Incident Intracranial Hemorrhage Research Articles

Direct Oral Anticoagulants Versus Warfarin Across the Spectrum of Kidney Function: Patient-Level Network Meta-Analyses From COMBINE AF.

There is uncertainty surrounding the use of direct oral anticoagulants (DOACs) in patients with kidney dysfunction. Using the COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) database (data from RE-LY [Randomized Evaluation of Long-term Anticoagulation Therapy], ROCKET AF [Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation], ARISTOTLE [Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation], and ENGAGE AF-TIMI 48 [Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48]), we performed an individual patient-level network meta-analysis to evaluate the safety and efficacy of DOACs versus warfarin across continuous creatinine clearance (CrCl). A multivariable Cox model including treatment-by-CrCl interaction with random effects was fitted to estimate hazard ratios for paired treatment strategies (standard-dose DOAC, lower-dose DOAC, and warfarin). Outcomes included stroke and systemic embolism (S/SE), major bleeding, intracranial hemorrhage (ICH), and death. Among 71 683 patients (mean age, 70.6±9.4 years; 37.3% female; median follow-up, 23.1 months), the mean CrCl was 75.5±30.5 mL/min. The incidence of S/SE, major bleeding, ICH, and death increased significantly with worsening kidney function. Across continuous CrCl values down to 25 mL/min, the hazard of major bleeding did not change for patients randomized to standard-dose DOACs compared with those randomized to warfarin (Pinteraction=0.61). Compared with warfarin, standard-dose DOAC use resulted in a significantly lower hazard of ICH at CrCl values <122 mL/min, with a trend for increased safety with DOAC as CrCl decreased (6.2% decrease in hazard ratio per 10-mL/min decrease in CrCl; Pinteraction=0.08). Compared with warfarin, standard-dose DOAC use resulted in a significantly lower hazard of S/SE with CrCl <87 mL/min, with a significant treatment-by-CrCl effect (4.8% decrease in hazard ratio per 10-mL/min decrease in CrCl; Pinteraction=0.01). The hazard of death was significantly lower with standard-dose DOACs for patients with CrCl <77 mL/min, with a trend toward increasing benefit with lower CrCl (2.1% decrease in hazard ratio per 10-mL/min decrease in CrCl; Pinteraction=0.08). Use of lower-dose rather than standard-dose DOACs was not associated with a significant difference in incident bleeding or ICH in patients with reduced kidney function but was associated with a higher incidence4 of death and S/SE. Standard-dose DOACs are safer and more effective than warfarin down to a CrCl of at least 25 mL/min. Lower-dose DOACs do not significantly lower the incidence of bleeding or ICH compared with standard-dose DOACs but are associated with a higher incidence of S/SE and death. These findings support the use of standard-dose DOACs over warfarin in patients with kidney dysfunction.

Intracranial Hemorrhage in the TST Trial.

Although statins are effective in secondary prevention of ischemic stroke, they are also associated with an increase risk of intracranial hemorrhage (ICH) in certain conditions. In the TST trial (Treat Stroke to Target), we prespecified an exploration of the predictors of incident ICH. Patients with ischemic stroke in the previous 3 months or transient ischemic attack within the previous 15 days and evidence of cerebrovascular or coronary artery atherosclerosis were randomly assigned in a 1:1 ratio to a target LDL (low-density lipoprotein) cholesterol of <70 mg/dL or 100±10 mg/dL, using statin or ezetimibe. Among 2860 patients enrolled, 31 incident ICH occurred over a median follow-up of 3 years (18 and 13 in the lower and higher target group, 3.21/1000 patient-years [95% CI, 2.38-4.04] and 2.32/1000 patient-years [95% CI, 1.61-3.03], respectively). While there were no baseline predictors of ICH, uncontrolled hypertension (HR, 2.51 [95% CI, 1.01-6.31], P=0.041) and being on anticoagulant (HR, 2.36 [95% CI, 1.00-5.62], P=0.047)] during the trial were significant predictors. On-treatment low LDL cholesterol was not a predictor of ICH. Targeting an LDL cholesterol of <70 mg/dL compared with 100±10 mg/dL in patients with atherosclerotic ischemic stroke nonsignificantly increased the risk of ICH. Incident ICHs were not associated with low LDL cholesterol. Uncontrolled hypertension and anticoagulant therapy were associated with ICH which has important clinical implications. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01252875; EUDRACT identifier: 2009-A01280-57.

