Loop diuretic choice does not reduce all-cause death in HF: TRANSFORM-HF
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CHICAGO — A treatment strategy of torsemide vs. furosemide did not improve long-term clinical outcomes for adults hospitalized with HF, including all-cause mortality and all-cause hospitalization, researchers reported.
Furosemide is the most commonly used loop diuretic to manage fluid buildup in HF; however, torsemide may offer more advantages, Robert J. Mentz, MD, associate professor of medicine and population health science at Duke University School of Medicine, said during a press conference at the American Heart Association Scientific Sessions.
“[Torsemide] has more consistent oral bioavailability, meaning absorption can be better, particularly in the setting of volume overload for our patients with HF,” Mentz said. “It also has a longer duration of action than furosemide. In addition, it has anti-aldosterone and ant-fibrotic effects, and prior observational studies have suggested potential outcome benefits. However, without a robust, randomized clinical trial, it is unknown whether torsemide improves clinical outcomes compared with furosemide.”
Diverse, real-world cohort
For TRANSFORM-HF, a pragmatic comparative effectiveness study, Mentz and colleagues analyzed data from 2,859 patients who were hospitalized with HF between 2018 and March 2022. Eligibility criteria were broad to allow for more diverse recruitment, Mentz said; patients were eligible regardless of ejection fraction, as long as there was a long-term plan for a loop diuretic. The mean age of participants was 65 years; 37% were women and 34% were Black; 30% of patients had newly diagnosed HF and two-thirds had HF with reduced EF.
Researchers randomly assigned patients to a diuretic strategy of open-label torsemide or furosemide, with dosing per the routine clinician. Participants continued with routine clinical follow-up with no in-person, study-specific visits. The primary endpoint was all-cause mortality, selected based on prior meta-analyses that suggested a reduction in mortality with torsemide vs. furosemide, Mentz said.
“Our hypothesis was that torsemide would reduce mortality by 20% compared with furosemide,” Mentz said.
During median follow-up of 17.4 months, 26.2% of participants in the furosemide group and 26.1% of participants in the torsemide group died, for an HR of 1.02 (95% CI, 0.89-1.18; P = .077)
“These data were consistent across all the prespecified subgroups,” Mentz said during the press conference.
Event rates were also similar for the secondary endpoint of all-cause mortality or all-cause hospitalization at 12 months, with 49.3% of patients in the furosemide arm and 47.3% of patients in the torsemide arm experiencing an event, for an HR of 0.92 (95% CI, 0.83-1.02; P = .011). The rate ratio for total hospitalizations at 12 months was 0.94 (95% CI, 0.84-1.07).
During a presentation, Mentz said all-cause outcomes may have been “too imprecise” for measuring differences, especially during the COVID-19 pandemic. Future work will characterize how nonadherence and dose may have affected the findings.
“There were a number of important insights that were learned related to the pragmatic trial design and execution,” Mentz said. “Broad eligibility criteria and streamlined study protocol embedded within routine care supported the inclusion of diverse participants, with 37% women and 34% self-identified Black individuals. The pragmatic elements lowered traditional barriers for patient and site participation and supported robust recruitment, even during the COVID-19 pandemic. This real-world, comparative effectiveness study provides generalizable results that are applicable to our patients.”
Mentz said clinical time should be spent ensuring patients with HF are prescribed the right dose for their loop diuretic and prioritizing therapies proven to improve clinical outcomes.
All-cause mortality ‘challenging endpoint’
In a discussion after the presentation, Biykem Bozkurt, MD, PhD, The Mary and Gordon Cain Chair and Professor of Medicine and director of the Winters Center for Heart Failure Research at Baylor College of Medicine, noted that all-cause mortality is a “very challenging endpoint” for any trial, particularly during the COVID-19 pandemic period. Alternative disease-specific endpoints, such as HF death or HF hospitalization, may have better reflected potential differences in the potency of decongestion in HF and the mechanistic differences in CVD, Bozkurt said.
“The results will likely not alter clinical practice,” Bozkurt said. “Clinicians will likely continue to use torsemide according to their discretion, especially for bioavailability and diuretic potency when it is desired, especially for people resistant to diuretics. However, pragmatic trials are very important for their simplicity, cost-effectiveness and the reflection of a real-life setting with diversity. It would be so wonderful if we could find a midway between the real experimental design in pragmatic trials and look into the mechanisms and capture those other intermediate endpoints.”
Perspective
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Manesh R. Patel, MD, FACC, FAHA, FSCAI
The findings of this broad, pragmatic trial show a neutral effect — no difference between torsemide and furosemide for all-cause mortality in HF. This is informing because there are many mechanistic reasons that torsemide would seem to be better. The trial was based on total events for mortality; some have asked about CV mortality as an alternative endpoint or what we might see with longer-term follow-up. Both are important questions. We will not know for sure. There are likely some patients who do benefit from torsemide vs. furosemide; however, as a broad strategy, going from furosemide to torsemide did not change outcomes.
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Mentz R. LBS.01: The Main Event: Changing Clinical Practice. Presented at: American Heart Association Scientific Sessions; Nov. 5-7, 2022; Chicago (hybrid meeting).
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