Hydralazine and Isosorbide Dinitrate in Heart Failure: Historical Perspective,

Mechanisms, and Future Directions

Robert T. Cole, Andreas P. Kalogeropoulos, Vasiliki V. Georgiopoulou, Mihai Gheorghiade,
Arshed Quyyumi, Clyde Yancy and Javed Butler

Circulation. 2011;123:2414-2422
doi: 10.1161/CIRCULATIONAHA.110.012781
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 Contemporary Reviews in Cardiovascular Medicine
Hydralazine and Isosorbide Dinitrate in Heart Failure
Historical Perspective, Mechanisms, and Future Directions
Robert T. Cole, MD; Andreas P. Kalogeropoulos, MD; Vasiliki V. Georgiopoulou, MD;
Mihai Gheorghiade, MD; Arshed Quyyumi, MD; Clyde Yancy, MD; Javed Butler, MD, MPH
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 depen-
dence of ventricular function on vascular resistance, and
drugs that reduced systemic vascular resistance improved
cardiac performance.25 A pivotal study by Franciosa et al6
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 improve-
ments 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 al13 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 al14 compared
H-ISDN with nitroprusside and showed that the 2 therapies
had similar effects on wedge pressure reduction and cardiac
index increase.
The VasodilatorHeart Failure Trials I and II
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
From Emory University, Atlanta, GA (R.T.C., A.P.K., V.V.G., A.Q., J.B.); Northwestern University, Chicago, IL (M.G.); and Baylor University
Medical Center, Dallas, TX (C.Y.).
Correspondence to Javed Butler, MD, MPH, Emory University Hospital, 1365 Clifton Road NE, Ste AT 430, Atlanta, GA 30322. E-mail
javed.butler@emory.edu
(Circulation. 2011;123:2414-2422.)
2011 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
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2414
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 con-
sumption improved by 0.6 and 0.8 mL kg1 min1 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 pro-
duction of BiDil, a single-pill equivalent to the generic
H-ISDN. After bioequivalence was proved, a New Drug
Application was filed to market BiDil, which the Food and
Drug Administration did not accept, arguing that the mortal-
ity benefit in V-HeFT I was of marginal statistical signifi-
cance, whereas V-HeFT II suggested that H-ISDN was
inferior to angiotensin-converting enzyme inhibitors.18
DOI: 10.1161/CIRCULATIONAHA.110.012781
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 Cole et al
Figure 1. Change in ejection fraction (A) and exercise capacity
(B) with hydralazineisosorbide dinitrate. Reprinted from Cohn
et al16 with permission of the publisher. Copyright 1991, Mas-
sachusetts Medical Society.
Racial Differences in Heart Failure Outcomes
Emerging data in the 1990s suggested that heart failure in
blacks was associated with worse outcomes. An analysis of
the Studies of Left Ventricular Dysfunction data revealed that
after adjustment for multiple confounders, blacks had higher
all-cause mortality, pump failure mortality, and combined
death or heart failure hospitalizations.19 On the basis of these
differences, it was conceivable that the response to therapy
might differ among races also. Indeed, retrospective analysis
of V-HeFT I and II suggested an association between race and
drug response. In V-HeFT I, blacks had a survival benefit
from H-ISDN (hazard ratio, 0.53; 95% confidence interval,
0.29 to 0.98), whereas whites did not (hazard ratio, 0.88; 95%
confidence interval, 0.63 to 1.24).20 Results from V-HeFT II
revealed that although whites had a better survival with
enalapril compared with H-ISDN (31% versus 39%;
P0.02), there was no difference with either therapy in
blacks (37% versus 36%; P0.96).20 With no placebo arm in
V-HeFT II, it cannot be determined whether the equivalence
of the 2 drugs in blacks was due to a better response to
H-ISDN or a worse response to enalapril. It should be noted,
however, that these data are limited by the wide confidence
intervals around the effect estimates, and that the study was
not powered to assess noninferiority among blacks. In addi-
tion, these were secondary analyses of observations within
clinical trials not designed to address this issue specifically.
Hence, these results may merely represent a chance finding.