Abstract P003: Effectiveness And Safety Of Direct Oral Anticoagulants Compared With Warfarin In Patients With Atrial Fibrillation Across Body Mass Index Categories

Background: Although direct oral anticoagulants (DOACs) are preferred for most patients needing anticoagulation for atrial fibrillation (AF), uncertainty remains in the effectiveness and safety of DOACs compared with warfarin in patients with obesity. Available data from large real-word cohorts are lacking. Purpose: To examine the effectiveness and safety of DOACs compared with warfarin in patients with obesity and AF. Methods: We conducted a retrospective cohort study at an integrated, multi-site healthcare system. We included patients with AF prescribed either a DOAC or warfarin with ≥ one year of follow-up between 2010-2017. The primary effectiveness outcome was ischemic stroke or systemic embolism (S/SE) and the primary safety outcome was incident intracranial hemorrhage (ICH). Using logistic regression, we calculated propensity scores (PS) of prescription for DOAC in each body mass index (BMI) category (&lt;25 kg/m2, 25.0-29.9 kg/m2, 30.0 to 34.9 kg/m2, and BMI≥35.0 kg/m2) using the following covariates: age, sex, race, ethnicity, BMI, systolic blood pressure, and CHA 2 DS 2 -VASc score. We used inverse probability weighting (IPW) based on the PS and IPW-weighted hazard ratios with 95% confidence intervals were calculated by Cox proportional hazard model. Results: Of a total of 17,905 patients included, mean (standard deviation [SD]) age was 70 ± 12 years and mean (SD) BMI was 29.9 ± 6.7 kg/m 2 ; nearly half received a prescription for DOAC (42.7%) and 57.3% for warfarin. During median follow-up of 3.8 years (interquartile range: 2.2-6.0), a total of 159 stroke and 376 intracranial hemorrhage events were observed. Patients on DOACs had a similar or lower HRs for both S/SE and ICH events compared with warfarin across each BMI category (Figure). Conclusion: In this retrospective study, DOACs were as safe and effective compared with warfarin across BMI categories in patients with AF.

Association of a history of falls or syncope with intracranial bleeding in patients with atrial fibrillation

Abstract Background In patients with atrial fibrillation (AF), anticoagulation effectively reduces the risk of ischemic stroke. However, up to 50% of patients are not receiving this treatment. A history of falls or syncope and an associated risk of intracranial hemorrhage are commonly reported reasons for undertreatment, though these have not been well studied. Purpose To investigate the association of a history of falls or syncope with the risk of intracranial hemorrhage in patients with AF. Methods Patients with a history of AF from the RE-LY, AVERROES and ACTIVE A and W trials were combined into a large cohort. “Critical injury” was defined as any injury that resulted in death, was deemed to be life-threatening or resulted in permanent disability. A “serious injury” was defined as an injury that required hospitalization. “Other injuries” were defined as those that did not meet criteria for critical or serious injury. We used logistic regression and propensity-matched Cox models to assess the association between falls or syncope and adverse outcomes. Results Among 37,973 patients, 11.9% (n=4503) had a history of falls, 17.5% (n=6655) had a history of syncope and 25.1% (n=9518) had a history of either falls or syncope. The mean age of the cohort was 71±9.3 years and 58% were male. The median CHADS2 score was 2. A history of falls or syncope was not associated with the risk of incident intracranial hemorrhage (HR 1.11, 95% CI 0.88–1.4). In propensity-matched multivariable models, a history of falls or syncope was associated with an increased risk of death (HR 1.14, 95% CI 1.07–1.22), stroke (HR 1.17, 95% CI 1.05–1.3), myocardial infarction (HR 1.28, 95% CI 1.09–1.52) and major bleeding (HR 1.27, 95% CI 1.16–1.4). Moreover, a history of falls or syncope was associated with increased risk of critical injury (OR 1.97, 95% CI 1.52–2.54), serious injury (OR 2.06, 95% CI 1.75–2.43) and “other injury” (OR 1.58, 95% CI 1.46–1.72). Conclusions A history of falls or syncope is common in patients with atrial fibrillation; however, neither history was associated with increased risk of intracranial hemorrhage. These patients were at an increased risk of death, stroke, myocardial infarction and major bleeding, suggesting that they should receive anticoagulation for stroke prevention. Funding Acknowledgement Type of funding source: None

Effects of Oral Antiplatelet Agents and Tirofiban on Functional Outcomes of Patients with Non-Disabling Minor Acute Ischemic Stroke

