Ischaemic stroke and 5‐fluorouracil or capecitabine: A systematic review and meta‐analysis of harms and a retrospective study of the WHO pharmacovigilance database

Aim Fluoropyrimidines, including 5‐fluorouracil (5‐FU) and capecitabine, are cornerstone antineoplastic agents for cancer. Case reports suggest that these drugs may be associated with an under‐recognised risk of ischaemic stroke or transient ischaemic attack (TIA). Methods A systematic search of MEDLINE, Cochrane Library and ClinicalTrial.gov was conducted, using terms related to 5‐FU/capecitabine and ischaemic stroke or TIA (PROSPERO registration number CRD42024576733). An additional bibliographic survey of eligible studies was carried out for adverse events (AEs). Randomised clinical trials (RCTs) were included if they reported at least one case of ischaemic stroke or TIA events in adult cancer patients treated with 5‐FU/capecitabine. Data extraction and quality assessment followed PRISMA guidelines. Pooled Peto's odds‐ratios (Peto OR) were calculated with random effects models. Results 13,115 patients from 23 RCTs were included, with 67 ischaemic strokes or TIAs reported. Treatment with 5‐FU/capecitabine was associated with a significantly increased risk of ischaemic stroke or TIA (Peto OR = 2.1; 95% CI [1.3–3.4]; P = 0.003; I 2 = 0%; χ 2 = 0.81). The association was similar for ischaemic stroke only (60 events; Peto OR = 2.2; 95% CI [1.3–3.4]; P = 0.001; I 2 = 0%; χ 2 = 0.83) and remained significant in RCTs using only 5‐FU (10 RCTs; various cancer sites; Peto OR = 3.1; 95% CI [1.2–7.8]; P = 0.017; I 2 = 0%; χ 2 = 0.83). Conclusion 5‐FU/capecitabine treatment was associated with an increased risk of ischaemic stroke or TIA. Clinicians should be aware of this rare, but serious, AE.