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Background: A one-dose-fits-all approach to use of aspirin has yielded only modest benefits in long-term prevention of cardiovascular events, possibly due to underdosing in patients of large body size and excess dosing in patients of small body size, which might also affect other outcomes., Methods: Using individual patient data, we analysed the modifying effects of bodyweight (10 kg bands) and height (10 cm bands) on the effects of low doses (≤100 mg) and higher doses (300-325 mg or ≥500 mg) of aspirin in randomised trials of aspirin in primary prevention of cardiovascular events. We stratified the findings by age, sex, and vascular risk factors, and validated them in trials of aspirin in secondary prevention of stroke. Additionally, we assessed whether any weight or height dependence was evident for the effect of aspirin on 20-year risk of colorectal cancer or any in-trial cancer., Results: Among ten eligible trials of aspirin in primary prevention (including 117 279 participants), bodyweight varied four-fold and trial median weight ranged from 60·0 kg to 81·2 kg (p<0·0001). The ability of 75-100 mg aspirin to reduce cardiovascular events decreased with increasing weight (p interaction =0·0072), with benefit seen in people weighing 50-69 kg (hazard ratio [HR] 0·75 [95% CI 0·65-0·85]) but not in those weighing 70 kg or more (0·95 [0·86-1·04]; 1·09 [0·93-1·29] for vascular death). Furthermore, the case fatality of a first cardiovascular event was increased by low-dose aspirin in people weighing 70 kg or more (odds ratio 1·33 [95% CI 1·08-1·64], p=0·0082). Higher doses of aspirin (≥325 mg) had the opposite interaction with bodyweight (difference p interaction =0·0013), reducing cardiovascular events only at higher weight (p interaction =0·017). Findings were similar in men and women, in people with diabetes, in trials of aspirin in secondary prevention, and in relation to height (p interaction =0·0025 for cardiovascular events). Aspirin-mediated reductions in long-term risk of colorectal cancer were also weight dependent (p interaction =0·038). Stratification by body size also revealed harms due to excess dosing: risk of sudden death was increased by aspirin in people at low weight for dose (p interaction =0·0018) and risk of all-cause death was increased in people weighing less than 50 kg who were receiving 75-100 mg aspirin (HR 1·52 [95% CI 1·04-2·21], p=0·031). In participants aged 70 years or older, the 3-year risk of cancer was also increased by aspirin (1·20 [1·03-1·47], p=0·02), particularly in those weighing less than 70 kg (1·31 [1·07-1·61], p=0·009) and consequently in women (1·44 [1·11-1·87], p=0·0069)., Interpretation: Low doses of aspirin (75-100 mg) were only effective in preventing vascular events in patients weighing less than 70 kg, and had no benefit in the 80% of men and nearly 50% of all women weighing 70 kg or more. By contrast, higher doses of aspirin were only effective in patients weighing 70 kg or more. Given that aspirin's effects on other outcomes, including cancer, also showed interactions with body size, a one-dose-fits-all approach to aspirin is unlikely to be optimal, and a more tailored strategy is required., Funding: Wellcome Trust and National Institute for Health Research Oxford Biomedical Research Centre., (Copyright © 2018 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: 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., (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: Aspirin is recommended for secondary prevention after transient ischaemic attack (TIA) or ischaemic stroke on the basis of trials showing a 13% reduction in long-term risk of recurrent stroke. However, the risk of major stroke is very high for only the first few days after TIA and minor ischaemic stroke, and observational studies show substantially greater benefits of early medical treatment in the acute phase than do longer-term trials. We hypothesised that the short-term benefits of early aspirin have been underestimated., Methods: Pooling the individual patient data from all randomised trials of aspirin versus control in secondary prevention after TIA or ischaemic stroke, we studied the effects of aspirin on the risk and severity of recurrent stroke, stratified by the following time periods: less than 6 weeks, 6-12 weeks, and more than 12 weeks after randomisation. We compared the severity of early recurrent strokes between treatment groups with shift