Ibrutinib Increases Risk of Select Cardiovascular AEs in Patients With Chronic Lymphocytic Leukemia

Treatment with ibrutinib in patients with chronic lymphocytic leukemia was linked with increased risk of cardiovascular adverse effects like atrial fibrillation, hospital-diagnosed bleeding, and heart failure, but was not linked with a higher risk of acute myocardial infarction or stroke.

Treatment with ibrutinib (Imbruvica) in patients with chronic lymphocytic leukemia (CLL) was linked with increased risk of cardiovascular adverse effects (AEs) like atrial fibrillation (AF), hospital-diagnosed bleeding, and heart failure (HF), but was not linked with a higher risk of acute myocardial infarction (AMI) or stroke, according to population-level data from a report published in the Journal of Clinical Oncology.1

Investigators matched patients with CLL who were treated with ibrutinib (n = 778) to a control group of unexposed patients with CLL who were treated with chemotherapy (n = 778). Results showed that the 3-year incidence of AF-related healthcare contact in patients treated with ibrutinib was 22.7% (95% CI, 19.0-26.6) vs 11.7% (95% CI, 9.0-14.8) in the control group.

Moreover, the 3-year risk of bleeding was 8.8% (95% CI, 6.5-11.7) in ibrutinib-treated patients vs 3.1% (95% CI, 1.9-4.6) in the control group. After adjusting for anticoagulation at a time-varying covariate, the BTK inhibitor continued to be positively associated with bleeding (HR, 2.58; 95% CI, 1.76-3.78). The 3-year risk of HF in patients treated with ibrutinib was 7.7% (95% CI, 5.4-10.6%) compared with 3.6% (95% CI, 2.2-5.4) in the control group.

Although a higher risk of those cardiovascular AEs was noted in those treated with ibrutinib, comparable rates of ischemic stroke were observed between the 2 groups (HR, 0.89; 95% CI, 0.34-2.29; P = .80) and AMI (HR, 1.23; 95% CI, 0.58-2.64; P = .59).

In a subgroup of patients (n = 1064) who were younger than 66 years and were not anticoagulated at baseline, the 3-year cumulative incidence of ischemic stroke for patients treated with ibrutinib was 1.6% (95% CI, 0.6%-3.7%) vs 2.1% (95% CI, 0.9%-4.2%) in the control group (P = .60). Furthermore, AMI incidence was 2.1% (95% CI, 1.0%-3.9%) in those treated with ibrutinib vs 1.2% (95% CI, 0.4%-2.6%) in the control group (P = .06).

“Most of our knowledge on the cardiovascular risk of ibrutinib comes from randomized control trials that tend to recruit healthier patients, or from observational studies that were limited by small sample size and/or a single-arm design,” lead study author Husam Abdel-Qadir, MD, PhD, cardiologist at Cleveland Clinic Canada, and his colleagues, wrote in the report. “We studied a larger number of patients than prior observational studies while providing comparison to controls, thus providing more precise risk estimates in a case mix that reflects routine clinical practice since.”

Ibrutinib is known to reduce mortality in patients with CLL;2 however, it also increases the risk for AF and bleeding.3 Limited information is available on cardiovascular risk linked with the use of the BTK inhibitor in routine practice. To this end, investigators launched a population-based cohort study aimed to describe the incidence of AF-associated health care contact, bleeding, stroke, HF, and AI in patients who received ibrutinib.

The objective was to develop a better understanding on risk of these effects in a population that is reflective of ibrutinib use beyond a clinical trial setting, and to provide a comparable control cohort of patients who received treatment for their disease but who were naïve to the BTK inhibitor.

Investigators leveraged the Ontario Cancer Registry records and the Canadian Institute of Health Information Discharge Abstract Database to identify patients diagnosed with CLL between 2007 and 2019 (n = 1556).

Patients were not included in the analysis if they had an invalid OHIP number, were missing age or sex information, were diagnosed after death, were younger than age 50 years or older than 105 years at the time of their diagnosis, did not reside in Ontario, were OHIP eligible less than 1 year prior to their diagnosis, they did not have documented exposure to chemotherapy or ibrutinib, they had an alternative cancer diagnoses 1 year prior to CLL diagnosis or between diagnosis and index date.

Study outcomes were AF-related health care contact, bleeding diagnosed during hospitalization, new HF diagnoses (in or out of the hospital), hospitalizations for ischemic stroke, and hospitalization for AMI. Investigators also evaluated anticoagulation use following the index date because of its link with AF onset and its impact on risk of bleeding and thrombotic effects.

The median age of matched ibrutinib-treated patients was 72 years (range, 67-80), and 66.1% were male. Patients in both groups were equally likely to have been anticoagulated at baseline, with 55 DOAC-treated patients (7.1%) in each group. Furthermore, 27 patients (3.5%) in each group were treated with warfarin or low-molecular–weight heparin. Three-year survival rates in the ibrutinib and control groups were estimated to be 73.9% (95% CI, 69.4%-77.9%) and 77.2% (95% CI, 73.0%-80.8%), respectively (P = .84).

The study authors also noted that hypertension is a frequent AE reported in ibrutinib-treated patients, which could increase the risk of AF.4 Additionally, these cardiovascular AEs linked with off-target ibrutinib has motivated the development of second-generation BTK inhibitors that have increased specificity. If ibrutinib is supplanted by second-generation agents, determining whether their favorable safety signal extends to patients treated outside clinical trials will be important, according to the authors.

“These data can inform the risk-benefit balance of this important medication and should prompt targeted cardiovascular monitoring in future studies involving ibrutinib and second-generation BTK inhibitors,” the study authors concluded.


  1. 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. 2021;39(31):3453-3462. doi:10.1200/JCO.21.00693
  2. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373:2425-2437. doi:10.1056/NEJMoa1509388
  3. Leong DP, Caron F, Hillis C, et al. The risk of atrial fibrillation with ibrutinib use: A systematic review and meta-analysis. Blood. 2016;128(1):138-140. doi:10.1182/blood-2016-05-712828
  4. McMullen JR, Boey EJ, Ooi JYY, et al. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood. 2014;124(25):3829-3830. doi:10.1182/blood-2014-10-604272