Patent Foramen Ovale Closure in Older Patients With Stroke: Patient Selection for Trial Feasibility.

BACKGROUND AND OBJECTIVES: Whether patent foramen ovale (PFO) closure benefits older patients with PFO and cryptogenic stroke is unknown because randomized controlled trials (RCTs) have predominantly enrolled patients younger than 60 years of age. Our objective was to estimate anticipated effects of PFO closure in older patients to predict the numbers needed to plan an RCT. METHODS: Effectiveness estimates are derived from major observational studies (Risk of Paradoxical Embolism [RoPE] Study and Oxford Vascular Study, together referred to as the "RoPE-Ox" database) and all 6 major RCTs (Systematic, Collaborative, PFO Closure Evaluation [SCOPE] Consortium). To estimate stroke recurrence risk, observed outcomes were calculated for patients older than 60 years in the age-inclusive observational databases (n = 549). To estimate the reduction in the rate of recurrent stroke associated with PFO closure vs medical therapy based on the RoPE score and the presence of high-risk PFO features, a Cox proportional hazards regression model was developed on the RCT data in the SCOPE database (n = 3,740). These estimates were used to calculate sample sizes required for a future RCT. RESULTS: Five-year risk of stroke recurrence using Kaplan-Meier estimates was 13.7 (95% CI 10.5-17.9) overall, 14.9% (95% CI 10.2-21.6) in those with high-risk PFO features. Predicted relative reduction in the event rate with PFO closure was 12.9% overall, 48.8% in those with a high-risk PFO feature. Using these estimates, enrolling all older patients with cryptogenic stroke and PFO would require much larger samples than those used for prior PFO closure trials, but selectively enrolling patients with high-risk PFO features would require totals of 630 patients for 90% power and 471 patients for 80% power, with an average of 5 years of follow-up. DISCUSSION: Based on our projections, anticipated effect sizes in older patients with high-risk features make a trial in these subjects feasible. With lengthening life expectancy in almost all regions of the world, the utility of PFO closure in older adults is increasingly important to explore.

Association of multimorbidity with mortality after stroke stratified by age, severity, etiology, and prior disability.

BACKGROUND: Multimorbidity is common in patients with stroke and is associated with increased medium- to long-term mortality, but its value for clinical decision-making and case-mix adjustment will depend on other factors, such as age, stroke severity, etiological subtype, prior disability, and vascular risk factors. AIMS: In the absence of previous studies, we related multimorbidity to long-term post-stroke mortality with stratification by these factors. METHODS: In patients ascertained in a population-based stroke incidence study (Oxford Vascular Study; 2002-2017), we related pre-stroke multimorbidity (weighted/unweighted Charlson comorbidity index (CCI)) to all-cause/vascular/non-vascular mortality (1/5/10 years) using regression models adjusted/stratified by age, sex, predicted early outcome (THRIVE score), stroke severity (NIH stroke scale (NIHSS)), etiology (Trial of Org 10172 in Acute Stroke Treatment (TOAST)), premorbid disability (modified Rankin Scale (mRS)), and non-CCI risk factors (hypertension, hyperlipidemia, atrial fibrillation, smoking, deprivation, anxiety/depression). RESULTS: Among 2454 stroke patients (M/SD age: 74.1/13.9 years; 48.9% male; M/SD NIHSS: 5.7/7.0), 1375/56.0% had ⩾ 1 CCI comorbidity and 685/27.9% had ⩾ 2. After age/sex adjustment, multimorbidity (unweighted CCI ⩾ 2 vs 0) predicted (all ps < 0.001) mortality at 1 year (aHR = 1.57, 95% CI = 1.38-1.78), 5 years (aHR = 1.73, 95% CI = 1.53-1.96), and 10 years (aHR = 1.79, 95% CI = 1.58-2.03). Although multimorbidity was independently associated with premorbid disability (mRS > 2: aOR = 2.76, 2.13-3.60) and non-CCI risk factors (hypertension: 1.56, 1.25-1.95; hyperlipidemia: 2.58, 2.03-3.28; atrial fibrillation: 2.31; 1.78-2.98; smoking: 1.37, 1.01-1.86), it predicted death after adjustment for all measured confounders (10-year-aHR = 1.56, 1.37-1.78, p < 0.001), driven mainly by non-vascular death (aHR = 1.89, 1.55-2.29). Predictive value for 10-year all-cause death was greatest in patients with lower expected early mortality: lower THRIVE score (pint < 0.001), age < 75 years (aHR = 2.27, 1.71-3.00), NIHSS < 5 (1.84, 1.53-2.21), and lacunar stroke (3.56, 2.14-5.91). Results were similar using the weighted CCI. CONCLUSION: Pre-stroke multimorbidity is highly prevalent and is an independent predictor of death after stroke, supporting its inclusion in case-mix adjustment models and in informing decision-making by patients, families, and carers. Prediction in younger patients and after minor stroke, particularly for non-vascular death, suggests potential clinical utility in targeting interventions that require survival for 5-10 years to achieve a favorable risk/benefit ratio. DATA ACCESS STATEMENT: Data requests will be considered by the Oxford Vascular Study (OXVASC) Study Director (P.M.R.-peter.rothwell@ndcn.ox.ac.uk).

