
==== Front
Kidney360
Kidney360
KIDNEY
Kidney360
Kidney360
2641-7650
American Society of Nephrology

38595200
K360-2023-000601
10.34067/KID.0000000000000342
00002
3
Debates in Nephrology
Torsemide Is a More Appropriate Oral Loop Diuretic for Patients with Heart Failure: CON
Lo Kevin Bryan 1
Rangaswami Janani 2
1 Department of Cardiology, Brigham and Women's Hospital, Boston, MA
2 Department of Nephrology, Washington DC VA Medical Center, Washington, DC
Correspondence: Dr. Janani Rangaswami, email: nephrologymd1@gmail.com
8 2024
29 8 2024
5 8 10691071
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

diuretics
heart failure
OPEN-ACCESSTRUE
Read-alongYES
==== Body
pmcIntroduction

Congestion is a central target for the management of heart failure and is associated with worsening kidney function, recurrent hospitalizations, and death. Loop diuretics are a cornerstone for the treatment of congestion, with furosemide being the most frequently used loop diuretic. Torsemide has been an alternate loop diuretic of interest given the preclinical data supporting favorable neurohormonal and inflammatory milieu modulation in heart failure, in addition to decongestion. In this debate, we summarize clinical data and point out key arguments (see Table 1) to present the viewpoint against the use of torsemide as the loop diuretic of choice.

Table 1 Key points on the disadvantages of the use of torsemide in acute heart failure

There are no high-quality data from randomized trials demonstrating benefits with clinical outcomes in heart failure with torsemide	
Ensuring adequacy of decongestion in heart failure management rather than the choice of loop diuretic use should be the focus to help improve clinical outcomes	
The long-acting pharmacokinetics of torsemide represent a challenge toward effective monitoring and rapid titration of diuretic therapy in response to natriuresis quantification, both in the inpatient and outpatient settings	
In the setting of rapid up-titration of GDMT, long-acting loop diuretics can interfere with ease of titration given the limited ability to adjust according to hemodynamic responses and degree of decongestion	
GDMT, guideline-directed medical therapy.

Background and Mechanisms

Torsemide has higher oral bioavailability, a longer half-life, and duration of action compared with furosemide.1 Torsemide also exerts antifibrotic effects via decreased enzyme activity involved in myocardial extracellular collagen generation and possibly through less neurohormonal stimulation and aldosterone antagonism.1 These pharmacokinetic differences and implications on downstream cardiac fibrosis make torsemide attractive as an alternative diuretic. Although some observational studies have noted a benefit with torsemide, newer data call this conclusion into question, as summarized below.

Nonrandomized Clinical Studies

The Torsemide In Congestive Heart Failure study was a multicenter open-label nonrandomized postmarketing surveillance study in Spain of more than 2000 patients comparing torsemide with furosemide/other diuretics.2 Although this study was not originally intended to look at hard clinical outcomes, mortality was significantly lower in the torsemide group compared with furosemide/other diuretics group (2.2% versus 4.5, P < 0.05).2 Other studies have since shown conflicting results, with some showing reductions in heart failure readmissions while other experiences showed a benefit with functional capacity and quality of life.3 In a recent meta-analysis, torsemide showed a trend toward a lower risk of heart failure hospitalization, odds ratio (OR) 0.72 (95% confidence interval [CI], 0.51 to 1.03), and a significant decrease in cardiac death OR 0.37 (95% CI, 0.20 to 0.66).3 This was predominantly driven by the effect size of the Torsemide In Congestive Heart Failure study. Although there was significant improvement in functional status, there was no significant difference in all-cause mortality.3

The Effect of Torsemide versus Furosemide after Discharge on All-Cause Mortality in Patients Hospitalized with Heart Failure Randomized Controlled Trial

The largest randomized trial to date, Effect of Torsemide versus Furosemide after Discharge on All-Cause Mortality in Patients Hospitalized with Heart Failure (TRANSFORM-HF), explored the use of torsemide versus furosemide in 2859 patients hospitalized for heart failure, across ejection fraction using a multicenter, pragmatic, open-label design.4 This trial showed no significant difference in the primary outcome of all-cause mortality (26.1% versus 26.2%) in the torsemide and furosemide group, respectively, hazard ratio 1.02 (95% CI, 0.89 to 1.18). This was consistent across different prespecified subgroups across ejection fraction and kidney function strata.4 All-cause mortality/all-cause hospitalization (a prespecified secondary outcome) was not different between groups, hazard ratio 0.92 (95% CI, 0.83 to 1.02).4 There was significant crossover (7%) from the torsemide to furosemide arm which may have biased the results toward the null. Other limitations include higher than anticipated rates of patient withdrawal, diuretic use cessation, and missing data. While TRANSFORM-HF trial may have had a smaller than expected sample size, it was powered for the primary outcome of all-cause mortality. Thus, the strategy of using a longer-acting diuretic, such as torsemide, to optimize decongestion to reduce adverse clinical outcomes in heart failure, including mortality, is ineffective despite the promising preclinical and observational body of data supporting this approach.