The results of these retrospective analyses led to the
granting of a new methods patent for the use of H-ISDN to
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Hydralazine and Isosorbide Dinitrate in HF 2415
treat blacks with heart failure.17 However, the Food and Drug
Administration decided, consistent with levels of evidence
typically needed for approval, that these results were inade-
quate for approving BiDil as a new drug in this population
and suggested the need for a prospective trial,21 leading to the
landmark African-American Heart Failure Trial (A-HeFT).
African-American Heart Failure Trial
The A-HeFT enrolled self-identified blacks with class III to
IV symptoms and evidence of left ventricular dysfunction
within 6 months preceding randomization, including left
ventricular ejection fraction of 35% or 45% with a left
ventricular internal end-diastolic diameter of 2.9 cm/m2
body surface area (or 6.5 cm).22 Patients were on optimal
therapy as tolerated, including angiotensin-converting en-
zyme inhibitors (69%) or angiotensin receptor blockers
(17%), -blockers (74%), aldosterone blockade (39%),
digoxin (60%), and diuretics (90%). The initial dose of
H-ISDN was a single pill containing 37.5 mg hydralazine and
20 mg ISDN taken 3 times a day, uptitrated to the goal of 2
pills 3 times a day, for a total daily dose of 120 mg ISDN and
225 mg hydralazine. The primary outcome was a weighted
composite score of death, heart failure hospitalization, and
change in quality of life.22 After enrolling 1050 patients, the
trial was terminated early because there was a 43% relative
mortality benefit with H-ISDN (10.2% versus 6.2%;
P0.01); there were also significant improvements in each
component of the composite score. After reviewing the
results and discussing the appropriateness of labeling a drug
for blacks only, the Cardiovascular and Renal Drugs Advi-
sory Committee voted unanimously in favor of approving
BiDil, making it the first drug ever approved for treatment in
a single race.23
Race-Based Indication
Not surprisingly, approval of H-ISDN specifically for blacks
resulted in dialogs in both the scientific and bioethical arenas.
Critics argued that approving a drug only for blacks would
prevent its use in other patients who might benefit, and that
race is at best a crude marker for underlying genetic and
physiological variations.24 Schwartz pointed out in an edito-
rial on racial profiling in medicine that race is a social
construct, not a scientific classification . After 400 years of
social disruption, geographic dispersion, and genetic inter-
mingling, there are no alleles that define the black people of
North America as a unique population or race.25 Interest-
ingly, in the 2000 Census, 7 million people identified them-
selves as members of 1 race.25 Other concerns were that this
approval was setting a new precedent that would incentivize
trials in less diverse populations and result in diversion of
resources away from searching for better therapeutics and
toward the quest for niche markets.26 Although several
participants in the Food and Drug Administration hearing
expressed concern about race-based labeling, only 2 of the 9
members voted against such labeling.23 Proponents argued
that although race is admittedly a poor marker of variation,
the benefits of the drug in blacks were too great to ignore.21
2416 Circulation May 31, 2011

Figure 2. Nitroso-redox balance. The balance between nitric oxide (NO) and reactive oxygen species is important in the maintenance of
many vital physiological processes, ranging from augmentation of cardiac contractility to maintenance of vasomotor tone to inhibition
of cell death. NOS indicates NO synthase; ISDN, isosorbide dinitrate. Adapted from Hare33 with permission of the publisher. Copyright
2004, Massachusetts Medical Society.

Race as a Surrogate of Alternate Mechanisms
of Benefit
Although the V-HeFT I and II trials primarily assessed the
balanced vasodilatory effects of the H-ISDN combination,
there was later a shift in the thinking, although not prospec-
tively studied, regarding the likely mechanism of this therapy
toward a pathophysiological construct that may (or may not)
be more operative in blacks than in whites.22,27 Subsequent
data suggested that blacks have differences in nitric oxide
(NO) homeostasis and impairments in NO-mediated cardio-
vascular effects compared with whites.28 32 Nitric oxide is an
important mediator of a wide range of processes, including
maintenance of vascular tone, myocardial hypertrophy and
remodeling, and maintenance of the cellular redox bal-
ance.3237 Because ISDN is an NO donor and hydralazine has
antioxidant properties that help prevent NO degradation, it is
possible that the NO-mediated effects of H-ISDN could be
responsible for the preferential treatment benefit in blacks.
