Efficacy and Safety of Combination Pharmacotherapies With Standard Diuretic Therapy in Acute Heart Failure: A Systematic Review and Meta-Analysis

Many patients hospitalized with acute heart failure (AHF) do not respond adequately to initial intravenous loop diuretic therapy, and residual congestion at discharge is associated with adverse outcomes. We conducted a systematic review and meta-analysis of randomized controlled trials comparing loop diuretics alone versus loop diuretics in combination with add-on pharmacotherapy in adults hospitalized with AHF. PubMed, Embase, and CENTRAL were searched from inception to May 7, 2025. Efficacy outcomes included mortality, hospital readmission, hospital length of stay (LOS), change in body weight, and urine output (UO). Safety outcomes included worsening renal function, worsening heart failure (WHF), hypokalemia, and serious adverse events. Twenty-four randomized studies were identified, with 22 included in the meta-analysis. Sodium-glucose cotransporter 2 (SGLT2) inhibitors significantly reduced mortality [risk ratio (RR), 0.60 (95% confidence interval [CI], 0.38-0.94)], WHF [RR, 0.64 (95% CI, 0.43-0.96)], serious adverse events [RR, 0.74 (95% CI, 0.60-0.92)], and body weight [mean difference (MD), -1.05 (95% CI, -1.97 to -0.13) kg]. Tolvaptan was associated with greater weight reduction [MD, -0.98 (95% CI, -1.25 to -0.70) kg] and increased UO [MD, 1.15 (95% CI, 0.16-2.14) L]. Add-on hydrochlorothiazide (HCTZ) increased UO [MD, 0.95 (95% CI, 0.47-1.43) L] and decreased LOS [MD, -1.38 (95% CI, -2.40 to -0.36) days] but increased the risk of worsening renal function [RR, 2.03 (95% CI, 1.10-3.74)] and hypokalemia [RR, 2.31 (95% CI, 1.51-3.52)]. Overall, the combination with SGLT2 inhibitors, tolvaptan, and HCTZ improved surrogate markers of decongestion in AHF. SGLT2 inhibitors were associated with reduced mortality and WHF, whereas HCTZ shortened hospital LOS but increased the risk of renal dysfunction and hypokalemia.