The African-American Heart Failure Trial (A-HeFT) studied the effects of adding a fixed dose of isosorbide dinitrate and hydralazine to standard heart failure therapies in Black patients with advanced heart failure. The trial found that combination therapy reduced all-cause mortality by 43%, reduced the risk of first hospitalization for heart failure by 33%, and improved patient quality of life compared to standard therapy alone in under 3 sentences.

1. Paul Pasco, PHCY 4011: Advanced Community Pharmacy Practice I, 04/21/2022
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Journal Article Analysis: African-American Heart Failure Trial (A-HeFT), 2004
Background
and
overview
Title: Combination of Isosorbide Dinitrate and Hydralazine in Blacks with Heart Failure (African-American Heart Failure
Trial, A-HeFT) - NEJM, 2004
Author(s): Taylor A, Ziesche S, Yancy C, Carson P, D'Agostino R, Ferdinand K, Taylor M, Adams K, Sabolinski M,
Worcel M, Cohn JN
Institution(s): University of Minnesota, Minneapolis Veterans Affairs Hospital, University of Texas Southwestern
Medical Center, Veterans Affairs Medical Center, Wake Forest University School of Medicine, Heartbeats Life Center,
Xavier University, Jackson Cardiology Associates, Association of Black Cardiologists, University of North Carolina
Chapel Hill, NitroMed.
Journal: New England Journal of Medicine
Funding: NitroMed
Journal citation: Taylor AL, Ziesche S, Yancy C, et al. Combination of Isosorbide Dinitrate and Hydralazine in Blacks
with Heart Failure. New England Journal of Medicine. 2004;351(20):2049-2057. doi:10.1056/nejmoa042934
Rationale: The rationale of this study was to determine if a fixed dose of isosorbide dinitrate/hydralazine provides benefit
beyond standard of care therapies for heart failure with dilated ventricles (dilated cardiomyopathy) in Black patients.
Clinical Question (PICO): In Black patients with advanced heart failure, how does treatment with a fixed dose of
isosorbide dinitrate/hydralazine, compared to standard of care therapies, affect mortality, morbidity, and quality of life?
Methods
Primary Objective: The primary objective of A-HeFT is to evaluate whether a fixed dose of isosorbide
dinitrate/hydralazine as add-on therapy in Black patients is superior to standard of care heart failure therapies alone.
Design: The A-HeFT trial is a multicenter (161 sites in USA), randomized, placebo-controlled, double-blinded trial of
1050 Black patients with advanced heart failure. Patients had predominantly NYHA class III (≥ 94% in all cases). Patients
were randomly assigned to receive a fixed dose of isosorbide dinitrate/hydralazine or placebo in addition to standard of
care therapies for advanced heart failure.
Population:
• Sample Size: 1050 Treatment (IDN/hydralazine): 518 Control (standard of care plus placebo): 532
• Randomization:
o Patients were randomized centrally by Medifacts International, a clinical research organization.
o Patients were stratified into groups according to the use or nonuse of beta-adrenergic antagonists as
background therapy for heart failure.
o Each site allocated 4 patients per group. Each site could randomize up to 6 groups (24 patients) lacking a
beta-adrenergic antagonist in background therapy and up to 10 groups (40 patients) taking a beta-adrenergic
antagonist as part of background therapy.
• Demographics: Other characteristics not listed (due to extreme similarity) include SBP, DBP, renal insufficiency, etc.
o Mean age: ~57 years (both groups)
o Biological sex: 55.8% male/44.2% female (treatment), 63.9% male/36.1% female (control)
o Primary cause of heart failure:
▪ Ischemic heart disease: 23.4% (treatment) vs. 22.7% (control)
▪ HTN: 40% (treatment) vs. 37.4% (control)
▪ Idiopathic: 24.5% (treatment) vs. 27.6% (control)
▪ Valvular disease: 2.5% (treatment) vs. 3.2% (control)
▪ Other: 9.7% (treatment) vs. 9.0% (control)
o NYHA Functional Classification (staging) of heart failure severity:
▪ Class I: None in either group
▪ Class II: 0.2% (treatment) vs. 0.0% (control)
▪ Class III: 96.7% (treatment) vs. 94.7% (control)
▪ Class IV: 3.1% (treatment) vs. 5.3% (control)
o Presence of diabetes mellitus:
▪ 44.8% (treatment) vs. 37.0% (control)
o Mean ejection fraction (at screening):
▪ 23.9% ± 7.3 (treatment) vs. 24.2% ± 7.5 (control)
o Medications for heart failure:
▪ Diuretic: 88.0% (treatment) vs. 91.5% (control)
▪ ACEI: 69.4% (treatment) vs. 69.5% (control)
▪ ARB: 17.2% (treatment) vs. 16.5% (control)
▪ BB: 74.1% (treatment) vs. 73.5% (control)
▪ Spironolactone: 40.2% (treatment) vs. 37.6% (control)

2. Paul Pasco, PHCY 4011: Advanced Community Pharmacy Practice I, 04/21/2022
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• Inclusion:
o Age ≥18 years.
