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Post by Admin on Sept 29, 2023 15:12:49 GMT
Aspirin was first used clinically as an anti-inflammatory drug in 1899, and 50 years ago its antiplatelet effects were also confirmed. Currently, aspirin is considered to be the most cost-effective drug among antiplatelet drugs and is frequently used in Japan. The antiplatelet effect of aspirin is exerted by inhibiting COX-1 action through selective acetylation of COX-1 in platelets. In addition, its antiplatelet effect is effective at low doses (81 to 330 mg/day), but it is known that at high doses, the inhibitory effect on platelet aggregation is lost. However, while aspirin has an excellent antiplatelet effect, it has been pointed out that it also has the drawback of causing side effects such as gastric and duodenal ulcers. Therefore, when using aspirin normally, drugs to treat peptic ulcers such as PPIs are used in combination, but PPIs that can be used in combination with low-dose aspirin therapy are indicated for "prevention of gastric and duodenal ulcer recurrence during drug administration." Only lansoprazole or esomeprazole (trade name Nexium) is available. Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: analysis of individual patient data from randomised trials Prof Peter M Rothwell, FMedSci Prof Nancy R Cook, ScD Prof J Michael Gaziano, MD Prof Jacqueline F Price, PhD Prof Jill F F Belch, MD Maria Carla Roncaglioni, PhD et al. Summary 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 (pinteraction=0·0072), with benefit seen in people weighing 50–69 kg (hazard ratio 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. Funding Wellcome Trust and National Institute for Health Research Oxford Biomedical Research Centre. www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31133-4/fulltext
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Post by Admin on Oct 1, 2023 20:06:14 GMT
Introduction Aspirin inhibits platelet aggregation by irreversible acetylation of the cyclo-oxygenase-1 (COX-1) enzyme, resulting in almost complete inhibition of thromboxane production by platelets.1 However, aspirin yields only modest long-term reductions in vascular events,2, 3 which has led investigators to develop alternative antiplatelet drugs and to study the effects of their combination with aspirin and of dual treatment with anticoagulant drugs. Yet the disparity between the effect of aspirin on thromboxane production and its clinical benefits might be due, at least in part, to the one-dose-fits-all approach used in trials and clinical practice, particularly the use of low doses in individuals with higher bodyweight. Obesity and increased body-mass index (BMI) are associated with reduced inhibition of COX-1 by low doses of aspirin, probably due to increased platelet activation or turnover,4, 5 but high lean body mass could also reduce the systemic bioavailability of aspirin. Aspirin is rapidly de-acetylated by esterases in the intestinal wall, plasma, red blood cells, and liver,6 and so the proportion of a fixed dose that reaches the systemic circulation will depend on the mass of these tissues, which is correlated with lean body size. Given that aspirin acetylates several highly abundant proteins such as albumin, haemoglobin, and fibrinogen, their masses might also affect the systemic bioavailability of aspirin. Although about 50% of an oral dose of aspirin reaches the portal circulation6—and can therefore inhibit circulating platelets—reduced systemic bioavailability could restrict inhibition of COX-1 in megakariocytes and, hence, in the 10–15% of new platelets that are released daily.7 Thus, reduced systemic bioavailability of once-daily, low-dose aspirin at higher lean body mass could reduce clinical effectiveness, especially if doses are missed. Total bodyweight could be a particularly powerful determinant of clinical effects if obesity also increases platelet turnover. Higher doses of aspirin should overcome any reduced bioavailability with increasing body size, but might be excessive in patients with low bodyweight because of reduced endothelial prostacyclin production due to high systemic levels of aspirin8 or possibly because of increased salicylate levels. If the effectiveness of lower doses decreases, and the effectiveness of higher doses increases, with increasing body size, then weight–dose interactions could explain why low-dose aspirin appears to prevent stroke only in women,9 and high doses only in men,10 despite them having similar BMIs. All randomised trials of aspirin in prevention of vascular events have tested a one-dose-fits-all approach (ie, one dose vs placebo or, occasionally, comparing two different doses applied to all), but have differed in the doses chosen. Previous analyses of aspirin trials have not found consistent effect modification for BMI,3, 11 but trials of different doses have been analysed together, and BMI is poorly correlated with lean body size. In the absence of previous analyses, we aimed to investigate the modifying effects of weight, height, BMI, and other measures of body size on the effectiveness of low and higher doses of aspirin in primary prevention of vascular events, with validation in trials in secondary prevention of stroke. Given that aspirin also has effects on risk of cancer,12, 13 which might partly depend on platelet inhibition,1 we also investigated whether the effect of aspirin on long-term risk of colorectal cancer, and on short-term, in-trial risk of any cancer, was affected by weight and height.
