Authors
Taylor AL, Ziesche S, Yancy C, et al.
Title
Combination of Isosorbide Dinitrate and Hydralazine in Blacks with Heart Failure
References
N Engl J Med 2004;351:2049-57.
Background
Previous trials have demonstrated that the beneficial effects of isosorbide dinitrate as a nitric oxide (NO) donor and hydralazine as an antioxidant in patients with moderate-severe heart failure. The literature also suggests that black patients have lower NO bioavailability and have a more favorable response to isosorbide dinitrate andhydralazine combination.
Purpose
To determine whether fixed doses of hydralazine and isosorbide dinitrate (H+ISDN), when added to evidence-based therapy positively affects clinical outcomes in black patients with left ventricular dysfunction and moderate-severe heart failure (NYHA Class III-IV).
Design
Randomized, double-blind, placebo-controlled trial 1050 patients self identified as black (of African descent), age ≥ 18 years, NYHA class III or IV for ≥ 3months Also evidence of left ventricular dysfunction defined as LVEF ≤ 35% or resting LVEF ≤ 45% and LVIDd > 2.9 cm/m2 or > 6.5 cm on echo Receiving standard therapy for HF as per their physicians (ACE inhibitor, ARB, beta-blocker, digoxin, spironolactone and diuretics)
Exclusion Criteria
Acute MI, ACS, revascularization (or pending) or stroke within last three months; clinical significant valvular disease, hypertrophic or restrictive cardiomyopathy, active myocarditis, uncontrolled HTN, symptomatic hypotension History of cardiac arrest or life threatening arrhythmia within last three months; use of iv inotropes within last one month; need for cardiac transplant Any other clinically significant, coexisting condition Contraindications to nitrate or hydralazine
Follow-Up
10 months (0 – 18 months; stopped early for survival benefits with H+ISDN)
Treatment Regimen
one tablet of hydralazine 37.5 mg + isosorbide dinitrate 20 mg three times daily, then two tablets (= hydralazine 75 mg + isosorbide dinitrate 40 mg) three times daily vs. placebo dose increase determined by investigator (in the absence drug side effects) quality of life assessed and follow-up clinic every three months, LVEF, LV internal diastolic dimension, LV wall thickness and BNP at month 6, and phone interviews monthly
Results
Primary Endpoints The study was terminated early. Composite score of weighted values for death from any cause, first HF hospitalization and change in quality of life: -0.1 ± 1.9 (H+ISDN) vs. -0.5 ± 2 (placebo); p=0.01 Death from any cause: 6.2% (H+ISDN) vs. 10.2% (placebo); HR 0.57, p=0.01 - survival differences emerged at approx 180 days by Kaplan-Meier survival analysis and widened thereafter First HF hospitalization: 16.4% (H+ISDN) vs. 24.4% (placebo); risk reduced by 33% with H+ISDN, p=0.001. Change in quality of life (at 6 months; lower scores indicate a better quality of life): -5.6 ± 20.6 (H+ISDN) vs. -2.7 ± 21.2 (placebo); p=0.02
Summary
Nitric-oxide enhancing and antioxidant therapy by fixed combination of isosorbide dinitrate + hydralazine improves survival rates, decreases hospitalizations and improves quality of life for black patients with moderate-severe heart failure as compared to placebo.