Abstract
BACKGROUND: Diuretic resistance complicates decongestion in heart failure (HF). Multiple add-on strategies are used, yet comparative efficacy and safety remain uncertain. OBJECTIVES: The objective of the study was to compare pharmacologic strategies for diuretic resistance in HF using a random-effects network meta-analysis of randomized controlled trials (RCTs). METHODS: We searched PubMed/Embase (January 2000-June 2024) for adult HF RCTs with diuretic resistance. Primary outcomes were 72-h urine output and standardized 72-h weight; secondary outcomes were heart-failure hospitalization and cardiovascular mortality; safety was acute kidney injury (AKI). A random-effects network meta-analysis pooled mean differences (MDs) for urine, standardized MDs (SMDs) for weight, and ORs for binary outcomes. Mortality was also assessed by follow-up-adjusted meta-regression of incidence rate ratios. RESULTS: Nineteen RCTs (n = 9,685) were included. Compared with low-dose loop diuretics, 72-hour urine output increased with tolvaptan (MD: 1,840 mL; 95% CI: 441-3,240) and low-dose loop plus tolvaptan (MD: 1,643 mL; 95% CI: 53-3,234). For 72-hour weight change, hydrochlorothiazide (SMD: 1.33; 95% CI: 0.49-2.18) and tolvaptan (SMD: 0.69; 95% CI: 0.09-1.29) produced the greatest standardized reductions. Dapagliflozin (OR: 0.15; 95% CI: 0.03-0.73) and empagliflozin (OR: 0.19; 95% CI: 0.04-0.94) reduced heart failure hospitalizations. Follow-up-adjusted mortality, expressed as incidence rate ratios, was neutral to favorable but imprecise and consistent in ≤60-day sensitivity analyses. High-dose loop diuretics (OR: 2.27; 95% CI: 1.20-4.30) and hydrochlorothiazide (OR: 4.14; 95% CI: 2.03-8.42) were associated with increased acute kidney injury. CONCLUSIONS: In HF with diuretic resistance, sodium-glucose cotransporter 2 inhibitors may lower rehospitalization with a favorable renal profile, whereas nephron-segment add-ons enhance short-term decongestion but warrant AKI/electrolyte monitoring; rankings are exploratory, and choices should emphasize absolute effects and 95% CIs.