Oral Anticoagulant-associated Intracerebral Hemorrhage Research Articles

Epidemiology and outcomes of intracerebral hemorrhage associated with oral anticoagulation over 10 years in a population-based stroke registry.

Recent years have seen a change in the use of anticoagulants in the general population due to the availability of direct oral anticoagulants (DOACs) as an alternative to vitamin K antagonists (VKAs) and increased detection of atrial fibrillation. It is important to have updated epidemiological data to understand how this change is impacting on the occurrence and outcome of intracerebral hemorrhage (ICH). Our prospective population-based registry included patients with first-ever ICH occurring from January 2011 to December 2020. Oral anticoagulants (OAC)-related ICH was defined as an ICH occurring within 48 h from the intake of DOAC or VKAs, regardless of the measured international normalized ratio on hospital admission. We included 748 first-ever ICH, of whom 108 (14.4%) were OAC-related. Specifically, 75 (69.4%) ICHs occurred on VKA and 33 (30.6%) on DOAC. The incidence of oral anticoagulation-associated intracerebral hemorrhage (OAC-ICH) was stable over time (p = 0.226). Among OAC-ICHs, we observed an increase in the overall incidence of DOAC-ICH (p for trend < 0.001) which overcome that of VKA-ICH in 2020 (incidence rate ratio (IRR) 4.71, 95% confidence interval (CI): 1.22-33.54; p = 0.022). Patients with OAC-ICH showed higher 30-day case fatality rates than those with non-OAC-ICH (48.1% vs 34.1%; p = 0.007). No changes over time were detected in the incidence of OAC-ICH, but throughout the study period, there was a change in OAC-ICH from mostly VKA-related to mostly DOAC-related. Mortality in patients with OAC-ICH was higher than in patients with non-OAC-ICH.

Impact of cerebral small vessel disease burden and drug level at admission on direct oral anticoagulant associated intracerebral hemorrhage.

Direct oral anticoagulant (DOAC)-associated intracerebral hemorrhage (ICH) is a catastrophic complication. The aim of this study was to investigate the association between computed tomography (CT)-based cerebrovascular small vessel disease (SVD) burden and DOAC-ICH as well as the DOAC concentration upon hospital admission and ICH outcome. The study included two cohorts: (1) DOAC-ICH: patients who suffered from DOAC-ICH and underwent drug level measurements upon admission; (2) DOAC-non-ICH: stable DOAC users who underwent head CT without ICH during treatment. We categorized the DOAC levels of the DOAC-ICH patients as low (<50 ng/mL), medium (50-300 ng/mL), and high (>300 ng/mL). The CT-based SVD burden (including white matter lesions [WML], lacunes, and cerebral atrophy) was evaluated, and SVD scores (range, 0-3) were used to evaluate SVD severity. A total of 43 DOAC-ICH patients and 177 DOAC-non-ICH patients were enrolled. DOAC-ICH patients were more likely to have WML, lacunes, or cerebral atrophy compared to DOAC-non-ICH patients. After adjustment, the SVD burden was associated with DOAC-ICH, with a higher risk of more severe SVD (SVD score of 2; odds ratio [OR], 10.3 [3.17, 33.3]; score of 3; OR, 16.8 [4.50, 62.6]). The proportions of patients with high, medium, and low drug levels in the DOAC-ICH group were 16.3%, 55.8%, and 27.9%, respectively. Additionally, the high-level group displayed a larger hematoma size and had worse functional outcomes at 3 months than the other two groups. The severity of SVD burden was associated with DOAC-ICH. Furthermore, high DOAC levels in ICH were associated with unfavorable clinical outcomes. To address the potential selection bias from these two cohorts, a prospective study to investigate the co-contribution of drug levels and SVD to DOAC-ICH is essential.

Hematoma Expansion and Clinical Outcomes in Patients With Factor-Xa Inhibitor-Related Atraumatic Intracerebral Hemorrhage Treated Within the ANNEXA-4 Trial Versus Real-World Usual Care.

