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Background: Exposure to ambient air pollution increases morbidity and mortality, and is a leading contributor to global disease burden. We explored spatial and temporal trends in mortality and burden of disease attributable to ambient air pollution from 1990 to 2015 at global, regional, and country levels., Methods: We estimated global population-weighted mean concentrations of particle mass with aerodynamic diameter less than 2·5 μm (PM 2·5 ) and ozone at an approximate 11 km × 11 km resolution with satellite-based estimates, chemical transport models, and ground-level measurements. Using integrated exposure-response functions for each cause of death, we estimated the relative risk of mortality from ischaemic heart disease, cerebrovascular disease, chronic obstructive pulmonary disease, lung cancer, and lower respiratory infections from epidemiological studies using non-linear exposure-response functions spanning the global range of exposure., Findings: Ambient PM 2·5 was the fifth-ranking mortality risk factor in 2015. Exposure to PM 2·5 caused 4·2 million (95% uncertainty interval [UI] 3·7 million to 4·8 million) deaths and 103·1 million (90·8 million 115·1 million) disability-adjusted life-years (DALYs) in 2015, representing 7·6% of total global deaths and 4·2% of global DALYs, 59% of these in east and south Asia. Deaths attributable to ambient PM 2·5 increased from 3·5 million (95% UI 3·0 million to 4·0 million) in 1990 to 4·2 million (3·7 million to 4·8 million) in 2015. Exposure to ozone caused an additional 254 000 (95% UI 97 000-422 000) deaths and a loss of 4·1 million (1·6 million to 6·8 million) DALYs from chronic obstructive pulmonary disease in 2015., Interpretation: Ambient air pollution contributed substantially to the global burden of disease in 2015, which increased over the past 25 years, due to population ageing, changes in non-communicable disease rates, and increasing air pollution in low-income and middle-income countries. Modest reductions in burden will occur in the most polluted countries unless PM 2·5 values are decreased substantially, but there is potential for substantial health benefits from exposure reduction., Funding: Bill & Melinda Gates Foundation and Health Effects Institute., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Acute coronary, cerebrovascular, and peripheral vascular events have common underlying arterial pathology, risk factors, and preventive treatments, but they are rarely studied concurrently. In the Oxford Vascular Study, we determined the comparative epidemiology of different acute vascular syndromes, their current burdens, and the potential effect of the ageing population on future rates., Methods: We prospectively assessed all individuals presenting with an acute vascular event of any type in any arterial territory irrespective of age in a population of 91 106 in Oxfordshire, UK, in 2002-05., Findings: 2024 acute vascular events occurred in 1657 individuals: 918 (45%) cerebrovascular (618 stroke, 300 transient ischaemic attacks [TIA]); 856 (42%) coronary vascular (159 ST-elevation myocardial infarction, 316 non-ST-elevation myocardial infarction, 218 unstable angina, 163 sudden cardiac death); 188 (9%) peripheral vascular (43 aortic, 53 embolic visceral or limb ischaemia, 92 critical limb ischaemia); and 62 unclassifiable deaths. Relative incidence of cerebrovascular events compared with coronary events was 1.19 (95% CI 1.06-1.33) overall; 1.40 (1.23-1.59) for non-fatal events; and 1.21 (1.04-1.41) if TIA and unstable angina were further excluded. Event and incidence rates rose steeply with age in all arterial territories, with 735 (80%) cerebrovascular, 623 (73%) coronary, and 147 (78%) peripheral vascular events in 12 886 (14%) individuals aged 65 years or older; and 503 (54%), 402 (47%), and 105 (56%), respectively, in the 5919 (6%) aged 75 years or older. Although case-fatality rates increased with age, 736 (47%) of 1561 non-fatal events occurred at age 75 years or older., Interpretation: The high rates of acute vascular events outside the coronary arterial territory and the steep rise in event rates with age in all territories have implications for prevention strategies, clinical trial design, and the targeting of funds for service provision and research.

