A-HeFT

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Taylor AL, et al. "Combination of Isosorbide Dinitrate and Hydralazine in Blacks with Heart Failure". The New England Journal of Medicine. 2004. 351(20):2049-2057.
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Clinical Question

Among self-identified black patients with HFrEF, does the combination of isosorbide dinitrate and hydralazine improve survival compared to placebo?

Bottom Line

Isosorbide dinitrate plus hydralazine improves survival and reduces hospitalization among black patients with HFrEF.

Major Points

Self-identified black individuals may have less activity of the renin-angiotensin-aldosterone system (RAAS), rendering ACE inhibitors, ARBs, and beta-blockers relatively less effective.[1] A subgroup analysis of self-described black patients in V-HeFT (1986) was the first to suggest a survival benefit to isosorbide dinitrate (ISDN)/hydralazine, a combination that targets non-RAAS pathways leading to increased nitric oxide and decreased reactive oxygen species.

The 2004 African-American Heart Failure (A-HeFT) trial sought to study the hypothesis that ISDN/hydralazine would provide a survival benefit in a prospective, randomized trial of self-identified blacks with HFrEF. A-HeFT was terminated early when it demonstrated that ISDN/hydralazine was associated with a nearly 40% reduction in all-cause mortality in addition to standard therapy with ACE inhibitors, beta-blockers, and diuretics. This combination of agents was also associated with a 33% reduction in first hospitalizations due to HF and a significant improvement in quality of life.

Some questioned the underpinnings of the trial, including the fact that V-HeFT studied patients in an era predating ACE inhibitors and beta-blockers.[1] Further, the self-identified black cohort in V-HeFT had a significantly higher BP, the control of which with ISDN/hydralazine may have accounted in large part for the therapeutic benefit seen in A-HeFT.[2]

Guidelines

AHA/ACCF Heart Failure (2013, adapted)[3]

  • Recommendation of nitrates/hydralazine for self-described African American patients with NYHA III-IV HFrEF on OMT with ACE-inhibitors and beta blockers unless contraindicated (class I, level A)
  • Suggestion of nitrates/hydralazine for all patients with current or previous symptomatic HFrEF who can't tolerate ACE-inhibitor or ARB therapy unless contraindicated (class IIa, level B)

Design

  • Multicenter, double-blinded, parallel-group, randomized, placebo-controlled trial
  • N=1,050
    • ISDN/hydralazine (n=518)
    • Placebo (n=532)
  • Setting: 161 centers in the US
  • Enrollment: 2001-2004
  • Trial was terminated due to significant mortality benefit
  • Mean follow-up: 10 months (range 0-18)
  • Analysis: Intention-to-treat
  • Primary outcome: Primary composite score (calculated from all-cause mortality, HF hospitalizations, and quality of life measurements)

Population

Inclusion Criteria

  • Age ≥18 years
  • Self-identified as black (of African descent)
  • NYHA class III-IV HF ≥3 months
  • Receiving stable doses of standard therapy, including ACE inhibitors or ARBs, β-blockers, digoxin, spironolactone, diuretics
  • LV dysfunction within previous 6 months defined as:
    • Resting LVEF <35%
    • Resting LVEF <45% with LV end-diastolic diameter >2.9cm/m² of BSA or >6.5cm by echocardiogram

Exclusion Criteria

  • Pregnant, nursing, or of childbearing age and not using an effective method of contraception
  • Contraindications to use of nitrates or hydralazine
  • Stroke or ACS within previous 3 months
  • Coronary revascularization (CABG, PCI) within previous 3 months or high likelihood of requiring these procedures during study period
  • Clinically significant valvular heart disease, hypertrophic or restrictive cardiomyopathy, active myocarditis, or uncontrolled HTN
  • History of cardiac arrest or life-threatening arrhythmias within previous three months (unless treated with ICD)
  • Symptomatic hypotension
  • Treatment with parenteral inotropic agents within previous month
  • High risk for cardiac transplantation
  • Illness other than HF likely to result in death within the study period

