Lars Marquardt

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.

Low Risk of Ipsilateral Stroke in Patients With Asymptomatic Carotid Stenosis on Best Medical Treatment A Prospective, Population-Based Study

Background and Purpose— The annual risk of ischemic stroke distal to ≥50% asymptomatic carotid stenoses was ≈2% to 3% in early cohort studies and subsequent randomized trials of endarterectomy. This risk might have fallen in recent years owing to improvements in medical treatment, but there are no published prognostic data from studies initiated within the last 10 years. Methods— In a population-based study of all patients with transient ischemic attack (TIA) or stroke in the Oxford Vascular Study, we studied the risk of TIA and stroke in patients with ≥50% contralateral asymptomatic carotid stenoses recruited consecutively from 2002 to 2009 and given intensive contemporary medical treatment. Results— Of 1153 consecutively imaged patients presenting with stroke or TIA, 101 (8.8%) had ≥50% asymptomatic carotid stenoses (mean age, 75 years; 39% women; 40% age ≥80 years). During 301 patient-years of follow-up (mean, 3 years), there were 6 ischemic events in the territory of an asymptomatic stenosis, 1 minor stroke (initially 50% to 69% stenosis), and 5 TIAs (2 initially 50% to 69% stenosis; 3 to 70% to 99% stenosis), 3 of which led to subsequent endarterectomy. The average annual event rates on medical treatment were 0.34% (95% CI, 0.01 to 1.87) for any ipsilateral ischemic stroke, 0% (95% CI, 0.00 to 0.99) for disabling ipsilateral stroke, and 1.78% (95% CI, 0.58 to 4.16) for ipsilateral TIA. Conclusions— In the first study of the prognosis of ≥50% asymptomatic carotid stenosis to be initiated in the last 10 years, the risk of stroke on intensive contemporary medical treatment was low. Larger studies are required to determine whether this apparent improvement in prognosis is generalizable.

Course of Platelet Activation Markers After Ischemic Stroke

Background and Purpose— The aim of this study was to evaluate the time course of platelet activation after ischemic stroke and to investigate whether platelet activation and inflammation are correlated with each other. Methods— We serially determined expression of p-selectin (CD62p) and lysosome-associated membrane protein (CD63) by platelets using flow cytometry at 10 time points between days 1 and 90 in patients after ischemic stroke (n=50), in healthy subjects (n=30), and in risk factor control subjects (n=20). Furthermore, we correlated leukocyte count, C-reactive protein, and fibrinogen levels with platelet activation markers. Results— CD62p and CD63 expression was higher on day 1 after stroke than in both control groups (P <0.005 for both). CD62p expression rapidly declined, whereas CD63 expression remained significantly elevated until day 90. Stroke severity and different medication for secondary stroke prevention did not influence CD62p or CD63 expression. Platelet activation markers and inflammatory parameters were not correlated with each other at any time point after stroke. Conclusions— The initial increase in both CD62p and CD63 expression by platelets is followed by a differential regulation of both parameters after stroke. The rapid decrease in CD62p expression may be caused by shedding from the cell surface. Its persistent elevation makes CD63 a good candidate for studies on predictors for stroke recurrence. Our findings suggest that the expression of CD62p and CD63 by platelets is regulated independently from inflammatory indexes.

Continuous Stroke Unit Electrocardiographic Monitoring Versus 24-Hour Holter Electrocardiography for Detection of Paroxysmal Atrial Fibrillation After Stroke

Background and Purpose— Cardioembolism in paroxysmal atrial fibrillation (pxAF) is a frequent cause of ischemic stroke. Sensitive detection of pxAF after stroke is crucial for adequate secondary stroke prevention; the optimal diagnostic modality to detect pxAF on stroke units is unknown. We compared 24-hour Holter electrocardiography (ECG) with continuous stroke unit ECG monitoring (CEM) for pxAF detection. Methods— Patients with acute ischemic stroke or transient ischemic attack were prospectively enrolled. After a 12-channel ECG on admission, all patients received 24-hour Holter ECG and CEM. Additionally, ECG monitoring data underwent automated analysis using dedicated software to identify pxAF. Patients with a history of atrial fibrillation or with atrial fibrillation on the admission ECG were excluded. Results— Four hundred ninety-six patients (median age, 69 years; 61.5% male) fulfilled all inclusion criteria (ischemic stroke: 80.4%; transient ischemic attack: 19.6%). Median stroke unit stay lasted 88.8 hours (interquartile range, 65.0–122.0). ECG data for automated CEM analysis were available for a median time of 64.0 hours (43.0–89.8). Paroxysmal AF was documented in 41 of 496 patients (8.3%). Of these, Holter detected pxAF in 34.1%; CEM in 65.9%; and automated CEM in 92.7%. CEM and automated CEM detected significantly more patients with pxAF than Holter (P<0.001), and automated CEM detected more patients than CEM (P<0.001). Conclusions— Automated analysis of CEM improves pxAF detection in patients with stroke on stroke units compared with 24-hour Holter ECG. The comparative usefulness of prolonged or repetitive Holter ECG recordings requires further evaluation.

