benefits and risks of aspirin in secondary and primary prevention of cardiovascular disease

8/21/2019 Benefits and Risks of Aspirin in Secondary and Primary Prevention of Cardiovascular Disease

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Official reprint from UpToDatewww.uptodate.com ©2015 UpToDate

Author Charles H Hennekens, MD, DrPH

Section EditorsFreek Verheugt, MD, FACC, FESCChristopher P Cannon, MD

Deputy Editor Gordon M Saperia, MD, FACC

Benefits and risks of aspirin in secondary and primary prevention of cardiovascular disease

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Mar 2015. | This topic last updated: Jul 28, 2014.

INTRODUCTION — Cardiovascular disease (CVD), which includes coronary heart disease, cerebrovascular

disease, and peripheral artery disease, is far and away the leading the cause of death in the United States

(US) and most developed countries and is rapidly becoming the leading cause of death in the world. In 2014, in

the US alone, CVD accounts for 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 decreasing the risk of CVD events in a wide range of patients at sufficient risk

[1]:

The evidence supporting the efficacy of aspirin for a wide range of patients at high or moderate risk of CVD,

including optimal dosing, and the relative and absolute risks of side effects will be reviewed here. The use of

aspirin in primary prevention of CVD as well as cancer is also reviewed elsewhere. (See "Aspirin in the primary

prevention of cardiovascular disease and cancer".)

Several large randomized trials, as well as their meta-analyses, have demonstrated statistically significant and

clinically important net benefits of the early initiation of aspirin in patients with acute coronary syndromes. This

issue is discussed separately. (See "Antiplatelet agents in acute non-ST elevation acute coronary syndromes"

and "Antiplatelet agents in acute ST elevation myocardial infarction".)

The net benefits of aspirin as adjunctive therapy after percutaneous coronary intervention or coronary artery

bypass graft surgery and as secondary prevention after stroke or during the treatment of acute ischemic stroke

are discussed separately. (See "Antithrombotic therapy for elective percutaneous coronary intervention:

General use" and "Coronary artery stent thrombosis: Incidence and risk factors" and "Coronary artery bypass

graft surgery: Causes and rates of graft failure" and "Antiplatelet therapy for secondary prevention of stroke"

and "Antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Aspirin' .)

MECHANISMS OF ACTION — Platelets, platelet products, and clotting factors all play important and

proximate causal roles in the occurrence of virtually all occlusive vascular events, including MI and ischemic

stroke. The disruption of platelet- and fibrin-rich atherosclerotic plaques may lead to enhanced platelet

deposition, and ultimately the formation of a thrombus that can precipitate an acute clinical cardiovascular

event [2]. (See "Platelet biology" and "The role of platelets in coronary heart disease" and "The role of the

vulnerable plaque in acute coronary syndromes".)

In addition to its well documented and clinically important antiplatelet effects, aspirin has been postulated tohave other biologic mechanisms that may play a role in decreasing risks of cardiovascular disease [ 3]. One

such mechanism may be via increased nitric oxide formation [ 4], and another may be a positive effect on

elevated levels of certain inflammatory markers, including proinflammatory cytokines and C-reactive protein.

The relationship between CRP and aspirin use is discussed elsewhere. (See "C-reactive protein in

®

®

In acute ischemic syndromes such as acute myocardial infarction (MI) and unstable angina, and longterm to reduce risks of recurrent MI, stroke, and vascular death.●

In acute occlusive stroke and long term to reduce risks of MI, recurrent stroke, and vascular death●

In secondary prevention of CVD after acute MI, occlusive stroke, transient ischemic attack, stable

angina, and coronary artery bypass surgery to reduce risks of MI, stroke, and vascular death.

●

In primary prevention of a first MI as an individual clinical judgment for apparently healthy men and

women at sufficient risk.

●

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cardiovascular disease".)

ASPIRIN NONRESPONSE AND RESISTANCE — The term "aspirin resistance" has been used to describe

the occurrence of cardiovascular events despite regular aspirin intake at recommended doses. Such treatment

failures resemble those with other drugs, including statins, beta blockers, and angiotensin converting enzyme

inhibitors, all of which are of proven benefit in the treatment of cardiovascular disease (CVD). When used for

secondary prevention, all of these drugs reduce nonfatal CVD by about one-fourth and fatal events by about

one-sixth. Thus, three-fourths of nonfatal and five-sixths of fatal events are not prevented by all these drugs,

but these circumstances do not necessarily imply the presence of "resistance."