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Post by Admin on Nov 9, 2023 21:27:07 GMT
Methods Search strategy and selection criteria Trials of aspirin versus control in primary prevention of vascular events were identified from the Antithrombotic Trialists' (ATT) Collaboration,3, 11 from other previous systematic reviews of trials of aspirin, and from the Cochrane Collaboration Database of Systematic Reviews. Trials were eligible if they randomly assigned participants to daily or alternate-day aspirin versus no aspirin. Trials that included factorial randomisation to other interventions were also eligible. Trials of aspirin versus control in secondary prevention of stroke that randomised at least 1000 participants were identified from a previous systematic review,14 along with any trials comparing different doses of aspirin in the secondary prevention of stroke identified by the ATT.3, 11 Trials of short-term (≤90 days) treatment were excluded. For all eligible trials, we obtained individual patient data on age, sex, weight, height, and vascular risk factors (including smoking status and diabetes status) at baseline, and on all major vascular events (including stroke [ischaemic, intracerebral, or subarachnoid haemorrhage], myocardial infarction, vascular death, other coronary death, and other major ischaemic vascular events, excluding unstable angina and transient ischaemic attack), major bleeds (intracerebral haemorrhage and extracranial bleeds that were fatal or required blood transfusion or hospital admission), cancers (first cancer, excluding non-melanoma skin cancer, diagnosed after randomisation), and deaths that occurred during follow-up. When possible, ATT Collaboration definitions of events were used.3, 11 When data were available, recurrences of pre-trial cancers were excluded, but all deaths due to cancer were included in analyses of that outcome. The designation of cancer death from the original trials was used. Data were also obtained if trials had coded sudden deaths (ie, collapse or unwitnessed death with no known non-cardiac cause and no clinical or autopsy evidence of fatal myocardial infarction). Dates of randomisation, of all events, of withdrawal from randomised treatment, and of final follow-up were also obtained. Data on 20-year risk of colorectal cancer were obtained from trials of aspirin in primary prevention of vascular events that did post-trial follow-up.15, 16, 17, 18, 19, 20 Methods of post-trial follow-up for cancer have been reported previously for four trials,12, 13, 21, 22 and methods used previously in the UK trials12, 13 were applied in two further trials.19, 20 Statistical analysis Trials were analysed separately according to whether they were investigating aspirin for primary or secondary prevention and whether they used low doses (≤100 mg) or higher doses (≥300 mg) of aspirin. Primary and secondary prevention trials were pooled only if the effect modification by weight or height was similar in both settings. Analyses of the effects of aspirin were done by intention to treat based on randomised allocation, unless otherwise specified. For analyses stratified by baseline characteristics, data on age and sex were complete, data on smoking were 99·9% complete, and data on weight or height were missing in about 0·1% of participants (range 0–1·05; appendix pp 2, 3); thus, participants with missing data were simply excluded. Participants in each trial were first dichotomised by bodyweight: those weighing less than 70 kg versus those weighing 70 kg or more. For each outcome, hazard ratios (HRs) were calculated for aspirin versus control in each trial, pooled estimates were obtained by fixed-effects meta-analysis (Mantel-Haenszel-Peto method), and heterogeneity was calculated with the χ2 test. In the absence of significant (p<0·05) heterogeneity in estimates between trials, individual patient data were pooled and the effects of aspirin in people weighing less than 70 kg versus those weighing 70 kg or more were estimated with a Cox model stratified by trial. Kaplan-Meier curves were also generated for time to event and dichotomised by bodyweight (<70 kg vs ≥70 kg), with significance established by use of the log-rank test stratified by trial. Participants without an event were censored on date of death or at the end of trial follow-up. This analysis was repeated with censoring at time of discontinuation of randomised treatment. Given that aspirin can affect the severity of vascular events,14 we also did weight-stratified analyses of the effects of aspirin on fatal events only, and on case fatality of events for stroke, myocardial infarction, and all cardiovascular events during trial