Background: Stroke is a major cause of death and disability in most populations of eastern Asia, and the incidence, particularly of haemorrhagic stroke, is generally higher than in western populations. This study aimed to assess the contributions of blood pressure and blood cholesterol concentrations to stroke risk in populations from eastern Asia., Methods: The project included 13 cohorts from the People's Republic of China and five from Japan (124,774 participants, 837,214 person-years of observation). All 18 cohorts provided data on blood pressure and 12 (69,767 participants) provided data on cholesterol concentrations. Parametric and non-parametric analyses were done, with adjustments for several potential confounding factors. Analyses were based on estimated usual diastolic blood pressure and cholesterol concentration during follow-up, rather than baseline measurements, to avoid regression dilution bias., Findings: Overall mean blood pressure was 124/78 mm Hg and mean cholesterol concentration was 4.5 mmol/L. 1798 strokes occurred; 751 (42%) were classified as haemorrhagic and 707 (39%) were confirmed by computed tomography or necropsy. Each 5 mm Hg lower usual diastolic blood pressure was associated with lower risk of non-haemorrhagic stroke (odds ratio 0.61 [95% CI 0.57-0.66]) and lower risk of haemorrhagic stroke (0.54 [0.50-0.58]). With decreasing cholesterol concentrations there were trends towards a decrease in risk of non-haemorrhagic stroke (odds ratio for 0.6 mmol/L decrease, 0.77 [0.57-1.06]) and an increase in risk of haemorrhagic stroke (1.27 [0.84-1.91]). Overall, there was no clear evidence of any interaction between cholesterol and diastolic blood pressure., Interpretation: Blood pressure is an important determinant of stroke risk in eastern Asian populations, whereas cholesterol concentration is less important, affecting the proportions of stroke subtypes more than overall stroke numbers. The association between blood pressure and stroke seems stronger than in western populations; a population-wide reduction of 3 mm Hg in diastolic blood pressure should eventually decrease the number of strokes by about a third.

Background: We aimed to evaluate low intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease (IHD)., Methods: 5499 men aged between 45 years and 69 years at high risk of IHD were recruited from 108 practices in the UK that belong to the Medical Research Council's General Practice Research Framework. Initially, warfarin or placebo was randomly allocated to 1427 men; 1013 of these men later moved to a factorial stage of the trial, retaining their warfarin or placebo warfarin allocation and adding randomly allocated active or placebo aspirin. Another 4072 men entered directly into the factorial stage making a total of 5085 men. The four factorial treatment groups were: active warfarin and active aspirin (WA, n = 1277), active warfarin and placebo aspirin (W, n = 1268), and placebo warfarin and active aspirin (A, n = 1268), and placebo warfarin and placebo aspirin (P, n = 1272). The primary end-point was all IHD defined as the sum of coronary death and fatal and non-fatal myocardial infarction (MI)., Findings: The mean International Normalised Ratio (INR) of those on active warfarin was 1.47. The mean warfarin dose was 4.1 mg a day (range 0.5 mg-12.5 mg). There were 410 IHD events (142 fatal, 268 non-fatal). The main effect of warfarin (i.e., WA and W vs A and P) was a reduction in all IHD of 21% (95% CI 4-35, p = 0.02) chiefly due to a 39% reduction (15-57, p = 0.003) in fatal events so that warfarin reduced the death rate from all causes by 17% (1-30, p = 0.04). The main effect of aspirin (i.e., WA and A vs W and P) was a reduction in all IHD of 20% (1-35, p = 0.04) almost entirely due to a 32% reduction (12-48, p = 0.004) in non-fatal events. Absolute reductions in all IHD due to warfarin or aspirin were 2.6 and 2.3 per 1000 person years, respectively. WA reduced all IHD by 34% (11-51, p = 0.006) compared with P. WA increased haemorrhagic and fatal strokes. Ruptured aortic or dissecting aneurysms occurred in 15 of those who were or had been on warfarin compared with three of those who had not (p = 0.01)., Interpretation: These results add to evidence that aspirin reduces non-fatal IHD. Warfarin reduced all IHD chiefly because of an effect on fatal events. Combined treatment with warfarin and aspirin is more effective in the reduction of IHD than either agent on its own.

