Elsevier

The American Journal of Medicine

Volume 132, Issue 11, November 2019, Pages 1295-1304.e3
The American Journal of Medicine

Clinical Research Study
A Meta-Analysis of Aspirin for the Primary Prevention of Cardiovascular Diseases in the Context of Contemporary Preventive Strategies

https://doi.org/10.1016/j.amjmed.2019.05.015Get rights and content

Abstract

Background

The role of aspirin for primary prevention of cardiovascular diseases remains controversial, particularly in the context of contemporary aggressive preventive strategies.

Methods

Relevant randomized clinical trials were included, and risk ratios (RRs) were calculated using random-effects models. Additional moderator analyses were performed to compare the pooled treatment effects from recent trials (those reported after the guidelines of the National Cholesterol Education Program Third Adult Treatment Panel were published in 2001; thus, conducted on the background of contemporary preventive strategies) to the results of older trials.

Results

Data from 14 randomized controlled trials involving 164,751 patients were included. Aspirin use decreased myocardial infarction risk by 16% compared with placebo (RR 0.84; 95% confidence interval [CI], 0.75-0.94); however, in the moderator analyses, aspirin was not associated with a decreased risk of myocardial infarction in recent trials, but was in older trials (P-interaction = .02). Overall, aspirin use significantly increased the occurrence of major bleeding (RR 1.49; 95% CI, 1.32-1.69) and hemorrhagic stroke (RR 1.25; 95% CI, 1.01-1.54). In moderator analyses, the risk of major bleeding (P-interaction = .12) or hemorrhagic stroke (P-interaction = .44) with aspirin was not significantly different between the older and new trials. Differences between aspirin and placebo in the risks for all-cause stroke, cardiac death, and all-cause mortality were not found.

Conclusions

In the context of contemporary primary prevention guidelines, the effect of aspirin on myocardial infarction risk was significantly attenuated, whereas its major bleeding and hemorrhagic stroke complications were retained. Therefore, in contemporary practice, routine use of aspirin for the primary prevention of cardiovascular events may have a net harmful effect.

Introduction

In patients with known cardiovascular diseases, aspirin is the cornerstone therapy based on robust evidence that it provides a net benefit in secondary prevention.1, 2 However, in primary prevention, its net balance between benefit and harm is unclear, given the most current evidence. Current guidelines also conflict, some recommending aspirin for primary prevention, and others not.1, 3, 4, 5 Individual randomized clinical trials (RCTs) have reached conflicting conclusions,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 but meta-analyses of those RCTs suggest that aspirin is effective in the primary prevention of cardiovascular diseases, a result predominantly driven by a small decrease in the risk of myocardial infarction.17, 18, 19 Prior meta-analyses have been criticized because they included older trials that enrolled patient populations with higher smoking rates and lower use of risk-modifying medications such as antihypertensive agents and statins.17, 20, 21

Since those trials, major advances have been made in cardiovascular diseases prevention strategies, including statins for primary prevention.22, 23, 24 Following some early RCTs supporting the use of statins for primary prevention,22, 23 the National Cholesterol Education Program Third Adult Treatment Panel (NCEP-ATP III) published clinical guidelines in 2001, recommending intensive cholesterol-lowering therapy in clinical practice.25 Those guidelines led to a significant increase in statin use among US adults as early as 2003, resulting in a substantive improvement in population low-density lipoprotein levels.26 Therefore, it is unclear whether aspirin is effective for primary prevention of cardiovascular events in contemporary clinical practice. Recent RCTs have investigated the current role of aspirin in primary prevention on the background of contemporary preventive strategies.27, 28, 29, 30 Therefore, an updated meta-analysis of RCTs was performed to evaluate the safety and efficacy of aspirin for the primary prevention of cardiovascular diseases. Additionally, a moderator analysis was performed using data from only those trials reported after the publication of the NCEP-ATP III guidelines to investigate the safety and efficacy of aspirin for primary prevention of cardiovascular disease in the context of contemporary preventive strategies.

Section snippets

Methods

This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews and meta-analyses.31

Study Selection and Patient Population

Fourteen RCTs including 164,751 patients (48% male) satisfied the inclusion criteria.6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 27, 28, 29, 30 The search flow diagram is shown in Supplementary Figure 1 (Appendix, available online), and the bias assessment for each RCT is shown in Supplementary Figure 2 (Appendix, available online). The majority of these studies were high-quality trials based on Cochrane Collaboration guidelines (Supplementary Figure 2). Supplementary Table 1 (Appendix, available

Discussion

In this study of 164,751 patients enrolled in 14 RCTs, we compared the efficacy and safety of aspirin use for the primary prevention of cardiovascular diseases. We found that aspirin use in patients without known cardiovascular diseases decreased the risk of myocardial infarction by 16% at the expense of increased risks for major bleeding and hemorrhagic stroke (49% and 25%, respectively). The risks for all-cause stroke, cardiovascular mortality, and all-cause mortality were not affected.

Conclusions

Based on this meta-analysis, in patients without known cardiovascular diseases, aspirin decreases the risk of myocardial infarction by 16%, at the expense of increasing risks for major bleeding and hemorrhagic stroke (49% and 25%, respectively) without affecting the risks for all-cause stroke, all-cause mortality, or cardiovascular mortality. Furthermore, in contemporary practice, where statins and other measures are used aggressively for primary prevention, aspirin might not even decrease

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      Meta-analysis results on the primary prevention of CEVDs and CAVDs using aspirin in the last three years show that aspirin is associated with a lower risk of MI and an increased risk of major bleeding, but not with a reduction in the incidence of all-cause mortality [23,47,51–56] (Table 3). Most meta-analysis results suggest that aspirin is not associated with a reduction in stroke [47,51,53,55,56] (Table 3). However, none of the meta-analyses analyzed the role of aspirin in the primary prevention of total CEVDs and CAVDs separately.

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      The ASCEND trial of 15,480 patients with diabetes mellitus to determine the effects of aspirin versus placebo on cardiovascular complications found a 12% decrease in serious cardiovascular events in the aspirin group, accompanied by a 29% increase in major bleeding problems (approximately 41% gastrointestinal, 21% intraocular, and 17% intracranial bleeds), with a median follow-up of 7.4 years.94 Subsequently published systematic reviews and meta-analyses concluded that, in contemporary practice, the routine use of aspirin for the primary prevention of cardiovascular events may have a net harmful effect.95–97 It is important to point out that all of these studies were designed for primary prevention (ie, persons with no past history of a thrombotic or vascular event), not for secondary prevention in patients with previous clinical events.

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      However, when analyzing only newer trials (published since 2005), aspirin had no effect on the rate of ASCVD events compared with placebo. Both older and newer trials found increased rates of major bleeding among participants randomized to aspirin.23 In addition to including the HOT trial,22 this meta-analysis also included the Early Treatment Diabetic Retinopathy Study (ETDRS).

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    Funding: None.

    Conflict of Interest: None.

    Authorship: All listed authors have access to the data and substantially contributed to the conception and design, acquisition of data, and revising it critically for important intellectual content.

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