analysis of modified Rankin Scale (mRS) score. To understand possible mechanisms of action, we also studied the time course of the interaction between effects of aspirin and dipyridamole in secondary prevention of stroke. In a further analysis we pooled data from trials of aspirin versus control in which patients were randomised less than 48 h after major acute stroke, stratified by severity of baseline neurological deficit, to establish the very early time course of the effect of aspirin on risk of recurrent ischaemic stroke and how this differs by severity at baseline., Findings: We pooled data for 15,778 participants from 12 trials of aspirin versus control in secondary prevention. Aspirin reduced the 6 week risk of recurrent ischaemic stroke by about 60% (84 of 8452 participants in the aspirin group had an ischaemic stroke vs 175 of 7326; hazard ratio [HR] 0·42, 95% CI 0·32-0·55, p<0·0001) and disabling or fatal ischaemic stroke by about 70% (36 of 8452 vs 110 of 7326; 0·29, 0·20-0·42, p<0·0001), with greatest benefit noted in patients presenting with TIA or minor stroke (at 0-2 weeks, two of 6691 participants in the aspirin group with TIA or minor stroke had a disabling or fatal ischaemic stroke vs 23 of 5726 in the control group, HR 0·07, 95% CI 0·02-0·31, p=0·0004; at 0-6 weeks, 14 vs 60 participants, 0·19, 0·11-0·34, p<0·0001). The effect of aspirin on early recurrent ischaemic stroke was due partly to a substantial reduction in severity (mRS shift analysis odds ratio [OR] 0·42, 0·26-0·70, p=0·0007). These effects were independent of dose, patient characteristics, or aetiology of TIA or stroke. Some further reduction in risk of ischaemic stroke accrued for aspirin only versus control from 6-12 weeks, but there was no benefit after 12 weeks (stroke risk OR 0·97, 0·84-1·12, p=0·67; severity mRS shift OR 1·00, 0·77-1·29, p=0·97). By contrast, dipyridamole plus aspirin versus aspirin alone had no effect on risk or severity of recurrent ischaemic stroke within 12 weeks (OR 0·90, 95% CI 0·65-1·25, p=0·53; mRS shift OR 0·90, 0·37-1·72, p=0·99), but dipyridamole did reduce risk thereafter (0·76, 0·63-0·92, p=0·005), particularly of disabling or fatal ischaemic stroke (0·64, 0·49-0·84, p=0·0010). We pooled data for 40,531 participants from three trials of aspirin versus control in major acute stroke. The reduction in risk of recurrent ischaemic stroke at 14 days was most evident in patients with less severe baseline deficits, and was substantial by the second day after starting treatment (2-3 day HR 0·37, 95% CI 0·25-0·57, p<0·0001)., Interpretation: Our findings confirm that medical treatment substantially reduces the risk of early recurrent stroke after TIA and minor stroke and identify aspirin as the key intervention. The considerable early benefit from aspirin warrants public education about self-administration after possible TIA. The previously unrecognised effect of aspirin on severity of early recurrent stroke, the diminishing benefit with longer-term use, and the contrasting time course of effects of dipyridamole have implications for understanding mechanisms of action., Funding: Wellcome Trust, the National Institute of Health Research (NIHR) Biomedical Research Centre, Oxford., (Copyright © 2016 Rothwell et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

Background: Daily aspirin reduces the long-term risk of death due to cancer. However, the short-term effect is less certain, especially in women, effects on cancer incidence are largely unknown, and the time course of risk and benefit in primary prevention is unclear. We studied cancer deaths in all trials of daily aspirin versus control and the time course of effects of low-dose aspirin on cancer incidence and other outcomes in trials in primary prevention., Methods: We studied individual patient data from randomised trials of daily aspirin versus no aspirin in prevention of vascular events. Death due to cancer, all non-vascular death, vascular death, and all deaths were assessed in all eligible trials. In trials of low-dose aspirin in primary prevention, we also established the time course of effects on incident cancer, major vascular events, and major extracranial bleeds, with stratification by age, sex, and smoking status., Results: Allocation to aspirin reduced cancer deaths (562 vs 664 deaths; odds ratio [OR] 0·85, 95% CI 0·76-0·96, p=0·008; 34 trials, 69,224 participants), particularly from 5 years onwards (92 vs 145; OR 0·63, 95% CI 0·49-0·82, p=0·0005), resulting