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Aspirin for the secondary prevention of atherosclerotic cardiovascular disease

Aspirin for the secondary prevention of atherosclerotic cardiovascular disease
Author:
Charles H Hennekens, MD, DrPH
Section Editors:
Joann G Elmore, MD, MPH
Freek Verheugt, MD, FACC, FESC
Christopher P Cannon, MD
Deputy Editors:
Jane Givens, MD, MSCE
Nisha Parikh, MD, MPH
Literature review current through: Nov 2022. | This topic last updated: Jun 14, 2021.

INTRODUCTION — Atherosclerotic cardiovascular disease (CVD), which includes coronary artery disease, cerebrovascular disease, and peripheral artery disease, is the leading cause of death in the United States and most developed countries and is rapidly becoming the leading cause of death in the world. In 2014, in the United States alone, CVD caused more than 900,000 deaths. The totality of evidence from basic research, clinical investigations, observational epidemiologic studies, and randomized trials has provided strong support for the net benefits of aspirin in secondary prevention of CVD events [1].

The following groups of patients with established cardiovascular disease, or at high risk, benefit from aspirin for the prevention of new cardiovascular events:

Patients with acute coronary artery syndromes such as acute myocardial infarction (MI) and unstable angina.

Patients with acute occlusive stroke.

Patients with stable CVD, such as those with chronic coronary syndrome, also referred to as stable ischemic heart disease (including those who have undergone revascularization with coronary artery bypass graft surgery); stable peripheral artery disease; or carotid artery disease.

Patients who have undergone coronary artery stenting.

The evidence supporting the efficacy of aspirin for secondary prevention of atherosclerotic CVD events will be reviewed here. The use of aspirin in primary prevention of CVD and cancer is reviewed elsewhere. (See "Aspirin in the primary prevention of cardiovascular disease and cancer".)

The potential benefits of aspirin in patients with non-atherosclerotic CVD, such as heart failure, atrial fibrillation, or venous thromboembolic disease, are discussed separately. (See "Antithrombotic therapy in patients with heart failure", section on 'Effect of aspirin' and "Atrial fibrillation in adults: Use of oral anticoagulants" and "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation".)

Other relevant topics include:

(See "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy" and "Acute ST-elevation myocardial infarction: Antiplatelet therapy".)

(See "Coronary artery stent thrombosis: Incidence and risk factors" and "Long-term antiplatelet therapy after coronary artery stenting in stable patients".)

(See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke" and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".)

(See "Coronary artery stent thrombosis: Incidence and risk factors" and "Coronary artery bypass graft surgery: Graft choices" and "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".)

MECHANISMS OF ACTION — This issue is discussed elsewhere. (See "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'Mechanisms of action'.)

EFFICACY — Aspirin produces statistically significant and clinically important reductions in the risk of subsequent myocardial infarction (MI), stroke, and vascular death among a wide range of patients who have survived an occlusive cardiovascular disease (CVD) event [2,3].

The benefits of long-term aspirin therapy in secondary prevention were suggested in individual randomized trials as well as conclusively demonstrated in a series of meta-analyses of randomized trials by the Antiplatelet Trialists’ Collaboration (which later changed its name to the Antithrombotic Trialists' Collaboration). A 2002 meta-analysis included individual patient data from 195 randomized trials of antiplatelet therapy, principally with aspirin, among more than 135,000 high-risk patients with prior evidence of CVD, including prior or acute MI, prior or acute stroke or transient ischemia attacks (TIA), and other high-risk groups such as those with unstable angina, stable angina, peripheral artery disease, coronary artery bypass graft surgery, percutaneous coronary intervention, atrial fibrillation, and valvular disease [2].

The major conclusions were as follows (table 1):

Antiplatelet therapy, primarily with aspirin, significantly reduced the risk of subsequent vascular events (nonfatal MI, nonfatal stroke, and vascular death) by approximately 22 percent.

