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1.  Secondary prevention of ischaemic cardiac events 
Clinical Evidence  2011;2011:0206.
Introduction
Coronary artery disease is the leading cause of mortality in resource-rich countries, and is becoming a major cause of morbidity and mortality in resource-poor countries. Secondary prevention in this context is long-term treatment to prevent recurrent cardiac morbidity and mortality in people who have had either a prior acute myocardial infarction (MI) or acute coronary syndrome, or who are at high risk due to severe coronary artery stenoses or prior coronary surgical procedures. Secondary prevention in people with an acute MI or acute coronary syndrome within the past 6 months is not included.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of antithrombotic treatment; other drug treatments; cholesterol reduction; blood pressure reduction; non-drug treatments; and revascularisation procedures? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 137 systematic reviews or RCTs that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: advice to eat less fat, advice to eat more fibre, advice to increase consumption of fish oils, amiodarone, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, angiotensin II receptor blockers plus ACE inhibitors, antioxidant vitamin combinations, antiplatelet agents, aspirin, beta-blockers, beta-carotene, blood pressure reduction, calcium channel blockers, cardiac rehabilitation including exercise, class I antiarrhythmic agents, coronary artery bypass grafting (CABG), fibrates, hormone replacement therapy (HRT), Mediterranean diet, multivitamins, non-specific cholesterol reduction, oral anticoagulants, oral glycoprotein IIb/IIIa receptor inhibitors, percutaneous coronary intervention (PCI), psychosocial treatment, smoking cessation, statins, vitamin C, and vitamin E.
Key Points
Coronary artery disease is the leading cause of mortality in resource-rich countries, and is becoming a major cause of morbidity and mortality in resource-poor countries. Secondary prevention in this context is long-term treatment to prevent recurrent cardiac morbidity and mortality in people who have had either a prior MI or acute coronary syndrome, or who are at high risk due to severe coronary artery stenoses or prior coronary surgical procedures.
Of the antithrombotic treatments, there is good evidence that aspirin (especially combined with clopidogrel in people with acute coronary syndromes or MI), clopidogrel (more effective than aspirin), and anticoagulants all effectively reduce the risk of cardiovascular events. Oral anticoagulants substantially increase the risk of haemorrhage. These risks may outweigh the benefits when combined with antiplatelet treatments.Adding oral glycoprotein IIb/IIIa receptor inhibitors to aspirin seems to increase the risk of mortality compared with aspirin alone.
Other drug treatments that reduce mortality include beta-blockers (after MI and in people with left ventricular dysfunction), ACE inhibitors (in people at high risk, after MI, or with left ventricular dysfunction), and amiodarone (in people with MI and high risk of death from cardiac arrhythmia). There is conflicting evidence on the effect of calcium channel blockers. Some types may be effective at reducing mortality in the absence of heart failure, whereas others may be harmful.Contrary to decades of large observational studies, multiple RCTs show no cardiac benefit from HRT in postmenopausal women.
Lipid-lowering treatments effectively reduce the risk of cardiovascular mortality and non-fatal cardiovascular events in people with CHD.
There is good evidence that statins reduce the risk of mortality and cardiac events in people at high risk, but the evidence is less clear for fibrates.
The magnitude of cardiovascular risk reduction in people with coronary artery disease correlates directly with the magnitude of blood pressure reduction.
Cardiac rehabilitation (including exercise) and smoking cessation reduce the risk of cardiac events in people with CHD. Antioxidant vitamins (such as vitamin E, beta-carotene, or vitamin C) have no effect on cardiovascular events in high-risk people, and in some cases may actually increase risk of cardiac mortality.We don't know whether changing diet alters the risk of cardiac episodes, although a Mediterranean diet may have some survival benefit over a Western diet. Advice to increase fish oil consumption or fish oil consumption may be beneficial in some population groups. However, evidence was weak.Some psychological interventions may be more effective than usual care at improving some cardiovascular outcomes. However, evidence was inconsistent.
In selected people, such as those with more-extensive coronary disease and impaired left ventricular function, CABG may improve survival compared with an initial strategy of medical treatment. We don't know how PTCA compares with medical treatment.
We found no consistent difference in mortality or recurrent MI between CABG and PTCA with or without stenting, because of varied results among subgroups and insufficient evidence on stenting when comparing the interventions. CABG may be more effective than PTCA with or without stenting at reducing some composite outcomes, particularly those including repeat revascularisation rates. PTCA with stenting may be more effective than PTCA alone.
PMCID: PMC3217663  PMID: 21875445
2.  Effect of Aspirin Dose on Mortality and Cardiovascular Events in People with Diabetes: A Meta-Analysis 
Journal of General Internal Medicine  2011;26(11):1336-1344.
Objectives
Pharmacologic evidence suggests adequate antiplatelet activity in diabetic patients requires >100 mg aspirin daily, yet recent trials have used ≤100 mg daily. This meta-analysis explored the relationship between aspirin dose and prevention of cardiovascular events.
Data Sources
Six electronic databases were searched using database-appropriate terms for aspirin, diabetes, and comparative study from inception until February 2010.
Review Methods
Randomized controlled trials and cohort studies comparing aspirin to no antiplatelet therapy were included if they reported cardiovascular events as pre-specified outcomes, aspirin dose, and number of diabetic patients. Studies were stratified by daily aspirin dose (≤100 mg; 101–325 mg; >325 mg) and pooled risk ratios (RR) were calculated using random effects models. All-cause mortality was the primary outcome of interest. Cardiovascular-related mortality, myocardial infarction, and stroke were secondary outcomes.
Results
Data for diabetic patients were available from 21 studies (n = 17,522). Overall, 1,172 (15.4%) of 7,592 aspirin users and 1,520 (18.4%) of 8,269 controls died (p = 0.31). The pooled RRs were 0.89 (95% CI: 0.72–1.10; p = 0.27) from 13 studies using ≤100 mg (I2 = 64%); 0.89 (95% CI: 0.61–1.30; p = 0.55) from four studies using 101–325 mg (I2 = 83%); and 0.96 (95% CI: 0.85–1.08; p = 0.50) from eight studies using >325 mg (I2 = 0%). Aspirin use was associated with a significantly lower risk of mortality (RR: 0.82; 95% CI: 0.69–0.98; p = 0.03) in 13 secondary prevention studies (I2 = 27%), whereas aspirin use in seven primary prevention studies (I2 = 0%) was not (RR: 1.01; 95% CI 0.85–1.19; p = 0.94). A substantial amount of heterogeneity was observed amongst studies in all outcomes. Although inclusion of cohort studies was a major source of heterogeneity, stratification by study design did not reveal a significant dose-response relationship.
Conclusions/Interpretation
This summary of available data does not support an aspirin dose-response effect for prevention of cardiovascular events in diabetic patients. However, the systematic review identified an important gap in randomized controlled trial evidence for using 101–325 mg aspirin daily in diabetes.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-011-1757-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s11606-011-1757-y
PMCID: PMC3208465  PMID: 21647746
aspirin; diabetes; mortality; myocardial infarction; stroke
3.  Secondary prevention of ischaemic cardiac events 
Clinical Evidence  2009;2009:0206.
Introduction
Coronary artery disease is the leading cause of mortality in resource-rich countries, and is becoming a major cause of morbidity and mortality in resource-poor countries. Secondary prevention in this context is long-term treatment to prevent recurrent cardiac morbidity and mortality in people who have had either a prior acute myocardial infarction (MI) or acute coronary syndrome, or who are at high risk due to severe coronary artery stenoses or prior coronary surgical procedures.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of antithrombotic treatment; other drug treatments; cholesterol reduction; blood pressure reduction; non-drug treatments; and revascularisation procedures? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 154 systematic reviews or RCTs that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review. we present information relating to the effectiveness and safety of the following interventions: advice to eat less fat; advice to eat more fibre; advice to increase consumption of fish oils; amiodarone; angiotensin-converting enzyme (ACE) inhibitors; angiotensin II receptor blockers; angiotensin II receptor blockers plus ACE inhibitors; antioxidant vitamin combinations; antiplatelet agents; beta-blockers; beta-carotene; blood pressure reduction; calcium channel blockers; cardiac rehabilitation including exercise; class I antiarrhythmic agents; coronary artery bypass grafting (CABG); percutaneous coronary intervention (PCI); fibrates; hormone replacement therapy (HRT); Mediterranean diet; multivitamins; non-specific cholesterol reduction; oral anticoagulants; oral glycoprotein IIb/IIIa receptor inhibitors; psychosocial treatment; smoking cessation; statins; vitamin C; and vitamin E.
