Warfarin is an oral anticoagulant that is used to

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1 J Neurosurg 119: , 2013 AANS, 2013 Mild elevations of international normalized ratio at hospital Day 1 and risk of expansion in warfarin-associated subdural hematomas Clinical article Marie Roguski, M.D., 1 Kyle Wu, B.A., 2 Ron I. Riesenburger, M.D., 1 and Julian K. Wu, M.D. 1 1 Department of Neurosurgery, Tufts Medical Center and Tufts University School of Medicine, Boston; and 2 University of Massachusetts Medical School, Worcester, Massachusetts Object. A primary goal in the treatment of patients with warfarin-associated subdural hematoma (SDH) is reversal of coagulopathy with fresh-frozen plasma. Achieving the traditional target international normalized ratio (INR) of 1.3 is often difficult and may expose patients to risks of volume overload and of thromboembolic complications. This retrospective study evaluates the risk of mild elevations of INR from 1.31 to 1.69 at 24 hours after admission in patients presenting with warfarin-associated SDH. Methods. Sixty-nine patients with warfarin-associated SDH and 197 patients with non warfarin-associated SDH treated at a single institution between January 2005 and January 2012 were retrospectively identified. Charts were reviewed for patient age, history of trauma, associated injuries, neurological status at presentation, size and chronicity of SDH, associated midline shift, INR at admission and at hospital Day 1 (HD1), concomitant aspirin or Plavix use, platelet count, and medical comorbidities. Patients were stratified according to use of warfarin and by INR at HD1 (INR , , , and 2). The groups were evaluated for differences the in rate of radiographic expansion of SDH and in the rate of clinically significant SDH expansion resulting in death, unplanned procedure, and/or readmission. Results. There was no difference in the rate of radiographic versus clinically significant expansion of SDH between patients not on warfarin and those on warfarin (no warfarin: 22.3% vs 20.3%, p = 0.866; warfarin: 10.7% vs 11.6%, p = 0.825), but the rate of medical complications was significantly higher in the warfarin subgroup (13.3% for patients who did not receive warfarin vs 26.1% for those who did; p = 0.023). For warfarin-associated SDH, there was no difference in the rate of radiographic versus clinically significant expansion between patients reversed to HD1 INRs of and (HD1 INR : 22.5% vs 20%, p = 1; HD1 INR : 15% vs 10%, p = 0.71). Conclusions. Mild INR elevations of in warfarin-associated SDH are not associated with a markedly increased risk of radiographic or clinically significant expansion of SDH. Larger prospective studies are needed to determine if subtherapeutic INR elevations at HD1 are associated with smaller increases in risk of SDH expansion. ( Key Words warfarin subdural hematoma coagulopathy Coumadin mortality rate Warfarin is an oral anticoagulant that is used to decrease the risk of stroke, pulmonary embolism, and other thromboembolic complications. Its clinical effect is monitored by frequent testing of the prothrombin time and INR; an INR of > 2.0 is generally considered to be therapeutic and is associated with a decreased risk of thrombotic events. 14,19 However, therapeutic INR elevations are also associated with risk of serious Abbreviations used in this paper: FFP = fresh-frozen plasma; GCS = Glasgow Coma Scale; HD1 = hospital Day 1; INR = international normalized ratio; LOS = length of stay; SDH = subdural hematoma. bleeding, including intracranial hemorrhage. Treatment with warfarin carries an annual risk of major bleeding of 0.5% 6.5% and an additional annual risk of fatal hemorrhage of 0.1% 1.0%. 2,4,5,10,12,16 Approximately 34 million prescriptions for warfarin are written annually, 8 and warfarin-associated intracranial hemorrhage is not uncommonly encountered in clinical practice. When patients present with intracranial hemorrhage while on warfarin, reversal of coagulopathy is a primary goal of treatment. 1,9 Although there is ample evidence to support a goal of as adequate for prevention of thrombotic events, there are very limited data regarding the ideal target for INR reversal. Furthermore, the risk of 1050 J Neurosurg / Volume 119 / October 2013

2 Effect of mild coagulopathy in acute subdural hematoma bleeding associated with subtherapeutic INR elevations (INR > but < 2.0) is also not well defined. A target INR of < has been used somewhat arbitrarily and variably as an indicator of adequate reversal. 