Heart Failure Therapy in Special Populations: The Same or Different

1
Heart Failure Therapy in Special Populations
The Same or Different?

• Clyde W. Yancy, MD
• The University of TexasSouthwestern Medical
  Center at Dallas
• Dallas, Texas

2
Survival BenefitACEIs and b-Blockers
Death at 1 Year

• Do these outcomes apply to all patients with HF?
• Combination of ACEI BB in Val-HeFT 5.6
• ? Additional benefit of aldosterone antagonism

SOLVD-T
15.6
16
MERIT-HF CIBIS II
14
12.4
11.9
12
10
Percent
7.8
8
6
4
2
0
Placebo
Active treatment
Adapted from McMurray JJV. Heart. 199982(suppl
IV)IV14IV22.
3
Demographic Projections
2010 US Population by Race
2020 US Population by Race
Asian/PacificIslander
Asian/PacificIslander
American Indian
American Indian
Hispanic
Hispanic
63
67
AfricanAmerican
AfricanAmerican
Non-Hispanic White
Non-HispanicWhite
In 2000 Non-Hispanic Whites 71.4 By 2050
Non-Hispanic Whites 53
4
Prevalence of Hypertension by Age, Gender, and
Race
80
White men
70
Black men
White women
60
Black women
50
Population ()
40
30
20
10
0
25-34
35-44
45-54
55-64
65-74
75
Age, years
American Heart Association. Heart Disease and
Stroke Statistics 2002 Update. Dallas, TX
American Heart Association2003.
5
Heart Failure Therapy in Special Populations
Similar or Different

• Who are the special populations?
• The elderly
• Women
• African Americans

6
ADHERE RegistryExecutive Summary
All Enrolled Discharges in the Last 12 Months
(July 1, 2002 June 30, 2003)
Indented percentages are calculated based on the
number of patients presented in the preceding
row, rather than the number of patients for the
column. The ADHERE Registry database. Second
Quarter 2003 National Benchmark Report.
Sunnyvale, CA Scios Inc. November, 2003
7
Clinical Characteristics and Outcomes in Patients
Admitted with Heart Failure with Preserved
Systolic Function A Report from the ADHERETM
DatabaseDemographics
LVEF LVEF 40
P 8
Heart Failure in Women Overview

• Affects older women disproportionately
• Risk factors include hypertension, diabetes,
  obesity
• More likely to have heart failure with preserved
  systolic function
• Better prognosis than in men
• Clinical trial data may be affected by higher
  representation of African American women
• Worrisome evidence of lesser responsiveness to
  ACE inhibitors similar responsiveness to
  b-blockers

9
OutcomesWomen and ACE Inhibitorsfor Heart
Failure
10
Combined Treatment and Prevention Study Outcomes
with ACE Inhibitors in Heart Failure
Female
Male
CONSENSUS
CONSENSUS
SAVE
SAVE
SOLVD (Prev)
SOLVD (Prev)
SOLVD (Tx)
SOLVD (Tx)
SMILE
SMILE
TRACE
TRACE
Combined
Combined
0.4
0.82
1.1
1.9
0.4
0.92
1
1.9
Relative Risk
Relative Risk
11
Prevention Study Outcomes with ACE Inhibitors in
Heart Failure
Prevention Studies
Female
Male
SAVE
SAVE
SOLVD (Prev)
SOLVD (Prev)
SMILE
SMILE
Combined
Combined
.45
0.96
1.9
1
.4
0.4
0.83
1.1
1.9
1
Relative Risk
Relative Risk
12
Treatment Study Outcomes with ACE Inhibitors in
Heart Failure
Treatment Studies
Female
Male
CONSENSUS
CONSENSUS
SOLVD (Tx)
SOLVD (Tx)
TRACE
TRACE
Combined
Combined
.45
0.8
1.9
1
.45
0.9
1.9
1
.4
Relative Risk
Relative Risk
13
OutcomesWomen and b-Blockers in HF
14
b-Blockers in Heart Failure Outcomes
No. of DeathsPlacebo/b-blockade
No. RandomizedPlacebo/b-blockade
Favorsb-blockade
FavorsPlacebo
CIBIS II
FemalesMalesAll
35/18193/138228/156
258/2571062/10701320/1327
MERIT-HF
33/31184/114217/145
447/4511554/15392001/1990
FemalesMalesAll
COPERNICUS
NPNP190/130
NPNP1133/1156
FemalesMalesAll
All 3 Studies
FemalesMalesAll
1.0
1.8
0.0
15
Heart Failure Therapy in Special Populations
Similar or Different

• How should the elderly and women with HF be
  treated?
• There are no compelling data to suggest that the
  elderly or women do not realize important
  survival benefits from the combination of ACE
  inhibitors and b-blockers, but subtle differences
  in the response to medical therapy may be
  present additional investigation may be
  warranted the elderly may actually have a
  greater response to medical therapy for HF

16
Heart Failure in African Americans Overview

• Affects 3 of the African American population
• Atypical natural history
• Unique epidemiology
• Lower incidence of associated epicardial coronary
  artery disease
• More likely to be associated with a historyof
  hypertension
• Worrisome prognosis
• Higher rate of hospitalization
• Likely to have similar mortality risk
• Question of altered responses to medical therapy

Yancy CW. J Card Fail. 20006183186.
17
Heart Failure in African Americans Etiology

• Unique natural history
• Occurs at an earlier age
• Associated with more advanced left ventricular
  dysfunction at time of diagnosis
• Worse clinical class at time of diagnosis
• Higher incidence of left ventricular hypertrophy,
  especially concentric hypertrophy
• Lack of definitive relationship between
  psychosocial factors and onset of disease

