Cerebral Ischaemia Of Arterial Origin Research Articles

No Additional Prognostic Value of Genetic Information in the Prediction of Vascular Events after Cerebral Ischemia of Arterial Origin: The PROMISe Study.

BackgroundPatients who have suffered from cerebral ischemia have a high risk of recurrent vascular events. Predictive models based on classical risk factors typically have limited prognostic value. Given that cerebral ischemia has a heritable component, genetic information might improve performance of these risk models. Our aim was to develop and compare two models: one containing traditional vascular risk factors, the other also including genetic information.Methods and ResultsWe studied 1020 patients with cerebral ischemia and genotyped them with the Illumina Immunochip. Median follow-up time was 6.5 years; the annual incidence of new ischemic events (primary outcome, n=198) was 3.0%. The prognostic model based on classical vascular risk factors had an area under the receiver operating characteristics curve (AUC-ROC) of 0.65 (95% confidence interval 0.61-0.69). When we added a genetic risk score based on prioritized SNPs from a genome-wide association study of ischemic stroke (using summary statistics from the METASTROKE study which included 12389 cases and 62004 controls), the AUC-ROC remained the same. Similar results were found for the secondary outcome ischemic stroke.ConclusionsWe found no additional value of genetic information in a prognostic model for the risk of ischemic events in patients with cerebral ischemia of arterial origin. This is consistent with a complex, polygenic architecture, where many genes of weak effect likely act in concert to influence the heritable risk of an individual to develop (recurrent) vascular events. At present, genetic information cannot help clinicians to distinguish patients at high risk for recurrent vascular events.

Thromboembolic complications of heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is an adverse effect of heparin therapy which can be responsible for thrombotic events with embolic consequences. Although ischemic stroke is a well known consequence of HIT, few cases of cerebral ischemia of arterial origin have been reported so far. A 38-year-old man was admitted because of acute multiple ischemic strokes and pulmonary embolism which occurred during treatment with low molecular weight heparin as prophylactic therapy for orthopedic surgery. Neuroimaging showed occlusion of the right common carotid artery with multiple acute cerebral infarcts. Testing for anti-platelet factor 4 antibodies confirmed the diagnosis. Systematic review of the literature revealed 55 cases of arterial stroke and three cases of carotid artery occlusion caused by HIT. Although arterial ischemic stroke is a rare complication of HIT, a high level of suspicion and a prompt diagnosis of this coagulation disorder are necessary to avoid life-threatening thromboembolic complications.

Prothrombotic Gene Variants and Mortality after Cerebral Ischemia of Arterial Origin

Background: Several functional prothrombotic gene variants have been associated with cerebral ischemia and myocardial infarction. We hypothesized that such gene variants may also be associated with mortality after cerebral ischemia of arterial origin because of an increased risk of fatal vascular events. Methods: We performed a case-control study in 316 long-term survivors and 887 patients with recent cerebral ischemia of arterial origin. False discovery rate q values were calculated to account for multiple testing. The mean duration between occurrence of cerebral ischemia and DNA collection was 16.8 years in long-term survivors and 3.2 months in recent patients. Results: Two of 23 variants were associated with mortality: the 95Arg allele of the coagulation factor XIII subunit B (F13B) His95Arg variant (OR, 1.5 for Arg/Arg and His/Arg vs. His/His genotype; 95% CI, 1.1–2.2, q = 0.29) and the 4G allele of the plasminogen activator inhibitor-1 (PAI-1) 4G/5G variant (OR, 1.5 for 4G/4G and 5G/4G vs. 5G/5G genotype; 95% CI, 1.1–2.0, q = 0.29). Both associations disappeared after accounting for multiple testing. Data analysis restricted to recently deceased patients (n = 133) yielded similar results. Conclusions: In this hospital-based study none of 23 prothrombotic gene variants were associated with long-term mortality after cerebral ischemia of arterial origin. Prothrombotic gene variants do not appear to play an important role in long-term mortality after cerebral ischemia.