Long-Term Impact of Urgent Secondary Prevention After Transient Ischemic Attack and Minor Stroke: Ten-Year Follow-Up of the EXPRESS Study.

BACKGROUND AND PURPOSE: Urgent assessment aimed at reducing stroke risk after transient ischemic attack or minor stroke is cost-effective over the short-term. However, it is unclear if the short-term impact is lost on long-term follow-up, with recurrent events being delayed rather than prevented. By 10-year follow-up of the EXPRESS study (Early Use of Existing Preventive Strategies for Stroke), previously showing urgent assessment reduced 90-day stroke risk by 80%, we determined whether that early benefit was still evident long-term for stroke risk, disability, and costs. METHODS: EXPRESS was a prospective population-based before (phase 1: April 2002-September 2004; n=310) versus after (phase 2: October 2004-March 2007; n=281) study of the effect of early assessment and treatment of transient ischemic attack/minor stroke on early recurrent stroke risk, with an external control. This report assesses the effect on 10-year recurrent stroke risk, functional outcomes, quality-of-life, and costs. RESULTS: A reduction in stroke risk in phase 2 was still evident at 10 years (55/23.3% versus 82/31.6%; hazard ratio=0.68 [95% CI, 0.48-0.95]; P=0.024), as was the impact on risk of disabling or fatal stroke (17/7.7% versus 32/13.1%; hazard ratio=0.54 [0.30-0.97]; P=0.036). These effects were due to maintenance of the early reduction in stroke risk, with neither additional benefit nor rebound catch-up after 90 days (post-90 days hazard ratio=0.88 [0.65-1.44], P=0.88; and hazard ratio=0.83 [0.42-1.65], P=0.59, respectively). Disability-free life expectancy was 0.59 (0.03-1.15; P=0.043) years higher in patients in phase 2, as was quality-adjusted life expectancy (0.49 [0.03-0.95]; P=0.036). Overall, 10-year costs were nonsignificantly higher in patients attending the phase 2 clinic ($1022 [-3865-5907]; P=0.66). The additional cost per quality-adjusted life year gained in phase 2 versus phase 1 was $2103, well below current cost-effectiveness thresholds. CONCLUSIONS: Urgent assessment and treatment of patients with transient ischemic attack or minor stroke resulted in a long-term reduction in recurrent strokes and improved outcomes, with little atrophy of the early benefit over time, representing good value for money even with a 10-year time horizon. Our results suggest that other effective acute treatments in transient ischemic attack/minor stroke in the short-term will also have the potential to have long-term benefit.

Risks of recurrent stroke and all serious vascular events after spontaneous intracerebral haemorrhage: pooled analyses of two population-based studies.

BACKGROUND: Patients with stroke due to spontaneous (non-traumatic) intracerebral haemorrhage (ICH) are at risk of recurrent ICH, ischaemic stroke, and other serious vascular events. We aimed to analyse these risks in population-based studies and compare them with the risks in RESTART, which assessed antiplatelet therapy after ICH. METHODS: We pooled individual patient data from two prospective, population-based inception cohort studies of all patients with an incident firs-in-a-lifetime ICH in Oxfordshire, England (Oxford Vascular Study; April 1, 2002, to Sept 28, 2018) and Lothian, Scotland, UK (Lothian Audit of the Treatment of Cerebral Haemorrhage; June 1, 2010, to May 31, 2013). We quantified the absolute and relative risks of recurrent ICH, ischaemic stroke, or any serious vascular event (non-fatal stroke, non-fatal myocardial infarction, or vascular death), stratified by ICH location (lobar vs non-lobar) and comorbid atrial fibrillation (AF). We compared pooled event rates with those after allocation to avoid antiplatelet therapy in RESTART. FINDINGS: Among 674 patients (mean age 74·7 years [SD 12·6], 320 [47%] men) with 1553 person-years of follow-up, 46 recurrent ICHs (event rate 3·2 per 100 patient-years, 95% CI 2·0-5·1) and 25 ischaemic strokes (1·7 per 100 patient-years, 0·8-3·3) were reported. Patients with lobar ICH (n=317) had higher risk of recurrent ICH (5·1 per 100 patient-years, 95% CI 3·6-7·2) than patients with non-lobar ICH (n=355; 1·8 per 100 patient-years, 1·0-3·3; hazard ratio [HR] 3·2, 95% CI 1·6-6·3; p=0·0010), but there was no evidence of a difference in the risk of ischaemic stroke (1·8 per 100 patient-years, 1·0-3·2, vs 1·6 per 100 patient-years, 0·6-4·4; HR 1·1, 95% CI 0·5-2·8). Conversely, there was no evidence of a difference in recurrent ICH rate in patients with AF (n=147; 3·3 per 100 patient-years, 95% CI 1·0-10·7) compared with those without (n=526; 3·2 per 100 patient-years, 2·2-4·7; HR 0·9, 95% CI 0·4-2·1), but the risk of ischaemic stroke was higher with AF (6·3 per 100 patient-years, 3·7-10·9, vs 0·7 per 100 patient-years, 0·1-5·6; HR 8·2, 3·3-20·3; p<0·0001), resulting in patients with AF having a higher risk of all serious vascular events than patients without AF (15·5 per 100 patient-years, 10·0-24·1, vs 6·8 per 100 patient-years, 3·6-12·5; HR 1·78, 95% CI 1·16-2·74; p=0·0090). Only for patients with lobar ICH without comorbid AF was the risk of recurrent ICH greater than the risk of ischaemic stroke (5·2 per 100 patient-years, 95% CI 3·6-7·5, vs 0·9 per 100 patient-years, 0·2-4·8; p=0·00034). Comparing data from the pooled population-based studies with that from patients allocated to not receive antiplatelet therapy in RESTART, there was no evidence of a difference in the rate of recurrent ICH (3·5 per 100 patient-years, 95% CI 1·9-6·0, vs 4·4 per 100 patient-years, 2·6-6·1) or ischaemic stroke (3·4 per 100 patient-years, 1·9-5·9, vs 5·3 per 100 patient-years, 3·3-7·2). INTERPRETATION: The risks of recurrent ICH, ischaemic stroke, and all serious vascular events after ICH differ by ICH location and comorbid AF. These data enable risk stratification of patients in clinical practice and ongoing randomised trials. FUNDING: UK Medical Research Council, Stroke Association, British Heart Foundation, Wellcome Trust, and the National Institute for Health Research Oxford Biomedical Research Centre.

