{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T03:43:30Z","timestamp":1786160610436,"version":"build-2736575974"},"reference-count":54,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T00:00:00Z","timestamp":1786147200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>Bruton\u2019s 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).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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\u2013Haenszel method, with between-study heterogeneity estimated using the DerSimonian\u2013Laird estimator, to derive pooled risk ratios with their 95% confidence intervals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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\u20132.53, P = .02), with substantial heterogeneity (I2 = 70%).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Registration<\/jats:title>\n                    <jats:p>PROSPERO, International Prospective Register of Systematic Reviews; registration number: CRD420251241020.<\/jats:p>\n                  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