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Aims To investigate the impact of patiromer on serum potassium level and its ability to enable specified target doses of renin-angiotensin-aldosterone system inhibitor (RAASi) use in patients with heart failure and reduced ejection fraction (HFrEF). Methods and results A total of 1642 patients with HFrEF and current or a history of RAASi-related hyperkalemia were screened and 1195 were enrolled in the run-in phase with patiromer and optimization of RAASi therapy (≥50% recommended dose of angiotensin-converting-enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, and 50 mg of mineralocorticoid receptor antagonist [MRA] spironolactone or eplerenone). Specified target doses of RAASi therapy were achieved in 878 (84.6%) patients; 439 were randomized to patiromer and 439 to placebo. All patients, physicians, and outcome assessors were blinded to treatment assignment. The primary endpoint was between-group difference in adjusted mean change in serum potassium. Five hierarchical secondary endpoints were assessed. At the end of treatment, the median (interquartile range) duration of follow-up was 27 (13, 43) weeks, the adjusted mean change in potassium was +0.03 mmol/L in the patiromer group and +0.13 mmol/L in the placebo group (difference in adjusted mean change between patiromer and placebo: -0.10 [95% confidence interval, CI -0.13, -0.07] mmol/L, P<0.001). Risk of hyperkalemia >5.5 mmol/L (hazard ratio [HR] 0.63; 95% CI 0.45, 0.87; P=0.006), reduction of MRA dose (HR 0.62; 95% CI 0.45, 0.87; P=0.006), and total adjusted hyperkalemia events/100 person-years (77.7 vs. 118.2; HR 0.66; 95% CI 0.53, 0.81; P<0.001) were lower with patiromer. Hyperkalemia-related morbidity-adjusted events (win ratio 1.53, P<0.001) and total RAASi use score (win ratio 1.25, P=0.048) favored the patiromer arm. Adverse events were similar between groups. Conclusion Concurrent use of patiromer and high-dose MRAs reduces the risk of recurrent hyperkalemia (ClinicalTrials.gov: NCT03888066).

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ImportanceAlthough furosemide is the most commonly used loop diuretic in patients with heart failure, some studies suggest a potential benefit for torsemide.ObjectiveTo determine whether torsemide results in decreased mortality compared with furosemide among patients hospitalized for heart failure.Design, Setting, and ParticipantsTRANSFORM-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.InterventionsLoop diuretic strategy of torsemide (n = 1431) or furosemide (n = 1428) with investigator-selected dosage.Main Outcomes and MeasuresThe 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.ResultsTRANSFORM-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 RelevanceAmong 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 RegistrationClinicalTrials.gov Identifier: NCT03296813