It is unestablished whether andexanet alfa, compared with guideline-based usual care including prothrombin complex concentrates, is associated with reduced hematoma expansion (HE) and mortality in patients with factor-Xa inhibitor-related intracerebral hemorrhage (ICH). We compared the occurrence of HE and clinical outcomes in patients treated either with andexanet alfa or with usual care during the acute phase of factor-Xa inhibitor-related ICH. Data were extracted from the multicenter, prospective, single-arm ANNEXA-4 trial (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors) and a multicenter observational cohort study, RETRACE-II (German-Wide Multicenter Analysis of Oral Anticoagulant-Associated Intracerebral Hemorrhage - Part Two). HE was based on computed tomography scans performed within 36 hours from baseline imaging. Inverse probability of treatment weighting was performed to adjust for baseline comorbidities and ICH severity. Patients presenting with atraumatic ICH while receiving apixaban or rivaroxaban within 18 hours of admission were included. Patients with secondary ICH or not fulfilling the inclusion criteria for the ANNEXA-4 trial were excluded. We compared ANNEXA-4 patients, who received andexanet alfa for hemostatic treatment, with RETRACE-II patients who were treated with usual care, primarily administration of prothrombin complex concentrates. Primary outcome was rate of HE defined as relative increase of ≥35%. Secondary outcomes comprised mean absolute change in hematoma volume, as well as in-hospital mortality and functional outcome. Overall, 182 patients with factor-Xa inhibitor-related ICH (85 receiving andexanet alfa versus 97 receiving usual care) were selected for analysis. There were no relevant differences regarding demographic or clinical characteristics between both groups. HE occurred in 11 of 80 (14%) andexanet alfa patients compared with 21 of 67 (36%) usual care patients (adjusted relative risk, 0.40 [95% CI, 0.20-0.78]; P=0.005), with a reduction in mean overall hematoma volume change of 7 mL. There were no statistically significant differences among in-hospital mortality or functional outcomes. Sensitivity analysis including only usual care patients receiving prothrombin complex concentrates demonstrated consistent results. As compared with usual care, andexanet alfa was associated with a lower rate of HE in atraumatic factor-Xa inhibitor-related ICH, however, without translating into significantly improved clinical outcomes. A comparative trial is needed to confirm the benefit on limiting HE and to explore clinical outcomes across patient subgroups and by time to treatment. Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT02329327 and NCT03093233.

Disability-Adjusted Life-Years Associated With Intracerebral Hemorrhage and Secondary Injury

Intracerebral hemorrhage (ICH) contributes significantly to the global burden of disease. To examine the association of ICH and secondary injury with disability-adjusted life-years (DALYs) for the individual patient. This cohort study was conducted using data from the Universitätsklinikum Erlangen Cohort of Patients With Spontaneous Intracerebral Hemorrhage study. Consecutive patients admitted to a single tertiary care center from January 1, 2006, to December 31, 2015, were included. The sample comprised patients with oral anticoagulation-associated ICH (OAC-ICH) or primary spontaneous ICH (non-OAC-ICH). Statistical analysis was conducted from October 1 to December 31, 2020. ICH occurrence and secondary injury. DALYs, years of life lost (YLL), and years lived with disability (YLD) were analyzed by hematoma location, ICH volume, and secondary injury (ie, hematoma expansion [HE], intraventricular hemorrhage [IVH], and perihemorrhagic edema [PHE]). Among 1322 patients with ICH, 615 (46.5%) were women and the mean (SD) age at hospital admission was 71 (13) years; ICH was associated with a mean (SD) of 9.46 (8.08) DALYs, 5.72 (8.29) YLL, and 3.74 (5.95) YLD. There were statistically significant differences in mean (SD) DALYs by extent of hematoma volume (< 10 mL ICH: 7.05 [6.79] DALYs; 10-30 mL ICH: 9.91 [8.35] DALYs; >30 mL ICH: 12.42 [8.47] DALYs; P < .001) and ICH location (deep location: 10.60 [8.35] DALYs; lobar location: 8.18 [7.63] DALYs; cerebellum: 8.14 [6.80] DALYs; brainstem: 12.63 [9.21] DALYs; P < .001). Regarding population-level disease burden of secondary injuries after ICH, there was a statistically significant difference in mean (SD) by injury type, with 0.94 (3.19) DALYs for HE, 2.45 (4.16) DALYs for IVH, and 1.96 (2.66) DALYs for PHE (P < .001) among the entire ICH cohort. Regarding individual-level exposure to secondary injuries after ICH, there were a mean (SD) 7.14 (6.62) DALYs for HE, 4.58 (4.75) DALYs for IVH, and 3.35 (3.28) DALYs for PHE among patients with ICH affected by secondary injuries. These findings suggest that there is a high burden of disability associated with ICH and secondary injuries, and the findings may guide public health strategies. The study findings further suggest that IVH and PHE may be relevant for the overall outcome of patients with ICH, that DALYs may represent a viable outcome parameter for studies to evaluate treatment outcomes in ICH research, and that IVH and PHE may represent potential treatment targets.