In absolute terms, antiplatelet therapy led to avoidance of approximately 36 vascular events per 1000 patients with a prior MI treated for a mean of 27 months, 38 events per 1000 patients with an acute MI treated for one month, 36 events per 1000 patients with a previous stroke or TIA treated for 29 months, 9 events per 1000 patients with an acute stroke treated for 0.7 months, and 22 events per 1000 patients with other high-risk features treated for 22 months.

There were no significant differences in efficacy or safety between doses of 75 to 150 mg/day (called low-dose aspirin) and 160 to 325 mg/day (called medium-dose aspirin).

Dose — The optimal daily dose of aspirin for long-term, secondary prevention of CVD events is unclear. Most of our contributors prescribe 75 to 100 mg/day. Some experts use higher doses, especially in individuals with overweight or obesity. The potential interrelationships of dose, body weight, and outcomes are discussed separately. (See "Nonresponse and resistance to aspirin", section on 'Body weight'.)

Aspirin in a dose range from 75 to 325 mg/day has been evaluated in numerous trials and their meta-analyses. In their meta-analysis of those trials, the Antithrombotic Trialists' Collaboration found that benefits were similar at all doses of aspirin from 75 to 1300 mg/day [2]. By contrast, the risk of bleeding began to increase with doses above 325 mg/day.

In the open-label ADAPTABLE trial, 15,076 patients with ASCVD were randomly assigned to receive either 81 or 325 mg of aspirin daily for a median follow-up of 26 months. The primary prespecified composite outcome of all-cause mortality, hospitalization for myocardial infarction, or hospitalization for stroke was comparable between those randomized to 81 mg (7.51 percent) or 325 mg (7.28 percent), yielding a hazard ratio of 1.02 (95% CI 0.91-1.14) [4]. Rates of hospitalization for major bleeding were also comparable. Those randomized to 325 mg were more likely to switch to 81 mg than vice versa (41.6 versus 7.1 percent). In addition, aspirin discontinuation rates were higher in the 325 than 81 mg dose (9 versus 7 percent). It is plausible that these differences would lead to underestimation of the true benefits as well as risks of the 325 mg dose.

The safety of aspirin with regard to bleeding, especially gastrointestinal bleeding, has been well studied, but interpretations of the available data differ. Some experts refer to the available direct comparisons from randomized trials to suggest safety equivalence across the dose range of 75 to 325 mg/day, while others refer to subgroup analyses and some observational and claims data to suggest a lower rate of bleeding at the lower end of the dose range.

In addition to direct randomized comparisons, there are indirect randomized comparisons as well as the even less reliable nonrandomized comparisons. In indirect and nonrandomized comparisons, higher doses may be prescribed to sicker patients, leading to more adverse clinical CVD outcomes due to confounding by indication [2,5-7]. In a post hoc subgroup analysis from the CHARISMA trial [8], there was no difference in efficacy between doses of 75 to 150 mg/day (called low-dose aspirin) and 160 to 325 mg/day (called medium-dose aspirin), as the proportional reductions in clinical CVD events were 32 and 26 percent, respectively. There were also no apparently greater clinical benefits in patients given higher doses up to 1500 mg/day.

In theory, it is also plausible that lower doses of aspirin might be more effective than higher doses because such low doses "spare" prostacyclin (a platelet antiaggregant and vasodilator) and cause less bleeding. In practice, however, the clinical relevance of prostacyclin sparing has never been demonstrated. With respect to efficacy, based on small numbers of events in three randomized trials, doses below 75 mg/day showed a nonsignificant benefit of about 13 percent, which was about one-half the significant overall benefit of about 25 percent seen with higher doses up to 1500 mg/day [2].

In patients with onset of acute occlusive CVD events, a loading dose of at least 162 mg of regular aspirin but preferably 325 mg should be given to achieve a rapid clinical antithrombotic effect. This issue is discussed in detail separately. (See "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy" and "Acute ST-elevation myocardial infarction: Antiplatelet therapy".)

Formulation — The formulation of aspirin (regular or enteric coated) should be an individual clinical decision made with each patient. Enteric-coated aspirin is designed to resist disintegration in the stomach; thus, health care providers and their patients may believe this to be an attractive alternative to conventional aspirin. Although this preparation may reduce erosions on endoscopy, enteric coating does not appear to protect against the clinically relevant endpoint of gastrointestinal bleeding [9]. This finding is not surprising, since injury severe enough to induce bleeding is likely to reflect systemic as well as local effects of aspirin. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity", section on 'Enteric-coated and buffered aspirin'.)

