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1.  Aspirin for primary prevention of cardiovascular disease in diabetes mellitus 
Nature reviews. Endocrinology  2010;6(11):619-628.
Aspirin is effective for the prevention of cardiovascular events in patients with a history of vascular disease, as so-called secondary prevention. In general populations with no history of previous myocardial infarction or stroke, aspirin also seems useful for primary prevention of cardiovascular events, although the absolute benefits are smaller than those seen in patients with previous cardiovascular disease. Patients with diabetes mellitus are at an increased risk of cardiovascular events, but new trials have raised questions about the benefit of aspirin for primary prevention in patients with this disorder. This Review comprehensively examines the basic pharmacology of aspirin and provides an overview of the randomized, controlled trials of aspirin therapy that have included patients with diabetes mellitus. On the basis of currently available evidence from primary prevention trials, aspirin is estimated to reduce the relative risk of myocardial infarction and stroke by about 10% in patients with diabetes mellitus; however, aspirin also increases the risk of gastrointestinal bleeding. As such, low-dose aspirin therapy (75–162 mg) is reasonable for patients with diabetes mellitus and a 10-year risk of cardiovascular events >10%. Results from upcoming large trials will help clarify the effects of aspirin with greater precision, including whether the benefits differ between men and women.
doi:10.1038/nrendo.2010.169
PMCID: PMC3145323  PMID: 20856266
2.  Determination of who may derive most benefit from aspirin in primary prevention: subgroup results from a randomised controlled trial 
BMJ : British Medical Journal  2000;321(7252):13-17.
Objective
To determine which groups of patients may derive particular benefit or experience harm from the use of low dose aspirin for the primary prevention of coronary heart disease.
Design
Randomised controlled trial.
Setting
108 group practices in the Medical Research Council's general practice research framework who were taking part in the thrombosis prevention trial.
Participants
5499 men aged between 45 and 69 years at entry who were at increased risk of coronary heart disease.
Main outcome measures
Myocardial infarction, coronary death, and stroke.
Results
Aspirin reduced coronary events by 20%. This benefit, mainly for non-fatal events, was significantly greater the lower the systolic blood pressure at entry (interaction P=0.0015), the relative risk at pressures 130 mm Hg being 0.55 compared with 0.94 at pressures >145 mm Hg. Aspirin also reduced strokes at low but not high pressures, the relative risks being 0.41 and 1.42 (P=0.006) respectively. The relative risk of all major cardiovascular events—that is, the sum of coronary heart disease and stroke—was 0.59 at pressures <130 mm Hg compared with 1.08 at pressures >145 mm Hg (P=0.0001).
Conclusion
Even with the limitations of subgroup analyses the evidence suggests that the benefit of low dose aspirin in primary prevention may occur mainly in those with lower systolic blood pressures, although it is not clear even in these men that the benefit outweighs the potential hazards. Men with higher pressures may be exposed to the risks of bleeding while deriving no benefit through reductions in coronary heart disease and stroke.
PMCID: PMC27417  PMID: 10875825
3.  COST-UTILITY OF ASPIRIN AND PROTON PUMP INHIBITORS FOR PRIMARY PREVENTION 
Archives of internal medicine  2011;171(3):218-225.
Background
Aspirin reduces myocardial infarction but increases gastrointestinal bleeding. Proton pump inhibitors (PPIs) may reduce upper gastrointestinal bleed. We estimate the cost-utility of aspirin treatment with or without PPI for coronary heart disease (CHD) prevention among men at different risks for CHD and gastrointestinal bleed.
Methods
We updated a Markov model to compare costs and outcomes of low-dose aspirin+PPI (omeprazole 20-mg daily), low-dose aspirin alone, or no treatment for CHD prevention. We performed lifetime analyses in men with different risks for cardiovascular events and gastrointestinal bleed. Aspirin reduced nonfatal myocardial infarction by 30%, increased total stroke by 6%, and increased gastrointestinal bleed risk 2-fold. Adding PPI reduced upper gastrointestinal bleed by 80%. Annual aspirin cost was $13.99; generic PPI was $200.
Results
In 45-year-old men with 10-year CHD risk of 10% and 0.8/1,000 annual gastrointestinal bleed risk, aspirin ($17,571 and 18.67 quality-adjusted life years [QALYs]) was more effective and less costly than no treatment ($18,483 and 18.44 QALYs). Compared with aspirin alone, aspirin+PPI ($21,037 and 18.68 QALYs) had an incremental cost/QALY of $447,077. Results were similar in 55- and 65-year-old men. The incremental cost/QALY of adding PPI was less than $50,000/QALY at annual gastrointestinal bleed probabilities greater than 4–6/1,000.
Conclusion
Aspirin for CHD prevention is less costly and more effective than no treatment in men over 45 with greater than 10-year, 10% CHD risks. Adding PPI is not cost-effective for men with average gastrointestinal bleed risk but may be cost-effective for selected men at increased risk for gastrointestinal bleed.
doi:10.1001/archinternmed.2010.525
PMCID: PMC3137269  PMID: 21325111
4.  Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials 
Objective To evaluate the benefits and harms of low dose aspirin in people with diabetes and no cardiovascular disease.
Design Meta-analysis of randomised controlled trials.
Data sources Medline (1966-November 2008), the Cochrane central register of controlled trials (Cochrane Library 2008;issue 4), and reference lists of retrieved articles.
