Prof. U. C. SAMALMD, FICC, FACC, FIACM, FIAE, FISE, FISC, FAPVSEx- Prof. Cardiology & Ex-HOD Medicine Patna Medical College, Patna, BiharPast President, Indian College of CardiologyPermanent & Chief Trustee, ICC-Heart Failure FoundationNational Executive Member, Cardiological Society of IndiaPresident, CSI Bihar

Acute Decompensated Heart Failure :

What Is New ?

1

AHFS : NOT VERIFIEDSimilarities and differences between acute MI & AHFS in

hospitalization in the USIncidence 1 million per year 1 million per year

Mortality Pre hospitalization In hospital After discharge [ 60-90 d]

High3-4%2%

?3-4%10%

Myocardial injury Yes LikelyPathophysiological target Clearly defined

[coronary thrombosis]Uncertain

Clinical benefits of interventions in published clinical trial

Beneficial Minimal / no benefit or deleterious compared with placebo

ACC / AHA recommendation LEVEL A NONE

2

Acute Heart Failure Syndrome(s)

• Acute heart failure (AHF) is defined as a rapid onset or change in the signs and symptoms of HF, resulting in the need for urgent therapy.

• Symptoms are primarily the result of severe pulmonary congestion due to elevated left ventricular (LV) filling pressures (with or without low cardiac output).

• AHFS can occur in patients with preserved or reduced ejection fraction (EF).

• Concurrent cardiovascular conditions such as coronary heart disease (CHD), hypertension, valvular heart disease, atrial arrhythmias, and/or

noncardiac conditions (including renal dysfunction, diabetes, anemia) are often present and may precipitate or contribute to the pathophysiology of this syndrome

3

ESC Guidelines

Mortality %

Frontiers in Cardiovascular Medicine EHJ 2010:31;784-7934

Mortality in AHFS

Proposed classification for patients who present with acute heart failure syndromes

ACCF/AHA stage

Explanation of stage

Worsening chronic HF (75%)

Stage C C: structural heart disease with prior or current symptoms of HF

Advanced HF (5%)

Stage D D: refractory HF requiring specialized interventions

De novo HF (20%)

Stage B most common, but also Stage A

Also neither A nor B

B: structural heart disease but without signs or symptoms of HF

A: at high risk for HF but without structural heart disease or symptoms of HF

5

Frontiers in Cardiovascular Medicine EHJ 2010:31;784-793

• diuretics• ultrafiltration

Vasodilators • nitroglycerin• nesiritide• nitroprusside

INOTROPES • dobutamine• dopamine• levosimendan• nitroprusside

Fluid retention or redistribution ?

“dry out” “warm up & “dry out”

Assessment of hemodynamic profile : therapeutic implications

Adapted from Stevenson L W, Eur Heart j

6

HF Management: Principal changes from the 2008 guidelines

o An expansion of the indication for mineralocorticoid receptor antagonists (MRAs)

o A new indication for the sinus node inhibitor Ivabradine

o An expanded indication for cardiac resynchronisation therapy (CRT)

o New information on the role of coronary revascularisation in HF (PCI / CABG)

o Recognition of the growing use of ventricular assist devices (LVAD)

o The emergence of transcatheter valve interventionsESC guidelines for the diagnosis and treatment of acute and chronic heart failure

2012

7

Linking Short- term intervention with long-term benefit:What is needed?

Better understanding of Acute Heart Failure pathophysiology

MORTALITY

• Myocardial injury [Tn release]

• Renal dysfunction [CRS]

• Liver dysfunction

PREVENTION OF END-ORGAN DAMAGE

Congestion Viable but

dysfunctional myocardium

Neurohormonal & inflammatory

activationMechanisms which

can be targetedMetabolic

factors

Hemodynamic deterioration

[↑LVFP,↓ CO, ↓ PERFUSION]

Vascular resistance /stiffness ↑

ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012 Reviewed by Ponikowski

NeurohormonesNorepinephrine

ReninAngiotensin II

CopeptinEndothelin

Vascular systemHomocysteine

Adhesion molecules(ICAM, P-selectin)

