Cognitive Predictors of Delirium on Long-Term Follow-Up after TIA and Stroke: Population-Based Cohort Study.

INTRODUCTION: TIA and stroke cause cognitive impairment with a typical "vascular" pattern, including prominent frontal/executive deficits. Cognitive impairment is associated with increased delirium risk and the few available data suggest that executive dysfunction is important. We therefore determined the predictive value of both severity and pattern of cognitive deficits for delirium on long-term follow-up after TIA/stroke. METHODS: Surviving TIA/stroke participants on October 1, 2013, in the Oxford Vascular Study (OXVASC) were assessed prospectively for delirium during all hospitalizations over the subsequent 6 months. Associations between OXVASC pre-admission mini-mental state examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores, and delirium during hospitalizations on follow-up were determined using logistic regression adjusted for covariates, including demographic factors, history of depression, baseline stroke severity, and admission illness severity. RESULTS: Among 1,565 TIA/stroke survivors, 158 patients (mean/SD age = 79.2/11.5 years) had ≥1 admission and 59 (37%) had ≥1 delirium episode. Mean/SD time between baseline TIA/stroke and admission was 4.7/3.6 years and between most recent OXVASC cognitive testing and admission was 1.7/1.8 years. MMSE and MoCA scores were associated with delirium: odds ratio (OR) = 1.16 (95% CI 1.07-1.27, p < 0.0001 per point decrease in MMSE) and OR = 1.20 (1.11-1.30, p < 0.0001 MoCA) and associations were robust to adjustment for all covariates, including stroke severity: OR = 1.11 (1.01-1.22, p = 0.03, MMSE) and OR = 1.15 (1.05-1.25, p = 0.003, MoCA). All 10 subtests on the MoCA and 4/11 on the MMSE were significantly associated with delirium with highest predictive value for frontal/executive and recall domains. CONCLUSIONS: Cognitive impairment of increasing severity after TIA/stroke predisposed to delirium particularly deficits in frontal/executive domains and recall. Long-term risk of delirium should be considered as part of the overall cerebrovascular disease burden.

Utility of white matter disease and atrophy on routinely acquired brain imaging for prediction of long-term delirium risk: population-based cohort study.

BACKGROUND: brain imaging done as part of standard care may have clinical utility beyond its immediate indication. Using delirium as an exemplar, we determined the predictive value of baseline brain imaging variables [white matter changes (WMC) and atrophy] for delirium risk on long-term follow-up after transient ischemic attack (TIA)/stroke in a population-based cohort study. METHODS: surviving TIA/stroke participants in the Oxford Vascular Study (OXVASC) were assessed prospectively for delirium during all hospitalisations over 6 months (2013-14). Using logistic regression, independent associations were determined between baseline OXVASC computed tomography or magnetic resonance brain imaging measures of WMC and cerebral atrophy (none/mild versus moderate/severe) and delirium adjusted for age, sex, baseline stroke severity, depression, illness severity and pre-admission cognition. RESULTS: among 1,565 TIA/stroke survivors with 194 hospital admissions (158 patients, mean/standard deviation age at admission = 79.2/11.5 years), delirium occurred in 59 (37%). WMC and atrophy on baseline imaging were associated with delirium [odds ratio (OR) = 3.41, 1.21-5.85, P = 0.001 and OR = 2.50, 1.23-5.08, P = 0.01 (unadjusted) and OR = 2.67, 1.21-5.85, P = 0.02 and OR = 2.18, 1.00-4.73, P = 0.05 (adjusted age and sex)]. Associations were strengthened when analyses were restricted to patients hospitalised within 5 years of baseline brain imaging [OR = 6.04, 2.39-15.24, P < 0.0001 and OR = 4.64, 1.46-14.82, P = 0.009 (unadjusted)] but only WMC remained significant after adjustment for all covariates including pre-admission cognition (OR = 4.83, 1.29-18.13, P = 0.02 for Mini-Mental State Examination and OR = 5.15, 1.26-21.09, P = 0.02 for Montreal Cognitive Assessment). CONCLUSIONS: WMC and atrophy on brain imaging done up to 5 years earlier predicted delirium and may have clinical utility in risk stratification. Associations with WMC but not atrophy were independent of pre-admission cognitive impairment.

