Cardiac Safety Profiles of First-Generation Vs. Second-Generation BTK Inhibitors: A Meta-Analysis

Introduction: Bruton's tyrosine kinase (BTK) inhibitors, including the first-generation ibrutinib and second-generation agents such as zanubrutinib, acalabrutinib, and pirtobrutinib, are critical in the treatment of B-cell hematologic malignancies such as chronic lymphocytic leukemia, Waldenström macroglobulinemia, and mantle cell and marginal zone lymphoma. While BTK inhibitors are highly effective, they are associated with cardiotoxicity. Emerging evidence suggests that second-generation BTK inhibitors, designed for greater selectivity, may mitigate these risks. This comprehensive meta-analysis compares the incidence of arrhythmias and other cardiac events between first- and second-generation BTK inhibitors. Methods: We conducted an extensive meta-analysis focusing on studies that included two distinct comparator arms: one arm treated with a first-generation BTK inhibitor (ibrutinib) and the other with a second-generation BTK inhibitor (such as acalabrutinib, zanubrutinib, or pirtobrutinib). Data were obtained from 11 studies involving 22,247 patients, with 19,746 treated with a first-generation BTK inhibitor and 2,501 with second-generation inhibitors. The primary outcomes assessed were the incidence of atrial fibrillation (AF), coronary artery disease (CAD), and total cardiac events (based on MedDRA cardiac system organ class terms). We used the random effects model for the Forest plot as the data was collected from different populations. A funnel plot was created to assess publication bias, followed by Egger's regression to quantify that and then the Duval and Tweedie's trim-and-fill method to adjust for potential publication bias. Results: Among patients treated with first-generation BTK inhibitors, 2,127 (10.8%) experienced AF, compared to 157 (6.3%) in the second-generation inhibitors. The pooled analysis showed significantly higher risk of AF with ibrutinib (odds ratio (OR) 2.829, 95% confidence interval (CI) [1.772-4.517], p < 0.001, I² = 53.319%). While the funnel plot suggested potential publication bias, trim-and-fill adjustment confirmed the elevated risk (adjusted OR 2.497, 95% CI [1.400-4.454]). Total cardiac events were also more frequent with first-generation inhibitors (OR 1.397, 95% CI [1.039-1.878], p = 0.027). No significant difference was observed in CAD risk (OR 1.020, 95% CI [0.715-1.455], p = 0.914). Second-generation inhibitors were associated with a lower risk of other arrhythmias (OR 0.659, 95% CI [0.436-0.996], p = 0.048). However, no significant differences were found for ventricular tachycardia, sudden cardiac death, or treatment discontinuation due to cardiac events. The first-generation inhibitor was linked to an increased risk of heart failure (OR 1.376, 95% CI [1.016-1.863], p = 0.039), though risk of hypertension did not significantly differ between the groups (OR 0.627, 95% CI [0.209-1.886], p = 0.406). Additionally, there were no significant differences in mortality (OR 0.864, 95% CI [0.698-1.071], p = 0.182), edema (OR 0.977, 95% CI [0.781-1.223], p = 0.842), or cerebrovascular accidents (OR 1.797, 95% CI [0.951-3.394], p = 0.071). Conclusion: Second-generation BTK inhibitors showed a significantly lower incidence of AF, total cardiac events, and heart failure compared to ibrutinib, likely due to improved BTK selectivity and fewer off-target effects. Despite these benefits, the risks of CAD, ventricular tachycardia, sudden cardiac death, hypertension, and treatment discontinuation due to cardiac events were similar between the two generations. These findings underscore the potential benefits of second-generation BTK inhibitors, particularly for patients at increased risk of cardiotoxicity.