3,15,17 We have noted that there are some patients whose INR is resistant to rapid reversal with FFP and who require substantial volumes of FFP to reverse the INR to 1.3 within 24 hours. There is some concern that transfusion of large volumes of FFP may place these high-risk patients at more risk of medical and thromboembolic complications than is necessary. In addition, it has been our clinical impression that patients whose INRs were not successfully fully reversed within 24 hours did not appear to exhibit a higher rate of SDH expansion. This clinical observation and concern for excessive medical risk made us question whether a target INR of 1.3 was overly aggressive. This study seeks further to characterize the risk of warfarin-associated coagulopathy in SDH and to help elucidate the optimal target INR for warfarin reversal. Methods Management Protocol Patients who present with warfarin-associated SDH to our institution are immediately triaged into operative and nonoperative management based on neurological examination, imaging findings, patient advanced directives, and other clinical features. Nonoperative management involves administration of vitamin K, transfusion of FFP until INR is 1.3, and hourly neurological checks in an ICU. Repeat imaging is performed routinely in most patients, except in those with very small SDHs and intact neurological examinations. Recombinant factor VII is not routinely used unless a patient requires operative treatment. In contrast, patients undergoing operative evacuation generally receive recombinant factor VII to enable surgery unless the repeat INR prior to incision is 1.3. Operative evacuation is done at the earliest possible time if it is deemed necessary. The reversal of coagulopathy and further treatment of patients with operative SDH is otherwise not significantly different from patients with nonoperative SDH. Patient Selection and Data Collection Approval for this retrospective review study was obtained from the Tufts Medical Center s Institutional Review Board. The inpatient database was queried for patients treated for SDH between January 2005 and January Sixty patients with warfarin-associated SDH and 537 patients with non warfarin-associated SDH were initially identified. Of the 537 patients with non warfarinassociated SDH, 250 were randomly chosen for review. Of these 250 patients, 9 were found to be taking warfarin with a therapeutic INR, 44 were excluded, and 197 patients with non warfarin-associated SDH were included (Fig. 1). Only patients with confirmed SDH, INR values obtained at admission and at 24 hours, and with at least 1 repeat CT scan of the head were included. Exclusion criteria included patients with incorrect diagnosis, patients without available laboratory studies or imaging, patients J Neurosurg / Volume 119 / October 2013 Fig. 1. Chart showing patient selection methods. with significant other intracranial injuries (for example, intraparenchymal hemorrhage), and patients who received comfort measures only immediately at admission. Patient charts were reviewed for age, sex, associated trauma, presence of skull fractures or cervical spine injury, loss of consciousness, presence of a neurological deficit, and GCS score at admission. Imaging was reviewed for laterality, maximum width of SDH, and associated midline shift. Laboratory studies were reviewed for INR and platelet count at admission and at 24 hours after admission. When a result was not available at exactly 24 hours, the nearest result was used; this was not to exceed 6 hours before or > 24 hours after admission. In addition, patient charts were reviewed for concomitant use of aspirin and Plavix. Patient charts were also evaluated for LOS, surgical intervention, medical complications, and death. Patient Outcomes Primary study end points included any expansion of SDH as defined by interval enlargement of SDH noted in the radiology report. When expansion was noted, the authors reviewed the patient s imaging to confirm the enlargement. In addition, secondary study end points included clinically significant expansion of SDH and inpatient medical complications, such as pulmonary edema, stroke, deep vein thrombosis, and pulmonary embolism. Clinically significant expansion was defined as any expansion in SDH that resulted in a change in management (for example, the initial plan for conservative manage- 1051

3 M. Roguski et al. ment converted to operative management), readmission to the hospital after discharge, or death. Statistical Analysis Two separate analyses were done. First, patients with warfarin-associated SDH were compared with patients who had SDH not associated with warfarin. Second, patients with warfarin-associated SDH were stratified into 4 groups based on HD1 INR, as follows: INR ; INR ; INR ; and INR 2.0. We used JMP 9 statistical software for data analysis. Categorical variables were analyzed with chi-square or Fisher exact tests, as appropriate. Continuous variables were analyzed with unpaired Student t-test or ANOVA, as appropriate. Results Warfarin-Associated Versus Non Warfarin-Associated SDH There were some differences in patient characteristics between patients with warfarin-associated and non warfarin-associated SDH (Table 1). Patients with warfarin-associated SDH were found to be older than patients with SDH not associated with warfarin (75.6 years vs 69.1 years, p = 0.003). Fewer patients with warfarin-associated SDH remembered a history of trauma (85.3% vs 96.4%, p = ), had associated skull fractures (0% vs 9.7%, p = ), and fewer reported loss of