Estados de hipercoagulabilidad e ictus isquémico en pacientes jóvenes

Introduction Hypercoagulable states have been reported as an established risk factor for cerebral venous thrombosis, but they have also been proposed as a predisposing factor for cerebral ischemia of arterial origin, especially among young patients. This may have implications on therapeutic management and secondary prevention. We have studied the frequency of prothrombotic abnormalities in young patients with ischaemic stroke, as other classic risk factors are less common in this group. Materials and methods Observational study with sequential inclusion of patients under 55 with stroke or transient ischaemic attack (TIA) admitted to the Stroke Unit from January 2005 through December 2007. We analysed demographic data, severity and subtype of stroke, risk factors, including the presence of hypercoagulable states, and outcome. Results We included 100 patients, of whom 65 were men. The mean age was 42.6 ± 8.9 years, 46% with a hypercoagulable state, and no sex differences. Acquired hyperhomocysteinemia was the most common abnormality (18%), followed by protein C or S deficiency (8%), factor V Leiden mutation (5%) and methyl-tetrahydro-folate-reductase (MTHFR) C677T mutation (5%). Other findings included anticardiolipin antibodies (3%), presence of lupus anticoagulant (2%), thrombocytosis (3%) and G20210A prothrombin gene mutation (3%). No association was found between these states and the presence of other vascular risk factors, or more severe stroke or worse outcomes. There was an increased presence of these abnormalities in patients who were classified as atherothrombotic stroke (p = 0.04). Conclusions The hypercoagulable states are common in young patients with ischaemic stroke, being present in up to 46% of them.

Secondary Stroke Prevention with Antithrombotic Drugs

This review addresses 2 fields: secondary prevention after cerebral ischaemia of cardiac origin (CICO) and that after cerebral ischaemia of arterial origin (CIAO). The major trial after CICO is the EAFT that showed the superiority of mild oral anticoagulation (INR 2-3) over aspirin and placebo. Despite several more recent trials with ximelagatran (e.g. SPORTIF and ACTIVE-W) the current standard remains mild oral anticoagulation. After CIAO several trials tried to improve the 13% relative risk reduction achieved with aspirin. Attempts with oral anticoagulation were disappointing: high INRs were not safe (SPIRIT), low INRs not effective (WARSS) and with a mild regimen (INR 2-3) the benefits for ischaemic events were cancelled by more major bleeding. Clopidogrel tended to be modestly more effective than aspirin after stroke (CAPRIE), but its combination with aspirin appeared not to be safe (MATCH, CHARISMA). Combination of aspirin with dipyridamole, however, was safe and more effective than aspirin alone (ESPS-2, ESPRIT). Recent American and European guidelines mention both the combination of aspirin and dipyridamole and clopidogrel monotherapy for secondary prevention after cerebral ischaemia of arterial origin. The recent PRoFESS trial found no differences in the efficacy of aspirin plus dipyridamole and clopidogrel, hence there is no need for major adaptation of the guidelines.

Hypercoagulability and ischemic stroke in young patients

Introduction Hypercoagulable states have been reported as an established risk factor for cerebral venous thrombosis, but they have also been proposed as a predisposing factor for cerebral ischemia of arterial origin, especially among young patients. This may have implications on therapeutic management and secondary prevention. We have studied the frequency of prothrombotic abnormalities in young patients with ischaemic stroke, as other classic risk factors are less common in this group. Materials and methods Observational study with sequential inclusion of patients under 55 with stroke or transient ischaemic attack (TIA) admitted to the Stroke Unit from January 2005 through December 2007. We analysed demographic data, severity and subtype of stroke, risk factors, including the presence of hypercoagulable states, and outcome. Results We included 100 patients, of whom 65 were men. The mean age was 42.6 ± 8.9 years, 46% with a hypercoagulable state, and no sex differences. Acquired hyperhomocysteinemia was the most common abnormality (18%), followed by protein C or S deficiency (8%), factor V Leiden mutation (5%) and methylenetetrahydrofolate reductase (MTHFR) C677T mutation (5%). Other findings included anticardiolipin antibodies (3%), presence of lupus anticoagulant (2%), thrombocytosis (3%) and G20210A prothrombin gene mutation (3%). No association was found between these states and the presence of other vascular risk factors, or more severe stroke or worse outcomes. There was an increased presence of these abnormalities in patients who were classified as atherothrombotic stroke (p = 0.04). Conclusions The hypercoagulable states are common in young patients with ischaemic stroke, being present in up to 46% of them.

Risk indicators for development of headache during dipyridamole treatment after cerebral ischaemia of arterial origin

A considerable proportion of patients discontinue dipyridamole therapy because of headache. Risk indicators for the development of dipyridamole induced headache were identified by means of an exploratory analysis of data...

