evidence and experi-ence. Prog Cardiovasc Dis. 2015;57:356-367.

14. Sallis R, Franklin B, Joy L, et al. Strategies for promotingphysical activity in clinical practice. Prog Cardiovasc Dis.2015;57:375-386.

15. O'Keefe JH, Lavie CJ, Guazzi M. Part 1: potential dangers of extremendurance exercise: howmuch is toomuch? Part 2: screening ofschool-age athletes. Prog Cardiovasc Dis. 2015;57:396-405.

16. MorinDP, Estes IIIM.Advances in the prevention and treatmenof atrial fibrillation. Prog Cardiovasc Dis. 2015;58:103-104.

17. Sheikh A, et al. Trends in hospitalization for atrial fibrillationepidemiology, cost, and implications for the future. ProgCardiovasc Dis. 2015;58:105-116.

18. Menezes AR, et al. Lifestyle modification in the prevention andtreatmentof atrial fibrillation.ProgCardiovascDis. 2015;58:117-12

19. Thihalolipavan S, Morin DP. Atrial fibrillation and heartfailure: update 2015. Prog Cardiovasc Dis. 2015;58:126-135.

20. Waldo AL. Rate control versus rhythm control in atrialfibrillation: lessons learned from clinical trials of atrialfibrillation. Prog Cardiovasc Dis. 2015;58:168-176.

21. Gerstenfeld EP, Duggirala S. Atrial fibrillation ablation: indi-cations, emerging techniques, and follow-up. Prog CardiovasDis. 2015;58:202-212.

22. Kumar P, Kiser AC, Gehi AK. Hybrid treatment of atrialfibrillation. Prog Cardiovasc Dis. 2015;58:213-220.

23. Lavie CJ, et al. Obesity and prevalence of cardiovasculardiseases and prognosis – the obesity paradox updated. ProgCardiovasc Dis. 2016;58:537-547.

24. O'Keefe EL, et al. Lifestyle choices fuel epidemics of diabetesand cardiovascular disease among Asian Indians. ProgCardiovasc Dis. 2016;58:505-513.

25. DiNicolantonio JJ, Lucan SC, O'Keefe JH. The evidence forsaturated fat and for sugar related to coronary heart diseaseProg Cardiovasc Dis. 2016;58:464-472.

26. DiNicolantonio JJ, O'Keefe JH. Hypertension due to toxic whitcrystals in the diet: should we blame salt or sugar? ProgCardiovasc Dis. 2016;59:219-225.

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27. Milani RF, et al. New concepts in hypertensionmanagement: apopulation-based perspective. Prog Cardiovasc Dis. 2016;59:289-29

28. Oktay AA, et al. Current perspectives on left ventricular geometrin systemic hypertension. Prog Cardiovasc Dis. 2016;59:235-246.

29. Kario K. Evidence and perspectives on the 24-hour manage-ment of hypertension: hemodynamic biomarker-initiated‘anticipation medicine’ for zero cardiovascular event. ProgCardiovasc Dis. 2016;59:262-281.

30. Reilly JP, White CJ. Renal denervation for resistant hypertension. Prog Cardiovasc Dis. 2016;59:295-302.

Carl J. Lavie, MDepartment of Cardiovascular Disease John Ochsner Heart &

Vascular Institute Ochsner Clinical SchooThe University of Queensland School of Medicin

1514 Jefferson Highway, New Orleans, LA 70121-248United State

[email protected]

http://dx.doi.org/10.1016/j.pcad.2017.08.00

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