1. Combination of Isosorbide Dinitrate and Hydralazine in Blacks with Heart Failure
Anne L. Taylor, M.D., Susan Ziesche, R.N., Clyde Yancy, M.D., Peter Carson, M.D., Ralph D'Agostino, Jr., Ph.D., Keith Ferdinand, M.D., Malcolm Taylor, M.D., Kirkwood Adams, M.D., Michael Sabolinski, M.D., Manuel Worcel, M.D., Jay N. Cohn, M.D., for the African-American Heart Failure Trial Investigators
Volume 351:
November 11, 2004
Number 20

2. Pharm Background Hydralazine Peripheral arterial vasodilator
Protection against degradation of NO induced by oxidative stress
Unclear mechanism of action
Isosorbide Dinitrate
Nitrate
Vasodilates arteries and veins
Enalapril
ACE Inhibitor

3. Background V-HeFT I (Vasodilator-Heart Failure Trial I)
Mortality of black patients receiving hydralazine plus isosorbide dinitrate (H-I) was reduced (P = .04), whereas white patients showed no difference from placebo.
V-HeFT II (Vasodilator-Heart Failure Trial II)
Only white patients showed a mortality reduction from enalapril therapy compared with H-I therapy (P = .02).
Carson P, Ziesche S, Johnson G, Cohn JN. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. J Card Fail 1999;5:

4. V-HeFT I : Survival Benefit in Subgroups
Non-African Americans
African Americans
80%
80%
Risk Ratio=0.53
P=.04
70%
70%
60%
60%
50%
50%
Cumulative Mortality
Cumulative Mortality
40%
40%
30%
30%
20%
20%
10%
n=480
10%
n=180 0% 0% 6 18 30 42 54 66 6 18 30 42 54 66
Months
Months
I/H
Placebo

5. Background
Conclusion: Whites and blacks showed differences in cause, neurohormonal stimulation, and pharmacological response in heart failure. This retrospective analysis suggests angiotensin converting enzyme inhibitors are particularly effective in whites, and the H-I combination can be equally effective in blacks. Prospective trials involving large numbers of black patients are needed to further clarify their response to therapy.
Carson P, Ziesche S, Johnson G, Cohn JN. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. J Card Fail 1999;5:

6. Background The Slavery Hypothesis, 1983 Debunked by major historians
Accepted without proof among many scientists today

7. Background Hypertension is most prevalent in African Americans
1 in 3 African Americans has hypertension
1 in 5 Americans has hypertension
In 2002 the death rates per 100,000 population from (complications of) high blood pressure were 14.4% for white males, 49.6% for black males, 13.7% for white females and 40.5% for black females.

8. Background
Blacks are affected by heart failure at a rate almost twice the rate of whites and are more likely to die from it at a younger age
The mortality rate and the hospitalization rate for African Americans with heart failure is significantly higher than for non-African Americans, even after adjustment for factors including access to medical care, management of heart failure and socioeconomic factors

9. Study Design Randomized Placebo-controlled Double blind 161 centers
1050 patients
No patients lost to follow-up

10. Inclusion Crieria 18+ years of age Self-identified as black
NYHA class III or IV heart failure for 3+ months
Receiving “standard therapy” for heart failure
Evidence of left ventricular dysfunction

11. Exclusion Criteria (selected)
Severe cardiovascular event (acute MI, cardiac arrest) or stroke in preceding 3 months
Cardiac surgery or PCI in preceding 3 months
Preexisting valvular disease, myocarditis, or hypertrophic cardiomyopathy
Inability to complete quality of life questionnaire
Contraindications to nitrates or hydralazine

14. Evaluation and Follow-Up
Initial evaluation: echocardiography, metabolic profile, BNP, hemoglobin, quality of life questionnaire
Every three months: quality of life questionnaire
Every six months: EF, LV diastolic dimension, LV wall thickness, BNP
Telephone interview every month, follow-up visit every six months
Follow-up period: 18 months

15. Randomization Stratified by use or nonuse of beta blockers
Randomized to:
Fixed dose isosorbide dinitrate + hydralazine
Placebo

16. Outcome Measure Composite Score: Death from any cause
First hospitalization for heart failure during 18 month follow-up period
Change in quality of life at 6 months

17. Scoring System

18. Statistical Analysis Intention-to-treat analysis
Worst case score used for missing data
Secondary analyses examined individual components of composite end point

22. A-HeFT: Primary Endpoint (Composite Score)
Placebo
Fixed-dose I/H
-0.25
-0.5
P=0.01

23. A-HeFT: Components of Composite Score
Change in Quality of Life
(lower score is better)
Death
First HF Hospitalization
-2.7
-5.6 15 30
24.4%
10.2% 10 -2
6.2% 20
16.4% 5 -4
N=54
N=130
N=85
N=32 10 -6
P=0.02
P=0.001
P=0.02
Placebo
Fixed-dose I/H