follow-up. Additionally, we determined the effects of aspirin on risk of all cardiovascular events or death from any cause. Because effects on fatal events in trials can be diluted by active treatment after non-fatal events,23 these analyses were limited to death and case fatality due to first events during follow-up and were also repeated with censoring at discontinuation of randomised treatment. Any interaction between the effect of aspirin on outcome and bodyweight was assessed by including in the Cox model an interaction term between weight and treatment for the analysis of participants weighing less than 70 kg versus those weighing 70 kg or more and with additional analyses with the interaction term based on weight as a continuous variable. Effects of aspirin were also determined in 10 kg bands of weight (<50, 50–59, 60–69, 70–79, 80–89, and ≥90), and in 0·1 m bands of height (<1·40, 1·40–1·49, 1·50–1·59, 1·60–1·69, 1·70–1·79, and ≥1·80), which were shown graphically as HRs (95% CIs). When height had been recorded in feet and inches, corresponding thresholds in metres were estimated. Effects of aspirin were also compared in tall (top quintile within each sex) versus shorter (lower four quintiles) individuals. Analyses stratified by weight were also repeated after exclusion of participants who were underweight (BMI <18·5 kg/m2) or who were obese (BMI ≥30 kg/m2). Effect modification by other measures of body size (including lean body mass, BMI, fat mass, and body surface area; definitions are in appendix p 13) and by vascular risk factors was also assessed by use of interaction terms in Cox models. Analysis of the effect of aspirin on risk of all cardiovascular events stratified by weight was further stratified by age (<70 years vs ≥70 years), sex, smoking status (current smoker vs previous or never smoker), BMI (<25 kg/m2 vs ≥25 kg/m2), formulation of aspirin tablet used (enteric coated or delayed release vs standard release), period of follow-up (<3 years vs ≥3 years), and whether or not the participant was also randomised to vitamin E in trials with this factorial design. For the effect of aspirin on risk of all cardiovascular events, the significance of any differences in effect modification by weight and height between low-dose (≤100 mg) and higher-dose (≥300 mg) aspirin was established with the Mantel-Haenszel-Peto heterogeneity statistic for difference between low-dose versus higher-dose interaction estimates derived from a Cox model for weight–treatment or height–treatment interactions. In the primary prevention trials with post-trial follow-up for cancer, the effect of aspirin on the 20-year risk of colorectal cancer was stratified by weight in the same way as described for vascular events, with additional stratification by age (<70 years vs ≥70 years) and dose of aspirin (75–100 mg vs ≥300 mg). In all primary prevention trials, the same analysis was done for risk of first cancer during trial follow-up, with additional stratification according to sex, diabetes status, and period of follow-up. In line with previous analyses,12, 13, 14 we selected follow-up periods of less than 3 years, 3–4·9 years, and 5 years or more. Role of the funding source The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
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Post by Admin on Nov 11, 2023 22:04:46 GMT
Results Trial inclusion We identified ten eligible trials15, 16, 17, 18, 19, 20, 24, 25, 26, 27 of aspirin versus control in primary prevention of cardiovascular events. All but one trial20 had collected data on weight or height, and individual patient data on baseline characteristics and all major cardiovascular events were available from nine trials (appendix pp 2, 3).15, 16, 17, 18, 19, 20, 24, 25, 26 Seven trials17, 18, 19, 20, 24, 25, 26 investigated low doses of aspirin (75–100 mg) versus control and two trials15, 16 investigated higher doses of aspirin versus control. We also identified five eligible trials28, 29, 30, 31, 32 of aspirin in secondary prevention of stroke and obtained individual patient data from the four largest trials: one of low-dose aspirin versus placebo,28 two of higher doses of aspirin versus placebo,29, 30 and one comparing two doses (appendix p 3).31 The only other eligible trial32 of low-dose aspirin in secondary prevention of stroke did not collect data on weight or height. Bodyweight varied approximately four-fold in each of the trials (appendix pp 2, 3). Median weight ranged from 60·0 kg to 81·2 kg (p<0·0001), in part due to sex differences (median weight was 81·0 kg in men and 68·0 kg in women). Trials also differed in age of participants and in number of participants who smoked.
