ACCP Cardiology PRN Journal Club1/30/2019

Dr. Rob DiDomenico

Dr. Rob DiDomenico is an associate professor at the UIC College of Pharmacy. He received his PharmD from UIC and went on to complete his PGY1 pharmacy residency and a cardiovascular pharmacotherapy fellowship at UIC. Dr. DiDomenico covers the inpatient cardiology service and serves as the director of the PGY2 cardiology pharmacy residency.

Dr. Kristen de Almeida

Dr. Kristen de Almeida is they PGY2 Cardiology Pharmacy Resident at West Palm Beach VA Medical Center. She earned her PharmD degree from Palm Beach Atlantic University and completed her PGY1 Pharmacy Residency at West Palm Beach VA Medical Center. Her professional interests include arrhythmias, heart failure, and valvular disease.

Tafamidis Treatment for Patients with Transthyretin Amyloid

Cardiomyopathy

Journal Club Kristen de Almeida, PharmD

PGY2 Cardiology WPB VA Medical Center

Mentor: Robert J. DiDomenico, PharmD, FCCP, FHFSA, FACC

Disclosure

• I, Kristen de Almeida, have no relevant relationships to disclose

Background

• Transthyretin amyloid cardiomyopathy (ATTR-CM) vs Amyloid light chain

• Characterized by accumulation of amyloid fibrils composed of misfolded transthyretin proteins

• Transthyretin is a protein produced by the liver • Functions to transport thyroxine and retinol

• Amyloid deposits in the myocardium lead to • cardiomyopathy • conduction system

• bundle-branch block, AV block, sinoatrial disease and atrial fibrillation

Circulation. 2012 Sep 4;126(10):1286-300. N Engl J Med. 2018 Aug 27.

Background

https://www.acc.org/latest-in-cardiology/articles/2015/10/13/08/35/emerging-therapies-for-transthyretin-cardiac-amyloidosis

Background

http://www.med.uottawa.ca/patho/eng/Public/cardio/amyloidgross.gif

Figure 2: Amyloid cardiomyopathy

Therapeutic Targets Therapeutic Targets

TTR

silencers

Patisiran FDA approved for ATTR neuropathy

Theoretically may improve ATTR-CM

Antisense Inotersen FDA approved for ATTR neuropathy

TTR stabilizer Diflunisal Studied in ATTR neuropathy

Small study phase II trial examined safety and tolerability in

ATTR-CM

Tafamidis Studied in ATTR-CM

Fibril degradation Doxycycline +

TUDCA

Small study phase II trial examined safety and tolerability in ATTR CM

Slowed disease progression

Cleve Clin J Med. 2017 Dec;84(12 Suppl 3):12-26.

Background

• Treatment is limited to supportive care• No guideline-recommended treatment

• Tafamidis:• Benzoxazole derivative lacking nonsteroidal anti-inflammatory drug activity

• Inhibits the dissociation of tetramers into monomers

• Shown to slow progression of peripheral neurologic impairment in ATTR polyneuropathy

• Prior studies showed tafamidis 20mg daily stabilized transthyretin in ATTR-CM

N Engl J Med. 2018 Aug 27. Orphanet J Rare Dis. 2013; 8: 31.

Tafamidis Treatment for Patients with Transthyretin Amyloid CardiomyopathyThe New England Journal of Medicine

August 27, 2018

N Engl J Med. 2018 Aug 27.

Study Design

Adapted from Engl J Med. 2018 Aug 27.

Screening

Ran

do

miz

atio

nTafamidis 20mg daily

Tafamidis 80mg daily

Placebo

Tafamidis long-term extension

study

30 month treatment phase, in addition to standard of care

Inclusion/Exclusion

• Key Inclusion Criteria• Presence of amyloid deposit in biopsy tissue (cardiac or non cardiac) and TTR

precursor protein identification by mass spectroscopy, immunohistochemistry or scintigraphy

• Evidence of cardiac involvement by echocardiography with end-diastolic interventricular septal wall thickness > 12 mm

• Past medical history of heart failure with at least 1 prior hospitalization for HF• NT-proBNP ≥ 600pg/ml• 6-minute walk test distance >100 meters

