Reassessing Loop Diuretic Strategies in HFrEF: A Case for Preferential Torsemide Use?

Heart failure with reduced ejection fraction (HFrEF) remains a major contributor to morbidity and mortality worldwide, necessitating optimization of all therapeutic strategies, including diuretic selection. Loop diuretics – chiefly furosemide, bumetanide, and torsemide – are foundational for managing congestion in HFrEF, yet the comparative effectiveness of these agents, particularly bumetanide versus torsemide, remains underexplored. The newly accepted study by Kido and Al-Mamun [1] offers valuable real-world insights into this question, presenting compelling evidence that torsemide is associated with superior outcomes compared to bumetanide in patients with HFrEF.Kido et al. conducted a retrospective analysis utilizing the expansive TriNetX database, comprising over 100 million de-identified patient records across 104 healthcare organizations globally. In this study, 45,088 patients with HFrEF receiving either bumetanide or torsemide were assessed. After 1:1 propensity score matching (PSM), 16,277 patients remained in each group, ensuring well-balanced baseline characteristics and minimizing confounding bias.The primary outcome was all-cause mortality over a 1-year follow-up, with secondary outcomes including all-cause hospitalization or emergency department visits, acute kidney injury (AKI), and hypokalemia. The study found that bumetanide use was associated with significantly higher risks across all endpoints. Notably, mortality was 19.7% in the bumetanide group versus 16.0% in the torsemide group (OR 1.28, 95% CI: 1.21–1.36), with consistent trends observed in secondary outcomes [1].This large-scale, well-powered, and methodologically sound study is one of the first to directly compare bumetanide and torsemide specifically in an HFrEF population. The use of PSM and subgroup analyses stratified by estimated glomerular filtration rate (eGFR) further reinforces the robustness of the findings.The superior outcomes associated with torsemide may be partially explained by pharmacokinetic and pharmacodynamic differences between the two agents. Torsemide offers several theoretical and empirically supported advantages:Greater bioavailability and longer half-life: torsemide has an oral bioavailability of approximately 80–100%, compared to 80–90% for bumetanide and a longer duration of action [2].Antifibrotic effects: torsemide has been shown to exert antifibrotic activity by modulating myocardial collagen turnover, potentially improving long-term cardiac remodeling [3, 4].Aldosterone antagonism: torsemide reduces aldosterone synthesis and receptor activity, which may translate to more favorable neurohormonal modulation and potassium preservation [5, 6].These pleiotropic effects could collectively contribute to improved clinical outcomes, including reductions in mortality, hospitalizations, and renal and electrolyte disturbances, as observed in the present study.Until now, the comparative efficacy of bumetanide and torsemide has been sparsely addressed. Prior observational studies have evaluated loop diuretics more broadly, typically focusing on furosemide versus torsemide. For example, the meta-analyses by Abraham et al. and Kido et al. [7, 8] suggested torsemide’s superiority over furosemide in reducing hospitalization risk, but data on bumetanide were limited. Similarly, the TRANSFORM-HF trial, which compared torsemide and furosemide in HF patients, did not show a mortality benefit for torsemide but did not include bumetanide as a comparator [9].Only two previous studies have directly compared bumetanide and torsemide, both of which were underpowered and yielded neutral findings likely due to type II error [10, 11]. The current study by Kido et al., with its significantly larger sample size and HFrEF-specific focus, thus represents a pivotal addition to the literature.These findings have meaningful implications for both guideline development and clinical decision-making. While US and European heart failure guidelines acknowledge the role of loop diuretics in symptom management, they do not currently provide specific recommendations regarding the choice among agents [12]. In light of this study, torsemide may warrant consideration as a preferred loop diuretic in HFrEF patients – especially those at risk for AKI or electrolyte imbalances.In practice, clinicians often escalate to torsemide or bumetanide when furosemide proves inadequate. The present findings support favoring torsemide in this scenario. This may be particularly relevant in outpatient settings, where diuretic choice can influence readmission risk, or in patients with impaired renal function, where bumetanide was associated with consistently worse outcomes across all eGFR strata [1].Despite its strengths, the study has inherent limitations due to its observational design. Although PSM was employed, residual confounding remains possible. Several important variables were not available in the TriNetX database:Dose and duration of diuretic therapy: without this, dose-response relationships could not be assessed.Baseline volume status and congestion severity: these could have influenced both drug choice and outcomes.Trajectory of renal function over time: only baseline eGFR stratification was available.Clinical classification: HFrEF was defined using ICD-10 coding, which may have misclassified some patients with HFmrEF or HFimpEF.Additionally, the lack of granular data on patient adherence and outpatient management limits generalizability. Nonetheless, the large cohort and consistent findings across multiple clinically relevant endpoints lend credence to the main conclusions.Given the consistent advantage seen with torsemide in this analysis, a randomized controlled trial comparing bumetanide and torsemide is warranted. Such a trial should incorporate patient-reported outcomes, such as symptom burden and quality of life; serial echocardiographic and biomarker assessments to evaluate reverse remodeling; health economic analyses to determine cost-effectiveness. In addition, subgroup analyses across racial/ethnic groups, comorbidity profiles, and advanced HF phenotypes (e.g., those with implantable devices or awaiting transplant) would be valuable.The findings by Kido et al. offer a compelling rationale for favoring torsemide over bumetanide in the management of HFrEF. The demonstrated reductions in mortality, hospitalization, AKI, and hypokalemia risk underscore the potential for torsemide to become the preferred loop diuretic in this population. While randomized controlled trial confirmation is needed, these real-world data should prompt clinicians to reevaluate their current prescribing patterns and consider torsemide as the more favorable agent when loop diuretic escalation is required.The authors thank the editorial team of Cardiology for the opportunity to contribute this commentary. No other individuals or organizations contributed substantively to the manuscript.The authors have no conflicts of interest to declare.This study was not supported by any sponsor or funder.W.-C.L. and Ü.Y.S. jointly conceptualized the commentary. W.-C.L. drafted the initial manuscript. Ü.Y.S. critically revised and expanded the content. Both authors approved the final version and take full responsibility for its accuracy and integrity.