MACE and BTK Inhibitors

Bruton's tyrosine kinase inhibitors (BTKis) have demonstrated substantial therapeutic efficacy across multiple B-cell malignancies. Their durable hematologic benefits confer a favorable benefit-risk profile compared with other treatments, positioning BTKis as a cornerstone of therapy in several B-cell malignancies. However, BTKis are associated with an increased risk of cardiovascular (CV) adverse events, ranging from common complications such as atrial fibrillation (AF) and hypertension to more severe outcomes, including ischemic MACE.

Accumulating evidence suggests that while CV toxicity is a class effect of BTKis, the incidence, magnitude, and risk of these events vary according to the specific agent used. Modest changes in systolic blood pressure or AF incidence and risk have been reported across BTKis in indirect comparisons; however, the clinical relevance of these findings remains uncertain, making it questionable to base BTKi selection solely on such differences. Moreover, if hematologic efficacy is assumed to be broadly comparable across BTKis and CV toxicity becomes the primary determinant of treatment choice, it would be logical to rely on robust, standardized CV endpoints traditionally used in the evaluation of CV therapies.

Taken together, these considerations highlight the need for direct comparisons between available BTKis to generate more robust cardiovascular evidence and ultimately guide hematologists toward selecting the least cardiotoxic agent. Although randomized controlled trials (RCTs) would be the ideal approach to address this question, no existing RCTs directly compare BTKis with cardiovascular events as a primary outcome. Recently, no significant differences in the risk of non-fatal MACE were observed among ibrutinib, acalabrutinib, and zanubrutinib, based on a network meta-analysis of safety outcomes from phase 3 RCTs primarily designed to assess BTKi efficacy . In this context, target trial emulation using observational data and propensity score-based methods offers a valuable alternative, enabling the generation of high-level evidence that closely approximates randomized conditions.

The primary objective of this study will therefore be to compare the risk of hospitalization for MACE among the three BTKis (ibrutinib, acalabrutinib, zanubrutinib) in patients with B-cell malignancies, using a nationwide target trial emulation framework based on the French National Health Data System (SNDS), which covers 98.8% of the French population.