• Key Exclusion Criteria• NYHA class IV• GFR <25 mL/min/1.73m2

• Concurrent treatment with NSAID drugs• Modified body mass index <600 kg/m2 g/L

N Engl J Med. 2018 Aug 27

Endpoints and Statistics

N Engl J Med. 2018 Aug 27

Endpoint Statistics

Primary efficacy: all-cause mortality and frequency of CV-related hospitalizations

Finkelstein-Schoenfeld

Secondary efficacy: 6 minute walk test (6MWT) ANCOVA

Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score

ANCOVA

Mortality Cox- proportional hazard model

CV hospitalizations Poisson regression

Baseline Characteristics Characteristics Pooled Tafamidis (N=264)) Placebo (N=177)

Age, mean (SD) 74.5 (7.2) 74.1 (6.7)

Male , n (%) 241 (91.3) 157 (88.7)

ATTRm, n (%) 63 (23.9) 43 (24.3)

ATTRwt, n (%) 201 (76.1) 134 (75.7)

LV ejection fraction, mean (SD) 48.4 (10.3) 48.6 (9.5)

Intraventricular wall thickness, mean (SD) 16.7 (3.8) 16.2 (3.5)

NYHA Class , n (%)

NYHA Class I 24 (9.1) 13 (7.3)

NYHA Class II 162 (61.4) 101 (57.1)

NYHA Class III 78 (29.5) 63 (35.6)

NT-pro BNP, median 2995.9 3161.0N Engl J Med. 2018 Aug 27

Results

Finkelstein-Schoenfeld Method

Win ratio (95% CI) 1.70 (1.26- 2.29) <0.001

N Engl J Med. 2018 Aug 27

Pooled Tafamidis n=264 Placebo n=177

Patients alive at month 30, n (%) 186 (70.5) 101 (57.1)

Average CV related hospitalizations during 30 (per pt per yr) among those alive at month 30

0.30 0.46

All-Cause Mortality Cox Proportional Hazard

N Engl J Med. 2018 Aug 27

Pooled Tafamidis

Placebo

1.0

0.8

0.6

0.4

0.2

0.00 6 12 18 24 30

Months from first dose

Surv

ival

pro

bab

ility

HR, 0.698 (95% CI, 0.508-0.958), P=0.0259

ResultsFrequency of CV related Hospitalizations

Pooled Tafamidis n=264 Placebo n=177

Total (%) number of patients with CV-related hospitalizations

138 (52.3) 107(60.5)

CV-related hospitalizations per yr 0.48 0.70

Pooled tafamidis vs placebo treatment differencerelative risk ratio (95% CI)

0.68 (0.56-0.81)

P-value <0.0001

N Engl J Med. 2018 Aug 27

Secondary Endpoints

6-minute Walk Test KCCQ-OS

N Engl J Med. 2018 Aug 27

Pooled Tafamidis

Pooled Tafamidis

Placebo Placebo

Mea

n C

han

ge f

rom

Bas

elin

ein

met

ers

Mea

n C

han

ge f

rom

Bas

elin

e

Month Month

0

-60

0

-10

-120

-1800 6 12 18 24 30 302418126

-20

-300

P<0.001

P<0.001

Safety

• No significant difference in adverse drug reactions in tafamidis vs placebo

• Previous studies with tafamidis reported higher rates of urinary tract infection, diarrhea, and abdominal pain

Critique

• Strengths:• Novel drug

• Appropriate statistical tests

• Compliance assessed

• 30 month duration

• Weakness:• Use of NSAIDs

• Cost

Upcoming trials

• Tafamidis received breakthrough therapy designation from FDA

• Long term safety tafamidis in ATTR-CM• 60 months

• Due 2024

• Coming therapies • Monoclonal antibody degrade TTR amyloid deposits

https://clinicaltrials.gov/ct2/show/NCT02319005?cond=Transthyretin+Cardiac+Amyloidosis&rank=3https://clinicaltrials.gov/ct2/show/NCT02791230?cond=Transthyretin+Cardiac+Amyloidosis&rank=10

Conclusion

• Patients with heart failure due to ATTR- CM, treatment with tafamidis reduced all-cause mortality and CV-related hospitalizations