Key Points
Coronary artery disease is the leading cause of mortality in resource-rich countries, and is becoming a major cause of morbidity and mortality in resource-poor countries. Secondary prevention in this context is long-term treatment to prevent recurrent cardiac morbidity and mortality in people who have had either a prior MI or acute coronary syndrome, or who are at high risk due to severe coronary artery stenoses or prior coronary surgical procedures.
Of the antithrombotic treatments, there is good evidence that aspirin (especially combined with clopidogrel in people with acute coronary syndromes or MI), clopidogrel (more effective than aspirin), and anticoagulants all effectively reduce the risk of cardiovascular events. Oral anticoagulants substantially increase the risk of haemorrhage. These risks may outweigh the benefits when combined with antiplatelet treatments. Adding oral glycoprotein IIb/IIIa receptor inhibitors to aspirin seems to increase the risk of mortality compared with aspirin alone.
Other drug treatments that reduce mortality include beta-blockers (after MI and in people with left ventricular dysfunction), ACE inhibitors (in people at high risk, after MI, or with left ventricular dysfunction), angiotensin II receptor blockers (in people with coronary artery disease), and amiodarone (in people with MI and high risk of death from cardiac arrhythmia). There is conflicting evidence on the effect of calcium channel blockers. Some types may be effective at reducing mortality in the absence of heart failure, whereas other may be harmful.Contrary to decades of large observational studies, multiple RCTs show no cardiac benefit from HRT in postmenopausal women.
Lipid-lowering treatments effectively reduce the risk of cardiovascular mortality and non-fatal cardiovascular events in people with CHD.
There is good evidence that statins reduce the risk of mortality and cardiac events in people at high risk, but the evidence is less clear for fibrates.
The magnitude of cardiovascular risk reduction in people with coronary artery disease correlates directly with the magnitude of blood pressure reduction.
Cardiac rehabilitation (including exercise), and smoking cessation all reduce the risk of cardiac events in people with CHD. Antioxidant vitamins (such as vitamin E, beta-carotene, or vitamin C) have no effect on cardiovascular events in high-risk people, and in some cases may actually increase risk of cardiac mortality.We don't know whether changing diet alters the risk of cardiac episodes, although a Mediterranean diet may have some survival benefit over a Western diet.
In selected people, such as those with more-extensive coronary disease and impaired left ventricular function, CABG may improve survival compared with an initial strategy of medical treatment. We don't know how PTCA compares with medical treatment.
We found no consistent difference in mortality or recurrent MI between CABG and PTCA with or without stenting,due to varied results among subgroups and insufficient evidence on stenting when comparing the interventions. PTCA with stenting may be more effective than PTCA alone.
PMCID: PMC2907785
4.  Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients 
BMJ : British Medical Journal  2002;324(7329):71-86.
Objective
To determine the effects of antiplatelet therapy among patients at high risk of occlusive vascular events.
Design
Collaborative meta-analyses (systematic overviews).
Inclusion criteria
Randomised trials of an antiplatelet regimen versus control or of one antiplatelet regimen versus another in high risk patients (with acute or previous vascular disease or some other predisposing condition) from which results were available before September 1997. Trials had to use a method of randomisation that precluded prior knowledge of the next treatment to be allocated and comparisons had to be unconfounded—that is, have study groups that differed only in terms of antiplatelet regimen.
Studies reviewed
287 studies involving 135 000 patients in comparisons of antiplatelet therapy versus control and 77 000 in comparisons of different antiplatelet regimens.
Main outcome measure
“Serious vascular event”: non-fatal myocardial infarction, non-fatal stroke, or vascular death.
Results
Overall, among these high risk patients, allocation to antiplatelet therapy reduced the combined outcome of any serious vascular event by about one quarter; non-fatal myocardial infarction was reduced by one third, non-fatal stroke by one quarter, and vascular mortality by one sixth (with no apparent adverse effect on other deaths). Absolute reductions in the risk of having a serious vascular event were 36 (SE 5) per 1000 treated for two years among patients with previous myocardial infarction; 38 (5) per 1000 patients treated for one month among patients with acute myocardial infarction; 36 (6) per 1000 treated for two years among those with previous stroke or transient ischaemic attack; 9 (3) per 1000 treated for three weeks among those with acute stroke; and 22 (3) per 1000 treated for two years among other high risk patients (with separately significant results for those with stable angina (P=0.0005), peripheral arterial disease (P=0.004), and atrial fibrillation (P=0.01)). In each of these high risk categories, the absolute benefits substantially outweighed the absolute risks of major extracranial bleeding. Aspirin was the most widely studied antiplatelet drug, with doses of 75-150 mg daily at least as effective as higher daily doses. The effects of doses lower than 75 mg daily were less certain. Clopidogrel reduced serious vascular events by 10% (4%) compared with aspirin, which was similar to the 12% (7%) reduction observed with its analogue ticlopidine. Addition of dipyridamole to aspirin produced no significant further reduction in vascular events compared with aspirin alone. Among patients at high risk of immediate coronary occlusion, short term addition of an intravenous glycoprotein IIb/IIIa antagonist to aspirin prevented a further 20 (4) vascular events per 1000 (P<0.0001) but caused 23 major (but rarely fatal) extracranial bleeds per 1000.
Conclusions
Aspirin (or another oral antiplatelet drug) is protective in most types of patient at increased risk of occlusive vascular events, including those with an acute myocardial infarction or ischaemic stroke, unstable or stable angina, previous myocardial infarction, stroke or cerebral ischaemia, peripheral arterial disease, or atrial fibrillation. Low dose aspirin (75-150 mg daily) is an effective antiplatelet regimen for long term use, but in acute settings an initial loading dose of at least 150 mg aspirin may be required. Adding a second antiplatelet drug to aspirin may produce additional benefits in some clinical circumstances, but more research into this strategy is needed.
What is already known on this topicAntiplatelet therapy is effective for short term treatment of patients with suspected acute myocardial infarction and unstable anginaLong term treatment is beneficial for patients who have had a myocardial infarction, stroke, or transient ischaemic attackDaily aspirin doses of 75-325 mg are effectiveWhat this study addsAntiplatelet therapy protects against vascular events among patients with stable angina, intermittent claudication, and (if oral anticoagulants are unsuitable) atrial fibrillationAntiplatelet therapy can be started promptly during acute presumed ischaemic stroke and continued long termDaily aspirin doses of 75-150 mg seem to be as effective as higher doses for long term treatments (and clopidrogel is an appropriate alternative for patients with a contraindication to aspirin)Short term addition of a glycoprotein IIb/IIIa antagonist to aspirin prevents vascular events in patients having percutaneous coronary intervention and those with unstable angina but causes increased bleeding
PMCID: PMC64503  PMID: 11786451
5.  Long-term Use of Aspirin and Nonsteroidal Anti-inflammatory Drugs and Risk of Colorectal Cancer 
Context
Randomized trials of short-term aspirin use for prevention of recurrent colorectal adenoma have provided compelling evidence of a causal relationship between aspirin and colorectal neoplasia. However, data on long-term risk of colorectal cancer according to dose, timing, or duration of therapy with aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) remain limited.
Objective
To examine the influence of aspirin and NSAIDs in prevention of colorectal cancer.
Design, Setting, and Participants
Prospective cohort study of 82 911 women enrolled in the Nurses’ Health Study providing data on medication use biennially since 1980 and followed up through June 1, 2000.
