APOE ε4 Status May Predict Intracranial Hemorrhage Risk in Patients Treated With Apixaban

Carriers of the APOE ε4 allele may have an increased risk for intracranial hemorrhage (ICH) while on apixaban therapy for atrial fibrillation, according to findings published in JAMA Neurology.

Previous studies have shown that APOE ε4 is a known risk factor for spontaneous ICH and for warfarin-related hemorrhage. However, its role in patients treated with direct oral anticoagulants such as apixaban was unclear.

Researchers conducted a cohort study using data from the All of Us Research Program. The analysis included 2038 adults over the age of 50 with a history of atrial fibrillation who initiated apixaban therapy between 2017 and 2022. Patients with prior ischemic stroke or ICH were excluded. APOE genotyping was determined using whole-genome sequencing, and participants were categorized as ε4 carriers (1 or 2 alleles) or noncarriers (no alleles). The primary outcome was incident ICH following apixaban initiation.

The mean (SD) age of the cohort was 71 (9) years, 55% were men, 83% had European ancestry, and 23.7% (n=483) were APOE ε4 carriers. Over a median follow-up of 2.9 (IQR, 1.7-3.0) years, 26 individuals experienced ICH, with a higher cumulative incidence in APOE ε4 carriers (3.10%; 95% CI, 1.7-5.3) compared with noncarriers (1.0%; 95% CI, 0.6-1.7; P =.007).

In multivariable Cox proportional hazards models, APOE ε4 carriership was associated with a more than 3-fold increased risk for ICH (hazard ratio [HR], 3.07; 95% CI, 1.42-6.65). This association remained consistent across sensitivity analyses restricted to individuals of European ancestry and those who maintained apixaban treatment throughout follow-up.

Secondary analyses showed that APOE ε4 carriers were also at greater risk for intraparenchymal hemorrhage (HR, 3.70; 95% CI, 1.36-8.38), though no significant differences were observed for ischemic stroke (HR, 0.82; 95% CI, 0.43-1.57) or for composite of ischemic stroke or ICH (HR, 1.33; 95% CI, 0.80- 2.21).

Importantly, the inclusion of APOE ε4 status in bleeding risk prediction models improved prognostic accuracy. When added to the Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly score, APOE ε4 increased the concordance statistic from 0.68 to 0.74 (P =.03), suggesting potential value for genetic information in individualized anticoagulation risk assessment.

Study limitations include the lack of participant diversity, no differentiation between hemorrhage types, and no external validation of risk models due to limited genetic data.

“[O]ur results address an important knowledge gap related to the role of APOE ε4 in this specific ICH population and support the need for future studies focused on developing and refining risk assessment tools that include genetic information,” the study authors concluded.

Disclosures: This research was supported by the National Institutes of Health and the American Heart Association. Multiple study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.