In some [10] but not all [11,12] studies, equivalent doses of enteric-coated aspirin are not as effective as plain aspirin. Lower bio-availability of these preparations and poor absorption from the higher pH environment of the small intestine may result in inadequate platelet inhibition, particularly in heavier subjects. These data contribute to the formulation of the hypothesis that low-dose, enteric-coated aspirin does not produce adequate platelet inhibition.

In acute occlusive CVD events such as acute coronary syndrome or stroke, regular aspirin should be used to achieve a rapid clinical antithrombotic effect. If the only available preparation is enteric coated, the single tablet or multiple tablets necessary to achieve the recommended dose of 325 mg should be crushed or chewed.

ALTERNATIVES TO ASPIRIN — In patients who are unable to take aspirin, or those with a history of gastrointestinal bleeding, clopidogrel is a reasonable alternative.

Some evidence from randomized trials suggests that clopidogrel or ticlopidine may be have somewhat greater efficacy than aspirin, a finding which should be weighed against much higher costs and greater likelihood of side effects. In this regard, clopidogrel seems to have a better safety profile than ticlopidine.

In the CAPRIE trial of 19,185 patients with a recent myocardial infarction (MI), stroke, or peripheral artery disease, those assigned to clopidogrel had a modest and marginally significant incremental benefit compared with those assigned to aspirin in the prevention of stroke, MI, and vascular disease (annual event rates 5.3 versus 5.8 percent) [13].

A small but significant reduction in serious cardiovascular events was also noted with clopidogrel compared with aspirin in the Antithrombotic Trialists' Collaboration (10.1 versus 11.1 percent) [2] and with ticlopidine or clopidogrel compared with aspirin in a meta-analysis of four trials that included 22,656 patients at high risk for vascular disease (12 versus 13 percent at approximately two years, odds ratio [OR] 0.91) [14].

In the latter report, ticlopidine and clopidogrel were associated with lower incidences of gastrointestinal hemorrhage and upper-gastrointestinal upset but with a higher incidence of rash, diarrhea, and, with ticlopidine, neutropenia [14].

BLEEDING — The primary safety concern with the chronic use of aspirin is major bleeding, chiefly from the gastrointestinal tract. In randomized comparisons against placebo, 325 mg/day of aspirin when used for five years leads to about a 1 percent absolute increase in risk of major gastrointestinal bleeding [15,16]. Further, there is a very small absolute increased risk of cerebral hemorrhage is about one event per 1000 patients treated for five years. Since these absolute increases in risk are far less than the absolute decrease in the risk of subsequent myocardial infarction (MI), stroke, and vascular death among a wide range of patients who have survived an occlusive cardiovascular disease (CVD) event, most secondary prevention patients should be prescribed aspirin for long-term use. (See 'Efficacy' above and "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'Bleeding'.)

CESSATION OF ASPIRIN FOR SURGERY OR PROCEDURES — The most plausible and proven benefits of aspirin are acute and likely result from irreversible inhibition of cyclooxygenase in platelets whose half-life is about eight days. Thus, even after one week of cessation, the beneficial effects of aspirin are no longer apparent. Therefore, after a short time, cessation of aspirin may increase risks of complications such as myocardial infarction (MI), stroke, or stent thrombosis. The major reasons for clinician-directed cessation of aspirin therapy have been minor surgery, endoscopy, and dental treatment. It is also important to note that aspirin may need to be continued in patients at high risk for perioperative occlusive vascular complications (eg, those undergoing coronary artery bypass graft or peripheral arterial surgery). This issue is discussed in detail elsewhere. (See "Long-term antiplatelet therapy after coronary artery stenting in stable patients" and "Perioperative medication management", section on 'Aspirin'.)