o Positive self-identification as black (defined as of African descent).
o NYHA class III or IV heart failure for ≥ 3-months.
o Receiving stable doses of standard of care therapies for heart failure, as determined to be appropriate by their
physicians. These therapies include ACEIs/ARBS/BBs for ≥ 3-months prior to randomization, digoxin,
spironolactone, and diuretics.
o Evidence of LVEF ≤ 35%, LVEF < 45% with a left ventricular internal end-diastolic diameter of > 2.9
cm/m2
BSA or > 6.5 cm as shown on echocardiography within the 6-months preceding randomization.
o < 2.5% change in body weight in the previous two weeks prior to randomization.
• Exclusion:
o Women who were pregnant, nursing, or of childbearing age and not using an effective method of
contraception.
o ACS, acute MI, or stroke within the preceding 3-months.
o Cardiac surgery or PCI during the preceding 3-months (or a high probability of requiring such interventions
during the study period).
o Clinically significant valvular disease.
o Hypertrophic or restrictive cardiomyopathy.
o Active myocarditis.
o Uncontrolled HTN.
o A history of cardiac arrest or life-threatening arrythmias within the preceding 3-months (unless received
AICD).
o Treatment with IV inotropes within 1-month before randomization.
o Potential need for cardiac transplantation.
o Symptomatic hypotension.
o Illness other than heart failure that was likely to result in mortality during the study period.
o Inability to complete the quality-of-life questionnaire.
o Contraindications to the use of nitrates or hydralazine.
o Not receiving stable doses of heart failure therapies.
o > 2.5% change in body weight in the previous two weeks prior to randomization.
• Dropouts:
o No patients were lost to follow-up.
• Interventions/Statistical Analysis: The researchers calculated that 1100 patients (550 per group) were required for
the study to have sufficient statistical power (P < 0.02). The three individual components of the composite endpoint
were examined separately for the secondary endpoints. Data analysis was performed by independent statisticians and
by the statistical consulting company Virtu Stat, Ltd.
o Descriptive statistics for patient characteristics:
▪ Mean ± SD or total number (and percentage).
o Two-sample t-test:
▪ Used to compare population means for the primary endpoint between the two independent groups.
▪ Used to assess changes in quality of life between the two independent groups at 6-months (or 3-
months if not available).
o Kaplan-Meier survival methods with the log-rank test:
▪ Analysis of all-cause mortality/survival of all randomized patients.
o Fisher’s exact test:
▪ Used to compare incidence rates of death and a first hospitalization for heart failure between
groups.
o Probability values (p-values).
o Chi-square tests:
▪ Used to compare adverse events between groups.
o Hazard ratio:
▪ Used to compare the difference in risk for developing the primary outcome between the two
independent groups (treatment/exposed group vs. control/non-exposed group).
o Intention-to-treat analysis:
▪ All participants who had undergone randomization were included.
• Interventions:
o Initial dose of 1 tablet of isosorbide dinitrate/hydralazine, 20 mg/37.5 mg, PO, TID.
▪ TDD: 60 mg/112.5 mg.

3. Paul Pasco, PHCY 4011: Advanced Community Pharmacy Practice I, 04/21/2022
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o The initial dose was increased to a target dose of 2 tablets isosorbide dinitrate/hydralazine, 20 mg/37.5
mg, PO, TID.
▪ TDD: 120 mg/225 mg.
▪ Increase in dose was dependent on the absence of drug-related side effects/ADRs as judged by the
principal investigator.
• Endpoints:
o Primary endpoint (composite):
▪ All-cause mortality, a first hospitalization for heart failure in the 18-month follow-up period, and
change in quality of life at 6-months, assessed by the Minnesota Living with Heart Failure
Questionnaire (↑ scores = ↓ QOL).
o Planned secondary endpoint (individual analyses of the components of primary endpoint):
▪ Death from cardiovascular causes.
▪ Total hospitalizations for heart failure.
▪ Total hospitalizations for any reason.
▪ Total number of days of hospitalization.
▪ Overall QOL throughout the trial.
▪ Number of unscheduled emergency room, office, and/or clinic visits.
▪ Change in BNP level at 6-months.
▪ New need for cardiac transplantation.
▪ Change in LVEF, LV internal diastolic dimension, and left ventricular wall thickness at 6-months.
• Compliance Measured:
o The target dose was achieved in 68% of patients in the treatment group vs. 88.9% in the placebo group (P <
0.001).
• Monitoring:
o LVEF, LV internal diastolic dimension, LV wall thickness, BNP level at 6-months, quality of life assessment
every 3-months with the Minnesota Living with Heart Failure Questionnaire (↑ scores = ↓ QOL).