Time course of blood pressure control prior to lacunar TIA and stroke: Population-based study.

OBJECTIVE: To determine the age-specific temporal trends in blood pressure (BP) before acute lacunar vs nonlacunar TIA and stroke. METHODS: In a population-based study of TIA/ischemic stroke (Oxford Vascular Study), we studied 15-year premorbid BP readings from primary care records in patients with lacunar vs nonlacunar events (Trial of Org 10172 in Acute Stroke Treatment [TOAST]) stratified by age (<65, ≥65 years). RESULTS: Of 2,085 patients (1,250 with stroke, 835 with TIA), 309 had lacunar events. In 493 patients <65 years of age, the prevalence of diagnosed hypertension did not differ between lacunar and nonlacunar events (46 [48.4%] vs 164 [41.2%], p = 0.20), but mean/SD premorbid BP (44,496 BP readings) was higher in patients with lacunar events (15-year records: systolic BP [SBP] 138.5/17.7 vs 133.3/15.0 mm Hg, p = 0.004; diastolic BP [DBP] 84.1/9.6 vs 80.9/8.4 mm Hg, p = 0.001), mainly because of higher mean BP during the 5 years before the event (SBP 142.6/18.8 vs 134.6/16.6 mm Hg, p = 0.0001; DBP 85.2/9.7 vs 80.6/9.0 mm Hg, p < 0.0001), with a rising trend (ptrend = 0.006) toward higher BP leading up to the event (<30-day pre-event SBP: 152.7/16.1 vs 135.3/23.1 mm Hg, p = 0.009; DBP 87.9/9.4 vs 80.8/12.8 mm Hg, p = 0.05; mean BP ≤1 year before the event 145.8/22.0 vs 134.7/16.1 mm Hg, p = 0.001; 86.1/10.7 vs 80.4/9.8 mm Hg, p = 0.0001). Maximum BP in the 5 years before the event was also higher in patients with lacunar events (SBP 173.7/26.6 vs 158.6/23.2 mm Hg, p = 0.0001; DBP 102.3/12.9 vs 94.2/11.2 mm Hg, p < 0.0001), as was persistently elevated BP (≥50% SBP >160 mm Hg, odd ratio 4.95, 95% confidence interval 1.99-12.31, p = 0.0002). However, no similar differences in BP were observed in patients ≥65 years of age. CONCLUSION: Recent premorbid BP control is strongly temporarily related to acute lacunar events at younger ages, suggesting a direct role of BP in accelerating causal pathology and highlighting the need to control hypertension quickly.

Methodological Factors in Determining Risk of Dementia After Transient Ischemic Attack and Stroke: (II) Effect of Attrition on Follow-Up.

BACKGROUND AND PURPOSE: Cognitive outcomes in cohorts and trials are often based only on face-to-face clinic assessment. However, cognitive impairment is strongly associated with increased morbidity and mortality, leading to substantial loss to clinic follow-up. In the absence of previous population-based data, we determined the effect of such attrition on measured risk of dementia after transient ischemic attack and stroke. METHODS: Patients with transient ischemic attack or stroke prospectively recruited (2002-2007) into the Oxford Vascular (OXVASC) study had baseline clinical/cognitive assessment and follow-up to 2014. Dementia was diagnosed through face-to-face clinic interview, supplemented by home visits and telephone assessment in patients unable to attend clinic and by hand-searching of primary care records in uncontactable patients. RESULTS: Of 1236 patients (mean age/SD, 75.2/12.1 years; 582 men), 527 (43%) died by 5-year follow-up. Follow-up assessment rates (study clinic, home visit, or telephone) of survivors were 947 in 1026 (92%), 857 in 958 (89%), 792 in 915 (87%), and 567 in 673 (84%) at 1, 6, 12 months and 5 years. Dementia developed in 260 patients, of whom 110 (42%; n=50 primary care records, n=49 home visit, and n=11 telephone follow-up) had not been available for face-to-face clinic follow-up at the time of diagnosis. The 5-year cumulative incidence of postevent dementia was 29% (26%-32%) overall but was only 17% (14% to 19%) in clinic assessed versus 45% (39%-51%) in nonclinic-assessed patients (P difference<0.001). CONCLUSIONS: Exclusion of patients unavailable for clinic follow-up reduces the measured risk of postevent dementia. Use of multiple follow-up methods, including home visits, telephone assessments, and consent, to access primary care records substantially increases ascertainment of longer-term dementia outcomes.