Low-dose aspirin In the initial meta-analysis of trials of low-dose aspirin in primary prevention, pooled odds ratios (ORs) for the effect of aspirin on risk of cardiovascular events were 0·77 (95% CI 0·68–0·87, p<0·0001; pheterogeneity=0·32) for participants weighing less than 70 kg versus 0·94 (0·86–1·04, p=0·24; pheterogeneity=0·50) for those weighing 70 kg or more (table 1). Given the lack of heterogeneity in these effects between studies, we proceeded to do the pooled analyses.
In the pooled analysis of trials of low-dose aspirin in primary prevention, the ability of 75–100 mg aspirin to reduce cardiovascular events decreased with increasing weight (pinteraction=0·0072; table 1, figure 1). Low-dose aspirin had the greatest effect on cardiovascular events in participants weighing 50–69 kg (383 events in 15 155 participants treated with aspirin vs 504 events in 15 145 participants treated with control; HR 0·75 [95% CI 0·65–0·85]; p<0·0001), particularly with daily use (172 of 4432 treated with aspirin vs 245 of 4400 treated with control; 0·68 [0·56–0·83], p=0·0001; figure 1). In the one trial18 of alternate-day dosing, 100 mg aspirin was effective in participants weighing 50–59 kg (72 of 4325 vs 102 of 4408; 0·72 [0·52–0·96], p=0·025; figure 1) and in those weighing 60–69 kg who were not allocated to vitamin E (appendix p 4). However, the reduction in cardiovascular events with 75–100 mg aspirin in people weighing 50–59 kg was not seen in people weighing less than 50 kg (1·25 [0·74–2·09], p=0·40; figure 1), who also had an increased risk of all-cause death (1·52 [1·04–2·21], p=0·031). No hazard was evident in people weighing less than 50 kg after exclusion of people with a BMI of less than 18·5 kg/m2 (19 of 724 vs 22 of 696; 0·80 [0·43–1·47], p=0·47; figure 1).