EndothelinAdiponectin

C-type natriuretic peptide

InflammationC-reactive protein

sST2Tumor necrosis

factorFAS (APO-1)

GDF-15Pentraxin 3AdipokinesCytokines

ProcalcitoninOsteoprotegerin

Myocardial stressNatriureticpeptides

Mid-regional pro-adrenomedullin

NeuregulinsST2

Myocardial injuryCardiac troponins

High sensitivity cardiac troponinsMyosin light-chain kinase 1Heart-type fatty acid binding

proteinPentraxin 3

Matrix and cellularremodelingGalectin-3

sST2GDF-15MMPsTIMPs

Collagen propeptidesOsteopontin

Cardio-renal syndromeCreatinineCystatin C

NGALß-Trace protein

Oxidative stressOxidized LDL

MyeloperoxidaseUrinary biopyrrins

Urinary and plasma isoprostanes

Plasma malondialdehyde

HF as a systemic illness & organ cross-talk

9Nature Review Cardiology

Vol.9 June 12 pg 349

And organ cross talk

Using Biomarkers across the ARC of Heart Failure Hospitalisation

Therapy decisions

Measure delta change

Look for decline

Obtain baseline

Monitor therapy

Present to ED

Decisions on triage

Determine prognosis In-hospital treatment

Discharge

Outpatient follow-up

Therapy decisions

Nov 1, 2013 - Dr Yancy interviews Drs Pang and Januzzi on the use of biomarkers ... Cardiac Intensive Care Unit, Massachusetts General Hospital, Boston,

BNP Status

This pilot study demonstrates that home BNP testing is feasible and that trials using home monitoring for guiding therapy are justifiable in high-risk patients. Daily weight monitoring is complementary to BNP, but BNP changes correspond to larger changes

in risk, both upward and downward. (Heart Failure [HF] Assessment with B-type Natriuretic Peptide [BNP] In the Home [HABIT]; NCT00946231)

Clinical RELEVANCE of promising novel biomarkers(AHFS)Biomarker Diagnosis Prognosis Therapy guidance Cardiac

ProductionNT-proBNP and BNP

++++ ++++ ++ Solely

Serum Sodium + +++ ++ No

Serum Creatinine - +++ ++ No

MR-proANP +++ ++++ Likely similar to NT-ProBNP/BNP

Solely

sST2 + ++++ ? Not ExclusivelyHs troponin-I [EFFECT]

+ ++++ ? Solely

MR-proADM - ++++ ? No

Cystatin C - ++++ ? NoNGAL - ++++ ? NoGDF-15 - +++ ? Not Exclusively- Trace protein - +++ ? NoGal-3 - +++ ? Not exclusivelyCRP - ++ ? NoTNF- - ++ ? NoIL-6 - ++ ? NoPTX3 - ++ ? UnknownMPO - ++ ? Not exclusivelyET-1 - ++ ? Not exclusivelyCopeptin - ++ ? NoPCT ++ ++ ++ No

12

Clinical Chemistry 58:1 127–138 (2012)

Pulmonary congestion evaluated by lung ultrasound predicts admission in pts with HF

•97 HF outpts followed up during a period of 106 ± 12 days

•21 hospitalizations for acute pulmonary edema

•Multivariate analysis showed that pulmonary congestion assessed by lung ultrasound is strongest predictor of hospital admission

Conclusion – in a HF outpt setting, B-lines assessment by lung ultrasound may help to identify pts who are most likely to decompensate

The four chest areas per side considered for complete eight zone lung ultrasound examination. These areas are used to evaluate for the presence of interstitial syndrome. Areas 1 and 2 denote the upper anterior and lower anterior chest areas, respectively. Areas 3 and 4 denote the upper lateral and basal lateral chest areas respectively. 14

Echo windows

Multiple reflections of ultrasound beams

ultrasound beams

ultrasound beams

Comet-tails echographic

imageNormal

echographic image horizontal

lines

Regular intervalReverberations

Transducer Transducer

Edematous Interlobular Septa

Normal Interlobular Septa

Ultrasound Comet-Tail Images: A Marker Of Pulmonary Edema

A: Typical comet-tail artifacts: hyperechogenic, coherent vertical bundles with narrow basis spreading from the transducer to the further border of the screen. This artifact is composed of multiple microreflections of the ultrasound beam.

