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1.  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
2.  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
3.  Comparative Efficacy and Safety of Different Antiplatelet Agents for Prevention of Major Cardiovascular Events and Leg Amputations in Patients with Peripheral Arterial Disease: A Systematic Review and Network Meta-Analysis 
PLoS ONE  2015;10(8):e0135692.
There is a lack of consensus regarding which type of antiplatelet agent should be used in patients with peripheral arterial disease (PAD) and little is known on the advantages and disadvantages of dual antiplatelet therapy. We conducted a systematic review and network meta-analysis of available randomized controlled trials (RCT) comparing different antiplatelet drugs (Aspirin, Ticlopidine, Clopidogrel, Ticagrelor, Cilostazol, Picotamide and Vorapaxar as monotherapies or in combination with aspirin) in PAD patients (PROSPERO public database; CRD42014010299).We collated evidence from previous relevant meta-analyses and searched online databases. Primary efficacy endpoints were: (1) the composite rate of major adverse cardiovascular events (MACE; including vascular deaths, non-fatal myocardial infarction and non-fatal stroke), and (2) the rate of major leg amputations. The primary safety endpoint was the rate of severe bleeding events. Bayesian models were employed for multiple treatment comparisons and risk-stratified hierarchies of comparative efficacy were produced to aid medical decision making. Number-Needed-to-Treat (NNT) and Number-Needed-to-Harm (NNH) are reported in case of significant results. We analyzed 49 RCTs comprising 34,518 patients with 88,358 person-years of follow-up with placebo as reference treatment. Aspirin, Cilostazol, Vorapaxar and Picotamide were ineffective in reducing MACE. A significant MACE reduction was noted with Ticagrelor plus aspirin (RR: 0.67; 95%CrI: 0.46–0.96, NNT = 66), Clopidogrel (RR: 0.72; 95%CrI: 0.58–0.91, NNT = 80), Ticlopidine (RR: 0.75; 95%CrI: 0.58–0.96, NNT = 87), and Clopidogrel plus aspirin (RR: 0.78; 95%CrI: 0.61–0.99, NNT = 98). Dual antiplatelet therapy with Clopidogrel plus aspirin significantly reduced major amputations following leg revascularization (RR: 0.68; 95%CrI: 0.46–0.99 compared to aspirin, NNT = 94). The risk of severe bleeding was significantly higher with Ticlopidine (RR: 5.03; 95%CrI: 1.23–39.6, NNH = 25), Vorapaxar (RR: 1.80; 95%CrI: 1.22–2.69, NNH = 130), and Clopidogrel plus aspirin (RR: 1.48; 95%CrI: 1.05–2.10, NNH = 215). Clopidogrel monotherapy showed the most favourable benefit-harm profile (79% cumulative rank probability best and 77% cumulative rank probability safest). In conclusion, Clopidogrel should be the indicated antiplatelet agent in PAD patients. Dual antiplatelet therapy with aspirin and Clopidogrel can reduce the rate of major leg amputations following revascularization, but carries a slightly higher risk of severe bleeding.
doi:10.1371/journal.pone.0135692
PMCID: PMC4537264  PMID: 26274912
4.  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
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.  The Use of Coronary Artery Calcium Testing to Guide Aspirin Utilization for Primary Prevention: Estimates from the Multi-Ethnic Study of Atherosclerosis 
Background
Aspirin for the primary prevention of coronary heart disease (CHD) is only recommended for individuals at high risk for CHD although the majority of CHD events occur in individuals who are low to intermediate risk.
Methods and Results
To estimate the potential of coronary artery calcium (CAC) scoring to guide aspirin use for primary prevention of CHD, we studied 4229 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) who were not on aspirin at baseline and were free of diabetes. Using data from median 7.6-year follow-up, five-year number-needed-to-treat (NNT5) estimations were calculated by applying an 18% relative CHD reduction to the observed event rates. This was contrasted to 5-year number-needed-to-harm (NNH5) estimations based on the risk of major bleeding reported in an aspirin meta-analysis. Results were stratified by a 10% 10-year CHD Framingham Risk Score (FRS). Individuals with CAC ≥ 100 had an estimated net benefit with aspirin regardless of their traditional risk status (estimated NNT5 of 173 for individuals <10% FRS and 92 for individuals ≥ 10% FRS, estimated NNH5 of 442 for a major bleed). Conversely, individuals with zero CAC had unfavorable estimations (estimated NNT5 of 2,036 for individuals <10% FRS and 808 for individuals ≥ 10% FRS, estimated NNH5 of 442 for a major bleed). Gender specific and age-stratified analyses showed similar results.
