Abstract Aims Ibrutinib increases cardiovascular adverse events, but the comparative cardiovascular safety of second-generation Bruton’s tyrosine kinase inhibitors (BTKi) remains uncertain. We compared cardiovascular adverse events among ibrutinib, acalabrutinib, zanubrutinib, and non-BTKi therapies. Methods and Results We conducted a systematic review and frequentist network meta-analysis of Phase II/III randomised trials of BTKi in adults with haematological malignancies. Outcomes included atrial fibrillation (AF), hypertension, bleeding, heart failure (HF), acute coronary syndrome, stroke, ventricular arrhythmias, and sudden death. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using non-BTKi therapy as the reference group where possible. Evidence certainty was assessed using GRADE. Twenty-five trials including 12,194 patients were analysed. Compared with non-BTKi therapy, the odds of AF were increased with ibrutinib (OR 4.48, 95% CI 3.48–5.75), acalabrutinib (OR 2.23, 95% CI 1.50–3.32), and zanubrutinib (OR 1.66, 95% CI 1.08–2.56). Bleeding odds were also increased with ibrutinib (OR 3.54, 95% CI 2.45–5.13), acalabrutinib (OR 3.95, 95% CI 2.32–6.73), and zanubrutinib (OR 3.75, 95% CI 2.01–7.00). Hypertension odds were increased with ibrutinib and zanubrutinib, but not acalabrutinib. Only ibrutinib was associated with significantly higher odds of HF and sudden death. No BTKi was associated with significantly higher odds of acute coronary syndrome, stroke, or ventricular arrhythmias than non-BTKi regimens. Conclusion Second-generation BTKi were associated with lower risk of AF than ibrutinib, whereas bleeding risk was increased comparably across all BTKi agents. Findings should be interpreted cautiously because several outcomes were rare and imprecisely estimated. (PROSPERO ID#: CRD42023436930).