Background: The effect of postmenopausal hormone replacement therapy (HRT) on the risk of subtypes of stroke is as yet unclear. To investigate the effect of oestrogen and combined oestrogen-progestagen therapy on the risk of non-fatal haemorrhagic and thromboembolic stroke, we carried out a case-control study., Methods: From the Danish National Patient Register we identified all Danish women aged 45-64 years who had a non-fatal, first-ever cerebrovascular attack during 1990-92. Two age-matched controls were randomly selected for each case from the Danish National Person Register. Important correlates of hormone use and stroke, on which information was obtained from postal questionnaires, were controlled for by multivariate analyses based on log-linear graphical models. The analyses included data on 1422 cases classified in four subtypes of stroke (160 subarachnoid haemorrhage, 95 intracerebral haemorrhage, 846 thromboembolic infarction, 321 transient ischaemic attack) and 3171 controls., Findings: After adjustment for confounding variables and correction for the trend in sales of HRT preparations, no significant associations were detected between current use of unopposed oestrogen replacement therapy and non-fatal subarachnoid haemorrhage (odds ratio 0.52 [95% CI 0.23-1.22]), intracerebral haemorrhage (0.15 [0.02-1.09]), or thromboembolic infarction (1.16 [0.86-1.58]), respectively, compared with never use. Current use of combined oestrogen-progestagen replacement therapy had no significant influence on the risk of subarachnoid haemorrhage (1.22 [0.79-1.89]), intracerebral haemorrhage (1.17 [0.64-2.13]), or thromboembolic infarction (1.17 [0.92-1.47]). A significantly increased incidence of transient ischaemic attacks among former users of HRT and among current users of unopposed oestrogen may to some extent be explained by selection--HRT users being more aware of symptoms than non-users., Interpretation: Unopposed oestrogen and combined oestrogen-progestagen replacement therapy have no influence on the risk of non-fatal thromboembolic or haemorrhagic stroke in women aged 45-64 years.

Background: The association between use of oral contraceptives (OCs) and cerebral infarction was established in studies from northern Europe and the USA during the 1960s and 1970s. Since then, the constituents of hormonal OCs have changed and now contain lower doses of oestrogen and progestagen. Current recommendations restrict OC use to younger women who do not have other risk factors for cardiovascular disease. In this international study we assessed the risk of OC-associated first stroke in women from Europe and other countries throughout the world., Methods: In this hospital-based, case-control study, we assessed the risk of ischaemic stroke in association with current use of combined OCs in 697 cases, aged 20-44 years, and 1962 age-matched hospital controls in 21 centres in Africa, Asia, Europe, and Latin America. The diagnosis of ischaemic stroke was almost exclusively based on computed tomography (CT), magnetic resonance imaging (MRI), or cerebral angiography carried out within 3 weeks of the clinical event. All cases and controls were interviewed while in hospital with the same questionnaire, which included information on medical and personal history, details of lifetime contraceptive use, and blood-pressure measurements before the most recent episode of OC use., Findings: The overall odds ratio of ischaemic stroke was 2.99 (95% CI 1.65-5.40) in Europe and 2.93 (2.15-4.00) in the non-European (developing) countries. Odds ratios were lower in younger women and those who did not smoke, and less than 2 in women who did not have hypertension and who reported that their blood pressure had been checked before the current episode of OC use. By contrast, among current OC users with a history of hypertension, the odds ratio was 10.7 (2.04-56.6) in Europe and 14.5 (5.36-39.0) in the developing countries. In Europe, the odds ratio associated with current use of low-dose OCs (< 50 micrograms oestrogen) was 1.53 (0.71-3.31), whereas for higher-dose preparations it was 5.30 (2.56-11.0). In the developing countries, there was no significant difference between overall estimates of risk associated with use of low-dose or higher-dose OCs (3.26 [2.19-4.86] vs 2.71 [1.75-4.19]). This differential effect of dose in Europe and the developing countries is likely to be due to different levels of other risk factors among users of low-dose and higher-dose OCs in the two groups of countries. There was no significant increase in odds ratios with increasing duration of OC use among current users; odds ratios were not significantly increased after cessation of OC use., Interpretation: The incidence of ischaemic stroke is low in women of reproductive age and any risk attributable to OC use is small. The risk can be further reduced if users are younger than 35 years, do not smoke, do not have a history of hypertension, and have blood pressure measured before the start of OC use. In such women OC preparations with low oestrogen doses may be associated with even lower risk.