Age-specific incidence, outcome, cost, and projected future burden of atrial fibrillation-related embolic vascular events: a population-based study.

BACKGROUND: Prevalence of atrial fibrillation (AF) is >10% at age ≥80 years, but the impact of population aging on rates of AF-related ischemic events is uncertain. METHODS AND RESULTS: We studied age-specific incidence, outcome, and cost of all AF-related incident strokes and systemic emboli from 2002 to 2012 in the Oxford Vascular Study (OXVASC). We determined time trends in incidence of AF-related stroke in comparison with a sister study in 1981 to 1986, extrapolated numbers to the UK population and projected future numbers. Of 3096 acute cerebral or peripheral vascular events in the 92 728 study population, 383 incident ischemic strokes and 71 systemic emboli were related to AF, of which 272 (59.9%) occurred at ≥80 years. Of 597 fatal or disabling incident ischemic strokes, 262 (43.9%) were AF-related. Numbers of AF-related ischemic strokes at age ≥80 years increased nearly 3-fold from 1981-1986 to 2002-2012 (extrapolated to the United Kingdom: 6621 to 18 176 per year), due partly to increased age-specific incidence (relative rate 1.52, 95% confidence interval 1.31-1.77, P=0.001), with potentially preventable AF-related events at age ≥80 years costing the United Kingdom £374 million per year. At current incidence rates, numbers of AF-related embolic events at age ≥80 years will treble again by 2050 (72 974/year), with 83.5% of all events occurring in this age group. CONCLUSIONS: Numbers of AF-related incident ischemic strokes at age ≥80 years have trebled over the last 25 years, despite the introduction of anticoagulants, and are projected to treble again by 2050, along with the numbers of systemic emboli. Improved prevention in older people with AF should be a major public health priority.

Population-based study of disability and institutionalization after transient ischemic attack and stroke: 10-year results of the Oxford Vascular Study.

BACKGROUND AND PURPOSE: Long-term outcome information after transient ischemic attack (TIA) and stroke is required to help plan and allocate care services. We evaluated the impact of TIA and stroke on disability and institutionalization over 5 years using data from a population-based study. METHODS: Patients from a UK population-based cohort study (Oxford Vascular Study) were recruited from 2002 to 2007 and followed up to 2012. Patients were followed up at 1, 6, 12, 24, and 60 months postevent and assessed using the modified Rankin scale. A multivariate regression analysis was performed to assess the predictors of disability postevent. RESULTS: A total of 748 index stroke and 440 TIA cases were studied. For patients with TIA, disability levels increased from 14% (63 of 440) premorbidly to 23% (60 of 256) at 5 years (P=0.002), with occurrence of subsequent stroke being a major predictor of disability. For stroke survivors, the proportion disabled (modified Rankin scale >2) increased from 21% (154 of 748) premorbidly to 43% (273 of 634) at 1 month (P<0.001), with 39% (132 of 339) of survivors disabled 5 years after stroke. Five years postevent, 70% (483 of 690) of patients with stroke and 48% (179 of 375) of patients with TIA were either dead or disabled. The 5-year risk of care home institutionalization was 11% after TIA and 19% after stroke. The average 5-year cost per institutionalized patient was $99,831 (SD, 67 020) for TIA and $125,359 (SD, 91 121) for stroke. CONCLUSIONS: Our results show that 70% of patients with stroke are either dead or disabled 5 years after the event. Thus, there remains considerable scope for improvements in acute treatment and secondary prevention to reduce postevent disability and institutionalization.

Cognitive outcomes after acute coronary syndrome: a population based comparison with transient ischaemic attack and minor stroke.

