Comparative Study of Cardiovascular Co-Morbidities between Ibrutinib and Non-Ibrutinib-Treated Chronic Lymphocytic Leukemia (CLL) Patients

OBJECTIVES

Cardiovascular disease (CV) is a common co-morbidity in CLL patients, especially as the median age at diagnosis is >70 years. Clinical trials that led to ibrutinib approval for CLL have suggested an incidence of atrial fibrillation (A-FIB) of 9-11% with a long-term follow-up. We aimed to study whether the risk of CV disease, including A-FIB, is associated with the use of ibrutinib in a large cohort of real world patients.

METHODS

Newly diagnosed CLL patients initiating any therapy between 01/01/2014-09/30/2016 were selected from the Inovalon Medical Outcomes Research for Effectiveness and Economics (MORE²) Registry payer claims and remittance dataset. CLL patients receiving ibrutinib (case) and those not being treated with ibrutinib (control) were matched on a 1:5 ratio using propensity matching based on age, gender, region and payer at the time of initiation of their first cycle of therapy. Incidence of CV morbidities was assessed from the date of their first cycle of therapy (or a proxy date for controls based on the distribution of ibrutinib start dates) to the date of the last administrative claim and reported as per-patient per-month (PPPM). Patients were required to be free of a CV event 3 years prior to the initiation of their first cycle of therapy to assure capture of incident CV events. We compared the incidence of atrial fibrillation (A-FIB), hypertension (HTN), peripheral vascular disease (PVD), coronary artery disease (CAD) and mycoradial infarction (MI). P-values were calculated using chi-square tests for categorical measures and t-tests for continuous measures.

RESULTS

Among the 1,488 matched CLL patients, 248 were treated with ibrutinib and 1,240 were treated with alternate therapies. Median age for all patients was 67 years (median 65 in ibrutinib patients and 68 in the control group); No differences in gender distribution between both cohorts and similar percentages of patients in both cohorts were on Medicare (56-57%). Median follow-up for the entire cohort was 183 days. Ibrutinib-treated patients had a slightly shorter median follow up than controls (174 days vs 185 days). There was a significantly higher incidence of HTN (16.1% vs 5.6%, p <0.001) and A-FIB (6.5% vs 3.1% p=0.009) in the ibrutinib-treated versus non-ibrutinib treated patients. There was also a higher incidence of PVD and CAD in the ibrutinib population (4% vs 2% and 2% vs.1%, respectively; p= NS). The incidence of MI was higher in the non-ibrutinib population (2.3 vs 0.8, p=NS)

CONCLUSIONS

CLL patients treated with ibrutinib in the real world have higher incidence of HTN and A-FIB compared with CLL patients not treated with ibrutinib. These data confirm results of 3 randomized clinical trials demonstrating increased incidence of A-FIB and HTN. More importantly these data are the first to demonstrate an increase in vascular-related (PVD, CAD but not acute MI) events in ibrutinib treated patients (vs. controls). These findings support implementing screening and therapeutic strategies for ibrutinib-treated patients to diminish adverse events and minimize any potential serious sequelae from HTN and/or A-FIB.