Cardiology · Medical Literature
Effectiveness and safety of acetazolamide plus loop diuretics in acute congestive heart failure: A living systematic review - Version 2026 1.0.
Abstract
This living systematic review Version 1.0 aims to provide a timely, rigorous and continuously updated summary of the evidence on the use of acetazolamide plus loop diuretics in acute congestive heart failure compared to loop diuretics. We conducted a comprehensive search in CENTRAL, EMBASE, MEDLINE, and between database inception and September 2025. No language, publication date or status restrictions were applied. Two reviewers independently screened eligible studies, according to predefined selection criteria, and extracted data using a predesigned form. We performed meta-analyses using random-effects models and assessed overall certainty in evidence using the GRADE approach. The quality of the evidence was assessed using the Cochrane risk-of-bias tool. This review was registered in PROSPERO (CRD42024575267). Of 732 records identified, five randomized trials were included, with a total of 1050 participants. The evidence is very uncertain about the effect of adding acetazolamide to loop diuretics in decongestion observed at 72 hours (risk ratio: 1.17, 95% confidence interval: 0.96 to 1.44). Low certainty evidence shows adding acetazolamide to loop diuretics may increase natriuresis at 24 hours (mean difference 38.43, 95% confidence interval: 19.42 to 57.43). No significant differences were found between groups in accumulative diuresis at 48 hours, all-cause mortality, readmission due to heart failure or worsening renal function. Evidence suggests that it is necessary to promote further investigations regarding the use of acetazolamide plus loop diuretics in acute congestive heart failure. More robust, standardized, long-term studies are needed, and conclusions may change as new data emerge.
Clinical relevance
Decongestion failure in acute congestive heart failure (AHF) remains a critical unmet need, with residual congestion at discharge strongly associated with 30-day readmission and mortality. This living systematic review addresses whether adjunctive acetazolamide — a carbonic anhydrase inhibitor that blocks proximal tubular sodium reabsorption and may counteract loop diuretic resistance — meaningfully improves decongestion outcomes beyond loop diuretics alone. Given the rising prevalence of AHF hospitalizations and the clinical challenge of diuretic resistance, cardiologists and hospitalists need a current, GRADE-appraised synthesis of this emerging strategy.
Key findings
1. Decongestion at 72 hours (primary endpoint): Adding acetazolamide to loop diuretics showed no statistically significant improvement in decongestion (RR 1.17, 95% CI 0.96–1.44); certainty of evidence rated as VERY LOW by GRADE, meaning the true effect remains highly uncertain. 2. Natriuresis at 24 hours: Low-certainty evidence suggests acetazolamide plus loop diuretics may increase natriuresis (MD +38.43 mmol/24h, 95% CI 19.42–57.43), representing a potentially clinically meaningful augmentation of urinary sodium excretion. 3. Cumulative diuresis at 48 hours: No statistically significant difference was detected between the combination therapy and loop diuretics alone; specific effect size not reported in the abstract. 4. All-cause mortality: No significant between-group difference was identified across the five included randomized trials (N = 1,050); precise RR/OR and CIs not reported in the abstract. 5. Readmission due to heart failure: No statistically significant difference was found between groups; quantitative data not extractable from the abstract. 6. Worsening renal function: No significant difference between acetazolamide plus loop diuretics versus loop diuretics alone; this is clinically relevant given theoretical concerns about carbonic anhydrase inhibition and renal tubular acidosis in cardiorenal syndrome. Note: NNT/NNH values were not reported in the abstract and are therefore not included.
Practice implications
Based on current very low-to-low certainty evidence pooled from five RCTs (N = 1,050), routine addition of acetazolamide to loop diuretics in AHF cannot be recommended as standard of care, as no significant benefit was demonstrated for decongestion at 72 hours, cumulative diuresis, mortality, or HF readmission. The signal toward increased 24-hour natriuresis (MD +38.43 mmol) may identify a physiologically plausible role for acetazolamide in patients with documented proximal tubular compensation or loop diuretic resistance, warranting individualized consideration in this subgroup pending higher-quality evidence. Clinicians should await results from forthcoming adequately powered, standardized trials before incorporating acetazolamide into institutional AHF protocols, and this living review (PROSPERO CRD42024575267, updated through September 2025) should be re-consulted as new data emerge.