Ziyah Mehta

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.

Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials

BACKGROUND Daily aspirin reduces the long-term incidence of some adenocarcinomas, but effects on mortality due to some cancers appear after only a few years, suggesting that it might also reduce growth or metastasis. We established the frequency of distant metastasis in patients who developed cancer during trials of daily aspirin versus control. METHODS Our analysis included all five large randomised trials of daily aspirin (≥75 mg daily) versus control for the prevention of vascular events in the UK. Electronic and paper records were reviewed for all patients with incident cancer. The effect of aspirin on risk of metastases at presentation or on subsequent follow-up (including post-trial follow-up of in-trial cancers) was stratified by tumour histology (adenocarcinoma vs other) and clinical characteristics. FINDINGS Of 17,285 trial participants, 987 had a new solid cancer diagnosed during mean in-trial follow-up of 6·5 years (SD 2·0). Allocation to aspirin reduced risk of cancer with distant metastasis (all cancers, hazard ratio [HR] 0·64, 95% CI 0·48-0·84, p=0·001; adenocarcinoma, HR 0·54, 95% CI 0·38-0·77, p=0·0007; other solid cancers, HR 0·82, 95% CI 0·53-1·28, p=0·39), due mainly to a reduction in proportion of adenocarcinomas that had metastatic versus local disease (odds ratio 0·52, 95% CI 0·35-0·75, p=0·0006). Aspirin reduced risk of adenocarcinoma with metastasis at initial diagnosis (HR 0·69, 95% CI 0·50-0·95, p=0·02) and risk of metastasis on subsequent follow-up in patients without metastasis initially (HR 0·45, 95% CI 0·28-0·72, p=0·0009), particularly in patients with colorectal cancer (HR 0·26, 95% CI 0·11-0·57, p=0·0008) and in patients who remained on trial treatment up to or after diagnosis (HR 0·31, 95% CI 0·15-0·62, p=0·0009). Allocation to aspirin reduced death due to cancer in patients who developed adenocarcinoma, particularly in those without metastasis at diagnosis (HR 0·50, 95% CI 0·34-0·74, p=0·0006). Consequently, aspirin reduced the overall risk of fatal adenocarcinoma in the trial populations (HR 0·65, 95% CI 0·53-0·82, p=0·0002), but not the risk of other fatal cancers (HR 1·06, 95% CI 0·84-1·32, p=0·64; difference, p=0·003). Effects were independent of age and sex, but absolute benefit was greatest in smokers. A low-dose, slow-release formulation of aspirin designed to inhibit platelets but to have little systemic bioavailability was as effective as higher doses. INTERPRETATION That aspirin prevents distant metastasis could account for the early reduction in cancer deaths in trials of daily aspirin versus control. This finding suggests that aspirin might help in treatment of some cancers and provides proof of principle for pharmacological intervention specifically to prevent distant metastasis. FUNDING None.

Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: Analysis of the time course of risks and benefits in 51 randomised controlled trials

