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Randomized Controlled Trial
. 2023 Jan 17;329(3):214-223.
doi: 10.1001/jama.2022.23924.

Effect of Torsemide vs Furosemide After Discharge on All-Cause Mortality in Patients Hospitalized With Heart Failure: The TRANSFORM-HF Randomized Clinical Trial

Robert J Mentz  1   2 , Kevin J Anstrom  3 , Eric L Eisenstein  1 , Shelly Sapp  1 , Stephen J Greene  1   2 , Shelby Morgan  1 , Jeffrey M Testani  4 , Amanda H Harrington  1 , Vandana Sachdev  5 , Fassil Ketema  5 , Dong-Yun Kim  5 , Patrice Desvigne-Nickens  5 , Bertram Pitt  6 , Eric J Velazquez  4 ; TRANSFORM-HF Investigators
Collaborators, Affiliations
Randomized Controlled Trial

Effect of Torsemide vs Furosemide After Discharge on All-Cause Mortality in Patients Hospitalized With Heart Failure: The TRANSFORM-HF Randomized Clinical Trial

Robert J Mentz et al. JAMA. .

Abstract

Importance: Although furosemide is the most commonly used loop diuretic in patients with heart failure, some studies suggest a potential benefit for torsemide.

Objective: To determine whether torsemide results in decreased mortality compared with furosemide among patients hospitalized for heart failure.

Design, setting, and participants: TRANSFORM-HF was an open-label, pragmatic randomized trial that recruited 2859 participants hospitalized with heart failure (regardless of ejection fraction) at 60 hospitals in the United States. Recruitment occurred from June 2018 through March 2022, with follow-up through 30 months for death and 12 months for hospitalizations. The final date for follow-up data collection was July 2022.

Interventions: Loop diuretic strategy of torsemide (n = 1431) or furosemide (n = 1428) with investigator-selected dosage.

Main outcomes and measures: The primary outcome was all-cause mortality in a time-to-event analysis. There were 5 secondary outcomes with all-cause mortality or all-cause hospitalization and total hospitalizations assessed over 12 months being highest in the hierarchy. The prespecified primary hypothesis was that torsemide would reduce all-cause mortality by 20% compared with furosemide.

Results: TRANSFORM-HF randomized 2859 participants with a median age of 65 years (IQR, 56-75), 36.9% were women, and 33.9% were Black. Over a median follow-up of 17.4 months, a total of 113 patients (53 [3.7%] in the torsemide group and 60 [4.2%] in the furosemide group) withdrew consent from the trial prior to completion. Death occurred in 373 of 1431 patients (26.1%) in the torsemide group and 374 of 1428 patients (26.2%) in the furosemide group (hazard ratio, 1.02 [95% CI, 0.89-1.18]). Over 12 months following randomization, 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 (hazard ratio, 0.92 [95% CI, 0.83-1.02]). There were 940 total hospitalizations among 536 participants in the torsemide group and 987 total hospitalizations among 577 participants in the furosemide group (rate ratio, 0.94 [95% CI, 0.84-1.07]). Results were similar across prespecified subgroups, including among patients with reduced, mildly reduced, or preserved ejection fraction.

Conclusions and relevance: Among patients discharged after hospitalization for heart failure, torsemide compared with furosemide did not result in a significant difference in all-cause mortality over 12 months. However, interpretation of these findings is limited by loss to follow-up and participant crossover and nonadherence.

Trial registration: ClinicalTrials.gov Identifier: NCT03296813.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Mentz reported receiving grants from American Regent and Novartis; personal fees from AstraZeneca, Boehringer Ingelheim/Eli Lilly, Cytokinetics, Bayer, Merck, and Pharmacosmos; and research support from Abbott, Amgen, Bayer, Boston Scientific, Fast BioMedical, Gilead, Innolife, Medtronic, Relypsa, Respicardia, Roche, Sanofi, Vifor, Windtree Therapeutics, and Zoll outside the submitted work. Dr Anstrom reported receiving grants from Merck, Bayer, the National Institutes of Health, and the Patient-Centered Outcomes Research Institute during the conduct of the study. Dr Eisenstein reported receiving grants from the National Heart, Lung, and Blood Institute (NHLBI) during the conduct of the study. Dr Sapp reported receiving grants from Duke Clinical Research Institute during the conduct of the study. Dr Greene reported receiving grants from the NHLBI and American Heart Association during the conduct of the study; personal fees from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim/Eli Lilly, Corteria Therapeutics, Cytokinentics, Merck, PharmaIN, Roche Diagnostics, Tricog Health, Sanofi, Urovant Pharmaceuticals, and CSL Vifor and nonfinancial support from AstraZeneca, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, Sanofi, scPharmaceuticals, and Pfizer outside the submitted work. Dr Testani reported receiving grants from the National Institutes of Health during the conduct of the study; personal fees from 3ive Labs, AstraZeneca, Novartis, Cardionomic, MagentaMed, Reprieve Inc, Sanofi, Sequana Medical, Merck, Windtree Therapeutics, Lexicon Pharmaceuticals, Precardia, Relypsa, Regeneron, BD, Edwards Lifesciences, Eli Lilly, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, and W. L. Gore, and grants from FIRE1, Sequana Medical, Otsuka, Abbott, Merck, Lexicon Pharmaceuticals, 3ive Labs, Boehringer Ingelheim, Bristol Myers Squibb, and Sanofi outside the submitted work. In addition, Dr Testani had a patent for treatment of diuretic resistance with royalties paid from Yale and Corvidia Therapeutics, a patent for formulations and methods for direct sodium removal in patients having severe renal dysfunction issued from Reprieve Inc, and a patent for formulations and methods for direct sodium removal in patients having severe renal dysfunction issued from Sequana Medical. Dr Pitt reported receiving personal fees from Bayer, scpharmaceuticals, Sqinnovation, Boehringer Ingelheim, Vifor, AstraZeneca, G3 Pharmaceuticals, Sarfez, Cereno Scientific, Phasebio, KPB Biosciences, Protonintel, Brainstorm Medical, and Merck outside the submitted work. In addition, Dr Pitt had a patent for US 9931413 issued, site specific delivery of eplerenone to the myocardium, and a patent for US 63/045,783 pending, histone modulating agents for the prevention and protection from organ injury. Dr Velazquez reported receiving grants from the NHLBI to Yale University as principal investigator of the clinical coordinating center during the conduct of the study; and personal fees from Novartis and consultant fees from Abiomed to Yale University and from Baim Institute to Yale University outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Participant Flow in the TRANSFORM-HF Randomized Clinical Trial
For patients randomized twice, the second randomizations were completely removed from this diagram. TRANSFORM-HF indicates Torsemide Comparison With Furosemide for Management of Heart Failure.
Figure 2.
Figure 2.. Primary Outcome of All-Cause Mortality
The cumulative incidence of the primary outcome in the 2 groups is shown. The whiskers represent 95% CIs at the months specified. Variables for the adjusted P value are listed in Table 2.
Figure 3.
Figure 3.. Primary Outcome in Prespecified Subgroups
Results of the primary outcome of the trial—all-cause mortality—are shown according to subgroups that were prespecified in the protocol. eGFR indicates estimated glomerular filtration rate and NYHA class, New York Heart Association symptom class at time of randomization. aAmerican Indian, Native Hawaiian, and “multiple” categories were not included due to very small sample sizes.
See this image and copyright information in PMC

Comment in

References

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