Ibrutinib increases major adverse cardiovascular events through initiation and exacerbation of hypertension

Background Ibrutinib, a Bruton’s tyrosine kinase inhibitor effective in the treatment against lymphoma, is associated with increased hypertension and adverse cardiovascular events. Underlying pathophysiological links were unclear. Objective To investigate the pathophysiological role of provoking hypertension in the off-target cardiotoxic mechanism of ibrutinib. Methods We carried out a retrospective cohort study of 50 patients from in a tertiary centre, who were diagnosed with lymphoma and treated with ibrutinib (mean age: 67.9 ± 11.7, 30% female). The primary endpoint was the composite clinical endpoint of Major Adverse Cardiovascular Events (MACE), defined as any incident occurrence of atrial fibrillation/ flutter, acute coronary syndrome, myocardial infarction, ischemic stroke, or congestive heart failure. Secondary Endpoint included new-onset hypertension subsequent to the use of ibrutinib, or requirement of initiation/ uptitration of antihypertensive treatment after ibrutinib use. Results Over a mean follow-up duration of 33.2 ± 23.4 months, the cumulative incidence of MACE was 30%. Incident atrial fibrillation/ flutter occurred in 26% of patients. Cumulative incidence of new-onset hypertension or a requirement for initiation/ uptitration of anti-hypertensive medications was 36%. Importantly, crude and multivariable logistic regression analyses showed that, both before and after adjustment for age and sex, new-onset hypertension or the clinical requirement for initiation/ uptitration of anti-hypertensive therapy was associated with 5-fold increased risk of incident MACE (OR=5.9 95%CI [1.11 to 31.5], P=0.038) (Figure 2). Conclusions Ibrutinib increases MACE at least partially through the initiation and exacerbation of hypertension.