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Post by Admin on Dec 11, 2023 21:29:16 GMT
Figure 1 Effect of low-dose aspirin versus control on risks of cardiovascular events, death, and major bleeding according to bodyweight in trials of aspirin in primary prevention The size of the circles representing the point estimates of the HRs is proportional to the inverse of the variance of the estimate. BMI=body-mass index. HR=hazard ratio. View Large ImageDownload Hi-res imageDownload (PPT) Low-dose aspirin (75–100 mg) prevented stroke in women but not in men (table 1; pinteraction=0·020), but no difference remained after accounting for weight (pinteraction=0·20; table 1; appendix p 5). The effect of low-dose aspirin on cardiovascular events was not modified by the presence of diabetes (weight-adjusted pinteraction=0·47) or by age (weight-adjusted pinteraction=0·94; table 1; appendix p 5) The weight dependence of the effect was similar for on-treatment analyses (intention to treat vs censoring at treatment discontinuation), for early follow-up (0–3 years), and for later (≥3 years) follow-up (appendix pp 6, 7). However, the effect of low-dose aspirin on cardiovascular events was reduced in smokers (pinteraction=0·0026; table 1; appendix p 5). Weight remained a significant effect modifier after inclusion of age, sex, and smoking interactions in the model (pinteraction=0·0035). The effects of weight and smoking were additive overall (table 2), and were generally consistent within individual trials (appendix p 8), with possible harm from aspirin in participants who smoked and weighed 70 kg or more (table 2). The dual interaction with weight and smoking also explained why low-dose aspirin prevented myocardial infarction in men (HR 0·77 [95% CI 0·66–0·90], p=0·0014) but not in women (1·00 [0·84–1·18], p=0·96; pinteraction=0·031), even when stratified by weight (table 1). The risk of myocardial infarction was only reduced in women who did not smoke and weighed less than 70 kg (HR 0·71 [95% CI 0·52–0·97, p=0·031] vs 1·33 [0·85–2·09, p=0·21] for women who smoked and weighed ≥70 kg). Table 2 Effect of low-dose aspirin versus control on risk of cardiovascular events according to weight and smoking status Aspirin Control HR (95% CI) pinteraction All cardiovascular events All participants .. .. .. <0·0001 Neither 275 377 0·73 (0·62–0·85) .. Either 675 775 0·86 (0·78–0·96) .. Both 259 222 1·18 (0·99–1·41) .. With diabetes .. .. .. 0·0009 Neither 64 92 0·68 (0·49–0·93) .. Either 159 177 0·89 (0·72–1·11) .. Both 64 39 1·58 (1·06–2·35) .. Without diabetes .. .. .. 0·0039 Neither 211 285 0·74 (0·62–0·88) .. Either 516 598 0·85 (0·76–0·96) .. Both 195 183 1·10 (0·90–1·34) .. Age <70 years .. .. .. 0·0004 Neither 170 237 0·72 (0·59–0·88) .. Either 540 652 0·82 (0·73–0·92) .. Both 240 207 1·18 (0·98–1·42) .. Age ≥70 years .. .. .. 0·0045 Neither 105 140 0·67 (0·52–0·86) .. Either 135 123 1·14 (0·89–1·46) .. Both 19 15 1·14 (0·58–2·25) .. Alternate-day dose .. .. .. 0·0007 Neither 142 197 0·72 (0·58–0·89) .. Either 257 267 0·96 (0·81–1·14) .. Both 72 53 1·40 (0·98–2·00) .. Daily dose .. .. .. 0·0051 Neither 133 180 0·74 (0·59–0·92) .. Either 418 508 0·82 (0·72–0·93) .. Both 187 169 1·12 (0·91–1·37) .. Women .. .. .. 0·0002 Neither 218 302 0·72 (0·61–0·86) .. Either 361 390 0·93 (0·80–1·07) .. Both 88 67 1·40 (1·02–1·92) .. Men .. .. .. 0·017 Neither 57 75 0·76 (0·54–1·08) .. Either 314 385 0·80 (0·69–0·93) .. Both 171 155 1·09 (0·88–1·35) .. All stroke .. .. .. 0·0002 Neither 138 201 0·69 (0·56–0·86) .. Either 275 323 0·85 (0·72–0·99) .. Both 86 56 1·55 (1·11–2·17) .. Myocardial infarction .. .. .. 0·025 Neither 97 135 0·71 (0·55–0·92) .. Either 304 351 0·87 (0·74–1·01) .. Both 145 138 1·06 (0·84–1·33) .. Cardiovascular-related death .. .. .. 0·20 Neither 87 109 0·79 (0·60–1·05) .. Either 248 236 1·05 (0·88–1·26) .. Both 89 88 1·02 (0·76–1·37) .. Neither refers to participants who weighed <70 kg and did not smoke, either refers to participants who weighed ≥70 kg or smoked, and both refers to participants who weighed ≥70 kg and smoked. Numbers of events are four fewer than listed in table 1 because of missing data on smoking status for four individuals. HR=hazard ratio.
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