GDMT Intensity at Hospital Discharge and Associated Clinical Outcomes in Heart Failure: A Systematic Review and Network Meta-Analysis

Background/Objectives: Contemporary heart failure (HF) guidelines recommend early initiation of four foundational drug classes in HFrEF. However, real-world prescription rates of guideline-directed medical therapy (GDMT) at discharge remain low, and comparative data in this setting is limited. We aimed to explore the association between GDMT intensity prescribed at or before hospital discharge and clinical outcomes. Methods: MEDLINE and EMBASE were searched through March 2026 (PROSPERO CRD420261352137). A frequentist random-effects network meta-analysis grouped regimens into four intensity nodes (single/none, double, triple, quadruple), with the primary analysis restricted to adjusted hazard ratios. The primary outcome was the composite of all-cause mortality (ACM) and HF hospitalization (HFH). Secondary outcomes were HFH alone, ACM, and cardiovascular mortality. Confidence was rated with CINeMA. Estimates are reported as associations, not treatment effects. Results: Twenty-seven studies (26 observational, 1 RCT; 73,174 patients) were included. Among SGLT2i-era cohorts, quadruple therapy was suboptimally prescribed (pooled 34%, range 11.6–55.2%). For the primary composite endpoint, more complete regimens were associated with progressively lower event rates versus single or no therapy (double: hazard ratio 0.76, 95% CI 0.68–0.84; triple: 0.72, 0.64–0.81; quadruple: 0.52, 0.36–0.75; τ2 = 0). A consistent ordinal gradient was seen across outcomes, with quadruple therapy ranking first numerically for every outcome in which it was estimable. The direction and ordering were preserved in a sensitivity analysis additionally incorporating risk ratios, on stratification by follow-up duration, and in an alternative network anchored to incomplete therapy. Because most evidence was observational, the magnitude of these associations should not be interpreted as a causal treatment effect and likely reflects residual confounding and selection bias. Conclusions: Discharge GDMT remains an important opportunity to improve outcomes in patients with HF. Adequately powered randomized trials are required to establish the incremental benefit of this approach and to close the gap between evidence and practice.