Age-specific risks, severity, time course, and outcome of bleeding on long-term antiplatelet treatment after vascular events: a population-based cohort study.

BACKGROUND: Lifelong antiplatelet treatment is recommended after ischaemic vascular events, on the basis of trials done mainly in patients younger than 75 years. Upper gastrointestinal bleeding is a serious complication, but had low case fatality in trials of aspirin and is not generally thought to cause long-term disability. Consequently, although co-prescription of proton-pump inhibitors (PPIs) reduces upper gastrointestinal bleeds by 70-90%, uptake is low and guidelines are conflicting. We aimed to assess the risk, time course, and outcomes of bleeding on antiplatelet treatment for secondary prevention in patients of all ages. METHODS: We did a prospective population-based cohort study in patients with a first transient ischaemic attack, ischaemic stroke, or myocardial infarction treated with antiplatelet drugs (mainly aspirin based, without routine PPI use) after the event in the Oxford Vascular Study from 2002 to 2012, with follow-up until 2013. We determined type, severity, outcome (disability or death), and time course of bleeding requiring medical attention by face-to-face follow-up for 10 years. We estimated age-specific numbers needed to treat (NNT) to prevent upper gastrointestinal bleeding with routine PPI co-prescription on the basis of Kaplan-Meier risk estimates and relative risk reduction estimates from previous trials. FINDINGS: 3166 patients (1582 [50%] aged ≥75 years) had 405 first bleeding events (n=218 gastrointestinal, n=45 intracranial, and n=142 other) during 13 509 patient-years of follow-up. Of the 314 patients (78%) with bleeds admitted to hospital, 117 (37%) were missed by administrative coding. Risk of non-major bleeding was unrelated to age, but major bleeding increased steeply with age (≥75 years hazard ratio [HR] 3·10, 95% CI 2·27-4·24; p<0·0001), particularly for fatal bleeds (5·53, 2·65-11·54; p<0·0001), and was sustained during long-term follow-up. The same was true of major upper gastrointestinal bleeds (≥75 years HR 4·13, 2·60-6·57; p<0·0001), particularly if disabling or fatal (10·26, 4·37-24·13; p<0·0001). At age 75 years or older, major upper gastrointestinal bleeds were mostly disabling or fatal (45 [62%] of 73 patients vs 101 [47%] of 213 patients with recurrent ischaemic stroke), and outnumbered disabling or fatal intracerebral haemorrhage (n=45 vs n=18), with an absolute risk of 9·15 (95% CI 6·67-12·24) per 1000 patient-years. The estimated NNT for routine PPI use to prevent one disabling or fatal upper gastrointestinal bleed over 5 years fell from 338 for individuals younger than 65 years, to 25 for individuals aged 85 years or older. INTERPRETATION: In patients receiving aspirin-based antiplatelet treatment without routine PPI use, the long-term risk of major bleeding is higher and more sustained in older patients in practice than in the younger patients in previous trials, with a substantial risk of disabling or fatal upper gastrointestinal bleeding. Given that half of the major bleeds in patients aged 75 years or older were upper gastrointestinal, the estimated NNT for routine PPI use to prevent such bleeds is low, and co-prescription should be encouraged. FUNDING: Wellcome Trust, Wolfson Foundation, British Heart Foundation, Dunhill Medical Trust, National Institute of Health Research (NIHR), and the NIHR Oxford Biomedical Research Centre.

Feasibility, safety and cost of outpatient management of acute minor ischaemic stroke: a population-based study.

BACKGROUND: Outpatient management safely and effectively prevents early recurrent stroke after transient ischaemic attack (TIA), but this approach may not be safe in patients with acute minor stroke. OBJECTIVE: To study outcomes of clinic and hospital-referred patients with TIA or minor stroke (National Institute of Health Stroke Scale score ≤3) in a prospective, population-based study (Oxford Vascular Study). RESULTS: Of 845 patients with TIA/stroke, 587 (69%) were referred directly to outpatient clinics and 258 (31%) directly to inpatient services. Of the 250 clinic-referred minor strokes (mean age 72.7 years), 237 (95%) were investigated, treated and discharged on the same day, of whom 16 (6.8%) were subsequently admitted to hospital within 30 days for recurrent stroke (n=6), sepsis (n=3), falls (n=3), bleeding (n=2), angina (n=1) and nursing care (n=1). The 150 patients (mean age 74.8 years) with minor stroke referred directly to hospital (median length-of-stay 9 days) had a similar 30-day readmission rate (9/150; 6.3%; p=0.83) after initial discharge and a similar 30-day risk of recurrent stroke (9/237 in clinic patients vs 8/150, OR=0.70, 0.27-1.80, p=0.61). Rates of prescription of secondary prevention medication after initial clinic/hospital discharge were higher in clinic-referred than in hospital-referred patients for antiplatelets/anticoagulants (p<0.05) and lipid-lowering agents (p<0.001) and were maintained at 1-year follow-up. The mean (SD) secondary care cost was £8323 (13 133) for hospital-referred minor stroke versus £743 (1794) for clinic-referred cases. CONCLUSION: Outpatient management of clinic-referred minor stroke is feasible and may be as safe as inpatient care. Rates of early hospital admission and recurrent stroke were low and uptake and maintenance of secondary prevention was high.

