Cardiac safety profiles of first-generation vs second-generation BTK inhibitors: a meta-analysis

The first-generation Bruton's tyrosine kinase inhibitor (BTKi), ibrutinib, is associated with significant cardiotoxicity. Second-generation agents were developed to mitigate this risk and offer an improved safety profile. This systematic review and meta-analysis of six direct comparator studies compares the cardiac safety profiles of first- and second-generation BTKi.

We systematically searched Medline, Embase, and Cochrane for studies directly comparing first- and second-generation BTKi. Data from 6 studies, encompassing 14 455 patients (12 816 in the first-generation arm and 1639 in the second-generation arm), were included. The primary outcomes were the incidence of atrial fibrillation (AF) and cardiac events, defined by the Medical Dictionary for Regulatory Activities system organ class. All pooled analyses were conducted using a random-effects model. Publication bias was evaluated visually using a funnel plot, quantitatively with Egger's regression test, and corrected using the Duval and Tweedie trim-and-fill method.

Compared to second-generation agents, ibrutinib was associated with a significantly higher risk of AF (OR 2.50, 95% CI, 1.97-3.17), total cardiac events (OR 1.53, 95% CI, 1.18-1.99), and heart failure (OR 2.08, 95% CI, 1.13-3.83). This translated to a 3-fold higher rate of treatment discontinuation for a cardiac cause (OR 3.32, 95% CI, 1.46-7.55). No significant difference in all-cause mortality was found.

Second-generation BTKi may provide a more favorable cardiovascular safety profile than ibrutinib, resulting in fewer key cardiac events and less treatment-limiting toxicity. These findings should inform clinical decision-making, especially for patients with increased risk for cardiovascular disease.