The current lack of cogent evidence to support the clinical relevance of aspirin "resistance" in the CVD events

that continue to occur is discussed in detail separately. (See "Nonresponse and resistance to aspirin".)

ASPIRIN SENSITIVITY — A minority of patients are unable to tolerate aspirin because of hypersensitivity,

which is most often manifested clinically as respiratory tract disease (rhinitis and asthma, 10 percent, rarely

with systemic symptoms) or urticaria/angioedema (0.07 to 0.2 percent) [ 5-7]. With some forms of aspirin

sensitivity, cross-reactions occur with other nonsteroidal antiinflammatory drugs. (See "NSAIDs (including

aspirin): Allergic and pseudoallergic reactions".)

The clear benefits of aspirin in reducing risks of CVD raise clinical challenges for high-risk patients who require

aspirin and have such sensitivities [8].

BLEEDING RISK — The main adverse effect of aspirin is an increased risk of bleeding, chiefly from the

gastrointestinal (GI) tract but also very rarely from intracranial vessels. Meta-analyses of randomized trials

have demonstrated that five years of treatment with 325 mg aspirin daily produces about a one percent

absolute increase in risk of GI bleeding compared to placebo (2.47 versus 1.42 percent with placebo at an

average of 28 months and 1.3 versus 0.5 percent at variable follow-up) [ 9,10]. A nonsignificant increase in the

risk of hemorrhagic stroke of about one-third has been observed in the meta-analyses of the primary prevention

trials. This relative increase corresponds to a very small absolute annual increase of around two hemorrhagic

strokes per 10,000 allocated to aspirin. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical

features, and diagnosis", section on 'Risk factors'.)

The incidence of major bleeding, as well as occlusive vascular events, are likely to be higher in the general

population than among willing and eligible participants in randomized trials. In a population-based study,186,425 Italian citizens with a new prescription for low-dose (≤300 mg) aspirin were compared with an equal

number not prescribed aspirin [11]. The primary outcome was hospitalization for major GI bleeding and or

cerebral hemorrhage. After a median follow-up of 5.7 years, the following findings were noted:

Dosing and bleeding risk — In indirect comparisons in the worldwide meta-analysis conducted by the

Antithrombotic Trialists' Collaboration, there were no significant differences between 75 and 325 mg aspirin and

risks of major extracranial bleeding based on data from three individual randomized trials [12].

For most patients with stable coronary disease, aspirin desensitization can be attempted, although this

technique may not be effective in patients with underlying chronic urticaria. (See "Diagnostic challenge

and desensitization protocols for NSAID reactions".)

●

For patients with an acute coronary syndrome or for those who cannot undergo aspirin desensitization,

clopidogrel may be an effective alternative. Depending upon the clinical presentation and the need for

percutaneous coronary intervention, other antithrombotic therapy may be added or substituted.

Randomized data are lacking on the optimal strategy.

●

Those who self-selected for aspirin use had a higher overall incidence of hemorrhagic events (5.58 versus

3.60 per 1000 person-years; incidence rate ratio 1.55, 95% CI 1.48-1.63). Subjects who self-selected for

aspirin had an increase in 20 major bleeding events for every 10,000 treated patients. The incidence rate

ratios were similar for the relatively common gastrointestinal bleeds and the rare intracranial bleeds.

●

In subgroup analyses of patients with diabetes, those who self-selected for aspirin use did not have a

significant increase in hemorrhagic events (incidence risk ratio 1.09, 95% CI 0.97-1.22). (See 'Impact of

diabetes' below.)

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In nonrandomized post-hoc subgroup analyses from the CURE and BRAVO trials, which are useful to

formulate but not test hypotheses, there was an increase in bleeding risk at higher doses within the low-dose

range [13,14] but confounding by indication was a plausible alternative explanation.

In a 2006 systematic review of 22 randomized trials of low-dose aspirin (75 to 325 mg/day) and clopidogrel for

adverse effects, the following findings were noted for aspirin [15]:

In a nonrandomized, post-hoc subgroup analysis from the CHARISMA trial of patients with either established

cardiovascular disease (about 12,000) or at high risk (about 4000) who were randomly assigned to clopidogrel

75 mg daily or placebo [16], all were given concurrent aspirin in a daily dose at the discretion of the

investigators. (See "Secondary prevention of cardiovascular disease", section on 'Antithrombotic therapy'.)