Poor performance of current prognostic scores for early risk of recurrence after minor stroke.

BACKGROUND AND PURPOSE: The ABCD(2) score predicts the early risk of stroke after transient ischemic attack. The early risk of recurrence after minor stroke is as high but the only validated prognostic scores for use in minor stroke predict long-term risk of recurrence: the Essen Stroke Risk Score and the Stroke Prognosis Instrument II. METHODS: We determined the prognostic value of the ABCD(2) score, Essen Stroke Risk Score, and Stroke Prognosis Instrument II in a prospective population-based study in Oxfordshire, UK, of all incident and recurrent stroke (Oxford Vascular Study). Minor stroke was defined as an National Institutes of Health Stroke Scale score ≤5 at the time of first assessment. The 90-day risks of recurrent stroke were determined in relation to each score. Areas under the receiver operator curves indicated predictive value. RESULTS: Of 1247 first events in the study period, 488 were transient ischemic attacks, 520 were minor strokes, and 239 were major strokes. The ABCD(2) score was modestly predictive (area under the receiver operator curve, 0.64; 0.53 to 0.74; P=0.03) of recurrence at 7 days after minor stroke and at 90 days (0.62; 0.54 to 0.70; P=0.004). Neither Essen Stroke Risk Score (0.50; 0.42 to 0.59; P=0.95) nor Stroke Prognosis Instrument II (0.48; 0.39 to 0.60; P=0.92) were predictive of 7-day or 90-day risk of recurrent stroke. Of the traditional vascular risk factors, etiologic classification (Trial of ORG 10172 in Acute Stroke Treatment) and variables in the ABCD(2) score, only blood pressure >140/90 mm Hg (hazard ratio, 2.75; 1.18 to 6.38; P=0.02) and large artery disease (hazard ratio, 2.21; 1.00 to 4.88; P=0.05) were predictive of 90-day risk. CONCLUSIONS: The predictive power of the ABCD(2) score is modest in patients with minor stroke, and neither the Essen Stroke Risk Score nor the Stroke Prognosis Instrument II predicts early recurrence. More reliable early risk prediction after minor stroke is required.

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 > or =50% asymptomatic carotid stenoses was approximately 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 > or =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 > or =50% asymptomatic carotid stenoses (mean age, 75 years; 39% women; 40% age > or =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 > or =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.

Population-based study of behavior immediately after transient ischemic attack and minor stroke in 1000 consecutive patients: lessons for public education.

BACKGROUND AND PURPOSE: Most guidelines now recommend that patients with minor stroke or high-risk transient ischemic attack (TIA) are assessed within 24 hours of their event, but the feasibility of this depends on patients' behavior. We studied behavior immediately after TIA and minor stroke according to clinical characteristics, patients' perception of the nature of the event, and their predicted stroke risk. METHODS: In a population-based study in Oxfordshire, UK, with face-to-face interview of 1000 consecutive patients with TIA and minor stroke (National Institutes of Health Stroke Scale < or =5) from 2002 to 2007 (Oxford Vascular Study), we studied delay in seeking medical attention and identified patients who did not seek attention after an initial event and only presented after a recurrent stroke. RESULTS: Of 1000 patients (459 TIAs, 541 minor strokes), 300 (67%) with TIA and 400 (74%) with minor stroke sought medical attention within 24 hours and 208 (47%) and 234 (46%), respectively, sought attention within 3 hours. Most patients (77%) first sought attention through their primary care physician. In patients with TIA, incorrect recognition of symptoms, absence of motor or speech symptoms, shorter duration of event, lower ABCD(2) score, no history of stroke or atrial fibrillation, and weekend presentation were associated with significantly longer delays. However, age, sex, social class, and educational level were all unrelated to either correct recognition of symptoms or to delay in seeking attention. Of 129 patients with TIA or minor stroke who had a recurrent stroke within 90 days, 41 (31%) did not seek medical attention after their initial event. These patients were more likely to have had a TIA (P=0.003), shorter duration of event (P=0.02), and a history of TIA (P=0.09) and less likely to have had motor (P=0.004) or speech symptoms (P=0.04) compared with those patients who sought medical attention for their initial event. CONCLUSIONS: Approximately 70% of patients do not correctly recognize their TIA or minor stroke, 30% delay seeking medical attention for >24 hours, regardless of age, sex, social class, or educational level, and approximately 30% of early recurrent strokes occur before seeking attention. Without more effective public education of all demographic groups, the full potential of acute prevention will not be realized.