A B

B: Normal subject, with regular, parallel, roughly horizontal hyperechogenic lines due to the lung-wall interface.

Chest. 2005;127(5):1690-1695. doi:10.1378/chest.127.5.169015

HF: Monitoring to predict/ prevent ADHF admissions

• Devices: Externally applied Impedance Cardiography (PREDICT study 211 pts)

• Internally placed devices measuring intra thoracic impedance(PARTNER 2HF: CRT device with Impedance monitoring): predicted subsequent admission for ADHF

• PA / LA/ LVEDP monitoring devices

Usefulness uncertain for mortality benefit

16

Heart Failure Risk ScoresCirc HF 2013

End point: Death/ transplant/ Assist device• Heart Failure Survival Score(200pts):

– IHD, QRS>120ms, LVEF, Resting HR, mean BP, O2 consumption, ser Na

• Seattle Heart Failure model: (1100pts)– Age, LVEF, NYHA class, SBP, Diuretic dose, Na+, uric

acid, ser. Chol., lymph. count - Sex, IHD, QRS >120ms, ICD, CRT, betablockers, ACEI, Statins, Allopurinol,

• SHOCKED predictor: (900pts): Age>75, NYHA>II, AF, COPD, CKD, LVEF<20%, DM

• PACE: (900 pts) PVD, Age >70, Creatinine >2, EF < 20%,• ADHERE registry( for acute mortality): SBP, Ser creatinine

and BUN• Frankenstein: BNP , 6′WT

… We found that in a large, diverse contemporary HF population, risk assessment was strikingly similar across all LVEF categories. These data suggest that, although many HF therapies are uniquely applied to patients with reducedLVEF, individual prognostic factor performance does not seem to be significantly related to level of left ventricular systolic function.

(Circ Heart Fail. 2013;6:635-646.)

AHF Treatment Goals

Immediate [ED/ICU/CCU]•Treat symptoms and restore oxygenation•Improve hemodynamic and organ perfusion

•Limit cardiac and renal damage•Prevent thromboembolism•Minimize length of ICU stay

Intermediate [in –hospital]• stabilise pt and optimize treatment strategy•Initiate and up-titrate disease modifying pharmacologic therapy

•Consider device therapy in appropriate pts• identify etiology and relevant comorbidities

Pre-discharge and long term management•Plan follow up stratergy •Enroll in ds management programme, educate and initiate life style adjustments•Plan to up-titrate / optimise disease modifying pharmacologic therapy

•Ensure assessed for appropriate device therapy•Prevent early readmission•Improve symptoms

Http://www.Peerviewpress.Com/01/r286

20

While pharmaceutical innovation has been highly successful in reducing mortality in chronic heart failure, this has not been matched by similar success in decompensated heart failure syndromes. Despite outstanding issues over definitions and end points, we argue in this paper that an unprecedented wealth of pharmacologic innovation may soon transform the management of these challenging patients. Agents that target contractility, such as cardiac myosin activators and novel adenosine triphosphate-dependent transmembrane sodium-potassium pump inhibitors, provide inotropic support without arrhythmogenic increases in cytosolic calcium or side effects of moretraditional agents. Adenosine receptor blockade may improve glomerular filtration and diuresis by exerting a direct beneficial effect on glomerular blood flow while vasopressin antagonists promote free water excretion without compromising renal function and may simultaneously inhibit myocardial remodeling. Urodilatin, the renally synthesized isoform of atrial natriuretic peptide, may improve pulmonary congestion via vasodilation and enhanced diuresis. Finally, metabolic modulators such as perhexiline may optimize myocardial energy utilization by shifting adenosine triphosphate production from free fatty acids to glucose, a unique and conceptually appealing approach to the management of heart failure. These advances allow optimism not only for the advancement of our understanding and management of decompensated heart failure syndromes but for the translational research effort in heart failure biology in general.

