A drug combination that once transformed outcomes for a specific group of heart failure patients has struggled to prove its worth when the circle of eligibility widens. The H-HeFT trial, presented at the 2026 European Society of Cardiology Congress, found that hydralazine paired with isosorbide dinitrate offered no statistically significant reduction in death or serious heart failure events among a broader, predominantly European population — a sobering counterpoint to the 43 percent mortality reduction it achieved in Black patients two decades prior. Medicine is reminded, once again, that a t
H-ISDN fails to show broad benefit in heart failure trial despite prior success
Success in one patient population does not guarantee success in another
Mark
So the drug worked brilliantly in Black patients with heart failure two decades ago, but now it doesn't work in a broader group. What changed?
Mimi
The drug itself didn't change. What changed is the patient population and the treatments available to them. When A-HeFT was done in the early 2000s, the background heart failure therapies were different. Patients in H-HeFT were on more modern medications, which may have already been doing much of what H-ISDN could do.
Luke
But we don't actually know that for certain, do we? The source says there were "substantial differences in trial design, duration of follow-up and background therapies." That's a lot of variables. It's possible the drug works and the trial just wasn't designed right to catch it.
Mimi
That's fair. And the meta-analysis did show mortality benefits when you pooled all three trials together. But those benefits were inconsistent across the different studies.
Mark
Why did so many patients stop taking it?
Mimi
The source doesn't specify the side effects, just that tolerability was an issue. If people can't tolerate a medication, it doesn't matter how well it works in theory.
Luke
Right, but "tolerability issues" is vague. We don't know if it was headaches, dizziness, or something serious. That matters for how we think about whether doctors should prescribe it.
Mark
So what happens now?
Mimi
Researchers say you'd need a new trial to figure this out. But designing that trial is tricky because you have to account for all the ways the earlier studies differed.
Luke
And that's expensive and takes years. So in the meantime, doctors are left uncertain about whether to use this drug in patients who aren't Black, or whether the original finding in Black patients still holds up.
Le Pouls
- A drug celebrated for saving lives in one patient group has now fallen short in a 592-patient trial designed to test whether that benefit could extend to heart failure patients more broadly.
- The numbers hinted at hope — 19.4% mortality in the treated group versus 24.2% in placebo — but the gap was too narrow and uncertain to cross the threshold of scientific confidence.
- High dropout rates haunted the trial, with many patients unable to tolerate the medication long enough to give it a fair chance, muddying what the results can actually tell us.
- A meta-analysis of three trials, covering over 2,100 patients, suggested possible mortality benefits, yet clashing study designs and different patient backgrounds made those signals hard to trust.
- Researchers are now calling for a new, rigorously designed randomized trial — acknowledging that without one, the drug remains suspended between its early triumph and its recent inconclusive performance.
A drug combination that once transformed outcomes for a specific group of heart failure patients has struggled to prove its worth when the circle of eligibility widens. The H-HeFT trial, presented at the 2026 European Society of Cardiology Congress, found that hydralazine paired with isosorbide dinitrate offered no statistically significant reduction in death or serious heart failure events among a broader, predominantly European population — a sobering counterpoint to the 43 percent mortality reduction it achieved in Black patients two decades prior. Medicine is reminded, once again, that a treatment's story is never fully told by a single chapter, and that the distance between promise and proof can stretch across populations, time, and tolerance.
A drug combination that once showed remarkable promise in heart failure treatment has failed to replicate its earlier success in a broader patient population. Hydralazine paired with isosorbide dinitrate — H-ISDN — produced no significant reduction in death or heart failure complications in the H-HeFT trial, presented at the European Society of Cardiology Congress in 2026.
The disappointment is sharpened by history. Over two decades ago, the A-HeFT study found that this same combination cut mortality by 43 percent in Black patients with heart failure — a striking result that established H-ISDN as a treatment option, though it was never systematically tested beyond that population. H-HeFT was designed to answer the logical next question.
