Mechanism Of Action
The mechanism of action underlying the beneficial effects
of BiDil in the treatment of heart failure has not been established.
Isosorbide dinitrate is a vasodilator affecting both
arteries and veins. Its dilator properties result from the release of nitric
oxide and the subsequent activation of guanylyl cyclase, and ultimate
relaxation of vascular smooth muscle.
Several well-controlled clinical trials have used
exercise testing to assess the anti-anginal efficacy of chronically-delivered
nitrates. In the large majority of these trials, active agents were no more
effective than placebo after 24 hours (or less) of continuous therapy. Attempts
to overcome nitrate tolerance by dose escalation, even to doses far in excess
of those used acutely, have consistently failed. Only after nitrates have been
absent from the body for several hours is response to nitrates restored.
Hydralazine hydrochloride is a selective dilator of
arterial smooth muscle. Animal data suggests that hydralazine may also mitigate
tolerance to nitrates.
The basis for the beneficial clinical effects of BiDil is
not known. In a small study of patients with chronic heart failure administered
single doses of hydralazine 75 mg, isosorbide dinitrate 20 mg, and the
combination, the combination elicited a statistically significant decrease in
pulmonary capillary wedge pressure compared to hydralazine alone. The increase
in cardiac output, renal blood flow and limb blood flow with the combination,
however, was not greater than with hydralazine alone. There is no study of
hemodynamic effects following multiple dosing.
BiDil: Following a single 75-mg oral dose of
hydralazine plus 40 mg of isosorbide dinitrate to 19 healthy adults, peak
plasma concentrations of hydralazine (88 ng/mL/65 kg) and isosorbide dinitrate
(76 ng/mL/65 kg) were reached in 1 hour. The half-lives were about 4 hours for
hydralazine and about 2 hours for isosorbide dinitrate. Peak plasma
concentrations of the two active metabolites, isosorbide-2- mononitrate and
isosorbide-5-mononitrate, were 98 and 364 ng/mL/65 kg, respectively, at about 2
hours. No information is currently available regarding the effect of food on
the bioavailability of hydralazine or isosorbide dinitrate from BiDil tablets.
Hydralazine hydrochloride: About 2/3 of a 50-mg
dose of C-hydralazine hydrochloride given in gelatin capsules was absorbed in
hypertensive subjects. In patients with heart failure, mean absolute bioavailability
of a single oral dose of hydralazine 75 mg varies from 10 to 26%, with the
higher percentages in slow acetylators. Administration of doses escalating from
75 mg to 1000 mg three times daily to congestive heart failure patients
resulted in an up to 9-fold increase in the dose normalized AUC, indicating non-linear
kinetics of hydralazine, probably reflecting saturable first pass metabolism.
Isosorbide dinitrate: Absorption of isosorbide
dinitrate from tablets after oral dosing is nearly complete. The average
bioavailability of isosorbide dinitrate is about 25%, but is highly variable
(10%-90%) because of first-pass metabolism, and increases progressively during
chronic therapy. Serum concentrations reach their maximum about one hour after
Hydralazine hydrochloride: After intravenous
administration of hydralazine in a dose of 0.3 mg/kg, the steady-state volume
of distribution in patients with congestive heart failure was 2.2 L/kg.
Isosorbide dinitrate: The volume of distribution
of isosorbide dinitrate is 2 to 4 L/kg. About 28% of circulating isosorbide
dinitrate is protein bound.
Under steady-state conditions, isosorbide dinitrate
accumulates significantly in muscle (pectoral) and vein (saphenous) wall
relative to simultaneous plasma concentrations.
Hydralazine is metabolized by acetylation, ring
oxidation and conjugation with endogenous compounds including pyruvic acid.
Acetylation occurs predominantly during the first-pass after oral
administration which explains the dependence of the absolute bioavailability on
the acetylator phenotype. About 50% of patients are fast acetylators and have
After oral administration of hydralazine, the major
circulating metabolites are hydralazine pyruvate hydrazone and
methyltriazolophthalazine. Hydralazine is the main pharmacologically active
entity; hydralazine pyruvate hydrazone has only minimal hypotensive and
tachycardic activity. The pharmacological activity of methyltriazolophthalazine
has not been determined. The major identified metabolite of hydralazine
excreted in urine is acetylhydrazinophthalazinone.