Review methods Randomised trials of aspirin compared with placebo or no aspirin in people with diabetes and no pre-existing cardiovascular disease were eligible for inclusion. Data on major cardiovascular events (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, and all cause mortality) were extracted and pooled with a random effect model. Results are reported as relative risks with 95% confidence intervals.
Results Of 157 studies in the literature searches, six were eligible (10 117 participants). When aspirin was compared with placebo there was no statistically significant reduction in the risk of major cardiovascular events (five studies, 9584 participants; relative risk 0.90, 95% confidence interval 0.81 to 1.00), cardiovascular mortality (four studies, n=8557, 0.94; 0.72 to 1.23), or all cause mortality (four studies, n=8557; 0.93, 0.82 to 1.05). Significant heterogeneity was found in the analysis for myocardial infarction (I2=62.2%; P=0.02) and stroke (I2=52.5%; P=0.08). Aspirin significantly reduced the risk of myocardial infarction in men (0.57, 0.34 to 0.94) but not in women (1.08, 0.71 to 1.65; P for interaction=0.056). Evidence relating to harms was inconsistent.
Conclusions A clear benefit of aspirin in the primary prevention of major cardiovascular events in people with diabetes remains unproved. Sex may be an important effect modifier. Toxicity is to be explored further.
doi:10.1136/bmj.b4531
PMCID: PMC2774388  PMID: 19897665
5.  Lack of benefits for prevention of cardiovascular disease with aspirin therapy in type 2 diabetic patients - a longitudinal observational study 
Background
The risk-benefit ratio of aspirin therapy in prevention of cardiovascular disease (CVD) remains contentious, especially in type 2 diabetes. This study examined the benefit and harm of low-dose aspirin (daily dose < 300 mg) in patients with type 2 diabetes.
Methods
This is a longitudinal observational study with primary and secondary prevention cohorts based on history of CVD at enrolment. We compared the occurrence of primary composite (non-fatal myocardial infarction or stroke and vascular death) and secondary endpoints (upper GI bleeding and haemorrhagic stroke) between aspirin users and non-users between January 1995 and July 2005.
Results
Of the 6,454 patients (mean follow-up: median [IQR]: 4.7 [4.4] years), usage of aspirin was 18% (n = 1,034) in the primary prevention cohort (n = 5731) and 81% (n = 585) in the secondary prevention cohort (n = 723). After adjustment for covariates, in the primary prevention cohort, aspirin use was associated with a hazard-ratio of 2.07 (95% CI: 1.66, 2.59, p < 0.001) for primary endpoint. There was no difference in CVD event rate in the secondary prevention cohort. Overall, aspirin use was associated with a hazard-ratio of 2.2 (1.53, 3.15, p < 0.001) of GI bleeding and 1.71 (1.00, 2.95, p = 0.051) of haemorrhagic stroke. The absolute risk of aspirin-related GI bleeding was 10.7 events per 1,000 person-years of treatment.
Conclusion
In Chinese type 2 diabetic patients, low dose aspirin was associated with a paradoxical increase in CVD risk in primary prevention and did not confer benefits in secondary prevention. In addition, the risk of GI bleeding in aspirin users was rather high.
doi:10.1186/1475-2840-8-57
PMCID: PMC2777137  PMID: 19878541
6.  Aspirin effect on the incidence of major adverse cardiovascular events in patients with diabetes mellitus: a systematic review and meta-analysis 
Background
Aspirin has been recommended for the prevention of major adverse cardiovascular events (MACE, composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death) in diabetic patients without previous cardiovascular disease. However, recent meta-analyses have prompted re-evaluation of this practice. The study objective was to evaluate the relative and absolute benefits and harms of aspirin for the prevention of incident MACE in patients with diabetes.
Methods
We performed a systematic review and meta-analysis on seven studies (N = 11,618) reporting on the use of aspirin for the primary prevention of MACE in patients with diabetes. Two reviewers conducted a systematic search of electronic databases (MEDLINE, EMBASE, the Cochrane Library, and BIOSIS) and hand searched bibliographies and clinical trial registries. Reviewers extracted data in duplicate, evaluated the quality of the trials, and calculated pooled estimates.
Results
A total of 11,618 participants were included in the analysis. The overall risk ratio (RR) for MACE was 0.91 (95% confidence intervals, CI, 0.82-1.00) with little heterogeneity among trials (I2 0.0%). Secondary outcomes of interest included myocardial infarction (RR, 0.85; 95% CI, 0.66-1.10), stroke (RR, 0.84; 95% CI, 0.64-1.11), cardiovascular death (RR, 0.95; 95% CI, 0.71-1.27), and all-cause mortality (RR, 0.95; 95% CI, 0.85-1.06). There were higher rates of hemorrhagic and gastrointestinal events. In absolute terms, these relative risks indicate that for every 10,000 diabetic patients treated with aspirin, 109 MACE may be prevented at the expense of 19 major bleeding events (with the caveat that the relative risk for the latter is not statistically significant).
Conclusions
The studies reviewed suggest that aspirin reduces the risk of MACE in patients with diabetes without cardiovascular disease, while also causing a trend toward higher rates of bleeding and gastrointestinal complications. These findings and our absolute benefit and risk calculations suggest that those with diabetes but without cardiovascular disease lie somewhere between primary and secondary prevention patients on the spectrum of benefit and risk. This underscores the importance of considering individual risk in clinical decision making regarding aspirin in those with diabetes.
doi:10.1186/1475-2840-10-25
PMCID: PMC3098148  PMID: 21453547
7.  Paradoxical Effect of Aspirin 
Thrombosis  2012;2012:676237.
