Ahmed BennisResults readoutHeart Failure / Cardiomyopathy · Centre Hospitalier Universitaire Hassan II
Neutral primary result, but the pooled meta-analysis on all-cause death keeps the door open
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H-HeFTHeart FailureOpen Access
Hydralazine-isosorbide dinitrate in patients with heart failure and reduced ejection fraction
What happened
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
- 8.6/100 pt-yr vs 9.3/100 pt-yr at Up to 7 years
Does this change practice?
Where experts agree
Both credentialed clinicians who offered substantive commentary agree the primary endpoint result is neutral and that the high discontinuation rate (around 57-58%) is a major limitation that clouds interpretation of any secondary signals.
What this trial adds
Experts read H-HeFT as a neutral trial for hydralazine-isosorbide dinitrate in HFrEF, but note a possible mortality signal and a meta-analysis that keeps the debate alive about whether the combination still has a role on top of modern therapy.
Published field read
Clinicians agree the primary endpoint was clearly missed, and high treatment discontinuation weakens confidence in any secondary signals. However, the accompanying meta-analysis pooling earlier trials showed a significant reduction in all-cause death, which some see as meaningful context while others dismiss it because of differences across eras and populations. The live question is whether these drugs deserve a place on top of contemporary guideline-directed therapy outside the African-descent population for which they already carry a recommendation.
Still open
Questions raised in published commentaryWhether the mortality signal (HR 0.72) is real or an artifact of an underpowered, high-discontinuation trial remains unresolved.
Experts also question how much weight to give the pooled meta-analysis given that the included trials span different eras, populations, and background therapies.
It is unclear whether guidelines will shift for non-African-descent patients on contemporary therapy.
Context from published commentary. Source summaries are not a new guideline recommendation.
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Full evidence
Why the trial, key points, tables, limitations, PICO, abstract, media & sources
Full evidence
Why the trial, key points, tables, limitations, PICO, abstract, media & sources
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?
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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
Discussion
No takes yet. Share an insight, caveat, or question.
Expert reaction
What experts said about H-HeFT
ESC Congress 2026
Expert labels are toward H-HeFT's result, from named public quotes (n=1). As of Aug 28, 2026.
Where experts stand
Experts read H-HeFT as a neutral trial for hydralazine-isosorbide dinitrate in HFrEF, but note a possible mortality signal and a meta-analysis that keeps the debate alive about whether the combination still has a role on top of modern therapy.
Clinicians agree the primary endpoint was clearly missed, and high treatment discontinuation weakens confidence in any secondary signals. However, the accompanying meta-analysis pooling earlier trials showed a significant reduction in all-cause death, which some see as meaningful context while others dismiss it because of differences across eras and populations. The live question is whether these drugs deserve a place on top of contemporary guideline-directed therapy outside the African-descent population for which they already carry a recommendation.
Agreement
Both credentialed clinicians who offered substantive commentary agree the primary endpoint result is neutral and that the high discontinuation rate (around 57-58%) is a major limitation that clouds interpretation of any secondary signals.
2 clinicians say this directly
2 takes classified by contention axis so far — the map appears as more land.
Still unclear
Whether the mortality signal (HR 0.72) is real or an artifact of an underpowered, high-discontinuation trial remains unresolved. Experts also question how much weight to give the pooled meta-analysis given that the included trials span different eras, populations, and background therapies. It is unclear whether guidelines will shift for non-African-descent patients on contemporary therapy.
Key expert perspectives
“@DrDerekConnolly @DLBHATTMD @ESC_President @PZoungas @vass_vassiliou @mmartinezheart @ShelleyZieroth @robmentz @JennaSkowronski @noshreza @gabrielsteg @co_kobo @elmir1omerovic @Aspirinbk @RizosKonsta @escardio @HighSTEACS @SimoneBiscaglia @KardiologieHH @Marta33717088 @Bweber04 @RonBlankstein @purviparwani @MariamElmegaard @ankeetbhatt @kpnorcal @ratika_parkash @DalhousieU @HeartDocSharon #HOTLINE 6 #ESCCongress #HeartFailure Old HF drugs get new questions (hydralazine-ISDN, metformin) in H-HeFT and Met-HeFT LUMINARA:new oral relaxin agonist in HF PA Denervation in PH Which trial will change your practice in HF? Are the old drugs the new drugs?”
Ahmed BennisHeart Failure / Cardiomyopathy · Centre Hospitalier Universitaire Hassan IIResults readoutAug 30Neutral primary result, but the pooled meta-analysis on all-cause death keeps the door open
Called the primary endpoint result clearly neutral for this DANHEART sub-trial. Highlighted the accompanying meta-analysis pooling V-HeFT I, A-HeFT, and H-HeFT, which showed HR 0.71 for all-cause death with no heterogeneity across trials, suggesting a possible class-level mortality benefit.
Primary endpoint missed, but the meta-analysis adds important context
Summarized the trial as failing its primary endpoint in 592 patients of non-African descent with HFrEF on maximally tolerated therapy, while noting the accompanying meta-analysis provides important additional perspective on the treatment effect.
Distilled from their postX post
Implication
Neutral results for hydralazine-isosorbide dinitrate in HFrEF do not support routine use; challenges broader application beyond prior select populations.
Abstract
H-HeFT was an investigator-initiated, double-blind trial at 23 centres in Denmark, run as part of DANHEART's factorial design alongside Met-HeFT. Eligible patients had symptomatic chronic heart failure, a left ventricular ejection fraction of up to 40%, systolic blood pressure of at least 100 mmHg and elevated natriuretic peptides (NT-proBNP >350 pg/mL or BNP >80 pg/mL). A total of 592 participants (mean age around 70 years; approximately 17% women) were randomised 1:1 to twice-daily hydralazine 37.5 mg plus isosorbide dinitrate 20 mg with uptitration, or matching placebo. The primary endpoint was a 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. Over follow-up of up to seven years there was no significant difference between H-ISDN and placebo for the primary endpoint (8.6 vs 9.3 events/100 patient-years; HR 0.90, 95% CI 0.67 to 1.21). All-cause death occurred in 19.4% of the H-ISDN group and 24.2% of the placebo group (HR 0.72, 95% CI 0.51 to 1.02). The investigators highlighted high treatment discontinuation and no apparent safety concerns. Source: ESC Congress 2026 press release, 30 August 2026.
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).