Management of warfarin-related intracerebral hemorrhage

Warfarin-related intracerebral hemorrhage (WICH) is a medical and neurosurgical emergency with a 1-month mortality of approximately 50%. Warfarin is commonly is used in patients with atrial fibrillation to prevent ischemic stroke and to prevent progression of deep vein thrombosis to pulmonary embolism. Owing to the ageing population, and increased incidence of atrial fibrillation with age and warfarin use, the incidence of WICH is expected to rise in the future. When WICH occurs, immediate discontinuation of warfarin with rapid warfarin reversal remains the first-line intervention, often with neurosurgical intervention. The optimal agent for rapid warfarin anticoagulation reversal remains to be defined owing to the lack of prospective randomized trials. We review current literature and prospects for future research for this devastating neurologic emergency.     

Safety of discontinuation of anticoagulation in patients with intracranial hemorrhage at high thromboembolic risk

BACKGROUND: Limited data are available to guide the management of anticoagulation in patients with intracranial hemorrhage (ICH) at high thromboembolic risk. OBJECTIVE: To review the management of anticoagulation in patients with ICH at high thromboembolic risk. PATIENTS AND METHODS: We reviewed the management of anticoagulation in 141 patients who have a high risk of ischemic stroke and have ICH while taking warfarin. The 30-day risk of ischemic stroke while not taking anticoagulation treatment was determined using Kaplan-Meier survival estimates. RESULTS: The indications for anticoagulation were a prosthetic heart valve (52 patients [group 1]), atrial fibrillation and cardioembolic stroke (53 patients [group 2]), and a recurrent transient ischemic attack or an ischemic stroke (36 patients [group 3]). A prior ischemic stroke occurred in 14 (27%) of group 1 patients and in 23 (43%) of group 2 patients. Death occurred in 43% of the 141 patients. The median time not taking warfarin in this cohort was 10 days. Three patients had an ischemic stroke within 30 days of warfarin therapy discontinuation. Using Kaplan-Meier survival estimates, the probability of having an ischemic stroke at 30 days following warfarin therapy cessation in groups 1, 2, and 3 was 2.9% (95% confidence interval, 0%-8.0%), 2.6% (95% confidence interval, 0%-7.6%), and 4.8% (95% confidence interval, 0%-13.6%), respectively. In the 35 patients who had warfarin therapy restarted, none had recurrence of ICH during the same hospitalization. CONCLUSIONS: Discontinuation of warfarin therapy for 1 to 2 weeks has a comparatively low probability of embolic events in patients at high embolic risk. This should be taken into consideration when deciding whether to continue or discontinue anticoagulation in these patients at high embolic risk. Early recurrence of ICH is exceedingly uncommon.     

Intracranial hemorrhage in patients with atrial fibrillation receiving anticoagulation with warfarin or edoxaban: An in-depth analysis from the ENGAGE AF-TIMI 48 randomized trial

Intracranial hemorrhage (ICH) is a known risk of oral anticoagulation; delineating ICH attributes may provide nuanced guidance regarding atrial fibrillation management. We evaluated ICH characteristics and outcomes from Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48), a randomized trial that compared two edoxaban regimens (higher-dose edoxaban regimen 60/30 mg (HDER), lower-dose edoxaban regimen 30/15 mg (LDER)) with warfarin in patients with atrial fibrillation. Patients who suffered ICH vs those who did not were compared and independent predictors of ICH were calculated. We also assessed ICH subtype and etiology. Of 21,105 randomized patients, 322 (1.53%) had ≥ 1 ICH for a total of 368 events. Intraparenchymal hemorrhage (HDER: HR 0.52 [95% CI 0.35–0.77], LDER: HR 0.22 [0.13–0.38]) and subdural hematoma (HDER: HR 0.29 [0.15–0.55], LDER: HR 0.26 [0.13–0.50]) were lower with both HDER and LDER vs warfarin. Subarachnoid hemorrhage frequency was similar in the HDER vs warfarin groups but lower in LDER. Compared to warfarin, edoxaban was associated with lower risk of spontaneous ICH (HDER: HR 0.47 [0.31–0.69], LDER: HR 0.34 [0.22–0.53]) and traumatic ICH (HDER: HR 0.32 [0.17–0.61], LDER: HR 0.31 [0.16–0.59]). In multivariable analysis, randomization to warfarin, increased age, and risk of falling remained independent predictors of ICH. In ENGAGE AF-TIMI 48, ICH was decreased in edoxaban-treated patients compared to warfarin-treated patients, including ICH of both spontaneous and traumatic causes. Both edoxaban regimens lowered intraparenchymal and subdural hemorrhages compared to warfarin. Patient characteristics and medical history may help guide anticoagulation management.     