Low-dose aspirin is an important therapeutic option in the secondary prevention of myocardial infarction (MI) and ischemic stroke, basedon its unique cost-effectiveness and widespread availability. In addition, based on the results of a number of large studies, aspirin is also widely used in the primary prevention of MI. This paper provides an update of the available data to offer greater clarity regarding the risks of aspirin with respect to hemorrhagic stroke. In the secondary prevention of cardiovascular, cerebrovascular, and ischemic events, the evidence supports that the benefits of aspirin treatment significantly outweigh the risk of a major hemorrhage. When considering whether aspirin is appropriate, the absolute therapeutic cardiovascular benefits of aspirin must be balanced with the possible risks associated with its use, being hemorrhagic stroke. Regarding these clinical facts, normal, COX 1 −/−, and COX 2 −/− mice were treated with a wide range of doses of aspirin and studied by induced hemorrhagic time. The results outlined three major conclusions: high doses of aspirin induce hemorrhage, while low doses of aspirin do not. In the absence of COX 1, ultra low doses of aspirin produce an antihemorrhagic effect not observed with intermediate doses. The absence of COX 2 induced a hemorrhagic effect that needs further research, probably originated in compensatory phenomena.
doi:10.1155/2012/676237
PMCID: PMC3265119  PMID: 22292117
8.  Aspirin in Primary Prevention of Cardiovascular Disease and Cancer: A Systematic Review of the Balance of Evidence from Reviews of Randomized Trials 
PLoS ONE  2013;8(12):e81970.
Background
Aspirin has been recommended for primary prevention of cardiovascular disease (CVD) and cancer, but overall benefits are unclear. We aimed to use novel methods to re-evaluate the balance of benefits and harms of aspirin using evidence from randomised controlled trials, systematic reviews and meta-analyses.
Methods and Findings
Data sources included ten electronic bibliographic databases, contact with experts, and scrutiny of reference lists of included studies. Searches were undertaken in September 2012 and restricted to publications since 2008. Of 2,572 potentially relevant papers 27 met the inclusion criteria. Meta-analysis of control arms to estimate event rates, modelling of all-cause mortality and L'Abbé plots to estimate heterogeneity were undertaken. Absolute benefits and harms were low: 60-84 major CVD events and 34-36 colorectal cancer deaths per 100,000 person-years were averted, whereas 46-49 major bleeds and 68-117 gastrointestinal bleeds were incurred. Reductions in all-cause mortality were minor and uncertain (Hazard Ratio 0.96; 95% CI: 0.90-1.02 at 20 years, Relative Risk [RR] 0.94, 95% CI: 0.88-1.00 at 8 years); there was a non-significant change in total CVD (RR 0.85, 95% CI: 0.69-1.06) and change in total cancer mortality ranged from 0.76 (95% CI: 0.66-0.88) to 0.93 (95% CI: 0.84-1.03) depending on follow-up time and studies included. Risks were increased by 37% for gastrointestinal bleeds (RR 1.37, 95% CI: 1.15-1.62), 54%-66% for major bleeds (Rate Ratio from IPD analysis 1.54, 95% CI: 1.30-1.82, and RR 1.62, 95% CI: 1.31-2.00), and 32%-38% for haemorrhagic stroke (Rate Ratio from IPD analysis 1.32; 95% CI: 1.00-1.74; RR 1.38; 95% CI: 1.01-1.82).
Conclusions
Findings indicate small absolute effects of aspirin relative to the burden of these diseases. When aspirin is used for primary prevention of CVD the absolute harms exceed the benefits. Estimates of cancer benefit rely on selective retrospective re-analysis of RCTs and more information is needed.
doi:10.1371/journal.pone.0081970
PMCID: PMC3855368  PMID: 24339983
9.  Aspirin for primary prevention of vascular events in women: individualized prediction of treatment effects 
European Heart Journal  2011;32(23):2962-2969.
Aims
To identify women who benefit from aspirin 100 mg on alternate days for primary prevention of vascular events by using treatment effect prediction based on individual patient characteristics.
Methods and results
Randomized controlled trial data from the Women's Health Study were used to predict treatment effects for individual women in terms of absolute risk reduction for major cardiovascular events (i.e. myocardial infarction, stroke, or cardiovascular death). Predictions were based on existing risk scores, i.e. Framingham (FRS), and Reynolds (RRS), and on a newly developed prediction model. The net benefit of different aspirin treatment-strategies was compared: (i) treat no one, (ii) treat everyone, (iii) treatment according to the current guidelines (i.e. selective treatment of women >65 years of age or having >10% FRS), and (iv) prediction-based treatment (i.e. selective treatment of patients whose predicted treatment effect exceeds a given decision threshold). The predicted reduction in 10-year absolute risk for major cardiovascular events was <1% in 97.8% of 27 939 study subjects when based on the refitted FRS, in 97.0% when based on the refitted RRS, and in 90.0% when based on the newly developed model. Of the treatment strategies considered, only prediction-based treatment using the newly developed model and selective treatment of women >65 years of age yielded more net benefit than treating no one, provided that the 10-year number-willing-to-treat (NWT) to prevent one cardiovascular event was above 50.