• Tafamidis significantly reduced the decline in functional capacity and quality of life

• Tafamidis is an effective therapy for patients with ATTR-CM

N Engl J Med. 2018 Aug 27

Tafamidis Treatment for Patients with Transthyretin Amyloid

Cardiomyopathy

Journal Club Kristen de Almeida, PharmD

PGY2 Cardiology WPB VA Medical Center

Mentor: Robert J. DiDomenico, PharmD, FCCP, FHFSA, FACC

Dr. Addy Schoening

Dr. Addy Schoening is the PGY2 Cardiology Pharmacy Resident at Abbott Northwestern Hospital. She earned her PharmD from the University of Iowa and completed her PGY1 Pharmacy Residency at Abbott Northwestern. Her professional interests include heart failure, pulmonary hypertension, transplant, and research.

Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure

Addy Schoening, PharmDPGY2 Cardiology Pharmacy Resident

Abbott Northwestern Hospital Minneapolis, MN

Velazquez EJ, et al. N Engl J Med. 2018; [Epub ahead of print]

Disclosures

• No actual or potential conflicts of interestrelated to the content of this presentation to disclose

27

• Standard of care for advanced heart failure exacerbation includes IV diuretics, IV vasodilators, IV inotropes

• Few recent therapies shown to alter outcomes in HF in acute setting

• Ideally, patients begin GDMT prior to discharge

• Recent trials assessing sacubitril-valsartan

– PARADIGM-HF

– TRANSITION

Background

McMurray JJV, et al. N Eng J Med. 2014. 371(11):993-1004.

• Design:– Prospective, randomized, active-controlled

– 3 phases• Screening period; single-blind run-in period; double-blind treatment period

• Population:– Ambulatory, adult patients with HFrEF with NYHA class II - IV already on

GDMT (N=8442)

• Primary endpoint: – Composite of death from CV causes or first hospitalization for HF

• Results: – Sacubitril-valsartan had significant reduction in mortality

• (HR 0.80; 95% CI, 0.73 to 0.87; P<0.001)

– Sacubitril-valsartan had significant reduction in first hospitalization for HF • (HR 0.79; 95% CI, 0.71-0.89; P<0.001)

PARADIGM-HF

McMurray JJV, et al. N Eng J Med. 2014. 371(11):993-1004.

• Design: • Multicenter, open‐label

• Population:• Adult patients hospitalized for ADHF (new or pre-existing HF) with NYHA Class II–IV

and LVEF ≤ 40%

• Intervention: • Initiation of sacubitril-valsartan prior to discharge vs. post-discharge

• Primary endpoint:• Proportion of patients in the pre‐discharge and post‐discharge treatment initiation

groups who achieve the target sacubitril-valsartan dose at the end of Week 10 after randomization

• Results (unpublished):• > 86% of patients were receiving sacubitril-valsartan for 2 weeks or longer without

interruption, roughly half of patients in the study achieved the primary endpoint which was a target dose of 200 mg of sacubitril-valsartan twice daily within 10 weeks in both groups

TRANSITION

Pascual-Figal D, et al. ESC Heart Fail. 2018. 5(2):327-336.Althoff E and Estes A. 2018. Accessed from http://www.novartis.com.

PIONEER-HF

Inclusion

• Hospitalized for ADHF• Within 24 hours – 10 days of

presentation meeting the following criteria:– SBP ≥ 100 mmHg within 6

hours of randomization– No intensification of IV

diuretics within 6 hours– No IV inotropes within 24

hours of randomization– No IV vasodilators including

nitrates within 6 hours of randomization

• LVEF ≤ 40% within past 6 months

• NT-proBNP ≥ 1600 pg/mL OR BNP ≥ 400 pg/mL

Exclusion

• Use of sacubitril-valsartan in previous 30 days

• Known history of angioedema to ACEi or ARB therapy

• eGFR < 30 ml/min/1.73m2• Serum K > 5.2 mEq/L at

screening• Hepatic impairment or

history of cirrhosis with evidence of portal hypertension

• ACS, stroke, TIA, cardiac, carotid, other major CV surgery; PCI, carotid angioplasty with the prior month