Main Outcome Measure
Incident colorectal cancer.
Results
Over a 20-year period, we documented 962 cases of colorectal cancer. Among women who regularly used aspirin (≥2 standard [325-mg] tablets per week), the multivariate relative risk (RR) for colorectal cancer was 0.77 (95% confidence interval [CI], 0.67–0.88) compared with nonregular users. However, significant risk reduction was not observed until more than 10 years of use (P≤.001 for trend). The benefit appeared related to dose: compared with women who reported no use, the multivariate RRs for cancer were 1.10 (95% CI, 0.92–1.31) for women who used 0.5 to 1.5 standard aspirin tablets per week, 0.89 (95% CI, 0.73–1.10) for 2 to 5 aspirin per week, 0.78 (95% CI, 0.62–0.97) for 6 to 14 aspirin per week, and 0.68 (95% CI, 0.49–0.95) for more than 14 aspirin per week (P<.001 for trend). Notably, women who used more than 14 aspirin per week for longer than 10 years in the past had a multivariate RR for cancer of 0.47 (95% CI, 0.31–0.71). A similar dose-response relationship was found for nonaspirin NSAIDs (P=.007 for trend). The incidence of reported major gastrointestinal bleeding events per 1000 person-years also appeared to be dose-related: 0.77 among women who denied any aspirin use; 1.07 for 0.5 to 1.5 standard aspirin tablets per week; 1.07 for 2 to 5 aspirin per week; 1.40 for 6 to 14 aspirin per week; and 1.57 for more than 14 aspirin per week.
Conclusions
Regular, long-term aspirin use reduces risk of colorectal cancer. Non-aspirin NSAIDs appear to have a similar effect. However, a significant benefit of aspirin is not apparent until more than a decade of use, with maximal risk reduction at doses greater than 14 tablets per week. These results suggest that optimal chemoprevention for colorectal cancer requires long-term use of aspirin doses substantially higher than those recommended for prevention of cardiovascular disease, but the dose-related risk of gastrointestinal bleeding must also be considered.
doi:10.1001/jama.294.8.914
PMCID: PMC1550973  PMID: 16118381
6.  Adherence to statin or aspirin or both in patients with established cardiovascular disease: exploring healthy behaviour vs. drug effects and 10-year follow-up of outcome 
Aims
To characterize adherence in patients with established cardiovascular disease taking statins and aspirin and to estimate the effects of adherence due to health behaviour, a lack of beneficial drug effect, or both on recurrence of cardiovascular disease or all-cause mortality over 10 years.
Methods
A population-based cohort study using a record-linkage database in Tayside, Scotland. Subjects with cardiovascular disease (n = 7657; 4185 aspirin-alone cohort, 671 statin-alone cohort and 2801 combination use cohort) were studied between 1993 and 2003. The effects of adherence on recurrence of cardiovascular disease or mortality were assessed using Poisson regression model.
Results
In subjects taking both aspirin and statins, those adherent to statins but not aspirin had a lower risk of recurrence [adjusted risk ratio (RR) 0.64; 95% confidence interval 0.49, 0.82], but those adherent to aspirin but not statins has no such effect (adjusted RR 0.91; 0.72, 1.15), suggesting that adherence behaviour alone was not responsible for the beneficial effect. Within the group adherent to aspirin, ≥80% adherence to statins was associated with reduced recurrence compared with those poorly adherent (adjusted RR 0.76; 0.62, 0.94), but no such effect of aspirin was seen in those adherent to statins. Similar results were found for all-cause mortality.
Conclusions
Poor health behaviour is not a sufficient explanation of adverse outcome in poorly adherent patients. Adverse outcome is more likely to be driven by foregone drug benefits.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Aspirin and statins are widely-used drugs in patients with cardiovascular disease.There is less information on healthy behaviour vs. drug effects.
WHAT THIS STUDY ADDS Long-term adherence to aspirin and statin treatments in patients with established cardiovascular disease has been investigated.Poor health behaviour is not a sufficient explanation of adverse outcome in poorly adherent patients.
doi:10.1111/j.1365-2125.2008.03212.x
PMCID: PMC2485263  PMID: 18492127
aspirin; cardiovascular recurrence; long-term adherence; statin
7.  Circulating Myeloid‐Related Protein–8/14 is Related to Thromboxane‐Dependent Platelet Activation in Patients With Acute Coronary Syndrome, With and Without Ongoing Low‐Dose Aspirin Treatment 
Background
Platelet activation is involved in acute coronary syndromes (ACS). Incomplete suppression by low‐dose aspirin treatment of thromboxane (TX) metabolite excretion (urinary 11‐dehydro‐TXB2) is predictive of vascular events in high‐risk patients. Myeloid‐related protein (MRP)‐8/14 is a heterodimer secreted on activation of platelets, monocytes, and neutrophils, regulating inflammation and predicting cardiovascular events. Among platelet transcripts, MRP‐14 has emerged as a powerful predictor of ACS.
Methods and Results
We enrolled 68 stable ischemic heart disease (IHD) and 63 ACS patients, undergoing coronary angiography, to evaluate whether MRP‐8/14 release in the circulation is related to TX‐dependent platelet activation in ACS and IHD patients and to residual TX biosynthesis in low‐dose aspirin–treated ACS patients. In ACS patients, plasma MRP‐8/14 and urinary 11‐dehydro‐TXB2 levels were linearly correlated (r=0.651, P<0.001) but significantly higher than those in IHD patients (P=0.012, P=0.044) only among subjects not receiving aspirin. In aspirin‐treated ACS patients, MRP‐8/14 and 11‐dehydro‐TXB2 were lower versus those not receiving aspirin (P<0.001) and still significantly correlated (r=0.528, P<0.001). Higher 11‐dehydro‐TXB2 significantly predicted higher MRP‐8/14 in both all ACS patients and ACS receiving aspirin (P<0.001, adj R2=0.463 and adj R2=0.497) after multivariable adjustment. Conversely, plasma MRP‐8/14 (P<0.001) and higher urinary 8‐iso‐prostaglandin F2α (P=0.050) levels were significant predictors of residual, on‐aspirin, TX biosynthesis in ACS (adjusted R2=0.384).
Conclusions
Circulating MRP‐8/14 is associated with TX‐dependent platelet activation in ACS, even during low‐dose aspirin treatment, suggesting a contribution of residual TX to MRP‐8/14 shedding, which may further amplify platelet activation. Circulating MRP‐8/14 may be a target to test different antiplatelet strategies in ACS.
doi:10.1161/JAHA.114.000903
PMCID: PMC4310373  PMID: 25037196
acute coronary syndrome; aspirin; platelet‐derived factors; platelets; thromboxane
8.  Aspirin for Primary Prevention of Cardiovascular Events: Meta-Analysis of Randomized Controlled Trials and Subgroup Analysis by Sex and Diabetes Status 
PLoS ONE  2014;9(10):e90286.
Objective
To evaluate the benefits and harms of aspirin for the primary prevention of CVD and determine whether the effects vary by sex and diabetes status.
Methods
We searched Medline, Embase, and Cochrane databases for randomized controlled trials comparing the effects of aspirin with placebo or control in people with no pre-existing CVD. Two investigators independently extracted data and assessed the study quality. Analyses were performed using Stata version 12.
Results
Fourteen trials (107,686 participants) were eligible. Aspirin was associated with reductions in major cardiovascular events (risk ratio, 0.90; 95% confidence interval, 0.85–0.95), myocardial infarction (0.86; 0.75–0.93), ischemic stroke (0.86; 0.75–0.98) and all-cause mortality (0.94; 0.89–0.99). There were also increases in hemorrhagic stroke (1.34; 1.01–1.79) and major bleeding (1.55; 1.35–1.78) with aspirin. The number needed to treat to prevent 1 major cardiovascular event over a mean follow-up of 6.8 years was 284. By comparison, the numbers needed to harm to cause 1 major bleeding is 299. In subgroup analyses, pooled results demonstrated a reduction in myocardial infarction among men (0.71; 0.59–0.85) and ischemic stroke among women (0.77; 0.63–0.93). Aspirin use was associated with a reduction (0.65; 0.51–0.82) in myocardial infarction among diabetic men. In meta-regression analyses, the results suggested that aspirin therapy might be associated with a decrease in stroke among diabetic women and a decrease in MI among diabetic men and risk reductions achieved with low doses (75 mg/day) were as large as those obtained with higher doses (650 mg/day).