consciousness at the time of trauma (21.9% vs 38.3%, p = 0.021). Patients in the 2 groups were otherwise similar with respect to the proportion presenting with a neurological deficit, GCS at presentation, platelet count at admission and at HD1, and proportion of patients reporting concomitant aspirin and Plavix use. Furthermore, the baseline radiographic characteristics of the SDHs were similar in both groups as well. Both groups had similar follow-up periods. The mean follow-up for warfarin-associated SDH was 5.2 weeks, which did not differ from the mean follow-up of 5.4 weeks for non warfarin-associated SDH (p = 0.82). In 25% of patients from the warfarin-associated and non warfarin-associated SDH groups the follow-up durations were < 4.2 days and 5.6 days, respectively. However, all patients had at least 1 follow-up CT scan. The outcomes of patients with warfarin-associated and non warfarin-associated SDH did not differ in any parameter measured except for LOS and inpatient medical complications (Table 2). The LOS was longer for patients with warfarin-associated SDH (7.5 days vs 5.6 days, p = ). Mortality rate was similar for both groups, and a similar percentage of patients required intubation. The percentage of SDHs exhibiting either any expansion (that is, radiographic expansion) or clinically significant expansion was similar in both groups. Regarding any expansion, 20.3% of warfarin-associated and 22.3% of non warfarin-associated SDH showed radiographic expansion (p = 0.866). Similarly, 11.6% of warfarin-associated and 10.7% of non warfarin-associated SDH exhibited clinically significant expansion (p = 0.825) (Fig. 2). Warfarin-Associated SDH Stratified by HD1 INR For the warfarin-associated SDH cohort, we further analyzed their outcomes by stratifying them into 4 groups based on INR at 24 hours after admission. The number of patients in the HD1 INR and HD1 INR 2.0 groups was too low for statistical analysis. The number of patients with warfarin-associated SDH in the HD1 INR group was 40, and the number of such patients in the HD1 INR group was 20. Patients in the TABLE 1: Demographic, clinical, and radiographic features in 266 patients presenting with SDH stratified by use of warfarin Feature No Warfarin Warfarin p Value no. of patients clinical & demographic mean age in yrs (95% CI) 69.1 ( ) 75.6 ( ) % male % w/ trauma % w/ skull fracture % w/ cervical spine injury % w/ loss of consciousness % w/ neurological deficit median GCS (10th 90th percentile) 15 (13 15) 15 (14 15) mean platelet count in thousands (95% CI) 205 ( ) 214 ( ) % w/ aspirin use % w/ Plavix use radiographic mean width of SDH in mm (95% CI) 9.7 ( ) 11 ( ) mean midline shift in mm (95% CI) 2.2 ( ) 2.4 ( ) % acute SDH w/ mixed densities mean follow-up in wks J Neurosurg / Volume 119 / October 2013

4 Effect of mild coagulopathy in acute subdural hematoma TABLE 2: Outcomes in 266 patients presenting with SDH stratified by use of warfarin Outcome No Warfarin Warfarin p Value no. of patients LOS in days (95% CI) 5.6 ( ) 7.5 ( ) range in days % requiring procedure % mortality % requiring intubation % w/ medical complications % w/ radiographic expansion of SDH % w/ clinically significant expansion of SDH HD1 INR group were more likely to report a history of trauma (100% vs 80%, p = 0.045), but there were no other differences in baseline characteristics (Table 3). The mean INR at admission was slightly higher in the HD1 INR group, but this did not reach statistical significance (3.7 vs 3.0, p = 0.296). The baseline radiographic characteristics of the SDH in each group were similar. Although most patients had acute SDH with blood of only one age, 30% and 25% of patients in the HD1 INR and HD1 INR groups had acute-on-chronic SDH, as evidenced by mixed densities on CT (p = 0.769). The follow-up interval was similar for the HD1 INR and HD1 INR groups. In 25% of patients in the HD1 INR and HD1 INR groups, the follow-up duration was < 3.5 days and 7 days, respectively. However, all patients had at least 1 follow-up CT scan. The outcomes of patients with warfarin-associated SDH with INR reversed to an HD1 INR of and with INR reversed to an HD1 INR of did not differ in any parameter evaluated (Table 4). The overall medical complication rate was higher in patients reversed to a lower INR (30% vs 20%), but this did not reach statistical significance. Finally, there was no difference in rates of radiographic or clinically significant expansion (Fig. 3). With regard to radiographic expansion, 22.5% of patients in the HD1 INR group and 20% in the HD group showed radiographic expansion on follow-up head CT scans (p = 1). Similarly, both groups had similar rates of clinically significant expansion, with 15% of patients in the HD1 INR group and 10% in the HD1 INR group showing significant expansion (p = 0.707). Discussion The initial study hypothesis was that the target INR for reversal used at our institution may be too aggressive in reversal of coagulopathy associated with warfarin treatment. Before being able to study this