Intracranial Hemorrhage Sparing Meningioma in an Anticoagulated Patient

BACKGROUND AND PURPOSE: The risk of intracerebral hemorrhage (ICH) in patients receiving antithrombotic therapy is well known. However, there is sparse literature regarding the risk of intracerebral hemorrhage in patients receiving warfarin, who have an intracranial meningioma. METHODS AND RESULTS: We report a case of a 66-year-old man who developed multifocal ICHs in the context of supratherapeutic anticoagulation. There was sparing of the intracranial meningioma despite the development and growth of multiple intraparenchymal hemorrhages that resulted in death. We also review the literature evaluating the risk of ICH in anticoagulated patients with an intracranial meningioma. CONCLUSIONS: The findings of this case lend further support to the gradually developing notion of relative safety of anticoagulation in patients with meningioma. They also underscore the importance of close monitoring of the INR.     

Atrial Fibrillation for the Neurologist: Preventing both Ischemic and Hemorrhagic Strokes

Purpose of Review

This review aims to help neurologists managing atrial fibrillation (AF) patients who had an ischemic stroke and/or with intracranial hemorrhage (ICH) markers, therefore at high embolic/hemorrhagic risks.

Recent Findings

Implantable loop recorders have substantially improved the accuracy of AF detection. Recent research yielded a set of powerful neuroimaging markers that can stratify ICH risk. Direct oral anticoagulants (DOAC) are easier to use with a lower ICH risk than warfarin in a general AF population. Finally, the FDA-approved left atrial appendage closure (LAAC) with the WATCHMAN device provides an option without the need for life-long anticoagulation.

Summary

In this review, we introduce the concept of preventing both ischemic and hemorrhagic strokes in AF patients through accurate AF diagnosis and stratification of both embolic and ICH risks. LAAC can be considered in patients at higher hemorrhagic risks while warfarin/DOAC use should be individualized in the majority of AF patients at a low risk of bleeding.

     

Secondary prevention in non-valvular atrial fibrillation patients: a practical approach with edoxaban

Patients with atrial fibrillation and prior stroke or transient ischemic attack exhibit a very high risk of recurrence. Secondary prevention with oral anticoagulants is mandatory. Overall, clinical guidelines recommend the use of target-specific oral anticoagulants over vitamin K antagonists for secondary prevention of stroke in patients with atrial fibrillation. However, many patients with atrial fibrillation and previous stroke are not receiving the appropriate antithrombotic treatment, perhaps due to the perceived risks of anticoagulation including the risk of hemorrhagic transformation of an ischemic stroke. The ENGAGE AF-TIMI 48 trial showed that although edoxaban 60 mg and warfarin reduced the risk of stroke to a similar extent, edoxaban exhibited a lesser risk of bleeding, particularly intracranial hemorrhage. Importantly, these data were independent of the presence of prior stroke or transient ischemic attack. Therefore, edoxaban can be used in both primary and secondary prevention of stroke in patients with non-valvular atrial fibrillation. The aim of this review was to update the available evidence about edoxaban in the clinical management of secondary prevention in individuals with non-valvular atrial fibrillation.     

The influence of fluid intake on stroke recurrence--a prospective study

PurposeA nationwide survey was conducted regarding anticoagulant therapy in patients with acute intracerebral hemorrhage (ICH) on warfarin with nonvalvular atrial fibrillation (NVAF).MethodsA questionnaire on standard therapeutic strategy for warfarin-related ICH in patients with NVAF was mailed to 416 institutes.ResultsA total of 329 physicians (79%) responded with a completed questionnaire. On admission, all respondents stopped warfarin medication and 94% normalized the international normalized ratio (INR) mainly by Vitamin K (63%), followed by fresh frozen plasma (20%), and prothrombin complex concentrate (10%). Afterwards, 91% of the respondents restarted anticoagulation and 3% used antiplatelet for prevention of thromboembolism, but the remaining 6% disagreed with restarting antithrombotic therapy. As contraindications for resuming anticoagulation, recurrent ICH (59%) and poor functional condition (59%) were often chosen. Of those who restarted anticoagulation, the timing was within 4 days in 7%, 5 to 7 days in 21%, 8 to 14 days in 25%, 15 to 28 days in 28% and 29 days or later in 18%. The major key finding on follow-up CT to restart anticoagulation was the absorption tendency of hematomas (47%). When restarting anticoagulation, 76% of the respondents used warfarin alone and 20% used either unfractionated heparin plus warfarin or heparin alone.ConclusionA large majority of respondents responsible for ICH management stopped oral warfarin medication and normalized INR on admission, and restarted anticoagulation after acute ICH in patients with NVAF. However, the strategies to normalize INR and to restart anticoagulant therapy varied greatly and depended on each individual physician's decision.     

