Antiplatelet Treatment After Transient Ischemic Attack and Ischemic Stroke in Patients With Cerebral Microbleeds in 2 Large Cohorts and an Updated Systematic Review.

BACKGROUND AND PURPOSE: In patients with transient ischemic attack/ischemic stroke, microbleed burden predicts intracerebral hemorrhage (ICH), and ischemic stroke, but implications for antiplatelet treatment are uncertain. Previous cohort studies have had insufficient follow-up to assess the time course of risks, have not stratified risks by antithrombotic use, and have not reported extracranial bleeds or functional outcome of ICH versus ischemic stroke. METHODS: In 2 independent prospective cohorts with transient ischemic attack/ischemic stroke (Oxford Vascular Study/mainly white; University of Hong Kong/mainly Chinese), antiplatelet treatment was started routinely irrespective of microbleed burden. Risks, time course and outcome of ICH, extracranial bleeds, and recurrent ischemic events were determined and stratified by microbleed burden (0 versus 1, 2-4, and ≥5), adjusting for age, sex, and vascular risk factors. RESULTS: Microbleeds were more frequent in the Chinese cohort (450 of 1003 versus 165 of 1080; P<0.0001), but risk associations were similar during 7433 patient-years of follow-up. Among 1811 patients on antiplatelet drugs, risk of major extracranial bleeds was unrelated to microbleed burden (Ptrend=0.87), but the 5-year risk of ICH was steeply related (Ptrend<0.0001), with 11 of 15 (73%) of ICH in 140 of 1811 (7.7%) patients with ≥5 microbleeds. However, risk of ischemic stroke also increased with microbleed burden (Ptrend=0.013), such that risk of ischemic stroke and coronary events exceeded ICH and major extracranial bleeds during the first year, even among patients with ≥5 microbleeds (11.6% versus 3.9%). However, this ratio changed over time, with risk of hemorrhage (11.2%) matching that of ischemic events (12.0%) after 1 year. Moreover, whereas the association between microbleed burden and risk of ischemic stroke was due mainly to nondisabling events (Ptrend=0.007), the association with ICH was accounted for (Ptrend<0.0001) by disabling/fatal events (≥5 microbleeds: 82% disabling/fatal ICH versus 40% disabling/fatal ischemic stroke; P=0.035). CONCLUSIONS: In white and Chinese patients with ≥5 microbleeds, withholding antiplatelet drugs during the first year after transient ischemic attack/ischemic stroke may be inappropriate. However, the risk of ICH may outweigh any benefit thereafter.

Clinical Correlates, Ethnic Differences, and Prognostic Implications of Perivascular Spaces in Transient Ischemic Attack and Ischemic Stroke.

BACKGROUND AND PURPOSE: Perivascular spaces (PVSs) are considered markers of small vessel disease. However, their long-term prognostic implications in transient ischemic attack/ischemic stroke patients are unknown. Ethnic differences in PVS prevalence are also unknown. METHODS: Two independent prospective studies were conducted, 1 comprising predominantly whites with transient ischemic attack/ischemic stroke (OXVASC [Oxford Vascular] study) and 1 comprising predominantly Chinese with ischemic stroke (University of Hong Kong). Clinical and imaging correlates, prognostic implications for stroke and death, and ethnic differences in basal ganglia (BG) and centrum semiovale (CS) PVSs were studied with adjustment for age, sex, vascular risk factors, and scanner strength. RESULTS: Whites with transient ischemic attack/ischemic stroke (n=1028) had a higher prevalence of both BG and CS-PVSs compared with Chinese (n=974; >20 BG-PVSs: 22.4% versus 7.1%; >20 CS-PVSs: 45.8% versus 10.4%; P<0.0001). More than 20 BG or CS-PVSs were both associated with increasing age and white matter hyperintensity, although associations with BG-PVSs were stronger (all P<0.0001). During 6924 patient-years of follow-up, BG-PVSs were also independently associated with an increased risk of recurrent ischemic stroke (adjusted hazard ratio compared with <11 PVSs, 11-20 PVSs: HR, 1.15; 95% confidence interval, 0.78-1.68; >20 PVSs: HR, 1.82; 1.18-2.80; P=0.011) but not intracerebral hemorrhage (P=0.10) or all-cause mortality (P=0.16). CS-PVSs were not associated with recurrent stroke (P=0.57) or mortality (P=0.072). Prognostic associations were similar in both cohorts. CONCLUSIONS: Over and above ethnic differences in frequency of PVSs in transient ischemic attack/ischemic stroke patients, BG and CS-PVSs had similar risk factors, but although >20 BG-PVSs were associated with an increased risk of recurrent ischemic stroke, CS-PVSs were not.