Conclusions
The use of low-dose aspirin was beneficial for primary prevention of CVD and the decision regarding an aspirin regimen should be made on an individual patient basis. The effects of aspirin therapy varied by sex and diabetes status. A clear benefit of aspirin in the primary prevention of CVD in people with diabetes needs more trials.
doi:10.1371/journal.pone.0090286
PMCID: PMC4215843  PMID: 25360605
9.  Aspirin for primary prevention of coronary heart disease: safety and absolute benefit related to coronary risk derived from meta-analysis of randomised trials 
Heart  2001;85(3):265-271.
OBJECTIVE—To determine the cardiovascular and coronary risk thresholds at which aspirin for primary prevention of coronary heart disease is safe and worthwhile.
DESIGN—Meta-analysis of four randomised controlled trials of aspirin for primary prevention. The benefit and harm from aspirin treatment were examined to determine: (1) the cardiovascular and coronary risk threshold at which benefit in prevention of myocardial infarction exceeds harm from significant bleeding; and (2) the absolute benefit expressed as number needed to treat (NNT) for aspirin net of cerebral haemorrhage and other bleeding complications at different levels of coronary risk.
MAIN OUTCOME MEASURES—Benefit from aspirin, expressed as reduction in cardiovascular events, myocardial infarctions, strokes, and total mortality; harm caused by aspirin in relation to significant bleeds and major haemorrhages.
RESULTS—Aspirin for primary prevention significantly reduced all cardiovascular events by 15% (95% confidence interval (CI) 6% to 22%) and myocardial infarctions by 30% (95% CI 21% to 38%), and non-significantly reduced all deaths by 6% (95% CI −4% to 15%). Aspirin non-significantly increased strokes by 6% (95% CI −24% to 9%) and significantly increased bleeding complications by 69% (95% CI 38% to 107%). The risk of major bleeding balanced the reduction in cardiovascular events when cardiovascular event risk was 0.22%/year. The upper 95% CI for this estimate suggests that harm from aspirin is unlikely to outweigh benefit provided the cardiovascular event risk is 0.8%/year, equivalent to a coronary risk of 0.6%/year. At coronary event risk 1.5%/year, the five year NNT was 44 to prevent a myocardial infarction, and 77 to prevent a myocardial infarction net of any important bleeding complication. At coronary event risk 1%/year the NNT was 67 to prevent a myocardial infarction, and 182 to prevent a myocardial infarction net of important bleeding.
CONCLUSIONS—Aspirin treatment for primary prevention is safe and worthwhile at coronary event risk ⩾ 1.5%/year; safe but of limited value at coronary risk 1%/year; and unsafe at coronary event risk 0.5%/year. Advice on aspirin for primary prevention requires formal accurate estimation of absolute coronary event risk.


Keywords: aspirin; coronary heart disease; primary prevention; meta-analysis
doi:10.1136/heart.85.3.265
PMCID: PMC1729640  PMID: 11179262
10.  Adherence to statin or aspirin or both in patients with established cardiovascular disease: exploring healthy behaviour vs. drug effects and 10-year follow-up of outcome 
Aims
To characterize adherence in patients with established cardiovascular disease taking statins and aspirin and to estimate the effects of adherence due to health behaviour, a lack of beneficial drug effect, or both on recurrence of cardiovascular disease or all-cause mortality over 10 years.
Methods
A population-based cohort study using a record-linkage database in Tayside, Scotland. Subjects with cardiovascular disease (n = 7657; 4185 aspirin-alone cohort, 671 statin-alone cohort and 2801 combination use cohort) were studied between 1993 and 2003. The effects of adherence on recurrence of cardiovascular disease or mortality were assessed using Poisson regression model.
Results
In subjects taking both aspirin and statins, those adherent to statins but not aspirin had a lower risk of recurrence [adjusted risk ratio (RR) 0.64; 95% confidence interval 0.49, 0.82], but those adherent to aspirin but not statins has no such effect (adjusted RR 0.91; 0.72, 1.15), suggesting that adherence behaviour alone was not responsible for the beneficial effect. Within the group adherent to aspirin, ≥80% adherence to statins was associated with reduced recurrence compared with those poorly adherent (adjusted RR 0.76; 0.62, 0.94), but no such effect of aspirin was seen in those adherent to statins. Similar results were found for all-cause mortality.
Conclusions
Poor health behaviour is not a sufficient explanation of adverse outcome in poorly adherent patients. Adverse outcome is more likely to be driven by foregone drug benefits.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECTAspirin and statins are widely-used drugs in patients with cardiovascular disease.There is less information on healthy behaviour vs. drug effects.
WHAT THIS STUDY ADDSLong-term adherence to aspirin and statin treatments in patients with established cardiovascular disease has been investigated.Poor health behaviour is not a sufficient explanation of adverse outcome in poorly adherent patients.
doi:10.1111/j.1365-2125.2008.03212.x
PMCID: PMC2485263  PMID: 18492127
aspirin; cardiovascular recurrence; long-term adherence; statin
11.  Aspirin overutilization for the primary prevention of cardiovascular disease 
Clinical Epidemiology  2014;6:433-440.
Background
Aspirin is commonly used for the primary prevention of cardiovascular disease (CVD) in the US. Previous research has observed significant levels of inappropriate aspirin use for primary CVD prevention in some European populations, but the degree to which aspirin is overutilized in the US remains unknown. This study examined the association between regular aspirin use and demographic/clinical factors in a population-based sample of adults without a clinical indication for aspirin for primary prevention.
Methods
A cross-sectional analysis was performed using 2010–2012 data from individuals aged 30–79 years in the Marshfield Epidemiologic Study Area (WI, USA). Regular aspirin users included those who took aspirin at least every other day.
Results
There were 16,922 individuals who were not clinically indicated for aspirin therapy for primary CVD prevention. Of these, 19% were regular aspirin users. In the final adjusted model, participants who were older, male, lived in northern Wisconsin, had more frequent medical visits, and had greater body mass index had significantly higher odds of regular aspirin use (P<0.001 for all). Race/ethnicity, health insurance, smoking, blood pressure, and lipid levels had negligible influence on aspirin use. A sensitivity analysis found a significant interaction between age and number of medical visits, indicating progressively more aspirin use in older age groups who visited their provider frequently.
Conclusion
There was evidence of aspirin overutilization in this US population without CVD. Older age and more frequent provider visits were the strongest predictors of inappropriate aspirin use. Obesity was the only significant clinical factor, suggesting misalignment between perceived aspirin benefits and cardiovascular risks in this subgroup of patients. Prospective studies that examine cardiac and bleeding events associated with regular aspirin use among obese samples (without CVD) are needed to refine clinical guidelines in this area.
doi:10.2147/CLEP.S72032
PMCID: PMC4259866  PMID: 25506245
aspirin; primary prevention; cardiovascular disease; adults; United States
12.  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
13.  Traditional Nonsteroidal Anti-Inflammatory Drugs and Postmenopausal Hormone Therapy: A Drug–Drug Interaction? 
PLoS Medicine  2007;4(5):e157.
Background
Suppression of prostacyclin (PGI2) is implicated in the cardiovascular hazard from inhibitors of cyclooxygenase (COX)-2. Furthermore, estrogen confers atheroprotection via COX-2–dependent PGI2 in mice, raising the possibility that COX inhibitors may undermine the cardioprotection, suggested by observational studies, of endogenous or exogenous estrogens.