The incidence of severe or life-threatening bleeding (primary safety end point) was evaluated at a median of 28

months in relation to the dose of aspirin (100 mg daily) and whether or not the patientreceived clopidogrel. There were no significant differences between the different aspirin dose groups in the

adjusted hazard ratio for the incidence of severe or life-threatening bleeding. In addition, there was no effect

modification by clopidogrel.

In a 2011 meta-analysis of randomized trials, low doses of aspirin alone decreased the risk for all-cause

mortality and increased the risk for GI bleeding, which further increased with concomitant use of clopidogrel

and anticoagulant therapies, but decreased in patients who took proton pump inhibitors [ 17].

Risk factors — Risk factors for aspirin-associated GI bleeding have been identified and are discussed

separately. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity", section on 'Risk

factors'.)

In the United States Preventive Services Task Force report on the use of aspirin for the primary prevention of

cardiovascular disease, the magnitude of increase in risk was estimated to be approximately two to three times

higher in patients with a history of GI ulcer, and twice as high for men as women [18]. (See "NSAIDs (including

aspirin): Primary prevention of gastroduodenal toxicity", section on 'Low dose aspirin for cardiovascular

protection' and "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity", section on 'Risk

factors'.)

Primary prevention of aspirin induced GI bleeding — Issues related to the primary prevention of GI toxicity

from nonsteroidal antiinflammatory drugs are discussed in detail elsewhere. (See "NSAIDs (including aspirin):

Primary prevention of gastroduodenal toxicity", section on 'Prevention strategies'.)

Many patients taking aspirin, such as those with acute coronary syndromes or placement of an intracoronary

stent, are also on clopidogrel. In 2008, the possibility was raised that proton pump inhibitors (PPIs) can

interfere with clopidogrel's ability to impair platelet function. This issue and our recommendations for PPI use in

patients taking long-term dual antiplatelet therapy with aspirin and clopidogrel are found elsewhere. (See

"Periprocedural and long-term gastrointestinal bleeding in patients undergoing percutaneous coronary

intervention", section on 'Prevention' and "Clopidogrel resistance and clopidogrel treatment failure", section on

'Interaction with other drugs'.)

Secondary prevention of GI bleeding — The risk associated with restarting antiplatelet therapy in patients

whose mean age was 70 to 72 and who have had an ulcer complication, mostly GI bleeding, has been

evaluated in two randomized trials in which patients were first treated for eradication of Helicobacter pylori andtherapy was restarted only if eradication of H. pylori and healing of the ulcer were documented [ 19,20]. (See

"NSAIDs (including aspirin): Secondary prevention of gastroduodenal toxicity", section on 'With continued low-

dose aspirin'.)

Low-dose aspirin increased the risk of any major bleeding, major GI bleeding, and intracranial bleeding 1.7

to 2.1 times compared to placebo. The absolute annual increase in risk was 1.3 per 1000 patients for all

major bleeding episodes (mostly GI) and 3 per 10,000 for intracranial bleeding.

●

There was no difference in bleeding risk at aspirin doses of >162 to 325 mg/day compared to 75 to 162

mg/day.

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The following risks of recurrent bleeding were noted at one year:

Not surprisingly, a PPI did not protect against lower GI bleeding (4.6 percent at one year in both groups) [20].

The efficacy of adding a PPI in patients treated with clopidogrel was not evaluated.

The high bleeding risk with clopidogrel was observed despite the fact that the ulcer risk with aspirin and other

nonsteroidal antiinflammatory drugs is thought to be mediated primarily by inhibition of cyclooxygenase, which

is not affected by clopidogrel. One plausible mechanism is impaired healing of spontaneous asymptomatic

ulcers that form at a rate of up to 2 percent per month [ 21]. (See "NSAIDs (including aspirin): Pathogenesis of

gastroduodenal toxicity".)

In summary, further research is needed to determine the optimal regimen among patients who have had a GI

bleed on low-dose aspirin. Based upon the currently available evidence, aspirin may be given with a PPI if the

estimated cardiovascular risk of the patient warrants continued therapy. In a meta-analysis of six secondary

prevention trials, it was estimated that 1.5 deaths could be prevented for every episode of nonfatal GI bleeding

[10]. (See "NSAIDs (including aspirin): Secondary prevention of gastroduodenal toxicity", section on 'Withcontinued low-dose aspirin'.)