question, we first needed to ascertain that the current treatment paradigm was effective in treating warfarin-associated coagulopathy in patients presenting with SDH. To do so, we first sought to determine if patients with warfarin-associated SDH had worse outcomes than those with non warfarinassociated SDH. Our results indicate that the patients in both categories had similar outcomes with respect to both radiographic and clinically significant expansion. This finding supports the hypothesis that the current treatment paradigm is successful in preventing expansion of SDH in patients taking warfarin. This is consistent with findings reported by Panczykowski and Okonkwo 17 and Oyama et al. 15 This study was powered at 0.80 and had an α level of 0.05 to detect a 21% difference in radiographic expansion and a 15.6% difference in clinically significant expansion Fig. 2. Bar graph showing radiographic and clinically significant expansion rates of SDH based on warfarin use. J Neurosurg / Volume 119 / October

5 TABLE 3: Demographic, clinical, and radiographic features in 60 patients with warfarin-associated SDH stratified by HD1 INR Feature INR INR p Value no. of patients clinical & demographic mean age in yrs (95% CI) 76.7 ( ) 78.3 ( ) % male % w/ trauma % w/ cervical spine injury % w/ loss of consciousness % w/ neurological deficit median GCS (10th 90th percentile) 15 (13 15) 15 (14 15) 0.56 mean INR at admission (95% CI) 3.7 ( ) 3.0 ( ) range of INR at admission distribution of INR (25th 75th percentile) mean platelet count in thousands (95% CI) 215 ( ) 213 ( ) 0.93 % w/ aspirin use % w/ Plavix use radiographic no. of patients mean width of SDH in mm (95% CI) 11.7 ( ) 10.7 ( ) 0.66 mean midline shift in mm (95% CI) 3.1 ( ) 2 (0 4.4) % acute SDH w/ mixed densities mean follow-up in wks M. Roguski et al. between patients presenting with non warfarin-associated SDH and warfarin-associated SDH. Although we can only confidently say that the true difference in these 2 parameters is no greater than 21% for radiographic expansion and no greater than 15.6% for clinically significant expansion, the observed rates of radiographic expansion (22.3% and 20.3%) and clinically significant expansion (10.7% and 11.6%) are very similar between these 2 groups, and therefore suggest that the true difference is actually small. Bershad et al. 3 reported that premorbid coagulopathy, defined as INR > 1.2, was independently associated with worse outcome in patients presenting with acute SDH; this is in direct contrast with the findings of this study. This difference may be due to differences in the study populations. Only 31 (58%) of 53 patients were taking oral anticoagulants at the time of presentation in the series reported by Bershad et al.; it is possible that patients presenting with severely elevated INRs in the absence of oral anticoagulation therapy may be at higher risk for SDH expansion or for serious medical complications specifically related to liver dysfunction, disseminated intravascular coagulation, or poor nutritional status. In addition, unlike the patients with coagulopathy in our study, the ones in the study by Bershad et al. were more likely to have a GCS score of < 8 at presentation and to receive nonoperative treatment. These differences limit our ability to compare the 2 studies. As mentioned previously, the patient demographics and clinical features were similar in both of these groups except with respect to age and reported history of trauma. Patients who were not taking warfarin were more likely to report a history of trauma, and were younger. Although it is reasonable to expect better outcomes in younger patients, this finding would tend to skew the results in favor of better outcomes in patients with non warfarin-associated SDH. Conversely, it is unclear whether a history of trauma would adversely affect the outcome of patients presenting with SDH. Further study is needed to determine what effect the difference in history of trauma has on overall prognosis. TABLE 4: Outcomes in 60 patients with warfarin-associated SDH stratified by HD1 INR Outcome INR INR p Value no. of patients LOS in days (95% CI) 8.5 ( ) 6.9 ( ) range in days % requiring procedure % mortality % requiring intubation % w/ medical complications % w/ radiographic expansion of SDH % w/ clinically significant expansion of SDH J Neurosurg / Volume 119 / October 2013