SPECIAL POPULATIONS

Anticoagulated patients — For patients with stable cardiovascular disease (CVD) or at high risk who are anticoagulated, we do not routinely add aspirin. We believe that any further reductions in occlusion are offset by increased risks of major bleeding. However, some studies suggest concomitant use with coumadin or apixaban.

Many patients with CVD receiving aspirin also need initiation of long-term oral anticoagulant or novel antiplatelet therapy for diagnoses such as atrial fibrillation. Conversely, many patients who are receiving long-term anticoagulant or novel antiplatelet therapy may develop an indication for aspirin. It has been estimated that between 5 and 10 percent of patients scheduled for percutaneous coronary intervention are taking oral anticoagulation. (See "Atrial fibrillation in adults: Use of oral anticoagulants" and "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Introduction'.)

For patients who have an indication for both antithrombotic interventions, it is important to know the absolute benefit on clinical CVD outcomes, the risk of major bleeding, and whether the addition of aspirin significantly improves outcomes (reduction in the risk of adverse ischemic cardiovascular events), since the risk of major bleeding increases significantly when both agents are used compared with warfarin alone. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Introduction'.)

In patients with stable CVD, the addition of aspirin to oral anticoagulants offers some protection against CVD events, but the risk of major bleeding is significantly increased compared with oral anticoagulant use alone.

In a 2003 meta-analysis of patients with established CVD, three trials (over 3000 patients) compared moderate- with high-intensity warfarin (international normalized ratio [INR] >2) plus aspirin with warfarin alone [17]. Combined therapy was associated with a nonsignificant lowering of the rate of cardiovascular death, myocardial infarction (MI), and stroke (12.5 versus 14.3 percent, respectively; odds ratio [OR] 0.86, 95% CI 0.70-1.06). The interpretation of these data should also be viewed in the context that the achieved INR target of 2.5 was somewhat lower than sometimes recommended.

Indirect evidence suggesting benefit from oral anticoagulation derives from the APRICOT-2 trial, not included in the meta-analysis, in which 308 patients with ST-elevation MI who underwent fibrinolytic therapy were randomly assigned to aspirin or to aspirin with moderate-intensity anticoagulation (INR 2 to 3) with warfarin [18]. At three-month follow-up, the rate of reocclusion was significantly lower in those assigned to both drugs (15 versus 28 percent; relative risk [RR] 0.46, 96% CI 0.21-0.89).

Aspirin nonresponse and resistance — Aspirin nonresponse and resistance are discussed separately. (See "Nonresponse and resistance to aspirin", section on 'Management of treatment failure'.)

Aspirin sensitivity — Aspirin sensitivity is discussed separately. (See "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'Aspirin sensitivity'.)

RECOMMENDATIONS OF OTHERS — All major societal guidelines recommend aspirin for secondary prevention in patients with established cardiovascular disease [19-21].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Secondary prevention of cardiovascular disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Beyond the Basics topic (see "Patient education: Aspirin in the primary prevention of cardiovascular disease and cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Aspirin produces clinically important and statistically significant reductions in the risk of subsequent myocardial infarction (MI), stroke, and vascular death among a wide range of patients who have survived an occlusive cardiovascular disease (CVD) event. (See 'Efficacy' above.)

Aspirin produces increased risks of major bleeding, particularly from the gastrointestinal tract that are small in relation to the far larger benefits on occlusive vascular events. The use of higher doses above 325 mg/day is associated with higher risks of bleeding. (See 'Bleeding' above.)

For patients with established and stable CVD or those at high risk, we recommend long-term aspirin therapy (Grade 1A). We give 75 to 100 mg/day. (See 'Efficacy' above.)

In patients who are unable to take aspirin, or those with a history of gastrointestinal bleeding, clopidogrel is a reasonable alternative. (See 'Alternatives to aspirin' above.)

We suggest aspirin rather than clopidogrel for secondary prevention (Grade 2B).

For most patients with either established CVD or at high risk who have an indication for long-term oral anticoagulant or novel therapy, we suggest not adding aspirin to reduce the risk of cardiovascular events due to the increased risk of bleeding (Grade 2C). (See 'Anticoagulated patients' above.)

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