NONASPIRIN NSAIDS — One concern with the concurrent administration of nonsteroidal antiinflammatory

drugs (NSAIDs) is a possible reduction of the cardioprotective effect of aspirin. Based upon the limited

evidence available, ibuprofen and probably other nonselective NSAIDs may have a deleterious interaction with

aspirin that may have clinical relevance [22,23]. It is possible that this deleterious interaction, if real, is

mitigated by administering aspirin at least two hours before the NSAID [ 22].

These issues as well as the effect of NSAID therapy (both nonselective and COX-2 selective) on

cardiovascular risk in patients not taking aspirin are discussed in detail separately. (See "COX-2 selective

inhibitors: Adverse cardiovascular effects" and "Nonselective NSAIDs: Adverse cardiovascular effects",section on 'Patients taking aspirin for prevention'.)

SECONDARY PREVENTION OF CVD

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 event [12,24].

The conclusive benefits of long-term aspirin therapy were best demonstrated by the Antithrombotic Trialists'

Collaboration’s meta-analyses of 195 randomized trials of antiplatelet therapy, principally with aspirin, among

more than 135,000 high-risk patients with prior evidence of cardiovascular disease, including prior or acute MI,

prior or acute stroke or transient ischemia attacks (TIA), and other high-risk groups such as unstable angina,

stable angina, peripheral artery disease, coronary artery bypass graft surgery, percutaneous coronary

intervention, atrial fibrillation, and valvular disease [12].

The major firm conclusions were as follows (table 1):

Restarting low-dose aspirin (100 mg/day) – 14.8 percent●

Substituting clopidogrel (75 mg/day) for low-dose aspirin – 8.6 percent●

Restarting low-dose aspirin (80 to 100 mg/day) with a PPI – 0.7 to 1.6 percent●

Antiplatelet therapy, primarily with aspirin, significantly reduced the relative 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,nine 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 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).

●

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Use in heart failure — The use of aspirin in patients with heart failure with or without vascular disease

(including coronary disease) is discussed separately. (See "Drugs that should be avoided or used with caution

in patients with heart failure", section on 'Aspirin' .)

Comparison to thienopyridines — Several randomized trials of secondary prevention did not test whether

thienopyridines added to the clinical benefits of aspirin, but instead compared aspirin with clopidogrel or

ticlopidine [25-28]. The CAPRIE trial, for example, found that clopidogrel had a modest, and marginally

significant advantage over aspirin for the prevention of stroke, MI, and vascular disease in 19,185 patients with

a recent stroke, MI, or peripheral artery disease (annual event rate 5.3 versus 5.8 percent) [25].

A small but significant reduction in serious cardiovascular events was also noted with clopidogrel compared to

aspirin in the Antithrombotic Trialists' Collaboration report (10.1 versus 11.1 percent) [12] and with ticlopidine or

clopidogrel compared to aspirin in a meta-analysis of four trials with 22,656 patients at high risk for vascular

disease (12 versus 13 percent at approximately two years, odds ratio 0.91) [ 29].

In the latter report, ticlopidine and clopidogrel were associated with lower incidences of gastrointestinal

hemorrhage and upper-gastrointestinal upset, but a higher incidences of rash, diarrhea, and, with ticlopidine,

neutropenia [29]. Clopidogrel is preferred to ticlopidine because it is safer. Any minimal improvement in efficacy

with clopidogrel or ticlopidine compared to aspirin must be weighed against their side effects and much higher

costs.

Cessation of aspirin — The benefits of aspirin are acute and likely result from antiplatelet effects for the life of

the platelet whose half-life is about eight days. Thus, cessation of aspirin may increase risks of complications

such as MI, stroke, or stent thrombosis. The major reasons for physician-directed cessation of aspirin therapy

in descriptions of complications have been minor surgery, endoscopy, and dental treatment. However, with

respect to surgery, there is increasing evidence that aspirin should be continued in patients at high risk for

perioperative occlusive vascular complications (eg, those undergoing coronary artery bypass graft or peripheral

arterial surgery). (See "Antiplatelet therapy after coronary artery stenting" and "Perioperative medication

management", section on 'Aspirin'.)