Study Timeline

Sacubitril-valsartan

24/26 mg BID49/51 mg BID

Sacubitril-valsartan

49/51 mg BID97/103 mg BID

Sacubitril-valsartan

49/51 mg BID97/103 mg BID

Sacubitril-valsartan

97/103 mg BID

Enalapril2.5 mg BID5 mg BID

Enalapril5 mg BID

10 mg BID

Enalapril5 mg BID

10 mg BID

Enalapril10 mg BID

Double-blind randomization = 1:1

Screening

Day -10 to -1 Day 0 Week 1 Week 2 Week 4 Week 8

R

N=440

N=441

Follow-up: Weeks 1, 2, 4, 6, 8, 10, 12 • Vitals, hematology, chemistry, serum and urinary biomarkers• Med reconciliation, patient- reported outcomes, adverse events

Velazquez EJ, et al. Am Heart J. 2018. 198:145-151.

Dosing Protocol

Randomization

SBP ≥ 100 - <120 mmHg

•Sacubitril-valsartan 24/26 mg BID

•Enalapril 2.5 mg BID

SBP ≥ 120 mmHg

•Sacubitril-valsartan 49/51 mg BID

•Enalapril 5 mg BID

Week 1

SBP < 110 mmHg

•Sacubitril-valsartan 24/26 mg BID

•Enalapril 2.5 mg BID

SBP ≥ 110 mmHg

•Sacubitril-valsartan 49/51 mg BID

•Enalapril 5 mg BID

SBP < 110 mmHg

•Sacubitril-valsartan 49/51 mg BID

•Enalapril 5 mg BID

SBP ≥ 110 mmHg

•Sacubitril-valsartan 97/103 mg BID

•Enalapril 10 mg BID

Week 2, 4, 6

SBP < 100 mmHg

•Sacubitril-valsartan 24/26 mg BID

•Enalapril 2.5 mg BID

SBP ≥ 100 mmHg

•Sacubitril-valsartan 49/51 mg BID

•Enalapril 5 mg BID

SBP < 100 mmHg

•Sacubitril-valsartan 49/51 mg BID

•Enalapril 5 mg BID

SBP ≥ 100 mmHg

•Sacubitril-valsartan 97/103 mg BID

•Enalapril 10 mg BID

• Time-averaged proportional change in NT-proBNP concentration from baseline through weeks 4 and 8

Primary

• Incidence of a composite of death

• Re-hospitalization for heart failure

• Implantation of a LVAD

• Listing for heart transplantation

• Unplanned visit for acute heart failure requiring IV diuretics, increase in dose of diuretics of > 50%, or the use of an additional drug for heart failure

Exploratory

• Incidence of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedemaSafety

Endpoints

• Assuming threshold for statistical significance of .05 and 85% power, assuming a value of 0.95 for enalapril group – Sample size needed to detect 18% reduction in geometric

mean= 882 patients

• Primary endpoint analysis: intention-to-treat– Least-squared means from an analysis of covariance model

• Exploratory endpoint: cumulative clinical-event rates were calculated according to the Kaplan–Meier method– Differences in clinical outcomes were assessed with the log-

rank test

– Hazard ratios and associated 95% confidence intervals were calculated with a Cox proportional-hazards model.

Statistics

Velazquez EJ, et al. Am Heart J. 2018. 198:145-151.

Results964 screened

887 randomized

443 assigned to sacubitril-valsartan-3 excluded for randomization error

444 assigned to enalapril-3 excluded for randomization error

91 discontinued treatment prematurely (20.4%)

-51 adverse event-4 died while receiving treatment drug

-5 lost to follow-up

96 discontinued treatment prematurely (21.7%)

-45 adverse event-6 died while receiving trial drug

-7 lost to follow-up

440 in efficacy analysis379 had data for primary efficacy

outcome at baseline and weeks 4,8

441 in efficacy analysis374 had data for primary efficacy

outcome at baseline and weeks 4,8

439 in safety analysis 436 in safety analysis

Variable Sacubitril-valsartan(N=440)

Enalapril(N=441)

Age (years), median (IQR) 61 (51-71) 63 (54-72)

Female sex, n (%) 113 (25.7) 133 (30.2)

