Background <p>Randomized controlled trials (RCTs) have identified the additive effects of angiotensin receptor–neprilysin inhibitors (ARNIs) and sodium–glucose cotransporter 2 (SGLT2) inhibitors on neurohormonal inhibition therapy in patients with heart failure with reduced ejection fraction (HFrEF). However, their additive effects on conventional baseline therapies in patients with severe HFrEF remain unclear.</p> Methods <p>A systematic review was conducted using the PubMed, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases until February 2025. Our review included RCTs that evaluated the effects of ARNIs or SGLT2 inhibitors in patients with severe HFrEF. The primary outcome was the composite endpoint of cardiovascular death or hospitalization for heart failure. The pooled hazard ratio (HR) was estimated through a network meta-analysis conducted using a frequentist statistical approach.</p> Results <p>Five relevant trials, or their New York Heart Association class III–IV subgroups, were identified, comprising a total of 4894 patients with severe HFrEF. For the addition of SGLT2 inhibitors to neurohormonal inhibitors, the HR was 0.87 (95% confidence interval 0.75–1.01). For the addition of ARNIs, the HR was 0.96 (95% confidence interval 0.83–1.12). The certainty of evidence was moderate for SGLT2 inhibitors and low for ARNIs according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach.</p> Conclusions <p>Evidence for the additive effects of SGLT2 inhibitors and ARNIs in severe HFrEF remains limited, and therefore, treatment intensification with these agents should be approached with caution.</p> Registration <p>International Prospective Register of Systematic Reviews (PROSPERO) identifier no. CRD42025641240.</p> Graphical Abstract <p></p>