OBJECTIVE: Acute coronary syndrome (ACS) is associated with increased risk of cognitive decline when compared with controls, but case:control studies are subject to selection bias. We therefore compared cognitive outcomes in ACS with transient ischaemic attack (TIA) and minor stroke, diseases with similar risk factor burden generally considered to be at high risk of cognitive decline. DESIGN: Prospective population based cohort study SETTING: Oxford Vascular Study (OXVASC) carried out within a defined population of 91 000 in Oxfordshire, UK. PATIENTS: 614 in total: 216 ACS, 182 TIA, 216 minor (non-disabling) stroke. OUTCOME MEASURES: Mini-Mental-State-Examination (MMSE), Telephone Interview for Cognitive Status-modified (TICSm), and Montreal Cognitive Assessment (MoCA) at 1 and 5 years. RESULTS: Overall risk factor burden was similar across groups but ACS patients had more smoking (27% vs 14%, p<0.001) and less hypertension (45% vs 53%, p<0.01) and atrial fibrillation (6% vs 14%, p<0.001). Cognitive outcomes were worse at 1 year in ACS versus TIA patients: mean±SD MMSE 26.6±2.7 vs 27.6±2.5, p<0.0001; OR=2.14, 95% CI 1.11 to 4.13 for moderate/severe cognitive impairment (MMSE <24) with a similar trend at 5 years, and ACS outcomes were more similar to minor stroke. Memory and language versus frontal/executive subtests were relatively more impaired in ACS than TIA and minor stroke patients. CONCLUSIONS: Risk of cognitive impairment after ACS is similar to minor stroke and higher than TIA with implications for clinical practice including consent and adherence with medication. Differences in cognitive domain performance suggest a greater role for degenerative brain pathology in ACS which may be linked to vascular risk profile and cardiac factors.

Telephone assessment of cognition after transient ischemic attack and stroke: modified telephone interview of cognitive status and telephone Montreal Cognitive Assessment versus face-to-face Montreal Cognitive Assessment and neuropsychological battery.

BACKGROUND AND PURPOSE: Face-to-face cognitive testing is not always possible in large studies. Therefore, we assessed the telephone Montreal Cognitive Assessment (T-MoCA: MoCA items not requiring pencil and paper or visual stimulus) and the modified Telephone Interview of Cognitive Status (TICSm) against face-to-face cognitive tests in patients with transient ischemic attack (TIA) or stroke. METHODS: In a population-based study, consecutive community-dwelling patients underwent the MoCA and neuropsychological battery >1 year after TIA or stroke, followed by T-MoCA (22 points) and TICSm (39 points) at least 1 month later. Mild cognitive impairment (MCI) was diagnosed using modified Petersen criteria and the area under the receiver-operating characteristic curve (AUC) determined for T-MoCA and TICSm. RESULTS: Ninety-one nondemented subjects completed neuropsychological testing (mean±SD age, 72.9±11.6 years; 54 males; stroke 49%) and 73 had telephone follow-up. MoCA subtest scores for repetition, abstraction, and verbal fluency were significantly worse (P<0.02) by telephone than during face-to-face testing. Reliability of diagnosis for MCI (AUC) were T-MoCA of 0.75 (95% confidence interval [CI], 0.63-0.87) and TICSm of 0.79 (95% CI, 0.68-0.90) vs face-to-face MoCA of 0.85 (95% CI, 0.76-0.94). Optimal cutoffs were 18 to 19 for T-MoCA and 24 to 25 for TICSm. Reliability of diagnosis for MCI (AUC) was greater when only multi-domain impairment was considered (T-MoCA=0.85; 95% CI, 0.75-0.96 and TICSm=0.83, 95% CI, 0.70-0.96) vs face-to-face MoCA=0.87; 95% CI, 0.76-0.97). CONCLUSIONS: Both T-MoCA and TICSm are feasible and valid telephone tests of cognition after TIA and stroke but perform better in detecting multi-domain vs single-domain impairment. However, T-MoCA is limited in its ability to assess visuoexecutive and complex language tasks compared with face-to-face MoCA.

Family history does not predict angiographic localization or severity of coronary artery disease.