Prothrombotic genetic variants and atherosclerosis in patients with cerebral ischemia of arterial origin

Objective Prothrombotic genetic variants associated with arterial disease probably affect arterial thrombus formation but may also promote atherosclerosis. We hypothesized that specific prothrombotic variants lead to advanced atherosclerosis in patients with cerebral ischemia of arterial origin. Methods and results We included 689 patients with nondisabling cerebral ischemia of arterial origin. Twenty-two variants in 14 genes were genotyped. None of the variants was associated with carotid intima-media thickness or younger age at the occurrence of cerebral ischemia. Factor V Leiden (mean prevalence difference 25%; 95% CI 11–40) and the glycoprotein 1b-alpha Thr145Met variant (mean prevalence difference 12%; 95% CI 2.3–22) were associated with symptomatic carotid stenosis. After accounting for multiple testing by determination of the false discovery rate, only the association between factor V Leiden and symptomatic carotid stenosis remained present. Conclusions Prothrombotic genetic variants showed no consistent association with three markers of advanced atherosclerosis in patients with cerebral ischemia of arterial origin. This study does not support the hypothesis that prothrombotic genetic variants have a direct role in the pathogenesis of atherosclerosis.

Prothrombotic gene variation and new vascular events after cerebral ischemia of arterial origin.

Several genetic variants involved in hemostasis have been associated with ischemic stroke or myocardial infarction (MI). Stroke patients who carry a prothrombotic genotype may also be at increased risk for subsequent vascular events. We included 887 patients with non-disabling cerebral ischemia of arterial origin, who were referred to the University Medical Center Utrecht in the Netherlands between 1995 and 2005 and followed them for the occurrence of ischemic stroke, MI or death. The primary outcome was a composite of death from all vascular causes, non-fatal ischemic stroke, non-fatal MI, whichever happened first. We selected 22 prothrombotic variants in 14 genes that were previously associated with ischemic stroke or MI or had evidence of functionality. During a 4.6-year mean follow-up period new vascular events occurred in 135 patients (annual event rate 3.3%). None of the 22 variants was associated with the occurrence of new vascular events. Eight additional analyses with secondary outcomes or among subgroups revealed four associations that were likely to be false positive after accounting for multiple testing. In this cohort, prothrombotic genetic variants do not affect the risk of new vascular events after cerebral ischemia of arterial origin. This study does not support the use of prothrombotic genetic variants to identify stroke patients at increased risk for new vascular events or to guide antithrombotic treatment.

Prothrombotic Gene Variation in Patients with Large and Small Vessel Disease

The classification of ischemic stroke into different subtypes is supported in genetic association studies. While several gene variants have been identified as being associated with ischemia subtypes, most studies have not been powered to study subtypes separately. We investigated 887 patients with nondisabling cerebral ischemia of arterial origin and classified ischemia as being caused by large or small vessel disease (LVD or SVD), primarily based on neuroimaging findings. In total, 621 patients had LVD and 266 SVD. The coagulation factor XIII subunit B gene (F13B) His95Arg variant was more common in patients with LVD (mean prevalence difference 9.9%; 95% CI 4.7–15). None of 21 other prothrombotic gene variants was associated with LVD or SVD. Many gene variants may not be specific for one subtype. We could not replicate the genetic associations identified in previous smaller previous studies. Thus claims about genetic associations with specific subtypes of ischemia should be interpreted with caution. The association between F13B His95Arg and LVD requires replication.

Dipyridamole for Preventing Stroke and Other Vascular Events in Patients With Vascular Disease

Graeme J. Hankey MD, FRCP Section Editor: Patients with limited cerebral ischemia of arterial origin are at risk of serious vascular events (4% to 11% annually). Aspirin reduces that risk by 13%. In one trial, adding dipyridamole to aspirin was associated with a 22% risk reduction compared with aspirin alone. However, a systematic review of all trials of antiplatelet agents by the Antithrombotic Trialists’ Collaboration showed that, in high-risk patients, there was virtually no difference between the aspirin-dipyridamole combination and aspirin alone. To assess the efficacy and safety of dipyridamole versus control in the secondary prevention of vascular events in patients with vascular disease. We searched the Cochrane Stroke Group trials register (searched June 2006), the Cochrane Central Register of Controlled Trials (CENTRAL) ( The Cochrane Library Issue 2, 2006), MEDLINE (1966 to May 2006) …