Perihematomal Edema and Clinical Outcome in Intracerebral Hemorrhage Related to Different Oral Anticoagulants.

Background: There is a need to examine the effects of different types of oral anticoagulant-associated intracerebral hemorrhage (OAC-ICH) on perihematomal edema (PHE), which is gaining considerable appeal as a biomarker for secondary brain injury and clinical outcome. Methods: In a large multicenter approach, computed tomography-derived imaging markers for PHE (absolute PHE, relative PHE (rPHE), edema expansion distance (EED)) were calculated for patients with OAC-ICH and NON-OAC-ICH. Exploratory analysis for non-vitamin-K-antagonist OAC (NOAC) and vitamin-K-antagonists (VKA) was performed. The predictive performance of logistic regression models, employing predictors of poor functional outcome (modified Rankin scale 4–6), was explored. Results: Of 811 retrospectively enrolled patients, 212 (26.14%) had an OAC-ICH. Mean rPHE and mean EED were significantly lower in patients with OAC-ICH compared to NON-OAC-ICH, p-value 0.001 and 0.007; whereas, mean absolute PHE did not differ, p-value 0.091. Mean EED was also significantly lower in NOAC compared to NON-OAC-ICH, p-value 0.05. Absolute PHE was an independent predictor of poor clinical outcome in NON-OAC-ICH (OR 1.02; 95%CI 1.002–1.028; p-value 0.027), but not in OAC-ICH (p-value 0.45). Conclusion: Quantitative markers of early PHE (rPHE and EED) were lower in patients with OAC-ICH compared to those with NON-OAC-ICH, with significantly lower levels of EED in NOAC compared to NON-OAC-ICH. Increase of early PHE volume did not increase the likelihood of poor outcome in OAC-ICH, but was independently associated with poor outcome in NON-OAC-ICH. The results underline the importance of etiology-specific treatment strategies. Further prospective studies are needed.

Thrombocytopenia and Clinical Outcomes in Intracerebral Hemorrhage

The impact of platelets on hematoma enlargement (HE) of intracerebral hemorrhage (ICH) is not yet sufficiently elucidated. Especially the role of reduced platelet counts on HE and clinical outcomes is still poorly understood. This study investigated the influence of thrombocytopenia on HE, functional outcome, and mortality in patients with ICH with or without prior antiplatelet therapy (APT). Individual participant data of multicenter cohort studies (multicenter RETRACE program [German-Wide Multicenter Analysis of Oral Anticoagulation-Associated Intracerebral Hemorrhage] and single-center UKER-ICH registry [Universitätsklinikum Erlangen Cohort of Patients With Spontaneous ICH]) were grouped into APT and non-APT ICH patients according to the platelet count, that is, with or without thrombocytopenia (cells <150×109/L). Of all patients, 51.5% (1124 of 2183) were on vitamin K antagonist. Imbalances in baseline characteristics including proportions of vitamin K antagonist patients were addressed using propensity score matching. Outcome analyses included HE (>33%), as well as mortality and functional outcome, after 3 months using the modified Rankin Scale, dichotomized into favorable (modified Rankin Scale score, 0-3) and unfavorable (modified Rankin Scale score, 4-6). Of overall 2252 ICH patients, 11.4% (52 of 458) under APT and 14.0% (242 of 1725) without APT presented with thrombocytopenia on admission. The proportion of patients with HE was not significantly different between patients with or without thrombocytopenia among APT and non-APT ICH patients after propensity score matching (HE: APT patients: 9 of 40 [22.5%] thrombocytopenia versus 27 of 115 [23.5%] nonthrombocytopenia, P=0.89; non-APT patients: 54 of 174 [31.0%] thrombocytopenia versus 106 of 356 [29.8%] nonthrombocytopenia, P=0.77). In both (APT and non-APT) propensity score matching cohorts, there were no significant differences regarding functional outcome. Mortality after 3 months did not differ among non-APT patients, whereas the mortality rate was significantly higher for APT patients with thrombocytopenia versus APT patients with normal platelet count (APT: 29 of 46 [63.0%] thrombocytopenia versus 58 of 140 [41.4%] nonthrombocytopenia, P=0.01; non-APT: 95 of 227 [41.9%] thrombocytopenia versus 178 of 455 [39.1%] nonthrombocytopenia, P=0.49). Our study implies that thrombocytopenia does not affect rates of HE and functional outcome among ICH patients, neither in patients with nor without APT. In light of increased mortality, the significance of platelet transfusions for ICH patients with thrombocytopenia and previous APT should be explored in future studies.

