Hydralazine and Isosorbide Dinitrate in Heart Failure

Abstract

U ntil the 1970s, treatment options for heart failure were limited to digitalis and diuretics. 1 Although effective for symptoms, there was no evidence of mortality benefit with this combination, and it was an inadequate option for many patients with advanced symptoms. The search for more effective options led to strategies that modulated hemody-namics. 1 Numerous physiological studies showed the dependence of ventricular function on vascular resistance, and drugs that reduced systemic vascular resistance improved cardiac performance. 2-5 A pivotal study by Franciosa et al 6 showed that sodium nitroprusside in patients with heart failure in the setting of acute myocardial infarction reduced left ventricular filling pressures from 22.72.0 to 11.31.6 mm Hg and led to a modest increase in cardiac output. A subsequent study revealed more striking improvements in patients with refractory heart failure, in whom nitroprusside reduced systemic vascular resistance by 50%, increased cardiac output by 56%, and reduced left ventricular filling pressure by 47%. 7 These hemodynamic benefits with nitroprusside led to studies with oral agents, including hydral-azine, isosorbide dinitrate (ISDN), prazosin, phentolamine, and minoxidil. Although these drugs did affect hemodynamics, none was as effective as nitroprusside individually. 8-12 In 1977, Massie et al 13 studied the combination of 2 oral agents, hydralazine and ISDN (H-ISDN) in class III to IV heart failure patients, proposing that simultaneously reducing pre-load with ISDN and afterload with hydralazine would result in a better response than with either drug individually. They found that H-ISDN reduced left ventricular filling pressure by 36%, increased cardiac index by 58%, and reduced systemic vascular resistance by 34%. Later, Pierpont et al 14 compared H-ISDN with nitroprusside and showed that the 2 therapies had similar effects on wedge pressure reduction and cardiac index increase. Considering these hemodynamic benefits with H-ISDN, 13,14 its effect on mortality was studied in the first Vasodilator-Heart Failure Trial (V-HeFT I), 15 the first major randomized, placebo-controlled trial in cardiovascular medicine. The study compared H-ISDN or prazosin with placebo in 642 men with impaired systolic function and found that H-ISDN was associated with a trend toward mortality reduction (44.0% versus 38.7%; P0.09), which was significant at a prespeci-fied 2-year end point (34% relative risk reduction; P0.028). In addition, H-ISDN improved ejection fraction at 8 weeks (2.9% versus 0.4%; P0.001) and 1 year (4.2% versus 0.1%; P0.001). Prazosin was not associated with either mortality or ejection fraction improvement. Subsequently, V-HeFT II compared H-ISDN and enalapril. 16 The V-HeFT II study population was similar to that of V-HeFT I, and the results showed a trend toward improved all-cause mortality with enalapril compared with H-ISDN (38.2% versus 32.8%; P0.08). Interestingly, despite lesser mortality reduction, H-ISDN resulted in greater improvements in ejection fraction and exercise tolerance than enalapril (Figure 1). At 13 weeks, the change in ejection fraction was 3.3% for H-ISDN compared with 2.1% for enalapril (P0.03). Peak exercise oxygen consumption improved by 0.6 and 0.8 mL kg 1 min 1 at 13 weeks and 6 months, respectively, with H-ISDN (P0.0001); no improvement was seen with enalapril. 16 Although there was no placebo arm in V-HeFT II, the mortality rates with H-ISDN in V-HeFT II mirrored those in V-HeFT I, suggesting a benefit. These findings suggested that H-ISDN might play a role in heart failure, particularly among those intolerant of angiotensin-converting enzyme inhibitors. 16 Development of a Combination Product On the basis of V-HeFT I and II results, an application was filed with the Food and Drug Administration for a methods patent on the H-ISDN combination in 1987, 17 which would give marketing rights for the combination specifically for heart failure. The patent was approved, leading to the production of BiDil, a single-pill equivalent to the generic H-ISDN.