in fewer non-vascular deaths overall (1021 vs 1173; OR 0·88, 95% CI 0·78-0·96, p=0·003; 51 trials, 77,549 participants). In trials in primary prevention, the reduction in non-vascular deaths accounted for 87 (91%) of 96 deaths prevented. In six trials of daily low-dose aspirin in primary prevention (35,535 participants), aspirin reduced cancer incidence from 3 years onwards (324 vs 421 cases; OR 0·76, 95% CI 0·66-0·88, p=0·0003) in women (132 vs 176; OR 0·75, 95% CI 0·59-0·94, p=0·01) and in men (192 vs 245; OR 0·77, 95% CI 0·63-0·93, p=0·008). The reduced risk of major vascular events on aspirin was initially offset by an increased risk of major bleeding, but effects on both outcomes diminished with increasing follow-up, leaving only the reduced risk of cancer (absolute reduction 3·13 [95% CI 1·44-4·82] per 1000 patients per year) from 3 years onwards. Case-fatality from major extracranial bleeds was also lower on aspirin than on control (8/203 vs 15/132; OR 0·32, 95% CI 0·12-0·83, p=0·009)., Interpretation: Alongside the previously reported reduction by aspirin of the long-term risk of cancer death, the short-term reductions in cancer incidence and mortality and the decrease in risk of major extracranial bleeds with extended use, and their low case-fatality, add to the case for daily aspirin in prevention of cancer., Funding: None., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Daily aspirin reduces the long-term incidence of some adenocarcinomas, but effects on mortality due to some cancers appear after only a few years, suggesting that it might also reduce growth or metastasis. We established the frequency of distant metastasis in patients who developed cancer during trials of daily aspirin versus control., Methods: Our analysis included all five large randomised trials of daily aspirin (≥75 mg daily) versus control for the prevention of vascular events in the UK. Electronic and paper records were reviewed for all patients with incident cancer. The effect of aspirin on risk of metastases at presentation or on subsequent follow-up (including post-trial follow-up of in-trial cancers) was stratified by tumour histology (adenocarcinoma vs other) and clinical characteristics., Findings: Of 17,285 trial participants, 987 had a new solid cancer diagnosed during mean in-trial follow-up of 6·5 years (SD 2·0). Allocation to aspirin reduced risk of cancer with distant metastasis (all cancers, hazard ratio [HR] 0·64, 95% CI 0·48-0·84, p=0·001; adenocarcinoma, HR 0·54, 95% CI 0·38-0·77, p=0·0007; other solid cancers, HR 0·82, 95% CI 0·53-1·28, p=0·39), due mainly to a reduction in proportion of adenocarcinomas that had metastatic versus local disease (odds ratio 0·52, 95% CI 0·35-0·75, p=0·0006). Aspirin reduced risk of adenocarcinoma with metastasis at initial diagnosis (HR 0·69, 95% CI 0·50-0·95, p=0·02) and risk of metastasis on subsequent follow-up in patients without metastasis initially (HR 0·45, 95% CI 0·28-0·72, p=0·0009), particularly in patients with colorectal cancer (HR 0·26, 95% CI 0·11-0·57, p=0·0008) and in patients who remained on trial treatment up to or after diagnosis (HR 0·31, 95% CI 0·15-0·62, p=0·0009). Allocation to aspirin reduced death due to cancer in patients who developed adenocarcinoma, particularly in those without metastasis at diagnosis (HR 0·50, 95% CI 0·34-0·74, p=0·0006). Consequently, aspirin reduced the overall risk of fatal adenocarcinoma in the trial populations (HR 0·65, 95% CI 0·53-0·82, p=0·0002), but not the risk of other fatal cancers (HR 1·06, 95% CI 0·84-1·32, p=0·64; difference, p=0·003). Effects were independent of age and sex, but absolute benefit was greatest in smokers. A low-dose, slow-release formulation of aspirin designed to inhibit platelets but to have little systemic bioavailability was as effective as higher doses., Interpretation: That aspirin prevents distant metastasis could account for the early reduction in cancer deaths in trials of daily aspirin versus control. This finding suggests that aspirin might help in treatment of some cancers and provides proof of principle for pharmacological intervention specifically to prevent distant metastasis., Funding: None., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Unexplained differences between classes of antihypertensive drugs in their effectiveness in preventing stroke might be due to class effects on intraindividual variability in blood pressure. We did a systematic review to assess any such effects in