Conclusion
For the primary prevention of CHD, MESA participants with CAC ≥ 100 had favorable risk/benefit estimations for aspirin use while participants with zero CAC were estimated to receive net harm from aspirin.
doi:10.1161/CIRCOUTCOMES.113.000690
PMCID: PMC4412344  PMID: 24803472
Aspirin; imaging; prevention; coronary disease
7.  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
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 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
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.  Effect of Including Cancer Mortality on the Cost-Effectiveness of Aspirin for Primary Prevention in Men 
Journal of General Internal Medicine  2013;28(11):1483-1491.
ABSTRACT
BACKGROUND
Recent data suggest that aspirin may be effective for reducing cancer mortality.
OBJECTIVE
To examine whether including a cancer mortality-reducing effect influences which men would benefit from aspirin for primary prevention.
DESIGN
We modified our existing Markov model that examines the effects of aspirin among middle-aged men with no previous history of cardiovascular disease or diabetes. For our base case scenario of 45-year-old men, we examined costs and life-years for men taking aspirin for 10 years compared with men who were not taking aspirin over those 10 years; after 10 years, we equalized treatment and followed the cohort until death. We compared our results depending on whether or not we included a 22 % relative reduction in cancer mortality, based on a recent meta-analysis. We discounted costs and benefits at 3 % and employed a third party payer perspective.
MAIN MEASURE
Cost per quality-adjusted life year (QALY) gained.
KEY RESULTS
When no effect on cancer mortality was included, aspirin had a cost per QALY gained of $22,492 at 5 % 10-year coronary heart disease (CHD) risk; at 2.5 % risk or below, no treatment was favored. When we included a reduction in cancer mortality, aspirin became cost-effective for men at 2.5 % risk as well (cost per QALY, $43,342). Results were somewhat sensitive to utility of taking aspirin daily; risk of death after myocardial infarction; and effects of aspirin on stroke, myocardial infarction, and sudden death. However, aspirin remained cost-saving or cost-effective (< $50,000 per QALY) in probabilistic analyses (59 % with no cancer effect included; 96 % with cancer effect) for men at 5 % risk.
CONCLUSIONS
Including an effect of aspirin on cancer mortality influences the threshold for prescribing aspirin for primary prevention in men. If such an effect is real, many middle-aged men at low cardiovascular risk would become candidates for regular aspirin use.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-013-2465-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s11606-013-2465-6
PMCID: PMC3797356  PMID: 23681842
aspirin; cancer mortality; coronary heart disease; guideline-based intervention; primary prevention
12.  Stroke: secondary prevention  
BMJ Clinical Evidence  2010;2010:0207.
Introduction
People with a history of stroke or transient ischaemic attack (TIA) are at high risk of all vascular events, such as myocardial infarction (MI), but are at particular risk of subsequent stroke (about 10% in the first year and about 5% each year thereafter).
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of preventive non-surgical interventions in people with previous stroke or transient ischaemic attack? What are the effects of preventive surgical interventions in people with previous stroke or transient ischaemic attack? What are the effects of preventive anticoagulant and antiplatelet treatments in people with atrial fibrillation and previous stroke or transient ischaemic attack? What are the effects of preventive anticoagulant and antiplatelet treatments in people with atrial fibrillation and without previous stroke or transient ischaemic attack? What are the effects of preventive anticoagulant and antiplatelet treatments in people with atrial fibrillation and without previous stroke or transient ischaemic attack and with low to moderate risk of stroke or transient ischaemic attack? We searched: Medline, Embase, The Cochrane Library, and other important databases up to February 2009 (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 130 systematic reviews, RCTs, or observational studies 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: alternative antiplatelet regimens to aspirin, anticoagulation (oral dosing, or in those with sinus rhythm), aspirin (high or low dose), blood pressure reduction, carotid and vertebral percutaneous transluminal angioplasty (PTA), carotid endarterectomy (in people with: asymptomatic but severe carotid artery stenosis, less than 0% symptomatic carotid artery stenosis, moderate [30%–49%] symptomatic carotid artery stenosis, moderately severe [50%–69%] symptomatic carotid artery stenosis, severe [greater than 70%] symptomatic carotid artery stenosis, or symptomatic near occlusion of the carotid artery), cholesterol reduction, vitamin B supplements (including folate), and different regimens to lower blood pressure.