Methods and Findings
To identify an interaction between hormone therapy (HT) and COX inhibition, we measured a priori the association between concomitant nonsteroidal anti-inflammatory drugs (NSAIDs), excluding aspirin, in peri- and postmenopausal women on HT and the incidence of myocardial infarction (MI) in a population-based epidemiological study. The odds ratio (OR) of MI in 1,673 individuals and 7,005 controls was increased from 0.66 (95% confidence interval [CI] 0.50–0.88) when taking HT in the absence of traditional (t)NSAIDs to 1.50 (95% CI 0.85–2.64) when taking the combination of HT and tNSAIDs, resulting in a significant (p < 0.002) interaction. The OR when taking aspirin at doses of 150 mg/d or more was 1.41 (95% CI 0.47–4.22). However, a similar interaction was not observed with other commonly used drugs, including lower doses of aspirin, which target preferentially COX-1.
Conclusions
Whether estrogens confer cardioprotection remains controversial. Such a benefit was observed only in perimenopausal women in the only large randomized trial designed to address this issue. Should such a benefit exist, these results raise the possibility that COX inhibitors may undermine the cardioprotective effects of HT.
It is controversial whether estrogens confer cardioprotection. This study suggests that even should such a benefit exist, COX inhibitors may undermine cardioprotective effects of hormone therapy.
Editors' Summary
Background.
There is currently a great deal of uncertainty regarding the effect of postmenopausal hormone therapy on heart disease in women. Premenopausal women are much less likely to experience heart attacks and strokes than men, a difference that does not exist between postmenopausal women and men. One mechanism that might explain these observations relates to the effect of estrogen, which is thought to have a protective effect on the heart. Hormone replacement therapy (HT) consisting of replacement estrogen, and sometimes progesterone as well, is often taken by women experiencing symptoms of menopause. Evidence from observational studies and the Womens' Health Initiative (WHI) trial has suggested that HT protects against heart disease in perimenopausal women. However, researchers have suggested that any beneficial effect of hormone replacement therapy on the heart might be counteracted by the effects of certain types of painkillers also being taken by women involved in the studies. These painkillers, nonsteroidal anti inflammatory drugs ( NSAIDs), prevent production of a molecule called prostacyclin. Prostacyclin plays a role in preventing blood clotting and is therefore thought to be important in protecting the heart. Estrogen, however, acts to increase production of prostacyclin, and it is therefore theoretically possible that hormone replacement therapy does have a beneficial effect on heart health, but which is counteracted by the negative effects of NSAIDs.
Why Was This Study Done?
In this study, the researchers wanted to find out whether there was any evidence for an interaction between NSAID use, hormone replacement therapy, and heart disease. Such understanding in turn might help to identify more clearly whether hormone replacement therapy protects against heart disease in specific subgroups of postmenopausal women.
What Did the Researchers Do and Find?
This study was carried out using information from the UK's General Practice Research Database, which is the largest computer database of anonymous medical records from primary care anywhere in the world. It contains information entered by UK general practitioners on their patients' drug prescriptions, diagnoses, referrals to hospital, and other data. The researchers here searched for all individuals from the database who were aged between 50 and 84 years on 1 January 1997, and then followed them up through the database for four years, or until the individual died, reached 85 years of age, or was diagnosed with a heart attack or cancer. From this search, the researchers found 1,673 women who had heart attacks or who died from coronary heart disease; these were considered “cases.” Then, these 1,673 women were matched against 20,000 “control” women of similar age. Information was pulled out for each case or control on their use of hormone replacement therapy, NSAIDs (covering 21 different drugs, but most commonly diclofenac, ibuprofen, and naproxen), and various risk factors for heart disease. The researchers then compared use of hormone replacement therapy and NSAIDs between the cases and controls, while making statistical adjustments for other risk factors (such as diabetes and smoking, for example).
  The researchers found that current use of hormone replacement therapy was associated with a lower risk of heart attack than non-use. The odds ratio (chance of a heart attack among HT users compared to the chance among non-users of HT) was 0.78. However, when looking at women who used NSAIDs at the same time as hormone replacement therapy, the researchers found no suggestion of a reduction in risk of heart attack: the odds ratio for the chance of heart attack among this group of women, as compared to nonusers of both NSAIDs and hormone replacement therapy, was 1.50.
What Do These Findings Mean?
These findings suggest that hormone replacement therapy and NSAIDs might interact, with NSAIDs acting against a role for hormone replacement therapy in preventing heart attacks. At face value, these results are in conflict with the findings of one large trial, the WHI trial, which failed to find a benefit of HT in preventing heart attacks. However, a recent analysis of WHI suggests cardioprotective effects of HT in women close to the time of the menopause and this coincides with the younger age of women in the observational studies such as the present one rather than in the WHI overall. Observational research studies, such as the present one, are often difficult to interpret because the groups being compared are not necessarily equivalent. It's possible that women who take hormone replacement therapy, or NSAIDs, are in some way different from women who do not, which will bias the findings. Determination of the clinical implications of these findings would most appropriately be resolved in future trials, designed to address the question of interest.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040157.
Resources from the US National Institutes of Health on menopausal hormone therapy, including links to information about the Women's Health Initiative trials, information about managing menopausal symptoms, and more
Resources from the US National Institutes of Health (MedlinePlus) about heart disease in women
Information from NHS Direct, the UK National Health Service, about hormone replacement therapy
The UK General Practice Research Database is the database utilized in this article
Wikipedia entry on nonsteroidal anti-inflammatory drugs (NSAIDs) (note: Wikipedia is an internet encyclopedia anyone can edit)
doi:10.1371/journal.pmed.0040157
PMCID: PMC1872041  PMID: 17518513
14.  Cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib 
Annals of the Rheumatic Diseases  2007;66(6):764-770.
Background
Evidence suggests that both selective cyclooxygenase (COX)‐2 inhibitors and non‐selective non‐steroidal anti‐inflammatory drugs (NSAIDs) increase the risk of cardiovascular events. However, evidence from prospective studies of currently available COX‐2 inhibitors and non‐selective NSAIDs is lacking in patients at high cardiovascular risk who are taking aspirin.
Objective
To determine the cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib.
Methods
The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) of 18 325 patients with osteoarthritis comprised two parallel substudies, comparing lumiracoxib (COX‐2 inhibitor) with either ibuprofen or naproxen. A post hoc analysis by baseline cardiovascular risk, treatment assignment, and low‐dose aspirin use was performed. The primary composite end point was cardiovascular mortality, non‐fatal myocardial infarction, and stroke at 1 year; a secondary end point was the development of congestive heart failure (CHF).
Results
In high risk patients among aspirin users, patients in the ibuprofen substudy had more primary events with ibuprofen than lumiracoxib (2.14% vs 0.25%, p = 0.038), whereas in the naproxen substudy rates were similar for naproxen and lumiracoxib (1.58% vs 1.48%, p = 0.899). High risk patients not taking aspirin had fewer primary events with naproxen than with lumiracoxib (0% vs 1.57%, p = 0.027), but not for ibuprofen versus lumiracoxib (0.92% vs 0.80%, p = 0.920). Overall, CHF developed more often with ibuprofen than lumiracoxib (1.28% vs 0.14%; p = 0.031), whereas no difference existed between naproxen and lumiracoxib.
Conclusions
These data suggest that ibuprofen may confer an increased risk of thrombotic and CHF events relative to lumiracoxib among aspirin users at high cardiovascular risk. The study indicates that naproxen may be associated with lower risk relative to lumiracoxib among non‐aspirin users. This study is subject to inherent limitations, and therefore should be interpreted as a hypothesis‐generating study.
doi:10.1136/ard.2006.066001
PMCID: PMC1954641  PMID: 17412741
coronary disease; osteoarthritis; anti‐inflammatory agents, non‐steroidal anti‐inflammatory drugs; COX‐2 inhibitors; aspirin
15.  Risk of Death and Cardiovascular Events in Initially Healthy Women with New-Onset Atrial Fibrillation 
Context
The risks associated with new-onset AF among middle-aged women and populations with a low co-morbidity burden are poorly defined.