Nitroso-Redox Balance and Heart Failure
Nitric oxide plays a complex role in the maintenance of
cardiovascular health and exerts its broad-ranging influence
through several mechanisms that rely on a balance between
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NO and reactive oxygen species, such as superoxide (Figure
2).33 Because heart failure is associated with elevations in
reactive oxygen species,38 40 maintenance of the NOreac-
tive oxygen species balance, called the nitroso-redox balance,
may play a central role in the pathophysiology of heart
failure. An understanding of the mechanisms of action of NO
and the deleterious effects of oxidative stress can help explain
some of the fundamental biochemical changes in heart
failure.33
One mechanism of NO signaling is accomplished through
S-nitrosylation of an assortment of effector proteins.
S-nitrosylation occurs when NO is directly transferred to
cysteine thiol residues of effector proteins, resulting in
activation of a wide range of signaling mechanisms.33,41
Downstream effects of this process include activation of the
cardiac ryanodine receptor, which is pivotal in regulating
intracellular calcium concentrations and contractility.42 Reac-
tive oxygen species facilitate S-nitrosylation when present at
physiological levels but disrupt the process when present at
high levels.42,43 When exposed to excessive superoxide, the
ryanodine receptor is hyponitrosylated, resulting in altered
calcium homeostasis and impaired contractility.43 Inhibiting
production of xanthine oxidase derived superoxide results in
 Cole et al Hydralazine and Isosorbide Dinitrate in HF 2417

improvement in calcium handling and contractility. Thus,

maintenance of the nitroso-redox balance is important in the
maintenance of cardiac contractility. In addition, S-nitrosylation
plays a role in a number of mechanisms that regulate endothelial
function, blood flow, and blood pressure through its effects on
smooth muscle Ca2-ATPase and other targets.44,45
A second mechanism of NO action is the activation of
guanylyl cyclase and production of intracellular cGMP, an
important regulator of many physiological processes,33,36,46
including endothelial function and vasomotor tone. Heart
failure is associated with endothelial dysfunction that is at
least partially a result of nitroso-redox imbalance.4751 In-
creasing heart failure severity is associated with worse
endothelial dysfunction.52,53 This impairment is likely both a
marker of disease severity and a contributor to heart failure
progression through increased afterload and myocardial
ischemia.5355
Another NO effect is through formation of peroxynitrite
(OONO), a toxic free radical that forms from the union of
superoxide and NO in the setting of high levels of both, eg,
heart failure.46 Peroxynitrite has many deleterious effects
ranging from induction of myocyte apoptosis to lipid peroxi-
dation, DNA damage, and cell necrosis.56 58 It also irrevers-
ibly inhibits the mitochondrial respiratory chain when present
in high concentrations.58,59 Figure 3. Treatment effects of hydralazineisosorbide dinitrate
(H-ISDN) by nitric oxide synthase-3 polymorphisms. (A) Change in
Considering the biological actions of NO and the conse- composite score and (B) Change in Quality of Life score. Signifi-
quences of oxidative stress and nitroso-redox imbalance, it is cant improvement in composite score and quality of life (QoL) with
conceivable that an intervention that increases NO availabil- H-ISDN in patients with the Glu298 codon, but not in those with
ity or decreases the production of ROS might improve heart the Asp298 codon, is seen. FDC I/H indicates fixed-dose combina-
tion isosorbide dinitrate/hydralazine. Reprinted from McNamara et
failure outcomes. al61 with permission of the publisher. Copyright 2009, Elsevier.

Nitric Oxide and Black Race
Blacks appear to have worse impairment in NO-mediated
mechanisms, which may explain the potential, but unproven,
race-related differences in heart failure outcomes and re-
sponses to therapy.28,31,32 Studies have shown alterations in
endothelial function and abnormal vascular responses to a
number of pharmacological and physiological stressors that
are surrogates of NO activity. Stein et al31 showed that
healthy blacks had an attenuated NO-mediated vasodilator
response to both methacholine (stimulant of endothelium-
dependent NO release) and nitroprusside (endothelium-
independent vasodilator/exogenous NO donor) compared
with whites. Cardillo et al28 showed that normotensive blacks
had blunted vasodilatory responses to both acetylcholine
(endothelium-dependent release of NO) and nitroprusside.
