Pharmacological treatments in adults with chronic heart failure: a systematic review and component network meta-analysis

Background Pharmacological treatments for patients with heart failure include monotherapies and combination therapies of classic and novel drugs. A systematic evaluation of the efficacy and safety for existing therapies is needed to inform clinical decision-making. Purpose The systematic review and component network meta-analysis (CNMA) examined comparative effects of single or combined use of pharmacological treatments for heart failure. Methods We searched Medline, Embase, and Cochrane Library from inception to 12 November 2024 for randomised controlled trials investigating one or combination of beta-blockers (BBs), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (analysed together as renin-angiotensin system inhibitors [RASi]), angiotensin receptor-neprilysin inhibitors (ARNI), mineralocorticoid receptor antagonists (MRAs), sodium-glucose cotransporter-2 inhibitors (SGLT2i), and glucagon-like peptide 1 receptor agonists (GLP-1RAs) in adults with chronic heart failure. Outcomes included mortality, hospitalisation for heart failure, stroke, myocardial infarction, kidney failure, health-related quality of life (HRQoL), and safety outcomes. A frequentist random-effects CNMA was conducted to estimate the effects of individual components and their combinations. Results 82 studies with 113,722 participants and a median follow-up of 12 months were included. Compared with placebo, BBs (RR: 0.79 [95% CI: 0.72 to 0.85]), MRAs (0.85 [0.77 to 0.95]), and RASi (0.92 [0.87 to 0.99]) reduced all-cause mortality; BBs (0.73 [0.66 to 0.81]), ARNI (0.77 [0.66 to 0.91]), MRAs (0.83 [0.74 to 0.93]), SGLT2i (0.88 [0.79 to 0.99]), and RASi (0.89 [0.83 to 0.96]) reduced cardiovascular mortality; BBs reduced myocardial infarction (0.70 [0.55 to 0.90]); no drugs had significant effects on stroke; all drugs except for GLP-1RAs reduced hospitalisation for heart failure (21% to 31% lower risk); SGLT2i improved kidney failure (0.68 [0.49 to 0.96]) and HRQoL (SMD: 0.18 [95% CI: 0.09 to 0.28]). The quadruple combination of BBs, MRAs, ARNI, and SGLT2i was the most effective to improve cardiovascular mortality (0.41 [0.32 to 0.53]) and hospitalisation for heart failure (0.26 [0.19 to 0.35]), followed by combined BBs, MRAs, RASi, and SGLT2i. The incremental effects of adding GLP-1RAs were uncertain. The risk of adverse events increased with more drugs but appeared to be little or no effect in the absolute term. No credible subgroup effects were identified across age, left ventricular ejection fraction, estimated glomerular filtration rate, and ischemic heart disease status. Conclusion The quadruple combination of BBs, MRAs, ARNI, and SGLT2i provided the largest benefits for people with heart failure. The individualised therapeutic decision should be made by weighing incremental absolute benefits and harms, with the consideration of patients’ preference and value. Further investigation is warranted to validate the findings in real-word setting.