Blood Pressure and Anticoagulation Reversal Management during Off-Hours in Oral Anticoagulation-Associated Intracerebral Hemorrhage

Background: Prevention of hematoma enlargement in oral anticoagulation-associated intracerebral hemorrhage (OAC-ICH) focuses on blood pressure (BP) reduction and OAC reversal. We investigated whether treatment efficiency and clinical outcomes differ between OAC-ICH patients admitted outside versus during regular working hours. Methods: Based on pooled data of multicenter cohort studies, we grouped OAC-ICH patients (vitamin K antagonist [VKA], non-vitamin K oral anticoagulant [NOAC]) according to on- vs. off-hour admission. Primary outcome was the functional outcome using the modified Rankin scale (mRS) dichotomized into favorable (mRS 0–3) and unfavorable (mRS 4–6) and mortality at 3 months. Secondary outcome measures included the occurrence of hematoma enlargement, the proportions of patients with systolic BP <140 mm Hg and with anticoagulation treatment achieving international normalized ratio (INR) levels <1.3 at 4 h. Propensity score matching (PSM) was performed to account for imbalances in baseline characteristics. Results: The study population consisted of 76/126 NOAC-ICH patients and 1,005/1,470 VKA patients presenting during off-hours. Functional outcome and mortality rates were not significantly different among PSM patients with VKA-ICH and NOAC-ICH during on- vs. off-hours (mRS 4–6 VKA-ICH: on-hour: 239/357 [66.9%] vs. 253/363 [69.7%] off-hour; p = 0.43; NOAC-ICH: on-hour 26/42 [61.9%] vs. off-hour: 37/57 [64.9%]; p = 0.76; mRS 6 VKA-ICH: on-hour: 127/357 [35.6%] vs. off-hour: 148/363 [40.8%]; p = 0.15; ­NOAC-ICH: on-hour 17/42 [40.5%] vs. off-hour: 16/57 [28.1%]; p = 0.20). There were no differences detectable regarding the secondary outcome measures (i.e., hematoma enlargement, the proportion of patients who achieved systolic BP levels <140 mm Hg at 4 h as well as anticoagulation treatment achieving INR levels <1.3 at 4 h) in OAC patients. Conclusion: Our study implies that BP reduction and anticoagulation reversal management are well established and associated with similar rates of hematoma enlargement and clinical outcomes in on- vs. off-hour admitted OAC-ICH patients.

Direct-Acting Oral Anticoagulants and Warfarin-Associated Intracerebral Hemorrhage Protocol Reduces Timing of Door to Correction Interventions.

Intracerebral hemorrhage (ICH) is a life-threatening complication of oral anticoagulant therapy that sometimes results in hematoma expansion after onset. Our facility did not have a standardized process for treating oral anticoagulant-associated ICH; this resulted in lag times from order to reversal agent administration. The aim of this study was to examine the impact of a rapid anticoagulant reversal protocol, combined with warfarin and direct-acting oral anticoagulant therapy, in decreasing door to first intervention times. This study used a retrospective quality assessment research approach in examining an oral anticoagulant reversal protocol to compare the control and intervention groups. Phytonadione was the first intervention treatment for most study participants diagnosed with warfarin-associated ICH with an international normalized ratio greater than 1.4. Factor IX was the first intervention treatment for all but one study participant with DOAC-associated ICH. Findings were statistically significant (P < .05) for door to first intervention treatments. Door to phytonadione in minutes decreased from 232.7 (SD, 199.4) to posttest findings of 111.4 (SD, 64.6). Door to factor IX in minutes decreased from 183.9 (SD, 230.2) to posttest findings of 116.6 (SD, 69.1). Study findings support the hypothesis that the new protocol was associated with lower door-to-treatment times for eligible patients.

Abstract WP448: Safety of Heparin for Prophylaxis of Venous Thromboembolism in Oral Anticoagulation-Associated Intracerebral Hemorrhage

