Background The presumed safety of paracetamol in high cardiovascular risk patients has been questioned. We sought to determine whether paracetamol or ibuprofen use is associated with major cardiovascular events or major bleeding in patients with recent ischaemic stroke or transient ischaemic attack (TIA) of mainly atherothrombotic origin.
Methods Using the PERFORM trial database, involving 19,120 patients with recent ischaemic stroke or TIA, we performed two nested case-control analysis (one with 2153 cases who had a major cardiovascular event during trial follow-up and 4306 controls matched on ESSEN score; a second with 809 cases with a major bleeding matched with 1616 controls). A separate time-varying analysis was performed.
Findings Of the 6459 cases and controls with or without major cardiovascular event, 11·2% were prescribed paracetamol and 2·5% ibuprofen. Median duration of treatment was 14 (IQR 5–145) days for paracetamol and 9 (5–30) days for ibuprofen. Paracetamol was associated with increased risk of a major cardiovascular event (odds ratio [OR] 1·21, 95% confidence interval [CI] 1·04–1·42) or a major bleeding (OR 1·60, 95% CI 1·26–2·03), with no impact of daily dose and duration of paracetamol treatment. There was no increased risk of major cardiovascular events (OR 1·03, 95% CI 0·73–1·34) or major bleeding with ibuprofen and no significant association with duration or dose. Time-varying analysis found an increased risk of major cardiovascular events with both paracetamol (OR 1·22, 95% CI1·05–1·43) and ibuprofen (OR 1·47, 95% CI 1·06–2·03) and of major bleeding with paracetamol (OR 1·95, 95% CI 1·45–2·62).
Interpretation There was a weak and inconsistent signal for association between paracetamol or ibuprofen and major cardiovascular events or major bleeding, which may be related to either a genuine but modest effect of these drugs, or to residual confounding. Given the uncertainty and the widespread use of paracetamol and ibuprofen, their safety among patients with stroke/TIA should be investigated in randomised studies.