Concomitant use of ACE inhibitors — Angiotensin converting enzyme (ACE) inhibitors are standard therapy

in patients with heart failure as well as most with prior MI or diabetic patients, especially those not at goal

blood pressure. Post-hoc subgroup analyses of completed randomized trials had erroneously raised the

possibility that aspirin might partially attenuate the benefit from ACE inhibitors. The totality of the evidence,

however, supports no deleterious interaction between ACE inhibitors and aspirin [30-32]. (See "Angiotensin

converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Recommendations for use"

and "ACE inhibitors in heart failure due to systolic dysfunction: Therapeutic use".)

A systematic review of the effects of long-term treatment with ACE inhibitors in the presence or absence of

aspirin was performed on data from six major trials of 22,060 patients with cardiovascular disease (eg, heart

failure, left ventricular dysfunction, or MI) [32]. The overall benefits of ACE inhibitors on major cardiovascular

outcomes (eg, death, stroke, and all major vascular events) were greater in patients who also were given

aspirin, except for the subgroup of MI, which may have been due to the play of chance.

In the absence of a contraindication, aspirin and ACE inhibitors can be used safely in patients at high risk for

major vascular events. As described in the next section, it may be prudent to use a maintenance aspirin dose

of 75 to 325 mg/day in such patients.

Recommendations of others — In the 1980s, the United States Food and Drug Administration (FDA)

approved professional labeling indications for aspirin in patients with prior MI or unstable angina [33] and for

men with prior TIAs [34]. In January 1997, at a joint meeting of the FDA's Nonprescription Drugs and

Cardiovascular and Renal Drugs Advisory Committees, expansion of the professional labeling indication was

recommended to include women as well as men with prior TIAs, prior occlusive stroke, or chronic stable

angina, and those who have undergone arterial revascularization procedures (either coronary artery bypass

graft or percutaneous coronary intervention).

The 2012 American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis

guideline on the primary and secondary prevention of cardiovascular disease makes a strong recommendation

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for either aspirin or clopidogrel for patients with established coronary artery disease [35].

Dosing and cardiovascular benefit — The most widely tested regimen in the secondary prevention trials

in the Antithrombotic Trialists' Collaboration was aspirin at a dose of 75 to 325 mg/day [12].

Indirect and nonrandomized comparisons, including a post-hoc subset analysis from the large CHARISMA trial

[16], showed 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 reduction in events was 32 and 26 percent,

respectively, or higher doses up to 1500 mg/day. In such comparisons, there is confounding by indication, as

most patients assigned to higher doses entered with cerebrovascular disease and most assigned to low doses

had prior cardiac events [3,12,36,37].

It has been suggested that aspirin doses below 75 mg/day might be more effective than higher doses because

such low doses are reported to "spare" prostacyclin (a platelet antiaggregant and vasodilator) and cause less

bleeding. The clinical relevance of prostacyclin sparing, however, has never been demonstrated. With respect

to efficacy, based on small numbers of events in only three randomized trials, doses below 75 mg daily

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 [12].

At present, the United States Food and Drug Administration recommends daily doses of 75 to 325 mg, while

the 2006 American College of Cardiology /American Heart Association guidelines on secondary preventionrecommends daily doses of 75 to 162 mg for secondary prevention [38]. The American College of Chest

Physicians recommends a daily dose of 75 to 100 mg [35].

We believe the totality of evidence suggests that doses of aspirin from 75 to 325 mg daily are associated with

the best risk/benefit ratio, while some experts recommend the 75 to 162 mg per day range.

In patients with acute occlusive events, a loading dose of at least 162 mg aspirin and preferably 325 mg should

be given to achieve a rapid clinical antithrombotic effect. This issue is discussed in detail separately. (See

"Antiplatelet agents in acute non-ST elevation acute coronary syndromes" and "Antiplatelet agents in acute ST

elevation myocardial infarction".)

Aspirin formulation — The formulation of aspirin (regular, buffered, or enteric coated) should be an individual

clinical decision made with the patient. Enteric coated aspirin is designed to resist disintegration in the

stomach; thus, healthcare 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 end point of gastrointestinal bleeding [39]. This finding is not

surprising, since injury severe enough to induce bleeding is thought to reflect the systemic rather than just the

local effects of aspirin. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity",

section on 'Enteric-coated and buffered aspirin' and "NSAIDs (including aspirin): Pathogenesis of

gastroduodenal toxicity", section on 'Systemic versus topical effects'.)

