Background <p>Heart failure, particularly heart failure with reduced ejection fraction (HFrEF), represents a major global health challenge due to its high prevalence, rapid progression, and substantial mortality rates. While the “New Tetralogy” drugs (angiotensin receptor-neprilysin inhibitors, sodium-glucose cotransporter 2 inhibitors, beta-blockers, and mineralocorticoid receptor antagonists) have significantly advanced HFrEF management, their comparative effects on ventricular remodeling remain unclear. This network meta-analysis systematically evaluates these therapeutic agents to inform optimal clinical decision-making.</p> Methods <p>We conducted a comprehensive search of PubMed, Cochrane Library, Embase, and Web of Science for randomized controlled trials (RCTs) evaluating ventricular remodeling parameters in HFrEF patients. Twenty-two RCTs involving 16,425 participants were included. Data were analyzed using Stata 14.2 and RevMan 5.3, with outcomes expressed as mean differences (MD) and 95% confidence intervals (CI).</p> Results <p>Our study showed markedly different therapeutic characteristics: sodium-glucose cotransporter 2 inhibitors significantly reduced left ventricular mass index (MD = -6.57, 95% CI: -11.98 to -1.16), while beta-blockers demonstrated superior improvement in left ventricular ejection fraction compared to mineralocorticoid receptor antagonists (MD = 3.54, 95% CI: 0.60 to 6.48) through indirect comparison. Mineralocorticoid receptor antagonists showed greater efficacy in reducing left ventricular end-systolic volume (MD = -22.10, 95% CI: -31.42 to -12.78). Angiotensin receptor-neprilysin inhibitors outperformed renin-angiotensin system inhibitors across multiple parameters, including left ventricular end-systolic volume (MD = -7.00, 95% CI: -13.91 to -0.09), end-systolic volume index (MD = -13.78, 95% CI: -25.98 to -1.58), and end-diastolic volume index (MD = -5.80, 95% CI: -9.76 to -1.84).</p> Conclusions <p>This network meta-analysis demonstrates that each component of the “New Tetralogy” applies unique beneficial effects on ventricular remodeling. Angiotensin receptor-neprilysin inhibitors, sodium-glucose cotransporter 2 inhibitors, and mineralocorticoid receptor antagonists predominantly improve ventricular volumes, while beta-blockers significantly enhance systolic function. These findings provide evidence-based guidance for personalized therapeutic strategies in HFrEF management, particularly for patients with persistent left ventricular systolic dysfunction.</p> Clinical trial number <p>Not applicable.</p> Registration number <p>CRD42023454737.</p>