BACKGROUND: Family history of MI is an established risk factor for coronary artery disease and subclinical atherosclerosis. Maternal MI and maternal stroke are more common in females than males presenting with acute coronary syndromes (ACS), suggesting sex-specific heritability, but the effects of family history on location and extent of coronary artery disease are unknown. METHODS: In a prospective, population-based study (Oxford Vascular Study) of all patients with ACS, family history data for stroke and MI were analysed by sex of proband and affected first degree relatives (FDRs), and coronary angiograms were reviewed, where available. RESULTS: Of 835 probands with one or more ACS, 623 (420 males) had incident events and complete family history data. 351 patients with incident events (56.3%; 266 males) underwent coronary angiography. Neither angiographic disease localization nor severity were associated with sex-of-parent/sex-of-offspring in men or women. CONCLUSIONS: Sex-specific family history data do not predict angiographic localization of coronary disease in patients presenting with ACS. Maternal stroke and maternal MI probably affect ACS in females by a mechanism unrelated to atherosclerosis or coronary anatomy. However, family history data may still be useful in risk prediction and prognosis of ACS.

Relative familial clustering of cerebral versus coronary ischemic events.

BACKGROUND: Few population-based studies have ascertained both cerebral and coronary events or considered their relative heritability. Differences in heritability of transient ischemic attack and ischemic stroke versus acute coronary syndromes (ACS) may inform risk prediction, genetic studies, and understanding of disease mechanisms. METHODS AND RESULTS: In a population-based study of all acute vascular events, irrespective of age, we studied family history of myocardial infarction (MI), stroke, and related risk factors in first-degree relatives. To allow for differences in rates of affected first-degree relatives caused by differences in disease incidence, we looked at the extent to which parental history was associated with affected siblings within disease category. Nine hundred six probands (604 men; mean age, 70 years) with ACS and 1015 (484 men; mean age, 73 years) with cerebral events had complete family history data. In ACS probands, parental MI was associated with MI in ≥1 sibling (1 parent with MI: odds ratio, 1.48; 1.04 to 2.10; P=0.03; both parents with MI: odds ratio, 5.97; 3.23 to 11.03; P<0.0001). In probands with cerebral events, however, parental stroke was not associated with sibling stroke. The overall frequency of ≥2 siblings with the same condition was also greater in probands with ACS than in those with cerebral events (odds ratio, 5.43; 3.03 to 9.76; P<0.00001), despite similar overall incidence of MI and stroke in our study population. One hundred forty-two (15.7%) cases of ACS occurred in families with ≥2 affected first-degree relatives compared with 56 (5.1%) transient ischemic attack/strokes. All results were similar when analyses were confined to probands with MI only versus stroke only, and independent of smoking. CONCLUSIONS: Heritability of coronary events was greater than that of cerebral events, such that MI was more likely to cluster in families than was stroke.

Familial history of stroke is associated with acute coronary syndromes in women.

BACKGROUND: Stroke in female first-degree relatives (FDRs) is a powerful risk factor for ischemic stroke in women, but its association with acute coronary syndromes (ACS) is unknown. Family history (FH) of stroke is omitted from existing myocardial infarction risk prediction tools, which perform less well in women than in men. Our objective was to study the sex-of-parent and sex-of-proband interactions for FH of stroke in ACS patients. METHODS AND RESULTS: In a prospective, population-based study (Oxford Vascular Study) of all patients with ACS or stroke/transient ischemic attack, FH data for stroke and myocardial infarction were analyzed by sex of proband and FDRs, and coronary angiograms were reviewed, where available; 942 of 1058 ACS probands and 1015 of 1152 stroke/transient ischemic attack probands had complete FH data; 24.1% of ACS probands and 24.3% of stroke/transient ischemic attack probands had history of stroke in ≥1 FDR. Maternal stroke was more common than paternal stroke in female ACS probands (odds ration [OR], 2.53; 1.39 to 4.61) but not in male probands (OR, 0.92; 0.64 to 1.32) (difference-P=0.004). Overall, female ACS probands were more likely to have female than male FDRs with stroke (OR, 2.09; 1.29 to 3.37), whereas the opposite trend was seen in male ACS probands (OR, 0.69; 0.50 to 0.97) (difference-P=0.0002). However, there was no association between parental history of stroke and disease localization or presence of multivessel disease on coronary angiography. CONCLUSIONS: FH of stroke is as common in ACS patients as in stroke/transient ischemic attack patients and sex-of-parent/sex-of-proband interactions are similar. Stroke in female FDRs may help to identify women at increased risk of ACS as well as ischemic stroke.

