Combination of diuretics to overcome diuretic resistance in acute heart failure: systematic review and updated network meta-analysis

Abstract Background Diuretic resistance in acute heart failure (AHF) presents a significant therapeutic challenge. While randomized clinical trials (RCTs) have compared various diuretics against furosemide, direct comparisons among these therapies are lacking. This network meta-analysis aims to fill this knowledge gap. Purpose To evaluate the efficacy and safety of various diuretic combination therapies in overcoming diuretic resistance in acute heart failure patients. Methods We conducted a systematic review and network meta-analysis of RCTs from January 2000 to December 2023. These RCTs included hospitalized AHF patients with evidence of diuretic resistance. We applied a frequentist random effects model to perform a network meta-analysis combining a total of 11 diuretic strategies compared with low-dose furosemide (reference group). Primary outcomes were urine output and weight loss at 72 hours. Secondary outcomes included cardiovascular mortality and heart failure hospitalization. The safety endpoint was the incidence of acute kidney injury across different diuretic strategies. Results Empagliflozin and high-dose furosemide showed the highest increase in urine output (SMDs: 363.94, P-score=0.64; and 306.31, P-score=0.68). For weight loss, hydrochlorothiazide led to the greatest losses (SMD: 1.33; P-score=0.20), followed by tolvaptan + furosemide low-dose (SMD: 0.85; P-score=0.43). Dapagliflozin ranked best for reducing heart failure hospitalizations (OR 0.15; P-score=0.94), and empagliflozin had the highest rank for mortality reduction (OR 0.31; P-score=0.91) but without statistical significance for mortality. Empagliflozin also showed a better safety profile (OR: 0.74; 95% CI: 0.32 to 1.71 P-score=0.87), (Figure 1 and 2). Conclusion Our findings indicate that SGLT2 inhibitors are a promising therapeutic avenue to mitigate the challenges of diuretic resistance in AHF, demonstrating potential benefits in enhancing urine output, reducing hospitalization rates, and maintaining favourable safety profile.Network and forest plots for U.O/ weightNetwork and forest plots for HHF/ AKI