Patel V, Zameer R, Kumar B, Das M. Adjunctive pharmacologic therapies for diuretic resistance in acute decompensated heart failure: Systematic review of randomized trials. World J Meta-Anal 2026; 14(1): 118496 [DOI: 10.13105/wjma.v14.i1.118496]
Corresponding Author of This Article
Mehta Das, MBBS, Associate Professor, FCPS, Department of Internal Medicine, Kabul Medical University, Ataturk Road, Jamal Mina, District 3, Kabul 100310, Afghanistan. mehtadas91@gmail.com
Research Domain of This Article
Cardiac & Cardiovascular Systems
Article-Type of This Article
Systematic Reviews
Open-Access Policy of This Article
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World J Meta-Anal. Mar 18, 2026; 14(1): 118496 Published online Mar 18, 2026. doi: 10.13105/wjma.v14.i1.118496
Adjunctive pharmacologic therapies for diuretic resistance in acute decompensated heart failure: Systematic review of randomized trials
Vaishvik Patel, Rabia Zameer, Beesham Kumar, Mehta Das
Vaishvik Patel, Department of Internal Medicine, UConn Health, Farmington, CT 06030, United States
Rabia Zameer, Department of Internal Medicine, Internal Medicine Residency (PGY-2), Larkin Community Hospital, Miami, FL 33143, United States
Rabia Zameer, Department of Internal Medicine, Fatima Jinnah Medical College, Lahore 54000, Punjab, Pakistan
Beesham Kumar, Department of Internal Medicine, Jinnah Medical and Dental College, Karachi 75500, Sindh, Pakistan
Mehta Das, Department of Internal Medicine, Kabul Medical University, Kabul 100310, Afghanistan
Author contributions: Patel V and Das M contributed to the conception and design of the study; Patel V led the literature search, data extraction, and analysis; Zameer R contributed to data acquisition, study selection, and critical appraisal of included trials; Kumar B assisted in data organization, verification of extracted outcomes, and manuscript drafting; Das M provided senior supervision, critical revision of the manuscript for important intellectual content, and overall guidance. All authors participated in drafting or critically revising the manuscript, approved the final version for publication, and agree to be accountable for all aspects of the work in accordance with ICMJE authorship criteria.
Conflict-of-interest statement: The authors declare that there are no conflicts of interest related to this study.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Corresponding author: Mehta Das, MBBS, Associate Professor, FCPS, Department of Internal Medicine, Kabul Medical University, Ataturk Road, Jamal Mina, District 3, Kabul 100310, Afghanistan. mehtadas91@gmail.com
Received: January 4, 2026 Revised: January 30, 2026 Accepted: February 24, 2026 Published online: March 18, 2026 Processing time: 65 Days and 20.9 Hours
Abstract
BACKGROUND
Diuretic resistance is a frequent and clinically important problem in acute decompensated heart failure (ADHF), leading to persistent congestion, prolonged hospitalization, and adverse outcomes. Although loop diuretics remain first-line therapy, many patients show inadequate natriuretic and diuretic responses. Adjunctive pharmacologic therapies targeting different nephron segments or renal sodium handling have been studied to enhance decongestion. However, randomized controlled trial evidence remains heterogeneous, and the relative effectiveness of these strategies in the acute setting is unclear. The study hypothesis is that mechanistically targeted adjunctive therapies improve diuretic response compared with standard therapy alone.
AIM
To determine the effectiveness and safety of adjunctive pharmacologic therapies for diuretic resistance in ADHF.
METHODS
Randomized controlled trials enrolling adults hospitalized with ADHF receiving loop diuretics were identified through PubMed, EMBASE, Scopus, and the Cochrane Central Register of Controlled Trials to February 2025. Adjunctive pharmacologic therapies were compared with placebo or usual care. Outcomes included decongestion, urine output, natriuresis, renal function, safety, and clinical events. Data extraction and risk of bias assessment using the Cochrane Risk of Bias tool were performed independently by two reviewers. Given substantial heterogeneity across study designs, definitions, and endpoints, no meta-analysis or statistical pooling was performed, and all effect estimates reflect study-level values reported in individual trials. A narrative synthesis was conducted.
RESULTS
Eight randomized controlled trials including 1758 participants were analyzed. Acetazolamide increased successful decongestion compared with placebo (42.2% vs 30.5%; risk ratios 1.46, 95% confidence interval: 1.17-1.82, study-level estimate). Thiazide augmentation produced greater weight loss at 72 hours (2.3 vs 1.5 kg) but increased renal dysfunction (46.5% vs 17.2%, study-level data). Sodium-glucose cotransporter 2 (SGLT2) inhibitors increased urine output and natriuresis and reduced worsening heart failure events in selected studies (10% vs 33%, based on individual trial findings). High-dose spironolactone, low-dose dopamine, and low-dose nesiritide showed no meaningful clinical benefit. Thiazide and thiazide-like diuretics were appropriately classified as distal convoluted tubule agents, whereas acetazolamide and SGLT2 inhibitors act primarily at the proximal nephron.
CONCLUSION
Adjunctive therapies targeting proximal sodium handling (acetazolamide, SGLT2 inhibitors) or distal sodium reabsorption (thiazide diuretics) improve decongestion and may serve as effective options when loop diuretics alone are insufficient. These findings reflect study-level evidence from individual randomized trials and support a mechanistically guided approach to treating diuretic resistance in ADHF.
Core Tip: Diuretic resistance remains a major obstacle to effective decongestion in acute decompensated heart failure (HF). This systematic review synthesizes randomized controlled trial evidence evaluating adjunctive pharmacologic therapies added to loop diuretics. Therapies targeting proximal tubular sodium handling, particularly acetazolamide, consistently improve decongestion and natriuresis without excess renal risk. Thiazide diuretics, which act at the distal convoluted tubule, enhance diuretic response but increase the risk of renal dysfunction and therefore require cautious use. Sodium-glucose cotransporter 2 inhibitors offer modest diuretic effects, reduce worsening HF events, and provide benefits that are not limited by baseline kidney function. In contrast, older adjuncts such as dopamine, nesiritide, and high-dose spironolactone show no clinical benefit in overcoming acute diuretic resistance.
