Hydralazine-Isosorbide Dinitrate Misses Endpoint in H-HeFT Trial

Hydralazine plus isosorbide dinitrate (H-ISDN) did not significantly reduce the composite risk of death or heart failure events in a broader population of patients with heart failure with reduced ejection fraction (HFrEF), and treatment discontinuation rates were high, according to results from the H-HeFT trial presented in a Hot Line session at the European Society of Cardiology (ESC) Congress 2026 in Munich, Germany.¹

A companion meta-analysis presented at the same session found H-ISDN associated with reduced mortality when pooled across trials, despite the negative primary result.¹

H-ISDN's origins trace to the A-HeFT trial, which found a 43% mortality reduction with the combination added to standard heart failure therapy in a trial population of self-identified Black patients with HFrEF.² Those results led the US Food and Drug Administration (FDA) to approve a fixed-dose combination product in 2005 specifically for Black patients, the first FDA approval of a drug restricted to a single racial group.

"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 therapy at that time," Lars Køber, MD, principal investigator of H-HeFT and professor at Rigshospitalet, Copenhagen University Hospital, said in a statement. "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."

H-HeFT Trial Design and Primary Results

The investigator-initiated, double-blind H-HeFT trial was conducted at 23 centers in Denmark as part of DANHEART, a factorial trial including the Met-HeFT trial of metformin in chronic heart failure with diabetes or prediabetes, presented separately at the same congress.¹ Eligible patients had symptomatic chronic heart failure, a left ventricular ejection fraction of ≤ 40%, systolic blood pressure of ≥ 100 mmHg, and elevated NT-proBNP (> 350 pg/mL) or BNP (> 80 pg/mL).¹

Investigators randomly assigned 592 participants in a 1:1 ratio 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% of patients were female.¹ The primary endpoint was a composite of death, worsening heart failure, an urgent outpatient visit requiring intravenous or metolazone therapy for heart failure, heart transplantation, or left ventricular assist device implantation.¹

During a follow-up of up to 7 years, there was no significant difference between H-ISDN and placebo for the primary endpoint (8.6 events per 100 patient-years vs 9.3 events per 100 patient-years; hazard ratio [HR], 0.90; 95% CI, 0.67-1.21).¹ All-cause death occurred in 19.4% of patients receiving H-ISDN compared with 24.2% of patients receiving placebo (HR, 0.72; 95% CI, 0.51-1.02).¹

H-ISDN Meta-Analysis and Clinical Context

Køber noted the trial's high discontinuation rate may have affected the results, though no safety concerns emerged. "Whether there could be a reduction in mortality with H-ISDN requires a new randomised controlled trial," he said.¹

Jawad Haider Butt, MD, presented a companion meta-analysis of 3 trials evaluating H-ISDN, including A-HeFT and H-HeFT, encompassing 2101 patients with heart failure.⁴ Results showed H-ISDN was associated with reductions 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), though results for heart failure hospitalizations were inconsistent across trials, with substantial differences in trial design, follow-up duration, and background therapies.⁴

However, Butt cautioned against drawing firm conclusions from the pooled analysis given this heterogeneity: "Given the heterogeneity and the tolerability issues, it is difficult to make firm conclusions on the effect of H-ISDN on cardiovascular outcomes.”

References

1. European Society of Cardiology. No demonstration of benefit with hydralazine plus isosorbide dinitrate in heart failure. Published August 30, 2026. Accessed August 30, 2026. https://www.escardio.org/news/press/press-releases/no-demonstration-of-benefit-with-hydralazine-plus-isosorbide-dinitrate-in-heart-failure/

2. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004;351:2049-2057.

3. Butt JH, et al. H-ISDN meta-analysis: hydralazine-isosorbide dinitrate in HFrEF. Presented at: ESC Congress 2026; August 30, 2026; Munich, Germany.