C. Michael GibsonResults readoutInterventional / Structural Cardiology · Beth Israel Deaconess Medical Center
Meta-analysis showed 29% reduction in all-cause mortality and 35% in CV mortality
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H-ISDN meta-analysisHeart FailureOpen Access
Hydralazine-isosorbide dinitrate in heart failure with reduced ejection fraction: a meta-analysis
What happened
Hydralazine-isosorbide dinitrate linked to ~29% lower all-cause death in heart failure patients.
- HR 0.71
- 95% CI 0.58-0.87
- n=2,101
Does this change practice?
What this trial adds
Experts are mostly reporting the headline mortality reduction from the H-ISDN meta-analysis rather than debating whether it should change practice, reflecting the investigators' own caution about heterogeneity and tolerability.
Published field read
The pooled analysis showed lower all-cause and cardiovascular death with hydralazine-isosorbide dinitrate in heart failure, but the underlying H-HeFT trial it drew on was stopped early and missed its primary endpoint. Most expert commentary so far has relayed the results without strong calls to change practice. The open question is whether the mortality signal from pooled older and newer trials is robust enough to influence guideline recommendations for a broader HFrEF population.
Still open
Questions raised in published commentaryIt remains unclear whether guideline committees will treat the pooled mortality reduction as sufficient evidence to broaden H-ISDN use beyond the populations already recommended, given the inconsistent hospitalisation results and substantial heterogeneity across the three trials.
No expert has yet weighed in on how the tolerability concerns and early stopping of H-HeFT should factor into that decision.
Context from published commentary. Source summaries are not a new guideline recommendation.
Who says what
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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?
Randomised trials of hydralazine-isosorbide dinitrate in heart failure span five decades and differ in populations and background therapy. Pooling them clarifies whether the combination reduces mortality across historical and contemporary settings.
Does hydralazine-isosorbide dinitrate reduce mortality in patients with heart failure with reduced ejection fraction?
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Key Points
- To evaluate the impact of hydralazine-isosorbide dinitrate on mortality and hospitalizations in patients with heart failure with reduced ejection fraction.
- Meta-analysis pooling 3 randomized controlled trials (including A-HeFT and H-HeFT) comprising 2,101 patients.
- Evaluated outcomes of all-cause death, cardiovascular death, and heart-failure hospitalization across trials with varying follow-up durations and background therapies.
- Hydralazine-isosorbide dinitrate was associated with a significant reduction in all-cause death (HR 0.71, 95% CI 0.58 to 0.87) and cardiovascular death (HR 0.65, 95% CI 0.47 to 0.90).
- Heart-failure hospitalization outcomes were inconsistent across trials, with marked heterogeneity in trial design, follow-up, background therapy, and tolerability issues.
Evidence details
Limitations & tradeoffs
Design limitations
substantial heterogeneity in trial design, follow-up duration and background therapy across the pooled trials.
Statistical certainty
heart-failure hospitalisation results were inconsistent across trials with no pooled estimate reported, and the investigators themselves concluded that firm conclusions about cardiovascular outcomes are difficult.
Patient burden
tolerability issues with H-ISDN complicate interpretation of the mortality findings.
Structured PICO
Does hydralazine-isosorbide dinitrate reduce mortality in patients with heart failure with reduced ejection fraction?
P
Population
2,101 patients with heart failure pooled from three randomised trials.
I
Intervention
Hydralazine-isosorbide dinitrate (H-ISDN)
O
Outcome
All-cause deathhard clinical
Main Result
Hazard Ratio: 0.71 (95% CI 0.58–0.87)
Limitations
- Substantial differences in trial design, duration of follow-up, and background therapy
- Heterogeneity across trials
- Tolerability issues
- Substantial differences in trial design
- Substantial differences in duration of follow-up
- Substantial differences in background therapy
- Heterogeneity
Discussion
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Expert reaction
What experts said about H-ISDN meta-analysis
ESC Congress 2026
1 expert has reacted so far. We show the split once 3 have.
Expert labels are toward H-ISDN meta-analysis's result, from named public quotes (n=1). As of Aug 30, 2026.
Where experts stand
Experts are mostly reporting the headline mortality reduction from the H-ISDN meta-analysis rather than debating whether it should change practice, reflecting the investigators' own caution about heterogeneity and tolerability.
The pooled analysis showed lower all-cause and cardiovascular death with hydralazine-isosorbide dinitrate in heart failure, but the underlying H-HeFT trial it drew on was stopped early and missed its primary endpoint. Most expert commentary so far has relayed the results without strong calls to change practice. The open question is whether the mortality signal from pooled older and newer trials is robust enough to influence guideline recommendations for a broader HFrEF population.
Still unclear
It remains unclear whether guideline committees will treat the pooled mortality reduction as sufficient evidence to broaden H-ISDN use beyond the populations already recommended, given the inconsistent hospitalisation results and substantial heterogeneity across the three trials. No expert has yet weighed in on how the tolerability concerns and early stopping of H-HeFT should factor into that decision.
Key expert perspectives
C. Michael GibsonInterventional / Structural Cardiology · Beth Israel Deaconess Medical CenterResults readoutAug 30Meta-analysis showed 29% reduction in all-cause mortality and 35% in CV mortality
Gibson highlighted that pooled data from 3 RCTs demonstrated significant reductions in all-cause death, CV death, and first HF hospitalization with hydralazine-isosorbide dinitrate. He also noted the H-HeFT trial was stopped early and did not reduce the primary composite of death or worsening HF.
MGMartha GulatiCardiologistResults readoutAug 30
H-HeFT missed its primary endpoint with HR 0.90
Gulati detailed the H-HeFT results, noting 592 patients were randomized and the primary endpoint showed HR 0.90 (95% CI 0.67-1.21), a non-significant result.
Distilled from their postX post
H-HeFT missed its primary endpoint but the meta-analysis adds important context
Sari framed the hotline presentation as a negative primary result from H-HeFT that gains meaning when read alongside the accompanying meta-analysis, noting the trial enrolled 592 patients of non-African descent with symptomatic HFrEF on maximally tolerated GDMT.
Distilled from their postX post
Implication
Although hydralazine-isosorbide dinitrate is associated with reduced all-cause and cardiovascular mortality in HFrEF, significant trial heterogeneity and tolerability issues prevent firm clinical conclusions.
Abstract
This meta-analysis pooled three randomised trials of hydralazine-isosorbide dinitrate in heart failure, including A-HeFT and H-HeFT, covering 2,101 patients. H-ISDN was associated with a reduction in all-cause death (HR 0.71, 95% CI 0.58 to 0.87) and cardiovascular death (HR 0.65, 95% CI 0.47 to 0.90), while results for heart-failure hospitalisation were inconsistent across trials. Substantial differences in trial design, duration of follow-up and background therapy were noted. Presented in Hot Line 6 at ESC Congress 2026, the investigators concluded that given the heterogeneity and the tolerability issues it is difficult to make firm conclusions about the effect of H-ISDN on cardiovascular outcomes. 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
Morten Schou (2026) conducted a meta-analysis in Heart failure with reduced ejection fraction (n=2,101). Hydralazine-isosorbide dinitrate (H-ISDN) was evaluated on All-cause death (HR 0.71, 95% CI 0.58-0.87). Hydralazine-isosorbide dinitrate was associated with a reduction in all-cause death (HR 0.71; 95% CI 0.58-0.87) and cardiovascular death (HR 0.65; 95% CI 0.47-0.90).