The trial enrolled 592 patients across 23 centers in Denmark, following them for up to seven years while measuring deaths, worsening heart failure, transplantation, and mechanical heart pump implantation. The results offered no clear advantage: 8.6 adverse events per 100 patient-years on H-ISDN versus 9.3 on placebo — a difference that did not reach statistical significance. Mortality trends leaned in the drug's favor but fell short of certainty, and a substantial number of patients stopped taking the medication due to tolerability problems.
A meta-analysis drawing on three trials and more than 2,100 patients suggested H-ISDN may reduce cardiovascular and all-cause death, yet the studies differed so substantially in design, duration, and background therapies that firm conclusions remained elusive. Principal investigator Professor Lars Køber of Rigshospitalet in Copenhagen noted that the high discontinuation rates may have shaped the H-HeFT outcome, and called for new, carefully designed trials to settle the question. For now, H-ISDN remains caught between its early promise and its failure to prove itself in a wider test — a reminder that what works for one population cannot be assumed to work for all.
A drug combination that once showed remarkable promise in treating heart failure has failed to deliver the same benefit when tested in a broader patient population. Hydralazine paired with isosorbide dinitrate, known as H-ISDN, produced no significant reduction in death or heart failure complications in the H-HeFT trial, researchers reported at the European Society of Cardiology Congress in 2026.
The disappointment runs deeper because of what came before. More than two decades ago, the A-HeFT study demonstrated that this same combination cut mortality by 43 percent in Black patients with heart failure and reduced ejection fraction. That finding was striking enough to establish H-ISDN as a treatment option, yet it was never tested systematically beyond that initial population. The H-HeFT trial was designed to answer a straightforward question: could the drug work for heart failure patients more broadly?
The trial enrolled 592 patients across 23 centers in Denmark, randomizing them to receive either H-ISDN or placebo alongside their existing heart failure medications. Participants had an average age around 70, with about 17 percent women. All had symptomatic chronic heart failure with reduced ejection function and elevated markers of heart strain. Researchers tracked them for up to seven years, measuring a composite endpoint that included death, worsening heart failure requiring urgent treatment, transplantation, or implantation of a mechanical heart pump.
The results offered no clear advantage for the drug. H-ISDN produced 8.6 adverse events per 100 patient-years compared to 9.3 per 100 patient-years in the placebo group—a difference that fell short of statistical significance. All-cause mortality occurred in 19.4 percent of patients receiving H-ISDN and 24.2 percent in the placebo group, a trend that suggested possible benefit but lacked the certainty needed to draw firm conclusions. The investigators noted that a substantial number of patients stopped taking H-ISDN during the trial, though no serious safety problems emerged.
The picture grew more complicated when researchers examined the evidence across multiple studies. A meta-analysis combining data from three trials, including both A-HeFT and H-HeFT, analyzed outcomes in 2,101 heart failure patients total. This broader look suggested H-ISDN was associated with reductions in all-cause death and cardiovascular death. Yet the trials differed markedly in their design, how long they ran, and what background therapies patients received. Those differences made it difficult to draw confident conclusions about whether the drug truly works or whether the variations in study methods explained the conflicting results.
Professor Lars Køber, the principal investigator from Rigshospitalet in Copenhagen, acknowledged that high discontinuation rates may have influenced the H-HeFT findings. Patients simply did not tolerate the medication well enough to stay on it. The question now is whether a new, carefully designed trial could clarify H-ISDN's true role in heart failure treatment. Without one, the drug remains caught between its early promise and its recent failure to prove itself in a wider test—a reminder that success in one patient population does not guarantee success in another.
Citations marquantes
The H-HeFT trial was designed to further evaluate H-ISDN in patients with heart failure after the drug showed a 43% mortality reduction in Black patients over two decades ago— Professor Lars Køber, principal investigator
Given the heterogeneity and the tolerability issues, it is difficult to make firm conclusions on the effect of H-ISDN on cardiovascular outcomes— Doctor Jawad Haider Butt, meta-analysis presenter
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