Androne et al60 assessed vascular function in heart failure
patients and showed a significant reduction in endothelium-
dependent, flow-mediated vasodilation in blacks compared
with whites. Kalinowski et al30 showed important differences
in the steady-state balance of NO, superoxide, and peroxyni-
trite in endothelial cells of blacks. Using nanosensor electrode
technology to measure levels of NO, O2, and OONO, they
found that increased production of superoxide by NAD(P)H-
oxidase in blacks results in excess peroxynitrite formation
and reduced levels of NO.30 From these data, it is conceivable
that therapies aimed at augmenting NO availability might
improve outcomes in blacks and could explain the potential,
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but unproven, racial differences in response to H-ISDN
therapy.
Genetic Heterogeneity and Race
The Genetic Risk Assessment and Heart Failure (GRAHF)
substudy of the A-HeFT assessed how genetic heterogeneity
in the endothelial NO synthase might account for the re-
sponse to H-ISDN.61 In this study, in which 352 patients
participated, there were 61 heart failure hospitalizations
(17.3%) and 12 deaths (3.4%); H-ISDN was associated with
a trend toward improved composite score and quality of life
score. When analyzed by genotype, H-ISDN improved the
composite score among Glu298 homozygotes but not among
those with the Asp298 allele (Figure 3). Neither the e786
promoter nor the intron 4 polymorphisms influenced H-ISDN
effect on composite score. There was a trend among Glu298
subjects for ejection fraction improvement that was not
evident among Asp298 subjects. The endothelial NO syn-
thase polymorphism of promoter, codon 298, and intron 4
polymorphisms did not affect event-free survival. The impact
of H-ISDN on event-free survival was similar in Glu298 and
Asp298 subjects. In the Genetic Risk Assessment of Cardiac
Events (GRACE) registry, the presence of the Asp298 variant
of endothelial NO synthase was associated with worse event-
free survival.62 In GRAHF, the Glu298 variant of endothelial
NO synthase was seen in 77.8% of blacks, whereas nearly
40% of whites in GRACE had the Glu298 variant, suggesting
2418 Circulation May 31, 2011
that some white patients might also benefit from H-ISDN.
Because of the small number of participants and the low
event rate in the GRAHF study, many of these analyses
should be considered exploratory and hypothesis generating.
Given the multiplicity of post hoc analyses performed in this
study, the statistical analyses did not meet the standard
criteria for adjudicating the finality of these findings. These
need to be systematically replicated in other populations.
HydralazineIsosorbide Dinitrate in White
Heart Failure Patients
Although A-HeFT proved the effectiveness of H-ISDN in
self-identified blacks, it did not show H-ISDN to be ineffec-
tive in other populations. Although white patients did not
appear to derive a mortality benefit in the retrospective
analysis of V-HeFT I,20 these data are from an era in which
optimal medical therapy was radically different. Rather than
reviewing individual subgroup findings, we should assess
treatment-by-subgroup interaction analyses, which were not
provided in these investigations. These secondary analyses
may represent a chance finding. In addition, despite the lack
of a mortality benefit, there was an improvement in ejection
fraction and exercise tolerance in whites treated with H-ISDN
in V-HeFT II20; in fact, these improvements were greater with
H-ISDN than with enalapril.20 Finally, there was no differ-
ence in the number of hospitalizations for heart failure or
all-cause hospitalization between whites and blacks in either
trial.20 Thus, the role of H-ISDN in nonblack patients with
heart failure remains uncertain.