Key Points
Prevention in this context is the long-term management of people with previous stroke or TIA, and of people at high risk of stroke for other reasons, such as atrial fibrillation. Risk factors for stroke include: previous stroke or TIA; increasing age; hypertension; diabetes; cigarette smoking; and emboli associated with atrial fibrillation, artificial heart valves, or MI.
Antiplatelet treatment effectively reduces the risk of stroke in people with previous stroke or TIA. High-dose aspirin (500–1500 mg/day) seems as equally effective as low-dose aspirin (75–150 mg/day), although it may increase GI adverse effects. Adding dipyridamole to aspirin is beneficial in reducing composite vascular end points and stroke compared with aspirin alone. Risk reduction appears greater with extended-release compared with immediate-release dipyridamole.The net risk of recurrent stroke or major haemorrhagic event is similar with clopidogrel and aspirin plus dipyridamole.
Treatments to reduce blood pressure are effective for reducing the risk of serious vascular events in people with previous stroke or TIA. Blood pressure reduction seems beneficial irrespective of the type of qualifying cerebrovascular event (ischaemic or haemorrhagic), or even whether people are hypertensive.Aggressive blood pressure lowering should not be considered in people with acute stenosis of the carotid or vertebral arteries, because of the risk of precipitating a stroke.
Carotid endarterectomy effectively reduces the risk of stroke in people with greater than 50% carotid stenosis, is not effective in people with 30% to 49% carotid stenosis, and increases the risk of stroke in people with less than 30% stenosis. However, it does not seem beneficial in people with near occlusion.
Cholesterol reduction using statins seems to reduce the risk of stroke irrespective of baseline cholesterol or coronary artery disease (CAD). Non-statin cholesterol reduction does not seem to reduce the risk of stroke.
We found insufficient evidence to judge the efficacy of carotid percutaneous transluminal angioplasty, carotid percutaneous transluminal angioplasty plus stenting, or vertebral percutaneous transluminal angioplasty in people with recent carotid or vertebral TIA or stenosis.
Vitamin B supplements (including folate) do not seem beneficial in reducing mortality or the risk of stroke.
Anticoagulation does not seem beneficial in reducing stroke in people with previous ischaemic stroke and normal sinus rhythm, but does increase the risk of intra- and extracranial haemorrhage. This is especially true for patients with TIAs or minor ischaemic stroke as the qualifying event.
In people with atrial fibrillation, oral anticoagulants reduce the risk of stroke in people with previous stroke or TIA, and in people with no previous stroke or TIA who are at high risk of stroke or TIA, but we don't know whether they are effective in people with no previous stroke or TIA who are at low risk of stroke or TIA. In people with atrial fibrillation, we don't know whether aspirin reduces the risk of stroke in people with previous stroke or TIA, or in people without previous stroke or TIA who are at low risk of stroke or TIA, but they may be unlikely to be effective in people without previous stroke or TIA who are at high risk of stroke or TIA.
PMCID: PMC2907594
13.  Secondary prevention of ischaemic cardiac events 
BMJ 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
14.  Aspirin for Primary Prevention of Cardiovascular Disease and Cancer. A Benefit and Harm Analysis 
PLoS ONE  2015;10(7):e0127194.
Background
Aspirin is widely used for prevention of cardiovascular disease. In recent years randomized trials also suggested a preventive effect for various types of cancer. We aimed to assess, in a quantitative way, benefits and harms of aspirin for primary prevention of both cardiovascular disease and cancer for a general US population between 40 and 85 years of age.
Methods
We used the Gail/National Cancer Institute approach for assessing benefits and harms. This approach provides a probability that a treatment is more beneficial than harmful and incorporates multiple outcomes, the importance of these outcomes, considers different outcome risks and treats mortality as a competing risk. Our main outcomes were the risks of seven types of cancer, myocardial infarction, ischemic and hemorrhagic stroke and gastrointestinal bleeding. We obtained effect estimates from recent meta-analyses of randomized trials and used baseline risks from the Centers for Disease Control. We conducted four sensitivity analyses to assess the influence of different assumptions about outcome risks and preferences and considered the sampling variation of the effect estimates for aspirin.