Background: The risk of haemorrhagic stroke associated with use of oral contraceptives (OCs) is less well-established than that for ischaemic stroke. We assessed the risk of haemorrhagic stroke associated with current use of modern OCs as now used throughout the world., Methods: In this WHO collaborative, case-control study, we assessed the association between risk of haemorrhagic stroke and use of combined OCs in 1068 cases, aged 20-44 years, and 2910 age-matched controls. We also assessed risks for all strokes combined (haemorrhagic, ischaemic, and unclassified) based on 2198 cases and 6086 controls., Findings: Overall, current use of combined OCs was associated with slightly increased risk of haemorrhagic stroke; the increase was significant in the developing countries (odds ratio 1.76 [95% CI 1.34-2.30]) but not in Europe (1.38 [0.84-2.25]). Use of OCs in women younger than 35 years did not affect risk of haemorrhagic stroke in either group of countries, whereas in women aged older than 35 years, odds ratios were greater than 2. Women who were current users of OCs and had a history of hypertension (detected before current episode of OC use, but not during pregnancy) had a substantially increased risk (ten-fold to 15-fold) of haemorrhagic stroke compared with women who did not use OCs and had no history of hypertension. Odds ratios among current OC users who were also current cigarette smokers were greater than 3. In both groups of countries, past use of OCs, dose of oestrogen, and dose and type of progestagen had no effect on risk, and risks were similar for subarachnoid and intracerebral haemorrhage. The odds ratios for any type of stroke associated with current use of low-dose (< 50 micrograms oestrogen) and higher-dose OCs were 1.41 (0.90-2.20) and 2.71 (1.70-4.32), respectively, in Europe and 1.86 (1.49-2.33) and 1.92 (1.48-2.50) in the developing countries. From these data we estimated that about 13% and 8% of all strokes in women aged 20-44 in Europe and the developing countries, respectively, are attributable to the use of OCs., Interpretation: The risk of haemorrhagic stroke attributable to OC use is not increased in younger women and is only slightly increased in older women. The estimated excess risk of all stroke types associated with use of low-oestrogen and higher-oestrogen dose OCs in Europe was about two and eight, respectively, per 100 000 woman-years of OC use. However, findings need to be considered in the context of other risks and benefits associated with OC use, as well as those associated with the use of other forms of contraception.

Background: The objective of this study was to assess whether carotid endarterectomy is an appropriate treatment for patients with recent cerebrovascular events in the territory supplied by a moderately stenosed (30-69%) internal carotid artery. Results have previously been reported for severe (70-99%) and mild (0-29%) stenosis., Methods: A multicentre randomised controlled trial recruited 1599 patients with moderate stenosis treated in 97 hospitals from 15 countries. 60% of patients were allocated to receive and 40% to avoid carotid endarterectomy. The analysis was by intention to treat., Findings: Nine patients were omitted from the analysis because no follow-up data were received. Stroke-free life expectancy (curtailed at 8 years) was shorter in the surgery patients than in the non-surgery control groups (patients with 30-49% stenosis, life expectancy = 6.16 years [controls: 6.63 years]; patients with 50-69% stenosis, life expectancy = 5.93 [6.14] years). It remains possible that patients might derive some benefit from surgery in the very long term; however, our data show that no benefit would be gained over a period of < 4-5 years in patients with 50-69% stenosis and < 6-7 years in patients with 30-49% stenosis., Interpretation: Previous interim results from this study showed that surgery is beneficial in patients with severe stenosis but harmful in those with mild stenosis. With more randomised patients and longer follow-up, the study now shows that endarterectomy is not indicated for most, possibly all, patients with moderate symptomatic carotid stenosis.

Background: A history of migraine has been proposed as a risk factor for cerebral ischaemia in women under 45., Methods: To investigate the association between history of migraine and cerebral ischaemia, we performed a case-control study of 308 patients aged 15-44, with either transient ischaemic attack (TIA) or stroke, and of 591 age- and sex-matched controls prospectively recruited in seven university hospitals. Crude and adjusted odds ratios were calculated using logistic regression analysis., Findings: A history of migraine was more frequent in patients than in controls (14.9% vs 9.1%; adjusted odds ratio 1.9, 95% confidence interval 1.1-3.1). In the prospectively designed subgroup analyses, a history of migraine reached the highest odds ratio (3.7, 95% CI 1.5-9) and was the only significant risk factor in women below age 35 (p=0.003); atherogenic risk factors were more relevant in men and in patients older than 35; previous migraine attacks with aura were more frequent in stroke patients (odds ratio 8.6, 95% CI 1-75)., Interpretation: Our findings indicated that the rare association between migraine and cerebral ischaemia is limited to women below age 35, and suggest a need for careful clinical evaluation of comorbidity in the presence of migraine with aura.

Background: A winter excess of ischaemic stroke has been found in mortality and hospital-based studies. It is often assumed that this is due to seasonal variation in stroke incidence and several pathophysiological explanations have been proposed. We studied the incidence of stroke in relation to season and outside temperature., Methods: The data came from a community-based study of first ever in a lifetime stroke in a defined population of about 105 000. 675 such strokes were registered over four years and the month of inset was analysed separately for cerebral infarction, primary intracerebral haemorrhage, and subarachnoid haemorrhage., Findings: There was no significant seasonal variation. The incidence of primary intracerebral haemorrhage was increased at low temperatures, but there was no significant relation between the incidence of ischaemic stroke or subarachnoid haemorrhage and temperature., Interpretation: The widely reported winter excess of ischaemic strokes may be an artifact due to referral bias in hospital-based studies and increased case fatality during the winter in mortality studies.