Temporal trends in the accuracy of hospital diagnostic coding for identifying acute stroke: A population-based study.

INTRODUCTION: Administrative hospital diagnostic coding data are increasingly being used in identifying incident and prevalent stroke cases, for outcome audit and for 'big data' research. Validity of administrative coding has varied in previous studies, but little is known about the temporal trends of coding accuracy, which could bias analyses. PATIENTS AND METHODS: Using all incident and recurrent strokes in a population-based cohort (Oxford Vascular Study/OXVASC) with multiple sources of ascertainment as the reference, we determined the temporal trends in sensitivity and positive predictive value of hospital diagnostic codes for identifying acute stroke from 2002 to 2017. RESULTS: Of 1883 hospitalised strokes, 1341 (71.2%) were correctly identified by coding. Sensitivity of coding improved over time for all strokes (ptrend = 0.005) and for incident cases (ptrend = 0.002). Of 1995 apparent stroke admissions identified by International Classification of Disease-10 stroke codes (I60-I68), 1588 (79.6%) used the stroke-specific codes (I60-I61/I63-I64). Positive predictive value was higher with the use of specific codes (83.2% vs. 69.2% for all codes) and highest if combined with the first admission only (88.5%), particularly during more recent time periods (2014-2017 = 90.3%). Of 2254 OXVASC incident strokes, 833 (37.0%) were not hospitalised. Sensitivity of coding increased over time for non-disabling stroke (ptrend = 0.001), but not for disabling/fatal stroke (ptrend = 0.40). CONCLUSIONS: Although accuracy of hospital diagnostic coding for identifying acute strokes improved over the last 15 years, residual insensitivity supports linkage to other sources in large epidemiological studies. Moreover, differences in the time trends of coding sensitivity in relation to stroke severity might bias studies of trends in stroke outcome if only administrative coding is used.

Ten-year risks of recurrent stroke, disability, dementia and cost in relation to site of primary intracerebral haemorrhage: population-based study.

BACKGROUND: Patients with primary intracerebral haemorrhage (ICH) are at increased long-term risks of recurrent stroke and other comorbidities. However, available estimates come predominantly from hospital-based studies with relatively short follow-up. Moreover, there are also uncertainties about the influence of ICH location on risks of recurrent stroke, disability, dementia and quality of life. METHODS: In a population-based study (Oxford Vascular Study/2002-2018) of patients with a first ICH with follow-up to 10 years, we determined the long-term risks of recurrent stroke, disability, quality of life, dementia and hospital care costs stratified by haematoma location. RESULTS: Of 255 cases with primary ICH (mean/SD age 75.5/13.1), 109 (42.7%) had lobar ICH, 144 (56.5%) non-lobar ICH and 2 (0.8%) had uncertain location. Annual rates of recurrent ICH were higher after lobar versus non-lobar ICH (lobar=4.0%, 2.7-7.2 vs 1.1%, 0.3-2.8; p=0.02). Moreover, cumulative rate of dementia was also higher for lobar versus non-lobar ICH (n/% lobar=20/36.4% vs 16/20.8%, p=0.047), and there was a higher proportion of disability at 5 years in survivors (15/60.0% vs 9/31.0%, p=0.03). The 10-year quality-adjusted life years (QALYs) were also lower after lobar versus non-lobar ICH (2.9 vs 3.8 for non-lobar, p=0.04). Overall, the mean 10-year censor-adjusted costs were £19 292, with over 80% of costs due to inpatient hospital admission costs, which did not vary by haematoma location (p=0.90). CONCLUSION: Compared with non-lobar ICH, the substantially higher 10-year risks of recurrent stroke, dementia and lower QALYs after lobar ICH highlight the need for more effective prevention for this patient group.