Managing the therapeutic dilemma: patients with spontaneous intracerebral hemorrhage and urgent need for anticoagulation

Physicians face a therapeutic dilemma in patients with acute hemorrhagic stroke requiring long-term, high-intensity anticoagulants because this treatment increases the risk of intracranial hemorrhage (ICH) 8- to 11-fold. We retrospectively studied 15 patients with ICH which occurred under anticoagulation with phenprocoumon, with an international normalized ratio (INR) of 2.5–6.5 on admission. Hemispheric, thalamic, cerebellar, intraventricular, or subarachnoid hemorrhage without aneurysm occurred. Absolute indications for anticoagulation were double, mitral, or aortic valve replacement, combined mitral valve failure with atrial fibrillation and atrial enlargement, internal carotid artery-jugular vein graft, frequently recurring deep vein thrombosis with risk of pulmonary embolism, and severe nontreatable ischemic heart disease. As soon as the diagnosis of ICH was established, INR normalization was attempted in all patients by administration of prothrombin complex, fresh frozen plasma, or vitamin K. After giving phenprocoumon antagonists (and neurosurgical therapy in four patients) heparin administration was started. Nine patients received full-dose intravenous and six low-dose subcutaneous heparin. The following observations were made: (a) All patients with effective, full-dose heparin treatment with a 1.5- to 2-fold elevation in partial thromboplastin time after normalization of the INR were discharged without complication. (b) Three of four of the patients with only incomplete correction of the INR (> 1.35) experienced relevant rebleeding within 3 days (all patients with an INR higher than 1.5), two of whom were on full-dose heparin. (c) Three of seven of the patients with normalized INR and without significant PTT elevation developed severe cerebral embolism. Although our data are based on a retrospective analysis, they support treatment with intravenous heparin (partial thromboplastin time 1.5–2 times baseline value) after normalization of the INR in patients with an ICH and an urgent need for anticoagulation. Received: 1 September 1999/Received in revised form: 28 October 1999/Accepted: 19 November 1999     

Stroke prevention in nonvalvular atrial fibrillation: a review of prospective randomized trials.

Patients with atrial fibrillation are at risk for cerebral embolism; however, the roles of chronic anticoagulation or antiplatelet therapy for stroke prevention in patients with nonvalvular atrial fibrillation have been controversial. Recently, the results of three large prospective randomized trials that examined the risks and benefits of warfarin or aspirin for stroke prophylaxis in patients with nonvalvular atrial fibrillation were reported. All three studies revealed a reduction in the stroke rate for patients treated with warfarin and a small incidence of major bleeding. One of the studies also reported a reduced stroke rate in aspirin-treated patients. The reduction of thromboembolic events associated with chronic warfarin therapy appears to outweigh the risks of significant bleeding for most patients with nonvalvular atrial fibrillation. Aspirin may offer an alternative for subgroups of patients who are at low risk for stroke or those who are not good candidates for anticoagulation.     

The risk of intracerebral hemorrhage during oral anticoagulant treatment: A population study

In a retrospective study of 166 patients, all admitted to the University Hospital, Leiden, The Netherlands, between January 1, 1970 and December 31, 1979, we estimated the relative risk of intracerebral hemorrhage from oral anticoagulant therapy. The risk was more than ten times higher for patients over 50 years of age than for similarly aged untreated individuals in the general population. Within this age group the risk was influenced by neither age nor sex. Hypertension, present in 80% of the patients, was the most important predisposing condition; the risk of bleeding rose with increasing intensity of anticoagulation. There was no substantial difference in clinical condition at onset, rate of Progression, mortality, or degree of recovery between patients with anticoagulant-associated hemorrhage and those with spontaneous intracranial hemorrhage.     