Incidence and prognosis of > or = 50% symptomatic vertebral or basilar artery stenosis: prospective population-based study.

The higher risk of early recurrent stroke after posterior circulation transient ischaemic attack or minor stroke versus after carotid territory events could be due to a greater prevalence of large artery stenosis, but there have been few imaging studies, and the prognostic significance of such stenoses is uncertain. Reliable data are necessary to determine the feasibility of trials of angioplasty and stenting and to inform imaging strategies. In the first-ever population-based study, we determined the prevalence of > or = 50% apparently symptomatic vertebral and basilar stenosis using contrast-enhanced MRA in consecutive patients, irrespective of age, presenting with posterior circulation transient ischaemic attack or minor ischaemic stroke in the Oxford Vascular Study and related this to the 90-day risk of recurrent transient ischaemic attack and stroke. For comparison, we also determined the prevalence of > or = 50% apparently symptomatic carotid stenosis on ultrasound imaging in consecutive patients with carotid territory events. Of 538 consecutive patients, 141/151 (93%) had posterior circulation events and had vertebral and basilar imaging, of whom 37 (26.2%) had > or = 50% vertebral and basilar stenosis, compared with 41 (11.5%) patients with > or = 50% ipsilateral carotid stenosis in 357/387 (92%) patients with carotid events who had carotid imaging (OR = 2.74; 95% CI = 1.67-4.51; P = 0.002). Presence of > or = 50% vertebral and basilar stenosis was unrelated to age, sex or vascular risk factors and, in contrast to > or = 50% carotid stenosis was not associated with evidence of coronary/peripheral atherosclerosis. In patients with posterior circulation events, > or = 50% vertebral and basilar stenosis was associated multiple transient ischaemic attacks at presentation (22% versus 3%; OR = 9.29; 95% CI = 2.31-37.27; P < 0.001) and with a significantly higher 90-day risk of recurrent events (OR = 3.2; 95% CI = 1.4-7.0; P = 0.006), reaching 22% for stroke and 46% for transient ischaemic attack and stroke. The prevalence of > or = 50% vertebral and basilar stenosis in posterior circulation transient ischaemic attack or minor stroke is greater than the prevalence of > or = 50% carotid stenosis in carotid territory events, and is associated with multiple transient ischaemic attacks at presentation and a high early risk of recurrent stroke. Trials of interventional treatment are therefore likely to be feasible, but more data are required on the long-term risk of stroke on best medical treatment.

Population-based study of risk and predictors of stroke in the first few hours after a TIA

Background: Several recent guidelines recommend assessment of patients with TIA within 24 hours, but it is uncertain how many recurrent strokes occur within 24 hours. It is also unclear whether the ABCD2 risk score reliably identifies recurrences in the first few hours. Methods: In a prospective, population-based incidence study of TIA and stroke with complete follow-up (Oxford Vascular Study), we determined the 6-, 12-, and 24-hour risks of recurrent stroke, defined as new neurologic symptoms of sudden onset after initial recovery. Results: Of 1,247 first TIA or strokes, 35 had recurrent strokes within 24 hours, all in the same arterial territory. The initial event had recovered prior to the recurrent stroke (i.e., was a TIA) in 25 cases. The 6-, 12-, and 24-hour stroke risks after 488 first TIAs were 1.2% (95% confidence interval [CI]: 0.2–2.2), 2.1% (0.8–3.2), and 5.1% (3.1–7.1), with 42% of all strokes during the 30 days after a first TIA occurring within the first 24 hours. The 12- and 24-hour risks were strongly related to ABCD2 score (p = 0.02 and p = 0.0003). Sixteen (64%) of the 25 cases sought urgent medical attention prior to the recurrent stroke, but none received antiplatelet treatment acutely. Conclusion: That about half of all recurrent strokes during the 7 days after a TIA occur in the first 24 hours highlights the need for emergency assessment. That the ABCD2 score is reliable in the hyperacute phase shows that appropriately triaged emergency assessment and treatment are feasible.