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The main stay of AHF Therapy

Some new therapeutic agents for acute heartfailure and their potential targets

Agent For patients with theseclinical features

Diuretics, vasopressin antagonists,adenosine antagonists

Patients with signs of fluidoverload, high BNP

Vasodilators Normal to high SBP, high BNP

Inotropes Low SBP, signs ofHypoperfusion

Renal preservation agents Renal dysfunction

Myocardial protection agents CAD, or ongoing ischaemia

22

Short- and long-term novel therapies for AHF syndromesShort term Long term Both Levosimendan [LIDO, CASINO, SURVIVE] ? ?

Nesiritide[ ASCEND-HF, ROSE-AHF]

Relaxin [RELAX-AHF]

Myosin Activators Omecamtiv Mecarbil [ATOMIC-AHF]

RyR2 stabilizers/ rycalsCinaciguat (UIT)Adenosine regulating agentsStresscopinIstaroxime [HORIZON-HF]Ularitide [TRUE-AHF, SIRIUS II, URGENT]

Urocrotins [UNICORN]

Hypertonic SalineUltrafiltration [RAPID-CHF, UNLOAD]

IABPEECP [PEECH]

CAFAIMT

Direct reninInhibitors (DRI)[ASTRONAUT]

MacronutrientsMicronutrientsCRT/AICD

Adenosine Antagonists[PROTECT, REACH UP rolofylline]

Vasopressin Antagonists [EVEREST, TACTICS-HF]

Digoxin [DIG]

CD-NP

Frontiers in Cardiovascular Medicine EHJ 2010:31;784-793 modified 201323

Newer Drugs/Devices and targeted Therapy

Group A• Managing fluids

• Preserving renal functionGroup B

• Contractility• Diastole/ Vascular Resistance

Group C• Vasomotion

24

Group AManaging fluids

Preserving renal function

25

• Loop diuretics are an essential component of therapy for patients with acute decompensated heart failure, but there are few prospective data to guide their use.

• In a prospective, double-blind, randomized trial, we assigned 308 patients with ADHF to receive furosemide administered intravenously by means of either a bolus every 12 hours or continuous infusion and at either a low dose (equivalent to the patient’s previous oral dose) or a high dose (2.5 times the previous oral dose).

• DOSE Trial: Among patients with ADHF, there were no significant differences in patients’ global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose as compared with a low dose.

• Low dose dopamine increases GFR and RBF. DAD-HF investigated 60 pts randomized to low dose furosemide (continuous infusion 05 mg/hr) and 5 µg/kg/min per eight hours was found effective in terms of dyspnoea relief with improved renal function. High dose combination though was equally effective caused WRF . 20 mg/hr F + 5µg/kg/min Dopamine.

Furosemide

26

• The study tests the hypothesis that in patients admitted with acutely decompensated heart failure (ADHF), achievement of adequate body hydration status with intensive medical therapy, modulated by combined bioelectrical vectorial impedance analysis (BIVA) and B-type natriuretic peptide (BNP) measurement, may contribute to optimize the timing of patient’s discharge and to improve clinical outcomes.

• 300 ADHF pts underwent serial BIVA and BNP measurement. Therapy was titrated to reach a BNP value of \250 pg/ml, whenever possible.

• Our study confirms the hypothesis that combined BNP/BIVA sequential measurements help to achieve adequate fluid balance status in patients with ADHF and can be used to drive a ‘‘tailored therapy,’’ allowing clinicians to identify high-risk patients and possibly to reduce the incidence of complications secondary to fluid management strategies. 27

Ultrafiltration

28

• UNLOAD(200pts): • superior to diuretics as it reduces volume at a rate

more than 500 ml/hr which is Isotonic ultrafiltrate (both salt and water)

• UF leads to a lower plasma renin, norepinephine and aldosterone levels as compared to diuretics.