心厉颤动患者口服抗凝药相关脑出血的研究进展

随着人口老龄化日益严重和口服抗凝剂(OAT)的使用增加,目前OAT相关脑出血的发生率较20世纪90年代相比10年间增加了5倍,其病死率高达67％,自发性脑出血病死率为30％～55％.OAT相关脑出血占脑出血的10％～12％.在世界范围内,OAT相关脑出血的发病率是不应用OAT的7～10倍.文中主要从OAT相关脑出血的流行病学、遗传学、主要危险因素、临床特点、预后、影像学特点及最新的治疗策略等进行文献分析,侧重于传统OAT与新型抗凝剂的对比,并且对抗凝药物相关脑出血尚存在争议的问题进行总结.     

Intracerebral hemorrhage following intravenous thrombolysis in Thai patients with acute ischemic stroke

In Asia, there is limited information regarding symptomatic intracerebral hemorrhage (ICH) in patients treated with intravenous (iv) recombinant tissue plasminogen activator (rtPA). The aim of this study was to identify independent factors associated with symptomatic ICH following iv rtPA. The study included 192 patients with acute ischemic stroke who were treated with iv rtPA. Baseline characteristics were compared between patients with or without ICH. Symptomatic ICH occurred in 5.7% of patients and asymptomatic ICH in 13.0% of patients. An international normalized ratio (INR) ≥1.0 (odds ratio [OR]=4.89, p=0.036), atrial fibrillation (OR=7.21, p=0.009) and blood glucose concentration >8.325 mmol/L (OR=9.00, p=0.004), were independent risk factors for symptomatic ICH. Atrial fibrillation (OR=3.56, p=0.012) and severe stroke (National Institutes of Health Stroke Scale ≥15; OR=8.94, p<0.001) were independent risk factors for asymptomatic ICH. The prevalence of symptomatic ICH following iv rtPA in Thai patients was comparable to previous studies.     

Oral anticoagulant-associated intracerebral hemorrhage

The incidence of oral anticoagulation-associated intracerebral hemorrhage (OAC-ICH) is growing due to the increasing use of warfarin and the older age of treated patients. Recent population studies reveal that OAC-ICH currently occurs at a frequency comparable to that of subarachnoid hemorrhage. Most frequently, OAC-ICH are located in deep or lobar regions of the brain, although it may also occur in the brainstem. These hemorrhages are larger than spontaneous hematomas and may be fatal in at least 50% of cases. The primary cause of brain injury in patients with OAC-ICH is the direct mechanical disruption of the brain tissue but secondary damage may occur through the intervention of matrix metalloproteinases, glutamate, cytokines, heme, iron, and the chemical toxicity of products such as thrombin, which are released from the clot. The pathogenesis of OAC-ICH also includes the effects of aging, the level of anticoagulation, genetic factors, and a high prevalence of concurrent cerebrovascular conditions, such as cerebral amyloid angiopathy, leukoaraiosis or previous strokes. The treatment of OAC-ICH is challenging and involves rapid reversal of anticoagulation with hemostatic drug therapies such as vitamin K, fresh frozen plasma, prothrombin complex concentrates or recombinant factor VIIa. These therapies may not always be sufficient to stabilize the patient’s clinical condition and lacking randomized controlled trials, the best hematological approach to reverse oral anticoagulation is debated. Other difficult decisions reviewed in this article are whether anticoagulation should be restarted after OAC-ICH, and when anticoagulant treatment should be resumed. The newer oral anticoagulants, which are increasingly being introduced for thromboembolism prevention, may confer a lower risk of intracranial bleeding than warfarin, although they do not have an antidote and their anticoagulant effect is difficult to monitor.     

New-onset atrial fibrillation and warfarin initiation: high risk periods and implications for new antithrombotic drugs

Atrial fibrillation is a common condition that increases the risk of stroke in many patients. Although warfarin has been shown to reduce the risk of stroke, many patients who might benefit from anticoagulation do not receive this therapy. Fear of bleeding is the most often cited reason. Several new anticoagulant medications are being studied to determine their efficacy and safety relative to warfarin. Unlike earlier trials that established the superiority of warfarin over placebo, recent trials in atrial fibrillation have enrolled a disproportionate number of patients already taking warfarin. This review suggests that the risk of both haemorrhage and stroke are highest when atrial fibrillation is newly diagnosed and during the initiation of anticoagulant medication. Randomised controlled trials designed to evaluate the safety and efficacy of new anti-thrombotic agents should include substantial numbers of patients without prior exposure to anticoagulation since these individuals are at the highest risk for bleeding and thromboembolism.     