Essen Risk Score in Prediction of Myocardial Infarction After Transient Ischemic Attack or Ischemic Stroke Without Prior Coronary Artery Disease.

Background and Purpose- More intensive secondary prevention with newer drugs may be cost-effective in patients with coronary artery disease (CAD). Whether some subgroups of patients who had a transient ischemic attack (TIA) or ischemic stroke, but no prior CAD are at similar high risk of myocardial infarction as those with prior CAD remains unclear. We determined whether the Essen score identified a subset of TIA/stroke patients without known prior CAD who, nevertheless, had a high risk of myocardial infarction on current secondary prevention management. Methods- In a population-based cohort (Oxford Vascular Study) of consecutive TIA or ischemic stroke patients recruited from 2002 to 2014, 10-year actuarial risks of myocardial infarction and of recurrent ischemic stroke were determined by face-to-face follow-up in patients with and without prior CAD using Kaplan-Meier analyses. Predictive value of the Essen score was assessed with C statistic. Results- Of 2555 patients with TIA/stroke (13 070 patient-years of follow-up), 10-year risk of myocardial infarction in those without prior CAD (n=2017, 78.9%) ranged from 0.9% (95% CI, 0-1.9) at Essen score ≤1 to 29.8% (95% CI, 7.7-46.6) in those with a score ≥5 (C statistic =0.64 [95% CI, 0.57-0.71]; P<0.001). The score tended to be less predictive (difference: P=0.0460) for the risk of recurrent ischemic stroke (C statistic =0.57 [95% CI, 0.54-0.60]). Compared with patients with prior CAD (n=538, 21.1%), an Essen risk score of ≥4 (n=294, 11.5%) in those without prior CAD identified a subgroup at similar high 10-year risks of myocardial infarction (17.2% [95% CI, 6.9-26.3] versus 16.9% [95% CI, 11.5-22.0]) and of recurrent stroke (40.4% [95% CI, 26.7-51.6] versus 32.4% [95% CI, 25.2-38.8]). Conclusions- The Essen score is a simple clinical score to risk-stratify patients with TIA/stroke without prior CAD and to identify subsets who may be at sufficiently high risk of myocardial infarction and recurrent stroke to justify more intensive treatment or inclusion in trials.

Effect of coexisting vascular disease on long-term risk of recurrent events after TIA or stroke.

OBJECTIVE: To determine whether patients with TIA or ischemic stroke with coexisting cardiovascular disease (i.e., history of coronary or peripheral artery disease) are still at high risk of recurrent ischemic events despite current secondary prevention guidelines. METHODS: In a population-based study in Oxfordshire, UK (Oxford Vascular Study), we studied consecutive patients with TIA or ischemic stroke for 2002-2014. Patients were treated according to current secondary prevention guidelines and we determined risks of coronary events, recurrent ischemic stroke, and major bleeding stratified by the presence of coexisting cardiovascular disease. RESULTS: Among 2,555 patients (9,148 patient-years of follow-up), those (n = 640; 25.0%) with coexisting cardiovascular disease (449 coronary only; 103 peripheral only; 88 both) were at higher 10-year risk of coronary events than those without (22.8%, 95% confidence interval 17.4-27.9; vs 7.1%, 5.3-8.8; p < 0.001; age- and sex-adjusted hazard ratio [HR] 3.07, 2.24-4.21) and of recurrent ischemic stroke (31.5%, 25.1-37.4; vs 23.4%, 20.5-26.2; p = 0.0049; age- and sex-adjusted HR 1.23, 0.99-1.53), despite similar rates of use of antithrombotic and lipid-lowering medication. However, in patients with noncardioembolic TIA/stroke, risk of extracranial bleeds was also higher in those with coexisting cardiovascular disease, particularly in patients aged <75 years (8.1%, 2.8-13.0; vs 3.4%, 1.6-5.3; p = 0.0050; age- and sex-adjusted HR 2.71, 1.16-6.30), although risk of intracerebral hemorrhage was not increased (age- and sex-adjusted HR 0.36, 0.04-2.99). CONCLUSIONS: As in older studies, patients with TIA/stroke with coexisting cardiovascular disease remain at high risk of recurrent ischemic events despite current management. More intensive lipid-lowering might therefore be justified, but benefit from increased antithrombotic treatment might be offset by the higher risk of extracranial bleeding.

Sensitivity of Administrative Coding in Identifying Inpatient Acute Strokes Complicating Procedures or Other Diseases in UK Hospitals.

Background Administrative hospital diagnostic coding data are increasingly used in "big data" research and to assess complication rates after surgery or acute medical conditions. Acute stroke is a common complication of several procedures/conditions, such as carotid interventions, but data are lacking on the sensitivity of administrative coding in identifying acute stroke during inpatient stay. Methods and Results Using all acute strokes ascertained in a population-based cohort (2002-2017) as the reference, we determined the sensitivity of hospital administrative diagnostic codes ( International Classification of Diseases, Tenth Revision; ICD-10) for identifying acute strokes that occurred during hospital admission for other reasons, stratified by coding strategies, study periods, and stroke severity (National Institutes of Health Stroke Score

Confounding by Pre-Morbid Functional Status in Studies of Apparent Sex Differences in Severity and Outcome of Stroke.

