Debate advances in Heart Failure
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Transcript of 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).
von Lueder T G et al. Circ Heart Fail. 2013;6:594-605
Copyright © American Heart Association, Inc. All rights reserved.
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
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
Copyright © American Heart Association, Inc. All rights reserved.
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.
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