Stroke Risk After Posterior Circulation Stroke/Transient Ischemic Attack and Its Relationship to Site of Vertebrobasilar Stenosis Pooled Data Analysis From Prospective Studies

Background and Purpose— Recent prospective studies have shown vertebrobasilar (VB) stenosis predicts stroke risk in posterior circulation stroke and transient ischemic attack. It is unclear whether this association is independent of other risk factors, and whether intracranial or extracranial stenosis confers different risks. Methods— A pooled individual patient analysis of data from 2 prospective studies was performed in 359 patients presenting with VB transient ischemic attack or stroke. Contrast-enhanced magnetic resonance angiography, or computed tomography angiogram, and clinical follow-up were available in 323 patients. Risk of stroke was calculated from any VB transient ischemic attack/stroke in the month before the presenting episode (first event) and from the presenting event. A systematic review of similar prospective studies was performed. Results— Ninety-day risk of stroke from the first event was 24.6% in patients with VB stenosis versus 7.2% in those without (odds ratio, 4.2; 95% confidence interval, 2.1–8.6; P<0.0001). Risk was higher (33%) with intracranial (odds ratio, 6.5; 2.8–15.0; P<0.0001) than extracranial stenosis (16.2%; odds ratio, 2.5; 0.9–6.8; P=0.06). Risk from the presenting event was 9.6% in patients with stenosis versus 2.8% in those without (odds ratio, 3.7; 1.2–11.0; P=0.012), and again the risk was higher with intracranial stenosis. Cox regression showed the risk associated with VB stenosis was independent of other cardiovascular risk factors. The systematic review identified only 1 other report, which included only 6 patients. Conclusions— Symptomatic VB stenosis, particularly intracranial stenosis, is a strong independent predictor of stroke recurrence. The high early risk of stroke provides a strong rationale for randomized trials to determine whether stenting can reduce risk.

Inflammatory response after acute ischemic stroke

BACKGROUND AND PURPOSE This study aimed to characterize the time course of inflammatory parameters after acute ischemic stroke. METHODS We serially determined high sensitivity C-reactive protein (CRP), fibrinogen, and leukocyte counts at 10 time points between days 1 and 90 after ischemic stroke and in control subjects. RESULTS CRP did not significantly change, whereas fibrinogen increased after stroke. At all time points, CRP and fibrinogen were higher than in healthy control subjects, but not risk factor control subjects. The leukocyte count declined after stroke and was significantly elevated as compared to both control groups only on day 1 but not later. NIHSS levels were positively correlated with CRP and fibrinogen at all time points. Larger infarcts were associated with a higher CRP and leukocyte counts on day 90. Treatment with aspirin was associated with lower values for all three inflammatory parameters in the subacute phase after ischemia. CONCLUSIONS The course after stroke was different between the parameters of inflammation. Only the leukocytes followed the paradigm of an acute phase response.

Lower Rates of Intervention for Symptomatic Carotid Stenosis in Women Than in Men Reflect Differences in Disease Incidence A Population-Based Study

Background and Purpose— Although there is little sex difference in the age-specific incidence of transient ischemic attack (TIA) and stroke, substantially more men than women undergo endarterectomy/stenting for symptomatic carotid stenosis. Sexism in referral for investigation or intervention has been proposed as an explanation; however, a lower incidence of carotid disease in women or reluctance to undergo intervention might also be responsible. Methods— We determined the sex-specific incidence of symptomatic carotid stenosis and subsequent endarterectomy/stenting from 2002 to 2009 in consecutive patients with TIA or nondisabling ischemic stroke in the Oxford Vascular Study. We studied equivalent data from routine clinical practices in the wider Oxfordshire population. Results— There was no sex difference in age-specific referral rates for carotid imaging in the Oxford Vascular Study (n=616; age-adjusted relative rate [RR] for males vs females=1.08; 95% CI, 0.79 to 1.46; P=0.64). However, rates of 50% to 99% symptomatic carotid stenosis were higher in men (RR=1.89; 95% CI, 1.31 to 2.71; P=0.0005). The same was seen in imaged patients (n=575) in the wider Oxfordshire population (RR=1.82; 95% CI, 1.31 to 2.53; P=0.003) and in pooled data (RR=1.87; 95% CI, 1.32 to 2.64; P=0.0003). Rates of symptomatic carotid occlusion were also higher in men in both populations (RR=3.19; 95% CI, 1.95 to 5.23; P<0.0001). Consequently, although men were more likely to undergo carotid intervention (RR=1.98; 95% CI, 1.43 to 2.75; P<0.0001), the proportion of patients with 50% to 99% symptomatic carotid stenosis who received intervention was similar for men and women (odds ratio=1.13; 95% CI, 0.57 to 2.25; P=0.72). Conclusion— Lower rates of intervention for 50% to 99% symptomatic carotid stenosis in women can be explained by sex differences in population-based incidence. We found no evidence of any investigation or intervention bias.

The effect of infections and vaccinations on stroke risk

There is increasing evidence that, in addition to conventional risk factors, acute and chronic infectious diseases increase the risk of stroke. Acute infection, mainly respiratory, and both bacterial and viral infection, represent temporarily active trigger factors for cerebral ischemia. Chronic infectious diseases that may increase the risk of stroke include periodontitis, chronic bronchitis and infections with microbial antigens, such as Helicobacter pylori and Chlamydia pneumoniae. From observational studies, there is evidence that vaccination against influenza is associated with a reduced risk of stroke, myocardial infarction and all-cause mortality. This report provides an overview on the influence of infection on stroke risk and potential anti-infective strategies that may play a future role in stroke prevention.