BACKGROUND AND PURPOSE: Several studies have reported unexplained worse outcomes after stroke in women but none included the full spectrum of symptomatic ischemic cerebrovascular events while adjusting for prior handicap. METHODS: Using a prospective population-based incident cohort of all transient ischemic attack/stroke (OXVASC [Oxford Vascular Study]) recruited between April 2002 and March 2014, we compared pre-morbid and post-event modified Rankin Scale score (mRS) in women and men and change in mRS score 1 month, 6 months, 1 year, and 5 years after stroke. Baseline stroke-related neurological impairment was measured with the National Institutes of Health Stroke Scale. RESULTS: Among 2553 patients (50.6% women) with a first transient ischemic attack/ischemic stroke, women had a worse handicap 1 month after ischemic stroke (age-adjusted odds ratio for mRS score, 1.35; 95% confidence interval, 1.12-1.63). However, women also had a higher pre-morbid mRS score compared with men (age-adjusted odds ratio, 1.58; 95% confidence interval, 1.36-1.84). There was no difference in stroke severity when adjusting for age and pre-morbid mRS (odds ratio, 1.10; 95% confidence interval, 0.90-1.35) and no difference in the pre-/poststroke change in mRS at 1 month (age-adjusted odds ratio, 1.00; 95% confidence interval, 0.82-1.21), 6 months, 1 year, and 5 years. Women had a lower mortality rate, and there was no sex difference in risk of recurrent stroke. CONCLUSIONS: We found no evidence of a worse outcome of stroke in women when adjusting for age and pre-morbid mRS. Failure to account for sex differences in pre-morbid handicap could explain contradictory findings in previous studies. Properties of the mRS may also contribute to these inconsistencies.

Time Course of Evolution of Disability and Cause-Specific Mortality After Ischemic Stroke: Implications for Trial Design.

BACKGROUND: Outcome in stroke trials is often based on a 3-month modified Rankin scale (mRS). How 3-month mRS relates to longer-term outcomes will depend on late recovery, delayed stroke-related deaths, recurrent strokes, and nonstroke deaths. We evaluated 3-month mRS and death/disability at 1 and 5 years in a population-based cohort study. METHODS AND RESULTS: In 3-month survivors of ischemic stroke (Oxford Vascular Study; 2002-2014), we related 3-month mRS to disability (defined as mRS >2) at 1 and 5 years and/or death rates (age/sex adjusted). Accrual of disability and index-stroke-related and nonstroke deaths in each poststroke year was categorized according to 3-month mRS. Among 1606 patients with acute ischemic stroke, 181 died within 3 months, but 126 index-stroke-related deaths and 320 other deaths occurred during the subsequent 4866 patient-years of follow-up up to 5 years. Although 69/126 (54.8%) post-3-month index-stroke-related deaths occurred after 1 year, mRS>2 at 1 year strongly predicted these deaths (adjusted hazard ratio=21.94, 95%CI 7.88-61.09, P<0.0001). Consequently, a 3-month mRS >2 was a strong independent predictor of death at both 1 year (adjusted hazard ratio=6.67, 95%CI 4.16-10.69, P<0.0001) and 5 years (adjusted hazard ratio=2.93, 95%CI 2.38-3.60, P<0.0001). Although mRS improved by ≥1 point from 3 months to 1 year in 317/1266 (25.0%) patients with 3-month mRS ≥1, improvement in mRS after 1 year was limited (improvement by ≥1 point: 91/858 [10.6%]; improvement to mRS ≤2: 13/353 [3.7%]). CONCLUSIONS: Our results reaffirm use of the 3-month mRS outcome in stroke trials. Although later recovery does occur, extending follow-up to 1 year would capture most long-term stroke-related disability. However, administrative mortality follow-up beyond 1 year has the potential to demonstrate translation of early disability gains into additional reductions in long-term mortality without much erosion by non-stroke-related deaths.

Population-Based Study of Incidence, Risk Factors, Outcome, and Prognosis of Ischemic Peripheral Arterial Events: Implications for Prevention.

