Debate advances in Heart Failure

1. 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

2. ACC ’15
joint ACC/ABC
Symposium
Clyde W. Yancy, MD,
MSc

3. 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 SocialSciences
Chief of Cardiology
NorthwesternUniversity,Feinberg Schoolof Medicine
&
AssociateMedicalDirector
Bluhm Cardiovascular Institute
Chicago,IL
cyancy@nmff.org

4. 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

5. 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

6. 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

7. The newest “Paradigm” in HF

8. 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.

9. Simplified schematic of the natriuretic peptide system (NPS).
von Lueder T G et al. Circ Heart Fail. 2013;6:594-605
Copyright © American Heart Association, Inc. All rights reserved.

10. Cardiac antiremodeling effects of angiotensin receptor
neprilysin inhibitors (ARNi) in vitro and in vivo.
von Lueder T G et al. Circ Heart Fail. 2013;6:594-605

11. 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

12. PARADIGM - HF

13. PARADIGM HF

14. PARADIGM-HF
ProspectivecomparisonofARNIwith ACEItoDetermine Impact on
GlobalMortalityandmorbidityin HeartFailuretrial
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

15. PARADIGM-HF
ProspectivecomparisonofARNIwithACEItoDetermine Impact on
GlobalMortalityandmorbidityin HeartFailuretrial
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
CumulativeProportionofPatients
WhoDiedfromAnyCause(%)
HR: 0.84 (0.76, 0.93)
P = 0.0009

16. Prespecified Subgroup Analyses.
McMurrayJJetal.NEnglJMed2014.DOI:10.1056/NEJMoa1409077

17. Adverse Events during Randomized Treatment.
McMurrayJJetal.NEnglJMed2014.DOI:10.1056/NEJMoa1409077

18. 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
Copyright © American Heart Association, Inc. All rights reserved.

19. 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
Copyright © American Heart Association, Inc. All rights reserved.

20. 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

21. 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 ordifferent studies?

22. 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%

23. 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. 24
A-HeFT Genetic Sub-study
GRAHF
Genetic Risk Assessment in Heart
Failure
in African Americans

25. 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
Primaryendpointcompositescore
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 failur
results from the A-HeFT trial. J Card Fail. 2009 Apr;15(3):191-8.

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

27. • 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

28. 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  17 12816 12617 0.290
BP diastolic 77  10 77 10 7611 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

29. -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 )

30. 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. 31
GRAHF
Genetic Risk Assessment in Heart
Failure
GRAHF2
Genomic Analysis of the Enhanced
Response to Heart Failure Therapy in
African Americans

32. 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)

33. 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

34. 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

35. 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

36. 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