debate advances in heart failure

DISCLOSURES

• Consultant/speaker/honoraria: none • Editorial Boards: American Heart Journal, American Journal of

Cardiology -associate editor; Circulation; Circulation-Heart Failure; Journal of the American College of Cardiology- associate editor (HF)

• Guideline writing committees: Chair, ACC/AHA, chronic HF; member, atrial fibrillation; Chair, Performance Measures, Sudden Cardiac Death

• Federal appointments: FDA: Immediate Past Chair, Cardiovascular Device Panel; ad hoc consultant; NIH – Scientific Management and Review Board for the Director; AHRQ- adhoc consultant; NHLBI- consultant; PCORI- methodology committee member

• Volunteer Appointments: American Heart Association- President, American Heart Association, 2009-2010; American College of Cardiology, Founder- CREDO

ACC ’15 joint ACC/ABC Symposium

Clyde W. Yancy, MD, MSc

ACC ‘15

ACC/ABC Joint Symposium

“:Advances in Heart Failure

For African Americans:

Paradigm Shift or Paradigm

Drift? (PRO)“

Clyde W. Yancy, MD, MSc, FACC, FAHA, MACP

Vice-Dean, Diversity & inclusion Magerstadt Professor of Medicine

Professor, Department of Medical Social Sciences Chief of Cardiology

Northwestern University, Feinberg School of Medicine &

Associate Medical Director Bluhm Cardiovascular Institute

Chicago, IL [email protected]

Case Presentation- Northwestern HF Clinic • 45 year old African American software engineer presents for

routine follow-up; has NYHA class I/II HF due to reduced ejection fraction; no evidence of CAD; positive history of hypertension. Doing well on carvedilol, lisinopril and spironolactone. Takes prn diuretics . EXAM- compensated with no evidence of congestion or volume overload. DATA – BNP 35 pg/ml. LVEF 0.40.

• Question: RE: Next step - is LCZ 696 or H-ISDN most appropriate? A. LCZ 696

B. H-ISDN

C. Both

D. Neither

Pharmacologic Treatment for Stage C HFrEF HFrEF Stage C

NYHA Class I – IV

Treatment:

For NYHA class II-IV patients.

Provided estimated creatinine

>30 mL/min and K+ <5.0 mEq/dL

For persistently symptomatic

African Americans,

NYHA class III-IV

Class I, LOE A

ACEI or ARB AND

Beta Blocker

Class I, LOE C

Loop Diuretics

Class I, LOE A

Hydral-Nitrates

Class I, LOE A

Aldosterone

Antagonist

AddAdd Add

For all volume overload,

NYHA class II-IV patients

Medical Therapy for Stage C HFrEF: Magnitude of Benefit Demonstrated in RCTs

GDMT RR Reduction

in Mortality

NNT for Mortality

Reduction

(Standardized to 36 mo)

RR Reduction

in HF

Hospitalizations

ACE inhibitor or

ARB 17% 26 31%

Beta blocker 34% 9 41%

Aldosterone

antagonist 30% 6 35%

Hydralazine/nitrate 43% 7 33%

Fonarow, G, … Yancy, C. American Heart Journal, 2012

The newest “Paradigm” in HF

Simplified schematic of the renin–angiotensin–aldosterone system.

von Lueder T G et al. Circ Heart Fail. 2013;6:594-605

Copyright © American Heart Association, Inc. All rights reserved.

Simplified schematic of the natriuretic peptide system (NPS).



Cardiac antiremodeling effects of angiotensin receptor neprilysin inhibitors (ARNi) in vitro and in vivo.


Natriuretic peptides BK, ADM

Subs-P, VIP, CGRP

Angiotensin II

• Vasoconstriction

• Sodium/water retention

• Fibrosis/hypertrophy

Degradation

products

Neprilysin AT1 Receptor

Angiotensin Receptor Neprilysin

Inhibition (ARNI): LCZ696

• Vasodilation

• Natriuresis

• Diuresis

• Inhibition of pathologic

growth/fibrosis

LCZ696

sacubitril valsartan

PARADIGM - HF

PARADIGM HF

PARADIGM-HF

Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial

Death from CV causes 20% risk reduction

HF hospitalization 21% risk reduction

693

558

658

537

McMurray, Packer et al NEJM 2014

P = 0.00008 P = 0.00008

Primary composite outcome

HR: 0.80 (0.73, 0.87) p = 0.0000004

PARADIGM-HF

Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial

Death from any cause

0

10

20

30

40

0 180 360 540 720 900 1080 1260

16% risk reduction

Enalapril

(n=4212)