BACKGROUND: There are few published data on the incidence and long-term outcomes of critical limb ischemia, acute limb ischemia, or acute visceral ischemia with which to inform health service planning, to monitor prevention, and to enable risk prediction. METHODS AND RESULTS: In a prospective population-based study (Oxfordshire, UK; 2002-2012), we determined the incidence and outcome of all acute peripheral arterial events in a population of 92,728. Risk factors were assessed by comparison with the underlying population. A total of 510 acute events occurred in 386 patients requiring 803 interventions. Two hundred twenty-one patients (59.3%) were ≥75 years of age, and 98 (26.3%) were ≥85 years old. Two hundred thirty patients (62.3%) were independent before the event, but 270 (73.4%) were dead or dependent at the 6-month follow-up, and 328 (88.9%) were dead or dependent at 5 years. The 30-day survival was lowest for patients with acute visceral ischemia (28.2%) compared with acute limb ischemia (75.3%) and critical limb ischemia (92.6%; P<0.001). Risk factors (all P<0.001) were hypertension (age- and sex-adjusted risk ratio, 2.75; 95% confidence interval, 1.95-3.90), smoking (adjusted risk ratio, 2.14; 95% confidence interval, 1.37-3.34), and diabetes mellitus (adjusted risk ratio, 3.01; 95% confidence interval, 1.69-5.35), particularly for critical limb ischemia (adjusted risk ratio, 5.96; 95% confidence interval, 3.15-11.26). Two hundred eighty-eight patients (77.2%) had known previous cardiovascular disease, and 361 (96.8%) had vascular risk factors, but only 203 (54.4%) were on an antiplatelet and only 166 (44.5%) were on a statin. Although 260 patients (69.7%) were taking antihypertensives, 42.9% of all blood pressures recorded during the 5 years before the event were >140/90 mm Hg. Of 88 patients (23.6%) with incident cardioembolic events, 62 had known atrial fibrillation (diagnosed before the event), of whom only 14.5% were anticoagulated despite 82.3% having a CHA2DS2VASC score ≥2 without contraindications. CONCLUSIONS: The clinical burden of peripheral arterial events is substantial. Although the vast majority of patients have known vascular disease in other territories and multiple treatable risk factors, premorbid control is poor.

Population-Based Study of Incidence of Acute Abdominal Aortic Aneurysms With Projected Impact of Screening Strategy.

BACKGROUND: Current abdominal aortic aneurysm (AAA) screening in men age 65 might have limited impact on overall AAA death rates if incidence is moving to older ages. Up-to-date population-based studies of age-specific incidence, risk factors, and outcome of acute AAA are needed to inform screening policy. METHODS AND RESULTS: In a prospective, population-based study (Oxfordshire, UK, 2002-2014), the incidence and outcome of acute AAA events were determined. Based on population projections and current incidence trends, the impact of screening strategies in the UK was estimated. Over the 12-year period, 103 incident acute AAA events occurred in the study population of 92 728. Incidence/100 000/year was 55 in men ages 65 to 74 years, but increased to 112 at 75 to 85 and 298 at ≥85, with 66.0% of all events occurring at age ≥75 years. Incidence at ages 65 to 74 was highest in male smokers (274), with 96.4% of events in men <75 years occurring in ever-smokers. Extrapolating rates to the UK population, using trial evidence of screening efficacy, the current UK screening program would prevent 5.6% of aneurysm-related deaths (315 200 scans/year: 1426/death prevented, 121/year-of-life saved). Screening only male smokers age 65 and then all men at age 75 would prevent 21.1% of deaths (247 900 scans/year; 297/death prevented, 34/year-of-life saved). By 2030, 91.0% of deaths will occur at age ≥75, 61.6% at ≥85, and 28.6% in women. CONCLUSIONS: Given that two thirds of acute AAA occurred at ≥75 years of age, screening older age groups should be considered. Screening nonsmokers at age 65 is likely to have very little impact on AAA event rates.

Methodological factors in determining rates of dementia in transient ischemic attack and stroke: (I) impact of baseline selection bias.

BACKGROUND AND PURPOSE: Many previous studies on dementia in stroke have restrictive inclusion criteria, which may result in underestimation of dementia rates. We undertook a large prospective population-based study of all transient ischemic attack and stroke to determine the impact of study entry criteria on measured rates of pre- and postevent dementia. METHODS: All patients with acute transient ischemic attack or stroke from a defined population of 92 728 are referred from primary care or at hospital admission to the Oxford Vascular Study (2002-2007) and have baseline clinical and cognitive assessment and follow-up. We examined the impact of early death, other nonavailability, and commonly used selection criteria, on measured rates of dementia. RESULTS: Among 1236 patients (mean age/SD 75.2/12.1 years, 582 men, 403 transient ischemic attack), 139 died or were otherwise unavailable for baseline assessment, 319 had prior dependency, 425 had comorbidity, 512 were aged ≥80 years, 85 were dysphasic, and 502 were hospitalized. Pre-event dementia was 3-fold higher in patients dying preascertainment (10/47, 21%) and twice as high in other nonassessed (14/92, 15%) versus assessed patients (69/1097, 6%; P=0.0006 and P=0.002) and was several-fold higher in those with prior functional impairment (24% versus 3%; P<0.0001), age >80 years (13% versus 3%; P<0.0001), dysphasia (11% versus 7%; P<0.0001), and comorbidity (10% versus 6%; P=0.04). Findings for postevent dementia were similar: prior functional impairment (40% versus 13%; P<0.0001), age >80 years (28% versus 10%; P<0.0001), dysphasia (39% versus 15%; P<0.0001), and comorbidity (20% versus 15%; P=0.04). CONCLUSIONS: Exclusion of patients unavailable for assessment, and other widely used selection criteria, results in underestimation of the measured rate of dementia associated with transient ischemic attack and stroke.

Population-based study of blood biomarkers in prediction of subacute recurrent stroke.

