Efficacy And Safety Of Combination Diuretic Therapy In Patients With Heart Failure: A Systematic Review And Meta-Analysis

Background: Persistent fluid overload is one of the hardest problems in heart failure (HF) care. Giving two or more diuretic classes together, for example metolazone with furosemide, has been suggested as a way to boost fluid removal and improve outcomes. Objective: To judge the benefits and risks of combination diuretic strategies in patients with HF. Methods: PubMed, the Cochrane Library, Embase and Web of Science were searched, yielding 61 records. Seven randomised controlled trials (RCTs) satisfied the eligibility criteria. Information on mortality, rehospitalisation, symptoms, electrolyte disturbance, kidney function and adverse events was extracted. Risk of bias was appraised with standard tools, and pooled estimates were produced with RevMan 5.4.0 using fixed- or random-effects models according to heterogeneity. Results: Combination therapy produced a statistically significant fall in body weight (P = 0.001) but no meaningful difference in mortality (risk ratio [RR] 0.99; 95% CI 0.90–1.09) or rehospitalisation (RR 1.05; 95% CI 0.98–1.12) relative to control. Electrolyte disturbances (low or high sodium, low potassium) and worsening kidney function were reported in the combination arms of several trials, whereas serious adverse events were reported more often in control arms. The pooled difference in Kansas City Cardiomyopathy Questionnaire (KCCQ) score was 2.43 points (95% CI 0.95–3.92). Heterogeneity was low for most outcomes (I² below 50%), and funnel plots suggested limited publication bias. Conclusions: Combination diuretics reduce fluid burden and weight but do not change mortality or readmission. Because they can disturb electrolytes and kidney function, close monitoring and individualised prescribing are essential. Future work should refine which combinations and doses are best