Background and purposeOver half of patients with acute ischemic stroke present with minor neurologic deficits. We investigated the effects of oral antiplatelet agents vs. tirofiban, a highly selective GP IIb/IIIa antiplatelet drug, on functional outcomes of stroke patients with non-disabling neurologic deficits. MethodsThis retrospective study analyzed data of 125 patients with minor stroke who had National Institutes of Health Stroke Scale (NIHSS) scores of 5 or less within 6 hours of stroke symptom onset between January 2010 and June 2018. All patients were selected from the Department of Neurology at the Third Affiliated Hospital of Army Medical University. There were 54 cases in each group after propensity score matching, in which patients received oral antiplatelet agents (n = 64) and tirofiban (n = 61). Safety outcomes were assessed by incident intracranial hemorrhage, systemic bleeding and death. Efficacy outcomes were assessed using the NIHSS score at 24 hrs, 7 days or at discharge, and clinical deterioration. The modified rankin scale (mRs) was assessed at 90 days. ResultsNo significant differences were found in the incidence of intracranial hemorrhage, systemic bleeding or death between groups (P>0.05). Although neurological function improved significantly in both groups, NIHSS scores were lower in the tirofiban group compared with those in the oral antiplatelet agents group at 24 hrs (1 versus 3, P = 0.000), 7 days or at discharge (0 versus 2, P = 0.000). The clinical deterioration rate was higher in the oral antiplatelet agents group than in the tirofiban group, but without significance (16.7% versus 5.6%, P = 0.126). Functional outcomes (mRs = 0) were more favorable in the tirofiban group than in the oral antiplatelet agents group (66.7% vs. 44.4%; adjusted odds ratio 3.32; 95% CI: 1.38–7.99; P = 0. 008). ConclusionIntravenous tirofiban seems to be safe and effective with more favorable functional outcomes than oral antiplatelet agents, suggesting that tirofiban is a viable treatment choice for selected patients with non-disabling minor acute ischemic stroke.

Anticoagulants in Older Patients with Nonvalvular Atrial Fibrillation after Intracranial Hemorrhage

Background and PurposePatients with nonvalvular atrial fibrillation (NVAF) who survive an intracranial hemorrhage (ICH) have an increased risk of ischemic stroke and systemic embolism (IS/ SE). We investigated whether starting oral anticoagulants (OACs) among older NVAF patients after an ICH was associated with a lower risk of IS/SE and mortality but offset by an increase in major bleeding. MethodsWe assembled a patient cohort from the Quebec Régie de l’Assurance Maladie du Québec (RAMQ) and Med-Echo administrative databases. We identified older adults with NVAF from 1995 to 2015. All patients with incident ICH and discharged in community were included. Patients were categorized according to OAC exposure. Outcomes included IS/SE, all-cause mortality, recurrent ICH and major bleeding after a quarantine period of 6 weeks. Crude event rates were calculated at 1-year of follow-up, and Cox proportional hazard models with a time-dependent binary exposure were used to assess adjusted hazard ratios (AHRs). ResultsThe cohort of 683 NVAF patients with ICH aged 83 years on average. The rates (per 100 person-years) for IS/SE, death, ICH and major bleeding were 3.3, 40.6, 11.4, and 2.7 for the no OAC group; and 2.6, 16.3, 5.2, and 5.2 for OAC group, respectively. The AHR for IS/SE and death was 0.10 (95% confidence interval [CI], 0.05 to 0.21), 0.43 (95% CI, 0.19 to 0.97) for recurrent ICH and 1.73 (95% CI, 0.71 to 4.20) for major extracranial bleeding comparing OAC exposure to non-exposed. ConclusionsInitiating OAC after ICH in older individuals with NVAF is associated with a reduction of IS/SE and mortality and a trend in recurrent ICH supporting its use after ICH.

Prognostic relevance of cortical superficial siderosis in cerebral amyloid angiopathy

To investigate the prognostic relevance of cortical superficial siderosis (cSS) in patients with cerebral amyloid angiopathy (CAA). A total of 302 patients fulfilling clinical and imaging criteria for probable or possible CAA were enrolled into a prospective, multicenter cohort study and followed for 12 months. cSS was assessed on T2*/susceptibility-weighted imaging MRI. The predefined primary composite endpoint was incident stroke or death in patients with cSS compared to those without. Secondary analyses included cerebrovascular events and functional outcome measured by the modified Rankin Scale (mRS). Multiple regression analysis was performed to adjust for possible confounders. cSS prevalence was 40%. The primary endpoint occurred more frequently in patients with cSS (22%, 27/121) compared to those without (8%, 15/181, p = 0.001). Rates of CAA-related incident intracranial hemorrhage were 17% (cSS) and 4% (no cSS, p = 0.0003). The proportion of patients being functionally independent (mRS 0-2) 12 months from baseline were 59% (cSS) and 82% (no cSS, p = 0.00002). Presence of cSS was associated with the primary endpoint (adjusted odds ratio [OR] 1.2, 95% confidence interval [CI] 1.1-1.3, p = 0.0005), incident intracranial hemorrhage (adjusted OR 1.2, 95% CI 1.1-1.3, p = 0.0003), and less favorable outcome as assessed by the mRS (common OR 1.9, 95% CI 1.2-3.1, p = 0.009). Similar results were obtained in analyses restricted to patients with probable CAA and to patients with disseminated cSS (all p < 0.005). Patients with cSS and suspected CAA are at high risk for CAA-related incident intracranial hemorrhage and poor functional outcome. Both the presence and extent of cSS have prognostic relevance and may influence clinical decision-making.