Background: In laboratory animals, cerebral ischaemia is worsened by hyperthermia and improved by hypothermia. Whether these observations apply to human beings with stroke is unknown. We therefore examined the relation between body temperature on admission with acute stroke and various indices of stroke severity and outcome., Methods: In a prospective and consecutive study 390 stroke patients were admitted to hospital within 6 h after stroke (median 2.4 h). We determined body temperature on admission, initial stroke severity, infarct size, mortality, and outcome in survivors. Stroke severity was measured on admission, weekly, and at discharge on the Scandinavian Stroke Scale (SSS). Infarct size was determined by computed tomography. Multiple logistic and linear regression outcome analyses included relevant confounders and potential predictors such as age, gender, stroke severity on admission, body temperature, infections, leucocytosis, diabetes, hypertension, atrial fibrillation, ischaemic heart disease, smoking previous stroke, and comorbidity., Findings: Mortality was lower and outcome better in patients with mild hypothermia on admission; both were worse in patients with hyperthermia. Body temperature was independently related to initial stroke severity (p < 0.009), infarct size (p < 0.0001), mortality (p < 0.02), and outcome in survivors (SSS at discharge) (p < 0.003). For each 1 degrees C increase in body temperature the relative risk of poor outcome (death or SSS score on discharge < 30 points) rose by 2.2 (95% CI 1.4-3.5) (p < 0.002)., Interpretation: We have shown that, in acute human stroke, an association exists between body temperature and initial stroke severity, infarct size, mortality, and outcome. Only intervention trials of hypothermic treatment can prove whether this relation is causal.

Individual studies of stroke have not clearly answered two questions: on the relation, if any, between total blood cholesterol and stroke; and on how the strength of the relation between diastolic blood pressure and stroke varies with age. The associations of blood cholesterol and diastolic blood pressure with subsequent stroke rates were investigated by review of 45 prospective observational cohorts involving 450,000 individuals with 5-30 years of follow-up (mean 16 years, total 7.3 million person-years of observation), during which 13,397 participants were recorded as having had a stroke. Most of these were fatal strokes in studies that recorded only mortality and not incidence, but about one-quarter were from studies that recorded both fatal and non-fatal strokes. After standardization for age, there was no association between blood cholesterol and stroke except, perhaps, in those under 45 years of age when screened. This lack of association was not influenced by adjustment for sex, diastolic blood pressure, history of coronary disease, or ethnicity (Asian or non-Asian). However, because the types of the strokes were not centrally available, the lack of any overall relation might conceal a positive association with ischaemic stroke together with a negative association with haemorrhagic stroke. When the highest and the lowest of the six blood pressure categories were compared, the difference in usual diastolic blood pressure was 27 mm Hg (102 vs 75 mm Hg), and there was a fivefold difference in stroke risk. This fivefold difference was seen both in those with a pre-existing history of coronary heart disease and in those without it. The proportional difference in stroke risk, however, was more extreme in middle than in old age. Among those aged < 45, 45-64, and 65+ when screened, the differences in the relative risks of stroke (between the highest diastolic blood pressure category and a combination of the lowest two categories) were tenfold, fivefold, and twofold, respectively. However, because the absolute stroke risks are greater in old age, the absolute differences in the annual stroke rates showed an opposite pattern, being 2, 5, and 8 per thousand, respectively. This suggests that the effects of therapeutic blood pressure reductions should be assessed separately in middle age and in old age.

Moderate hyperhomocysteinaemia is common in the general population and has been linked with cardiovascular disease. However, there are no data from prospective, population-based studies. We examined the association between serum total homocysteine (tHcy) concentration and stroke in a nested case-control study within the British Regional Heart Study cohort. Between 1978 and 1980 serum was saved from 5661 men, aged 40-59 years, randomly selected from the population of one general practice in each of 18 towns in the UK. During follow-up to December, 1991, there were 141 incident cases of stroke among men with no history of stroke at screening. Serum tHcy was measured in 107 cases and 118 control men (matched for age-group and town, without a history of stroke at screening, who did not develop a stroke or myocardial infarction during follow-up). tHcy concentrations were significantly higher in cases than controls (geometric mean 13.7 [95% CI 12.7-14.8] vs 11.9 [11.3-12.6] mumol/L; p = 0.004). There was a graded increase in the relative risk of stroke in the second, third, and fourth quarters of the tHcy distribution (odds ratios 1.3, 1.9, 2.8; trend p = 0.005) relative to the first. Adjustment for age-group, town, social class, body-mass index, hypertensive status, cigarette smoking, forced expiratory volume, packed-cell volume, alcohol intake, diabetes, high-density-lipoprotein cholesterol, and serum creatinine did not attenuate the association. These findings suggest that tHcy is a strong and independent risk factor for stroke.

