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Background: Disparities in treatment and outcomes of infective endocarditis (IE) between people who use drugs (PWUD) and non-PWUD have been reported, but long-term data on cardiovascular and cerebrovascular outcomes are limited. We aim to compare 5-year rates of mortality, cardiovascular and cerebrovascular events after IE between PWUD and non-PWUD. Methods: Using data from the TriNetX Research Network, we examined 5-year cumulative incidence of mortality, myocardial infarction, heart failure, atrial fibrillation/flutter, ventricular tachyarrhythmias, ischemic stroke, and intracranial hemorrhage in 7132 PWUD and 7132 propensity score-matched non-PWUD patients after a first episode of IE. We used the Kaplan–Meier estimate for incidence and Cox proportional hazards models to estimate relative risk. Results: Matched PWUD were 41 ± 12 years old; 52.2% men; 70.4% White, 19.8% Black, and 8.0% Hispanic. PWUD had higher mortality vs. non-PWUD after 1 year (1–3 year: 9.2% vs. 7.5%, p = 0.032; and 3–5-year: 7.3% vs. 5.1%, p = 0.020), which was largely driven by higher mortality among female patients. PWUD also had higher rates of myocardial infarction (10.0% vs. 7.0%, p < 0.001), heart failure (19.3% vs. 15.2%, p = 0.002), ischemic stroke (8.3% vs. 6.3%, p = 0.001), and intracranial hemorrhage (4.1% vs. 2.8%, p = 0.009) compared to non-PWUD. Among surgically treated PWUD, interventions on the tricuspid valve were more common; however, rates of all outcomes were comparable to non-PWUD. Conclusions: PWUD had higher 5-year incidence of cardiovascular and cerebrovascular events after IE compared to non-PWUD patients. Prospective investigation into the causes of these disparities and potential harm reduction efforts are needed.

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