- Loop diuretics are routinely used to manage congestion in heart failure (HF) but have never been directly compared in a large-scale randomized trial.
- The TRANSFORM-HF trial compared torsemide vs. furosemide for long-term clinical outcomes among patients hospitalized with HF.
- At median follow up of 17.4 months, there was no significant difference in clinical outcomes (all-cause mortality) between torsemide and furosemide in HF patients.
- The pragmatic nature of the TRANSFORM-HF study allowed for diverse patient recruitment, high site engagement and clinically generalizable results.
Though diuresis is a cornerstone for symptomatic management of all heart failure types, the optimal strategy for achieving decongestion in heart failure patients is often a matter of heated debate. Loop diuretics work by inhibiting the Na-K-2Cl carrier in the luminal membrane in the thick ascending limb of the loop of Henle, thereby reducing sodium chloride reabsorption. Both furosemide and torsemide work via this mechanism and prior observational data suggested that torsemide is superior in achieving decongestion with other potential advantages as well due to its longer half-life and anti-aldosterone effects. However, the long-term clinical benefit of one loop diuretic over another has not been established.
Dr. Robert Mentz at Duke University Medical Center and investigator team sought to answer this question in the ToRsemide compArisoN With furoSemide FOR Management of Heart Failure (TRANSFORM-HF) trial (NCT03296813), with study results announced at the 2022 American Heart Association Scientific Sessions on November 5th. TRANSFORM-HF was a large-scale, pragmatic, randomized, unblinded clinical effectiveness study in which patients hospitalized with heart failure were randomized to receiving torsemide or furosemide upon discharge. The pragmatic features of the study included: broad inclusion criteria, inclusion of all hospitalized patients with HF regardless of EF, few exclusion criteria, and lack of routine clinical visits Call center at 30 days, 6 month and 12 months. Oral dosing of torsemide compared to furosemide was standardized at 1mg:2-4mg, with dosing per the clinician. Patients then received follow up per standard care without any study-specific visits, though they were monitored with 30-day, 6-month and 12-month follow-up phone calls as well as the national death index to assess for clinical outcomes. The primary endpoint was all-cause mortality with secondary endpoints of all-cause mortality and all-cause hospitalization as well as total hospitalizations. Analysis of additional endpoints including health-related quality of life and depression symptoms is forthcoming.
The TRANSFORM-HF study enrolled 2,859 patients at 60 centers across the United States. Baseline characteristics were similar among patients in the torsemide and furosemide groups. In an exclusive interview, Dr. Mentz points out that the trial was able to enroll 37% women and 34% Black patients which are important groups to include in contemporary trials especially given historical underrepresentation. He states, “the idea was to be embedded in routine care” and highlights the success of designing and executing this pragmatic trial.
The TRANSFORM-HF study had a relatively high event rate with 747 deaths (26%) across the 29-month study period. Dr. Mentz believes this number of events is likely due to incorporating a broad population including nearly all patients discharged on loop diuretics. The primary endpoint showed no difference in survival between the two groups with 374 events (26.2%) in the furosemide group and 373 events (26.1%) in the torsemide group (HR 1.02 [95% CI, 0.89 to 1.18]; P-value 0.77). Similarly, the secondary endpoint showed there were nominally fewer hospitalizations in the torsemide group, but the combination of all-cause mortality or hospitalization was not significantly different among the diuretic strategies (HR 0.92 [95% CI, 0.83 to 1.02]; P-value 0.11).
When commenting on the results of the trial Dr. Mentz states, “we looked at a foundational and common clinical question, and definitively answered this question with a clinical trial that showed no difference in outcomes between the two groups”. He believes this trial is clinically applicable because it will shift clinician focus away from switching diuretics towards more effective pursuits such as titrating diuretic doses and incorporating other guideline directed medical therapies for heart failure. Finally, he believes that the pragmatic nature of the TRANSFORM-HF trial helped streamline participation for both patients and trial sites. As a result, this trial’s results are generalizable to routine clinical practice and may inform the design of future pragmatic trials.