835

LCZ696

(n=4187)

711

Days after Randomization

Cu

mu

lative

Pro

po

rtio

n o

f P

atie

nts

Wh

o D

ied

fro

m A

ny C

au

se

(%

)

HR: 0.84 (0.76, 0.93)

P = 0.0009

Prespecified Subgroup Analyses.

McMurray JJ et al. N Engl J Med 2014. DOI: 10.1056/NEJMoa1409077

Adverse Events during Randomized Treatment.

McMurray JJ et al. N Engl J Med 2014. DOI: 10.1056/NEJMoa1409077

Kaplan–Meier curve for the time to first hospitalization for heart failure during first 30 days

after randomization, according to study group.

Packer M et al. Circulation. 2015;131:54-61


Cumulative number of hospitalizations for heart failure in the enalapril and LCZ696 groups

per 100 patients.

Packer M et al. Circulation. 2015;131:54-61


Pharmacologic Treatment for Stage C HFrEF HFrEF Stage C

NYHA Class I – IV

Treatment:

For NYHA class II-IV patients.

Provided estimated creatinine

>30 mL/min and K+ <5.0 mEq/dL

For persistently symptomatic

African Americans,

NYHA class III-IV

Class I, LOE A

ACEI or ARB AND

Beta Blocker

Class I, LOE C

Loop Diuretics

Class I, LOE A

Hydral-Nitrates

Class I, LOE A

Aldosterone

Antagonist

AddAdd Add

For all volume overload,

NYHA class II-IV patients

ARNI

PARADIGM HF vs. A-HEFT

PARADIGM HF

• 5% “Black”; 7% North America

(perhaps < 100 AA patients)

• NYHA class II HF

• LVEF < 0.45

• Up-regulates natriuretic peptides leading to activation of cGMP

• May be beneficial in NO deficient patients, i.e., African Americans

• Instead of ACE-I

• Ideal candidate: clinically stable with mild HF but elevated BNP

A-HEFT

• 100% African American; n= 1,024

• NYHA class III

• LVEF < 0.35; mean LVEF 0.24

• Restores NO balance resulting in up-regulation of cGMP

• Likely most beneficial in loss of GNB3 and NO3 phenotypes

• In addition to ACE-I

• Ideal candidate: moderate to moderately severe HF with very reduced EF and especially with at-risk genotype

Similar or different studies?

Paradigm Shift or Paradigm Drift?

•Only if you don’t know the data…

•AND, only if you believe that the use of ISDN/Hyd is already robust

penetration of ISDN/HyD in appropriate patients remains < 20%

- adherence, i.e., refilling Rx, is <<50%

PRECISION MEDICINE INITIATIVE

• Announced by President Obama, Feb 7, 2015

• Definition: “… an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment and lifestyle for each person… a bold new enterprise to revolutionize medicine and generate the scientific evidence needed to move the concept of precision medicine into everyday clinical practice.”

• www.nih.gov

24

A-HeFT Genetic Sub-study

GRAHF

Genetic Risk Assessment in Heart

Failure

in African Americans

Impact of ISDN/HYD in GRAHF Composite Score Primarily in NOS 3' Glu298Glu Subjects

0.29

-0.22

0.38

0.18

-0.3

-0.2

-0.1

0

0.1

0.2

0.3

0.4

0.5 Placebo (n=189)

ISDN/HYD (=169)

Asp (n=80) Glu-Glu (n=277)

P=.82

P=.051

Pri

ma

ry e

nd

po

int

co

mp

os

ite

sc

ore

McNamara DM, Tam SW, Sabolinski ML, Tobelmann P, Janosko K, Venkitachalam L, Ofili E,

Yancy C, Feldman AM, Ghali JK, Taylor AL, Cohn JN, Worcel M.