Introduction: Patients with intracerebral hemorrhage (ICH) have a high risk of venous thromboembolism (VTE). Next to intermittent pneumatic compressions low-dose subcutaneous heparins represent the most intuitive treatment for VTE prophylaxis. However, in the specific setting of ICH their safety remains to be verified as randomized controlled trials are missing. The present study pooled individual data of patients with spontaneous primary ICH and OAC-ICH to explore the incidence of hemorrhagic complications during hospital stay among subgroups treated with heparins for VTE prophylaxis. Methods: We integrated both parts of the RETRACE-program (part-1: 2006-2010; part-2:2011-2015) and the single-center UKER-ICH registry (2006-2015). Including all patients receiving low-dose subcutaneous heparin for VTE prevention we pooled individual patient data of 1702 vitamin-K antagonist-(VKA) or non-VKA oral anticoagulants(NOAC)-related ICH patients treated at 22 tertiary-care centers across Germany and of 1022 primary spontaneous ICH patients from UKER. We defined intracranial hemorrhagic complications (IHC) during hospital stay as primary safety outcome measure. Secondary outcomes included mortality and functional outcome (modified Rankin Scale, mRS) at 3 months of patients with and without IHC. Results: IHC occurred in 1.7%(42/2416) of ICH patients. There were no differences in crude incidence rates among patients with VKA-ICH, NOAC-ICH and non-OAC-ICH (Log rank p=0.645; Breslow p=0.753; VKA-ICH: 27/1406[1.9%], NOAC-ICH 1/130[0.8%], non-OAC-ICH 14/880[1.6%];p=0.577). Detailed analysis according to days spent on heparin prophylaxis revealed no differences in rates of IHC per 1000 patient days (VKA-ICH: 1.49[1.00-2.14], NOAC-ICH 0.63[0.03-3.13], non-OAC-ICH 1.45[0.82-2.37]; p=0.687). Secondary outcomes showed differences in functional outcome (mRS=4-6: IHC: 29/37[78.4%] vs no-IHC: 1213/2048[59.2%];p=0.019) and mortality (IHC: 14/37[37.8%] vs no-IHC: 485/2048[23.7%];p=0.045) in disfavor of IHC-patients. Conclusions: Heparin administration for VTE prophylaxis in ICH patients appears to be safe without differently increased risks of IHC among non-OAC-ICH, VKA-ICH and NOAC-ICH.

Management of Oral Anticoagulant-associated Intracerebral Hemorrhage

Introduction: Oral anticoagulant-associated intracerebral hemorrhages (OAC-ICHs) account for nearly 20% of all ICH and are associated with high mortality. The number of patients with an indication for oral anticoagulant therapy (OAT) is increasing with the aging population; therefore, despite the improved safety profile of non-vitamin K oral anticoagulants (NOACs), the number of patients with OAC-ICH will increase. OAT was simplified with the introduction of NOACs, which are easy to handle and show a favorable risk-benefit profile. The rate of ICH is lower than for vitamin K antagonists (VKA) and routine coagulation testing is not required. Nevertheless, OAC-ICH does occur and is still a devastating disease, thus representing the most feared complication in OAT, irrespective of treatment with VKA or NOAC. Purpose: The aim of this article is to address the clinical problem of bleeding management in patients with ICH due to OAC and will consider anticoagulation with NOAC and VKA. Recommendations: Restoring coagulation as soon as possible is the main goal and, therefore, knowledge of the actual coagulation status is essential. In VKA-associated ICH, the international normalized ratio (INR) should be lowered to below 1.3. However, laboratory measurement of anticoagulant activity in NOAC patients is more complex, rendering OAC-ICH treatment more complicated. The best assays are specialized and not widely available, whereas more accessible tests such as prothrombin time and activated partial thromboplastin time have important limitations. For VKA-ICH, prothrombin complex concentrate (PCC) should be administered to reverse the INR. For dabigatran-related ICH, 5 g idarucizumab should be administered. For factor Xa inhibitors, PCC is recommended in the absence of andexanet alfa as soon as an OAC-related ICH evolves. Resuming OAC after ICH should be considered, depending on risk factors and a risk-benefit evaluation.

Antiplatelet Therapy in Primary Spontaneous and Oral Anticoagulation-Associated Intracerebral Hemorrhage.

