The prevalence of cardiovascular diseases requiring long-term oral anticoagulation (OAC) is increasing the incidence and prevalence of atrial fibrillation. The most significant complication of OAC is intracerebral hemorrhage (ICH). Based on OAC-induced coagulopathy, large hematoma (a solid swelling of clotted blood within the tissue) volumes and increased rates of hematoma enlargement are characteristics of OAC-associated ICH (OAC-ICH) and contribute to an even higher mortality when compared with ischemic stroke or primary ICH.
Two of the most pressing unsettled questions are how to prevent hematoma enlargement and how to manage anticoagulation in the long-term. Consensus exists that elevated international normalized ratio (INR) levels should be reversed to minimize hematoma enlargement, yet mode, timing, and extent of INR reversal are unclear. This study investigated (1) the relationship between anticoagulation reversal and blood pressure with hematoma enlargement and (2) the association of restarting anticoagulation with the incidence of hemorrhagic and ischemic complications with outcomes among patients with OAC-ICH.
Although the use of oral anticoagulants (OACs) is increasing, there is a substantial lack of data on how to treat OAC-associated intracerebral hemorrhage (ICH). Large hematoma volumes and increased rates of hematoma enlargement are characteristics of OAC-associated ICH (OAC-ICH). The objective of this study is to assess the association of anticoagulation reversal and blood pressure (BP) with hematoma enlargement and the effects of OAC resumption.
Data was collected from all consecutive adult patients with spontaneous ICH related to anticoagulation admitted to neurological departments between the years 2006 and 2010 with a 1-year follow-up period ending in January 2012. ICH patients with secondary etiologies, i.e., ICH related to trauma, tumor, arteriovenous malformation, aneurysmal subarachnoid hemorrhage, acute thrombolysis, or other coagulopathies, were excluded from the study. The study was titled as RETRACE (German-wide Multicenter Analysis of Oral Anticoagulation-associated Intracerebral Hemorrhage) and was conducted on behalf of IGNITE (Initiative of German Neurointensive Trial Engagement).
Data were extracted on demographics, prior comorbidities, in-hospital parameters, and laboratory data through review of patients’ medical records and institutional prospective databases. Follow-up data on mortality, functional outcome, long-term treatment, and complications by mailed questionnaires and—if not returned or incomplete—by semi-quantitative telephone interviews were obtained.
**Data Synthesis and Analysis**
Hematoma enlargement were analyzed in relation to INR reversal and blood pressure. Hematoma enlargement was defined as a relative parenchymal volume increase of more than 33% from initial to follow-up imaging. All available computed tomography and magnetic resonance imaging scans of each patient and calculated parenchymal ICH volume according to hematoma shape were evaluated as previously described. When comparing different imaging modalities, validated conversion models for precise volume calculation were used. Intraventricular hemorrhage was recorded and its extent scored by the Graeb score summation.
All different agents and dosages used for INR reversal as well as timing and extent of achieved INR levels were recorded. Specifically, all available laboratory results of coagulation parameters were evaluated for 72 hours after admission and chose laboratory accessioning times as data points for monitoring of serial INR values. For the accuracy of data on INR reversal, the initial laboratory parameters for transferred patients were retrieved from referring hospitals. For the association of hematoma enlargement with blood pressure, mean arterial blood pressure and systolic and diastolic blood pressures were recorded in 4-hour intervals from admission for 24 hours. Resumption analysis included noting during the 1-year follow-up any new ischemic events, classified as either cerebral (ischemic stroke including transient ischemic attacks) or noncerebral. The latter included peripheral arterial emboli in lungs, gastrointestinal organs, or extremities and myocardial infarction.
Analyses of hematoma enlargement used multivariable regression analysis to identify associated parameters, which were prioritized for consecutive analysis according to relative risk ratio (RR). First, receiver operating characteristics determined the highest Youden index of the best INR cut point to prevent hematoma enlargement. Second, optimal timing of INR reversal was assessed by analyzing categorized frequency distributions over selected INR and time intervals.
A univariate logistic regression model using generalized estimating equations was used to examine the association of INR reversal with hematoma enlargement over time. Third, associations of systolic blood pressure with hematoma enlargement were observed. Blood pressure was categorized in 20–mm Hg intervals (range, <120-≥180 mm Hg), assessed (at 4-hour intervals) from time of hospital admission for 24 hours. To display the combined associations of timing and extent of INR reversal and systolic blood pressure with hematoma enlargement, multivariable regression analysis was used adjusting for associated covariates.
For statistical analyses, SPSS version 20.0 and R version 2.12.0 were used. Statistical tests were 2-sided, and the significance level was set at α = .05 and consequently corrected for multiple comparisons by the Bonferroni method.