Endothelial nitric oxide synthase (NOS3) polymorphisms in African Americans with heart failure:

results from the A-HeFT trial. J Card Fail. 2009 Apr;15(3):191-8.

JACC-HF 2014, Online Publication; 10/10/14

• Alpha-2 adrenergic signaling occurs via specific heterotrimeric G-proteins including the G-protein ß3 subunit (GNB3 )

• A common C825T polymorphism exists for GNB3, with the T allele linked with enhanced alpha receptor intracellular signalling.

• The “T-allele” is also linked to hypertension and low plasma renin, and has a much higher prevalence in black cohorts than among whites

GNB3 T825C polymorphism

All

(N=350)

TT

(N=184)

TC+CC

(N=166)

p value*

Age (years) 57 13 57 12 58 13 0.699

Female (%) 40 40 40 0.930

NYHA Class

(%/III/IV)

97/3 97/3 97/3 0.894

Ischemic (%) 25 24 26 0.755

LVEF qualifying 0.25 0.08 0.25 0.08 0.24 0.09 0.137

BP systolic 127 17 12816 12617 0.290

BP diastolic 77 10 77 10 7611 0.520

ACE Inhibitor (%) 76 76 76 0.743

Aldosterone

receptor

antagonist

36 35 37 0.782

Beta Blocker (%) 84 85 83 0.569

GRAHF : Genetic Sub-study of AHeFT

Baseline Characteristics by GNB3 Genotype

*No significant differences by GNB3 genotype

-0.11-0.09

0.50

-0.05

-0.2

0

0.2

0.4

0.6

0.8

Placebo I/H

GNB3 TT only GNB3 TC+CC

*p=0.016, n=184 p=0.871, n=166

Impact of I/H on composite score in A-HeFT:

GNB3 TT genotype subset versus C allele (TC+CC )

0.24

0.14

0.69

0.28

0

0.2

0.4

0.6

0.8

Placebo I/H

GNB3 TT only GNB3 TC+CC

*p=0.039, n=184 p=0.563, n=166

Impact of I/H on Quality of Life (QoL) Score:

GNB3 TT genotype versus C allele (TC+CC )

31

GRAHF

Genetic Risk Assessment in Heart

Failure

GRAHF2

Genomic Analysis of the Enhanced

Response to Heart Failure Therapy in

African Americans

GRAHF2: Hypothesis and Analysis

Primary Hypothesis: The GNB3 TT genotype will identify subjects with the greatest clinical benefit from treatment with Hydralazine/Isosorbide Dinitrate

Comparison

• Composite Score of GNB3 TT subjects compared to subjects with the C allele (GNB3 CC plus TC)

GRAHF2: Outcome Measure

Primary Outcome: AHeFT Composite score (survival, HF hospitalization, change in QoL at 6 months)

Secondary

• Individual components of the score: Survival, Survival free from hospitalization, Change in QoL at 6 months

• Change in 6 minute walk at 6 months

• Remodeling (by echo) at 6 months

GRAHF2: Genomics

Replicate the GRAHF SNP “Panel”

• GNB3, NOS, Beta receptors, Aldosterone synthase, ACE D/I

Perform admixture analysis

• Determine % African Genomic Heritage for each subject and analyze as a “modifier” of HYD/ISDN effect

• Search for Genomic loci responsible for impact by admixture analysis

SUMMARY

• Clinical evidence supports a role for NO modulation in the treatment of heart failure

• Certain patient populations, now described by ancestry, may exhibit a unique response to the restoration of NO homeostasis

• A portfolio of genotypes are associated with a positive response to NO upregulation

• The possibility of truly personalized medical therapy may emerge with NO as the target

Context of GRAPH II

Case Presentation- Northwestern HF Clinic 02.15 • 45 year old African American software engineer presents for

routine follow-up; has NYHA class I/II HF due to reduced ejection fraction; no evidence of CAD; positive history of hypertension. Doing well on carvedilol, lisinopril and spironolactone. Takes prn diuretics . EXAM- compensated with no evidence of congestion or volume overload. DATA – BNP 35 pg/ml. LVEF 0.40.

• Question: RE: Next step - is LCZ 696 or H-ISDN most appropriate? A. LCZ 696

B. H-ISDN

C. Both

D. Neither

debate advances in heart failure

Healthcare