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 (r(2)=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 > or =27, whereas only 5 patients had MoCA > or =26 and MMSE <27 (P<0.0001). In patients with MMSE > or =27, MoCA <26 was associated with higher Rankin scores (P=0.0003) and deficits in delayed recall, abstraction, visuospatial/executive function, and sustained attention. CONCLUSIONS: 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.

Sex-specific familial clustering of myocardial infarction in patients with acute coronary syndromes.

BACKGROUND: Family history of premature myocardial infarction (MI) in first-degree relatives is a risk factor for MI and an indication for primary prevention. Although excess mother-to-daughter "transmission" occurs in ischemic stroke, no published studies have considered sex-of-parent/sex-of-proband interactions in the heritability of MI. METHODS AND RESULTS: In a population-based study (Oxford Vascular Study) of all patients with acute coronary syndromes (ACS), irrespective of age, family history of all acute vascular events and related risk factors were analyzed by sex and age of both probands and first-degree relatives. Premature events were categorized as occurring at age <65 years. Of 835 probands with 1 or more ACS, 623 (420 men) had incident events and complete family history data. In probands with premature ACS, maternal history of both MI and of all vascular events were more common in female than male probands (odds ratio [OR], 2.25; 95% CI, 1.02 to 4.94; P=0.04 and OR, 3.03; 95% CI, 1.47 to 6.26; P=0.002, respectively). No such effect existed for paternal history (OR, 1.00; 95% CI, 0.46 to 2.10; P=0.99 and OR, 1.19; 95% CI, 0.58 to 2.43; P=0.63, respectively). Age at ACS in probands was highly correlated with age at MI in mothers (r=0.46, P<0.001), regardless of the proband's sex. Consequently, history of premature maternal MI was strongly associated with premature ACS and premature MI in female (OR, 10.52; 95% CI, 2.17 to 56.6; P=0.001 and OR, 7.31; 95% CI, 1.55 to 34.6; P=0.004, respectively) and male probands (OR, 3.88; 95% CI, 1.20 to 12.6; P=0.01 and OR, 3.63; 95% CI, 1.13 to 11.60; P=0.02, respectively). CONCLUSIONS: Important sex-of-parent/sex-of-proband interactions exist in the family history of MI in patients with ACS. Greater emphasis should be placed on maternal than paternal history of MI, particularly in women aged <65 years.

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.

Genetic variation in dopaminergic pathways and short-term effectiveness of the nicotine patch.

Polymorphisms in the dopamine D2 receptor (DRD2 C/T and DRD2 A/G) and in dopamine beta hydroxylase (DBH A/G) have been implicated in modulation of smoking and other reward-seeking behaviours. We hypothesized that these alleles would predict the outcome of nicotine patch therapy for smoking cessation. In 1991-93, we performed a randomized controlled trial of the nicotine patch on 1686 heavy smokers (> or = 15 cigarettes/day). In 1999-2000, we contacted 1532 of the 1612 subjects still available; 767 (50%) completed a questionnaire and gave a blood sample. In the 755 cases in which DNA was successfully genotyped, we examined associations between the polymorphisms in DRD2 and DBH, and smoking cessation. At 1 week, the patch was more effective for smokers with DRD2 CT/TT genotype [patch/placebo odds ratio (OR) 2.8, 95% confidence interval (CI) 1.7-4.6] than with CC (OR 1.4, 0.9-2.1; P for difference in ORs 0.04). Smokers with both DRD2 CT/TT and DBH GA/AA genotypes had an OR of 3.6 (2.0-6.5) compared to 1.4 (1.0-2.1) for others (P = 0.01). At 12 weeks, the ORs for these genotypic groups were 3.6 (1.7-7.8) and 1.4 (0.9-2.3), respectively (P = 0.04). There was no association between patch effectiveness and DRD2 exon 8. Short-term effectiveness of the nicotine patch may be related to dopamine beta-hydroxylase and dopamine D2 receptor genotype. Our results support the need for further investigation into personalized therapies for smoking cessation based on individual genotype.