• CARESS study: High risk ADHF pts.: Similar outcome for weight reduction, but higher rise in ser creatinine, need for dialysis, and other adverse events…. UF a new therapy as primary beyond diuresis resistance in ADHF??

• AVOID HF: Ongoing trial (to be completed in 2016)

J Am Coll Cardiol 2012:59:2145-53

Investigational drugs in ADHFAdenosine A1 receptor antagonist:

Rolofylline• A1 receptor blockade results in afferent arteriolar

vasodilation which leads to improved GFR and enhanced diuresis and natriuresis without activation of tubuloglomerular feedback.

• Preserve GFR, improve diuresis, increase sodium excretion by kidney.

• Phase 2 trial: better relief of dyspnoea and lesser renal dysfunction.

• Phase 3 trial: PROTECT:2033 pts.: negative trial with none of the primary end points significant and safety was questioned due to neurological side effects: seizure and stroke.

29

• Small studies have indicated that adenosine A1 receptor antagonists enhance diuresis and may improve renal function in patients with chronic heart failure or AHF.

• 2,033 AHF pts, volume overload, eCrCl 20 - 80 ml/min, and elevated BNP randomized (2:1) within 24 h of hospital presentation to rolofylline 30 mg/day or intravenous placebo for up to 3 days.

• In this large, phase III clinical trial, the adenosine A1 receptor antagonist rolofylline did not prevent persistent worsening renal function in AHF patients with volume overload and renal dysfunction.

Rolofylline

30

SCr↑

BUN↑

•Effects of rolofylline on endpoints in relation to baseline renal function.

•The secondary morbidity/mortality endpoint, the risk of death or cardiovascular or renal rehospitalization through day 60, was lower in the rolofylline group compared with the placebo group only in patients with a baseline eCrCl 30 ml/min (hazard ratio: 0.64; 95% CI: 0.43 to 0.95), but not in the other subgroups

Rolofylline

31

Group BContractility

Diastole/ Vascular Resistance

32

Levosimendan enhances contractility by increasing responsiveness of myofilaments to calcium. The cardiac myosin activator Omecamtiv mecarbil stimulates myosin adenosine triphosphatase (ATPase), thereby increasing force generation. Istaroxime inhibits activity of plasma membrane sodium-potassium ATPase and increases the activity of sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA).

Mechanism of action of novel contractility-enhancing medications.

Omecamtiv mecarbil

(Modified from Tavares M, Rezlan E, Vostroknoutova I, et al. New pharmacologic therapies for acute heart failure. Crit Care Med 2008; 36[Suppl]:S112-S120.)

33

Istaroxime

Levosimendan

Omecamtiv Mecarbil (OM) is a Novel Selective Cardiac Myosin Activator

Malik Fl, et al. Science 2011; 331:1439-43Teerlink JR, et al. Lancet 2011; 378:667-75; Cleland JGF, et al. Lancet 2011; 378:676-83

Mechanochemical Cycle of Myosin

• • Increases duration of systole• Increases stroke volume• No Increase in myocyte calcium• No change in dp/dtmax

• No increase in MVO2

ATOMIC-AHF Phase 2; 613 pts .X 48 hrs random IV dose 115; 230; 310 ng/ml.COSMIC-HF chronic oral therapy; oral alone or IV to oral transition.