Antithrombotic and anticoagulation therapy after stroke and transient ischemic attacks

Patients with a transient ischemic attack (TIA) or ischemic stroke are at high risk for a recurrent stroke. Platelet inhibitors can reduce this risk in patients with non-cardioembolic stroke or TIA. Aspirin is used for secondary prevention in patients with a low risk of recurrent stroke while the combination of aspirin and dipyridamole or clopidogrel is recommended in patients with a higher risk. Patients with atrial fibrillation have a five-fold increased risk of stroke. In comparison to placebo oral anticoagulation reduces the risk of stroke by 60-70% in primary and secondary stroke prevention. Aspirin can still reduce the relative stroke risk by 22% in patients with atrial fibrillation who have contraindications against anticoagulation. Given the limitations of oral anticoagulation with vitamin K antagonists a new generation of anticoagulants is currently being investigated which include factor Xa inhibitors and direct thrombin antagonists. Dabigatran has been shown to be as efficacious as warfarin given at a lower dose and significantly more efficacious when administered at a higher dosage. Both cerebral and intracranial hemorrhages were reduced by 60-80% in patients treated with dabigatran when compared to warfarin.     

Cerebral venous sinus thrombosis associated with cerebral hemorrhage: is anticoagulant treatment safe?

The current recommended treatment for cerebral venous sinus thrombosis (CVST) is anticoagulation, and the presence of intracranial hemorrhage (ICH) is not a contraindication. We present a case of ICH associated with CVST in which heparin treatment was associated with rebleeding, and we review current evidence of anticoagulation safety in patients with ICH associated with CVST. A 65-year-old man presented with right hemiparesis and loss of consciousness. Brain computed tomography showed a left frontoparietal hemorrhage. Angiographic studies with magnetic resonance imaging showed the presence of a partial superior saggital sinus thrombosis. With a diagnosis of CVST, intravenous heparin was administered. After 24 hours the patient had a symptomatic increase in ICH size, and 2 days later the patient developed a status epilepticus with new evidence of rebleeding. Anticoagulant treatment was stopped and the patient experienced neurological improvement, with no new episodes of rebleeding. Evidence for the safety of anticoagulants in CVST comes from 2 small trials involving a total of 79 patients, but only 18 had some degree of bleeding in baseline computed tomography. A meta-analysis suggested that in CVST patients who are treated with anticoagulants, the risk of ICH is low, but acknowledged that an impact of up to 9% of new ICH cannot be ruled out. As there is not enough evidence for the safety of anticoagulant therapy in patients with early ICH associated with CVST, the therapeutic decision must be individualized and the rebleeding risk should be weighed in those patients.     

Pre-admission warfarin use in patients with acute ischemic stroke and atrial fibrillation: The appropriate use and barriers to oral anticoagulant therapy

INTRODUCTION: Warfarin reduces the risk of stroke in patients with atrial fibrillation. Despite strong guideline recommendations, studies continue to demonstrate the under-use of warfarin in clinical practice. PURPOSE: To determine the prevalence and predictors of warfarin use in patients presenting with atrial fibrillation and acute ischemic stroke who do not have a documented contraindication to anticoagulants. METHODS: We conducted a retrospective chart review of all patients admitted to the Hamilton General Hospital with a primary diagnosis of ischemic stroke and a coded diagnosis of atrial fibrillation between 1999 and 2004. Using a standardized data abstraction form, the following variables were recorded: baseline demographics, past medical history including risk factors for stroke and major bleeding and known predictors of warfarin under-use. In cases where warfarin was not prescribed, charts were also reviewed for documented contraindications to warfarin use. The following were considered valid contraindications to warfarin: patient refusal, non-compliance with INR monitoring, bleeding diathesis, history of major bleeding or significant alcohol consumption. RESULTS: In total, 196 patients with ischemic stroke and atrial fibrillation were identified. Of these patients, 106 were considered to be appropriate candidates for anticoagulation after excluding patients with no known diagnosis of atrial fibrillation prior to admission (N=59), a valid contraindication to warfarin use (N=18), a CHADS2 score <1 (N=6) or a competing diagnosis for warfarin use (N=7). Of the patients deemed to be suitable candidates for warfarin, 57 (54%) were receiving warfarin therapy on admission. On multivariable analyses, increasing age (OR 0.7; 95% CI 0.5-0.9) was associated with a reduced odds of warfarin use while a history of stroke or TIA (OR 2.6; 95% CI 1.1-6.5) and a history of congestive heart failure (OR 3.2; 95% CI 1.1-9.0) were associated with an increased odds of warfarin use in patients without a contraindication to warfarin. While 75% of patients <75 years old were anticoagulated, only 33% of those >85 years were prescribed warfarin on admission to hospital. CONCLUSIONS: early half of all patients presenting with atrial fibrillation and acute ischemic stroke who were suitable candidates for anticoagulation were not prescribed warfarin. In patients not prescribed warfarin, very few had a documented contraindication. Advanced age appears to be the strongest predictor of warfarin non-use.     

