Ibrutinib for CLL Leads to Higher Risk of Certain Cardiovascular Events

Ibrutinib for treating patients with chronic lymphocytic leukemia increased the risk of atrial fibrillation, bleeding, and heart failure in results of a cohort study.

Ibrutinib (Imbruvica) versus treatment with chemotherapy was found to result in a higher risk of atrial fibrillation, bleeding, and heart failure, but was not associated with a heightened risk of acute myocardial infraction or stroke, in patients with chronic lymphocytic leukemia (CLL), according to a population-based cohort study published in the Journal of Clinical Oncology.

For patients taking ibrutinib, the 3-year incidence of atrial fibrillation–related health care contact was 22.7% (95% CI, 19.0%-26.6%) vs 11.7% (95% CI, 9.0%-14.8%) in the control group. The 3-year risk of hospital-diagnosed bleeding in the ibrutinib patients was 8.8% (95% CI, 6.5%-11.7%) and 3.1% (95% CI, 1.9%-4.6%), respectively. The 3-year risk of heart failure in ibrutinib-treated patients was 7.7% (95% CI, 5.4%-10.6%) and 3.6% (95% CI, 2.2%-5.4%) in the controls.

However, investigators did not find a significant difference in patient outcomes regarding the risk of stroke or acute myocardial infraction.

There were 778 patient pairs matched by prior atrial fibrillation, age of 66 years or greater, anticoagulant exposure, and propensity for ibrutinib who were treated with either ibrutinib or chemotherapy. The survival rates at 3 years were 73.9% (95% CI, 69.4%-77.9%) for patients taking ibrutinib and 77.2% (95% CI, 73.0%-80.8%) for patients in the control group (P = .84). With a median follow-up at 570 days, 532 patients in the ibrutinib group were alive at 12 months, of whom 29.8% did not dispense an ibrutinib prescription between months 6 to 12 and fewer than 6 of these had atrial fibrillation or bleeding in that year.

There were 137 patients (17.6%) in the ibrutinib group and 71 (9.1%) in the control group who fulfilled criteria for atrial fibrillation during follow-up. For patients with ibrutinib exposure, the cause-specific hazard ratio for atrial fibrillation–related health care contact was 2.04 (95% CI, 1.55-2.68; P <.001). Patients had a higher risk of atrial fibrillation if they had pre-existing atrial fibrillation before the index date.

Of note, it was found that there was a shorter time from diagnosis to index date, at 1349.3 vs 1461.0 days and a greater prevalence of heart failure, at 28.6% vs 23.8%, in the patients pre-existing atrial fibrillation who were treated with ibrutinib vs chemotherapy, respectively.

At 3 years, the cumulative incidence of anticoagulation was 23.5% (95% CI, 19.9%-27.3%) in the ibrutinib group and 18.4% (95% CI, 15.0%-22.0%) in the control group (P = .002). During follow-up, patients on ibrutinib had more frequent bleeding events with a number needed to harm score of 18 at 3 years (P <.001). The cause-specific hazard ratio for bleeding on ibrutinib was 2.49 (95% CI, 1.56-3.99; P <.001).

Investigators looked at 1064 patients 66 years of age or older to understand the risk of bleeding without anticoagulation. In this group, the bleeding risk with ibrutinib was 5.7% (95% CI, 3.4%-8.8%) vs 3.2% (95% CI, 1.7%-5.3%) in the controls (P = .12). Similarly, in a 180 matched patients who were anticoagulated at baseline, the 3-year bleeding risks were 23.9% (95% CI, 13.9%-35.5%) vs 6.8% (95% CI, 2.4%-14.6%), respectively (P = .01), indicating that the magnitude of increased risk with ibrutinib was higher in this group.

There were 62 patients within the propensity score–matched cohorts who were newly diagnosed with heart failure during follow-up. The cause specific hazard ratio for heart failure with ibrutinib was 1.73 (95% CI, 1.02-2.93; P =.04).

For patients taking ibrutinib, the hazard ratios for ischemic stroke and acute myocardial infarction were 0.89 (95% CI, 0.34-2.29; P =.80) and 1.23 (95% CI, 0.58-2.64; P =.59), respectively. In the subgroup of 1064 individuals who weren’t anticoagulated at baseline, the 3-year cumulative incidence of ischemic stroke was 1.6% (95% CI, 0.6%-3.7%) for those taking ibrutinib and 2.1% (95% CI, 0.9%-4.2%) in the control group (P = .60) whereas cumulative incidence of acute myocardial infractions was 2.1% (95% CI, 1.0%-3.9%) and 1.2% (95% CI, 0.4%-2.6%), respectively (P = .06).


Abdel-Qadir H, Sabrie N, Leong D, et al. Cardiovascular risk associated with ibrutinib use in chronic lymphocytic leukemia: A population-based cohort study. J Clin Oncol. Published online August 31, 2021. doi:10.1200/JCO.21