Achieving Adequate Decongestion and Neurohormonal Blockade

The mortality rate of a quarter of enrolled patients in TRANSFORM-HF during the course of the trial is sobering and calls for urgent attention to optimizing congestion and aberrant neurohormonal activation in heart failure. In the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry, discharge loop diuretic prescription was not associated with outcomes such as heart failure readmission or death; rather, the association between loop diuretics and outcomes was modified by the degree of congestion, with better outcomes with diuretics in patients with persistent congestion.5 The use of torsemide with its unique pharmacokinetics of once-a-day dosing1 to achieve decongestion might potentially lead to less aggressive and decreased frequency of monitoring of volume status. This contrasts with using shorter-acting diuretics, such as furosemide, where doses may be more aggressively titrated and given in doses several times a day depending on natriuretic response.6 Monitoring adequacy of natriuretic response can be accomplished by simple bedside tests, such as monitoring of spot urine sodium in 2 hours after diuretic dose administration and urine output at 6 hours.6,7 This is simply not feasible when a long-acting diuretic, such as torsemide, is used. Even in the outpatient setting, studies have shown that the individual diuretic needs significantly change over time, in the setting of guideline-directed medical therapy (GDMT) initiation,6 and the long-acting pharmacokinetics of torsemide make adjustments of loop diuretic dose challenging.

Strategies such as multisegment nephron blockade to augment decongestion represent a growing space of interest. In a randomized trial, addition of acetazolamide to loop diuretic therapy in patients with acute decompensated heart failure resulted in higher decongestion rates (absence of signs of volume overload such as edema, pleural effusion, or ascites using a congestion score within 3 days after randomization) (risk ratio, 1.46 [95% CI, 1.17 to 1.82]).8 In a meta-analysis of nine randomized trials, addition of Sodium glucose cotransporter-2 inhibitor to standard diuretic therapy for acute heart failure resulted in a reduction in all-cause death, OR, 0.75 (95% CI, 0.56 to 0.99) and heart failure readmissions, OR, 0.54 (95% CI, 0.44 to 0.66).9 There was also an increased mean daily urinary output in liters (mean difference, 0.45; 95% CI, 0.03 to 0.87) and decreased mean daily doses of loop diuretics (milligram of furosemide equivalents), mean difference, −34.90; (95% CI, −52.58 to −17.21),9 which represent incremental benefits to decongestion. Again, these findings underscore the importance of adequacy of decongestion as the major driver of improving clinical outcomes in heart failure, not a longer-acting loop diuretic, per se.

Attenuating the neurohormonal axis pathway vis a vis sodium avidity in heart failure by optimizing GDMT in conjunction with diuresis is necessary to achieve and maintain decongestion, especially in the setting of diuretic braking and resistance.7 Even in the TRANSFORM-HF pragmatic contemporary trial, there was room to optimize GDMT (β blockers was at 81%, renin-angiotensin system inhibitor/angiotensin receptor neprilysin inhibitor at 67.5, mineralocorticoid receptor antagonists at 44%, and Sodium glucose cotransporter-2 inhibitor use at 7.8%), despite including about 70% of patients with an ejection fraction <40%.4 In a recent randomized trial of more than 1000 patients hospitalized for acute heart failure, rapid up-titration of oral medications reduced 180-day death and heart failure rehospitalization after acute heart failure hospitalization irrespective of ejection fraction.10 Reducing diuretic doses depending on hemodynamic responses6 as components of GDMT are rapidly initiated can particularly present a challenge because of the long-acting pharmacokinetics of torsemide, making this a less attractive choice when optimizing GDMT especially in the hospitalized setting.

In conclusion, torsemide does not represent the ideal loop diuretic because of the lack of benefit on clinical outcomes, difficulty with rapid drug titration, and precise control/monitoring of achieving adequate natriuresis. Decongestion using standard short-acting loop diuretics with/without combination therapies for sequential nephron blockade and rapid GDMT titration are necessary to mitigate the adverse clinical outcomes associated with heart failure.

