Factors contributing to AF associated with BTK inhibitors: a systematic review and meta-analysis of harms
J Alexandre, J F Font, S H Haddad, D L Legallois, C D Dolladille, A D S Da SilvaAbstract
Background
Bruton’s tyrosine kinase inhibitors (BTKis) are associated with an increased risk of atrial fibrillation (AF), with substantial heterogeneity observed across studies. However, the factors underlying this heterogeneity and contributing to AF remain largely unknown.
Methods
We systematically reviewed all phase 3 randomized controlled trials (RCTs) studying BTKis (ibrutinib, acalabrutinib and zanubrutinib) in adult patients with B-cell malignancies. on the ClinicalTrials.gov register, the EudraCT register, MEDLINE and Cochrane CENTRAL from inception to December 17, 2025. The primary objective was to identify factors associated with AF using pre-specified subgroup and bivariate meta-regression analyses, in the presence of significant heterogeneity in AF risk between BTKi and control groups. We performed a random-effects meta-analysis to compute Mantel-Haenszel summary risks-differences (RDs) with 95% confidence-intervals (CIs).
Results
Nineteen unique phase 3 RCTs (7 placebo-RCTs and 12 non placebo-RCTs) met the predefined criteria. A total of 8,227 adult patients were enrolled, of whom 4,647 were in the BTKi-containing arms (56.5%) and 3,580 were in the control arms (43.5%). BTKis significantly increased the risk of AF (RD: 0.11, 95% CI: 0.07-0.14, p<0.0001, Figure 1) with a significant heterogeneity (I2=91%, τ²=0.006, p<0.0001). Sub-group and bivariate meta-regression analyses (Figure 2) revealed that the effect size was positively associated with ibrutinib use (vs other BTKis; p<0.0001), longer median BTKi exposure (p=0.02) and higher AF incidence in control groups (p=0.001).
Conclusions
In phase 3 RCTs evaluating BTKIs, AF was associated with ibrutinib use, median BTKi duration exposure and AF incidence in control groups. These factors might help to identify patients at increased risk of developing AF during BTKi therapy.Figure 1 Figure 2