BACKGROUND Daily aspirin reduces the long-term risk of death due to cancer. However, the short-term effect is less certain, especially in women, effects on cancer incidence are largely unknown, and the time course of risk and benefit in primary prevention is unclear. We studied cancer deaths in all trials of daily aspirin versus control and the time course of effects of low-dose aspirin on cancer incidence and other outcomes in trials in primary prevention. METHODS We studied individual patient data from randomised trials of daily aspirin versus no aspirin in prevention of vascular events. Death due to cancer, all non-vascular death, vascular death, and all deaths were assessed in all eligible trials. In trials of low-dose aspirin in primary prevention, we also established the time course of effects on incident cancer, major vascular events, and major extracranial bleeds, with stratification by age, sex, and smoking status. RESULTS Allocation to aspirin reduced cancer deaths (562 vs 664 deaths; odds ratio [OR] 0·85, 95% CI 0·76-0·96, p=0·008; 34 trials, 69,224 participants), particularly from 5 years onwards (92 vs 145; OR 0·63, 95% CI 0·49-0·82, p=0·0005), resulting in fewer non-vascular deaths overall (1021 vs 1173; OR 0·88, 95% CI 0·78-0·96, p=0·003; 51 trials, 77,549 participants). In trials in primary prevention, the reduction in non-vascular deaths accounted for 87 (91%) of 96 deaths prevented. In six trials of daily low-dose aspirin in primary prevention (35,535 participants), aspirin reduced cancer incidence from 3 years onwards (324 vs 421 cases; OR 0·76, 95% CI 0·66-0·88, p=0·0003) in women (132 vs 176; OR 0·75, 95% CI 0·59-0·94, p=0·01) and in men (192 vs 245; OR 0·77, 95% CI 0·63-0·93, p=0·008). The reduced risk of major vascular events on aspirin was initially offset by an increased risk of major bleeding, but effects on both outcomes diminished with increasing follow-up, leaving only the reduced risk of cancer (absolute reduction 3·13 [95% CI 1·44-4·82] per 1000 patients per year) from 3 years onwards. Case-fatality from major extracranial bleeds was also lower on aspirin than on control (8/203 vs 15/132; OR 0·32, 95% CI 0·12-0·83, p=0·009). INTERPRETATION Alongside the previously reported reduction by aspirin of the long-term risk of cancer death, the short-term reductions in cancer incidence and mortality and the decrease in risk of major extracranial bleeds with extended use, and their low case-fatality, add to the case for daily aspirin in prevention of cancer. FUNDING None.

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.

Effects of antihypertensive-drug class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta-analysis

INTRODUCTION Unexplained differences between classes of antihypertensive drugs in their effectiveness in preventing stroke might be due to class effects on intraindividual variability in blood pressure. We did a systematic review to assess any such effects in randomised controlled trials. METHODS Baseline and follow-up data for mean (SD) of systolic blood pressure (SBP) were extracted from trial reports. Effect of treatment on interindividual variance (SD2) in blood pressure (a surrogate for within-individual variability), expressed as the ratio of the variances (VR), was related to effects on clinical outcomes. Pooled estimates were derived by use of random-effects meta-analysis. FINDINGS Mean (SD) SBP at follow-up was reported in 389 (28%) of 1372 eligible trials. There was substantial heterogeneity between trials in VR (p<1 x 10(-40)), 68% of which was attributable to allocated drug class. Compared with other drugs, interindividual variation in SBP was reduced by calcium-channel blockers (VR 0.81, 95% CI 0.76-0.86, p<0.0001) and non-loop diuretic drugs (0.87, 0.79-0.96, p=0.007), and increased by angiotensin-converting enzyme (ACE) inhibitors (1.08, 1.02-1.15, p=0.008), angiotensin-receptor blockers (1.16, 1.07-1.25, p=0.0002), and beta blockers (1.17, 1.07-1.28, p=0.0007). Compared with placebo only, interindividual variation in SBP was reduced the most by calcium-channel blockers (0.76, 0.67-0.85, p<0.0001). Effects were consistent in parallel group and crossover design trials, and in analyses of dose-response. Across all trials, effects of treatment on VR of SBP (r2=0.372, p=0.0006) and on mean SBP (r2=0.328, p=0.0015) accounted for effects on stroke risk (eg, odds ratio 0.79, 0.71-0.87, p<0.0001, for VR< or =0.80), and both remained significant in a combined model. INTERPRETATION Drug-class effects on interindividual variation in blood pressure can account for differences in effects of antihypertensive drugs on risk of stroke independently of effects on mean SBP. FUNDING None.

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.

Underestimation of Cognitive Impairment by Mini-Mental State Examination Versus the Montreal Cognitive Assessment in Patients With Transient Ischemic Attack and Stroke A Population-Based Study

