Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose:analysis of individual patient data from randomised trials

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 (pand#60;0·0001). The ability of 75–100 mg aspirin to reduce cardiovascular events decreased with increasing weight (pinteraction=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 pinteraction=0·0013), reducing cardiovascular events only at higher weight (pinteraction=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 (pinteraction=0·0025 for cardiovascular events). Aspirin-mediated reductions in long-term risk of colorectal cancer were also weight dependent (pinteraction=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 (pinteraction=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

The association between smoking during pregnancy and hospital inpatient costs in childhood

Although the health sequelae of smoking during pregnancy are well documented, relatively little is known about its long-term economic implications. The objective of this study was to analyse individual-level data on maternal smoking behaviour and sociodemographic, perinatal and resource utilisation variables in order to estimate the association between smoking during pregnancy and hospital inpatient service utilisation and costs through the first 5 years of the infant's life. Data from the Oxford Record Linkage Study, a collection of birth registrations, death certificates and statistical abstracts of hospital inpatient and day case admissions formed the basis of the investigation. The study population comprised all infants born to women who both lived and delivered in Oxfordshire or West Berkshire during the period 1 January 1980-31 December 1989 (n=119,028). The cost of each hospital admission, including the initial birth admission, was estimated by multiplying the length of stay by the per diem cost of the respective specialty (£ 1998-1999 sterling). The effect of maternal smoking behaviour on cumulative 5-year hospital inpatient service utilisation and costs was analysed in a series of multivariate analyses, taking account of confounding clinical and sociodemographic factors. Infants born to women who reported smoking during pregnancy were hospitalised for a significantly greater number of days than infants born to women who had either never smoked or had smoked in the past (PSmoking Pregnancy Inpatient service utilisation Inpatient service costs Multivariate UK

Effects of antihypertensive-drug class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta-analysis

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

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

Objective To determine the age-specific temporal trends in blood pressure (BP) prior to acute lacunar vs. non-lacunar TIA and stroke. Methods In a population-based study of TIA/ischaemic stroke (Oxford Vascular Study), we studied 15-year premorbid BP readings from primary care records in patients with lacunar vs. non-lacunar events (TOAST) stratified by age ( Results Of 2085 patients (1250-stroke/835-TIA), 309 had lacunar events. In 493 patients aged Conclusion Recent premorbid BP control is strongly temporarily related to acute lacunar events at younger ages, suggesting a direct role of BP in accelerating causal pathology and highlighting the need to control hypertension quickly.</p

Effects of aspirin on risk and severity of early recurrent stroke after transient ischaemic attack and ischaemic stroke : time-course analysis of randomised trials

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

Delirium risk stratification in consecutive unselected admissions to acute medicine: validation of externally derived risk scores

reliable delirium risk stratification will aid recognition, anticipation and prevention and will facilitate targeting of resources in clinical practice as well as identification of at-risk patients for research. Delirium risk scores have been derived for acute medicine, but none has been prospectively validated in external cohorts. We therefore aimed to determine the reliability of externally derived risk scores in a consecutive cohort of older acute medicine patients.consecutive patients aged ≥65 over two 8-week periods (2010, 2012) were screened prospectively for delirium using the Confusion Assessment Method (CAM), and delirium was diagnosed using the DSM IV criteria. The reliability of existing delirium risk scores derived in acute medicine cohorts and simplified for use in routine clinical practice (USA, n = 2; Spain, n = 1; Indonesia, n = 1) was determined by the area under the receiver operating characteristic curve (AUC). Delirium was defined as prevalent (on admission), incident (occurring during admission) and any (prevalent + incident) delirium.among 308 consecutive patients aged ≥65 (mean age/SD = 81/8 years, 164 (54%) female), existing delirium risk scores had AUCs for delirium similar to those reported in their original internal validations ranging from 0.69 to 0.76 for any delirium and 0.73 to 0.83 for incident delirium. All scores performed better than chance but no one score was clearly superior.externally derived delirium risk scores performed well in our independent acute medicine population with reliability unaffected by simplification and might therefore facilitate targeting of multicomponent interventions in routine clinical practice