A pathogenetic role in thrombotic disease, particularly in young people, has been postulated for anticardiolipin antibody (ACA). We have carried out a prospective controlled study of 262 unselected patients with acute stroke and 226 controls to assess the prevalence and relation to age and vascular risk factors of ACA. Titres of IgG, IgA, or IgM ACA were above the upper normal limit in 38% of patients. The proportions of patients and controls with raised titres did not differ significantly (13 vs 8% IgG, 22 vs 29% IgA, 11 vs 7% IgM). IgG titres were higher among patients than among controls (mean 3.88 vs 2.86 u/mL [95% CI for difference 0.62-0.87], p = 0.0004), whereas IgA and IgM titres were lower in patients than in controls (IgA 4.82 vs 5.98 u/mL [1.12-1.60], p = 0.01; IgM 3.00 vs 3.64 u/mL [1.01-1.45], p = 0.04). However, within age tertiles the only significant difference between patients and controls for IgG ACA was in the oldest tertile. Analysis by number of risk factors for stroke showed a significant difference between the groups only for subjects with one risk factor. IgA and IgM ACA titres were higher among controls only in those with no vascular risk factors. We found no evidence to support the hypothesis that ACA is an independent risk factor for stroke in young people. The increase in IgG titre with age and number of vascular risk factors in stroke patients suggests that ACA may be a non-specific accompaniment of vascular disease. Routine testing for ACA in stroke patients is not justified.

Few haematological or lipid risk factors have been identified for stroke, by contrast with coronary heart disease. To find out whether a marker of endogenous fibrinolytic function might be associated with stroke risk, we measured tissue plasminogen activator (tPA) antigen concentrations in baseline plasma samples from 88 healthy participants in the Physicians' Health Study who subsequently had first-ever strokes (71 thromboembolic, 12 haemorrhagic, 5 indeterminate) and from 471 participants who remained free of cardiovascular disease during 5 years of follow-up (controls). Mean baseline tPA concentrations were significantly higher among men who later had strokes than in the controls (11.14 [SE 0.80] vs 9.59 [0.27] ng/mL, p = 0.03). The difference was largely due to an excess of abnormally high values among stroke cases. The age-adjusted relative risk for stroke among men with baseline tPA concentrations above the 95th percentile of the control distribution was 3.51 (95% CI 1.72-7.17, p = 0.0006) for total stroke and 3.89 (1.83-8.26, p = 0.0004) for thromboembolic stroke. These findings did not change substantially in analyses that also controlled for stroke risk factors (high blood pressure, body-mass index, smoking, presence of diabetes, and parental history of myocardial infarction) or the plasma lipid profile. This prospective study shows that high concentrations of tPA antigen among apparently healthy men are independently associated with high risks of future stroke, especially thromboembolic stroke. This finding is consistent with the hypothesis that activation of the endogenous fibrinolytic system occurs years in advance of arterial vascular occlusion.

The explanation for the substantial decline in stroke death rates can be investigated only by measuring trends in stroke incidence and case-fatality. Two community-based studies carried out in Auckland, New Zealand, in 1981 and 1991 used comparable methods and definitions, met criteria for well-designed studies, and had the power to detect small changes in incidence and case-fatality rates. 703 events (representing 50% of all strokes) were registered in 1981 and 1735 events in 1991. 521 (74.1%) and 1255 (72.3%) events in 1981 and 1991, respectively, were first-ever (in a lifetime) strokes. Although there was no change in overall stroke incidence between 1981 and 1991, there were changes in age and sex groups. The incidence rate among women younger than 75 years rose by a fifth (rate ratio 1.23 [95% CI 1.04-1.47]), whereas that in men of 75 years and older fell by a third (rate ratio 0.67 [0.54-0.82]). The 28-day case-fatality declined from 27.1 (21.7-32.6)% to 21.9 (18.1-25.7)% in men and from 37.6 (31.8-43.5)% to 25.8 (22.3-29.4)% in women from 1981 to 1991, but the decline was not statistically significant in any age or sex group. These findings suggest that we need to reappraise strategies for the prevention of stroke and assess the implications of improved survival in elderly stroke patients.