Conclusion
Aspirin was ineffective or even harmful in the majority of patients. Age was positively related to treatment effect, whereas current smoking and baseline risk for cardiovascular events were not. When the NWT is 50 or lower, the aspirin treatment strategy that is associated with optimal net benefit in primary prevention of vascular events in women is to treat none.
Trial registration information: Clinicaltrials.gov identifier number: NCT00000479.
doi:10.1093/eurheartj/ehr423
PMCID: PMC3227855  PMID: 22090661
Aspirin; Primary prevention; Treatment effect prediction; Net benefit
10.  Effects of Combined Aspirin and Clopidogrel Therapy on Cardiovascular Outcomes: A Systematic Review and Meta-Analysis 
PLoS ONE  2012;7(2):e31642.
Background
Aspirin and clopidogrel monotherapies are effective treatments for preventing vascular disease. However, new evidence has emerged regarding the use of combined aspirin and clopidogrel therapy to prevent cardiovascular events. We therefore performed a comprehensive systematic review and meta-analysis to evaluate the benefits and harms of combined aspirin and clopidogrel therapy on major cardiovascular outcomes.
Methodology/Principal Findings
We systematically searched Medline, Embase, the Cochrane Central Register of Controlled Trials, reference lists of articles, and proceedings of major meetings to identify studies to fit our analysis. Eligible studies were randomized controlled trials assessing the effect of combined aspirin and clopidogrel therapy compared with aspirin or clopidogrel monotherapy. We identified 7 trials providing data with a total of 48248 patients. These studies reported 5134 major cardiovascular events, 1626 myocardial infarctions, 1927 strokes, and 1147 major bleeding events. Overall, the addition of aspirin to clopidogrel therapy as compared to single drug therapy resulted in a 9% RR reduction (95%CI, 2 to 17) in major cardiovascular events, 14% RR reduction (95%CI, 3 to 24) in myocardial infarction, 16% RR reduction (95%CI, 1 to 28) in stroke, and 62% RR increase (95%CI, 26 to 108) in major bleeding events. We also present the data as ARR to explore net value as the reduction in cardiovascular events. Overall, we observed that combined therapy yielded 1.06% decrease (95%CI, 0.23% to 1.99%) in major cardiovascular events and 1.23% increase (95%CI, 0.52% to 2.14%) in major bleeding events.
Conclusion/Significance
Although the addition of aspirin to clopidogrel resulted in small relative reductions in major cardiovascular events, myocardial infarction, and stroke, it also resulted in a relative increase in major bleeding events. In absolute terms the benefits of combined therapy, a 1.06% reduction in major cardiovascular events, does not outweigh the harms, a 1.23% increase in major bleeding events.
doi:10.1371/journal.pone.0031642
PMCID: PMC3278459  PMID: 22348116
11.  Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials 
Lancet  2009;373(9678):1849-1860.
Summary
Background
Low-dose aspirin is of definite and substantial net benefit for many people who already have occlusive vascular disease. We have assessed the benefits and risks in primary prevention.
Methods
We undertook meta-analyses of serious vascular events (myocardial infarction, stroke, or vascular death) and major bleeds in six primary prevention trials (95 000 individuals at low average risk, 660 000 person-years, 3554 serious vascular events) and 16 secondary prevention trials (17 000 individuals at high average risk, 43 000 person-years, 3306 serious vascular events) that compared long-term aspirin versus control. We report intention-to-treat analyses of first events during the scheduled treatment period.
Findings
In the primary prevention trials, aspirin allocation yielded a 12% proportional reduction in serious vascular events (0·51% aspirin vs 0·57% control per year, p=0·0001), due mainly to a reduction of about a fifth in non-fatal myocardial infarction (0·18% vs 0·23% per year, p<0·0001). The net effect on stroke was not significant (0·20% vs 0·21% per year, p=0·4: haemorrhagic stroke 0·04% vs 0·03%, p=0·05; other stroke 0·16% vs 0·18% per year, p=0·08). Vascular mortality did not differ significantly (0·19% vs 0·19% per year, p=0·7). Aspirin allocation increased major gastrointestinal and extracranial bleeds (0·10% vs 0·07% per year, p<0·0001), and the main risk factors for coronary disease were also risk factors for bleeding. In the secondary prevention trials, aspirin allocation yielded a greater absolute reduction in serious vascular events (6·7% vs 8·2% per year, p<0.0001), with a non-significant increase in haemorrhagic stroke but reductions of about a fifth in total stroke (2·08% vs 2·54% per year, p=0·002) and in coronary events (4·3% vs 5·3% per year, p<0·0001). In both primary and secondary prevention trials, the proportional reductions in the aggregate of all serious vascular events seemed similar for men and women.
Interpretation
In primary prevention without previous disease, aspirin is of uncertain net value as the reduction in occlusive events needs to be weighed against any increase in major bleeds. Further trials are in progress.
Funding
UK Medical Research Council, British Heart Foundation, Cancer Research UK, and the European Community Biomed Programme.
doi:10.1016/S0140-6736(09)60503-1
PMCID: PMC2715005  PMID: 19482214
12.  Discontinuation of low dose aspirin and risk of myocardial infarction: case-control study in UK primary care 
Objectives To evaluate the risk of myocardial infarction and death from coronary heart disease after discontinuation of low dose aspirin in primary care patients with a history of cardiovascular events.
Design Nested case-control study.
Setting The Health Improvement Network (THIN) database in the United Kingdom.
