Comparison of Loop Diuretics Shows No Difference in Heart Failure Survival

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Among adults discharged after hospitalization for heart failure (HF), torsemide compared with furosemide did not result in a significant difference in all-cause mortality over 12 months, according to findings from the TRANSFORM-HF clinical trial.

“However, interpretation of these findings is limited by loss to follow-up and participant crossover and nonadherence,” wrote study authors in the Journal of the American Medical Association.

Furosemide is the most commonly used loop diuretic to manage congestion in HF, but preclinical and clinical data suggest potential benefits of torsemide, a similar loop diuretic, compared with furosemide.

“Torsemide has increased bioavailability and a longer half-life than furosemide. Torsemide may also have beneficial effects on myocardial fibrosis, aldosterone production, sympathetic activation, ventricular remodeling, and natriuretic peptides,” wrote Robert J. Mentz, MD, associate professor of medicine and population health science at Duke University School of Medicine, and colleagues. “Several small studies of torsemide vs furosemide and meta-analyses suggest a decrease in morbidity and potentially mortality with torsemide compared with furosemide. However, in light of the lack of an adequately powered clinical outcomes study, there is insufficient evidence to recommend torsemide over furosemide.”

TRANSFORM-HF was an open-label, pragmatic randomized clinical trial supported by the National Institutes of Health (NIH) designed to compare the effect of torsemide with furosemide in patients hospitalized with HF.

Mentz and colleagues analyzed data from 2859 patients (median age, 65 years) who were hospitalized with HF at 60 medical centers across the US. Recruitment occurred from June 2018 to March 2022, with follow-up through 30 months for mortality and 12 months for hospitalizations. A total of 1431 participants were randomly assigned to receive torsemide and 1428 to receive furosemide, and patient characteristics at baseline were similar in the 2 groups. Approximately 37% of participants were women and 34% were Black, a population often underrepresented in clinical trials, according to researchers.

Results

Over a median follow-up of 17.4 months, investigators found that 26.1% of patients in the torsemide group and 26.2% of those in the furosemide group died (hazard ratio [HR], 1.02; 95% CI, 0.89-1.18; P=.76). All-cause mortality or all-cause hospitalization occurred in 677 patients (47.3%) in the torsemide group and 704 patients (49.3%) in the furosemide group over 12 months following randomization (HR, 0.92; 95% CI, 0.83-1.02; P=.11). There were 940 total hospitalizations among 536 participants (37.5%) in the torsemide group and 987 total hospitalizations among 577 participants (40.4%) in the furosemide group (rate ratio, 0.94; 95% CI, 0.84-1.07).

The results were consistent across prespecified subgroups (eg, age, sex, race and ethnicity), including among participants with reduced, mildly reduced, or preserved ejection fraction.

Although there are mechanistic studies, observational analyses, and meta-analyses that do suggest clinical advantages of torsemide, this study, the authors reiterate, showed no treatment benefit over furosemide.

“We’re not saying that patients don’t need diuretics. We’re saying that there’s no difference in the survival benefit of these two therapies,” said Mentz in a NIH press release. “This suggests we should be spending more time focusing on the right diuretic dose for our patients and working to treat patients with therapies that improve clinical outcomes in heart failure.”

Limitations to the study include the fact that the sample size was approximately half that originally planned, the all-cause outcomes may have been too imprecise for measuring subtle differences between groups in HF-specific outcomes, and loop diuretic dose was left to clinician discretion, which could have influenced results.

“Future work will characterize how nonadherence and dose titration may have affected these findings including via the evaluation of varying definitions of ‘as-treated’ and incorporation of time-varying factors,” wrote Mentz et al.

Reference: Mentz RJ, Anstrom KJ, Eisenstein EL, et al. Effect of torsemide vs furosemide after discharge on all-cause mortality in patients hospitalized with heart failure: The TRANSFORM-HF randomized clinical trial. JAMA. 2023;329:214-223.