Caroline E. Lovelock

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.

Population-based study of event-rate, incidence, case fatality, and mortality for all acute vascular events in all arterial territories (Oxford Vascular Study).

BACKGROUND Acute coronary, cerebrovascular, and peripheral vascular events have common underlying arterial pathology, risk factors, and preventive treatments, but they are rarely studied concurrently. In the Oxford Vascular Study, we determined the comparative epidemiology of different acute vascular syndromes, their current burdens, and the potential effect of the ageing population on future rates. METHODS We prospectively assessed all individuals presenting with an acute vascular event of any type in any arterial territory irrespective of age in a population of 91 106 in Oxfordshire, UK, in 2002-05. FINDINGS 2024 acute vascular events occurred in 1657 individuals: 918 (45%) cerebrovascular (618 stroke, 300 transient ischaemic attacks [TIA]); 856 (42%) coronary vascular (159 ST-elevation myocardial infarction, 316 non-ST-elevation myocardial infarction, 218 unstable angina, 163 sudden cardiac death); 188 (9%) peripheral vascular (43 aortic, 53 embolic visceral or limb ischaemia, 92 critical limb ischaemia); and 62 unclassifiable deaths. Relative incidence of cerebrovascular events compared with coronary events was 1.19 (95% CI 1.06-1.33) overall; 1.40 (1.23-1.59) for non-fatal events; and 1.21 (1.04-1.41) if TIA and unstable angina were further excluded. Event and incidence rates rose steeply with age in all arterial territories, with 735 (80%) cerebrovascular, 623 (73%) coronary, and 147 (78%) peripheral vascular events in 12 886 (14%) individuals aged 65 years or older; and 503 (54%), 402 (47%), and 105 (56%), respectively, in the 5919 (6%) aged 75 years or older. Although case-fatality rates increased with age, 736 (47%) of 1561 non-fatal events occurred at age 75 years or older. INTERPRETATION The high rates of acute vascular events outside the coronary arterial territory and the steep rise in event rates with age in all territories have implications for prevention strategies, clinical trial design, and the targeting of funds for service provision and research.

A simple score (ABCD) to identify individuals at high early risk of stroke after transient ischaemic attack

BACKGROUND Effective early management of patients with transient ischaemic attacks (TIA) is undermined by an inability to predict who is at highest early risk of stroke. METHODS We derived a score for 7-day risk of stroke in a population-based cohort of patients (n=209) with a probable or definite TIA (Oxfordshire Community Stroke Project; OCSP), and validated the score in a similar population-based cohort (Oxford Vascular Study; OXVASC, n=190). We assessed likely clinical usefulness to front-line health services by using the score to stratify all patients with suspected TIA referred to OXVASC (n=378, outcome: 7-day risk of stroke) and to a hospital-based weekly TIA clinic (n=210; outcome: risk of stroke before appointment). RESULTS A six-point score derived in the OCSP (age [> or =60 years=1], blood pressure [systolic >140 mm Hg and/or diastolic > or =90 mm Hg=1], clinical features [unilateral weakness=2, speech disturbance without weakness=1, other=0], and duration of symptoms in min [> or =60=2, 10-59=1, <10=0]; ABCD) was highly predictive of 7-day risk of stroke in OXVASC patients with probable or definite TIA (p<0.0001), in the OXVASC population-based cohort of all referrals with suspected TIA (p<0.0001), and in the hospital-based weekly TIA clinic-referred cohort (p=0.006). In the OXVASC suspected TIA cohort, 19 of 20 (95%) strokes occurred in 101 (27%) patients with a score of 5 or greater: 7-day risk was 0.4% (95% CI 0-1.1) in 274 (73%) patients with a score less than 5, 12.1% (4.2-20.0) in 66 (18%) with a score of 5, and 31.4% (16.0-46.8) in 35 (9%) with a score of 6. In the hospital-referred clinic cohort, 14 (7.5%) patients had a stroke before their scheduled appointment, all with a score of 4 or greater. CONCLUSIONS Risk of stroke during the 7 days after TIA seems to be highly predictable. Although further validations and refinements are needed, the ABCD score can be used in routine clinical practice to identify high-risk individuals who need emergency investigation and treatment.

Time trends in outcome of subarachnoid hemorrhage Population-based study and systematic review

Background: Treatment of aneurysmal subarachnoid hemorrhage (SAH) has changed substantially over the last 25 years but there is a lack of reliable population-based data on whether case-fatality or functional outcomes have improved. Methods: We determined changes in the standardized incidence and outcome of SAH in the same population between 1981 and 1986 (Oxford Community Stroke Project) and 2002 and 2008 (Oxford Vascular Study). In a meta-analysis with other population-based studies, we used linear regression to determine time trends in outcome. Results: There were no reductions in incidence of SAH (RR = 0.79, 95% confidence interval [CI] 0.48–1.29, p = 0.34) and in 30-day case-fatality (RR = 0.67, 95% CI 0.39–1.13, p = 0.14) in the Oxford Vascular Study vs Oxford Community Stroke Project, but there was a decrease in overall mortality (RR = 0.47, 0.23–0.97, p = 0.04). Following adjustment for age and baseline SAH severity, patients surviving to hospital had reduced risk of death or dependency (modified Rankin score > 3) at 12 months in the Oxford Vascular Study (RR = 0.51, 0.29–0.88, p = 0.01). Among 32 studies covering 39 study periods from 1980 to 2005, 7 studied time trends within single populations. Unadjusted case-fatality fell by 0.9% per annum (0.3–1.5, p = 0.007) in a meta-analysis of data from all studies, and by 0.9% per annum (0.2–1.6%, p = 0.01) within the 7 population studies. Conclusion: Mortality due to subarachnoid hemorrhage fell by about 50% in our study population over the last 2 decades, due mainly to improved outcomes in cases surviving to reach hospital. This improvement is consistent with a significant decrease in case-fatality over the last 25 years in our pooled analysis of other similar population-based studies.