6 Effect of mild coagulopathy in acute subdural hematoma Fig. 3. Bar graph showing radiographic and clinically significant expansion rates of warfarin-associated SDH based on HD1 INR. Premorbid warfarin use has been associated with worse outcomes in patients with blunt TBI. 6,7,13,18 These studies combine all patients with TBI, including those with SDHs, epidural hematomas, and intraparenchymal contusions. It is possible that the worse mortality rate associated with premorbid warfarin use is closely related to the specific type of TBI the patient has. Thus, we elected to limit our study to patients with SDHs, because we believed that the outcome of patients with intraparenchymal contusions was dependent on factors that were difficult to quantitate, such as hematoma location and associated cerebral edema. In addition, in this study we excluded all patients who did not have a repeat CT head scan and those who received comfort measures only at admission. It is possible that a higher percentage of patients taking warfarin had devastating neurological injuries at presentation and that the warfarin population in this study was biased toward patients with less severe injuries. The differences in reported history of trauma and associated skull fracture between patients taking warfarin and those not taking warfarin supports this hypothesis. The results of this study clearly only apply to patients already admitted to the hospital with acute SDH and do not comment on the initial risk of developing an SDH or the risk of death associated with acute SDH in outpatients taking warfarin. The second goal of this study was to evaluate the risk of mild INR elevations at 24 hours after admission (that is, at HD1). We stratified patients with warfarin-associated SDH into 4 INR classes as defined earlier. At our institution we have traditionally used an INR of 1.3 as our goal for reversal, and for this reason we chose to include this INR as the high end of normal in this study. We previously mentioned that INR > 2.0 is considered therapeutic and is known to be associated with an increased rate of bleeding complications; thus, we chose an INR of 2.0 to be defined as our highest category. We divided the remaining INR values into 2 categories to complete our stratification J Neurosurg / Volume 119 / October 2013 scheme, and classified INR elevations of and as mild and moderate, respectively. There is little existing literature regarding the risk of thromboembolic and bleeding complications associated with INR elevation of or Larson et al. 11 reported that an INR of seemed to be effective at preventing thromboembolic complications in high-risk patients undergoing significantly invasive surgical procedures, with only 2 of 93 patients experiencing major bleeding. However, no neurosurgical procedures were included in this study. We did not find an increased risk of hematoma expansion in patients with warfarin-associated SDH whose INRs were reversed to an HD1 INR of over those patients whose HD1 INRs were This study is powered at 0.80 and has an α level of 0.05, at which a 30% difference in radiographic expansion and a 22.8% difference in clinically significant expansion was detected in patients with warfarin-associated SDH reversed to an HD1 INR of and Although we can only confidently say that the true difference in these 2 parameters is no greater than 30% for radiographic expansion and no greater than 22.8% for clinically significant expansion, the observed rates of radiographic expansion (22.5% and 20%) and clinically significant expansion (15% and 10%) between these 2 groups are very similar, and suggest that the true difference is small. A larger study would be needed to confirm this finding. A higher percentage of patients with warfarin-associated SDH experienced medical complications as inpatients, including deep vein thrombosis, volume overload, and stroke. However, we were not able to show that patients reversed to an INR from 1.31 to 1.69 had lower complication rates than patients reversed to an INR < 1.3. It is unclear if this finding is due to an inadequate patient population or if there is indeed no significant difference between these groups. Our study was powered at 1055

7 M. Roguski et al to detect a difference in medical complications of 24% between patients reversed to HD1 INRs of and ; thus, we can confidently say that the true difference is not likely to be > 24%. The observed rates of medical complications were 30% and 20% for patients reversed to an HD1 INR of and , respectively. This difference, although relatively large, was not statistically significant (p = 0.54). It is possible that this difference of 10% may become significant with inclusion of more study participants. In addition, we were not able to quantify how many units of FFP were given to each patient. It may be that the probability of experiencing a medical complication may be more dependent on the volume of FFP, the administration of factor VII, or on other unknown variables than on the actual HD1 INR. This study has some limitations. First, it is a retrospective study, and patients were not randomized into HD1 INR and groups. Thus, it is difficult to account for confounding variables. Furthermore, although the mean follow-up was several weeks in all of the groups and although all patients had at least 1 repeat head CT scan, almost 25% of patients did not have followup beyond 1 week. A number of patients presenting with SDH do so in the setting of alcohol or drug intoxication, and therefore are sometimes unreliable with regard to follow-up. In addition, many patients are transferred to our medical center from community hospitals and may receive follow-up from local neurosurgeons