FDA Approved Drugs » 2005
Medical Areas: Cardiology/Vascular Diseases | Family Medicine
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The following drug information is obtained from various newswires, published
medical journal articles, and medical conference presentations.
Approval Status: Approved June, 2005
Treatment Area: Heart Failure
BiDil is a single-pill, fixed-dose combination of two generic
drugs, isosorbide dinitrate and hydralazine hydrochloride. The
combination exerts vasodialtory effects on both arterial and
veinous vascular systems.
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 tollerated dose as required,
but should not exceed 2 tablets thrice daily.
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.
Adverse events associated with the use of BiDil may include, but
are not limited to, the following:
The specific mechanism of action of the comnbination 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.
Franciosa JA, Taylor AL, Cohn JN, Yancy CW, Ziesche S,
Olukotun A, Ofili E, Ferdinand K, Loscalzo J, Worcel M; A-HeFT
Investigators.African-American Heart Failure Trial
(A-HeFT): rationale, design, and methodology. Journal of
Cardiac Failure 2002 Jun;8(3):128-35.
Taylor AL, Ziesche S, Yancy C, Carson P, D'Agostino
R Jr, Ferdinand K, Taylor M, Adams K, Sabolinski M, Worcel M, Cohn
JN; African-American Heart Failure Trial Investigators.
Combination of isosorbide dinitrate and hydralazine in blacks with
heart failure. New England Journal of Medicine 2004 Nov
Kalus JS, Nappi JM. Role of race in the
pharmacotherapy of heart failure. Annals of
Pharmacotherapy 2002 Mar;36(3):471-8
Wolf DL, Metzler CM, Froeschke MO, Luderer JR.
Dose-Related Hepatic Blood Flow Effects Differentiate Nicorandil,
Hydralazine, and Isosorbide Dinitrate in Healthy Subjects.
American Journal of Therapeutics 1994
For additional information regarding BiDil or heart failure,
please visit the BiDil web page.