Participants Individuals aged 50-84 with a first prescription for aspirin (75-300 mg/day) for secondary prevention of cardiovascular outcomes in 2000-7 (n=39 513).
Main outcome measures Individuals were followed up for a mean of 3.2 years to identify cases of non-fatal myocardial infarction or death from coronary heart disease. A nested case-control analysis assessed the risk of these events in those who had stopped taking low dose aspirin compared with those who had continued treatment.
Results There were 876 non-fatal myocardial infarctions and 346 deaths from coronary heart disease. Compared with current users, people who had recently stopped taking aspirin had a significantly increased risk of non-fatal myocardial infarction or death from coronary heart disease combined (rate ratio 1.43, 95% confidence interval 1.12 to 1.84) and non-fatal myocardial infarction alone (1.63, 1.23 to 2.14). There was no significant association between recently stopping low dose aspirin and the risk of death from coronary heart disease (1.07, 0.67 to 1.69). For every 1000 patients, over a period of one year there were about four more cases of non-fatal myocardial infarction among patients who discontinued treatment with low dose aspirin (recent discontinuers) compared with patients who continued treatment.
Conclusions Individuals with a history of cardiovascular events who stop taking low dose aspirin are at increased risk of non-fatal myocardial infarction compared with those who continue treatment.
doi:10.1136/bmj.d4094
PMCID: PMC3139911  PMID: 21771831
13.  Clinical evidence for the use of aspirin in the treatment of cancer 
ecancermedicalscience  2013;7:297.
Although the anti-cancer effects of aspirin were first identified in pre-clinical models four decades ago, a clear role for the drug in either the prevention or treatment of cancer has not been established. Concerns about toxicity, particularly major haemorrhage, and a lack of randomised evidence demonstrating efficacy have limited its use in primary prevention; there was also doubt that a simple aspirin could have a significant therapeutic effect against established malignancy. Three new pieces of evidence: a series of meta-analyses focusing on cancer outcomes from randomised-controlled trials designed to assess the vascular benefits of daily aspirin; the first positive results from a randomised-controlled trial designed to demonstrate that aspirin can prevent cancer in those with a hereditary predisposition; and observational data showing that aspirin use after a cancer diagnosis improves both cancer mortality and overall survival; have led to a re-evaluation of aspirin as a potential anti-cancer agent both for the prevention and treatment of cancer.
doi:10.3332/ecancer.2013.297
PMCID: PMC3622409  PMID: 23589726
aspirin; cancer; treatment; toxicity; mechanisms
14.  Clinical Use of Aspirin in Treatment and Prevention of Cardiovascular Disease 
Thrombosis  2011;2012:245037.
Cardiovascular disease (CVD), principally heart disease and stroke, is the leading cause of death for both males and females in developed countries. Aspirin is the most widely used and tested antiplatelet drug in CVD, and it is proven to be the cornerstone of antiplatelet therapy in treatment and prevention of CVD in clinical trials in various populations. In acute coronary syndrome, thrombotic stroke, and Kawasaki's disease, acute use of aspirin can decrease mortality and recurrence of cardiovascular events. As secondary prevention, aspirin is believed to be effective in acute coronary syndrome, stable angina, revascularization, stroke, TIA, and atrial fibrillation. Aspirin may also be used for patients with a high risk of future CVD for primary prevention, but the balance between benefits and the possibility of side effects must be considered.
doi:10.1155/2012/245037
PMCID: PMC3236445  PMID: 22195280
15.  Use of Aspirin Among Diabetics in the Primary Prevention of Cardiovascular Disease: Need For Reliable Randomized Evidence and Astute Clinical Judgment 
Journal of General Internal Medicine  2009;24(11):1248-1250.
ABSTRACT
BACKGROUND
The American Heart Association Guidelines recommend aspirin for all apparently healthy individuals whose 10-year risk of a first coronary heart disease (CHD) event is >10%.
METHODS
The United States (US) Preventive Services Task Force (USPSTF) has recently updated its guidelines to encourage men 45 to 79 years and women 55 to 79 years to use aspirin when the potential benefit outweighs the potential harm. In addition, in some US guidelines, diabetes is considered to be a CHD risk equivalent.
RESULTS
Two recently published trials, the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) and the Prevention of Progression of Arterial Disease and Diabetes (POPADAD), concluded that aspirin did not reduce risks of CHD. Both JPAD and POPADAD had inadequate statistical power. Reliable randomized evidence is necessary to provide a sufficient totality of evidence about benefits and risks among diabetics.
CONCLUSION
At present, astute individual clinical judgments are necessary.
doi:10.1007/s11606-009-1095-5
PMCID: PMC2771233  PMID: 19771482
diabetes; cardiovascular disease; prevention; risk assessment; evidenced-based medicine
16.  Aspirin resistance: Fact or fiction? A point of view 
World Journal of Cardiology  2010;2(9):280-288.