Objective
To examine the association between incident AF and mortality in initially healthy women, and to evaluate the influence of associated cardiovascular co-morbidities on risk.
Design, Setting and Participants
Between 1993 and March 16, 2010, 34722 women participating in the Women's Health Study underwent prospective follow-up. Participants (95% white) were >45 years (median (interquartile range) 53 (49–59) years) and free of AF and cardiovascular disease at baseline. Cox proportional-hazards models with time-varying covariates were utilized to determine the risk of events among women with incident AF. Secondary analyses were performed among women with paroxysmal AF.
Main outcome measure
Primary outcomes included total, cardiovascular, and non-cardiovascular mortality. Secondary outcomes included stroke, congestive heart failure and myocardial infarction.
Results
During a median (interquartile range) follow-up of 15.4 (14.7–15.8) years, 1011 women developed AF. Incidence rates (95% confidence intervals (CIs)) per 1000 person-years among women with and without AF were 10.8 (8.1–13.5) and 3.1 (2.9–3.2) for all-cause, 4.3 (2.6–6.0) and 0.57 (0.5–0.6) for cardiovascular and 6.5 (4.4–8.6) and 2.5 (2.4–2.6) for non-cardiovascular mortality, respectively. In multivariable models, hazard ratios (HRs) (95% CIs) of new-onset AF for all-cause, cardiovascular and non-cardiovascular mortality were 2.14 (1.64–2.77), 4.18 (2.69–6.51) and 1.66 (1.19–2.30), respectively. Adjustment for non-fatal cardiovascular events potentially on the causal pathway to death attenuated these risks, but incident AF remained associated with all mortality components (HR 1.70 (1.30–2.22)), 2.57 (1.63–4.07) and 1.42 (1.02–1.98)). Among women with paroxysmal AF (n=656), the increase in mortality risk was limited to cardiovascular causes (HR 2.94 (1.55–5.59)).
Conclusion
Among a group of healthy women, new-onset AF was independently associated with cardiovascular, non-cardiovascular and all-cause mortality, with some of the risk potentially explained by non-fatal cardiovascular events.
doi:10.1001/jama.2011.659
PMCID: PMC3105776  PMID: 21610240
Atrial fibrillation; lone atrial fibrillation; women; cardiovascular disease; death; epidemiology; stroke
16.  The polypill in the primary prevention of cardiovascular disease: cost-effectiveness in the Dutch population 
BMJ Open  2011;1(2):e000363.
Objectives
The aim of the present study was to estimate the cost-effectiveness of the polypill in the primary prevention of cardiovascular disease.
Design
A health economic modelling study.
Setting
Primary healthcare in the Netherlands.
Participants
Simulated individuals from the general Dutch population, aged 45–75 years.
Interventions
Opportunistic screening followed by prescription of the polypill to eligible individuals. Eligibility was defined as having a minimum 10-year risk of cardiovascular death as assessed with the Systematic Coronary Risk Evaluation function of alternatively 5%, 7.5% or 10%. Different versions of the polypill were considered, depending on composition: (1) the Indian polycap, with three different types of blood pressure-lowering drugs, a statin and aspirin; (2) as (1) but without aspirin and (3) as (2) but with a double statin dose. In addition, a scenario of (targeted) separate antihypertensive and/or statin medication was simulated.
Primary outcome measures
Cases of acute myocardial infarction or stroke prevented, quality-adjusted life years (QALYs) gained and the costs per QALY gained. All interventions were compared with usual care.
Results
All scenarios were cost-effective with an incremental cost-effectiveness ratio between €7900 and 12 300 per QALY compared with usual care. Most health gains were achieved with the polypill without aspirin and containing a double dose of statins. With a 10-year risk of 7.5% as the threshold, this pill would prevent approximately 3.5% of all cardiovascular events.
Conclusions
Opportunistic screening based on global cardiovascular risk assessment followed by polypill prescription to those with increased risk offers a cost-effective strategy. Most health gain is achieved by the polypill without aspirin and a double statin dose.
Article summary
Article focus
Cardiovascular diseases continue to be still a major, partly preventable, cause of illness and death.
A polypill that lowers by targeting several risk factors simultaneously is in line with the concept that the aim in primary prevention should be to bring down ‘global’ cardiovascular risk.
The aim of this study was to estimate the potential cost-effectiveness of polypill prescription after opportunistic screening.
Key messages
The results of this study suggest that opportunistic screening and offering a polypill to people with a minimum 10-year risk of cardiovascular mortality of alternatively 5%, 7.5% or 10% is a cost-effective strategy.
A polypill without aspirin but with a double dose of simvastatin leads to most health gains at all risk thresholds considered. At a 10-year risk of cardiovascular death of ≥7.5%, such a strategy would lead to an estimated decrease in the incidence of myocardial infarction and stroke of about 3.5%, at a cost of €8900 per quality-adjusted life year.
Opportunistic screening of the population of ≥40 years to select individuals with a mild to moderately increased risk for cardiovascular diseases, followed by polypill prescription would prevent approximately 3.5% of all cardiovascular events.
Strengths and limitations of this study
Strong point of the study is that different compositions of the polypill have been modelled. Also, realistic estimates for adherence and compliance have been used.
As only preliminary results of a phase II clinical trial on efficacy of the polypill were available, we had to apply mathematical modelling to estimate cost-effectiveness. This provides insight into the range of health benefits that can be expected. Pending results with regard to established clinical endpoints from large-scale phase III trials, the results of this study should not be taken as a precise estimate of the cost-effectiveness of the polypill.
doi:10.1136/bmjopen-2011-000363
PMCID: PMC3278482  PMID: 22189351
17.  Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration. 
BMJ : British Medical Journal  1994;308(6921):81-106.
OBJECTIVE--To determine the effects of "prolonged" antiplatelet therapy (that is, given for one month or more) on "vascular events" (non-fatal myocardial infarctions, non-fatal strokes, or vascular deaths) in various categories of patients. DESIGN--Overviews of 145 randomised trials of "prolonged" antiplatelet therapy versus control and 29 randomised comparisons between such antiplatelet regimens. SETTING--Randomised trials that could have been available by March 1990. SUBJECTS--Trials of antiplatelet therapy versus control included about 70,000 "high risk" patients (that is, with some vascular disease or other condition implying an increased risk of occlusive vascular disease) and 30,000 "low risk" subjects from the general population. Direct comparisons of different antiplatelet regimens involved about 10,000 high risk patients. RESULTS--In each of four main high risk categories of patients antiplatelet therapy was definitely protective. The percentages of patients suffering a vascular event among those allocated antiplatelet therapy versus appropriately adjusted control percentages (and mean scheduled treatment durations and net absolute benefits) were: (a) among about 20,000 patients with acute myocardial infarction, 10% antiplatelet therapy v 14% control (one month benefit about 40 vascular events avoided per 1000 patients treated (2P < 0.00001)); (b) among about 20,000 patients with a past history of myocardial infarction, 13% antiplatelet therapy v 17% control (two year benefit about 40/1000 (2P < 0.00001)); (c) among about 10,000 patients with a past history of stroke or transient ischaemic attack, 18% antiplatelet therapy v 22% control (three year benefit about 40/1000 (2P < 0.00001)); (d) among about 20,000 patients with some other relevant medical history (unstable angina, stable angina, vascular surgery, angioplasty, atrial fibrillation, valvular disease, peripheral vascular disease, etc), 9% v 14% in 4000 patients with unstable angina (six month benefit about 50/1000 (2P < 0.00001)) and 6% v 8% in 16,000 other high risk patients (one year benefit about 20/1000 (2P < 0.00001)). Reductions in vascular events were about one quarter in each of these four main categories and were separately statistically significant in middle age and old age, in men and women, in hypertensive and normotensive patients, and in diabetic and nondiabetic patients. Taking all high risk patients together showed reductions of about one third in non-fatal myocardial infarction, about one third in non-fatal stroke, and about one third in vascular death (each 2P < 0.00001). There was no evidence that non-vascular deaths were increased, so in each of the four main high risk categories overall mortality was significantly reduced. The most widely tested antiplatelet regimen was "medium dose" (75-325 mg/day) aspirin. Doses throughout this range seemed similarly effective (although in an acute emergency it might be prudent to use an initial dose of 160-325 mg rather than about 75 mg). There was no appreciable evidence that either a higher aspirin dose or any other antiplatelet regimen was more effective than medium dose aspirin in preventing vascular events. The optimal duration of treatment for patients with a past history of myocardial infarction, stroke, or transient ischaemic attack could not be determined directly because most trials lasted only one, two, or three years (average about two years). Nevertheless, there was significant (2P < 0.0001) further benefit between the end of year 1 and the end of year 3, suggesting that longer treatment might well be more effective. Among low risk recipients of "primary prevention" a significant reduction of one third in non-fatal myocardial infarction was, however, accompanied by a non-significant increase in stroke. Furthermore, the absolute reduction in vascular events was much smaller than for high risk patients despite a much longer treatment period (4.4% antiplatelet therapy v 4.8% control; five year
PMCID: PMC2539220  PMID: 8298418
18.  Aspirin Use and Risk of Colorectal Cancer According to BRAF Mutation Status 
Importance
Aspirin use reduces the risk of colorectal carcinoma. Experimental evidence implicates a role of RAF kinases in upregulation of PTGS2 (cyclooxygenase-2), suggesting that BRAF-mutant colonic cells might be less sensitive to the anti-tumor effects of aspirin than BRAF-wild-type neoplastic cells.