Obesity increases risk of anticoagulation reversal failure with prothrombin complex concentrate in those with intracranial hemorrhage

Background: Not all patients with warfarin-related acute intracranial hemorrhage (ICH) achieve full reversal of international normalized ratio (INR) after the first dose of weight-based prothrombin complex concentrate (PCC). We sought to identify factors associated with anticoagulation reversal failure after the first dose of PCC. Methods: Consecutive patients who were hospitalized with warfarin-related acute ICH at a tertiary center between 1 January 2010 and 31 December 2012 were studied. Anticoagulation reversal failure was defined as INR ≥ 1.5 after the first dose of PCC. Logistic regression was performed to determine the predictors of anticoagulation reversal failure. Results: Fifty-one patients with acute ICH received PCC for warfarin reversal using a weight-based protocol. Overall, 23 (45%) patients did not achieve full reversal of INR after the first dose. Those with anticoagulation reversal failure were obese (body mass index > 30 kg/m²) (41% vs. 14%, p = 0.03), had a higher initial INR (3.0 ± 1.4 vs. 2.0 ± 0.7, p = 0.001), and had a higher prevalence of initial INR >2.0 (22% vs. 67%, p = 0.001), compared with those who were successfully reversed. Multivariable logistic regression identified obesity (odds ratio 7.88, 95% CI 1.12 to 55.68) and initial INR >2.0 (odds ratio 12.49, 95% CI 2.27 to 68.87) as independent predictors of anticoagulation reversal failure. Conclusions: Obesity and elevated initial INR are independently associated with anticoagulation reversal failure using the weight-based PCC protocol in patients with warfarin-related acute ICH. Further studies are needed to determine more effective dosing protocols and individualized strategies for anticoagulation reversal after acute ICH, especially among obese patients.     

Prevention of Stroke in Patients with High-Risk Atrial Fibrillation

Atrial fibrillation (AF) causes nearly 10% of all ischemic strokes. Long-term oral anticoagulation with warfarin currently is the best treatment for preventing stroke in patients with AF and other stroke risk factors. However, many eligible patients do not receive warfarin, and some patients with AF are unsuitable for this treatment. Recent clinical trials have tested alternatives to long-term warfarin, and some new treatment options have emerged. Nonpharmacologic approaches to stroke prevention in atrial fibrillation also are under development. In addition, new diagnostic modalities may detect paroxysmal AF with more sensitivity, potentially expanding the population to be treated and the potential impact of stroke preventive strategies on the population. This review provides a practical guide to current treatment and diagnostic options.     

Anticoagulation in ischemic stroke: opportunities in arterial disease

In the acute phase of ischemic stroke, there is no evidence that anticoagulants provide any benefit in terms of death or dependency. A small reduction in the incidence of recurrent stroke is offset by an equally small increase in intracranial hemorrhage (ICH). In the secondary prevention of stroke, in patients with transient ischemic attacks (TIAs) and moderately disabling ischemic stroke, the relative risk reduction of major vascular events by aspirin is rather modest: 13% (or 19% in a systematic review of arterial disease in general). Anticoagulants might well offer stronger protection, since they provide a 35-50% risk reduction after myocardial infarction or in patients with TIAs or nondisabling ischemic stroke in the presence of atrial fibrillation. Meanwhile, it has become clear that anticoagulation with high intensity (INR 3.0-4.5) is associated with a high risk of ICH in patients with cerebral ischemia who are in sinus rhythm, while INR values around 1.9 do not offer protection against major vascular events. An international clinical trial of anticoagulation with INR values between 2.0 and 3.0 (ESPRIT) is still in progress. In cerebral venous sinus thrombosis, anticoagulant treatment is associated with a nonsignificant reduction of the risk of death or dependence, but the treatment has nevertheless become widely adopted because it seems safe: no increase in the proportion of patients with hemorrhagic transformation of infarction has so far been demonstrated.