Advancing the evidence for diuretic therapy for heart failure: implications of the ADVOR and TRANSFORM-HF trials
Year: 2023
Type: article
Abstract: Although diuretics have long been foundational therapy in the management of heart failure (HF), the specific utilization of diuretic therapy remains variable with limited high-quality data to guide best practices.1 In this setting, results from two diuretic trials in HF took centre stage in 2022 at major European and US scientific sessions. The Acetazolamide in Decompensated Heart Failure With Volume Overload (ADVOR) trial randomized 519 patients with acute HF and demonstrated that the addition of IV acetazolamide (500 mg daily for 3 days) to background IV loop diuretic improved decongestion in acute HF.2 ADVOR represents one of the only definitively positive diuretic trials in several decades, meeting its primary endpoint of successful decongestion within 3 days of randomization, defined as the absence of signs of volume overload without an indication for escalation of decongestive therapy. The in-hospital safety profile showed similar rates of worsening kidney function, hypokalaemia, and hypotension in each arm. The benefits of acetazolamide on congestion persisted throughout the hospitalization, contributing to a 1 day reduction in length of stay. Additionally, key limitations of ADVOR should be noted. First, the trial was not powered for post-discharge outcomes. In this setting, there was a non-significant, numerically greater rate of all-cause mortality (15.2% vs. 12.0%) at 3 months in the acetazolamide arm. While this likely represents a chance finding, it nonetheless warrants further investigation in larger trials. Second, the trial excluded patients receiving sodium–glucose cotransporter-2 inhibitor (SGLT2i) therapy, a medication now foundational across the spectrum of ejection fraction and with a mechanism targeting the proximal tubule, the same segment of the nephron as acetazolamide. In addition to proven benefits for clinical outcomes, SGLT2i have been shown to improve decongestion. The degree to which the decongestive effects of acetazolamide and SGLT2i are additive, sub-additive, or synergistic remains unknown. Third, the median home maintenance diuretic dose of 60 furosemide equivalents was relatively modest and much less than the home maintenance dose in the diuretic optimization strategies evaluation (DOSE) trial (mean ∼130 mg furosemide equivalents). Thus, the intravenous (IV) diuretic dosing in ADVOR was substantially lower than the high-dose arm of the DOSE trial. Whether the addition of IV acetazolamide would have maintained its incremental decongestive in the setting of higher background, IV loop diuretic dosing is unclear. Lastly, assessment of IV acetazolamide in broader racial/ethnic populations (nearly all self-reported white race in the study) is warranted. The Torsemide Comparison with Furosemide for Management of Heart Failure (TRANSFORM-HF) trial demonstrated no significant difference in all-cause mortality or composite all-cause mortality or hospitalization with a strategy of torsemide vs. furosemide in patients hospitalized with HF. TRANSFORM-HF was a pragmatic, open-label, strategy trial where patients were assigned to the specific oral diuretic agent with dosing left to the discretion of the treating clinician.3 Consistent with the pragmatic design, the trial included no study-specific in-person follow-up visits, with monitoring instead centralized via a call centre. This facilitated rapid recruitment of a large, diverse population (n = 2859, 37% women, 34% black race, 46% HFmrEF/HFpEF). Yet, the limitations of TRANSFORM-HF should be noted. The trial should be interpreted in the context of its target population in which there was clinician equipoise regarding the use of torsemide or furosemide. Further studies are needed to determine whether patients with refractory congestion or diuretic resistance despite high-dose furosemide would benefit from switching to torsemide. The all-cause endpoints may have been insensitive for the detection of a potential treatment effect and cardiovascular-specific outcomes are not reported. Moreover, assessment of treatment effect was limited by early crossover (8% in the torsemide arm and 5.5% in the furosemide arm at 30 days) and diuretic discontinuation (7.5% in the torsemide arm and 6.5% in the furosemide arm at 30 days) in the subset of patients with known loop diuretic status. Nonetheless, while these features may have biased results toward the null, the pragmatic design supports strong generalizability to routine practice and supports similar long-term effectiveness of these two common diuretic agents on all-cause clinical outcomes. National Heart Lung and Blood Institute (T32HL069749) to A.E.P.; Duke University Department of Medicine Chair's Research Award, American Heart Association (#929 502) to S.J.G. Conflict of interest: A.E.P. has received honoraria from Cytokinetics. R.J.M. has received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Eli Lilly, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Medtronic, Merck, Novartis, Relypsa, Respicardia, Roche, Sanofi, Vifor, Windtree Therapeutics, and Zoll. S.J.G. has received research support from the National Heart Lung and Blood Institute, Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, Pfizer, and Sanofi; has served on advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim/Lilly, Bristol Myers Squibb, Cytokinetics, Roche Diagnostics, scPharmaceuticals, and Sanofi; serves as a consultant for Amgen, Bayer, Bristol Myers Squibb, Boehringer Ingelheim/Lilly, Corteria Pharmaceuticals, CSL Vifor, Merck & Co., Inc., PharmaIN, Roche Diagnostics, Sanofi, Tricog Health, and Urovant Pharmaceuticals; and has received speaker fees from Boehringer Ingelheim and Cytokinetics. No new data were generated or analysed in support of this research.
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4315928949