H-HeFT Trial Finds No Benefit for Hydralazine–Isosorbide Dinitrate in Heart Failure
核心洞察
The H-HeFT trial found no significant difference between hydralazine–isosorbide dinitrate (H-ISDN) and placebo for the composite primary endpoint of death or heart failure (搜索) events (8.6 vs. 9.3 events/100 patient-years; HR 0.90; 95% CI 0.67–1.21).
Treatment discontinuation rates were high, underscoring the need to carefully weigh the tolerability profile of H-ISDN in clinical practice.
All-cause death occurred in 19.4% of H-ISDN patients versus 24.2% of placebo patients (HR 0.72; 95% CI 0.51–1.02), a non-significant difference.
In patients with heart failure (搜索), the combination of hydralazine with isosorbide dinitrate (H-ISDN) did not significantly improve the incidence of death or heart failure events, and treatment discontinuation rates were high, according to the main findings of the H-HeFT trial presented in a Hot Line session at ESC Congress 2026 in Munich, Germany.
The investigator-initiated, double-blind H-HeFT trial was conducted in 23 centres in Denmark as part of the broader DANHEART study. DANHEART used a factorial design, evaluating H-ISDN in patients with chronic heart failure (搜索) (the H-HeFT trial) and metformin in patients with chronic heart failure and diabetes or prediabetes (the Met-HeFT trial, also presented at ESC Congress 2026).
Principal Investigator Professor Lars Køber from Rigshospitalet – Copenhagen University Hospital, Copenhagen, Denmark, explained that the trial was designed to assess whether an existing drug could bring benefits to a wider population. "Over two decades ago, the A-HeFT study demonstrated a 43% reduction in mortality with the combination of hydralazine with isosorbide dinitrate (H-ISDN) when given on top of established heart failure (搜索) therapy at that time," he noted. "The study population consisted of Black patients with heart failure and reduced ejection fraction and the H-ISDN combination has never been tested more broadly. The H-HeFT trial was designed to further evaluate H-ISDN in patients with heart failure."
Trial Design and Patient Population
Eligible patients had symptomatic chronic heart failure (搜索), a left ventricular ejection fraction (LVEF) of up to 40%, and were required to have systolic blood pressure of at least 100 mmHg and elevated levels of a heart strain marker (NT-proBNP >350 pg/mL or BNP >80 pg/mL). A total of 592 participants were randomised (1:1) to twice-daily hydralazine 37.5 mg plus isosorbide dinitrate 20 mg (with uptitration) or matching placebo. The mean age was around 70 years, and approximately 17% were women.
The primary endpoint was a composite of death, worsening heart failure (搜索), an urgent outpatient visit resulting in intravenous therapy or metolazone therapy for heart failure, heart transplantation, or left ventricular assist device implantation.
Primary Results
Over follow-up of up to seven years, there was no significant difference between H-ISDN and placebo for the primary endpoint (8.6 events/100 patient-years vs. 9.3 events/100 patient-years; hazard ratio [HR] 0.90; 95% confidence interval [CI] 0.67 to 1.21). All-cause death occurred in 19.4% of patients in the H-ISDN group and 24.2% of patients in the placebo group (HR 0.72; 95% CI 0.51 to 1.02).
Professor Køber commented that the results of the trial may have been impacted by the high number of patients who discontinued H-ISDN treatment, although there did not appear to be any safety concerns. "Whether there could be a reduction in mortality with H-ISDN requires a new randomised controlled trial," he said.
Meta-Analysis Findings
Also at the congress, Doctor Jawad Haider Butt, from the same institution, presented a meta-analysis of three trials evaluating H-ISDN treatment, including A-HeFT and H-HeFT. Data from 2,101 patients with heart failure (搜索) were analysed. 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), but results on hospitalisations for heart failure were inconsistent. Substantial differences in trial design, duration of follow-up, and background therapies were noted across the trials. "Given the heterogeneity and the tolerability issues, it is difficult to make firm conclusions on the effect of H-ISDN on cardiovascular outcomes," concluded Doctor Butt.
The findings differ from the earlier A-HeFT trial, which demonstrated a 43% reduction in mortality with H-ISDN plus established heart failure (搜索) therapy in Black patients with heart failure and reduced ejection fraction. The high treatment discontinuation rates observed in H-HeFT emphasise the need for careful consideration of the tolerability profile of H-ISDN in clinical practice.