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H-HeFTHeart FailureOpen Access
Hydralazine-isosorbide dinitrate in patients with heart failure and reduced ejection fraction
Key result
Hydralazine-isosorbide dinitrate shows no benefit over placebo for the primary composite outcome.
- HR 0.90
- 95% CI 0.67 to 1.21
- n=592
Why the trial?
The evidence for hydralazine-isosorbide dinitrate in HFrEF predates modern guideline-directed therapy and rests heavily on one self-identified Black population. H-HeFT asked whether the combination still reduces death or heart-failure events when added to contemporary treatment in an unselected population.
Does hydralazine-isosorbide dinitrate reduce the composite of death, worsening heart failure, urgent HF visits, heart transplantation, or LVAD implantation in patients with symptomatic chronic HFrEF?
Population
592 patients with symptomatic HFrEF (LVEF <=40%), elevated NPs; ~17% women
Comparison
Hydralazine 37.5 mg + ISDN 20 mg twice daily (uptitrated) vs placebo
Design
Investigator-initiated double-blind RCT, 23 Danish centres (DANHEART factorial)
Follow-up
Up to 7 years
Authors
Discussion
Key questions
No takes yet. Share an insight, caveat, or question.
Where experts stand
Experts read H-HeFT as a neutral trial that does not establish hydralazine-isosorbide dinitrate as a beneficial add-on in contemporary heart failure, though a possible mortality signal and supportive meta-analysis keep the question alive.
The primary endpoint missed, and commentators broadly agree this is a neutral result, but most note the trial was underpowered and plagued by high treatment discontinuation. A pooled meta-analysis combining older and newer trials showed a mortality benefit, dividing opinion on whether that rescues the clinical case for the drug combination. The live question is whether the meta-analysis signal and tolerability challenges together justify guideline reconsideration or simply call for better-designed trials.
Agreement
Commentators agree H-HeFT is a neutral trial on its primary endpoint, with the high discontinuation rate undermining interpretation and limiting conclusions about efficacy.
2 clinicians say this directly
2 takes classified by contention axis so far — the map appears as more land.
Still unclear
Whether the pooled meta-analysis mortality signal (combining V-HeFT I, A-HeFT, and H-HeFT) is strong enough to support broader use in non-African-descent populations given the heterogeneous eras and study designs. Whether the 57-58% discontinuation rate reflects a fundamental tolerability problem that limits real-world applicability regardless of efficacy signals. Whether guidelines will revisit the recommendation for hydralazine-isosorbide dinitrate beyond the current indication in self-identified African American patients.
Key expert perspectives
Ahmed BennisHeart Failure / Cardiomyopathy · Centre Hospitalier Universitaire Hassan IIResults readoutAug 30Neutral primary result, but the H-ISDN meta-analysis on mortality deserves attention
Calls H-HeFT a neutral result for DANHEART, with HR 0.90 on the primary composite. Notes the accompanying meta-analysis pooling V-HeFT I, A-HeFT, and H-HeFT showed an overall HR 0.71 for all-cause death with no heterogeneity across trials, framing it as important additional context.
Novi Yanti Sari · Universitas Muhammadiyah Palembang · Aug 30 Results readout Highlights that the primary endpoint was not met but says the accompanying meta-analysis adds important context. X post
Edgardo Alania · Aug 30 Endpoint critique Flags a possible mortality signal (HR 0.72) as inconclusive in an underpowered trial with 57% discontinuation, and cautions the pooled meta-analysis is not proof of universal add-on benefit given heterogeneous eras and populations. X postX post
Implication
Neutral results for hydralazine-isosorbide dinitrate in HFrEF do not support routine use; challenges broader application beyond prior select populations.
Key Points
- To evaluate the efficacy and safety of hydralazine plus isosorbide dinitrate in patients with symptomatic chronic heart failure and reduced ejection fraction.
- Investigator-initiated, double-blind randomized trial conducted across 23 centres in Denmark (N=592; mean age ~70 years; ~17% women).
- Participants with symptomatic chronic heart failure, LVEF ≤40%, SBP ≥100 mmHg, and elevated natriuretic peptides were randomized 1:1 to twice-daily hydralazine (37.5 mg) plus isosorbide dinitrate (20 mg) with uptitration or matching placebo, followed for up to 7 years.
- The primary composite outcome (death, worsening heart failure, urgent outpatient visits requiring IV or metolazone therapy, transplantation, or LVAD implantation) did not differ significantly between H-ISDN and placebo (8.6 vs 9.3 events/100 patient-years; HR 0.90, 95% CI 0.67 to 1.21).
- All-cause mortality occurred in 19.4% of the H-ISDN group versus 24.2% of the placebo group (HR 0.72, 95% CI 0.51 to 1.02), alongside high treatment discontinuation and no apparent safety concerns.
Evidence details
What drove the result?
| Outcome | H-ISDN | Placebo |
|---|---|---|
| Death, worsening HF, urgent HF visit needing IV/metolazone therapy, transplant, or LVAD | 8.6/100 pt-yr | 9.3/100 pt-yr |
| HR 0.90 (95% CI 0.67-1.21) · not significant | ||
| All-cause death | 19.4% | 24.2% |
| Secondary outcome · HR 0.72 (95% CI 0.51-1.02), CI crosses 1 | ||
Limitations & tradeoffs
Safety
no safety concerns were apparent per the investigators, though treatment discontinuation was highlighted as high (rates not reported) and reduced effective exposure to H-ISDN.
Subgroup caution
the all-cause death signal is a secondary outcome with a confidence interval crossing 1.
Representation
a Danish cohort with only ~17% women differs from the self-identified Black population in which A-HeFT showed benefit.
Structured PICO
Does hydralazine-isosorbide dinitrate reduce the composite of death, worsening heart failure, urgent HF visits, heart transplantation, or LVAD implantation in patients with symptomatic chronic HFrEF?
P
Population
592 patients (mean age 70, 17% women) with symptomatic chronic heart failure, LVEF ≤40%, and elevated natriuretic peptides, followed for up to seven years.
I
Intervention
Hydralazine 37.5 mg plus isosorbide dinitrate 20 mg twice-daily with uptitration
C
Comparator
Matching placebo
O
Outcome
Composite of death, worsening heart failure, an urgent outpatient visit resulting in intravenous or metolazone therapy for heart failure, heart transplantation, or left ventricular assist device implantationcomposite
Main Result
Hazard Ratio: 0.9 (95% CI 0.67–1.21)
Absolute Event Rate: 8.6% vs 9.3%
In a Danish cohort of patients with HFrEF, the addition of hydralazine-isosorbide dinitrate did not significantly improve the composite primary outcome of death or worsening heart failure compared to placebo.
Limitations
- High treatment discontinuation
- high treatment discontinuation
Coverage & sources
Journal, society, and media accounts. Useful signal, not independent expert judgment.
Cite This Study
Lars Køber (2026) conducted an RCT in Heart failure with reduced ejection fraction (n=592). Hydralazine-isosorbide dinitrate vs. Matching placebo was evaluated on Composite of death, worsening heart failure, an urgent outpatient visit resulting in intravenous or metolazone therapy for heart failure, heart transplantation, or left ventricular assist device implantation (HR 0.90, 95% CI 0.67 to 1.21). Hydralazine-isosorbide dinitrate did not significantly reduce the primary composite endpoint compared to placebo (8.6 vs 9.3 events/100 patient-years; HR 0.90, 95% CI 0.67-1.21).