Heart failure remains a significant clinical challenge due to the difficulty in managing refractory fluid overload. Combination diuretic strategies, involving various combinations, such as metolazone and furosemide, have been proposed to improve diuresis and patient outcomes. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of combination therapies. A comprehensive search of PubMed, Cochrane Library, Embase, and Web of Science identified 61 articles, of which seven randomised controlled trials met the inclusion criteria. Data on mortality, hospital readmission rates, symptom improvement, electrolyte imbalances, renal function, and adverse events were extracted and analysed. The risk of bias was assessed using the established guidelines. The analysis revealed that combination diuretic therapies significantly reduced body weight (P=0.001) but did not significantly impact mortality (RR: 0.99, 95% CI: 0.90-1.09) or hospital readmission rates (RR: 1.05, 95% CI: 0.98-1.12) compared to placebo. Adverse effects, particularly electrolyte imbalances, such as hypo and hypernatraemia and hypokalaemia, and renal function deterioration were noted in the combined diuretic group. In contrast, serious adverse events were observed more in the placebo group. The mean difference of the Kansas City Cardiomyopathy Questionnaire (KCCQ) score was 2.43 (95% CI: 0.95-3.92). The risk ratio for hospital readmission was 1.05 (95% CI: 0.98-1.12), which was statistically non-significant. We used fixed-effect models for most variables due to less heterogeneity between the studies, and the corresponding I2 values were <50% for most variables. Funnel plots indicated minimal publication bias, although some heterogeneity was observed. Comparisons with other studies in the literature, such as the DAPA-HF and EVEREST trials, supported these findings but also highlighted the need for individualised treatment approaches. Combination diuretic therapies effectively manage fluid overload and reduce body weight in patients with heart failure but do not significantly affect mortality or hospital readmission rates. The potential for adverse events, particularly electrolyte imbalances and renal function deterioration, underscores the need for careful monitoring and personalised treatment plans. Future research should focus on optimising diuretic combinations and dosing strategies to enhance their safety and efficacy. These findings align with the current guidelines emphasising individualised treatment in heart failure management and highlight the importance of integrating combination diuretics into a comprehensive care plan to improve patient outcomes.
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