Atherosclerotic cardiovascular events associated with BTK inhibitors: a systematic review and meta-analysis of harms

Abstract Background Bruton's tyrosine kinase inhibitors (BTKis) have proven to be effective therapeutic drugs for multiple B-cell malignancies. BTKis exhibit antiplatelet properties via several distinct platelet signaling pathways. Objectives Our aim was to estimate the risk ad incidence of incident atherosclerotic cardiovascular events (ACEs) associated with BTKis exposure as compared with controls in patients with B-cell malignancy using a systematic review and a meta-analysis of harms of randomized controlled trials (RCTs). Methods We systematically reviewed all RCTs studying BTKis (ibrutinib, acalabrutinib and zanubrutinib) with available safety data on ACEs (on clinical trial website (https://clinicaltrials.gov/) or on the EudraCT website (https://eudract.ema.europa.eu/) or on MEDLINE) from inception to December 13, 2024. The primary outcome was the summary risk of ACEs associated with BTKis (ibrutinib, acalabrutinib and zanubrutinib) vs. controls in adult patients with hematological malignancies. We performed a random-effects meta-analysis to compute Mantel-Haenszel summary risks-differences (RDs) with 95% confidence-intervals (CIs). Results Seventeen unique phase 3 RCTs with unique identifiers on ClinicalTrials.gov (6 placebo-RCTs and 11 non placebo-RCTs) with available ACEs met the predefined criteria. A total of 6,838 adult patients were enrolled, of whom 3,776 were in the BTKi-containing arms (55.2%) and 3,062 were in the control arms (44.8%). The median age for the entire population ranged from 57 to 73 years and the median follow-up duration ranged from 14.4 to 84.7 months. The administered BTKi was ibrutinib in 82.3%, acalabrutinib in 11.8% and zanubrutinib in 5.9%. CLL/SLL was the most frequent B-cell malignancy (70.6%). BTKs significantly increased the risk of ACEs (RD: 0.03, 95% CI: 0.00-0.05, p=0.03) with a significant heterogeneity (I2=76%, p0.01). Conclusions BTKs significantly increased the risk of ACEs in phase 3 RCTs.