General Information

BiDil is a single-pill, fixed-dose combination of isosorbide dinitrate, a nitrate vasodilator, and hydralazine hydrochloride, an arteriolar vasodilator.

BiDil is specifically indicated for the adjunctive treatment of heart failure in self identified black patients, in addition to standard therapy. Addition of BiDil to standard regimens is aimed at prolonging time to hospitalization, improving patient-reported functional status, and reducing all-cause mortality. BiDil was not significantly efficacious in treating broader patient populations or other self-identified racial groups.

BiDilis supplied as a biconvex film-coated orange tablet. The recommended initial dose is one tablet of BiDil (20 mg isosorbide dinitrate, 37.5 mg hydralazine hydrochloride) thrice daily. Regimens may be titrated to maximum tolerated dose as required, but should not exceed 2 tablets thrice daily.

Mechanism of Action

The specific mechanism of action of the combination of isosorbide dinitrate and hydralazine hydrochloride has not been established. Independently, isosorbide dinitrate has been shown to exert vasodilatory effects in both arteries and veins. The drug releases nitric oxide, activating guanylyl cyclase and relaxing vascular smooth muscle. Hydralazine has also been shown to relax arterial smooth muscle, and may mitigate tolerance to nitrate therapy, thus exerting synergistic activity with isosorbide.

Clinical Trial Results

Approval of BiDil was based on two placebo-controlled clinical trials (V-HeFT I and A-HeFT) and one active-controlled clinical trial (V-HeFT II), which compared BiDil to enalapril. V-HeFT I enrolled 459 men with impaired cardiac function and reduced exercise tolerance, who were randomized to receive 75 mg/40 mg qid (n=186) or placebo (n=273), in addition to continuation of standard therapy with digitalis glycosides and diuretics. Trial data from the general patient cohort yielded no significant difference in all-cause mortality between the treatment group and placebo, though a trend towards improvement was noted. Retrospective analysis showed that this trend correlated with patients’ self-identified racial group: patients who self-identified as black or African-American showed improvements in survival, while self identified white or Caucasian-American patients showed no difference from placebo.

The V-HeFT II trial enrolled 804 men with impaired cardiac function and reduced exercise tolerance, who were randomized to receive either 75 mg/40 mg or enalapril, in addition to continuation of standard therapy with digitalis glycosides and diuretics. Trial data indicated that the drug combination was inferior to enalapril. Retrospecitve analysis again indicated that efficacy correlated with self-identified race: inferiority was observed only in the white population (n=574), with no significant difference in black patients (n=215).

The A-HeFT trial enrolled 1,050 self- identified black patients (men and women) with stable symptomatic heart failure across 169 sites in the United States. Subjects were randomized to receive either BiDil (n=518) or placebo (n=532) for up to 18 months, in addition to maintained stable background therapy. BiDil dosing was initiate at 20 mg isosorbide dinitrate/37.5 mg hydralazine hydrochloride three times daily, and titrated to a target dose of 40/75 mg three times daily or to the maximum tolerated dose. Trial results yielded significant efficacy in the primary endpoint, a composite score of all-cause mortality, first-hospitalization for heart failure, and responses to the Minnesota Living with Heart Failure (MLHF) questionnaire. Specifically, BiDil produced a 43% reduction in all cause mortality (p=0.012) and 8% fewer first-hospitalizations (16.4% vs. 24.4%; p<0.001), and a highly significant reduction in MLHF score (p<0.01) at 12 months vs. placebo; these strongly positive results produced significant improvement in the composite score (p<0.021), and lead to early termination of the trial so that subjects receiving placebo could be switched to the BiDil regimen. Secondary results indicated that the drug produced a reduction in mean blood pressure (3/3 mmHg lower) compared to placebo; whether this effect contributed to improved primary patient outcomes was unknown