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# Which people should take aspirin for primary prevention of cardiovascular disease?

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### Abstract

Dear editor A single trial, ISIS-2,1 in 1988, demonstrated the utility of daily aspirin in the setting of acute myocardial infarction, reducing the risk of vascular death by 23%. In addition, aspirin has also proven effective in the setting of acute ischemic stroke.2 Thus, for a subset of the general population, aspirin may help to prevent heart attacks and strokes. In fact, at low doses, in the range of 75 to 100 mg per day, aspirin prevents the progression of existing cardiovascular disease (CVD), including coronary heart disease, stroke and peripheral arterial disease, and reduces the frequency of cardiovascular events in patients with history of CVD,3,4 referred to as secondary prevention. Although the benefits of aspirin for secondary prevention of CVD are well known, its use in primary prevention of CVD, defined as prevention of the first occurrence of CVD for all patients without clinical CVD, including those with diabetes mellitus and those without clinical evidence of atherosclerotic disease who are at higher CVD risk, is less clear and controversial results have been obtained. In fact, the results of several studies using aspirin for primary prevention of CVD have generally shown more modest reductions of major vascular events compared with secondary prevention (12% vs 23%).3,5 In this regard, the health study of women,6 the hypertension optimal treatment (HOT) study,7,8 the primary prevention project,9,10 the health study research group,11 the British doctors’ trial,12 and the thrombosis prevention trial,13 indicate that aspirin therapy is associated with a significant reduction of 19% in the risk of stroke and no reduction in the risk of myocardial infarction in women; and a significant reduction of 32% in the risk of myocardial infarction and a non-significant increase in the risk of stroke in men. However, in all cases, aspirin significantly increased the risk of bleeding, as the main important side effect.14 In this context, because fatal and non-fatal thrombotic events (eg, stroke and/or myocardial infarction events) are usually prevented by aspirin, in an order of magnitude lower than in secondary prevention, and overall risk for bleeding events (eg, intracranial and/or subarachnoid hemorrhage events) are generally increased by aspirin, in an order of magnitude equal to secondary prevention, aspirin appears to offer little benefit for the primary prevention of CVD. Moreover, in the vast majority of primary prevention studies, the overall risk level for CVD events was very low5 and the events rate was much lower than expected, leading to studies with less power to detect differences in the primary prevention of CVD. In addition to this, it must add a greater use in general population of preventive medications for different atherosclerotic risk factors, such as antihypertensive and lipid-lowering drugs, and other preventive measures, which together result in fewer events than expected.15 Accordingly, it was more difficult to achieve an overall risk reduction of cardiovascular events than in secondary prevention,2,3,5 and most studies concluded that low-dose aspirin does not significantly reduce the risk of cardiovascular death, non-fatal stroke (ischemic or hemorrhagic) or non-fatal myocardial infarction in subjects without prior CVD.16 Thus, using aspirin, in a cost-effective manner and with a good risk–benefit balance, for primary prevention of CVD, we must consider that patients are affected by different atherosclerotic risk factors (eg, hypertension, dyslipidemia, and diabetes mellitus) and, therefore, the preventive effects of aspirin on CVD will be heterogeneous. So, it will be necessary to study these preventive effects, for each type of individual cardiovascular event (eg, ischemic or hemorrhagic stroke, fatal or non-fatal myocardial infarction) among the different subgroups of patients, stratified according to cardiovascular risk factors studied, eg, hypertension, dyslipidemia, diabetes mellitus, sex, age, smoking, family history of premature CVD, blood pressure (<120/75 mmHg, 120–129/75–84 mmHg, 130–139/85–89 mmHg, and $140/$90 mmHg), body mass index (<25.0, 25.0–29.9, and \$30.0) and/or 10-year cardiovascular risk of 6%–10%.16 This would be the case for the following ongoing clinical trials: the ASCEND study, involving aspirin for patients 40 years and older with type 1 or type 2 diabetes;17 the ARRIVE study, testing aspirin in middle aged and older patients who are at moderate risk based on the presence of multiple risk factors for CVD;18 and the ASPREE study, testing aspirin in individuals older than 70 years.19 With these data, it will be possible to demonstrate the presence or absence of a preventive effect of low-dose aspirin and, consequently, the benefit of aspirin treatment for primary prevention in certain types of patients. However, so long as clinical trials are conducted and until completion, the use of aspirin for primary prevention of CVD should target patients at high cardiovascular risk: physicians should evaluate the risks and benefits of aspirin therapy for primary prevention and incorporate patient preferences.

### Most cited references17

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### Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.

(2002)
To determine the effects of antiplatelet therapy among patients at high risk of occlusive vascular events. Collaborative meta-analyses (systematic overviews). 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. 287 studies involving 135 000 patients in comparisons of antiplatelet therapy versus control and 77 000 in comparisons of different antiplatelet regimens. "Serious vascular event": non-fatal myocardial infarction, non-fatal stroke, or vascular death. 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. 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.
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### A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women.

