Bruton's tyrosine kinase inhibitors and cardiovascular risk: a meta-analysis.

BACKGROUND AND AIMS: Bruton's tyrosine kinase inhibitors (BTK-I) affect platelet function, increasing bleeding risk, and are also associated with hypertension and atrial fibrillation. This study aimed to assess the risk of incident non-fatal ischaemic major adverse cardiovascular events (MACE) associated with BTK-I exposure through a systematic review and meta-analysis of randomized controlled trials (RCTs). METHODS: ClinicalTrials.gov, EudraCT, MEDLINE, and Cochrane CENTRAL were systematically searched to identify Phase 3 RCTs of BTK-I (ibrutinib, acalabrutinib, zanubrutinib) reporting non-fatal ischaemic MACE up to 19 December 2024. The primary outcome was the summary risk of incident non-fatal ischaemic MACE (defined as a partial MACE composite of myocardial ischaemic syndromes and ischaemic stroke/transient ischaemic attack) associated with BTK-I exposure vs controls in adults with B-cell malignancies. A random-effects meta-analysis for binary outcomes was performed using the Mantel-Haenszel method, with between-study heterogeneity estimated using the DerSimonian-Laird estimator, to derive pooled risk ratios with their 95% confidence intervals. RESULTS: Seventeen Phase 3 RCTs including 6799 patients were analysed (55.5% BTK-I arms). Most patients received ibrutinib (77.2%), followed by acalabrutinib (13.5%) and zanubrutinib (9.3%). BTK-I exposure was associated with an increased risk of non-fatal ischaemic MACE (risk ratio 1.66, 95% confidence interval 1.09-2.53, P = .02), with substantial heterogeneity (I2 = 70%). CONCLUSIONS: Based on adverse-event reporting from Phase 3 RCTs that does not permit adjustment for competing risks, BTK-I exposure is associated with an increased risk of non-fatal ischaemic MACE. REGISTRATION: PROSPERO, International Prospective Register of Systematic Reviews; registration number: CRD420251241020.