Sex and Outcomes in the African-American
Heart Failure Trial
Women with heart failure are underrepresented in many
clinical trials.63 66 Importantly, V-HeFT I and II included
only men.15,16 In A-HeFT, women made up nearly 40% of the
study.22 In a post hoc analysis of A-HeFT,66 women treated
with H-ISDN appeared to have a survival benefit (hazard
ratio, 0.33; 95% confidence interval, 0.16 to 0.71), whereas
men did not (hazard ratio, 0.79; 95% confidence interval,
0.46 to 1.35). However, there was no significant treatment
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Figure 4. Hydralazine and nitrates in acutely
decompensated heart failure. Oxidative stress
disrupts nitric oxide (NO) signaling, affecting
ventricular function, vascular tone, vasocon-
striction, and renal Na excretion. Isosorbide
dinitrate (ISDN) is an NO donor, and hydral-
azine has antioxidant properties; this combina-
tion has the potential to restore the disrupted
nitroso-redox balance and to reverse the dis-
rupted NO signaling. NOS indicates NO syn-
thase; ET-1, endothelin-1.
interaction by sex (P0.470), and no differences were seen in
quality of life or heart failure hospitalizations. Moreover,
there were several differences in the A-HeFT trial between
the sexes, with women at baseline having lower hemoglobin
and creatinine levels, less renal insufficiency, higher body
mass index and systolic blood pressure, and more diabetes
mellitus. Thus, these analyses are at best exploratory and do
not prove a differential sex response to H-ISDN.
Role in Acute Decompensated Heart Failure
Acute decompensated heart failure is associated with oxida-
tive stress67 69 and disrupted NO signaling,70 affecting ven-
tricular and vascular function related to hemodynamic sta-
tus71,72 (Figure 4). There are multiple theoretical benefits of
H-ISDN in acute decompensated heart failure. It can help
restore NO balance,73,74 can modulate systemic hemodynam-
ics in acute decompensated heart failure patients presenting
with elevated blood pressure,7577 and provides seamless
therapy spanning inpatient to outpatient care.78 In-hospital
initiation of H-ISDN has been associated with lower all-cause
mortality78 and improved hemodynamics,79 suggesting a need
for prospectively assessing this therapy in acute decompen-
sated heart failure.
Pulmonary Hypertension and Right
Ventricular Function
Pulmonary hypertension is common in heart failure80 83 and
affects right ventricular function,81,84,85 both of which, in turn,
affect heart failure prognosis.81,86 91 Elevated pulmonary
vascular resistance in heart failure is a result of dysregulation
of smooth muscle tone and remodeling of the pulmonary
vasculature.92 These abnormalities are partially attributed to
pulmonary vascular endothelial dysfunction resulting from
impaired NO availability and increased endothelin expres-
sion.92 In the pulmonary vasculature, NO plays an important
role in determining both basal vascular tone and dilation to
endothelium-dependent stimuli.9395 Studies have shown that
NO-dependent pulmonary vasodilation is impaired in heart
failure,96 98 suggesting a potential role for agents that im-
prove NO bioavailability. In systolic heart failure, H-ISDN
 Cole et al
had marked short-term effects on pulmonary vascular resis-
tance99 and result in more reduction than either agent alone
over 3 months.100 In short-term studies, a decrease in pulmo-
nary artery pressures in response to vasodilators is associated
with improved right ventricular function.84,85 Although
H-ISDN improves left ventricular ejection fraction,16,20,101 the
large mortality benefit observed in A-HeFT relative to the
modest 2.8-unit improvement in left ventricular ejection
fraction101105 raises the possibility of alternative explana-
tions, including potential effects on right ventricular function.
The responses of pulmonary artery pressures and right ven-
tricular function to H-ISDN, however, have never been
assessed.
Synergistic Effects Between Hydralazine and
Isosorbide Dinitrate
It should be noted that, although the data suggest benefit with
the H-ISDN combination in heart failure, the synergistic
effects of hydralazine and ISDN on outcome benefit, as
opposed to hemodynamic modulation, have never been tested
or established. The rationale that hydralazine potentiates
ISDN through an antioxidant effect has been hypothesized on
the basis of observations, without examination of outcomes
with each drug individually compared with the combination.
Thus, the more rigorous criterion for defining the superiority
of combination therapy, ie, demonstrating that the combina-
tion is superior to either constituent agent alone, has never
been studied with respect to H-ISDN therapy in heart failure.