BACKGROUND AND PURPOSE: Risk of recurrent stroke is high in the first few weeks after transient ischemic attack or stroke and clinical risk prediction tools have only limited accuracy, particularly after the hyperacute phase. Previous studies of the predictive value of biomarkers have been small, been done in selected populations, and have not concentrated on the acute phase or on intensively treated populations. We aimed to determine the predictive value of a panel of blood biomarkers in intensively treated patients early after transient ischemic attack and stroke. METHODS: We studied 14 blood biomarkers related to inflammation, thrombosis, atherogenesis, and cardiac or neuronal cell damage in early transient ischemic attack or ischemic stroke in a population-based study (Oxford Vascular Study). Biomarker levels were related to 90-day risk of recurrent stroke as hazard ratio (95% confidence interval) per decile increase, adjusted for age and sex. RESULTS: Among 1292 eligible patients, there were 53 recurrent ischemic strokes within 90 days. There were moderate correlations (r=0.40-0.61; P<0.0001) between the inflammatory biomarkers and between the cell damage and thrombotic subsets. Associations with risk of early recurrent stroke were weak, with significant associations limited to interleukin-6 (adjusted hazard ratio, 1.12; 1.01-1.24; P=0.033) and C-reactive protein (adjusted hazard ratio, 1.15; 1.02-1.30; P=0.022) after adjusting for age, sex, hypertension, smoking, and diabetes mellitus although P-selectin seemed to predict stroke after transient ischemic attack (adjusted hazard ratio, 1.28; 1.00-1.63; P=0.046). CONCLUSIONS: In the largest study to date, we found limited predictive use for early recurrent stroke for a panel of inflammatory, thrombotic, and cell damage biomarkers.

Acute post-stroke blood pressure relative to premorbid levels in intracerebral haemorrhage versus major ischaemic stroke: a population-based study.

BACKGROUND: It is often assumed that blood pressure increases acutely after major stroke, resulting in so-called post-stroke hypertension. In view of evidence that the risks and benefits of blood pressure-lowering treatment in acute stroke might differ between patients with major ischaemic stroke and those with primary intracerebral haemorrhage, we compared acute-phase and premorbid blood pressure levels in these two disorders. METHODS: In a population-based study in Oxfordshire, UK, we recruited all patients presenting with stroke between April 1, 2002, and March 31, 2012. We compared all acute-phase post-event blood pressure readings with premorbid readings from 10-year primary care records in all patients with acute major ischaemic stroke (National Institutes of Health Stroke Scale >3) versus those with acute intracerebral haemorrhage. FINDINGS: Of 653 consecutive eligible patients, premorbid and acute-phase blood pressure readings were available for 636 (97%) individuals. Premorbid blood pressure (total readings 13,244) had been measured on a median of 17 separate occasions per patient (IQR 8-31). In patients with ischaemic stroke, the first acute-phase systolic blood pressure was much lower than after intracerebral haemorrhage (158·5 mm Hg [SD 30·1] vs 189·8 mm Hg [38·5], p<0·0001; for patients not on antihypertensive treatment 159·2 mm Hg [27·8] vs 193·4 mm Hg [37·4], p<0·0001), was little higher than premorbid levels (increase of 10·6 mm Hg vs 10-year mean premorbid level), and decreased only slightly during the first 24 h (mean decrease from <90 min to 24 h 13·6 mm Hg). By contrast with findings in ischaemic stroke, the mean first systolic blood pressure after intracerebral haemorrhage was substantially higher than premorbid levels (mean increase of 40·7 mm Hg, p<0·0001) and fell substantially in the first 24 h (mean decrease of 41·1 mm Hg; p=0·0007 for difference from decrease in ischaemic stroke). Mean systolic blood pressure also increased steeply in the days and weeks before intracerebral haemorrhage (regression p<0·0001) but not before ischaemic stroke. Consequently, the first acute-phase blood pressure reading after primary intracerebral haemorrhage was more likely than after ischaemic stroke to be the highest ever recorded (OR 3·4, 95% CI 2·3-5·2, p<0·0001). In patients with intracerebral haemorrhage seen within 90 min, the highest systolic blood pressure within 3 h of onset was 50 mm Hg higher, on average, than the maximum premorbid level whereas that after ischaemic stroke was 5·2 mm Hg lower (p<0·0001). INTERPRETATION: Our findings suggest that systolic blood pressure is substantially raised compared with usual premorbid levels after intracerebral haemorrhage, whereas acute-phase systolic blood pressure after major ischaemic stroke is much closer to the accustomed long-term premorbid level, providing a potential explanation for why the risks and benefits of lowering blood pressure acutely after stroke might be expected to differ. FUNDING: Wellcome Trust, Wolfson Foundation, UK Medical Research Council, Stroke Association, British Heart Foundation, National Institute for Health Research.

Population-based study of incidence and outcome of acute aortic dissection and premorbid risk factor control: 10-year results from the Oxford Vascular Study.

