Jawad Butt, MD, PhD, is a research fellow in the department of cardiology at Copenhagen University Hospital and the University of Glasgow.

Jawad Butt, MD, PhD

A prespecified meta-analysis of three placebo-controlled trials found hydralazine plus isosorbide dinitrate (H-ISDN) reduced all-cause and cardiovascular death in patients with heart failure with reduced ejection fraction (HFrEF). Jawad Haider Butt, MD, PhD, presented the pooled findings, drawn from 2101 patients across V-HeFT I, A-HeFT, and the newly completed H-HeFT trial, at the European Society of Cardiology (ESC) Congress 2026 in Munich, Germany.¹

H-ISDN cut the risk of all-cause death by 29%, though the effect on heart failure hospitalization proved less consistent.³

H-ISDN Meta-Analysis Cuts Mortality Risk in Heart Failure

Guidelines currently reserve H-ISDN for patients unable to tolerate an ACE inhibitor, ARB, or ARNI, and for patients who self-identify as Black with NYHA class III or IV symptoms on foundational therapy. This guidance traces to the 2004 A-HeFT trial, which showed a 43% mortality reduction with H-ISDN added to standard therapy at the time.² The H-HeFT trial set out to test whether similar benefit extended to a broader, contemporary population.

Guideline recommendations for H-ISDN stem from small, older trials individually underpowered for mortality. The meta-analysis sought to strengthen the evidence base by combining all available placebo-controlled data in HFrEF.

H-ISDN Meta-Analysis Design and Mortality Findings

Butt and colleagues combined trial-level data from V-HeFT I (1986), A-HeFT (2004), and H-HeFT to answer a question neither trial alone was powered to resolve: does H-ISDN reduce mortality? In the primary fixed-effect analysis, H-ISDN was associated with reduced all-cause death (HR, 0.71; 95% CI, 0.58-0.87) and cardiovascular death (HR, 0.65; 95% CI, 0.47-0.90) compared with placebo.³ A reduction in heart failure hospitalizations also emerged, but significant between-trial heterogeneity prompted a sensitivity analysis using a random-effects model.

Under the random-effects model, mortality estimates held steady, but the hospitalization benefit lost statistical significance.³ Butt noted 2 of the 3 trials were underpowered for mortality alone, part of the rationale for pooling the data. The meta-analysis was prespecified before H-HeFT's primary results were unblinded.

H-HeFT Trial Results and Clinical Implications

H-HeFT, presented separately by principal investigator Lars Køber, MD, enrolled 592 patients with HFrEF who did not self-identify as Black, all receiving foundational therapy. Over up to 7 years of follow-up, H-ISDN failed to reduce the composite primary endpoint of death, worsening heart failure, urgent intravenous or metolazone therapy, transplantation, or ventricular assist device implantation compared with placebo.¹

Event rates were 8.6 vs 9.3 per 100 patient-years (HR, 0.90; 95% CI, 0.67-1.21). All-cause death occurred in 19.4% of the H-ISDN group versus 24.2% of the placebo group (HR, 0.72; 95% CI, 0.51-1.02), a gap not statistically significant on its own.¹

Treatment discontinuation rates were high in H-HeFT, a factor that may have diluted the drug's apparent effect.¹ Because the primary endpoint in H-HeFT was neutral, Butt considers the meta-analysis findings hypothesis-generating rather than practice-changing.

Køber said a new randomized trial will be needed to establish whether H-ISDN truly reduces mortality.¹ Butt agreed such a trial remains justified, given the residual risk for death and hospitalization left by current four-pillar HFrEF therapy, though he noted the absence of commercial sponsorship makes investigator-initiated trials difficult to mount.

Editors’ Note: Butt reports disclosures with AstraZeneca, Bayer, and Novartis.

European Society of Cardiology. No demonstration of benefit with hydralazine plus isosorbide dinitrate in heart failure. Published August 30, 2026. Accessed September 4, 2026.

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.

Butt JH. H-ISDN Meta-Analysis: Hydralazine-Isosorbide Dinitrate in HFrEF. Presented at: ESC Congress 2026; August 30, 2026; Munich, Germany.

Videos

Pooled data from 3 trials show H-ISDN cuts all-cause and cardiovascular death in HFrEF, though heterogeneity limits clinical impact.

H-ISDN Meta-Analysis Lowers Mortality in Heart Failure, With Jawad Butt, MD, PhD

Finerenone Efficacy in HF Unchanged by Ischemic Heart Disease, With Jawad Butt, MD, PhD

heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF)

, finerenone’s beneficial effects were consistent regardless of ischemic heart disease (IHD) status, according to a prespecified analysis of the FINEARTS-HF trial.