PCV31 - ANTICOAGULANTS IN OLDER PATIENTS WITH NON-VALVULAR ATRIAL FIBRILLATION AFTER INTRACRANIAL HEMORRHAGE

Patients with non-valvular atrial fibrillation (NVAF) who survive an intracranial hemorrhage (ICH) have an increased risk of ischemic stroke and systemic emboli (IS/SE). We investigated whether starting oral anticoagulants (OAC) among older NVAF patients after an ICH was associated with a lower risk of IS/SE and mortality, but offset by an increase in major bleeding. Cohort study assembled from administrative data from the Quebec RAMQ and Med-Echo databases. We identified older adults (> 65 years) with NVAF from 1995 to 2015 who were discharged in the community. All patients with incident ICH were included. Patients were categorized as no or OAC exposure. Outcomes included IS/SE, all-cause mortality, recurrent ICH and other major bleeding after a quarantine period of 6 weeks. Crude event rates were calculated at 1-year of follow-up, and Cox proportional Hazard models and a time-dependent binary exposure were used to calculate adjusted HRs (AHR). Cohort of 681 NVAF patients with ICH aged 83 years on average. The rate (per 100 person-years) for IS/SE, death, ICH and major bleeding were 3.3, 40.6, 11.4 and 2.7 for the no OAC group; and 2.6, 16.3, 5.2 and 5.2 for OAC group, respectively. The AHR for IS/SE and death was 0.23 (0.14-0.39) (95% confidence interval), 0.40 (0.18-0.89) for recurrent ICH and 2.26 (0.96-5.36) for major bleeding comparing OAC exposure to non-exposed. Initiating OAC after ICH in older individuals with NVAF is associated with a reduction of IS/SE and mortality as well as recurrent ICH supporting it’s use after ICH.

Outcomes Associated With Resuming Warfarin Treatment After Hemorrhagic Stroke or Traumatic Intracranial Hemorrhage in Patients With Atrial Fibrillation

The increase in the risk for bleeding associated with antithrombotic therapy causes a dilemma in patients with atrial fibrillation (AF) who sustain an intracranial hemorrhage (ICH). A thrombotic risk is present; however, a risk for serious harm associated with resumption of anticoagulation therapy also exists. To investigate the prognosis associated with resuming warfarin treatment stratified by the type of ICH (hemorrhagic stroke or traumatic ICH). This nationwide observational cohort study included patients with AF who sustained an incident ICH event during warfarin treatment from January 1, 1998, through February 28, 2016. Follow-up was completed April 30, 2016. Resumption of warfarin treatment was evaluated after hospital discharge. No oral anticoagulant treatment or resumption of warfarin treatment, included as a time-dependent exposure. One-year observed event rates per 100 person-years were calculated, and treatment strategies were compared using time-dependent Cox proportional hazards regression models with adjustment for age, sex, length of hospital stay, comorbidities, and concomitant medication use. A total of 2415 patients with AF in this cohort (1481 men [61.3%] and 934 women [38.7%]; mean [SD] age, 77.1 years [9.1 years]) sustained an ICH event. Of these events, 1325 were attributable to hemorrhagic stroke and 1090 were secondary to trauma. During the first year, 305 patients with a hemorrhagic stroke (23.0%) died, whereas 210 in the traumatic ICH group (19.3%) died. Among patients with hemorrhagic stroke, resuming warfarin therapy was associated with a lower rate of ischemic stroke or systemic embolism (SE) (adjusted hazard ratio [AHR], 0.49; 95% CI, 0.24-1.02) and an increased rate of recurrent ICH (AHR, 1.31; 95% CI, 0.68-2.50) compared with not resuming warfarin therapy, but these differences did not reach statistical significance. For patients with traumatic ICH, resuming warfarin therapy also was associated with a lower rate of ischemic stroke or SE (AHR, 0.40; 95% CI, 0.15-1.11); however, in contrast to patients with hemorrhagic stroke, therapy resumption was associated with a significantly lower rate of recurrent ICH (AHR, 0.45; 95% CI, 0.26-0.76). A reduction in mortality was associated with resuming warfarin therapy among patients with hemorrhagic stroke (AHR, 0.51; 95% CI, 0.37-0.71) and those with traumatic ICH (AHR, 0.35; 95% CI, 0.23-0.52). Resumption of warfarin therapy after spontaneous hemorrhagic stroke in patients with AF was associated with a lower rate of ischemic events and a higher rate of recurrent ICH. Among patients with a traumatic ICH, a similar lower rate of ischemic events was found; however, a lower relative risk for recurrent ICH despite resuming warfarin treatment was also revealed.

Effect of Anticoagulation on Hospitalization Costs After Intracranial Hemorrhage in Atrial Fibrillation: A Registry Study.