Background and Purpose- This study determined the influence of concomitant antiplatelet therapy (APT) on hematoma characteristics and outcome in primary spontaneous intracerebral hemorrhage (ICH), vitamin K antagonist (VKA)- and non-VKA oral anticoagulant-associated ICH. Methods- Data of retrospective cohort studies and a prospective single-center study were pooled. Functional outcome, mortality, and radiological characteristics were defined as primary and secondary outcomes. Propensity score matching and logistic regression analyses were performed to determine the association between single or dual APT and hematoma volume. Results- A total of 3580 patients with ICH were screened, of whom 3545 with information on APT were analyzed. Three hundred forty-six (32.4%) patients in primary spontaneous ICH, 260 (11.4%) in VKA-ICH, and 30 (16.0%) in non-VKA oral anticoagulant-associated ICH were on APT, and these patients had more severe comorbidities. After propensity score matching VKA-ICH patients on APT presented with less favorable functional outcome (modified Rankin Scale score, 0-3; APT, 48/202 [23.8%] versus no APT, 187/587 [31.9%]; P=0.030) and higher mortality (APT, 103/202 [51.0%] versus no APT, 237/587 [40.4%]; P=0.009), whereas no significant differences were present in primary spontaneous ICH and non-VKA oral anticoagulant-associated ICH. In VKA-ICH, hematoma volume was significantly larger in patients with APT (21.9 [7.4-61.4] versus 15.7 [5.7-44.5] mL; P=0.005). Multivariable regression analysis revealed an association of APT and larger ICH volumes (odds ratio, 1.80 [1.20-2.70]; P=0.005), which was more pronounced in dual APT and supratherapeutically anticoagulated patients. Conclusions- APT does not affect ICH characteristics and outcome in primary spontaneous ICH patients; however, it is associated with larger ICH volume and worse functional outcome in VKA-ICH, presumably by additive antihemostatic effects. Combination of anticoagulation and APT should, therefore, be diligently evaluated and restricted to the shortest possible time frame.

Non-Vitamin K Oral Anticoagulants Associated Bleeding and Its Antidotes.

Oral anticoagulant-associated intracerebral hemorrhage (OAC-ICH) accounts for nearly 20% of all ICH. The number of patients with an indication for oral anticoagulant therapy (OAT) increases with increasing age. OAT became less complicate with the introduction of non-vitamin K oral anticoagulants (NOAC) OAT because of easier handling, favorable risk-benefit profile, reduced rates of ICH compared to vitamin K antagonists and no need for routine coagulation testing. Consequently, despite a better safety profile of NOAC the number of patients with OAC-ICH will increase. The mortality and complication rates of OAC-ICH are high and therefore they are the most feared complication of OAT. Immediate normalization of coagulation is the main goal and therefore knowledge of pharmacodynamics and coagulation status is essential. Laboratory measurements of anticoagulant activity in NOAC patients is challenging as specific tests are not widely available. More accessible tests such as the prothrombin time and activated partial thromboplastin time have important limitations. In dabigatran-associated ICH 5 g Idarucizumab should be administered. In rivaroxaban and apixaban-associated ICHs administration of andexanet alpha should be considered. Prothrombin complex concentrate may be considered if andexanet alpha is not available or in case of an ICH associated with edoxaban.

Outcomes and Costs of Patients Admitted to the ICU Due to Spontaneous Intracranial Hemorrhage.

Spontaneous intracranial hemorrhage, including subarachnoid hemorrhage and intracerebral hemorrhage, is associated with significant morbidity and mortality. Although many of these patients will require ICU admission, little is known regarding their outcomes and the costs incurred. We evaluated this population in order to identify outcomes and cost patterns. Retrospective cohort analysis of a health administrative database. Two ICUs within a single hospital system. Eight-thousand four-hundred forty-seven patients admitted to ICU from 2011 to 2014, of whom 332 had a diagnosis of spontaneous intracranial hemorrhage. Control patients were defined as randomly selected age, sex, and comorbidity index-matched nonintracranial hemorrhage ICU patients (1:4 matching ratio). None. Mean age of ICU intracranial hemorrhage patients was 60.1 years, and 120 (36.1%) died prior to discharge. Intracranial hemorrhage was associated with a mean total cost of $75,869, compared with $52,471 in control patients (p < 0.01). Mean cost per survivor of intracranial hemorrhage patients was $118,813. Subarachnoid hemorrhage was associated with significantly higher mean total costs than intracerebral hemorrhage ($92,794 vs $53,491; p < 0.01) and higher mean cost per day ($4,377 vs $3,604; p < 0.01). Patients with intracranial hemorrhage who survived to hospital discharge were significantly costlier than decedents ($100,979 vs $30,872; p < 0.01). Intracranial hemorrhage associated with oral anticoagulant use had a mean total cost of $152,373, compared with $66,548 in nonoral anticoagulant intracranial hemorrhage (p < 0.01). Patients admitted to ICU with intracranial hemorrhage have high costs and high mortality, leading to elevated cost per survivor. Subarachnoid hemorrhage patients incur greater costs than intracerebral hemorrhage patients, and oral anticoagulant-associated intracerebral hemorrhage is particularly costly. Our findings provide novel information regarding financial impact of this common ICU population.

Hematoma Expansion Following Intracerebral Hemorrhage: Mechanisms Targeting the Coagulation Cascade and Platelet Activation.