Antithrombotic drug use, cerebral microbleeds, and intracerebral hemorrhage: a systematic review of published and unpublished studies.

BACKGROUND AND PURPOSE: Cerebral microbleeds (MB) are potential risk factors for intracerebral hemorrhage (ICH), but it is unclear if they are a contraindication to using antithrombotic drugs. Insights could be gained by pooling data on MB frequency stratified by antithrombotic use in cohorts with ICH and ischemic stroke (IS)/transient ischemic attack (TIA). METHODS: We performed a systematic review of published and unpublished data from cohorts with stroke or TIA to compare the presence of MB in: (1) antithrombotic users vs nonantithrombotic users with ICH; (2) antithrombotic users vs nonusers with IS/TIA; and (3) ICH vs ischemic events stratified by antithrombotic use. We also analyzed published and unpublished follow-up data to determine the risk of ICH in antithrombotic users with MB. RESULTS: In a pooled analysis of 1460 ICH and 3817 IS/TIA, MB were more frequent in ICH vs IS/TIA in all treatment groups, but the excess increased from 2.8 (odds ratio; range, 2.3-3.5) in nonantithrombotic users to 5.7 (range, 3.4-9.7) in antiplatelet users and 8.0 (range, 3.5-17.8) in warfarin users (P difference=0.01). There was also an excess of MB in warfarin users vs nonusers with ICH (OR, 2.7; 95% CI, 1.6-4.4; P<0.001) but none in warfarin users with IS/TIA (OR, 1.3; 95% CI, 0.9-1.7; P=0.33; P difference=0.01). There was a smaller excess of MB in antiplatelet users vs nonusers with ICH (OR, 1.7; 95% CI, 1.3-2.3; P<0.001), but findings were similar for antiplatelet users with IS/TIA (OR, 1.4; 95% CI, 1.2-1.7; P<0.001; P difference=0.25). In pooled follow-up data for 768 antithrombotic users, presence of MB at baseline was associated with a substantially increased risk of subsequent ICH (OR, 12.1; 95% CI, 3.4-42.5; P<0.001). CONCLUSIONS: The excess of MB in warfarin users with ICH compared to other groups suggests that MB increase the risk of warfarin-associated ICH. Limited prospective data corroborate these findings, but larger prospective studies are urgently required.

Substantial observer variability in the differentiation between primary intracerebral hemorrhage and hemorrhagic transformation of infarction on CT brain imaging.

BACKGROUND AND PURPOSE: CT remains the most commonly used imaging technique in acute stroke but is often delayed after minor stroke. Interobserver reliability in distinguishing hemorrhagic transformation of infarction from intracerebral hemorrhage may depend on delays to CT but has not been reported previously despite the clinical importance of this distinction. METHODS: Initial CT scans with intraparenchymal hematoma from the first 1000 patients with stroke in the Oxford Vascular Study were independently categorized as intracerebral hemorrhage or hemorrhagic transformation of infarction by 5 neuroradiologists, both blinded and unblinded to clinical history. Thirty scans were reviewed twice. Agreement was quantified by the kappa statistic. RESULTS: Seventy-eight scans showed intraparenchymal hematoma. Blinded pairwise interrater agreements for a diagnosis of intracerebral hemorrhage ranged from kappa=0.15 to 0.48 with poor overall agreement (kappa=0.35; 95% CI, 0.15 to 0.54) even after unblinding (kappa=0.41; 0.21 to 0.60). Blinded intrarater agreements ranged from kappa=0.21 to 0.92. Lack of consensus after unblinding was greatest in patients scanned >or=24 hours after stroke onset (67% versus 25%, P=0.001) and in minor stroke (National Institutes of Health Stroke Scale or=24 hours after minor stroke and in 48% of all 30-day stroke survivors in whom reliable diagnosis would be expected to influence long-term management. CONCLUSIONS: Reliability of diagnosis of intraparenchymal hematoma on CT brain scan in minor stroke is poor, particularly if scanning is delayed. Immediate brain imaging is justified in patients with minor stroke.