Results
The main analysis as well as the sensitivity analyses showed that aspirin has more benefits than harms. In the main analysis, the index (positive if number of prevented events > excess number of harm events over 10 years per 1,000 persons) ranged from 2 (95% CI 0.0 to 11.8; in women age 45 to 54 years) to 8 (95% CI -0.1 to 83.7; in men age 65 to 74 years). In the sensitivity analyses, the index was also positive for all age categories suggesting more benefits than harms.
Conclusion
This study suggests an overall benefit of aspirin for primary prevention of cardiovascular disease and cancer based on population-based data. For individual preventive counseling, additional benefit harm analyses should explore which individuals should or should not take aspirin based on their risk profile for cardiovascular, cancer and gastrointestinal outcomes and based on their outcome preferences. Thereby, risk-stratified and preference-sensitive prevention could become a reality.
doi:10.1371/journal.pone.0127194
PMCID: PMC4494891  PMID: 26151751
15.  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
16.  Benefit-harm analysis and charts for individualized and preference-sensitive prevention: example of low dose aspirin for primary prevention of cardiovascular disease and cancer 
BMC Medicine  2015;13:250.
Background
Clinical practice guidelines provide separate recommendations for different diseases that may be prevented or treated by the same intervention. Also, they commonly provide recommendations for entire populations but not for individuals. To address these two limitations, our aim was to conduct benefit-harm analyses for a wide range of individuals using the example of low dose aspirin for primary prevention of cardiovascular disease and cancer and to develop Benefit-Harm Charts that show the overall benefit-harm balance for individuals.
Methods
We used quantitative benefit-harm modeling that included 16 outcomes to estimate the probability that low dose aspirin provides more benefits than harms for a wide range of men and women between 45 and 84 years of age and without a previous myocardial infarction, severe ischemic stroke, or cancer. We repeated the quantitative benefit-harm modeling for different combinations of age, sex, and outcome risks for severe ischemic and hemorrhagic stroke, myocardial infarction, cancers, and severe gastrointestinal bleeds. The analyses considered weights for the outcomes, statistical uncertainty of the effects of aspirin, and death as a competing risk. We constructed Benefit-Harm Charts that show the benefit-harm balance for different combinations of outcome risks.
Results
The Benefit-Harm Charts (http://www.benefit-harm-balance.com) we have created show that the benefit-harm balance differs largely across a primary prevention population. Low dose aspirin is likely to provide more benefits than harms in men, elderly people, and in those at low risk for severe gastrointestinal bleeds. Individual preferences have a major impact on the benefit-harm balance. If, for example, it is a high priority for individuals to prevent stroke and severe cancers while severe gastrointestinal bleeds are deemed to be of little importance, the benefit-harm balance is likely to favor low dose aspirin for most individuals. Instead, if severe gastrointestinal bleeds are judged to be similarly important compared to the benefit outcomes, low dose aspirin is unlikely to provide more benefits than harms.
Conclusions
Benefit-Harm Charts support individualized benefit-harm assessments and decision making. Similarly, individualized benefit-harm assessments may allow guideline developers to issue more finely granulated recommendations that reduce the risk of over- and underuse of interventions. The example of low dose aspirin for primary prevention of cardiovascular disease and cancer shows that it may be time for guideline developers to provide combined recommendations for different diseases that may be prevented or treated by the same intervention.
doi:10.1186/s12916-015-0493-2
PMCID: PMC4589917  PMID: 26423305
Prevention; Personalized; Cardiovascular; Cancer; Benefit-risk; Aspirin; Harm; Randomized trials; Guidelines
17.  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
18.  Twelve or 30 Months of Dual Antiplatelet Therapy After Drug-eluting Stents 
The New England journal of medicine  2014;371(23):2155-2166.
Background
Dual antiplatelet therapy is recommended after coronary stenting to prevent thrombotic complications, yet the benefits and risks of treatment beyond 1 year are uncertain.