Intracranial hemorrhage (ICH) is the most feared adverse event with oral anticoagulant therapy in patients with atrial fibrillation. The health economic aspects of resuming oral anticoagulant therapy after ICH are unknown. The aim was to estimate hospitalization costs of thromboembolism and hemorrhage subsequent to ICH in 2 patient groups with atrial fibrillation surviving the first 90 days post ICH: (1) patients resuming warfarin therapy within 90 days post ICH and (2) patients discontinuing therapy. Retrospective data from Danish national registries were linked to identify patients with atrial fibrillation who suffered an ICH between January 1, 1997, and April 1, 2011. Study start was 90 days after incident ICH. Mortality was evaluated using the Kaplan-Meier estimate. Occurrence of hospitalization-requiring thromboembolism and hemorrhage was used to estimate hospitalization costs by linkage of International Classification of Diseases, Tenth Revision, codes to Danish Diagnosis-Related Group tariffs. The effect of resuming warfarin therapy on average 3-year hospitalization costs was estimated by regression analysis adjusted for between-group differences in baseline characteristics. In the inclusion period, 2162 patients had an ICH; 1098 survived the first 90 days and were included for analysis, and of those, 267 resumed warfarin therapy. Therapy resumption reduced the mean 3-year hospitalization cost of hospitalized patients significantly by US$ 1588 (95% confidence interval, -2925 to -251) and was significantly correlated with fewer hospitalization days per hospitalized patient (-4.6 [95% confidence interval, -7.6 to -1.6]). The marginal effect of therapy resumption on hospitalization costs per patient was US$ -407 (95% confidence interval, -815 to 2). Resuming warfarin therapy within 90 days after ICH in patients with atrial fibrillation is associated with a decrease in average hospitalization costs.

Abstract WMP95: Cerebral Amyloid Angiopathy Patients With Convexity Subarachnoid Hemorrhage Present Higher Risk of Subsequent Hemorrhage Than Those With Lobar Intracranial Hemorrhage

Background: Acute convexity subarachnoid hemorrhage (cSAH) is increasingly recognized as a marker of cerebral amyloid angiopathy (CAA). Little is known about the risk of subsequent hemorrhage in such CAA presentation, whereas CAA-related lobar intracranial hemorrhage (ICH) is associated with a high risk of recurrence. The aim of this study was to compare clinical outcome among patients with an acute CAA related- cSAH to those with an acute CAA-related lobar ICH. Hypothesis: We hypothesized that the risk of subsequent hemorrhage is different between patients with acute cSAH and lobar ICH related to CAA. Methods: We retrospectively reviewed the clinical outcomes (death, subsequent transient focal neurological episodes (TFNE), rates of ICH and acute cSAH) of 45 consecutive patients (75 ± 7 years) with an acute cSAH related to probable CAA compared to 70 consecutive patients (78 ± 7 years) with an acute lobar ICH meeting the Boston criteria for probable CAA. Results: cSAH-patients presented essentially with TFNE (84.4% vs 0%; p&lt;0.001) whereas ICH-patients had a persistent neurological deficit (98.6% vs 15.6%; p&lt;0.001). Five patients with lobar ICH died in the first days. Thirty nine cSAH-patients and 60 lobar ICH-patients had available follow-up data. The mean time of follow-up (± SD) was 364 ± 358 days. Mortality did not differ between cSAH-patients and ICH-patients who survived (10.2 % vs 16.7%; p = 0.38). Patients with cSAH had a higher rate of TFNE (48.7 % vs 0 %; p&lt;0.001) and acute cSAH recurrence (20.5 % vs 1.7 %; p = 0.002). In the other hand, 20.5 % of cSAH-patients presented a subsequent ICH, not different from patients with acute ICH (15.0 %; p = 0.45). Conclusions: In the context of CAA, patients with acute cSAH present more clinical recurrences than lobar ICH-patients, due to higher risk of subsequent TFNE and acute cSAH. Although the clinical presentation of cSAH-patients may appear benign, their outcome regarding the risk of incident ICH and mortality, does not seem different from CAA-related lobar ICH survivors.

Risk of Ischemic Stroke after Intracranial Hemorrhage in Patients with Atrial Fibrillation.

BackgroundWe aimed to estimate the risk of ischemic stroke after intracranial hemorrhage in patients with atrial fibrillation.Materials and MethodsUsing discharge data from all nonfederal acute care hospitals and emergency departments in California, Florida, and New York from 2005 to 2012, we identified patients at the time of a first-recorded encounter with a diagnosis of atrial fibrillation. Ischemic stroke and intracranial hemorrhage were identified using validated diagnosis codes. Kaplan-Meier survival statistics and Cox proportional hazard analyses were used to evaluate cumulative rates of ischemic stroke and the relationship between incident intracranial hemorrhage and subsequent stroke.ResultsAmong 2,084,735 patients with atrial fibrillation, 50,468 (2.4%) developed intracranial hemorrhage and 89,594 (4.3%) developed ischemic stroke during a mean follow-up period of 3.2 years. The 1-year cumulative rate of stroke was 8.1% (95% CI, 7.5–8.7%) after intracerebral hemorrhage, 3.9% (95% CI, 3.5–4.3%) after subdural hemorrhage, and 2.0% (95% CI, 2.0–2.1%) in those without intracranial hemorrhage. After adjustment for the CHA2DS2-VASc score, stroke risk was elevated after both intracerebral hemorrhage (hazard ratio [HR], 2.8; 95% CI, 2.6–2.9) and subdural hemorrhage (HR, 1.6; 95% CI, 1.5–1.7). Cumulative 1-year rates of stroke ranged from 0.9% in those with subdural hemorrhage and a CHA2DS2-VASc score of 0, to 33.3% in those with intracerebral hemorrhage and a CHA2DS2-VASc score of 9.ConclusionsIn a large, heterogeneous cohort, patients with atrial fibrillation faced a substantially heightened risk of ischemic stroke after intracranial hemorrhage. The risk was most marked in those with intracerebral hemorrhage and high CHA2DS2-VASc scores.