Omecamtiv mecarbil increases the entry rate of myosin into the tightly-

bound, force-producing state with actin

“More hands pulling on the rope”

34

Study Design: Sequential Dosing Cohort

Cohort 1 Cohort 2 Cohort 3Omecamtiv

Placebo1:1 Randomization (n≈200)

Omecamtiv

Placebo1:1 randomization (n≈200)

Placebo

Omecamtiv1:1 randomization (n≈200)

DMC DMC

Cohort 1 Cohort 2 Cohort 315 mg/hr @ 0-4 hr3 mg/hr @ 4-48 hr

Target: 230 ng/mLCmax: 75-500

ng/mLSET: ~8-55 msec

20 mg/hr @ 0-4 hr4 mg/hr @ 4-48 hrTarget: 310 ng/mL

Cmax: 125-700 ng/mL

SET: ~14-78 msec

7.5 mg/hr @ 0-4 hr1.5 mg/hr @ 4-48 hrTarget: 115 ng/mL

Cmax: 30-250 ng/mL SET: ~3-28 msec

Pharmacokinetic simulations

Teerlink JR, et al. Lancet 2011; 378: 667–75; Cleland JGF, et al. Lancet 2011; 378: 676–83.

ATOMIC –AHF Omecamtiv Mecarbil Dyspnea Response

Teerlink J R ESC 2013, Symposium 4503

Response rate ratio

1.02 1.02 1.41

95% CI [0.74 -1.42] [0.76 – 1.37] [1.02 -1.93]

Response rate ratio : ratio of response rate to placebo with each cohort

Omecamtiv Mecarbil : time dependent changes in echocardiogram measures

Http://www.Peerviewpress.Com/01/r286

• Efficacy– OM did not meet the 1° endpoint of dyspnoea relief– Appeared to improve dyspnoea in Cohort 3– Trends towards reduction of worsening HF

• Safety– Overall SAE profile and tolerability similar to placebo– Increase in troponin; no clear relationship to OM concentration– Numerical imbalance in MIs in Cohort 3 – No evidence of pro-arrhythmia

• Pharmacology– PK similar to healthy volunteers and stable HF patients – Systolic ejection time significantly increased consistent with MOA– Small fall in heart rate & rise in systolic BP at higher doses

ATOMIC- AHF Summary

Though at present investigational the drug of the future in AHF Janccin B: New Heart failure inotrope could be ‘Holy Grail’. IMNG Medical Media September 5, 2013

John J. V. McMurray et al, on behalf of the ATOMIC-AHF Investigators and Patients

• Istaroxime is a novel intravenous agent with inotropic and lusitropic properties related to inhibition of Na/K adenosine triphosphatase (ATPase) and stimulation of sarcoplasmic reticulum calcium ATPase.

• 120 AHF pts and reduced systolic function. Three sequential cohorts of 40 patients each were randomized 3:1 istaroxime:placebo to a continuous 6-h infusion. The first cohort received 0.5 g/kg/min, the second 1.0 g/kg/min, and the third 1.5 g/kg/min istaroxime or placebo.

• In patients hospitalized with HF, istaroxime improved PCWP and possibly diastolic function. In contrast to available inotropes, istaroxime increased SBP and decreased HR.

Istaroxime

Mihai Gheorghiade et al JACC 2008:03;01539

[HORIZON-HF Trial]

•Urocortins are a recently discovered group of peptide hormones of the corticotropin releasing factor family. They bind with a strong affinity to the CRH-R2 receptor, which is highly expressed in the myocardium and in the vascular endothelium.

•Urocortins exhibit potent inotropic and lusitropic effects on rat and sheep hearts and activates a group of myocyte protective pathways collectively known as ‘reperfusion injury salvage kinase’.

•In healthy humans show that brief intravenous infusions of urocortin 2 in healthy humans induce pronounced dose-related increases in cardiac output, heart rate, and left ventricular ejection fraction while decreasing systemic vascular resistance; similar effects were seen in HF patients.

Urocortins

40

StresscopinHuman stresscopin is a corticotropin-releasing factor type 2 receptor selective agonist and a member of the CRF peptide family. Stimulation of CRFR2 improves cardiac output and LVEF.

62 pts with HF and LVEF ≤ 35% were instrumented with a pulmonary artery catheter and randomly assigned (ratio 3:1) to receive an intravenous infusion of stresscopin or placebo. The main study was an ascending dose study of three doses (5, 15, and 30 ng/kg/min) of study drug or placebo administered in sequential 1 h intervals (3 h total). Statistically significant increases in CI and reduction in SVR were observed with both the 15 ng/kg/min (2 h time point) and 30 ng/kg/min (3 h time point) doses of stresscopin without significant changes in HR or SBP. No statistically significant reductions in PCWP were seen with any dose tested in the primary analysis, although a trend towards reduction was seen.