ABCD2 score predicts severity rather than risk of early recurrent events after transient ischemic attack.

BACKGROUND AND PURPOSE: The ABCD(2) score predicts the early risk of stroke after transient ischemic attack (TIA). However, data on the severity of recurrent events would also be useful. Do patients with high scores also have more severe early recurrent strokes, perhaps further justifying hospital admission? Do patients with low scores have a low early risk of recurrent TIA as well as recurrent stroke? METHODS: We completed a prospective, population-based study in Oxfordshire, England, of 500 consecutive patients presenting with TIA from April 1, 2002, by using multiple methods of case ascertainment (Oxford Vascular Study). Recurrent TIA, minor stroke, and major stroke (National Institutes of Health Stroke Scale score >3 at the time of first assessment) were identified by face-to-face follow-up. Predictive value was expressed as the area under the receiver operating characteristic curve. RESULTS: Of 500 patients with TIA, 55 had a recurrent TIA (11.0%; 95% CI, 8.3% to 13.7%) and 50 had a recurrent stroke (10.0%; 95% CI, 7.5% to 12.0%) within 7 days. The ABCD(2) score was highly predictive of major recurrent stroke (area under the receiver operating characteristic curve=0.80; 95% CI, 0.72 to 0.87, P<0.0001), weakly predictive of minor stroke (area under the receiver operating characteristic curve=0.57; 95% CI, 0.43 to 0.71, P=0.26), and inversely related to risk of recurrent TIA (area under the receiver operating characteristic curve=0.37; 95% CI, 0.29 to 0.44, P=0.001) (overall heterogeneity, P<0.0001). The score predicted stroke-related disability, length of stay for recurrent stroke, and hence, overall acute hospital care costs. CONCLUSIONS: The ABCD(2) score predicts severity of recurrent events after TIA, high scores being associated with major recurrent stroke and low scores with high rates of recurrent TIA. These findings have implications for cost-benefit analyses of policies on hospital admission for patients with high scores and for the advice given to patients with low scores.

Development and Internal Validation of a Prediction Model for In-Hospital Mortality in Geriatric Patients With a Hip Fracture.

OBJECTIVE: To develop and validate a prediction model for in-hospital mortality in patients with hip fracture 85 years of age or older undergoing surgery. DESIGN: A multicenter prospective cohort study. SETTING: Six Dutch trauma centers, level 2 and 3. PARTICIPANTS: Patients with hip fracture 85 years of age or older undergoing surgery. INTERVENTION: Hip fracture surgery. MAIN OUTCOME MEASUREMENTS: In-hospital mortality. RESULTS: The development cohort consisted of 1014 patients. In-hospital mortality was 4%. Age, male sex, American Society of Anesthesiologists classification, and hemoglobin levels at presentation were independent predictors of in-hospital mortality. The bootstrap adjusted performance showed good discrimination with a c-statistic of 0.77. CONCLUSION: Age, male sex, higher American Society of Anesthesiologists classification, and lower hemoglobin levels at presentation are robust independent predictors of in-hospital mortality in patients with geriatric hip fracture and were incorporated in a simple prediction model with good accuracy and no lack of fit. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Incidence, outcome, risk factors, and long-term prognosis of cryptogenic transient ischaemic attack and ischaemic stroke: a population-based study.