Association between Liver Disease and Intracranial Hemorrhage

Liver disease is common and associated with clinical and laboratory evidence of coagulopathy. The association between liver disease and intracranial hemorrhage (ICH) remains unclear. Our aim was to assess whether liver disease increases the risk of ICH. We performed a retrospective cohort study based on administrative claims data from California, Florida, and New York acute care hospitals from 2005 through 2011. Of a random 5% sample, we included patients discharged from the emergency department or hospital after a diagnosis of liver disease and compared them to patients without liver disease. Patients with cirrhotic liver disease were additionally analyzed separately. Kaplan-Meier survival statistics were used to calculate cumulative rates of incident ICH, and Cox proportional hazard analysis was used to adjust for demographic characteristics, vascular disease, and Elixhauser comorbidities. Multiple models tested the robustness of our results. Among 1,909,816 patients with a mean follow-up period of 4.1 (±1.8) years, the cumulative rate of ICH after a diagnosis of liver disease was 1.70% (95% confidence interval [CI], 1.55%-1.87%) compared to .40% (95% CI, .39%-.41%) in patients without liver disease (P <.001 by the log-rank test). Liver disease remained associated with an increased hazard of ICH after adjustment for demographic characteristics and vascular risk factors (hazard ratio [HR], 1.8; 95% CI, 1.6-2.0). This was attenuated in models additionally adjusted for general comorbidities (HR, 1.3; 95% CI, 1.2-1.5). There is a modest, independent association between liver disease and the risk of ICH.

Risk of thromboembolism, recurrent hemorrhage, and death after warfarin therapy interruption for intracranial hemorrhage

BackgroundWhether and when to resume oral anticoagulant therapy for patients who survive warfarin-related intracranial hemorrhage (ICH) remains a dilemma lacking consensus recommendations and high-quality evidence to guide clinical decision making. ObjectiveTo determine the incidences of recurrent ICH, thrombosis, and death in relation to resumption or non-resumption of warfarin therapy during the 365days after incident ICH. MethodsWe conducted a retrospective cohort study of adult patients in an integrated healthcare delivery system who were receiving warfarin therapy at the time of incident (index) ICH between 1/1/2000 and 12/31/2007 and survived to hospital discharge. The primary outcomes were recurrent ICH, thrombosis (stroke, systemic embolism, and venous thromboembolism), and all-cause mortality during the 365days following index ICH. Patients were assigned to one of two groups defined by warfarin therapy resumption after the index ICH. ResultsThere were 160 patients discharged from the hospital following warfarin-related index ICH; of these 54 (33.8%) resumed warfarin therapy and 106 (66.2%) did not. Recurrent ICH occurred in a numerically greater, but statistically non-significant, proportion of patients who did not resume warfarin therapy (7.6% vs. 3.7%, p=0.497). Similarly, patients who did not resume warfarin had a three-fold higher (12.3% vs. 3.7%, p=0.092) and approximately two-fold higher (31.1% vs. 18.5%, p=0.089) rates of thrombosis and all-cause mortality, respectively, during follow up. ConclusionResumption of warfarin therapy following warfarin-associated ICH appeared not to be associated with increased risk of recurrent ICH but trended toward reduced thrombosis and all-cause mortality.

Restarting Anticoagulant Treatment After Intracranial Hemorrhage in Patients With Atrial Fibrillation and the Impact on Recurrent Stroke, Mortality, and Bleeding: A Nationwide Cohort Study.