(2005)
Randomized trials have shown that low-dose aspirin decreases the risk of a first myocardial infarction in men, with little effect on the risk of ischemic stroke. There are few similar data in women. We randomly assigned 39,876 initially healthy women 45 years of age or older to receive 100 mg of aspirin on alternate days or placebo and then monitored them for 10 years for a first major cardiovascular event (i.e., nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes). During follow-up, 477 major cardiovascular events were confirmed in the aspirin group, as compared with 522 in the placebo group, for a nonsignificant reduction in risk with aspirin of 9 percent (relative risk, 0.91; 95 percent confidence interval, 0.80 to 1.03; P=0.13). With regard to individual end points, there was a 17 percent reduction in the risk of stroke in the aspirin group, as compared with the placebo group (relative risk, 0.83; 95 percent confidence interval, 0.69 to 0.99; P=0.04), owing to a 24 percent reduction in the risk of ischemic stroke (relative risk, 0.76; 95 percent confidence interval, 0.63 to 0.93; P=0.009) and a nonsignificant increase in the risk of hemorrhagic stroke (relative risk, 1.24; 95 percent confidence interval, 0.82 to 1.87; P=0.31). As compared with placebo, aspirin had no significant effect on the risk of fatal or nonfatal myocardial infarction (relative risk, 1.02; 95 percent confidence interval, 0.84 to 1.25; P=0.83) or death from cardiovascular causes (relative risk, 0.95; 95 percent confidence interval, 0.74 to 1.22; P=0.68). Gastrointestinal bleeding requiring transfusion was more frequent in the aspirin group than in the placebo group (relative risk, 1.40; 95 percent confidence interval, 1.07 to 1.83; P=0.02). Subgroup analyses showed that aspirin significantly reduced the risk of major cardiovascular events, ischemic stroke, and myocardial infarction among women 65 years of age or older. In this large, primary-prevention trial among women, aspirin lowered the risk of stroke without affecting the risk of myocardial infarction or death from cardiovascular causes, leading to a nonsignificant finding with respect to the primary end point. Copyright 2005 Massachusetts Medical Society.
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### Final report on the aspirin component of the ongoing Physicians' Health Study. Steering Committee of the Physicians' Health Study Research Group.

(1989)
The Physicians' Health Study is a randomized, double-blind, placebo-controlled trial designed to determine whether low-dose aspirin (325 mg every other day) decreases cardiovascular mortality and whether beta carotene reduces the incidence of cancer. The aspirin component was terminated earlier than scheduled, and the preliminary findings were published. We now present detailed analyses of the cardiovascular component for 22,071 participants, at an average follow-up time of 60.2 months. There was a 44 percent reduction in the risk of myocardial infarction (relative risk, 0.56; 95 percent confidence interval, 0.45 to 0.70; P less than 0.00001) in the aspirin group (254.8 per 100,000 per year as compared with 439.7 in the placebo group). A slightly increased risk of stroke among those taking aspirin was not statistically significant; this trend was observed primarily in the subgroup with hemorrhagic stroke (relative risk, 2.14; 95 percent confidence interval, 0.96 to 4.77; P = 0.06). No reduction in mortality from all cardiovascular causes was associated with aspirin (relative risk, 0.96; 95 percent confidence interval, 0.60 to 1.54). Further analyses showed that the reduction in the risk of myocardial infarction was apparent only among those who were 50 years of age and older. The benefit was present at all levels of cholesterol, but appeared greatest at low levels. The relative risk of ulcer in the aspirin group was 1.22 (169 in the aspirin group as compared with 138 in the placebo group; 95 percent confidence interval, 0.98 to 1.53; P = 0.08), and the relative risk of requiring a blood transfusion was 1.71. This trial of aspirin for the primary prevention of cardiovascular disease demonstrates a conclusive reduction in the risk of myocardial infarction, but the evidence concerning stroke and total cardiovascular deaths remains inconclusive because of the inadequate numbers of physicians with these end points.
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### Author and article information

###### Journal
Ther Clin Risk Manag
Ther Clin Risk Manag
Therapeutics and Clinical Risk Management
Therapeutics and Clinical Risk Management
Dove Medical Press
1176-6336
1178-203X
2015
02 July 2015
: 11
: 1043-1045
###### Affiliations
[1 ]Pharmacy Department, Hospital Real de Nuestra Señora de Gracia, Zaragoza, Spain
[2 ]Haematology Department, Hospital Real de Nuestra Señora de Gracia, Zaragoza, Spain
###### Author notes
Correspondence: Roberto Lozano, Pharmacy Department, Hospital Real de Nuestra Señora de Gracia, C/Ramón y Cajal 60, 50004 Zaragoza, Spain, Tel +34 976 764 522, Fax +34 976 764 555, Email rlozano@ 123456salud.aragon.es
###### Article
tcrm-11-1043
10.2147/TCRM.S88091
4494605

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Medicine