Methods
Subjects were enrolled after a drug-eluting coronary stent procedure. After 12 months of thienopyridine (clopidogrel bisulfate [Plavix] or prasugrel [Effient/Efient]) with aspirin, subjects were randomized to continued thienopyridine or placebo for another 18 months; all continued aspirin. The co-primary effectiveness end points were stent thrombosis and major adverse cardiovascular and cerebrovascular events (a composite of death, myocardial infarction, or stroke) at 12 to 30 months. The primary safety end point was moderate or severe bleeding.
Results
Subjects (N=9,961) were randomized to continued thienopyridine or placebo. Continued thienopyridine reduced stent thrombosis (0.4% vs. 1.4%, hazard ratio 0.29, 95% confidence interval [CI] 0.17-0.48, P<0.001) and major adverse cardiovascular and cerebrovascular events (4.3% vs. 5.9%, hazard ratio 0.71, 95% CI 0.59-0.85, P<0.001). Myocardial infarction was reduced (2.1% vs. 4.1%, hazard ratio 0.47, P<0.001). Rates of all-cause mortality in the continued thienopyridine and placebo groups were 2.0 and 1.5%, respectively (hazard ratio 1.36, 95% CI 1.00-1.85, P=0.052). Moderate or severe bleeding was increased with continued thienopyridine (2.5% vs. 1.6%, P=0.001). An elevated hazard for stent thrombosis and myocardial infarction was observed in both groups during the 3 months following thienopyridine discontinuation.
Conclusion
Dual antiplatelet therapy beyond one year after drug-eluting stent placement significantly reduced the risks of stent thrombosis and major adverse cardiovascular and cerebrovascular events compared with aspirin alone, but was associated with increased bleeding.
doi:10.1056/NEJMoa1409312
PMCID: PMC4481318  PMID: 25399658
19.  New insights into the mechanisms of action of aspirin and its use in the prevention and treatment of arterial and venous thromboembolism 
The antithrombotic action of aspirin has long been recognized. Aspirin inhibits platelet function through irreversible inhibition of cyclooxygenase (COX) activity. Until recently, aspirin has been mainly used for primary and secondary prevention of arterial antithrombotic events. The aim of this study was to review the literature with regard to the various mechanisms of the newly discovered effects of aspirin in the prevention of the initiation and development of venous thrombosis. For this purpose, we used relevant data from the latest numerous scientific studies, including review articles, original research articles, double-blinded randomized controlled trials, a prospective combined analysis, a meta-analysis of randomized trials, evidence-based clinical practice guidelines, and multicenter studies. Aspirin is used in the prevention of venous thromboembolism (VTE), especially the prevention of recurrent VTE in patients with unprovoked VTE who were treated with vitamin K antagonists (VKAs) or with non-vitamin K antagonist oral anticoagulants (NOACs). Numerous studies have shown that aspirin reduces the rate of recurrent VTE in patients, following cessation of VKAs or NOACs. Furthermore, low doses of aspirin are suitable for long-term therapy in patients recovering from orthopedic or other surgeries. Aspirin is indicated for the primary and secondary prevention as well as the treatment of cardiovascular diseases, including acute coronary syndrome, myocardial infarction, peripheral artery disease, acute ischemic stroke, and transient ischemic attack (especially in atrial fibrillation or mechanical heart valves). Aspirin can prevent or treat recurrent unprovoked VTEs as well as VTEs occurring after various surgeries or in patients with malignant disease. Recent trials have suggested that the long-term use of low-dose aspirin is effective not only in the prevention and treatment of arterial thrombosis but also in the prevention and treatment of VTE. Compared with VKAs and NOACs, aspirin has a reduced risk of bleeding.
doi:10.2147/TCRM.S92222
PMCID: PMC4590672  PMID: 26445544
arterial thrombosis; cyclooxygenase inhibitor; recurrent VTE; platelet
20.  Secondary prevention of ischaemic cardiac events 
BMJ 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
21.  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
22.  A Meta-Analysis of Randomized Controlled Trials on Antiplatelet Agents Versus Placebo/Control for Treating Peripheral Artery Disease 
Medicine  2015;94(31):e1293.
Abstract
Effect of aspirin (antiplatelet agents) in patients with peripheral artery disease (PAD) was still controversial. Varying studies reported varying results. Therefore, we did this meta-analysis to investigate if aspirin could reduce cardiovascular events in patients with PAD.