Intracranial hemorrhage is the most feared complication of oral anticoagulant treatment. The optimal treatment option for patients with atrial fibrillation who survive an intracranial hemorrhage remains unknown. We hypothesized that restarting oral anticoagulant treatment was associated with a lower risk of stroke and mortality in comparison with not restarting. Linkage of 3 Danish nationwide registries in the period between 1997 and 2013 identified patients with atrial fibrillation on oral anticoagulant treatment with incident intracranial hemorrhage. Patients were stratified by treatment regimens (no treatment, oral anticoagulant treatment, or antiplatelet therapy) after the intracranial hemorrhage. Event rates were assessed 6 weeks after hospital discharge and compared with Cox proportional hazard models. In 1752 patients (1 year of follow-up), the rate of ischemic stroke/systemic embolism and all-cause mortality (per 100 person-years) for patients treated with oral anticoagulants was 13.6, in comparison with 27.3 for nontreated patients and 25.7 for patients receiving antiplatelet therapy. The rate of ischemic stroke/systemic embolism and all-cause mortality (per 100 person-years) for recurrent intracranial hemorrhage, the rate of ischemic stroke/systemic embolism, and all-cause mortality (per 100 person-years) patients treated with oral anticoagulants was 8.0, in comparison with 8.6 for nontreated patients and 5.3 for patients receiving antiplatelet therapy. The adjusted hazard ratio of ischemic stroke/systemic embolism and all-cause mortality was 0.55 (95% confidence interval, 0.39-0.78) in patients on oral anticoagulant treatment in comparison with no treatment. For ischemic stroke/systemic embolism and for all-cause mortality, hazard ratios were 0.59 (95% confidence interval, 0.33-1.03) and 0.55 (95% confidence interval, 0.37-0.82), respectively. Oral anticoagulant treatment was associated with a significant reduction in ischemic stroke/all-cause mortality rates, supporting oral anticoagulant treatment reintroduction after intracranial hemorrhage as feasible. Future trials are encouraged to guide clinical practice in these patients.

Abstract W MP66: Rates of Ischemic Stroke after Intracranial Hemorrhage in a Population-Based Sample of Patients with Atrial Fibrillation

Introduction: Patients with atrial fibrillation (AF) who experience intracranial hemorrhage (ICH) often cannot tolerate anticoagulant therapy and presumably face a higher risk of thromboembolism. However, there are little population-based data on long-term rates of stroke after ICH in patients with AF. Methods: Using validated diagnosis codes and administrative claims data from all nonfederal acute care hospitals and emergency departments in California, Florida, and New York from 2005 to 2012, we identified patients at their first encounter with a recorded diagnosis of AF. We excluded patients with diagnoses of stroke or ICH prior to their index visit or a diagnosis of stroke at the index visit. A time-varying covariate was used to account for ICH (intracerebral or subarachnoid hemorrhage) at the index visit or during follow-up. Kaplan-Meier survival statistics were used to calculate cumulative rates of stroke, and Cox proportional hazard analysis was used to evaluate the relationship between incident ICH and stroke while adjusting for the CHA 2 DS 2 VASc score. Results: During a mean 3.2 years of follow-up among 2,376,207 patients with AF, 25,243 (1.06%) developed ICH and 93,183 (3.92%) developed stroke. The cumulative 1-year rate of stroke was 6.50% (95% CI, 6.06-6.96%) after ICH versus 2.22% (95% CI, 2.20-2.24) in those without ICH. ICH remained associated with higher stroke risk after adjusting for the CHA 2 DS 2 VASc score (HR, 2.29; 95% CI, 2.18-2.40). Among patients with ICH, stroke risk rose in step with the CHA 2 DS 2 VASc score. Conclusions: In a large population-based cohort, patients with AF faced a substantially higher risk of stroke after ICH. This risk rose proportionally with increasing CHA 2 DS 2 VASc score. These findings point to patients with AF and ICH as a vulnerable population who may especially benefit from therapeutic alternatives to anticoagulant therapy for preventing thromboembolism in AF.

Effect of warfarin on intracranial hemorrhage incidence and fatal outcomes

Avoiding intracranial hemorrhage (ICH) during warfarin therapy is critical but little is known about factors that affect warfarin-related ICH outcomes. We aimed to define the impact of warfarin on ICH incidence rates and to identify baseline clinical characteristics of patients who experienced ICH and factors associated with fatal ICH. The primary outcome of this retrospective cohort study was the incident ICH rate per 10,000 person-years for patients receiving and not receiving warfarin therapy. Cox proportional hazards modeling was used to adjust for potential confounding factors in assessment of the association of warfarin with fatal ICH. A total of 1348 patients with incident ICH, 259 (19%) who were receiving warfarin therapy, were included. The incident ICH rates were 74/10,000 (warfarin) and 5/10,000 (non-warfarin) person-years (p<0.001). Warfarin patients were older and carried a higher burden of chronic disease. The unadjusted hazard ratio (HR) for fatal ICH was 1.64 (95% confidence interval [CI] 1.31-2.05) for warfarin patients compared to non-warfarin patients. However, the HR was no longer significant after adjustment for confounding variables (1.10; 95% CI 0.84-1.42). An INR greater than 3.5 at presentation doubled the adjusted risk for fatal ICH with warfarin therapy. Subarachnoid and subdural ICHs were less likely to be fatal than other ICH types, and each year increase in age was associated with 4% increased risk of fatal ICH. Although warfarin use increases the rate of incident ICH, other factors impact the risk of fatal ICH, even among anticoagulated patients.

