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 351:2049-2057 November 11, 2004 Number 20

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

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;5:178-187

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 http://www.a-heft.org/AHeFTSlideDeck.ppt

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;5:178-187

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

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.

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 http://www.nitromed.com/BiDil.asp

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

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

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

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

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

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

Scoring System

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

A-HeFT: Primary Endpoint (Composite Score) Placebo Fixed-dose I/H -0.25 -0.5 P=0.01 http://www.a-heft.org/AHeFTSlideDeck.ppt

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 http://www.a-heft.org/AHeFTSlideDeck.ppt