Prognostic Modelling in Ischaemic Stroke Study, Additional Value of Genetic Characteristics

Background and Aim: The prediction of prognosis after cerebral infarction might be improved by genetic information. The aim of the Prognostic Modelling in Ischaemic Stroke study is to develop 2 different prognostic models on the basis of traditional vascular risk factors and genetic information in patients who have suffered from cerebral ischaemia of arterial origin, 1 concerning new ischaemic and the other new haemorrhagic events. Methods: Polymorphisms and haplotypes describing the haemostatic system and those that influence antithrombotic drug activity will be identified in a cohort of 1,200 patients with cerebral ischaemia of arterial origin who will be followed up for a mean of 6.5 years. In total, 312 ischaemic and 78 haemorrhagic events are anticipated. With a prevalence of a genetic characteristic of 10% a relative risk of 1.4 (95% confidence interval = 1.1–1.8) for ischaemic events and of 1.8 (95% confidence interval = 1.0–3.2) for haemorrhagic events can be estimated with sufficient precision. To determine the additional prognostic value of genetic characteristics the area under the ROC curves of 2 separate models will be compared: 1 based on non-genetic risk factors only, the other also including genetic data.

Long-term occurrence of death and cardiovascular events in patients with transient ischaemic attack or minor ischaemic stroke: comparison between arterial and cardiac source of the index event

Background and aim: Published data suggest that patients with cerebral ischaemia and atrial fibrillation (CIAF) have higher inhospital mortality than patients with cerebral ischaemia of arterial origin (CIAO). Data on...

Haemostatic genetic variants, ABO blood group and bleeding risk during oral anticoagulant treatment after cerebral ischaemia of arterial origin

Oral anticoagulant treatment for secondary prevention after cerebral ischaemia of presumed arterial origin is associated with a higher bleeding rate than cardioembolic stroke. This discrepancy is only partly explained by known bleeding risk factors. Haemostatic genetic variants and AB0 blood group may be involved. We performed a nested casecontrol study in patients with cerebral ischaemia of presumed arterial origin on anticoagulant treatment (International Normalized Ratio between 3.0-4.5). All 34 cases with non-fatal haemorrhage (10 intracranial and 24 extracranial) and 68 control patients on anticoagulant treatment without such a bleeding were selected from the SPIRIT study. AB0 blood group and 11 haemostatic genetic variants were investigated. The Thr312Ala variant of the alpha fibrinogen gene was associated with a decreased bleeding risk (odds ratio (OR) 0.3 for Ala/Ala and Thr/Ala versus Thr/Thr genotype; 95% CI 0.1-0.8). Factor V Leiden was associated with an increased bleeding risk (OR 11.6; 95% CI 1.3-103). The APOE2 allele (OR 0.5; 95% CI 0.2-1.7) and the Tyr204Phe variant in the factor XIII subunit A (OR 2.1; 0.9-5) had nonsignificant relationships with bleeding risk. AB0 blood group and 7 other genetic variants in coagulation factors II and XIII, vitamin K epoxide reductase complex, beta fibrinogen and apolipoprotein E were not related with the risk of haemorrhage. The Ala312Thr variant in the alpha fibrinogen gene is associated with a decreased and factor V Leiden with an increased bleeding risk in patients on anticoagulant treatment after cerebral ischaemia of presumed arterial origin.

ABO(H) blood groups and vascular disease: a systematic review and meta-analysis.

Associations between vascular disease and ABO(H) blood groups have a long history, but no consensus exists regarding its magnitude and significance, or whether it relates to all disorders equally. An accurate calculation of risk would allow direct assessment of whether the effects of non-O status on thrombosis risk are of the magnitude predicted by its effect on von Willebrand factor/FVIII levels. We conducted a systematic review and meta-analysis of studies reporting associations with non-O blood groups. This gave pooled odds ratios of 1.25 [95% confidence interval (CI) 1.14-1.36] for myocardial infarction (MI), 1.03 (95% CI 0.89-1.19) for angina, 1.45 (95% CI 1.35-1.56) for peripheral vascular disease, 1.14 (95% CI 1.01-1.27) for cerebral ischemia of arterial origin, and 1.79 (95% CI 1.56 to 2.05) for venous thromboembolism (VTE). However, restriction to prospective MI studies only did not confirm the association (OR 1.01; 95% CI 0.84-1.23), although these studies may have failed to capture early-onset disease. For VTE, using a combined group of OO/A(2)A(2)/A(2)O as index, the combination of A(1)A(1)/A(1)B/BB gave an OR of 2.44 (95% CI 1.79-3.33) and A(1)O/ BO/A(2)B an OR of 2.11 (95% CI 1.66-2.68). This study confirms the historical impression of linkage between some vascular disorders and non-O blood group status. Although the odds ratios are similar to those predicted by the effect of ABO(H) on von Willebrand factor levels, further work is required to assess risk prospectively and to refine the effect of reducing O(H) antigen expression on thrombosis. However, as non-O and particularly A(1)A(1), A(1)B, BB constitute a significant proportion of the population attributable fraction of VTE, there may be a role for more widespread adoption of ABO(H) typing in testing strategies.