Thirty-Day Mortality After Ischemic Stroke and Intracranial Hemorrhage in Patients With Atrial Fibrillation On and Off Anticoagulants

Prescribing warfarin for atrial fibrillation depends in large part on the expected reduction in ischemic stroke risk versus the expected increased risk of intracranial hemorrhage (ICH). However, the anticoagulation decision also depends on the relative severity of such events. We assessed the impact of anticoagulation on 30-day mortality from ischemic stroke versus ICH in a large community-based cohort of patients with atrial fibrillation. We followed 13,559 patients with atrial fibrillation enrolled in an integrated healthcare delivery system for a median 6 years. Incident ischemic strokes and ICHs were identified from computerized databases and validated through medical record review. The association of warfarin and international normalized ratio at presentation with 30-day mortality was modeled using multivariable logistic regression adjusting for clinical factors. We identified 1025 incident ischemic strokes and 299 ICHs during follow-up. Compared with no antithrombotic therapy, warfarin was associated with reduced Rankin score and lower 30-day mortality from ischemic stroke (adjusted OR, 0.64; 95% CI, 0.45-0.91) but a higher mortality from ICH (OR, 1.62; 95% CI, 0.88-2.98). Therapeutic international normalized ratios (2-3) were associated with an especially low ischemic stroke mortality (OR, 0.38; 95% CI, 0.20-0.70), whereas international normalized ratios>3 increased the odds of dying of ICH by 2.66-fold (95% CI, 1.21-5.86). Warfarin reduces 30-day mortality from ischemic stroke but increases ICH-related mortality. Both effects on event severity as well as on event rates need to be incorporated into rational decision-making about anticoagulants for atrial fibrillation.

The relationship of coexisting extranidal aneurysms to intracranial hemorrhage in patients harboring brain arteriovenous malformations.

We hypothesized that coexisting extranidal arterial aneurysms (EAs) would be associated with an increased risk of incident intracranial hemorrhage (ICH) from brain arteriovenous malformation (BAVM) rupture. To determine the presence of EAs and compare the sources and locations of ICH, we retrospectively reviewed the computed tomographic, magnetic resonance imaging, and angiographic studies of patients who presented between 1990 and 1999. EAs were defined as saccular luminal dilations of the parent feeding vessels that were proximally flow-related (i.e., at the circle of Willis), distally flow-related (i.e., distal to the circle of Willis), and unrelated (i.e., in circulation distant from the BAVM). Of 314 BAVM patients, 138 (44%) presented with ICH. In the ICH group, 22 patients (16%) had aneurysmal ICH, 100 (72%) had BAVM ICH, and 16 (12%) had ICH from an indeterminate source. There were 61 patients with 1 or more EAs (29 patients with 42 flow-related proximal aneurysms, 39 patients with 48 flow-related distal aneurysms, and 10 patients with 20 unrelated aneurysms). Multivariate regression analysis revealed that ICH patients were more likely than non-ICH patients to have a coexisting EA (35 versus 13%; odds ratio = 3.9; 95% confidence interval, 2.1-7.5; P < 0.001), but this effect was not present when only BAVM-related ICH was considered (odds ratio = 0.3; 95% confidence interval, 0.1-1.0; P = 0.052). Other independent predictors of ICH included small AVM size (<3 cm), exclusively deep venous drainage, and the presence of an intranidal aneurysm. Clinical presentation with ICH was associated with EA aneurysms, but the association was due to aneurysmal rather than BAVM rupture, suggesting that EAs and the BAVM ICH risks may be considered as separate entities in future studies.

Longitudinal Risk of Intracranial Hemorrhage in Patients With Arteriovenous Malformation of the Brain Within a Defined Population

Accurate estimates for risk and rates of intracranial hemorrhage (ICH) in the natural course of patients harboring brain arteriovenous malformation (BAVM) are needed to provide a quantitative basis for planning clinical trials to evaluate interventional strategies and to help guide practice management. We identified patients with BAVM at the Kaiser Permanente Northern California health maintenance organization and documented their clinical course. The influences of age at diagnosis, gender, race-ethnicity, ICH at presentation, venous draining pattern, and BAVM size on ICH subsequent to presentation were studied using the multivariate Cox proportional hazards model and Kaplan-Meier curves. We identified 790 patients with BAVM (51% female; 63% white; mean age+/-SD at diagnosis: 38+/-19 years) between 1961 and 2001. Patients who presented with ICH experienced a higher rate of subsequent ICH than those who presented without ICH under multivariate analysis (hazard ratio, 3.6; 95% CI, 1.1 to 11.9; P<0.032). The effect was similar across race-ethnicity and gender. This difference in ICH rates was greatest in the first year (7% versus 3% per year) and converged over time. The effect of subsequent ICH on functional status was similar to that of the initial ICH. Presentation with ICH was the most important predictor of future ICH, confirming previous studies. Future ICH had similar impact on functional outcome as incident ICH. Intervention to prevent ICH would be of potentially greater benefit to patients presenting with ICH, although the advantage decreases over time.