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.

Change in incidence and aetiology of intracerebral haemorrhage in Oxfordshire, UK, between 1981 and 2006: a population-based study.

BACKGROUND UK stroke mortality data suggest that the incidence of haemorrhagic stroke has fallen in the past 20 years, but these data do not include deaths of individuals aged 75 years or over. Trends in the older population might differ, since cause varies with age. Our aim was to investigate changes in the population-based incidence of intracerebral haemorrhage according to age and likely aetiology. METHODS We used data from the Oxford Community Stroke Project (OCSP; 1981-86) and the Oxford Vascular Study (OXVASC; 2002-06) to investigate changes in the incidence of intracerebral haemorrhage with time, above and below age 75 years, together with associated risk factors and premorbid medications. Incidences were standardised to the 2001 census population of England and Wales. FINDINGS In the population aged under 75 years the incidence of intracerebral haemorrhage decreased substantially (rate ratio 0.53, 95% CI 0.29-0.95; p=0.03), but the number of cases of intracerebral haemorrhage at all ages were similar in OXVASC and OCSP (52 vs 55 cases) as the proportion of cases occurring at 75 years and over tended to increase (2.0, 0.8-4.6; p=0.09). The incidence of intracerebral haemorrhage associated with premorbid hypertension (blood pressure >or=160/100 mm Hg) fell overall (0.37, 0.20-0.69; p=0.002), but the incidence of intracerebral haemorrhage associated with antithrombotic use was increased (7.4, 1.7-32; p=0.007). Above age 75 years the proportion of cases who were non-hypertensive with lobar bleeds and presumed to have had mainly amyloid-related haemorrhages, also increased (4.0, 1.1-17; p=0.003). INTERPRETATION There has been a substantial fall in hypertension-associated intracerebral haemorrhage over the past 25 years, but not in the overall number of cases of intracerebral haemorrhage in older age-groups, in part due to a rise in intracerebral haemorrhage associated with antithrombotic use. These trends, along with the expected increase in prevalence of amyloid angiopathy with the ageing population, suggest that, in contrast to projections based on mortality data below age 75 years, absolute number of cases of intracerebral haemorrhage might increase in future.

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.

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 &kgr; statistic. Results— Seventy-eight scans showed intraparenchymal hematoma. Blinded pairwise interrater agreements for a diagnosis of intracerebral hemorrhage ranged from &kgr;=0.15 to 0.48 with poor overall agreement (&kgr;=0.35; 95% CI, 0.15 to 0.54) even after unblinding (&kgr;=0.41; 0.21 to 0.60). Blinded intrarater agreements ranged from &kgr;=0.21 to 0.92. Lack of consensus after unblinding was greatest in patients scanned ≥24 hours after stroke onset (67% versus 25%, P=0.001) and in minor stroke (National Institutes of Health Stroke Scale ≤5: 56% versus 29%, P=0.04) with disagreement in 75% of patients scanned ≥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. Conclusion— 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.

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.

Reliable estimation of the proportion of minor stroke due to intracerebral haemorrhage

Background A previous hospital clinic-based study estimated that 3·5% of minor strokes are due to primary intracerebral haemorrhage, but the confidence intervals were wide. Moreover this figure may be an underestimate in older patients, who are less likely to be referred to secondary care, and who may have higher rates of intracerebral haemorrhage. Further studies are required to validate and increase the precision of this estimate and to determine any association with age, in order to plan appropriate services for minor stroke. Method We determined the frequency of intracerebral haemorrhage and haemorrhagic transformation of infarction in consecutive patients presenting with minor stroke (National Institute of Health Stroke Scal ≥ 3) in two separate cohorts: a population-based study (Oxford Vascular Study) scanned early with computed tomography, and a hospital-based stroke clinic cohort, scanned with magnetic resonance imaging. We then pooled these data in a meta-analysis with published data from similar studies identified from a systematic literature review. Results In the Oxford Vascular Study, of 334 cases with minor stroke (58% men, median age 75 years), 17 had intracerebral haemorrhage (5·1%, 95% confidence interval 3·2-8·0%) and four had haemorrhagic transformation of infarction (1·2%, 0·5-3·0%). In the hospital-clinic cohort, of 280 patients with minor stroke (59% men, median age 73 years), 15 had intracerebral haemorrhage (5·4%, 3·3-8·7%) and six had haemorrhagic transformation of infarction (2·1%, 1·0-4·6%). There was no trend for an increase in the frequency of intracerebral haemorrhage with age, with the lowest frequency in patients aged ≥85 years (0-3%). We identified only one previous study with a reliable estimate of the proportion of minor stroke due to intracerebral haemorrhage, and in a pooled analysis including 842 patients, the overall frequency of intracerebral haemorrhage was 4·8% (4·5-5·0%). Conclusion We have shown that the proportion of minor stroke due to intracerebral haemorrhage was very similar in a population-based cohort and a hospital clinic-based cohort using different imaging strategies, and that the frequency is independent of age. A frequency of between 4·5 and 5·0% appears to be a reliable estimate at all ages.