Two major heart failure (HF) studies presented at ESC Congress 2026 delivered neutral results on commonly used therapies, raising important questions about their role in patient management. The H-HeFT trial found that hydralazine plus isosorbide dinitrate (H-ISDN) did not significantly reduce the incidence of death or HF events in patients with HF, while treatment discontinuation rates were high. Similarly, the Met-HeFT trial and accompanying meta-analysis showed that metformin did not significantly affect the risk of cardiovascular outcomes in patients with HF with reduced ejection fraction (HFrEF) who had diabetes or were at risk of developing diabetes.

H-HeFT Trial
In the H-HeFT trial, conducted at multiple centers in Denmark as part of the broader DANHEART study, 592 patients were randomized to twice-daily hydralazine 37.5 mg plus isosorbide dinitrate 20 mg (with uptitration) or matching placebo. All patients had symptomatic chronic HF, 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). The mean age was 70 years and approximately 17% were women.

Over the roughly seven-year follow-up period, researchers found no significant difference between those receiving H-ISDN and those receiving placebo for the composite primary endpoint of death, worsening HF, an urgent outpatient visit resulting in intravenous therapy or metolazone therapy for HF, heart transplantation or left ventricular assist device implantation (8.6 events/100 patient-years vs. 9.3 events/100 patient-years).

The findings differ from earlier results from the A-HeFT trial, which demonstrated a 43% reduction in mortality with H-ISDN plus established HF therapy in Black patients with HFrEF, according to Lars Køber, MD, who presented the H-HeFT findings. “The H-HeFT trial was conducted to assess whether an existing drug could bring benefits to a wider population,” he said.

Presenting on a meta-analysis of three trials assessing H-ISDN treatment, including both A-HeFT and H-HeFT, Jawad Haider Butt, MD, noted substantial differences in trial design, duration of follow-up and background therapies 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,” he said.

Met-HeFT Trial
In the Met-HeFT trial, also part of the broader DANHEART study, there was no evidence for improved cardiovascular outcomes with metformin vs. placebo in patients with HFrEF and diabetes, prediabetes or at increased risk of diabetes.

A total of 940 participants (mean age 70 years; 16% women) with symptomatic chronic HF, an LVEF of up to 40% and type 2 diabetes, prediabetes or increased risk of type 2 diabetes were randomized to receive metformin or placebo.

Results showed no significant difference between metformin and placebo for the primary endpoint of death, worsening HF, acute myocardial infarction or stroke. In addition, metformin did not significantly affect secondary endpoints such as all-cause death, unplanned HF events, new-onset diabetes or change in the heart strain marker, NT-proBNP.

Henrik Wiggers, MD, who presented the findings, said the limited enrollment of participants with type 2 diabetes (10%), “likely reflected the existing widespread use of metformin and the reluctance of patients and clinicians to discontinue ongoing metformin treatment, which was a requirement for inclusion.”

In a meta-analysis of seven randomized placebo-controlled trials of metformin, including Met-HeFT, Anders Hostrup Larsen, MD, PhD, said “there was no significant difference in cardiovascular outcomes with metformin in patients with HFrEF and no significant effect in established ischemic heart disease.”

Going forward, researchers said metformin was not associated with any harm and remains beneficial for glucose lowering but does not appear to have additional cardioprotective benefits.

Visit ACC’s ESC Congress 2026 coverage page to explore the latest science and key takeaways shaping cardiovascular care.


Clinical Topics:
Cardiovascular Care Team, Heart Failure and Cardiomyopathies, Acute Heart Failure, Chronic Heart Failure


Keywords:
ESC Congress, ESC26, Heart Failure, Heart Failure, Systolic, Ventricular Dysfunction, Left, Hydralazine, Isosorbide Dinitrate, Metformin