Objective
To examine if the association of aspirin intake with colorectal cancer risk differs according to status of tumor BRAF oncogene mutation.
Design and Setting
We collected biennial questionnaire data on aspirin use and followed participants from 1980 (in the Nurses’ Health Study) or 1986 (in the Health Professionals Follow-up Study) until July 1, 2006 for cancer incidence and until January 1, 2012 for cancer mortality. Duplication-method Cox proportional cause-specific hazards regression for competing risks data was used to compute hazard ratio (HR) for colorectal carcinoma incidence according to BRAF mutation status.
Results
Among 127,865 individuals, with 3,165,985 person-years of follow-up, we identified 1,226 incident rectal and colon cancers with available molecular data. Compared with non-use, regular aspirin use was associated with lower BRAF-wild-type cancer risk (multivariable HR=0.73 [95% CI, 0.64–0.83]; age-adjusted incidence rate difference [IRD]=−9.7 [95% CI, −12.6 to −6.7] per 100,000 person-years). This association was observed irrespective of status of tumor PTGS2 expression or PIK3CA or KRAS mutation. In contrast, regular aspirin use was not associated with a lower risk of BRAF-mutated cancer (multivariable HR=1.03 [95% CI, 0.76–1.38]; age-adjusted IRD=0.7 [95% CI, −0.3 to 1.7] per 100,000 person-years) (Pheterogeneity=0.037, between BRAF-wild-type vs. BRAF-mutated cancer risks). Compared with no aspirin use, aspirin use of >14 tablets per week was associated with a lower risk of BRAF-wild-type cancer (multivariable HR=0.43 [95% CI, 0.25–0.75]; age-adjusted IRD=−19.8 [95% CI, −26.3 to −13.3] per 100,000 person-years). The relationship between the number of aspirin tablets per week and colorectal cancer risk differed significantly by BRAF mutation status (Pheterogeneity=0.005).
Conclusions and Relevance
Regular aspirin use was associated with lower risk of BRAF-wild-type colorectal cancer, but not with BRAF-mutated cancer risk. These findings suggest that BRAF-mutant colon tumor cells may be less sensitive to the effect of aspirin. Given the modest absolute risk difference, further investigations are necessary to determine clinical implications of our findings.
doi:10.1001/jama.2013.6599
PMCID: PMC3743040  PMID: 23800934
colon cancer; rectal cancer; adenocarcinoma; epigenomics; epigenetics
19.  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
20.  Kidney function and risk of cardiovascular disease and mortality in women: a prospective cohort study 
Objective To evaluate the association of kidney function with cardiovascular disease and mortality among apparently healthy women.
Design Prospective cohort study.
Setting Women’s Health Study, United States.
Participants 27 939 female health professionals aged ≥45 who were free of cardiovascular disease and other major disease and who provided a blood sample at study entry.
Main outcome measures Time to cardiovascular disease (non-fatal stroke, non-fatal myocardial infarction, coronary revascularisation procedures, or death from cardiovascular cause), specific cardiovascular disease events, and all-cause mortality. End points were confirmed after review of medical records and death certificates.
Results Glomerular filtration rate (GFR) was estimated with the abbreviated Modification of Diet in Renal Disease Study equation. At baseline, 1315 (4.7%) women had GFR <60 ml/min/1.73 m2. During 12 years of follow-up, 1199 incident cardiovascular disease events and 856 deaths (179 from cardiovascular disease) occurred. Compared with women with GFR ≥90 ml/min/1.73 m2, the multivariable adjusted hazard ratios for any first cardiovascular disease were 0.95 (95% CI 0.83 to 1.08), 0.84 (0.70 to 1.00), and 1.00 (0.79 to 1.27) among women with GFR of 75-89.9, 60-74.9, and <60 ml/min/1.73 m2, respectively; the equivalent hazard ratios for all cause mortality were 0.93 (0.79 to 1.09), 1.03 (0.85 to 1.26), and 1.09 (0.83 to 1.45). Similar null findings were observed for myocardial infarction, stroke, coronary revascularisation, and non-cardiovascular death. However, an increased risk of death from cardiovascular disease was found among women with GFR <60 ml/min/1.73 m2 (hazard ratio 1.68 (1.02 to 2.79)).
Conclusions In this large cohort of women, a glomerular filtration rate <60 ml/min/1.73 m2 was associated with increased risk of cardiovascular disease death but not other cardiovascular disease events or non-cardiovascular disease mortality. We observed no increase in risk of any of the outcomes among women with less severe impairment of kidney function.
doi:10.1136/bmj.b2392
PMCID: PMC2704981  PMID: 19564178
21.  Aspirin in the primary prevention of cardiovascular disease in the Women’s Health Study: Effect of noncompliance 
European Journal of Epidemiology  2012;27(6):431-438.
Randomized evidence for aspirin in the primary prevention of cardiovascular disease (CVD) among women is limited and suggests at most a modest effect for total CVD. Lack of compliance, however, can null-bias estimated effects. We used marginal structural models (MSMs) to estimate the etiologic effect of continuous aspirin use on CVD events among 39,876 apparently healthy female health professionals aged 45 years and older in the Women’s Health Study, a randomized trial of 100 mg aspirin every other day versus placebo. As-treated analyses and MSMs controlled for time-varying determinants of aspirin use and CVD. Predictors of aspirin use differed by randomized group and prior use and included medical history, CVD risk factors, and intermediate CVD events. Previously reported intent-to-treat analyses found small non-significant effects of aspirin on total CVD (hazard ratio (HR) =0.91, 95% confidence interval (CI) =0.81–1.03) and CVD mortality (HR=0.95, 95% CI=0.74–1.22). As-treated analyses were similar for total CVD with a slight reduction in CVD mortality (HR=0.88, 95%CI=0.67–1.16). MSMs, which adjusted for non-compliance, were similar for total CVD (HR=0.93; 95% CI: 0.81, 1.07) but suggested lower CVD mortality with aspirin use (HR = 0.76; 95% CI: 0.54, 1.08). Adjusting for non-compliance had little impact on the estimated effect of aspirin on total CVD, but strengthened the effect on CVD mortality. These results support a limited effect of low-dose aspirin on total CVD in women, but potential benefit for CVD mortality.
doi:10.1007/s10654-012-9702-x
PMCID: PMC3383873  PMID: 22699516
Aspirin; cardiovascular disease; marginal structural model; myocardial infarction; stroke
22.  Aspirin Use Is Associated with an Improved Long-term Survival in an Unselected Population Presenting with Unstable Angina 
Clinical cardiology  2010;33(9):553-558.