Isosorbide dinitrate undergoes extensive
first-pass metabolism in the liver and is cleared at a rate of 2 to 4 L/minute
with a serum half-life of about 1 hour. Isosorbide dinitrate's clearance is
primarily by denitration to the 2-mononitrate (15 to 25%) and the 5-mononitrate
(75 to 85%). Both metabolites have biological activity, especially the
5-mononitrate which has an overall half-life of about 5 hours. The 5- mononitrate
is cleared by denitration to isosorbide, glucuronidation to the 5-mononitrate
glucuronides, and by denitration/hydration to sorbitol. The 2-mononitrate
appears to participate in the same metabolic pathways with a half-life of about
Hydralazine: Metabolism is the main route for the
elimination of hydralazine. Negligible amounts of unchanged hydralazine are
excreted in urine.
Isosorbide dinitrate: Most isosorbide dinitrate is
eliminated renally as conjugated metabolites.
No pharmacokinetic studies in special populations were
conducted with BiDil. Pharmacokinetics in special populations is based on
The pharmacokinetics of
hydralazine and isosorbide dinitrate, alone or in combination, have not been
determined in patients over 65 years of age.
The pharmacokinetics of
hydralazine and isosorbide dinitrate, alone or in combination, have not been
determined in patients below the age of 18 years.
There are no studies of gender-dependent
effects with hydralazine. In a single dose study with isosorbide dinitrate, no
gender-dependent differences in the pharmacokinetics of isosorbide dinitrate and
its mononitrate metabolites were found.
The effect of renal impairment
on the pharmacokinetics of hydralazine has not been determined. In a study with
49 hypertensive patients on chronic therapy with hydralazine in daily doses of
25-200 mg, the daily dose of hydralazine in 19 subjects with severely impaired
renal function (creatinine clearance 5-28 mL/min) and in 17 subjects with
normal renal function (creatinine clearance >100 mL/min) using a population
PK approach was not different, suggesting no need for dose adjustment in
patients with renal impairment. The dialyzability of hydralazine has not been
determined. In three studies, renal insufficiency did not affect the
pharmacokinetics of isosorbide dinitrate. Dialysis is not an effective method
for removing isosorbide dinitrate or its metabolite isosorbide-5-mononitrate
from the body.
The effect of hepatic
impairment on the pharmacokinetics of hydralazine alone has not been
determined. Isosorbide dinitrate concentrations increase in patients with
No pharmacokinetic drug-drug interaction studies were
conducted with BiDil.
Hydralazine: Administration of hydralazine can
increase the exposure to a number of drugs including beta-blockers. In healthy
males administered a single oral dose of hydralazine 50 mg and propranolol 1 mg/kg,
the Cmax and AUC for propranolol approximately doubled. In healthy subjects
administered a single oral dose of hydralazine 50 mg and metoprolol 100 mg, the
Cmax and AUC for metoprolol increased by 50% and 30%, respectively. In
pre-eclamptic women, twice-daily doses of hydralazine 25 mg and metoprolol 50
mg increased the Cmax and AUC for metoprolol by 90% and 40%, respectively.
In healthy males administered single oral doses of
hydralazine 25 mg and either lisinopril 20 mg or enalapril 20 mg, Cmax and AUC
for lisinopril were each increased 30%, but enalapril concentrations were
Intravenous co-administration of 0.2 mg/kg hydralazine
HCl and 40 mg furosemide in Japanese patients with congestive heart failure
resulted in a 20% increase in the clearance of furosemide.
Isosorbide dinitrate: The vasodilating effects of
coadministered isosorbide dinitrate may be additive to those of other
vasodilators, including alcohol.
A single dose of 20 mg of isosorbide dinitrate was
administered to healthy subjects after pretreatment with 80 mg propranolol
three times daily for 48 hours, resulting in no impact on the pharmacokinetics of
isosorbide dinitrate and isosorbide-5-mononitrate.
When single 100-mg oral doses of atenolol were
administered 2 hours before isosorbide dinitrate at a 10-mg dose no differences
in the pharmacokinetics of isosorbide dinitrate or its mononitrates were observed.