Background and Purpose— The Mini-Mental State Examination (MMSE) is insensitive to mild cognitive impairment and executive function. The more recently developed Montreal Cognitive Assessment (MoCA), an alternative, brief 30-point global cognitive screen, might pick up more cognitive abnormalities in patients with cerebrovascular disease. Methods— In a population-based study (Oxford Vascular Study) of transient ischemic attack and stroke, the MMSE and MoCA were administered to consecutive patients at 6-month or 5-year follow-up. Accepted cutoffs of MMSE <27 and MoCA <26 were taken to indicate cognitive impairment. Results— Of 493 patients, 413 (84%) were testable. Untestable patients were older (75.5 versus 69.9 years, P<0.001) and often had dysphasia (24%) or dementia (15%). Although MMSE and MoCA scores were highly correlated (r2=0.80, P<0.001), MMSE scores were skewed toward higher values, whereas MoCA scores were normally distributed: median and interquartile range 28 (26 to 29) and 23 (20 to 26), respectively. Two hundred ninety-one of 413 (70%) patients had MoCA <26 of whom 162 had MMSE ≥27, whereas only 5 patients had MoCA ≥26 and MMSE <27 (P<0.0001). In patients with MMSE ≥27, MoCA <26 was associated with higher Rankin scores (P=0.0003) and deficits in delayed recall, abstraction, visuospatial/executive function, and sustained attention. Conclusion— The MoCA picked up substantially more cognitive abnormalities after transient ischemic attack and stroke than the MMSE, demonstrating deficits in executive function, attention, and delayed recall.

MoCA, ACE-R, and MMSE Versus the National Institute of Neurological Disorders and Stroke–Canadian Stroke Network Vascular Cognitive Impairment Harmonization Standards Neuropsychological Battery After TIA and Stroke

Background and Purpose— The Montreal Cognitive Assessment (MoCA) and Addenbrookes Cognitive Examination–Revised (ACE-R) are proposed as short cognitive tests for use after stroke, but there are few published validations against a neuropsychological battery. We studied the relationship between MoCA, ACE-R, Mini-Mental State Examination (MMSE) and mild cognitive impairment (MCI) in patients with cerebrovascular disease and mild cognitive impairment (MCI). Methods— One hundred consecutive non-institutionalized patients had the MMSE, MoCA, ACE-R, and National Institute of Neurological Disorders and Stroke–Canadian Stroke Network Vascular Cognitive Impairment Harmonization Standards Neuropsychological Battery ≥1 year after transient ischemic attack or stroke in a population-based study. MCI was diagnosed using modified Petersen criteria in which subjective cognitive complaint is not required (equivalent to cognitive impairment–no dementia) and subtyped by number and type of cognitive domains affected. Results— Among 91 nondemented subjects completing neuropsychological testing (mean/SD age, 73.4/11.6 years; 44% female; 56% stroke), 39 (42%) had MCI (amnestic multiple domain=10, nonamnestic multiple domain=9, nonamnestic single domain=19, amnestic single domain=1). Sensitivity and specificity for MCI were optimal with MoCA <25 (sensitivity=77%, specificity=83%) and ACE-R <94 (sensitivity=83%, specificity=73%). Both tests detected amnestic MCI better than nonamnestic single-domain impairment. MMSE only achieved sensitivity >70% at a cutoff of <29, mainly due to relative insensitivity to single-domain impairment. Conclusions— The MoCA and ACE-R had good sensitivity and specificity for MCI defined using the Neurological Disorders and Stroke–Canadian Stroke Network Vascular Cognitive Impairment Battery ≥1 year after transient ischemic attack and stroke, whereas the MMSE showed a ceiling effect. However, optimal cutoffs will depend on use for screening (high sensitivity) or diagnosis (high specificity). Lack of timed measures of processing speed may explain the relative insensitivity of the MoCA and ACE-R to single nonmemory domain impairment.

From subgroups to individuals: general principles and the example of carotid endarterectomy

Clinicians often have to make treatment decisions based on the likelihood that an individual patient will benefit. In this article we consider the relevance of relative and absolute risk reductions, and draw attention to the importance of expressing the results of trials and subgroup analyses in terms of absolute risk. We describe the limitations of univariate subgroup analysis in situations in which there are several determinants of treatment effect, and review the potential for targeting treatments with risk models, especially when benefit is probably going to be dependent on the absolute risk of adverse outcomes with or without treatment. The ability to systematically take into account the characteristics of an individual patient and their interactions, to consider the risks and benefits of interventions separately if needed, and to provide patients with personalised estimates of their likelihood of benefit is shown using the example of endarterectomy for symptomatic carotid stenosis.