Use of HydralazineIsosorbide Dinitrate in
Clinical Practice
The heart failure management guidelines give a Class I
recommendation for the use of H-ISDN in self-identified
black patients with symptomatic systolic heart failure on
optimal therapy.106 Use of H-ISDN in addition to optimal
therapy is a Class IIA recommendation for nonblack patients
and a Class IIB recommendation for those intolerant of
angiotensin-converting enzyme inhibition or angiotensin re-
ceptor blocker therapy. However, a recent study showed that
only 7.3% of eligible black outpatients are actually receiving
H-ISDN.107 In a registry of hospitalized heart failure patients,
only 4.5% of blacks and 2.6% of whites were discharged
home on H-ISDN.108 The reasons for this trend are multiple.
Despite the mean systolic blood pressure of 127.2
17.4 mm Hg in the treatment arm of A-HeFT, almost 30% of
the patients complained of dizziness with H-ISDN use. Is it
possible that dizziness and other side effects are more
common in real-life heart failure patients who, in general,
tend to be older, to have more comorbidities, and to take more
medications. A large pill burden related to thrice-a-day
dosing could further deter some patients and result in subop-
timal compliance. In addition, in the practice setting, titration
of the combination therapy to maximum doses, perhaps more
slowly than in the trial setting, may impose practical logistic
barriers for both patients and physicians. Many heart failure
patients have erectile dysfunction and wish to use medica-
tions like sildenafil that limit the concomitant use of nitrate
therapy. In the case of BiDil specifically, cost may be an
important consideration. Regardless of all these issues, there
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Hydralazine and Isosorbide Dinitrate in HF 2419
remains a huge gap between guideline recommendations and
clinical use of H-ISDN.
Generic Versus Combination
HydralazineIsosorbide Dinitrate Preparation
There has been no head-to-head comparison of the generic
and combination H-ISDN (BiDil) preparations. Interestingly,
all 3 trials, VHeFT I, VHeFT II, and A-HeFT, used different
H-ISDN preparations. Both V-HeFT I and V-HeFT II used
Isordil, an ISDN tablet; V-HeFT I used 37.5-mg hydralazine
capsules; V-HeFT II used 37.5-mg hydralazine tablets; and
A-HeFT used the combination pill. To investigate the phar-
macokinetic differences between these formulations, Tam et
al109 performed a bioequivalence study in healthy volunteers
18 to 40 years of age. All subjects received reference H-ISDN
solution (37.5 mg/10 mg) orally, and slow acetylators (59%
of the study population, n55) were identified and random-
ized to receive a single oral dose of H-ISDN (37.5 mg/10 mg)
from a hydralazine capsule plus an ISDN tablet, a hydralazine
tablet plus an ISDN tablet, or fixed-dose combination. The
maximum concentrations (Cmax) and areas under the curve
were similar for ISDN preparations. The Cmax values were
65.953.9, 28.215.8, and 51.554.3 ng/mL, and the area
under the curve values were 32.613.4, 23.315.1, and
32.618.5 ng h/mL for hydralazine and the V-HeFT I,
V-HeFT II, and A-HeFT formulations, respectively. In addi-
tion, Cmax and area under the curve normalized to body
weight and Cmax and area under the curve ratios were
compared. The 3 formulations were not bioequivalent, with
the hydralazine concentrations of the tablet form being lower
than in the capsule or the combination pill. Whether these
differences affected clinical outcomes is not known. Consid-
ering that the study population for the bioequivalence study
consisted of normal volunteers, and that there are no head-
to-head outcome trials, it is difficult to draw any specific
conclusions regarding generic versus the combination prepa-
ration. Because BiDil is also a thrice-a-day regimen, there is a
general feeling that generic therapy may be a cheaper alternative
without any compliance downside. Indeed, the American Col-
lege of Cardiology and the American Heart Association heart
failure guidelines recommend using a combination of hydral-
azine and nitrates.106 If a once- or twice-a-day combination
preparation becomes available, it may have a potential benefit in
terms of both pharmacokinetics and compliance compared with
the thrice-a-day preparations.
Conclusions
There remain many promises and unanswered questions
regarding H-ISDN therapy in heart failure, ranging from
efficacy and mechanism of action to defining optimal patient
population and timing of therapy. Considering the persistent
suboptimal outcomes and a significant opportunity for im-
provement in therapy for these patients, further research
related to the use of H-ISDN in heart failure seems warranted.
Disclosures
None.
2420 Circulation May 31, 2011
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KEY WORDS: heart failure hydralazine isosorbide dinitrate nitric oxide