Black race, n (%) 158 (35.9) 158 (35.8)

Previous HF, n (%) 298 (67.7) 278 (63)

Previous use of ACEi/ARB, n (%) 208 (47.3) 214 (48.5)

NYHA class III, n (%) 283 (64.3) 269 (61)

NT-proBNP at randomization (pg/mL), median (IQR)

2883 (1610–5403) 2536 (1363-4917)

SBP (mmHg), median (IQR) 118 (110-133) 118 (109-132)

Estimated GFR (ml/min/1.73m2), median (IQR)

58.4 (47.5 -71.5) 58.9 (47.4-70.9)

Serum potassium (mmol/L), median (IQR)

4.2 (4-4.5) 4.25 (3.9-4.6)

Percentage of patients receivingtarget dose at 8 weeks, %

55.2 60.8

Results – Demographics

Variable Sacubitril-valsartan(N=440)

Enalapril (N=441)

Risk risk (95% CI)

P-value

Ratio of Change in NT-proBNP at weeks 4 and 8 vs Baseline

0.53 0.75 0.71 (0.63-0.81) <0.001

Results - Primary

Weeks since randomization

Ch

ange

in N

T-p

roB

NP

fr

om

Bas

elin

e (%

)10

0

-10

-20

-30

-40

-50

-60

-70

1 2 3 4 5 6 7 8 Baseline

Variable Sacubitril-valsartan(N=440)

Enalapril(N=441)

Relative risk (95% CI)

Worsening renal function, n (%) 60 (13.6) 65 (14.7) 0.93 (0.67-1.28)

Hyperkalemia 51 (11.6) 41 (9.3) 1.25 (0.84-1.84)

Symptomatic hypotension 66 (15) 56 (12.7) 1.18 (0.85-1.64)

Angioedema 1 (0.2) 6 (1.4) 0.17 (0.02-1.38)

Results – Safety

Variable Sacubitril-valsartan(N=440)

Enalapril(N=441)

Relative risk (95% CI)

Composite of clinical events 249 (56.6) 264 (59.9) 0.93 (0.78-1.1)

Death 10 (2.3) 15 (3.4) 0.66 (0.3-1.48)

Rehospitalization for HF 35 (8) 61 (13.8) 0.56 (0.37-0.84)

Implantation of LVAD 1 (0.2) 1 (0.2) 0.99 (0.06-15.97)

Listed for heart transplantation 0 0 NA

Unplanned outpatient visit leading to use of IV diuretics

2 (0.5) 2 (0.5) 1 (0.14-7.07)

Use of additional drug for HF 78 (17.7) 84 (19) 0.92 (0.67-1.25)

Increase in dose of diuretics >50%

218 (49.5) 222 (50.3) 0.98 (0.81-1.18)

Results - Exploratory

• Sacubitril-valsartan successful in lowering NT-proBNP when initiated prior to discharge

– Clinical outcomes?

• Sacubitril-valsartan is safe to start in hospitalized patients

– Black race, new diagnosis of HF, ACEi/ARB naïve

– Increase in hospital initiation

• Cost-effectiveness

Discussion

Critiques

Strengths

• Prospective, double-blind, randomized clinical trial

• Active comparator

• Relevant clinical question

• Underrepresented population

• Inclusive of low-dose sacubitril-valsartan in dosing protocol

Weaknesses

• Surrogate endpoint

• Exploratory analysis of clinical outcomes

• Local clinician-investigators initiating without central validation

• Monitoring required could prolong hospitalization

• Improvements in transitions of care

– Increased utilization of GDMT

– Reduction in readmissions

• Increased access to sacubitril-valsartan

– More data may allow increased inclusion on insurance formularies

Impact on Clinical Practice

• Robert DiDomenico, PharmD, BCPS-AQ Cardiology, FCCP, FHFSA, FACC

• Matt Lillyblad, PharmD, BCCCP, BCPS-AQ Cardiology

Acknowledgments

Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure

Addy.Schoening@allina.comPGY2 Cardiology Resident

Abbott Northwestern HospitalMinneapolis, MN

Velazquez EJ, et al. N Engl J Med 2018; [Epub ahead of print]

Questions???