Several studies have established the value of anticoagulation for primary prevention of thromboembolic events in patients with non-rheumatic atrial fibrillation (NRAF). However, in patients with a recent transient ischaemic attack (TIA) or minor ischaemic stroke the preventive benefit of anticoagulation or aspirin remains unclear. Physicians in 108 centres from 13 countries collaborated to study this question. 1007 NRAF patients with a recent TIA or minor ischaemic stroke were randomised to open anticoagulation or double-blind treatment with either 300 mg aspirin per day or placebo (group 1, 669). Patients with contraindications to anticoagulation were randomised to receive aspirin or placebo (group 2,338). The measure of outcome was death from vascular disease, any stroke, myocardial infarction, or systemic embolism. During mean follow-up of 2.3 years, the annual rate of outcome events was 8% in patients assigned to anticoagulants vs 17% in placebo-treated patients in group 1 (hazard ratio [HR] 0.53; 95% confidence interval [CI] 0.36-0.79). The risk of stroke alone was reduced from 12% to 4% per year (HR 0.34; 95% CI 0.20-0.57). Among all patients assigned to aspirin (groups 1 and 2), the annual incidence of outcome events was 15%, against 19% in those on placebo (HR 0.83; 95% CI 0.65-1.05). Anticoagulation was significantly more effective than aspirin (HR 0.60; 95% CI 0.41-0.87). The incidence of major bleeding events was low, both on anticoagulation (2.8% per year) and on aspirin (0.9% per year). No intracranial bleeds were identified in patients assigned to anticoagulation. We conclude that anticoagulation is effective in reducing the risk of recurrent vascular events in NRAF patients with a recent TIA or minor ischaemic stroke. In absolute terms: 90 vascular events (mainly strokes) are prevented if 1000 patients are treated with anticoagulation for one year. Aspirin is a safe, though less effective, alternative when anticoagulation is contraindicated; it prevents 40 vascular events each year for every 1000 treated patients.

There are 14 unconfounded randomised trials of antihypertensive drugs (chiefly diuretics or beta-blockers): total 37,000 individuals, mean treatment duration 5 years, mean diastolic blood pressure (DBP) difference 5-6 mm Hg. In prospective observational studies, a long-term difference of 5-6 mm Hg in usual DBP is associated with about 35-40% less stroke and 20-25% less coronary heart disease (CHD). For those dying in the trials, the DBP difference had persisted only 2-3 years, yet an overview showed that vascular mortality was significantly reduced (2p less than 0.0002); non-vascular mortality appeared unchanged. Stroke was reduced by 42% SD 6 (95% confidence interval 35-50%; 289 vs 484 events, 2p less than 0.0001), suggesting that virtually all the epidemiologically expected stroke reduction appears rapidly. CHD was reduced by 14% SD 5 (95% CI 4-22%; 671 vs 771 events, 2p less than 0.01), suggesting that just over half the epidemiologically expected CHD reduction appears rapidly. Although this significant CHD reduction could well be worthwhile, its size remains indefinite for most circumstances (though beta-blockers after myocardial infarction are of substantial benefit). At present, therefore, a sufficiently high risk of stroke (perhaps because of age, blood pressure, or, in particular, history of cerebrovascular disease) may be the clearest indication for antihypertensive treatment.

The associations of diastolic blood pressure (DBP) with stroke and with coronary heart disease (CHD) were investigated in nine major prospective observational studies: total 420,000 individuals, 843 strokes, and 4856 CHD events, 6-25 (mean 10) years of follow-up. The combined results demonstrate positive, continuous, and apparently independent associations, with no significant heterogeneity of effect among different studies. Within the range of DBP studied (about 70-110 mm Hg), there was no evidence of any "threshold" below which lower levels of DBP were not associated with lower risks of stroke and of CHD. Previous analyses have described the uncorrected associations of DBP measured just at "baseline" with subsequent disease rates. But, because of the diluting effects of random fluctuations in DBP, these substantially underestimate the true associations of the usual DBP (ie, an individual's long-term average DBP) with disease. After correction for this "regression dilution" bias, prolonged differences in usual DBP of 5, 7.5, and 10 mm Hg were respectively associated with at least 34%, 46%, and 56% less stroke and at least 21%, 29%, and 37% less CHD. These associations are about 60% greater than in previous uncorrected analyses. (This regression dilution bias is quite general, so analogous corrections to the relations of cholesterol to CHD or of various other risk factors to CHD or to other diseases would likewise increase their estimated strengths.) The DBP results suggest that for the large majority of individuals, whether conventionally "hypertensive" or "normotensive", a lower blood pressure should eventually confer a lower risk of vascular disease.