BACKGROUND: Acute aortic dissection is a preventable life-threatening condition. However, there have been no prospective population-based studies of incidence or outcome to inform an understanding of risk factors, strategies for prevention, or projections for future clinical service provision. METHODS AND RESULTS: We prospectively determined incidence and outcomes of all acute aortic dissections in a population of 92 728 in Oxfordshire, United Kingdom, from 2002 to 2012. Among 155 patients with 174 acute aortic events, 54 patients had 59 thoracoabdominal aortic dissections (52 incident events: 6/100 000, 95% confidence interval, 4-7; 37 Stanford type A, 15 Stanford type B; 31 men, mean age=72.0 years). Among patients with type A incident events, 18 (48.6%) died before hospital assessment (61.1% women). The 30-day fatality rate was 47.4% for patients with type A dissections who survived to hospital admission and 13.3% for patients with type B dissections, although subsequent 5-year survival rates were high (85.7% for type A; 83.3% for type B). Even though 67.3% of patients were on antihypertensive drugs, 46.0% of all patients had at least 1 systolic BP ≥180 mm Hg in their primary care records over the preceding 5 years, and the proportion of blood pressures in the hypertensive range (>140/90 mm Hg) averaged 56.0%. Premorbid blood pressure was higher in patients with type A dissections that were immediately fatal than in those who survived to admission (mean/standard deviation pre-event systolic blood pressure=151.2/19.3 versus 137.9/17.9; P<0.001). CONCLUSIONS: Uncontrolled hypertension remains the most significant treatable risk factor for acute aortic dissection. Prospective population-based ascertainment showed that hospital-based registries will underestimate not only incidence and case fatality, but also the association with premorbid hypertension.

Hospitalization resource use and costs before and after TIA and stroke: results from a population-based cohort study (OXVASC).

OBJECTIVES: High hospitalization rates, prolonged length of stay, and increased risks of subsequent events mean a steep increase in health care usage after stroke. No study, however, has examined to what extent increased costs after transient ischemic attack (TIA) or stroke are due to hospitalizations for the initial event, recurrent events, and/or nonvascular hospitalizations, and how costs compare with the year prior to the event. METHODS: We studied patients in a population-based cohort study (Oxford Vascular Study) in the United Kingdom from 2003 to 2007. Hospitalization and cost details were obtained from patients' individualized Hospital Episode Statistics records. RESULTS: A total of 295 incident TIA and 439 incident stroke patients were included. For patients with stroke, average costs increased from £1437 in the year pre-event to £6629 in the year post-event (P<0.0001). Sixty-four percent (£4224) of poststroke costs were due to hospitalizations linked to the index stroke, more than 30% of which were given nonvascular primary diagnoses on Hospital Episode Statistics, and £653 (10%) were due to hospitalizations linked to subsequent vascular events. For patients with TIA, costs increased from £876 1 year before the event to £2410 in the year post-event (P<0.0001). Patients with TIA incurred nonsignificantly higher costs due to hospitalizations linked to subsequent vascular events (£774) than for hospitalizations linked to the index TIA (£720). CONCLUSIONS: Hospital costs increased after TIA or stroke, primarily because of increased initial cerebrovascular hospitalizations. The finding that costs due to nonvascular diagnoses also increased after TIA or stroke appears, in part, to be explained by the miscoding of TIA/stroke-related hospitalizations in electronic information systems.

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.

Transient cognitive impairment in TIA and minor stroke.

BACKGROUND AND PURPOSE: Acute cognitive impairment and delirium occur after major stroke and are associated with poor cognitive outcome. We conducted a population-based study to determine whether transient cognitive impairment (TCI) is seen acutely after cerebral transient ischemic attack (TIA) or minor stroke, and whether it predicts long-term cognitive decline. METHODS: Mini-mental-state examination was performed in consecutive testable patients with TIA or minor stroke (National Institutes of Health Stroke Scale ≤3) seen acutely (1-7 days) in the Oxford Vascular Study (2002-2005) versus after 7 days, and in referrals seen acutely who had a subsequent noncerebrovascular diagnosis. We defined TCI as a baseline Mini-mental-state examination score ≥2 points below the 1-month follow-up score, and identified cognitive impairment (Montreal Cognitive Assessment [MoCA] <26/30) and severe dementia at 1-, 2-, and 5-year follow-up. RESULTS: In 280 TIA and minor stroke patients (mean age/SD 73.5/11.8 years), TCI was more frequent in those seen at 1 to 7 days (80/206; 38.9%) versus later (14/74; 19%; P=0.002) or in noncerebrovascular patients (10/47; 21%; P=0.004). TCI was associated with acute confusion (OR, 5.5; 95% CI, 2.5-11.7; P<0.0001), acute infarct on computed tomography (OR, 2.0; 1.2-3.5; P=0.01), and with residual focal deficits (OR,1.94; 1.13-3.34; P=0.01). However, it was still seen acutely in those whose focal deficits had resolved by time of assessment (41/120; 34%). Although patients with TCI had similar Mini-mental-state examination score by 1 month compared with those without TCI, their 5-year risks of cognitive impairment (OR, 4.3; 1.2-15.7; P=0.03) and severe dementia (OR, 4.9; 1.0-25.8; P=0.05) were increased. CONCLUSIONS: TCI is a manifestation of TIA and minor stroke, and may persist beyond resolution of focal symptoms. Our findings have implications for definitions in TIA and minor stroke and suggest that cognitive fragility may be revealed by minor cerebrovascular events.