• Follow-up:
o Patients were followed for up to 18-months.
o Patients were interviewed by telephone monthly and participated in follow-up visits every 3-months.
Results
Findings/Results:
• General:
o Mean duration of follow-up was 10-months (ranged from 0-18 months).
o The trial was terminated early after approximately 3-years (when 1050/1100 patients were randomized) due
to unambiguous evidence of the significant benefit of the treatment (initiated 06/12/2001 and terminated
07/19/2004). Data indicated the treatment group had a significantly lower mortality rate than the control
group.
o Adverse events were higher in the treatment group: headache (47.5% treatment vs. 19.2% control,
P < 0.001), dizziness (29.3% treatment vs. 12.3% control, P < 0.001).
o Both all and severe exacerbations of CHF were lower in the treatment group: all exacerbations (8.7%
treatment vs. 12.8% control, P = 0.04), severe only (3.1% treatment vs. 7.0% control, P = 0.005).
• Primary Endpoint:
o At the time the trial ended, 32 patients (6.2%) in the treatment group vs. 54 patients (10.2%) in the control
group had died.
o Primary composite score: -0.1 ± 1.9 (treatment) vs. -0.5 ± 2.0 (control), P = 0.01.
▪ Scores can range from -6 to 2, with ↑ scores (more positive/less negative) indicating a better
outcome.
o NNT = 25 patients.
• Secondary Endpoints:
o All-cause mortality:
▪ As above, 32 patients (6.2%) vs. 54 patients (10.2%), P = 0.02.
▪ HR: 0.57, P = 0.01 by the log rank test ➔ 43% reduction in all-cause mortality.
o Survival changes began at ~180-days and widened progressively thereafter (P = 0.01 by the log-rank test).
o Rate of first hospitalizations for heart failure ↓ 33% in treatment group vs. control group.
▪ 85 patients (16.4%) in treatment group vs. 130 patients (24.4%) in control group, P = 0.001.
o Overall QOL higher in treatment group:
▪ -5.6 ± 20.6 (treatment) vs. -2.7 ± 21.2 (control), P = 0.02.
▪ ↑ scores (more positive/less negative) = ↓ QOL.

4. Paul Pasco, PHCY 4011: Advanced Community Pharmacy Practice I, 04/21/2022
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Critique
Data Analysis: Analysis was performed with double-blinding to treatment groups.
• Strengths:
o The study identified a relationship of overall clinical superiority when comparing a fixed dose of isosorbide
dinitrate/hydralazine to control (standard of care GDMT) in both the primary (composite) and secondary
(individual) endpoints.
o Moderate sample size (N = 1050).
o Prospective study.
o Directly confirms findings from subpopulation analyses in previous studies.
o Double-blinding was used to protect against the placebo effect.
• Limitations:
o Some of the sickest patients were excluded (e.g., ACS, acute MI, or stroke within the preceding 3-months;
cardiac surgery or PCI during the preceding 3-months; treatment with IV inotropes within 1-month before
randomization; potential need for cardiac transplantation; symptomatic hypotension). As a result, in these
strata of patient subpopulations, the utility of this intervention is less clear.
• Internal Validity:
o Given the referenced data, there appears to be consistent evidence of a causal relationship between the use of
a fixed dose of isosorbide dinitrate/hydralazine and improved patient outcomes.
o No confounding variables, such as differences in relevant baseline patient characteristics (e.g., NYHA stage)
were identified.
• External Validity:
o The exceptionally low NNT (25 patients) represents compelling evidence that the treatment, which has
been demonstrated as effective in reducing the primary outcome of all-cause mortality, preventing a first
hospitalization for heart failure, and improving quality of life holds significant utility for many Black
patients with advanced heart failure.
o The homogeneity of demographic characteristics in the study’s participants represents a strength, rather than
a weakness. That is, the homogeneity reinforces the applicability of the intervention in this select patient
population.
Authors’ Conclusions:
• This study provides robust evidence that in Black patients with advanced heart failure, a fixed dose of isosorbide
dinitrate/hydralazine (TDD: 120 mg/225 mg) may provide independent benefit beyond the previous standard of
care therapies, including ACEIs/ARBs, BBs, and aldosterone antagonists/K+
-sparing diuretics, for slowing
progression of heart failure.
o These benefits include reducing all-cause mortality (43% reduction), preventing a first hospitalization
for heart failure, and improving quality of life.
Recommendations:
➢ Devise a similar study to evaluate the potential benefits of this intervention in other races/ethnicities (e.g.,
Caucasians, Asians, the Latino/Hispanic population) on appropriate GDMT therapies for advanced heart failure.
➢ Devise a similar study with the above and add in genotypic/phenotypic testing. This testing would be used to
delineate various genotypes and the corresponding phenotypes, with respect to basal nitric oxide levels and
endothelial function. Information gleaned would be useful in targeting specific subpopulations who are likely to
benefit from this therapy.
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