BiDil or a combination of isosorbide dinitrate and
hydralazine hydrochloride was studied in two placebo-controlled clinical trials
in 1,692 patients with mild to severe heart failure (mostly NYHA class II and
III) and one active control trial (vs. enalapril) in 804 patients. The results
of the trials follow:
In the multicenter trial
V-HeFT I, the combination of hydralazine and isosorbide dinitrate 75 mg/40 mg 4
times daily (n=186) was compared to placebo (n=273) in men with impaired
cardiac function and reduced exercise tolerance (primarily NYHA class II and
III) and on therapy with digitalis glycosides and diuretics. There was no
overall significant difference in mortality between the two treatment groups.
There was, however, a trend favoring hydralazine and isosorbide dinitrate,
which on retrospective analysis, was attributable to an effect in blacks
(n=128). Survival in white patients (n=324) was similar on placebo and the
In a second study of
mortality, V-HeFT II, the combination of hydralazine and isosorbide dinitrate
75 mg/40 mg 4 times daily was compared to enalapril in 804 men with impaired cardiac
function and reduced exercise tolerance (NYHA class II and III), and on therapy
with digitalis glycosides and diuretics. The combination of hydralazine and
isosorbide dinitrate was inferior to enalapril overall, but retrospective
analysis showed that the difference was observed in the white population
(n=574); there was essentially no difference in the black population (n=215).
Based on these retrospective analyses suggesting an
effect on survival in black patients, but showing little evidence of an effect
in the white population, a third study was conducted among black patients with
The A-HeFT trial
evaluated BiDil vs. placebo among 1,050 self-identified black patients (over
95% NYHA class III) at 169 centers in the United States. All patients had stable
symptomatic heart failure. Patients were required to have LVEF ≤ 35% or
left ventricular internal diastolic dimension > 2.9 cm/m plus LVEF < 45%.
Patients were maintained on stable background therapy and randomized to BiDil
(n=518) or placebo (n=532). BiDil was initiated 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. Patients were
treated for up to 18 months.
The randomized population was 60% male, 1% NYHA class II,
95% NYHA class III and 4% NYHA class IV, with a mean age of 57 years, and was
generally treated with standard treatments for heart failure including
diuretics (94%, almost all loop diuretics), beta-blockers (87%), angiotensin converting
enzyme inhibitors (ACE-I; 78%), angiotensin II receptor blockers (ARBs; 28%),
either ACE-I or ARB (93%), digitalis glycosides (62%) and aldosterone
The primary endpoint was a composite score consisting of
all-cause mortality, first hospitalization for heart failure, and responses to
the Minnesota Living with Heart Failure questionnaire. The trial was terminated
early, at a mean follow-up of 12 months, primarily because of a statistically
significant 43% reduction in all-cause mortality in the BiDil-treated group
(p=0.012; see Table 2 and Figure 1). The primary endpoint was also
statistically in favor of BiDil (p ≤ 0.021). The BiDil-treated group also
showed a 39% reduction in the risk of a first hospitalization for heart failure
(p < 0.001; see Table 2 and Figure 2) and had statistically significant
improvement in response to the Minnesota Living with Heart Failure
questionnaire, a self-report of the patient's functional status, at most time
points (see Figure 3). Patients in both treatment groups had mean baseline
questionnaire scores of 51 (out of a possible 105).
Table 2: Results of A-HeFT (Intent-To-Treat
|Hazard Ratio (95% CI)
|Hospitalization for heart failure
| < 0.001
Figure 1: Kaplan-Meier Plot of Time toÂ Death by All
Cause in Black Patients (A-HeFT)
Figure 2: Kaplan-Meier Plot of Time toÂ First
Hospitalization for Heart Failure in Black Patients (A-HeFT)
Figure 3: Change in Minnesota Living With Heart
Effects on survival and hospitalization for heart failure
were similar in subgroups by age, gender, baseline disease, and use of
concomitant medications, as shown in Figure 4.
Figure 4: Results for Demographic, Baseline Medication
and Clinical Characteristic Subgroups in Black Patients (A-HeFT)
Patients treated with BiDil in the A-HeFT study had
randomly measured blood pressures on average 3/3 mmHg lower than did patients
on placebo. The contribution of the difference in blood pressure to the overall
outcome difference is unknown. Whether both hydralazine and isosorbide
dinitrate contribute to the overall outcome difference has not been studied in
outcome trials. Isosorbide dinitrate and hydralazine have not been systematically
studied for the treatment of heart failure as separate agents, and neither drug
is indicated for heart failure.