by Henry I. Bussey, Pharm.D., FCCP
Editor’s note: This is perhaps the largest every study of oral anticoagulation (OAC)-related intracerebral hemorrhage (ICH). Although this is a retrospective study, it examines how best to treat this emergency and the risk/benefit of resuming OAC. The study was carried out in 19 tertiary centers in Germany and identified 10,208 cases of ICH. Only 1,322 (12.9%) of ICH cases were OAC-related. Various exclusion criteria reduced the study population to 1,176. Progression in hematoma size was a major criterion of the study and because 853 patients had follow-up imaging, this group provided most of the data analyzed. The mean age was 74.1 years and the mean INR on admission was 2.77 with an inter-quartile range (50% of patients) of 2.28 to 3.50. It should be noted that the risk of spontaneous ICH increases with age so that the data from this analysis may not be as applicable as we would like to younger patients or to those whose ICH is associated with a more severe elevation in the INR.
Intracerebral hemorrhage (ICH) is the most feared, disabling, and deadly complication of oral anticoagulation. Further, information on how to manage such an event and when (or if) to resume anticoagulation therapy are areas of significant controversy. In the February 24, 2015 issue of JAMA, Kuramatsu and colleagues provide insightful information based on a retrospective analysis of 853 cases of oral anticoagulated related ICH (OACICH). See http://www.ncbi.nlm.nih.gov/pubmed/?term=JAMA.+2015%3B313(8)%3A824-836.+doi%3A10.1001%2Fjama.2015.0846.
Although the study was retrospective, the statistical analysis (at least to this non-statistician) appears to be strong with multiple corrections for interacting factors.
Control of the INR and Blood Pressure: The analysis found that achieving an INR of less than 3 and/or a systolic blood pressure (SBP) of less than 160 mm Hg at 4 hours after admission were associated with the absence of hematoma expansion [Table 1]. Achieving both INR and SBP targets at 4 hours after admission had an additive effect [Table 1]. Achieving an INR of < 1.2, however, provided no further benefit (as measured by reduced risk of hematoma expansion).
Resumption of Anticoagulation: OAC was resumed in approximately 24% of patients at a median of 31 days. Patients with atrial fibrillation (AF) constituted the largest subgroup of patients (n=566) and this subgroup was used to assess the impact of resumption of OAC. Because the AF patients who resumed anticoagulation were younger, less severely affected at the time of admission, and had better functional status at discharge, the investigators developed two propensity matched cohorts to evaluate the association of resumption of OAC with rates of ischemic stroke, recurrent ICH, and death. As illustrated in Table 2, resumption of oral anticoagulaiton was associated with a marked reduction in ischemic stroke and mortality without an increase in ICH.
Summary: These data would appear to indicate that we should quickly lower the INR to less than 1.3 and control the SBP to less than 160 mmHg in the initial 4 hours of management of patients with OAC-related ICH. However, it should be emphasized that these are retrospectively derived data and may not predict response or outcomes. How these data may apply to patients with subdural (rather than intracerebral) bleeds is not clear. Individual patient-specific factors also must be considered in treatment decision. And, as mentioned in the “editor’s note” above, how these data relate to OACICH in younger patients and those with higher initial INR values remains in question. Furthermore, resumption of OAC should be considered (perhaps at approximately 30 days), at least in patients with AF. Lastly, even though better outcomes were associated with certain maneuvers in the study, we should not lose sight of the severity of this condition. The investigators found that 78.9% of patients had poor functional status (modified Rankin scale of 4 to 6) at discharge and improvement at one year only reduced this value to 72.5%. Because antiplatelet therapy or an elevation of 9 mmHg in SBP is associated with a doubling of the ICH risk in OAC-treated patients, we should remain vigilant to control SBP and avoid unwarranted antiplatelet therapy in order to minimize the risk of ICH . For example, in the recent large trials of new oral anticoagulants vs. warfarin in AF, approximately 25 to 35% of patients were taking aspirin and enrollment criteria allowed patients to enter the trials with SBP as high as 180 mmHg.
- Hart RG, Tonarelli SB, Pearce LA. Avoiding central nervous system bleeding during antithrombotic therapy, recent data and ideas. Stroke 2005; 36:1588-1593.