or primary care physicians for convenience. All groups were similar in the number of patients who were lost to follow-up; we hope that the error introduced due to the loss to followup is evenly distributed among the groups, but we cannot ascertain that this is true. Despite these limitations, this study is an important first step in helping determine the optimal target INR for reversal of coagulopathy in patients presenting with warfarin-associated SDH. To our knowledge, this is the first study comparing outcomes of patients with warfarin-associated SDH in whom the HD1 INR is reversed aggressively to and to This study has several potential implications in patient care. First, warfarin-associated SDH is a very common condition treated by neurosurgeons and intensivists. Therefore, if a higher INR was chosen as the reversal goal, less FFP may be required in each patient s care. This could potentially translate to significant cost savings. Second, although this study did not reveal a large difference in medical complications between patients with warfarin-associated SDH, less aggressive reversal of INR may still translate to lower rates of medical complications. Further study is needed for better identification of the actual risk associated with subtherapeutic INR elevations and to characterize which factors predispose patients to developing medical complications. Specifically, a prospective study with greater patient numbers and including the volume of FFP transfused in each patient would be helpful in answering this question. Conclusions Mild INR elevations of in warfarin-associated SDH were not associated with a markedly increased risk of radiographic or clinically significant expansion of SDH in this retrospective study. Further prospective studies must be done for definitive assessment of the risk associated with mild INR elevations in the immediate postadmission period. Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Author contributions to the study and manuscript preparation include the following. Conception and design: JK Wu, Ro guski. Ac qui sition of data: Roguski. Analysis and interpretation of data: JK Wu, Roguski, K Wu. Drafting the article: Roguski, K Wu, Riesenburger. Crit i cally revising the article: all authors. Re viewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: JK Wu. Sta tis tical analysis: Roguski. Study su per vision: JK Wu, Roguski, Riesen burger. References 1. Appelboam R, Thomas EO: Warfarin and intracranial haemorrhage. Blood Rev 23:1 9, Atrial Fibrillation Investigators: Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 154: , 1994 (Erratum in Arch Intern Med 154:2254, 1994) 3. Bershad EM, Farhadi S, Suri MF, Feen ES, Hernandez OH, Selman WR, et al: Coagulopathy and inhospital deaths in patients with acute subdural hematoma. Clinical article. 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8 Effect of mild coagulopathy in acute subdural hematoma sche J, et al: Factors associated with failure to correct the international normalized ratio following fresh frozen plasma ad ministration among patients treated for warfarin-related major bleeding. Thromb Haemost 107: , Mountain D, Sistenich V, Jacobs IG: Characteristics, management and outcomes of adults with major trauma taking preinjury warfarin in a Western Australian population from 2000 to 2005: a population-based cohort study. Med J Aust 193: , Oake N, Jennings A, Forster AJ, Fergusson D, Doucette S, van Wal raven C: Anticoagulation intensity and outcomes among pa tients prescribed oral anticoagulant therapy: a systematic re view and meta-analysis. CMAJ 179: , Oyama H, Kito A, Maki H, Hattori K, Noda T, Wada K: Acute subdural hematoma in patients with medication associated with risk of hemorrhage. Neurol Med Chir (Tokyo) 51: , Palareti G, Leali N, Coccheri S, Poggi M, Manotti C, D Angelo A, et al: Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Lancet 348: , Panczykowski DM, Okonkwo DO: Premorbid oral antithrombotic therapy and risk for reaccumulation, reoperation, and mor tality in acute subdural hematomas. Clinical article. J Neu rosurg 114:47 52, Pieracci FM, Eachempati SR, Shou J, Hydo LJ, Barie PS: Degree of anticoagulation, but not warfarin use itself, predicts adverse outcomes after traumatic brain injury in elderly trauma patients. J Trauma 63: , Singer DE, Chang Y, Fang MC, Borowsky LH, Pomernacki NK, Udaltsova N, et al: Should patient characteristics influence target anticoagulation intensity for stroke prevention in nonvalvular atrial fibrillation? The ATRIA study. Circ Cardiovasc Qual Outcomes 2: , 2009 Manuscript submitted October 12, Accepted March 8, Portions of this work were presented in poster form at the annual meeting of the CNS in Chicago, Illinois, on October 8, Please include this information when citing this paper: published online April 12, 2013; DOI: / JNS Address correspondence to: Julian K. Wu, M.D., Department of Neurosurgery, Tufts Medical Center, 800 Washington Street, Boston, Massachusetts jwu3@tuftsmedicalcenter.org. J Neurosurg / Volume 119 / October