Baseline Characteristics

  • Demographics: Age 57 years, male 56% vs. 64% (P=0.008)
  • Baseline health data: Weight 93 kg, SBP 126 mmHg, DBP 77.6 vs. 75.6 mmHg (P=0.002)
  • Primary cause of HF:
    • Ischemic heart disease: 23%
    • HTN: 39%
    • Idiopathic: 26%
    • Valvular: 3%
    • Other: 9%
  • NYHA III: 96%
  • NYHA IV: 4%
  • Cardiac resynchronization therapy: 2%
  • ICD: 17%
  • LVEF: 24%
  • LV internal diastolic diameter: 6.5 cm
  • Minnesota Living with Heart Failure Questionnaire mean score: 50.8
  • PMH: Diabetes 44.8% vs. 37.0% (P=0.01), renal insufficiency 17%, AF 16.5%
  • Medications: Diuretics 90%, ACE inhibitors 70%, ARBs 17%, β-blockers 74% (carvedilol: 56%), digoxin 60%, spironolactone 39%

Interventions

  • Randomized to ISDN/hydralazine or placebo, stratified according to use or nonuse of background β-blockers
  • Initial dose: ISDN/hydralazine 20mg/37.5mg tablet TID vs. placebo
  • Dose increased to 2 tablets TID (total ISDN 120mg and hydralazine 225mg) if no drug-induced side effects
  • Follow-up: 18 months
    • Assessment of LVEF, LV internal diastolic diameter, LV wall thickness, BNP at baseline and 6 months
    • Assessment of quality of life at baseline and every 3 months by Minnesota Living with Heart Failure questionnaire
    • Telephone interviews monthly and follow-up visits every 3 months
  • Primary outcome was the composite score of weighted values from the following, for a total score of -6 to +2:
    • Death from any cause (-3)
    • First hospitalization for heart failure (-1)
    • Change in quality of life at 6 months:
      • Change by ≥10 units
      • Change by 5-9 units

Outcomes

Comparisons are ISDN/hydralazine vs. placebo.

Primary Outcomes

Primary composite score
-0.1 vs. -0.5 (P=0.01)

Secondary Outcomes

All-cause mortality
6.2% vs. 10.2% (RR 0.61; P=0.02; survival differences emerged at ~180 days by Kaplan-Meier survival analysis, P=0.01; NNT=25)
First HF hospitalization
16.4% vs. 24.4% (RR 0.67; P=0.001; NNT=13)
Change in quality of life score at 6 months
-5.6 vs. -2.7 (P=0.02; lower scores are better)

Other Outcomes

Change in mean SBP
-1.9 vs. +1.2 mmHg (P=0.02)
Change in mean DBP
-2.4 vs. +0.8 mmHg (P<0.001)
Change in HR
P=NS

Adverse Events

HF exacerbations
8.7% vs. 12.8% (P=0.04)
Severe HF exacerbation
3.1% vs. 7.0% (P=0.005)
Headache
47.5% vs. 19.2% (P<0.001)
Dizziness
29.3% vs. 12.3% (P<0.001)

Funding

NitroMed licensed patents for hydralazine and isosorbide dinitrate combination pill, they subsequently produced the medication under the brand name BiDil.

Criticisms

  • As prior trials involving multiple racial groups did not involve the current standard of care, it is unclear if hydralazine/ISDN would have provided benefit outside of the population of A-HeFT[1]
  • Race and genetic variations do not always strongly correlate[1]
  • The mortality difference for self-identified blacks in V-HeFT trial may have been due to lower incidence of CAD and higher incidence of HTN and the benefit may have, in fact, been due to treatment of the underlying HF causes rather than an intrinsic process in a specific racial group[2]
  • No report of baseline CCB use[2]
  • The composite score is not reasonably weighted[2]
  • No power calculation explanation[2]
  • No reporting of the known complication of hydralazine-induced lupus-like symptoms as an adverse event[2]

Further Reading

  1. 1.0 1.1 1.2 1.3 Bloche MG. "Race-based therapeutics." The New England Journal of Medicine. 2004;351(20):2035-2037.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 Multiple authors. "Correspondence: Isosorbide dinitrate and hydralazine in blacks with heart failure." The New England Journal of Medicine. 2005;352(10):1041-1043.
  3. Yancy CW, et al. "2013 ACCF/AHA guideline for the management of heart failure." Circulation. 2013;128:e240-e327.