A-HeFT study rationale

African Americans are underrepresented in major cardiovascular prevention and treatment trials. A review found that African Americans accounted for <20% of subjects in cardiovascular trials, while another review found that only 15% of nonwhite minorities were represented in heart failure (HF) trials.1

Use of various therapies is often predicated on the idea that overall response to medication is indicative of an individual's or subgroup's response to therapy. Recent insights into physiologic variability have supported the concept of differences in a heterogeneous population that may result in therapeutic efficacy in some subgroups being overlooked, and lack of efficacy in others being obscured.2

The African American Heart Failure Trial (A-HeFT) was a landmark HF clinical study, based on 3 distinct pillars of information

  • The hypothesis that treating African Americans with HF with a combination of isosorbide dinitrate/hydralazine may have potential benefit2,3

Unlike other HF studies, the A-HeFT enrolled 100% self-identified African American patients. Even more unusual, the study population was 60% men and 40% women, making BiDil one of the only medications studied in a randomized, placebo-controlled, double-blind, multicenter HF trial that included almost as many women as men.2

Baseline characteristics of patients enrolled in A-HeFT*2

CharacteristicIsosorbide Dinitrate plus Hydralazine (N=518)Placebo
(N=532)
Age (yr)56.7±12.756.9±13.3
Male sex (% of patients)55.863.9
Weight (kg)92.5±21.494.1±25.5
Primary cause of HF (%)
Ischemic heart disease23.422.7
Hypertension40.037.4
Idiopathic24.527.6
Valvular cause2.53.2
Other9.79.0
NYHA class (%)
I00
II0.20
III96.794.7
IV3.15.3
Diabetes (%)44.8§37.0
Renal insufficiency (%)16.218.2
Atrial fibrillation (%)15.018.0
Cardiac resynchronization therapy (%)2.02.1
Implantable cardiac defibrillator (%)16.617.3
Ejection fraction (%)23.9±7.324.2±7.5
LVIDD (cm)6.5±0.96.5±1.0
Blood pressure (mm Hg)
Systolic127.2±17.4125.3±18.1
Diastolic77.6±10.375.6±10.5
Minnesota Living with Heart Failure Questionnaire score (range 0-105)50.9±24.950.7±25.5
Medications for HF (%)
Diuretic88.091.5
ACE inhibitor69.469.5
ARB17.216.5
Beta-blocker74.173.5
Carvedilol55.255.8
Digoxin58.560.7
Spironolactone40.237.6

NYHA=New York Heart Association; LVIDD=left ventricular internal diastolic dimension; ACE=angiotensin-converting enzyme; ARB=angiotensin-receptor blocker.

*Plus-minus values are means ±SD. Due to rounding, percentages may not total 100.
P=0.008 for the placebo group comparison.
Data obtained at screening.
§P=0.01 for the placebo group comparison.
P=0.002 for the placebo group comparison.

Study design: Randomized, placebo-controlled, double-blind, multicenter trial of 1,050 self-identified African American patients aged 18 years or older with NYHA class III or IV heart failure. Patients were required to be on standard HF therapy (angiotensin-converting enzyme [ACE] inhibitors, beta blockers, and diuretics) and have evidence of left ventricular dysfunction within 6 months preceding enrollment. Primary efficacy endpoint was a composite score made up of weighted values for death from any cause, first hospitalization for HF during the 18-month follow-up period, and QoL change at 6 months. 2


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IMPORTANT SAFETY INFORMATION

BiDil is contraindicated in patients who are allergic to organic nitrates, or who take a phosphodiesterase type 5 (PDE5) inhibitors, such as avanafil, sildenafil, tadalafil, or vardenafil, or soluble guanylate cyclase (sGC) stimulator (riociguat). Concomitant use can cause hypotension.

INDICATIONS AND USAGE

BiDil is indicated for the treatment of heart failure as an adjunct to standard therapy in self-identified black patients to improve survival, to prolong time to hospitalization for heart failure, and to improve patient-reported functional status. There is little experience in patients with NYHA class IV heart failure. Most patients in the clinical trial supporting effectiveness (A-HeFT) received a loop diuretic, an angiotensin converting enzyme inhibitor or an angiotensin II receptor blocker, and a beta blocker, and many also received a cardiac glycoside or an aldosterone antagonist.

IMPORTANT SAFETY INFORMATION

BiDil is contraindicated in patients who are allergic to organic nitrates, or who take a phosphodiesterase type 5 (PDE5) inhibitors, such as avanafil, sildenafil, tadalafil, or vardenafil, or soluble guanylate cyclase (sGC) stimulator (riociguat). Concomitant use can cause hypotension.

WARNINGS AND PRECAUTIONS

Hydralazine hydrochloride has been reported to cause a drug-induced systemic lupus erythematosus (SLE) syndrome. Symptoms and signs usually regress when hydralazine hydrochloride is discontinued.

Symptomatic hypotension, particularly with upright posture, may occur with even small doses of BiDil. Hypotension is most likely to occur in patients who have been volume or salt depleted; correct prior to initiation of BiDil. Hydralazine hydrochloride can cause tachycardia and hypotension potentially leading to myocardial ischemia and angina, particularly in patients with hypertrophic cardiomyopathy.

Hydralazine hydrochloride has been associated with peripheral neuritis, evidenced by paresthesia, numbness, and tingling, which may be related to an antipyridoxine effect. Pyridoxine should be added to BiDil therapy if such symptoms develop.

ADVERSE REACTIONS

Most common adverse reactions (> 5% more on BiDil than on placebo) were headache and dizziness.

The full Prescribing Information for BiDil is available here.

References: 1. Mitchell JE, Ferdinand KC, Watson KE, et al. Treatment of heart failure in African Americans—a call to action. J Natl Med Assoc. 2011;103(2):86-98. 2. Taylor AL, Ziesche S, Yancy CW, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004;351(20):2049-2057. 3. Ferdinand KC, Elkayam U, Mancini D, et al. Use of isosorbide dinitrate and hydralazine in African-Americans with heart failure 9 years after the African-American Heart Failure Trial. Am J Cardiol. 2014;114:151-159.