Outcome after spontaneous and arteriovenous malformation-related intracerebral haemorrhage: population-based studies.

Spontaneous (non-traumatic) intracerebral haemorrhage (ICH) has a high case-fatality and leaves many survivors disabled. Clinical characteristics and outcome seem to vary according to the cause of ICH, but population-based comparisons are scarce. We studied two prospective, population-based cohorts to determine differences in outcome [case-fatality and modified Rankin Scale (mRS)] after incident ICH due to brain arteriovenous malformations (AVM) [Scottish Intracranial Vascular Malformation Study (SIVMS), n = 90] and spontaneous ICH [Oxford Vascular Study (OXVASC), n = 60]. Patients with AVM-ICH were younger, had lower pre-stroke and admission blood pressure (BP), higher admission Glasgow Coma Scale (GCS) and were more likely to have an ICH in a lobar location than patients with spontaneous ICH (sICH). Case fatality throughout 2-year follow-up was greater following sICH than AVM-ICH [34/56 (61%) versus 11/90 (12%) at 1 year, odds ratio (OR) 11 (95% Confidence Interval (CI) 5-25)], as was death or dependence (mRS >or= 3) [40/48 (83%) versus 26/65 (40%) at 1 year, OR 8 (3-19)]. Differences in outcome persisted following stratification by age and sensitivity analyses. In multivariable analyses of 1 year outcome, independent predictors of death were sICH (OR 21, 4-104) and increasing ICH volume (OR 1.03, 1.01-1.05), and independent predictors of death or dependence were sICH (OR 11, 2-62) and GCS on admission (OR 0.79, 0.67-0.93). Outcome after AVM-ICH is better than after sICH, independent of patient age and other known predictors of ICH outcome.

Effect of urgent treatment of transient ischaemic attack and minor stroke on early recurrent stroke (EXPRESS study): a prospective population-based sequential comparison.

BACKGROUND: The risk of recurrent stroke is up to 10% in the week after a transient ischaemic attack (TIA) or minor stroke. Modelling studies suggest that urgent use of existing preventive treatments could reduce the risk by 80-90%, but in the absence of evidence many health-care systems make little provision. Our aim was to determine the effect of more rapid treatment after TIA and minor stroke in patients who are not admitted direct to hospital. METHODS: We did a prospective before (phase 1: April 1, 2002, to Sept 30, 2004) versus after (phase 2: Oct 1, 2004, to March 31, 2007) study of the effect on process of care and outcome of more urgent assessment and immediate treatment in clinic, rather than subsequent initiation in primary care, in all patients with TIA or minor stroke not admitted direct to hospital. The study was nested within a rigorous population-based incidence study of all TIA and stroke (Oxford Vascular Study; OXVASC), such that case ascertainment, investigation, and follow-up were complete and identical in both periods. The primary outcome was the risk of stroke within 90 days of first seeking medical attention, with independent blinded (to study period) audit of all events. FINDINGS: Of the 1278 patients in OXVASC who presented with TIA or stroke (634 in phase 1 and 644 in phase 2), 607 were referred or presented direct to hospital, 620 were referred for outpatient assessment, and 51 were not referred to secondary care. 95% (n=591) of all outpatient referrals were to the study clinic. Baseline characteristics and delays in seeking medical attention were similar in both periods, but median delay to assessment in the study clinic fell from 3 (IQR 2-5) days in phase 1 to less than 1 (0-3) day in phase 2 (p<0.0001), and median delay to first prescription of treatment fell from 20 (8-53) days to 1 (0-3) day (p<0.0001). The 90-day risk of recurrent stroke in the patients referred to the study clinic was 10.3% (32/310 patients) in phase 1 and 2.1% (6/281 patients) in phase 2 (adjusted hazard ratio 0.20, 95% CI 0.08-0.49; p=0.0001); there was no significant change in risk in patients treated elsewhere. The reduction in risk was independent of age and sex, and early treatment did not increase the risk of intracerebral haemorrhage or other bleeding. INTERPRETATION: Early initiation of existing treatments after TIA or minor stroke was associated with an 80% reduction in the risk of early recurrent stroke. Further follow-up is required to determine long-term outcome, but these results have immediate implications for service provision and public education about TIA and minor stroke.