Aspirin is a wonder drug that has been used for well over 100 years for its analgesic and antipyretic effects. For the past three decades, it has increasingly been used for the prevention of primary and secondary cardiovascular events. Lately, it has been suggested that a significant number of individuals taking aspirin have become resistant to this drug. The phenomenon of “aspirin resistance” is based on the observation of clinical events in some patients taking aspirin, and/or a diminished platelet aggregation inhibitory response to aspirin therapy. Unfortunately, laboratory assays used to monitor the efficacy of aspirin are far from accurate and the results are not reproducible. Furthermore, results of different platelet function tests are often not congruent. In addition, platelet aggregation studies show marked inter-individual and intra-individual variability. Patients with coronary heart disease take many drugs that interfere with the effect of aspirin on platelet aggregation. Besides inhibiting formation of thromboxane A2 from arachidonic acid, aspirin has a host of platelet-independent effects that complement its platelet inhibitory effects. Laboratory assays designed to measure platelet function do not take into account these pleiotropic effects of aspirin. In our view, use of the term “aspirin resistance” based on inadequate knowledge of imperfect laboratory tests does a disservice to physicians and patients.
doi:10.4330/wjc.v2.i9.280
PMCID: PMC2998828  PMID: 21160604
Aspirin; Cardiovascular diseases; Drug resistance; Treatment outcome
17.  Patient Preferences for the Chemoprevention of Colorectal Cancer 
Digestive diseases and sciences  2008;54(10):2207-2214.
Although evidence suggests that aspirin and celecoxib may reduce the risk of colorectal cancer (CRC), these drugs can also cause harmful side effects. The aim of this study was to characterize patient preferences for celecoxib and aspirin. Participants completed a computer-based patient decision-making questionnaire that included an educational component outlining the benefits and harms of celecoxib and aspirin. Under the base conditions 7.4% would take celecoxib and 43.6% would take aspirin; males were more willing than females to take aspirin. Patients identified the increased risk of myocardial infarction and gastrointestinal events as the primary reasons for their unwillingness to take celecoxib and aspirin, respectively. A majority of subjects would not take either drug, after considering their benefits and harms, although participants were almost six times more likely to take aspirin than celecoxib. These data serve to inform physicians and researchers regarding the variability and factors that affect patient preferences for CRC chemoprevention.
doi:10.1007/s10620-008-0609-z
PMCID: PMC3737565  PMID: 19057995
Colorectal cancer; Chemoprevention; Aspirin; Celecoxib; Patient preferences
18.  The role of aspirin in women’s health 
Background
The aim of this review is to discuss the role of aspirin for various conditions in women.
Methods
A nonsystematic review of articles published on PubMed® that examines the role of aspirin in women.
Results
Aspirin is associated with a significant reduction of stroke risk in women, which may be linked to age. However, despite this evidence, underutilization of aspirin in eligible women is reported. In women of reproductive age, it may also have a role to play in reducing early-onset preeclampsia and intrauterine growth restriction, and in the prevention of recurrent miscarriage in women with antiphospholipid antibodies; it may also reduce cardiovascular risk in associated systemic conditions such as lupus. Aspirin may reduce colorectal cancer risk in women, but its role in breast cancer warrants further data from controlled trials.
Conclusions
The risk–benefit threshold for aspirin use in women has been established for several conditions. Reasons why women are less likely to be prescribed aspirin have not been established, but the overall underuse of aspirin in women needs to be addressed.
doi:10.2147/IJWH.S18033
PMCID: PMC3140811  PMID: 21792337
CVD; cancer; menopause; preeclampsia
19.  Coronary and cardiovascular risk estimation for primary prevention: validation of a new Sheffield table in the 1995 Scottish health survey population 
BMJ : British Medical Journal  2000;320(7236):671-676.
Objective
To examine the accuracy of a new version of the Sheffield table designed to aid decisions on lipids screening and detect thresholds for risk of coronary heart disease needed to implement current guidelines for primary prevention of cardiovascular disease.
Design
Comparison of decisions made on the basis of the table with absolute risk of coronary heart disease or cardiovascular disease calculated by the Framingham risk function. The decisions related to statin treatment when coronary risk is ⩾30% over 10 years; aspirin treatment when the risk is ⩾15% over 10 years; and the treatment of mild hypertension when the cardiovascular risk is ⩾20% over 10 years.
Setting
The table is designed for use in general practice.
Subjects
Random sample of 1000 people aged 35-64 years from the 1995 Scottish health survey.
Main outcome measures
Sensitivity, specificity, and positive and negative predictive values of the table.
Results
13% of people had a coronary risk of ⩾15%, and 2.2% a risk of ⩾30%, over 10 years. 22% had mild hypertension (systolic blood pressure 140-159 mm Hg). The table indicated lipids screening for everyone with a coronary risk of ⩾15% over 10 years, for 95% of people with a ratio of total cholesterol to high density lipoprotein cholesterol of ⩾8.0, but for <50% with a coronary risk of <5% over 10 years. Sensitivity and specificity were 97% and 95% respectively for a coronary risk of ⩾15% over 10 years; 82% and 99% for a coronary risk of ⩾30% over 10 years; and 88% and 90% for a cardiovascular risk of ⩾20% over 10 years in mild hypertension.
Conclusion
The table identifies all high risk people for lipids screening, reduces screening of low risk people by more than half, and ensures that treatments are prescribed appropriately to those at high risk, while avoiding inappropriate treatment of people at low risk.
PMCID: PMC27307  PMID: 10710573
20.  Migraine and Cardiovascular Disease in Women: the Role of Aspirin – Subgroup Analyses in the Women’s Health Study 
Background
Migraine with aura (MA) has been associated with increased risk of cardiovascular disease (CVD). The role of aspirin on this association remains unclear.
Methods
Post-hoc subgroup analyses of the Women’s Health Study, a randomized trial testing 100mg aspirin on alternate days in primary prevention of CVD among 39,876 women aged ≥45.
