Cardiovascular safety of next-generation BTK inhibitors versus ibrutinib in CLL/SLL: a systematic review and meta-analysis of randomised controlled trials

Background Bruton tyrosine kinase inhibitors are effective for chronic lymphocytic leukaemia/small lymphocytic lymphoma, but ibrutinib has been consistently associated with cardiovascular toxicity, particularly atrial fibrillation/flutter (AF/AFl) and hypertension. Whether next-generation, more selective BTK inhibitors reduce these cardiovascular events versus ibrutinib remains unclear. Purpose To compare cardiovascular safety outcomes of next-generation BTK inhibitors versus ibrutinib in adults with CLL/SLL in randomised controlled trials (RCTs). Methods PubMed, Embase, and CENTRAL were searched from inception to 21 January 2026 for RCTs comparing next-generation BTK inhibitors with ibrutinib in CLL/SLL. The primary endpoint was treatment-emergent AF/AFl (any grade). Secondary endpoints were AF/AFl grade ≥3, hypertension (any grade and grade ≥3), and adverse events leading to treatment discontinuation. Risk ratios (RR) were pooled using a random-effects model; heterogeneity was assessed with I². Results We included 1,832 patients from three RCTs; 920 (50.2%) received next-generation BTK inhibitors (pirtobrutinib, zanubrutinib and acalabrutinib). Across trials, median follow-up ranged from 21.8 to 40.9 months, median age was 66-67 years and 68.8% were male. The primary endpoint treatment-emergent AF/AFl occurred in 50/920 (5.4%) with next-generation BTKi versus 129/912 (14.1%) with ibrutinib (RR 0.37, 95% CI 0.20–0.68; p=0.002; I²=72%) (Fig. 1). AF/AFl grade ≥3 was numerically lower but not statistically significant (RR 0.62; 95% CI 0.25-1.54; p=0.31; I²=63%) (Fig. 2A). Hypertension of any grade (RR 0.68; 95% CI 0.40-1.16; p=0.15; I²=84%) (Fig. 2B) and grade ≥3 (RR 0.74; 95% CI 0.42-1.32; p=0.31; I²=63%) (Fig. 2C) were numerically lower without statistical significance. Discontinuation due to adverse events was significantly reduced with next-generation BTKi (RR 0.73, 95% CI 0.59–0.90; p=0.004; I²=0) (Fig. 2D). Conclusion In randomised trials in CLL/SLL, next-generation BTK inhibitors were associated with substantially fewer treatment-emergent AF/AFl events and fewer discontinuations versus ibrutinib. Given between-trial heterogeneity, drug-specific and population-specific effects should be considered; nonetheless, these data support consideration of more selective BTK inhibitors when cardiovascular safety is a key factor in treatment selection.Figure 1.Forest Plot of Primary EndpointFigure 2.