Background: Right-sided infective endocarditis is classically linked to intravenous drug use (IVDU), yet contemporary reports suggest substantial left-sided and multivalvular disease. The true burden across valves and its clinical implications have not been quantified in a comprehensive synthesis. Hypothesis: We hypothesize that left-sided valve involvement represents a significant and underrecognized proportion of IVDU-associated infective endocarditis and is associated with higher rates of surgery and death compared with isolated right-sided disease. Methods: Following PRISMA 2020 and a PROSPERO-registered protocol (CRD420251010004), we searched PubMed, Embase, Scopus, and Web of Science (January 2021–December 2025) for studies enrolling adults (≥18 years) with echocardiography-confirmed IVDU-associated infective endocarditis. Random-effects meta-analysis (DerSimonian–Laird) estimated pooled prevalence and relative risk (RR) with 95% confidence intervals (CIs). Heterogeneity was assessed with I 2 , risk of bias with ROBINS-E, and small-study effects with funnel plots and sensitivity analyses. When reported, side-specific prevalences allowed both-sided cases to contribute to each side. Results: Fourteen studies (n=1,783 patients) met eligibility criteria. Pooled prevalence was 61% (95% confidence interval (CI)=57–65) for right-sided involvement, 41% (95% CI=35–47) for left-sided involvement, and 7% (95% CI=5–10) for both-sided disease. Valve-level involvement was tricuspid 61%, mitral 23%, aortic 17%, and pulmonic 1%. Compared with left-sided disease, right-sided involvement was more frequent (relative risk (risk ratio)=1.49; 95% CI=1.15–1.95; p=0.008). Staphylococcus aureus was the leading pathogen (73%), including methicillin-resistant strains in 17%. Valve surgery occurred in 21% and all-cause mortality in 17%. Findings were robust in leave-one-out and subgroup analyses with minimal evidence of publication bias. Conclusions: Left-sided valve involvement occurs in approximately two in five cases of IVDU-associated infective endocarditis, which is far higher than traditionally appreciated, and frequently affects the mitral and aortic valves. These data challenge the assumption of predominantly right-sided disease and support routine transesophageal echocardiography, early surgical evaluation, and integrated addiction care to improve outcomes in this high-risk population.
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