The objective of this study is to determine the long-term mortality benefit of aspirin in unselected patients with unstable angina (UA). For that goal, all residents of Olmsted County, Minnesota presenting to local emergency departments with acute chest pain from January 1985 through December 1992 having symptoms consistent with UA were identified through medical records. A total of 1628 patients were identified with UA and were stratified by aspirin use in-hospital and at discharge. Cardiovascular mortality and non-fatal myocardial infarction and stroke were assessed over a median of 7.5 years follow-up, and all-cause mortality data over a median of 16.7 years. The mean age of patients with UA was 65 years, and 60% were men. After a median of 7.5 years follow-up, all-cause and cardiovascular-mortality rates were lower among patients prescribed versus not prescribed aspirin on discharge. There were 949 post-discharge deaths over the median follow-up of 16.7 years. After multivariable adjustment, aspirin use at discharge was associated with a lower long-term mortality (hazard ratio 0.78; 95% CI 0.65 - 0.93). In conclusion, aspirin use at hospital discharge following UA is associated with a reduction in long-term mortality. This long-term study extends prior trial results from select populations to a population-based cohort.
doi:10.1002/clc.20769
PMCID: PMC3785089  PMID: 20842739
23.  Aspirin Use and Survival After Diagnosis of Colorectal Cancer 
Context
Aspirin reduces risk of colorectal neoplasia in randomized trials and inhibits tumor growth and metastases in animal models. However, the influence of aspirin on survival after diagnosis of colorectal cancer is unknown.
Objective
To examine the association between aspirin use after colorectal cancer diagnosis on colorectal cancer–specific and overall survival.
Design, Setting, and Participants
Prospective cohort study of 1279 men and women diagnosed with stage I, II, or III colorectal cancer. Participants were enrolled in 2 nationwide health professional cohorts in 1980 and 1986 prior to diagnosis and followed up through June 1, 2008.
Main Outcome Measure
Colorectal cancer–specific and overall mortality.
Results
After a median follow-up of 11.8 years, there were 193 total deaths (35%) and 81 colorectal cancer–specific deaths (15%) among 549 participants who regularly used aspirin after colorectal cancer diagnosis, compared with 287 total deaths (39%) and 141 colorectal cancer–specific deaths (19%) among 730 participants who did not use aspirin. Compared with nonusers, participants who regularly used aspirin after diagnosis experienced a multivariate hazard ratio (HR) for colorectal cancer–specific mortality of 0.71 (95% confidence interval [CI], 0.53-0.95) and for overall mortality of 0.79 (95% CI, 0.65-0.97). Among 719 participants who did not use aspirin before diagnosis, aspirin use initiated after diagnosis was associated with a multivariate HR for colorectal cancer–specific mortality of 0.53 (95% CI, 0.33-0.86). Among 459 participants with colorectal cancers that were accessible for immunohistochemical assessment, the effect of aspirin differed significantly according to cyclooxygenase 2 (COX-2) expression (P for interaction = .04). Regular aspirin use after diagnosis was associated with a lower risk of colorectal cancer–specific mortality among participants in whom primary tumors overexpressed COX-2 (multivariate HR, 0.39; 95% CI, 0.20-0.76), whereas aspirin use was not associated with lower risk among those with primary tumors with weak or absent expression (multivariate HR, 1.22; 95% CI, 0.36-4.18).
Conclusion
Regular aspirin use after the diagnosis of colorectal cancer is associated with lower risk of colorectal cancer–specific and overall mortality, especially among individuals with tumors that overexpress COX-2.
doi:10.1001/jama.2009.1112
PMCID: PMC2848289  PMID: 19671906
24.  Use and Associated Risks of Concomitant Aspirin Therapy with Oral Anticoagulation in Patients with Atrial Fibrillation: Insights from the ORBIT-AF Registry 
Circulation  2013;128(7):721-728.
Background
The role of concomitant aspirin therapy in patients with atrial fibrillation (AF) receiving oral anticoagulation (OAC) is unclear. We assessed concomitant aspirin use and its association with clinical outcomes among AF patients treated with OAC.
Methods and Results
The Outcomes Registry for Better Informed Treatment (ORBIT) of Atrial Fibrillation registry enrolled 10,126 AF patients from 176 US practices from June, 2010 through August, 2011. The study population was limited to those on OAC (n=7,347).
Hierarchical multivariable logistic regression models were used to assess factors associated with concomitant aspirin therapy. Primary outcomes were 6-month bleeding, hospitalization, ischemic events, and mortality. Overall, 35% (n=2543) of AF patients on OAC also received aspirin (OAC+ASA). Patients receiving OAC+ASA were more likely male (66% vs. 53%, p<0.0001) and had more comorbid illness than those on OAC alone. Over one-third (39%) of OAC+ASA did not have a history of atherosclerotic disease, yet 17% had elevated ATRIA bleeding risk scores (≥5). Major bleeding (adjusted HR 1.53, 95% CI 1.20–1.96) and bleeding hospitalizations (adjusted HR 1.52, 95% CI 1.17–1.97) were significantly higher in those on OAC+ASA versus OAC alone. Rates of ischemic events were low.
Conclusions
Patients with AF receiving OAC are often treated with concomitant aspirin, even when they do not have cardiovascular disease. Use of OAC+ASA was associated with significantly increased risk for bleeding, emphasizing the need to carefully determine if and when the benefits of concomitant aspirin outweigh the risks in AF patients already on OAC.
doi:10.1161/CIRCULATIONAHA.113.002927
PMCID: PMC3908483  PMID: 23861512
atrial fibrillation; anticoagulants; aspirin; hemorrhage; outcomes research
25.  Is clopidogrel better than aspirin following breakthrough strokes while on aspirin? A retrospective cohort study 
BMJ Open  2014;4(12):e006672.
Objective
There is insufficient evidence on which to base a recommendation for optimal antiplatelet therapy following a stroke while on aspirin. The objective was to compare clopidogrel initiation vs aspirin reinitiation for vascular risk reduction among patients with ischaemic stroke on aspirin at the time of their index stroke.
Design
Retrospective.
Setting
We conducted a nationwide cohort study by retrieving all hospitalised patients (≥18 years) with a primary diagnosis of ischaemic stroke between 2003 and 2009 from Taiwan National Health Insurance Research Database.
Participants
Among 3862 patients receiving aspirin before the index ischaemic stroke and receiving either aspirin or clopidogrel after index stroke during follow-up period, 1623 were excluded due to a medication possession ratio <80%. Also, 355 were excluded due to history of atrial fibrillation, valvular heart disease or coagulopathy. Therefore, 1884 patients were included in our final analysis.
Interventions
Patients were categorised into two groups based on whether clopidogrel or aspirin was prescribed during the follow-up period. Follow-up was from time of the index stroke to admission for recurrent stroke or myocardial infarction, death or the end of 2010.
Primary and secondary outcome measures
The primary end point was hospitalisation due to a new-onset major adverse cardiovascular event (MACE: composite of any stroke or myocardial infarction). The leading secondary end point was any recurrent stroke.
Results
Compared to aspirin, clopidogrel was associated with a lower occurrence of future MACE (HR=0.54, 95% CI 0.43 to 0.68, p<0.001, number needed to treat: 8) and recurrent stroke (HR=0.54, 95% CI 0.42 to 0.69, p<0.001, number needed to treat: 9) after adjustment of relevant covariates.
Conclusions
Among patients with an ischaemic stroke while taking aspirin, clopidogrel initiation was associated with fewer recurrent vascular events than aspirin reinitiation.
doi:10.1136/bmjopen-2014-006672
PMCID: PMC4256539  PMID: 25468508
CLINICAL PHARMACOLOGY; EPIDEMIOLOGY

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