Combinations of diuretics for acute heart failure: a systematic review with network meta-analysis and trial sequential analysis

Background Acute heart failure (AHF) is a severe clinical syndrome associated with high morbidity and mortality. Effective management of congestion is a primary treatment goal and often requires hospitalisation. While loop-diuretics remain the cornerstone of AHF therapy, the optimal combination of diuretics to an effective decongestion remains uncertain. This systematic review aims to evaluate the efficacy and safety of various diuretic combinations compared with usual care in AHF patients. Methods The search was conducted across the databases: Medline, Embase, Latin American and Caribbean Health Sciences Literature, Web of Science, Scopus and The Cochrane Central Register of Controlled Trials. Network meta-analysis was used to compare the relative efficacy of different diuretic combinations. Trial sequential analysis (TSA) was conducted to evaluate the sufficiency of cumulative evidence for definitive conclusions. Risk of bias was assessed using the Cochrane Risk of Bias tool for randomised trials V.2. Statistical heterogeneity was evaluated via visual inspection of forest plots through the I² statistic. The primary outcome was all-cause mortality, and secondary outcomes included serious adverse events (SAEs), hospital readmissions and kidney failure. Exploratory outcomes included changes in body weight and urinary output. Results 35 randomised clinical trials involving 11 743 patients were included. In pairwise meta-analyses, none of the diuretics demonstrated an influence on all-cause mortality, SAEs, hospital readmissions or kidney failure. Likewise, TSA showed no influence of combination therapy on mortality. Aggregate data meta-analyses revealed that combinations involving acetazolamide (−2.60 kg; 95% CI −4.23 to −0.97; p<0.001; I 2 = 0.00%), thiazides (−0.80 kg; 95% CI −1.40 to −0.21; p=0.01; I 2 = 38.53%) and vaptans (−1.00 kg; 95% CI −1.53 to −0.48; p < 0.001; I 2 = 89.53%) caused significant in-hospital body weight reduction, indicating enhanced decongestion. Network meta-analysis showed similar results, and TSA indicated that there was enough information to accept secondary diuretics influencing decongestion. Conclusions Combination diuretic therapy improves short-term decongestion but does not reduce all-cause mortality, SAEs, hospital readmissions or kidney failure in patients with AHF.