Hematoma expansion (HE), defined as a greater than 33% increase in intracerebral hemorrhage (ICH) volume within the first 24 hours, results in significant neurological deficits, and enhancement of ICH-induced primary and secondary brain injury. An escalation in the use of oral anticoagulants has led to a surge in the incidences of oral anticoagulation-associated ICH (OAT-ICH), which has been associated with a greater risk for HE and worse functional outcomes following ICH. The oral anticoagulants in use include vitamin K antagonists, and direct thrombin and factor Xa inhibitors. Fibrinolytic agents are also frequently administered. These all act via differing mechanisms and thus have varying degrees of impact on HE and ICH outcome. Additionally, antiplatelet medications have also been increasingly prescribed, and result in increased bleeding risks and worse outcomes after ICH. Aspirin, thienopyridines, and GPIIb/IIIa receptor blockers are some of the most common agents in use clinically, and also have different effects on ICH and hemorrhage growth, based on their mechanisms of action. Recent studies have found that reduced platelet activity may be more effective in predicting ICH risk, hemorrhage expansion, and outcomes, than antiplatelet agents, and activating platelets may thus be a novel target for ICH therapy. This review explores how dysfunctions or alterations in the coagulation and platelet cascades can lead to, and/or exacerbate, hematoma expansion following intracerebral hemorrhage, and describe the mechanisms behind these effects and the drugs that induce them. We also discuss potential future therapy aimed at increasing platelet activity after ICH.

Early Clinical and Radiological Course, Management, and Outcome of Intracerebral Hemorrhage Related to New Oral Anticoagulants.

Intracerebral hemorrhage (ICH) is the most devastating adverse event in patients receiving oral anticoagulation. There is only sparse evidence regarding ICH related to the use of non-vitamin K antagonist oral anticoagulant (NOAC) agents. To evaluate the early clinical and radiological course, acute management, and outcome of ICH related to NOAC use. Prospective investigator-initiated, multicenter observational study. All diagnostic and treatment decisions, including administration of hemostatic factors (eg, prothrombin complex concentrate), were left to the discretion of the treating physicians. The setting was 38 stroke units across Germany (February 1, 2012, to December 31, 2014). The study included 61 consecutive patients with nontraumatic NOAC-associated ICH, of whom 45 (74%) qualified for the hematoma expansion analysis. Hematoma expansion, intraventricular hemorrhage, and reversal of anticoagulation during the acute phase. Recorded were the 3-month functional outcome, factors associated with an unfavorable outcome (modified Rankin Scale score, 3-6), any new intraventricular extension or an increase in the modified Graeb score by at least 2 points, and the frequency of substantial hematoma expansion (defined as relative [≥ 33%] or absolute [≥ 6-mL] volume increase). In total, 41% (25 of 61) of patients with NOAC-associated ICH were female, and the mean (SD) patient age was 76.1 (11.6) years. At admission, the median National Institutes of Health Stroke Scale score was 10 (interquartile range, 4-18). The mean (SD) baseline hematoma volume was 23.7 (31.3) mL. In patients with sequential imaging for the hematoma expansion analysis, substantial hematoma expansion occurred in 38% (17 of 45). New or increased intraventricular hemorrhage was observed in 18% (8 of 45). Overall mortality was 28% (17 of 60 [follow-up data were missing in 1 patient]) at 3 months, and 65% (28 of 43) of survivors had an unfavorable outcome (modified Rankin Scale score, 3-6). Overall, 57% (35 of 61) of the patients received prothrombin complex concentrate, with no statistically significant effect on the frequency of substantial hematoma expansion (43% [12 of 28] for prothrombin complex concentrate vs 29% [5 of 17] for no prothrombin complex concentrate, P = .53), or on the occurrence of an unfavorable outcome (modified Rankin Scale score, 3-6) (odds ratio, 1.20; 95% CI, 0.37-3.87; P = .76). Non-vitamin K antagonist oral anticoagulant-associated ICH has a high mortality and an unfavorable outcome, and hematoma expansion is frequent. Larger-scale prospective studies are needed to determine whether the early administration of specific antidotes can improve the poor prognosis of NOAC-associated ICH.

Endovascular Treatment of Stroke, Oral Anticoagulant-associated Intracerebral Hemorrhage, and Treatment of Extracranial Dissection.

Endovascular Treatment of Stroke, Oral Anticoagulant-associated Intracerebral Hemorrhage, and Treatment of Extracranial Dissection.