In HF patients with reduced LVEF and CI, ascending doses of stresscopin were associated with progressive increases in CI and reductions in SVR without significant effects on PCWP, HR, or SBP.

41

Group CVasomotion

42

Vaso active drugs in ADHFRelaxin: Serelaxin

• A recombinant human relaxin -2- a naturally occurring peptide that regulates maternal adaptations

• RELAX AHF:1160 pt. of ADHF with preserved SBP >115 mmHg.• Serelaxin 30 ug/kg/day x48 hrs or Placebo• Significant improvement in dyspnoea scale• No impact on short term mortality/ HF readmission at 60 days,

though 180 day mortality was significantly lower.• Hypotensive episodes higher but renal dysfunction less than

placebo group• No limitation: dobutamine milrinone (increase intercellular calcium

in myocytes leading to tachycardia and arrhythmias, levosimendon calcium sensitiser causes atrial and ventricular arrhythmias, and like milrinone may be limited by hypotension.

• FDA grants Breakthrough Therapy designation to Novartis' serelaxin (RLX030) for acute heart failure.

43

Biology of Relaxin and Potential Beneficial Effects in HF

Teichman SL, Unemori E, Teerlink JR, Cotter G, Metra M - Curr Heart Fail Rep (2010)

Endogenous peptide associated with pregnancy, and acts through relaxin receptor: reduce inflammation, decrease fibrosis, attenuate ventricular remodeling, increase vasodilation, promote renal blood flow, increase vascular endothelial growth factor, and angiogenesis.

↓Inflammation ↓Fibrosis ↑Vasodilation Renal effects Angiogenesis

Relaxin Receptor

RelaxinPregnancy associated endogenous peptide

Relaxin ReceptorRelaxin

44

Pre-RELAX-AHF : Rapid dyspnea improvement through 24 hours [Likert Scale]

Teerlink J R Lancet 2009,373:1429-1439

RELAX-AHF : Cardiovascular and All Cause Mortality

Teerlink J R Lancet 2013, 381:29-39

RELAX-AHF : Biomarker Changes

Metra M Et Al J Am Coll Cardiol 2013, 61: 196 -206

RELAX-AHF• 1161 pts with AHF• 19% improvement in dyspnea• Decreases in worsening HF• Improvement of in-hospital signs and symptoms of HF• Decreased length of hospital stay• No significant difference in second primary efficacy endpoint of the proportion of pts with dyspnea relief• No significant effect on secondary endpoints of cardiovascular death or hospital readmission for HF or renal failure [RELAX –AF was not powered as a mortality trial]

Teerlink J R Lancet 2013, 381:29-39

Seralaxin

• Increased renal function

• Improved vascular compliance

• Improved cardiac output

Beneficial effects on dyspnea and post-discharge clinical outcomes

• Cinaciguat (BAY 58-2667) is a soluble guanylate cyclase (sGC, second messenger that internalizes the message carried by intercellular messengers such as peptide hormones and NO) activator that is being developed as a first-in-class treatment for acute decompensated heart failure (ADHF). It acts independently of the sGC ligand nitric oxide.

• Cardioprotective effects in animal models, and pilot clinical studies found that it was well tolerated, unloaded the heart and increased cardiac output.

• This placebo-controlled, randomized, double-blind, multicenter, international phase IIb study investigated the safety and efficacy of intravenous cinaciguat (per-protocol) as add-on to standard therapy in 139 patients with ADHF (NYHA functional class III and IV; pulmonary capillary wedge pressure [PCWP] ≥ 18 mmHg).

• Cinaciguat rapidly and significantly reduced PCWP and PVR and increased cardiac output in patients with ADHF, without impairing cardiac or renal function. Hypotension occurred in some patients; further dose titration studies are therefore required to establish the optimal dosing strategy for this promising new therapy.