Within a group of 1026 men aged 47-54, cause-specific death-rates and the incidence of non-fatal myocardial infarction and stroke in treatment group of 635 hypertensive men (casual systolic B.P. greater than 175 or diastolic B.P. greater than 115 mm Hg on two occasions) treated at a hypertension clinic were compared with those in a control group of 391 men (causal systolic B.P. greater than 175 or diastolic greater than 115 mm Hg on only one occasion) who remained mainly untreated during their 4.3 years of follow-up. The predicted risk of coronary heart-disease (C.H.D.) at entry, calculated by a multiple logistic function, was slightly higher in the treatment group. Total death-rate during follow-up was significantly lower in the treatment group (3.3%) than in the control group (6.1%). The difference in death-rate for C.H.D. was of the same relative order (0.8% versus 1.5%), as was the incidence of non-fatal myocardial infarction (2.8% versus 5.4%), although none of the differences reached statistical significance. However, the pooled incidence of fatal and non-fatal C.H.D. was significantly lower in the treatment group (3.6%) than in the control group (6.9%). The results suggest that antihypertensive treatment might be effective in preventing or postponing C.H.D. in middle-aged men.

During ten years of follow-up 701 deaths occurred among 8006 45-68-year-old Honolulu Japanese men who were originally examined in 1965-68. Mortality was highest in both the leanest and fattest men and lowest in the fourth quintile of body mass index (BMI). The excess deaths in the top quintile were due primarily to coronary heart disease which was directly and positively related to BMI. In the bottom two quintiles excess mortality was due to cancer and "other" causes and was confined to men who had lost weight between age 25 and examination. This finding suggests that excess mortality in thin middle-aged men is due to occult antecedent disease rather than leanness per se. When BMI at age 25 was considered, men in the bottom quintile had the lowest mortality in middle age. It is concluded that upward revision of tables of desirable weight for young men would be unwarranted. A modest increase in the upper limit in middle-aged men may be justifiable, but the evidence is incomplete.

In 242 neurologically symptomless patients with at least one non-occlusive carotid stenosis on ultrasonography (continuous wave doppler and echotomography-B mode imaging) 171 carotids showed 0-50% stenosis, 150 showed 50-75% stenosis, and 78 showed more than 75% stenosis. The mean follow-up was 29.4 months, with stroke and death as end points. Of the 56 deaths 2 were causally linked to a stroke (crude annual mortality index 9.57%). Of the 10 strokes 7 were judged to be infarctions in carotid territory. 7 out of 20 patients with transient ischaemic attacks (TIA) had ischaemic symptoms definitely related to carotid territory. The crude annual indices of specific stroke or TIA were 0.45% for nonstenotic carotid, 0.23% for 0-50% stenosis, 2.48% for 50-75% stenosis, and 1.71% for 75-99% stenosis. Stenoses of greater than 50% were associated with more ischaemic events than were lesser degrees of narrowing (p less than 0.01).

Estimates of the risk of stroke for men with non-rheumatic atrial fibrillation were obtained from two large cohort studies--the Whitehall Study of London Civil Servants and the British Regional Heart Study. The first cohort provided an estimated relative risk of stroke of 6.9 compared with controls. This increased risk confirms that of the other prospective estimate, 5.6, found in the Framingham study. In the second cohort only one of the men at risk had a stroke, and the risk estimate did not differ significantly from unity. The absolute rates of stroke in both cohorts were lower than those reported in the Framingham study, implying a lesser potential benefit from preventive measures. These lower rates should be considered in the planning of trials. The risk of stroke was significantly associated with raised systolic or diastolic blood pressure but not with age or coronary heart disease.

Visuospatial neglect, a frequent consequence of unilateral (usually right-hemisphere) stroke, is associated with poor functional recovery and in many patients is resistant to remedial treatment. Studies of the nature and prevalence of the disorder have been hindered by problems of definition and assessment. In this study 80 unselected stroke patients were assessed for the presence and severity of neglect on the behavioural inattention test. The six subtests of this battery all intercorrelated highly, and a subsequent factor analysis showed that all tests loaded significantly on one underlying factor. The construct of neglect as defined by performance on the battery is therefore robust. Nonetheless, the individual tests differed substantially in their sensitivity. Star cancellation was the most sensitive measure of neglect and correctly diagnosed all patients whose aggregate score on the full battery fell below that of the control population.