BACKGROUND: A third of transient ischaemic attacks (TIAs) and ischaemic strokes are of undetermined cause (ie, cryptogenic), potentially undermining secondary prevention. If these events are due to occult atheroma, the risk-factor profile and coronary prognosis should resemble that of overt large artery events. If they have a cardioembolic cause, the risk of future cardioembolic events should be increased. We aimed to assess the burden, outcome, risk factors, and long-term prognosis of cryptogenic TIA and stroke. METHODS: In a population-based study in Oxfordshire, UK, among patients with a first TIA or ischaemic stroke from April 1, 2002, to March 31, 2014, we compared cryptogenic events versus other causative subtypes according to the TOAST classification. We compared markers of atherosclerosis (ie, risk factors, coronary and peripheral arterial disease, asymptomatic carotid stenosis, and 10-year risk of acute coronary events) and of cardioembolism (ie, risk of cardioembolic stroke, systemic emboli, and new atrial fibrillation [AF] during follow-up, and minor-risk echocardiographic abnormalities and subclinical paroxysmal AF at baseline in patients with index events between 2010 and 2014). FINDINGS: Among 2555 patients, 812 (32%) had cryptogenic events (incidence of cryptogenic stroke 0·36 per 1000 population per year, 95% CI 0·23-0·49). Death or dependency at 6 months was similar after cryptogenic stroke compared with non-cardioembolic stroke (23% vs 27% for large artery and small vessel subtypes combined; p=0·26) as was the 10-year risk of recurrence (32% vs 27%; p=0·91). However, the cryptogenic group had fewer atherosclerotic risk factors than the large artery disease (p<0·0001), small vessel disease (p=0·001), and cardioembolic (p=0·008) groups. Compared with patients with large artery events, those with cryptogenic events had less hypertension (adjusted odds ratio [OR] 0·41, 95% CI 0·30-0·56; p<0·0001), diabetes (0·62, 0·43-0·90; p=0·01), peripheral vascular disease (0·27, 0·17-0·45; p<0·0001), hypercholesterolaemia (0·53, 0·40-0·70; p<0·0001), and history of smoking (0·68, 0·51-0·92; p=0·01), and compared with small vessel and cardioembolic subtypes, they had no excess risk of asymptomatic carotid disease (adjusted OR 0·64, 95% CI 0·37-1·11; p=0·11) or acute coronary events (adjusted hazard ratio [HR] 0·76, 95% CI 0·49-1·18; p=0·22) during follow-up. Compared with large artery and small vessel subtypes combined, patients with cryptogenic events also had no excess of minor-risk echocardiographic abnormalities (cryptogenic 37% vs 45%; p=0·18) or paroxysmal AF (6% vs 10%; p=0·17) at baseline or of new AF (adjusted HR 1·23, 0·78-1·95; p=0·37) or presumed cardioembolic events (1·16, 0·62-2·17; p=0·64) during follow-up. INTERPRETATION: The clinical burden of cryptogenic TIA and stroke is substantial. Although stroke recurrence rates are comparable with other subtypes, cryptogenic events have the fewest atherosclerotic markers and no excess of cardioembolic markers. FUNDING: Wellcome Trust, Wolfson Foundation, UK Stroke Association, British Heart Foundation, Dunhill Medical Trust, National Institute for Health Research, Medical Research Council, and the NIHR Oxford Biomedical Research Centre.

Understanding the pharmacology of stroke and multiple sclerosis through imaging.

Stroke and multiple sclerosis (MS) illustrate how clinical imaging can facilitate early phase drug development and most effective medicine use in the clinic. Imaging has enhanced understanding of the dynamics of evolution of disease pathophysiology, better defining treatment targets. Imaging measures can enable stratification of patients for clinical trials and for most cost-effective use in the clinic. In MS, imaging has allowed smaller Phase II clinical trials and contributed to medicine differentiation. It also has led to consideration of suppression of inflammation and neurodegeneration as meaningfully distinct pharmacodynamic concepts. Similar imaging measures can be used in preclinical and clinical studies. Testing translational pharmacological hypotheses using clinical imaging more explicitly could improve the success of the next generation of stroke therapeutics.

The emerging agenda of stratified medicine in neurology.

Stratified medicine can reduce the costs of neurological care, bringing benefits to both patients and physicians. The availability of routine genetic testing, new biomarkers and advanced imaging, as well as new technologies for patient-centred data collection, has expanded the potential for patient stratification. Several neurology subspecialities, including stroke, epilepsy and behavioural neurology, have already applied stratification for disease prognosis, optimization of disease management and reduction of treatment-related adverse events. Stratification approaches could improve the cost-effectiveness of neurological care that involves treatments with high costs or risks of adverse reactions, as well as guide the use of emerging, highly individualized therapies. There are still major challenges in the development of clinically actionable stratification concepts, and practical barriers can limit adoption of these concepts into clinical practice. However, improved technologies and disease understanding are making more precise stratification practical. We believe that neurologists should become leaders in the development and validation of these practices, and that use of these approaches should be part of a broader strategy for addressing both the growing needs of an ageing population and the rising pressures for rapid improvements in the cost-effectiveness of therapeutics.