Results
During 10 years, 998 major CVD events were confirmed in 39,757 women with complete migraine information. Aspirin reduced risk of ischemic stroke (RR=0.76; 95%CI=0.63–0.93) but not other CVD. Migraine or MA did not modify the effect of aspirin on CVD except for myocardial infarction (MI) (p-interaction=0.01). Women with MA on aspirin had increased risk of MI (RR=3.72, 95%CI=1.39–9.95). Further exploratory analyses indicate this is only apparent among women with MA on aspirin who ever smoked or had history of hypertension (p-interaction<0.01).
Conclusion
In post-hoc subgroup analyses, aspirin had similar protective effects on ischemic stroke for women with or without migraine. By contrast, our data suggest that women with MA on aspirin had increased risk of MI. The small number of outcome events in subgroups, the exploratory nature of our analyses, and lack of plausible mechanisms raise the possibility of a chance finding, which must caution the interpretation.
doi:10.1177/0333102411412628
PMCID: PMC3143294  PMID: 21673005
21.  Targeted use of heparin, heparinoids, or low-molecular-weight heparin to improve outcome after acute ischaemic stroke: an individual patient data meta-analysis of randomised controlled trials 
Lancet Neurology  2013;12(6):539-545.
Summary
Background
Many international guidelines on the prevention of venous thromboembolism recommend targeting heparin treatment at patients with stroke who have a high risk of venous thrombotic events or a low risk of haemorrhagic events. We sought to identify reliable methods to target anticoagulant treatment and so improve the chance of avoiding death or dependence after stroke.
Methods
We obtained individual patient data from the five largest randomised controlled trials in acute ischaemic stroke that compared heparins (unfractionated heparin, heparinoids, or low-molecular-weight heparin) with aspirin or placebo. We developed and evaluated statistical models for the prediction of thrombotic events (myocardial infarction, stroke, deep vein thrombosis, or pulmonary embolism) and haemorrhagic events (symptomatic intracranial or significant extracranial) in the first 14 days after stroke. We calculated the absolute risk difference for the outcome “dead or dependent” in patients grouped by quartiles of predicted risk of thrombotic and haemorrhagic events with random effect meta-analysis.
Findings
Patients with ischaemic stroke who were of advanced age, had increased neurological impairment, or had atrial fibrillation had a high risk of both thrombotic and haemorrhagic events after stroke. Additionally, patients with CT-visible evidence of recent cerebral ischaemia were at increased risk of thrombotic events. In evaluation datasets, the area under a receiver operating curve for prediction models for thrombotic events was 0·63 (95% CI 0·59–0·67) and for haemorrhagic events was 0·60 (0·55–0·64). We found no evidence that the net benefit from heparins increased with either increasing risk of thrombotic events or decreasing risk of haemorrhagic events.
Interpretation
There was no evidence that patients with ischaemic stroke who were at higher risk of thrombotic events or lower risk of haemorrhagic events benefited from heparins. We were therefore unable to define a targeted approach to select the patients who would benefit from treatment with early anticoagulant therapy. We recommend that guidelines for routine or selective use of heparin in stroke should be revised.
Funding
MRC.
doi:10.1016/S1474-4422(13)70079-6
PMCID: PMC3671273  PMID: 23642343
22.  Aspirin for Primary Prevention of Cardiovascular Events 
OBJECTIVE
The use of aspirin for primary prevention of cardiovascular events in the general population is controversial. The purpose of this study was to create a versatile model to evaluate the effects of aspirin in the primary prevention of cardiovascular events in patients with different risk profiles.
DESIGN
A Markov decision-analytic model evaluated the expected length and quality of life for the cohort's next 10 years as measured by quality-adjusted survival for the options of taking or not taking aspirin.
SETTING
Hypothetical model of patients in a primary care setting.
PATIENTS
Several cohorts of patients with a range of risk profiles typically seen in a primary care setting were considered. Risk factors considered included gender, age, cholesterol levels, systolic blood pressure, smoking status, diabetes, and presence of left ventricular hypertrophy. The cohorts were followed for 10 years. Outcomes were myocardial infarction, stroke, gastrointestinal bleed, ulcer, and death.
MAIN RESULTS
For the cases considered, the effects of aspirin varied according to the cohort's risk profile. By taking aspirin, the lowest-risk cohort would be the most harmed with a loss of 1.8 quality-adjusted life days by taking aspirin; the highest risk cohort would achieve the most benefit with a gain of 11.3 quality-adjusted life days. Results without quality adjustment favored taking aspirin in all the cohorts, with a gain of 0.73 to 8.04 days. The decision was extremely sensitive to variations in the utility of taking aspirin and to aspirin's effects on cardiovascular mortality. The model was robust to other probability and utility changes within reasonable parameters.
CONCLUSIONS
The decision of whether to take aspirin as primary prevention for cardiovascular events depends on patient risk. It is a harmful intervention for patients with no risk factors, and it is beneficial in moderate and high-risk patients. The benefits of aspirin in this population are comparable to those of other widely accepted preventive strategies. It is especially dependent on the patient's risk profile, patient preferences for the adverse effects of aspirin, and on the level of beneficial effects of aspirin on cardiovascular-related mortality.
doi:10.1046/j.1525-1497.1998.00246.x
PMCID: PMC1497039  PMID: 9844080
aspirin; primary prevention; cardiovascular disease; decision analysis; risk stratification
23.  Underutilization of Aspirin Persists in US Ambulatory Care for the Secondary and Primary Prevention of Cardiovascular Disease 
PLoS Medicine  2005;2(12):e353.