American College of Cardiology (ACC) Scientific Sessions 2026

 in New Orleans, Louisiana, by Jawad Butt, MD, PhD, a research fellow in the department of cardiology at Copenhagen University Hospital and the University of Glasgow.

“For clinicians, we know that the management of heart failure with a mildly reduced or preserved ejection fraction is complex,” Butt told 

 in an exclusive interview. “We know that ischemic heart disease is prevalent – we meet these patients in our everyday clinic. So the main take-home message for clinicians is that this treatment makes clinical decision-making so much easier, since we don’t have to differentiate between patients who do and do not have a history of IHD.”

FINEARTS-HF was a randomized, double-blind, placebo-controlled trial incorporating patients with symptomatic HF. Eligible patients were ≥40 years with New York Heart Association (NYHA) class II-IV HF, left ventricular ejection fraction (LVEF) ≥40%, or n-terminal prohormone B-type natriuretic peptide (NT-proBNP) ≥300 pg/mL in sinus rhythm, among other criteria. Patients were excluded if they exhibited an estimated glomerular filtration rate (eGFR) <25 mL/min/1.73m2 at screening or randomization, serum/plasma potassium >5 mmol/L at screening or randomization, or myocardial infarction, among other criteria.

The study included a primary outcome of a composite of total worsening HF events, which were defined as first or recurrent unplanned hospitalization or urgent visit for HF and death from cardiovascular causes. The individual components were also assessed. The trial included a median follow-up period of 32 months.

During the study, 3003 patients were randomized to receive finerenone, while 2998 were randomized to placebo. After the follow-up period, 1083 primary outcome events occurred in 624 patients in the treatment arm, and 1283 occurred among 719 patients in the placebo arm. The trial ultimately determined that finerenone reduced total worsening HF event rates and death from cardiovascular causes in these patients.

The present secondary analysis included all 6001 patients, of whom 3236 had a history of IHD. After comparing these patients to those without IHD, Butt and colleagues noted a significantly higher risk of the primary outcome among those with IHD (risk ratio [RR], 1.54; 95% CI, 1.33-1.79), as well as each of the endpoint’s components (total HF events: RR, 1.54; 95% CI, 1.03-1.82; CV death: HR, 1.58; 95% CI, 1.29-1.94; all-cause death; HR, 1.34; 95% CI, 1.16-1.55), even after adjustment for known prognostic variables.

However, the beneficial effect of finerenone on this primary outcome did not differ based on the presence of IHD (no IHD: RR, 0.81; 95% CI, 0.67-0.99; IHD: RR, 0.86; 95% CI, 0.73-1.01; 

 interaction = 0.68). Consistent effects were observed for all components of the primary outcome and all-cause death. Ultimately, Butt and colleagues determined that a history of IHD had no significant bearing on finerenone’s effects in HFmrEF/HFpEF.

“Historically, we haven’t had many effective treatments in patients with HFmrEF/HFpEF, until SGLT2 inhibitors were approved some years ago,” Butt said. “Last year, the FDA approved finerenone for the treatment and management of these patients. Now that we have done several analyses, including looking at the efficacy and safety of finerenone on top of SGLT2 inhibitors, I definitely think this will get a place in international guidelines for the management of HFmrEF/HFpEF.”

Butt J, Jhund P, Henderson A, et al. Ischemic Heart Disease Does Not Modify the Beneficial Effects of Finerenone in HFmrEF/HFpEF: A Prespecified Analysis of the FINEARTS-HF Trial. Abstract presented at the American College of Cardiology Scientific Sessions 2026, New Orleans, LA. March 28-30, 2026.

Bayer. Study to Evaluate the Efficacy (Effect on Disease) and Safety of Finerenone in Participants With Heart Failure and Left Ventricular Ejection Fraction (Proportion of Blood Expelled per Heart Stroke) Greater or Equal to 40% (FINEARTS-HF). ClinicalTrials.gov Identifier: NCT04435626. Updated August 26, 2025. Accessed April 7, 2026. 

https://clinicaltrials.gov/study/NCT04435626

Solomon SD, McMurray JJV, Vaduganathan M, et al. Finerenone in heart failure with mildly reduced or preserved ejection fraction. 

Butt discusses his secondary analysis of the FINEARTS-HF trial, which demonstrated consistent treatment efficacy in patients with and without a history of IHD.

Jawad Butt, MD, PhD

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