Association of loop diuretics use and dose with outcomes in outpatients with heart failure: a systematic review and meta-analysis of observational studies involving 96,959 patients

There is ongoing controversy regarding the association between loop diuretics (LD), especially in high doses, and adverse clinical outcomes in outpatients with heart failure (HF). We performed a systematic review of the evidence for LD in outpatients with HF. We searched MEDLINE, EMBASE, and Cochrane Clinical Trial Collection to identify controlled studies, evaluating the association between LD and morbidity and mortality in patients with HF. The primary endpoint was all-cause mortality and secondary endpoint HF hospitalizations. Quantitative analysis was performed by generating forest plots and pooling adjusted risk estimates across studies using random effects models. Between-study heterogeneity was assessed through Q and I2 statistics. Twenty-four studies with a total of 96,959 patients were included. No randomized studies were identified. Use of LD was associated with increased all-cause mortality compared with non-use (pooled adjusted risk estimates, 1.18; P = 0.001) and increased HF hospitalization rates (pooled adjusted risk estimates, 1.81; P