Yancy CW. J Card Fail. 20006183186.
18
Etiology of Heart Failure inAfrican Americans
Patients With Coronary Artery Disease-Based HF
80
60
40
Percent
20
0
V-HeFT I
V-HeFT II
SOLVD
US Carv
BEST
MERIT-HF
Patients With Hypertension-Based HF
80
60
Percent
40
20
0
V-HeFT I
V-HeFT II
SOLVD
US Carv
BEST
MERIT-HF
AA
non-AA
The BEST Investigators. N Engl J Med.
200134416591657 Packer M et al. N Engl J Med.
199633413491355 MERIT-HF Study Group. Lancet.
199935320012007 Cohn JN et al. N Engl J Med.
198631415471552Cohn JN et al. N Engl J Med.
1991325303310 The SOLVD Investigators. N Engl
J Med. 1991325293302.
19
Heart Failure inAfrican Americans

• The emerging influence of genetic polymorphisms
  ie, heart failure in African Americans

20
Candidate Genetic Polymorphisms That May
Participate in the Pathogenesis of Hypertension
in African Americans

• Transforming growth factor-b1
• Endothelin-1
• b1-receptor polymorphisms
• Aldosterone synthase
• Nitric oxide synthase
• 825 T-allele G-protein subunit

21
Potential Mechanisms of Heart Failure in African
Americans

• ?1-adrenergic receptor polymorphism
• Described polymorphism at amino acid position 389
  (Gly 0.26 or Arg 0.74)
• Isoproterenol-stimulated adenyl cyclase activity
  markedly higher with Arg-389
• Increased coupling with Gs with Arg-389
• Gly-389 associated with decreased adenyl cyclase
  activity and decreased Gs coupling
• These findings could be operative in the
  pathophysiology of HF or response to ?-blockers

Mason DA et al. J Biol Chem. 19992741267012674.
22
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23
OutcomesAfrican Americansand ACE Inhibitors
24
Ethnic Reanalysisof SOLVD Trial
Exner DV et al. N Eng J Med. 200134413511357.
25
CHF Mortality in White Patients V-HeFT II
0.8
Enalapril (E)HYDISO (HI)
0.7
0.6
0.5
Cumulative Mortality
0.4
0.3
0.2
0.1
E vs HI P0.0
0
6
12
18
24
30
36
42
48
54
60
66
Months
HYD-ISO, hydalazyne plus isosorbide
dinitrate. Carson P et al. J Card Fail.
19995178187.
26
CHF Mortality in African American Patients
V-HeFT II
0.8
Enalapril (E)HYDISO (HI)
0.7
0.6
0.5
Cumulative Mortality
0.4
0.3
0.2
0.1
E vs HI P0.0
0
6
12
18
24
30
36
42
48
54
60
66
Months
Carson P et al. J Card Fail. 19995178187.
27
OutcomesAfrican Americansand b-Blockers
28
Outcomes with b-Blockersin Heart Failure
White/nonblack
BEST
COPERNICUS
MERIT-HF
US Carvedilol HF
Combined
.2
.69
2
1
Relative Risk
29
Outcomes with b-Blockers in Heart Failure
Black
BEST
COPERNICUS
MERIT-HF
US Carvedilol HF
Combined
.2
.97
2
1
Relative Risk
30
BEST All-Cause Mortalityby Race
1.0
1.0
17
18
0.8
0.8
Bucindolol
Placebo
Probability of Survival
Placebo
Bucindolol
0.6
0.6
P.01 Total Events 652
P.27 Total Events 208
0.4
0.4
0
6
12
18
24
30
36
42
0
6
12
18
24
30
36
42
Months Post-randomization
Months Post-randomization
Nonblacks (n2081)
Blacks (n627)
The b-Blocker Evaluation of Survival Trial
Investigators. N Engl J Med. 200134416591667.
31
Effect of Carvedilol in Black Patients With Heart
Failure
All-cause mortality all-cause hospitalization
COPERNICUS1 (n121)
US Carvedilol Trials2 (n217)
All-cause mortality cardiovascular
hospitalization
All-cause mortality heart failure
hospitalization
All-cause mortality
0
0.4
0.8
1.2
1.6
2
Favors carvedilol
Favors placebo
1. Packer M. Presentation at AHA 2000 (mean
duration 10.5 months).2. Yancy CW. N Engl J Med.
200134413581365. (mean duration 6.5 months).
32
US Carvedilol Trials Effect of Race on Change
in Hemodynamic Variables
African Americans
Non-African Americans
Placebo
Carvedilol
Placebo
Carvedilol
Interaction
(n90)
(n127)
(n308)
(n569)
P-Value
D
LVEF
0.02
0.10
0.02
0.08
.16
D
SBP
(
mm Hg)
1.9
1.2
0.5
-0.3
.89
D
DBP
(
mm Hg)
-0.1
-0.9
0.2
-1.4
.75
D
HR
(
bpm)
1.4
-13.4
-2.2
-13.0
.03
Within-group P.0001, P Engl J Med. 200134413581365.
33
COPERNICUS Effect of Race on Outcomes
All-cause mortality all-cause hospitalization
Blacks (n121)
Nonblacks (n2168)
All-cause mortality cardiovascular
hospitalization
All-cause mortality heart failure
hospitalization
All-cause mortality
0
0.4
0.8
1.2
1.6
2
Favors carvedilol
Favors placebo
Mean duration 10.5 months. Packer M. Presentation
at AHA 2000.
34
Heart Failure Therapy in Special Populations
Similar or Different

• How should African Americans with heart failure
  be treated?
• The treatment for all patients with heart failure
  is similar and no variations, other than as
  indicated by individual patient presentation, are
  appropriate. The therapy of HF should never be
  focused from a race- or gender-based perspective