Background
Despite the proven benefits of aspirin therapy in the primary and secondary prevention of cardiovascular disease (CVD), utilization rates of aspirin remain suboptimal in relation to recommendations. We studied national trends of aspirin use among intermediate- to high-risk patients in the US ambulatory care settings and compared the priority given to aspirin versus statins for CVD risk reduction. We also examined patient and health care provider contributors to the underuse of aspirin.
Methods and Findings
We used the 1993–2003 US National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey to estimate aspirin use by cardiovascular risk. Physician-noted cardiovascular diseases defined high risk. Intermediate risk was defined as having diabetes mellitus or multiple major risk factors. The proportion of patient visits in which aspirin was reported increased from 21.7% (95% confidence interval: 18.8%–24.6%) in 1993–1994 to 32.8% (25.2%–40.4%) in 2003 for the high-risk category, 3.5% (2.0%–5.0%) to 11.7% (7.8%–15.7%) for visits by patients diagnosed with diabetes, and 3.6% (2.6%–4.6%) to 16.3% (11.4%–21.2%) for those with multiple CVD risk factors. Beginning in 1997–1998, statins were prioritized over aspirin as prophylactic therapy for reducing CVD risk, and the gaps remained wide through 2003. In addition to elevated CVD risk, greater aspirin use was independently associated with advanced age, male gender, cardiologist care, and care in hospital outpatient departments.
Conclusion
Improvements in use of aspirin in US ambulatory care for reducing risks of CVD were at best modest during the period under study, particularly for secondary prevention, where the strongest evidence and most explicit guidelines exist. Aspirin is more underused than statins despite its more favorable cost-effectiveness. Aggressive and targeted interventions are needed to enhance provider and patient adherence to consensus guidelines for CVD risk reduction.
Aspirin is underused compared with statins especially for secondary prevention of cardiovascular disease, despite being more cost-effective.
doi:10.1371/journal.pmed.0020353
PMCID: PMC1283363  PMID: 16277554
24.  Hyperuricemia and untreated gout are poor prognostic markers among those with a recent acute myocardial infarction 
Introduction
Patients with a history of myocardial infarction (MI) are often at risk for complications, including subsequent MI and death. Use of prognostic markers may aid in preventing these poor outcomes. Hyperuricemia is associated with increased risk for coronary heart disease (CHD) and/or mortality; however, it is unknown if serum urate (sUA) levels predict outcomes in patients with previous MI. The purpose of this study was to assess hyperuricemia as a biomarker of CHD outcomes in such patients.
Methods
These were post hoc analyses of datasets from the Aspirin Myocardial Infarction Study, a 1:1 randomized, double-blind clinical trial, conducted from 1975 to 1979, that examined mortality rates following daily aspirin administration over three years in individuals with documented MI. The primary outcome measures were all-cause death, CHD mortality, coronary incidence, and stroke by quartile of baseline sUA. A sub-analysis of all outcome measures in the presence or absence of gouty arthritis was also performed.
Results
Of 4,524 enrolled participants, data on 4,352 were analyzed here. All outcomes were greatest for patients in the fourth sUA quartile. In multivariate regression models, the hazard ratios (HR) for patients in the highest quartile were 1.88 for all-cause mortality (95% confidence interval (CI), 1.45 to 2.46), 1.99 for CHD mortality (95% CI, 1.49 to 2.66), and 1.36 for coronary incidence (95% CI, 1.08 to 1.70). Participants with untreated gout had an adjusted hazard ratio ranging from 1.5 to 2.0 (all P < 0.01) for these outcomes. Participants with gout who were receiving treatment did not exhibit this additional risk.
Conclusions
sUA and untreated gout may be independent prognostic markers for poor all-cause and CHD mortality in patients with recent acute MI.
doi:10.1186/ar3684
PMCID: PMC3392798  PMID: 22251426
25.  Epidemiological modelling of routine use of low dose aspirin for the primary prevention of coronary heart disease and stroke in those aged ≥70 
BMJ : British Medical Journal  2005;330(7503):1306.
Objective To investigate the routine use of low dose aspirin in people aged ≥ 70 without overt cardiovascular disease.
Design Epidemiological modelling in a hypothetical population.
Setting Reference populations of men and women in the year 2000 from the state of Victoria, Australia.
Subjects 10 000 men and 10 000 women aged 70-74 with no cardiovascular disease.
Main outcome measures First ever myocardial infarction or unstable angina, ischaemic or haemorrhagic stroke, and major gastrointestinal haemorrhage. Health adjusted years of life lived.
Results The proportional benefit gained from the use of low dose aspirin by the prevention of myocardial infarctions (-389 in men, -321 in women) and ischaemic stroke (-19 in men and -35 in women) is offset by excess gastrointestinal (499 in men, 572 in women) and intracranial (76 in men, 54 in women) bleeding. The results in health adjusted years of life lived (which take into account length and quality of life) are equivocal for aspirin causing net harm or net benefit.
Conclusion Epidemiological modelling suggests that any benefits of low dose aspirin on risk of cardiovascular disease in people aged ≥ 70 are offset by adverse events. These findings are tempered by wide confidence intervals, indicating that the overall outcome could be beneficial or adverse.
doi:10.1136/bmj.38456.676806.8F
PMCID: PMC558207  PMID: 15908442

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