Quality of life in type 2 diabetic patients is affected by complications but not by intensive policies to improve blood glucose or blood pressure control (UKPDS 37)

OBJECTIVE - To determine in patients with type 2 diabetes the effects on quality of life (QOL) of therapies for improving blood glucose control and for improving blood pressure (BP) control, diabetic complications, and hypoglycemic episodes. RESEARCH DESIGN AND METHODS - We performed two cross- sectional studies of patients enrolled in randomized controlled trials of 1) an intensive blood glucose control policy compared with a conventional blood glucose control policy, and 2) a tight BP control policy compared with a less tight BP control policy. Also undertaken was a longitudinal study of patients in a randomized controlled trial of an intensive blood glucose control policy compared with a conventional blood glucose control policy. Subjects' QOL was assessed before or at the time of randomization and from 6 months to 6 years after randomization. Two cross-sectional samples of type 2 diabetic patients were randomized to therapies for blood glucose control: 1) 2,431 patients, mean age 60, duration from randomization 8.0 years, completed a 'specific' questionnaire coveting four aspects of QOL, and 2) 3,104 patients, mean age 62, duration from randomization 11 years, completed a 'genetic' QOL measure. Of these samples, 628 and 747 patients, respectively, were also randomized to therapies for BP control. A sample of 122 nondiabetic control subjects, average age 62, were also given the specific questionnaire. A longitudinal sample of 374 type 2 diabetic patients randomized to either intensive or conventional blood glucose policies, mean age at randomization 52, were given the specific questionnaire. Sample sizes at 6 months and 1, 2, 3, 4, 5, and 6 years after randomization were 322, 307, 280, 253, 225, 163, and 184, respectively. The specific questionnaire assessed specific domains of QOL, including mood disturbance (Profile of Mood State), cognitive mistakes (Cognitive Failures Questionnaire), symptoms, and work satisfaction; the generic questionnaire (EQ5D) assessed general health. Both questionnaires were self-administered. RESULTS - The cross-sectional studies showed that allocated therapies were neutral in effect, with neither improvement nor deterioration in QOL scores for mood, cognitive mistakes, symptoms, work satisfaction, or general health. The longitudinal study also showed no difference in QOL scores for the specific domains assessed, other than showing marginally more symptoms in patients allocated to conventional than to intensive policy in the cross-sectional studies, patients who had had a macrovascular complication in the last year had worse general health, as measured by the generic questionnaire, than those without complications, with scale scores median 60 and 78 respectively (P = 0.0006) and tariff scores median 0.73 and 0.83 respectively (P = 0.0012); more problems with mobility, 64 and 36%, respectively (P &lt; 0.0001); and more problems with usual activities, 48 and 28% respectively (P = 0.0023). As measured by the specific questionnaire, they also showed reduced vigor (P = 0.0077). Patients who had had a microvascular complication in the last year reported more tension (P = 0.0082) and total mood disturbance (P = 0.0054), as measured by the specific questionnaire, than patients without complications. Patients treated with insulin who had had two or more hypoglycemic episodes during the previous year reported more tension (P = 0.0023), more overall mood disturbance (P = 0.0009), and less work satisfaction (P = 0.0042), as measured by the specific questionnaire, than those with no hypoglycemic attacks, after adjusting for age, duration from randomization, systolic BP, HbA(1c), and sex in a multivariate polychotomous regression. CONCLUSIONS - In patients with type 2 diabetes, complications of the disease affected QOL, whereas therapeutic policies shown to reduce the risk of complications had no effect on QOL. It cannot be discerned whether frequent hypoglycemic episodes affect QOL, or whether patients with certain personality traits or many symptoms also reported increased numbers of hypoglycemic attacks.</p

Effect of daily aspirin on risk of cancer metastasis:a study of incident cancers during randomised controlled trials

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