Cinaciguat

JACC Mar 9,2010 Vol:55 issue 10A

50

These molecules have been engineered to combine the beneficial aspects of different natriuretic peptides into a single molecule while minimizing potentially negative actions.

CD-NP is a combination of C-type natriuretic peptide (CNP) and Dendroapsis NP(DNP).

Although lacking natriuretic effects, CNP is a more selective venodilator than BNP, thus reducing the risk of significant hypotension. On the other side, DNP possesses significant natriuretic activity, at the expense of possible hypotensive effects.

The chimeric peptide CD-NP combines the favourable natriuretic effects of DNP with the venodilatory profile of CNP, reducing the risk for harmful side effects.

Preliminary studies in AHFS patients are ongoing.

Chimeric natriuretic peptides

51

Adenosine regulating agents

•This new class of drugs, whose prototype is represented by acadesine, has been developed to mimic the protective effects of adenosine during ischaemia.

•Acadesine exerts its pharmacological actions by increasing adenosine bioavailability and by activating 50adenosine monophosphate (AMP) signalling cascade via its metabolite 5-aminoimidazole-4-carboxamide riboside (ZMP).

•The first mechanism leads to multiple anti-ischaemic effects (maintenance of endothelial function and vasodilation, inhibition of platelet aggregation and neutrophil activation), whereas the latter ameliorates glucose uptake and free fatty acid oxidation thus increasing ATP synthesis. Importantly, acadesine exerts its actions only in areas undergoing net ATP catabolism (such as ischaemic tissues) thereby avoiding potentially harmful peripheral vasodilator effects.

Acadesine

52

• Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent.

• We randomly assigned 7141 patients [ASCEND-HF trial]

• Co-primary end points were the change in dyspnea at 6 and 24 hours, and the composite end point of rehospitalization for heart failure or death within 30 days.

• Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies.

• It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure.

Nesiritide

53

Ularitide

• Synthetic form of Urodilantin: human natriuretic peptide produced in kidney: induces natriuresis and diuresis. Also potent vasodilator( increases intracellular cyclic GMP) and increased renal blood flow) : Two double blind studies have shown favorable outcome in ADHF by symptom improvement and hemodynamics.

• Phase 3 trial(TRUE-AHF >2110 pts) - ongoing study.

54

Summary• AHFS is a complex condition with heterogenous pathophysiology and varied etiology with unpredictable and often stormy course.

• Present management rests on therapeutic optimisation of congestion, perfusion & protection against kidney injury & finally myocardial preservation and enhancement. Needless to point out, too much reliance on inotropics and pressor amines could be ominous.

• Simplistic biometrics like HR, B.P. and eGFR are inexpensive and dependable. Measures of clinical assesment while BNP and other monitoring devices may be superior but often unaffordable and expensive and make HF management imposible.

• The safe path on part of ED Physician is to follow updated guideline pathways till future breakthrough and safe newer drugs are available.

• All stabilised discharged pts must have GDMT/ Devices/ revascularisation as could be indicated. Multi disciplinary care approach is inevitable at all stage.

• Serelaxin, Omecamtiv Mecarbil , Istaroxime & Ularitide appear to be new drugs of the near future.

• … Future trials conducted in aHFs must abandon the ‘one-sizefits- all’ approach in favor of an approach that takes into account the varied and distinct pathophysiologies of aHFs.

55

56

(1) Symptom relief.(2) Measures of congestion relief (i.e. improvement in clinical signs).(3) Index hospitalization data (e.g. length of stay).(4) Prevention of end-organ damage (heart and kidney).(5) Post-discharge: death and rehospitalization data.

Federal Drug Administration (FDA) Study Group as a generalguide for choosing the components of the endpoints to beincluded when testing different types of drugs in different patientsubgroups, although not all of them would be necessary in asingle trial

Position Statement European Journal of Heart Failure (2011)59