Dipyridamole for preventing stroke and other vascular events in patients with vascular disease

Patients with limited cerebral ischaemia of arterial origin are at risk of serious vascular events (4% to 11% annually). Aspirin reduces that risk by 13%. In one trial, adding dipyridamole to aspirin was associated with a 22% risk reduction compared with aspirin alone. However, a systematic review of all trials of antiplatelet agents by the Antithrombotic Trialists' Collaboration showed that, in high-risk patients, there was virtually no difference between the aspirin-dipyridamole combination and aspirin alone. To assess the efficacy and safety of dipyridamole versus control in the secondary prevention of vascular events in patients with vascular disease. We searched the Cochrane Stroke Group trials register (searched June 2006), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2006), MEDLINE (1966 to May 2006) and EMBASE (1980 to May 2006). We contacted authors and pharmaceutical companies in the search for further data on published and unpublished studies. We selected randomised long-term secondary prevention trials with concealed treatment allocation, treatment for more than one month, starting within six months after presentation of an arterial vascular disease. Treatment consisted of dipyridamole with or without other antiplatelet drugs compared with no drug or an antiplatelet drug other than dipyridamole. Two review authors independently selected trials for inclusion, assessed trial quality and extracted data. Data were analysed according to the intention-to-treat principle. Twenty-nine trials were included, with 23019 participants, among whom 1503 vascular deaths and 3438 fatal and non-fatal vascular events occurred during follow up. Compared with control, dipyridamole had no clear effect on vascular death (relative risk (RR) 0.99, 95% confidence interval (CI) 0.87 to 1.12). This result was not influenced by the dose of dipyridamole or type of presenting vascular disease. Compared with control, dipyridamole appeared to reduce the risk of vascular events (RR 0.88, 95% CI 0.81 to 0.95). This effect was only statistically significant in patients presenting with cerebral ischaemia. For patients who presented with arterial vascular disease, there was no evidence that dipyridamole, in the presence or absence of another antiplatelet drug reduced the risk of vascular death, though it reduces the risk of further vascular events. This benefit was found only in patients presenting after cerebral ischaemia. There was no evidence that dipyridamole alone was more efficacious than aspirin.

Emerging Therapies: ESPRIT

To the Editor: It was with great anticipation and interest that I read the ESPRIT results1 and the accompanying Editorial in Stroke .2 The study reports superiority of aspirin plus dipyridamole over aspirin alone in patients with minor or transient cerebral ischemic symptoms, for the composite outcome of vascular mortality, cerebrovascular event, myocardial infarction, and major hemorrhage.1 In reviewing the outcome measure details, several concerns arose regarding the interpretation of this study by the authors and by the editorialist. In recent cardiovascular trials, a beneficial effect of combination antiplatelet therapy for preventing myocardial ischemia greatly contributed to the benefit seen for cumulative vascular outcomes.3–5 Similarly, in ESPS-2 …

Medium intensity oral anticoagulants versus aspirin after cerebral ischaemia of arterial origin (ESPRIT): a randomised controlled trial

