Incidence of cardiac events associated with next-generation bruton tyrosine kinase (BTK) inhibitors compared to control in hematologic malignancies: A meta-analysis of randomized trials

Abstract

Abstract Background: Bruton tyrosine kinase inhibitors (BTKi) have revolutionized the treatment of B-cell malignancies by offering highly targeted therapy as they bind and inhibit Bruton tyrosine kinase (BTK) leading to improved outcomes. Despite their efficacy, concerns have emerged regarding cardiovascular safety, including risks of atrial fibrillation, arrhythmias, and myocardial infarction. Most existing data are derived from studies of ibrutinib, the first generation BTKi which has known off-target receptor binding that may contribute to cardiotoxicity. As such, new generation BTKis such as acalabrutinib, zanubrutinib, and pirtobrutinib were developed to improve selectivity and tolerability. However their long-term cardiovascular safety remains unclear. Given the growing use of these agents, a better understanding of their cardiac adverse effects is essential for informed clinical decision making. This study analyzes data from randomized trials evaluating cardiovascular events associated with these next-generation BTKi. Methods: A systematic literature search included MEDLINE and EMBASE from inception through July 22, 2025 following PRISMA guidelines. Phase II/III randomized controlled trials (RCTs) involving adults with hematologic cancers who received acalabrutinib, zanubrutinib, or pirtobrutinib and reported cardiac events were included. Trials that used ibrutinib as a comparator were excluded. Cardiac outcomes of interest included any-grade and high-grade cardiac events, specific arrhythmias such as atrial fibrillation or ventricular tachycardia, and myocardial infarctions leading to either treatment discontinuation or death. We calculated pooled risk ratios (RRs) and 95% confidence intervals (CIs) using a random-effects model. Heterogeneity across studies was measured using the I² statistic. Risk of bias was assessed using the Cochrane Risk of Bias 2.0 tool. Results: Seven randomized controlled trials comprising 3,278 patients were included in the analysis. Acalabrutinib was evaluated in four trials (ECHO, ELEVATE-TN, ASCEND, AMPLIFY), zanubrutinib in two (SEQUOIA, ROSEWOOD), and pirtobrutinib in one (BRUIN CLL-321). Overall, treatment with next-generation BTKi was associated with a significantly higher incidence of any-grade cardiac events compared to control (15.2% vs 8.9%; RR 1.90, 95% CI: 1.33-2.73; p=0.0004). Although high-grade cardiac events occurred more frequently in the BTKi group (4.0% vs 3.3%), the difference was not statistically significant (RR 1.29, 95% CI: 0.88-1.87; p=0.19). Atrial fibrillation or flutter of any grade was also more common among BTKi-treated patients (3.7% vs 1.6%; RR 2.11, 95% CI: 1.28-3.49; p=0.003). However, although the incidence of high-grade atrial fibrillation or flutter was slightly higher in the BTKi arm (1.5% vs 1.2%), it did not reach statistical significance (RR 1.43, 95% CI: 0.77-2.66; p=0.26).No significant differences were observed in other arrhythmias, such as any-grade ventricular tachyarrhythmias (1.0% vs 1.0%; RR 0.88, 95% CI: 0.44-1.78; p=0.72), ventricular tachycardia (0.7% vs 0.4%; RR 1.25, 95% CI: 0.46-3.39; p=0.66), or ventricular/supraventricular extrasystoles (0.6% vs 0.6%; RR 1.03, 95% CI: 0.19-5.42; p=0.98). Similarly, myocardial infarction leading to treatment discontinuation (0.2% vs 0.2%; RR 0.80, 95% CI: 0.19-3.40; p=0.76) or resulting in death (0.1% vs 0.2%; RR 0.54, 95% CI: 0.09-3.41; p=0.51) was rare and did not differ significantly between groups. These findings indicate that while next-generation BTKi are associated with an elevated risk of atrial arrhythmias, particularly atrial fibrillation or flutter, the incidence of more severe cardiac events is not significantly increased. Conclusion: This analysis of seven RCTs found that next-generation BTKi were associated with an elevated risk of atrial arrhythmias, particularly atrial fibrillation or flutter; however, the incidence of more severe cardiac events such as ventricular arrhythmias and myocardial infarction remains low and not significantly different between groups. The increased incidence of atrial rhythm disturbances may have important clinical implications, especially for patients with underlying cardiovascular risk. As use of these agents expands, clinicians should remain vigilant regarding potential cardiac effects and consider baseline evaluation and ongoing monitoring. Further research and long-term follow-up are needed to clarify the full extent of cardiovascular risk with these therapies.