Combining Imaging and Genetics to Predict Recurrence of Anticoagulation-Associated Intracerebral Hemorrhage

Background and Purpose: For survivors of oral anticoagulation therapy (OAT)-associated intracerebral hemorrhage (OAT-ICH) who are at high risk for thromboembolism, the benefits of OAT resumption must be weighed against increased risk of recurrent hemorrhagic stroke. The epsilon 2/epsilon 4 alleles of theapolipoprotein E(APOE) gene, MRI-defined cortical superficial siderosis, and cerebral microbleeds are the most potent risk factors for recurrent ICH. We sought to determine whether combining MRI markers andAPOEgenotype could have clinical impact by identifying ICH survivors in whom the risks of OAT resumption are highest. Methods: Joint analysis of data from 2 longitudinal cohort studies of OAT-ICH survivors: (1) MGH-ICH study (Massachusetts General Hospital ICH) and (2) longitudinal component of the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage). We evaluated whether MRI markers andAPOEgenotype predict ICH recurrence. We then developed and validated a combinedAPOE-MRI classification scheme to predict ICH recurrence, using Classification and Regression Tree analysis. Results: Cortical superficial siderosis, cerebral microbleed, andAPOE epsilon 2/epsilon 4 variants were independently associated with ICH recurrence after OAT-ICH (allP<0.05). CombiningAPOEgenotype and MRI data resulted in improved prediction of ICH recurrence (Harrell C: 0.79 versus 0.55 for clinical data alone,P=0.033). In the MGH (training) data set, CSS, cerebral microbleed, andAPOE epsilon 2/epsilon 4 stratified likelihood of ICH recurrence into high-, medium-, and low-risk categories. In the ERICH (validation) data set, yearly ICH recurrence rates for high-, medium-, and low-risk individuals were 6.6%, 2.5%, and 0.9%, respectively, with overall area under the curve of 0.91 for prediction of recurrent ICH. Conclusions: Combining MRI andAPOEgenotype stratifies likelihood of ICH recurrence into high, medium, and low risk. If confirmed in prospective studies, this combinedAPOE-MRI classification scheme may prove useful for selecting individuals for OAT resumption after ICH.