How to Reverse Oral Anticoagulant-Associated Intracerebral Hemorrhage

How to Reverse Oral Anticoagulant-Associated Intracerebral Hemorrhage

Abstract W MP71: Effect of Race/Ethnicity on Oral Anticoagulant-Associated Intracerebral Hemorrhage

Background: Oral anticoagulant (OAC) use is associated with poor outcome in intracerebral hemorrhage (ICH). The aim of this study was to determine if race/ethnic differences exist in this condition. Methods: Data were obtained from the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study which is a prospective multicenter study of ICH. Exclusion criteria included missing initial hematoma volume or being on heparin or LMWH. Baseline and clinical characteristics, laboratory and imaging data at presentation and 24h, and mortality at 3 months were compared by OAC use and race/ethnicity. ANOVA was used to identify factors affecting initial hematoma volume by location and OAC use. Logistic regression was performed to evaluate risk of hemorrhage based on race/ethnicity. Results: A total of 2,020 of 2,276 cases met the inclusion criteria and were included in the analysis (627 whites, 739 blacks, and 654 Hispanics) of which 214 (10.5%) were on OAC (54% white, 22% black, and 23% Hispanic). History of hypertension, diabetes, hypercholesterolemia, previous stroke, and atrial fibrillation, elevated INR at admission, infratentorial location, and dementia were associated with OAC use (p&lt;.001). There were no differences in initial hemorrhage volume by race/ethnicity. Among OAC users, median INRs were 2.10 (1.67-2.80) white, 1.89 (1.30-3.05) black, and 2.53 (1.60-3.60) Hispanic (p=0.06). Compared with whites, blacks on OAC were more likely to have deep hemorrhages (OR=1.5, 95%CI=1.2-1.9). Lobar ICH was less commonly seen in blacks (OR= 0.6, 95%CI 0.5-0.7) and Hispanics (OR 0.7, 95%CI 0.5-0.9). No differences were seen in infratentorial ICH. Use of OAC predicted higher case fatality at 3-months (OR=1.7, CI=1.1-2.6). In the subgroup analysis this association remained statistically significant for blacks only (OR=3.2, CI=1.4-7.0). Conclusion: In the largest prospective study in ICH we found that location and outcome in OAC-associated ICH differ among subjects of different racial/ethnic background. Our findings indicate that OAC-associated ICH is a heterogeneous condition and identifies blacks as a group with increased case fatality rate.

Blood-Fluid level: A Sign of Oral Anticoagulant-Associated Intracerebral Hemorrhage in a Patient with Ischemic Stroke

A 65 year-old female patient with past medical history of diabetes mellitus, hypertension and ischemic heart disease presented with acute onset of right hemiplegia, right facial palsy and dysphasia. Urgent CT brain showed hypodensity involving the territory of the lower division of left middle cerebral artery denoting recent infarction. On admission the patient was found to have Atrial Fibrillation (AF) and LMW Heparin was started followed by Warfarin. One week after initiation of Warfarin the patient started to have headache, increased weakness with deterioration of the level of consciousness. Urgent NECT brain was done and showed hemorrhagic transformation, mass effect and “Blood-fluid level” (Figure 1). Her international normalized ratio (INR) was 3.5.

Warfarin pretreatment reduces cell death and MMP-9 activity in experimental intracerebral hemorrhage.

Little is known about the pathophysiology of oral anticoagulation-associated intracerebral hemorrhage (OAC-ICH). We compared hematoma volume, number of terminal deoxynucleotidyl dUTP nick-end labeling (TUNEL)-positive cells (indicating cell death), MMP-9 levels, and perilesional edema formation between warfarin-treated mice and controls. Intracerebral hemorrhage was induced by an injection of collagenase into the right striatum. Twenty-four hours later, hematoma volume was measured using a photometric hemoglobin assay. Cell death was quantified using TUNEL staining. MMP-9 levels were determined by zymography, and edema formation was assessed via the wet-dry method. Warfarin increased hematoma volume by 2.6-fold. The absolute number of TUNEL-positive cells in the perihematomal zone was lower in warfarin-treated animals (300.5 ± 39.8 cells/mm2) than in controls (430.5 ± 38.9 cells/mm2; p = 0.034), despite the larger bleeding volume. MMP-9 levels were reduced in anticoagulated mice as compared to controls (p = 0.018). Perilesional edema formation was absent in warfarin mice and modestly present in controls. Our results suggest differences in the pathophysiology of OAC-ICH compared to intracerebral hemorrhage occurring under normal coagulation. A likely explanation is that thrombin, a strong inductor of apoptotic cell death and blood-brain barrier disruption, is produced to a lesser extent in OAC-ICH. In humans, however, we assume that the detrimental effects of a larger hematoma volume in OAC-ICH by far outweigh potential protective effects of thrombin deficiency.