Abstract
OBJECTIVE: To examine whether long-term opioid use after total knee arthroplasty (TKA) is associated with subsequent risks of major adverse cardiovascular events (MACE) and all-cause mortality in patients with knee osteoarthritis (OA). METHODS: This retrospective, population-based cohort study used Taiwan’s Longitudinal Health Insurance Database (LHID) 2005 to identify patients with knee OA undergoing TKA (2002–2018). Opioid exposure was assessed during the 1-year post discharge window (long-term > 3 months vs. non-long-term < 3 months), and the index date was set at 360 days after discharge (landmark design). The primary outcome was first MACE after the index date. After 1:2 propensity score matching (PSM), adjusted hazard ratios (aHRs) were estimated using Cox models; Fine–Gray models were used for nonfatal components. RESULTS: In the matched cohort (2,351 long-term vs. 4,702 non-long-term users), long-term opioid use was associated with higher risks of MACE (aHR = 1.16; 95% CI, 1.06–1.26) and all-cause mortality (aHR = 1.16; 95% CI, 1.05–1.29), as well as AMI (aHR = 1.30; 95% CI, 1.03–1.64) and CHF (aHR = 1.15; 95% CI, 1.00–1.32), but not ischemic or hemorrhagic stroke. Effect modification by Charlson Comorbidity Index (CCI) was observed for MACE (P-interaction = 0.0278) and mortality (P-interaction = 0.0006), with the strongest associations in CCI ≥ 5. Time-stratified analyses for MACE showed the excess risk was greatest early after the index date and remained significant through 1–5 years, with attenuation thereafter. CONCLUSIONS: Long-term opioid use after TKA was associated with increased risks of MACE and mortality, particularly among patients with high comorbidity burden, underscoring the importance of opioid-sparing strategies and closer cardiovascular risk assessment in patients requiring prolonged opioid therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12871-026-03775-2.