Acknowledgments

The content of this article reflects the personal experience and views of the author(s) and should not be considered medical advice or recommendation. The content does not reflect the views or opinions of the American Society of Nephrology (ASN) or Kidney360. Responsibility for the information and views expressed therein lies entirely with the author(s).

Disclosures

J. Rangaswami reports the following: Consultancy: Bayer, Boehringer-Lily, and Edwards Lifesciences; Advisory or Leadership Role: Medical Advisory Board; Procyrion Inc. (Aortix); Speakers Bureau: Boehringer-Ingelheim/Lily; and Other Interests or Relationships: AHA, Chair, Council on the Kidney in Cardiovascular Disease. The remaining author has nothing to disclose.

Funding

None.

Author Contributions

Conceptualization: Kevin Bryan Lo, Janani Rangaswami.

Data curation: Kevin Bryan Lo, Janani Rangaswami.

Methodology: Janani Rangaswami.

Supervision: Janani Rangaswami.

Validation: Janani Rangaswami.

Writing – original draft: Kevin Bryan Lo, Janani Rangaswami.

Writing – review & editing: Kevin Bryan Lo, Janani Rangaswami.

See related debate, “Torsemide Is a More Appropriate Oral Loop Diuretic for Patients with Heart Failure: PRO,” and commentary, “Torsemide Is a More Appropriate Oral Loop Diuretic for Patients with Heart Failure: COMMENTARY” on pages 1072–1074 and 1075–1076, respectively.
==== Refs
References

1. Peters AE Mentz RJ DeWald TA Greene SJ . An evaluation of torsemide in patients with heart failure and renal disease. Expert Rev Cardiovasc Ther. 2022;20 (1 ):5–11. doi:10.1080/14779072.2022.2022474 34936522
2. Cosín J Díez J .; TORIC investigators. Torasemide in chronic heart failure: results of the TORIC study. Eur J Heart Fail. 2002;4 (4 ):507–513. doi:10.1016/s1388-9842(02)00122-8 12167392
3. Abraham B Megaly M Sous M , . Meta-analysis comparing torsemide versus furosemide in patients with heart failure. Am J Cardiol. 2020;125 (1 ):92–99. doi:10.1016/j.amjcard.2019.09.039 31699358
4. Mentz RJ Anstrom KJ Eisenstein EL , .; TRANSFORM-HF Investigators. Effect of torsemide vs furosemide after discharge on all-cause mortality in patients hospitalized with heart failure: the TRANSFORM-HF randomized clinical trial. JAMA. 2023;329 (3 ):214–223. doi:10.1001/jama.2022.23924 36648467
5. Faselis C Lam PH Patel S , . Loop diuretic prescription and long-term outcomes in heart failure: association modification by congestion. Am J Med. 2021;134 (6 ):797–804. doi:10.1016/j.amjmed.2020.11.019 33359271
6. Mullens W Damman K Harjola VP , . The use of diuretics in heart failure with congestion - a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2019;21 (2 ):137–155. doi:10.1002/ejhf.1369 30600580
7. Rangaswami J Bhalla V Blair JEA , .; American Heart Association Council on the Kidney in Cardiovascular Disease and Council on Clinical Cardiology. Cardiorenal syndrome: classification, pathophysiology, diagnosis, and treatment strategies: a scientific statement from the American heart association. Circulation. 2019;139 (16 ):e840–e878. doi:10.1161/CIR.0000000000000664 30852913
8. Mullens W Dauw J Martens P , .; ADVOR Study Group. Acetazolamide in acute decompensated heart failure with volume overload. N Engl J Med. 2022;387 (13 ):1185–1195. doi:10.1056/NEJMoa2203094 36027559
9. Carvalho PEP Veiga TMA Simões E Silva AC , . Cardiovascular and renal effects of SGLT2 inhibitor initiation in acute heart failure: a meta-analysis of randomized controlled trials. Clin Res Cardiol. 2023;112 (8 ):1044–1055. doi:10.1007/s00392-022-02148-2 36592186
10. Pagnesi M Metra M Cohen-Solal A , . Uptitrating treatment after heart failure hospitalization across the spectrum of left ventricular ejection fraction. J Am Coll Cardiol. 2023;81 (22 ):2131–2144. doi:10.1016/j.jacc.2023.03.426 37257948