randomised controlled trials., Methods: Baseline and follow-up data for mean (SD) of systolic blood pressure (SBP) were extracted from trial reports. Effect of treatment on interindividual variance (SD2) in blood pressure (a surrogate for within-individual variability), expressed as the ratio of the variances (VR), was related to effects on clinical outcomes. Pooled estimates were derived by use of random-effects meta-analysis., Findings: Mean (SD) SBP at follow-up was reported in 389 (28%) of 1372 eligible trials. There was substantial heterogeneity between trials in VR (p<1 x 10(-40)), 68% of which was attributable to allocated drug class. Compared with other drugs, interindividual variation in SBP was reduced by calcium-channel blockers (VR 0.81, 95% CI 0.76-0.86, p<0.0001) and non-loop diuretic drugs (0.87, 0.79-0.96, p=0.007), and increased by angiotensin-converting enzyme (ACE) inhibitors (1.08, 1.02-1.15, p=0.008), angiotensin-receptor blockers (1.16, 1.07-1.25, p=0.0002), and beta blockers (1.17, 1.07-1.28, p=0.0007). Compared with placebo only, interindividual variation in SBP was reduced the most by calcium-channel blockers (0.76, 0.67-0.85, p<0.0001). Effects were consistent in parallel group and crossover design trials, and in analyses of dose-response. Across all trials, effects of treatment on VR of SBP (r2=0.372, p=0.0006) and on mean SBP (r2=0.328, p=0.0015) accounted for effects on stroke risk (eg, odds ratio 0.79, 0.71-0.87, p<0.0001, for VR< or =0.80), and both remained significant in a combined model., Interpretation: Drug-class effects on interindividual variation in blood pressure can account for differences in effects of antihypertensive drugs on risk of stroke independently of effects on mean SBP., Funding: None., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Background: The risk of recurrent stroke is up to 10% in the week after a transient ischaemic attack (TIA) or minor stroke. Modelling studies suggest that urgent use of existing preventive treatments could reduce the risk by 80-90%, but in the absence of evidence many health-care systems make little provision. Our aim was to determine the effect of more rapid treatment after TIA and minor stroke in patients who are not admitted direct to hospital., Methods: We did a prospective before (phase 1: April 1, 2002, to Sept 30, 2004) versus after (phase 2: Oct 1, 2004, to March 31, 2007) study of the effect on process of care and outcome of more urgent assessment and immediate treatment in clinic, rather than subsequent initiation in primary care, in all patients with TIA or minor stroke not admitted direct to hospital. The study was nested within a rigorous population-based incidence study of all TIA and stroke (Oxford Vascular Study; OXVASC), such that case ascertainment, investigation, and follow-up were complete and identical in both periods. The primary outcome was the risk of stroke within 90 days of first seeking medical attention, with independent blinded (to study period) audit of all events., Findings: Of the 1278 patients in OXVASC who presented with TIA or stroke (634 in phase 1 and 644 in phase 2), 607 were referred or presented direct to hospital, 620 were referred for outpatient assessment, and 51 were not referred to secondary care. 95% (n=591) of all outpatient referrals were to the study clinic. Baseline characteristics and delays in seeking medical attention were similar in both periods, but median delay to assessment in the study clinic fell from 3 (IQR 2-5) days in phase 1 to less than 1 (0-3) day in phase 2 (p<0.0001), and median delay to first prescription of treatment fell from 20 (8-53) days to 1 (0-3) day (p<0.0001). The 90-day risk of recurrent stroke in the patients referred to the study clinic was 10.3% (32/310 patients) in phase 1 and 2.1% (6/281 patients) in phase 2 (adjusted hazard ratio 0.20, 95% CI 0.08-0.49; p=0.0001); there was no significant change in risk in patients treated elsewhere. The reduction in risk was independent of age and sex, and early treatment did not increase the risk of intracerebral haemorrhage or other bleeding., Interpretation: Early initiation of existing treatments after TIA or minor stroke was associated with an 80% reduction in the risk of early recurrent stroke. Further follow-up is required to determine long-term outcome, but these results have immediate implications for service provision and public education about TIA and minor stroke.

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