Oral anticoagulants are better than aspirin for secondary prevention after myocardial infarction and after cerebral ischaemia in combination with non-rheumatic atrial fibrillation. The European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) aimed to determine whether oral anticoagulation with medium intensity is more effective than aspirin in preventing future vascular events in patients with transient ischaemic attack or minor stroke of presumed arterial origin. In this international, multicentre trial, patients were randomly assigned within 6 months after a transient ischaemic attack or minor stroke of presumed arterial origin either anticoagulants (target INR range 2.0-3.0; n=536) or aspirin (30-325 mg daily; n=532). The primary outcome was the composite of death from all vascular causes, non-fatal stroke, non-fatal myocardial infarction, or major bleeding complication, whichever occurred first. In a post hoc analysis anticoagulants were compared with the combination of aspirin and dipyridamole (200 mg twice daily). Treatment was open, but auditing of outcome events was blinded. Primary analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial (number ISRCTN73824458) and with ClinicalTrials.gov (NCT00161070). The anticoagulants versus aspirin comparison of ESPRIT was prematurely ended because ESPRIT reported previously that the combination of aspirin and dipyridamole was more effective than aspirin alone. Mean follow-up was 4.6 years (SD 2.2). The mean achieved INR was 2.57 (SD 0.86). A primary outcome event occurred in 99 (19%) patients on anticoagulants and in 98 (18%) patients on aspirin (hazard ratio [HR] 1.02, 95% CI 0.77-1.35). The HR for ischaemic events was 0.73 (0.52-1.01) and for major bleeding complications 2.56 (1.48-4.43). The HR for the primary outcome event comparing anticoagulants with the combination treatment of aspirin and dipyridamole was 1.31 (0.98-1.75). Oral anticoagulants (target INR range 2.0-3.0) are not more effective than aspirin for secondary prevention after transient ischaemic attack or minor stroke of arterial origin. A possible protective effect against ischaemic events is offset by increased bleeding complications.

Severity of cerebral white matter lesions and infarcts in patients with transient or moderately disabling cerebral ischaemia: reproducibility of grading by neurologists

Diffuse or multifocal ischaemic white matter lesions increase the risk of intracranial haemorrhage in patients using oral anticoagulants for secondary prevention after cerebral ischaemia of arterial origin. We studied whether neurologists could reliably assess the presence of these white matter abnormalities. As part of the European/Australian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT), the severity of white matter lesions and presence of ischaemic lesions were twice assessed in a consensus meeting of three neurologists (from a pool of nine) as absent, moderate or severe, in a sample of 126 randomly selected CT or MRI scans. The neurologists were not aware of the duplicate grading. The degree of agreement between the first and second observation was calculated with kappa statistics. The kappa value for agreement between the first and second assessment of white matter lesions was 0.58 (95% CI 0.40-0.76). The kappa value for the presence of clinically relevant and/or irrelevant ischaemic lesions was 0.68 (95% CI 0.58-0.78). Clinicians can assess the presence of white matter lesions with sufficient reliability. Such assessment may prevent unnecessary risk with oral anticoagulation in secondary prevention after cerebral ischaemia of arterial origin, of which the efficacy is currently being assessed in ESPRIT.

Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial

Results of trials of aspirin and dipyridamole combined versus aspirin alone for the secondary prevention of vascular events after ischaemic stroke of presumed arterial origin are inconsistent. Our aim was to resolve this uncertainty. We did a randomised controlled trial in which we assigned patients to aspirin (30-325 mg daily) with (n=1363) or without (n=1376) dipyridamole (200 mg twice daily) within 6 months of a transient ischaemic attack or minor stroke of presumed arterial origin. Our primary outcome event was the composite of death from all vascular causes, non-fatal stroke, non-fatal myocardial infarction, or major bleeding complication, whichever happened first. Treatment was open, but auditing of outcome events was blinded. Primary analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial (number ISRCTN73824458) and with (NCT00161070). Mean follow-up was 3.5 years (SD 2.0). Median aspirin dose was 75 mg in both treatment groups (range 30-325); extended-release dipyridamole was used by 83% (n=1131) of patients on the combination regimen. Primary outcome events arose in 173 (13%) patients on aspirin and dipyridamole and in 216 (16%) on aspirin alone (hazard ratio 0.80, 95% CI 0.66-0.98; absolute risk reduction 1.0% per year, 95% CI 0.1-1.8). Addition of the ESPRIT data to the meta-analysis of previous trials resulted in an overall risk ratio for the composite of vascular death, stroke, or myocardial infarction of 0.82 (95% CI 0.74-0.91). Patients on aspirin and dipyridamole discontinued trial medication more often than those on aspirin alone (470 vs 184), mainly because of headache. The ESPRIT results, combined with the results of previous trials, provide sufficient evidence to prefer the combination regimen of aspirin plus dipyridamole over aspirin alone as antithrombotic therapy after cerebral ischaemia of arterial origin.