A comprehensive literature search (PubMed, CCTR, Embase, Web of Science, CNKI, CBM-disc, and relevant websites) was conducted from 1990 to September 2014. The key search terms (“aspirin,” “PAD,” “peripheral arterial occlusive diseases,” and “claudication”) produced 9 high-quality randomized controlled trials (RCTs) of aspirin versus placebo/control. Mantel–Haenszel random-effects model was used to analysis of the 9 RCTs. The primary outcome was the cardiovascular events.
Nine RCTs, composed of 9526 patients (4786 aspirin-treated and 4740 placebo or control-treated patients), were meta-analyzed. The results indicated that compared to placebo/control, aspirin could not significantly reduce the cardiovascular events (OR = 0.81, 95% CI = 0.56–1.15). Moreover, aspirin could not produce better effect on prevention of nonfatal myocardial infarction (OR = 0.98, 95% CI = 0.52–1.84), nonfatal stroke (OR = 0.89, 95% CI = 0.69–1.14), cardiovascular death (OR = 0.97, 95% CI = 0.68–1.38), any death (OR = 1.05, 95% CI = 0.85–1.30), and major bleeding (OR = 1.16, 95% CI = 0.82–1.65) than placebo/control. But aspirin, as monotherapy therapy, did significantly reduce the risk of nonfatal stroke (OR = 0.42, 95% CI = 0.21–0.84).
Aspirin, as monotherapy or combination therapy, did not result in a significant decrease in the cardiovascular events. But aspirin, as monotherapy therapy, did significantly reduce the risk of nonfatal stroke. Our conclusion might help clinicians in clinical treating PAD. Future studies are needed to draw firm conclusions about the clinical benefit and risks of aspirin and other antiplatelet agents.
doi:10.1097/MD.0000000000001293
PMCID: PMC4616615  PMID: 26252306
23.  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
24.  Antiplatelet regimens in the long-term secondary prevention of transient ischaemic attack and ischaemic stroke: an updated network meta-analysis 
BMJ Open  2016;6(3):e009013.
Objective
To examine the comparative efficacy and safety of different antiplatelet regimens in patients with prior non-cardioembolic ischaemic stroke or transient ischaemic attack.
Design
Systematic review and network meta-analysis.
Data sources
As on 31 March 2015, all randomised controlled trials that investigated the effects of antiplatelet agents in the long-term (≥3 months) secondary prevention of non-cardioembolic transient ischaemic attack or ischaemic stroke were searched and identified.
Outcome measures
The primary outcome measure of efficacy was serious vascular events (non-fatal stroke, non-fatal myocardial infarction and vascular death). The outcome measure of safety was any bleeding.
Results
A total of 36 randomised controlled trials (82 144 patients) were included. Network meta-analysis showed that cilostazol was significantly more effective than clopidogrel (OR 0.77, 95% credible interval 0.60–0.98) and low-dose (75–162 mg daily) aspirin (0.69, 0.55–0.86) in the prevention of serious vascular events. Aspirin (50 mg daily) plus dipyridamole (400 mg daily) and clopidogrel reduced the risk of serious vascular events compared with low-dose aspirin; however, the difference was not statistically significant. Furthermore, low-dose aspirin was as effective as higher daily doses. Cilostazol was associated with a significantly lower bleeding risk than most of the other regimens. Moreover, aspirin plus clopidogrel was associated with significantly more haemorrhagic events than other regimens. Direct comparisons showed similar results as the network meta-analysis.
Conclusions
Cilostazol was significantly more effective than aspirin and clopidogrel alone in the long-term prevention of serious vascular events in patients with prior non-cardioembolic ischaemic stroke or transient ischaemic attack. Cilostazol was associated with a significantly lower bleeding risk than low-dose aspirin (75–162 mg daily) and aspirin (50 mg daily) plus dipyridamole (400 mg daily). Low-dose aspirin was as effective as higher daily doses. However, further large, randomised, controlled, head-to-head trials are needed, especially in non-Asian ethnic groups.
doi:10.1136/bmjopen-2015-009013
PMCID: PMC4800132  PMID: 26988347
cerebral infarction; meta-analysis; platelet aggregation inhibitors; secondary prevention; transient ischemic attack
25.  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

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