In some [40] but not all [41,42] studies, equivalent doses of enteric coated aspirin are not as effective as plainaspirin. 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 vascular events (eg, acute coronary syndrome), the necessity to achieve a rapid clinical

antithrombotic effect precludes the recommendation of enteric coated aspirin because of its delayed

absorption. If the only available preparation is enteric coated, the single tablet or multiple tablets necessary to

achieve the recommended dose of 325mg should be crushed or chewed.

PRIMARY PREVENTION OF CVD — This section presents an in-depth review of the evidence on aspirin in

the primary prevention of cardiovascular events. The evidence on aspirin in the primary prevention of cancer is

presented separately. (See "Aspirin in the primary prevention of cardiovascular disease and cancer".)

Based on evidence from nine large-scale primary prevention trials of men and women without established

cardiovascular disease (CVD), aspirin produces a statistically significant and clinically important reduction in

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the risk of a first myocardial infarction (MI), but not stroke or cardiovascular death.

We believe that any decision to prescribe aspirin for primary prevention of CVD should be an individual clinical

judgment that weighs the absolute benefit in reducing the risk of a first MI against the absolute risk of major

bleeding with long-term administration. The higher the risk of cardiovascular events, the greater the likely

benefit from aspirin. (See 'Estimating the benefit to risk ratio' below.)

Meta-analyses — A comprehensive 2009 meta analysis of six trials that included individual patient level data

among over 95,000 men and women who were randomly assigned to either aspirin (at dose between 75 and

500 mg per day) or placebo showed the following [43]:

Three meta-analyses, published in 2011 and 2012 added approximately 6000 additional patients from threetrials [44-46] to the comprehensive meta-analysis of over 95,000 patients published in 2009 [47-49]. Not

surprisingly, these meta-analyses came to similar conclusions to the 2009 study. In the 2012 meta-analysis,

net cardiovascular benefit exceeded the bleeding risk at higher baseline CVD events rates [49].

Individual trials — The following are the nine randomized trials comparing aspirin to placebo that are included

in the above meta-analyses. Nearly 80 percent of patients who received aspirin came from the Physician’s

Health Study, the Women’s Health Study, and the Hypertension Optimal Treatment Trial, so the 10-year risk of

a first event in these patients is far lower than the 10 percent, which indicates moderate risk.

Estimating the benefit to risk ratio — Individual clinical decision making for aspirin in the primary prevention

Aspirin significantly reduced the incidence of serious vascular events, defined as a prespecified combined

end point of MI, death from a vascular cause (including sudden death, pulmonary embolism, hemorrhage),

or stroke (0.51 versus 0.57 percent per year). This significant reduction was attributable principally to a

significant reduction in first non-fatal MI (0.18 versus 0.23 percent per year).

●

Aspirin significantly increased the rate of major gastrointestinal (GI) and extracranial bleeds (0.10 versus

0.07 percent per year).

●

The proportional reductions were similar for women and men●

Physician’s Health Study – The United States Physician's Health Study was the first to demonstrate that

aspirin reduces the risk of a first MI [50]. Aspirin was given at a dose of 325 mg daily every other day.

●

British Doctor’s Trial – In the British Doctor's Trial, aspirin was given at a dose of 500 mg daily [51].●

Thrombosis Prevention Trial - The relative benefit of low-dose (75 mg) aspirin and warfarin therapy

(international normalized ratio [INR] goal of 1.5) in patients at high risk was addressed in the Thrombosis

Prevention Trial [52]. This trial used a 2-by-2 factorial design to evaluate low-dose aspirin (75 mg/day)

and/or warfarin (target INR 1.5).

●

Hypertension Optimal Treatment Trial – In the Hypertension Optimal Treatment Trial, aspirin was given at

a dose of 75 mg daily [53].

●

Primary Prevention Project – In the Primary Prevention Project, enteric-coated aspirin was given at adose of 100 mg daily [54].

●

Women’s Health Study – In the Women's Health Study, aspirin was given at a dose of 100 mg on

alternate days for a mean of 10.1 years [55].

●

Aspirin for Asymptomatic Atherosclerosis trial – In the Aspirin for Asymptomatic Atherosclerosis trial,

aspirin was given at a dose of 100 mg daily [44].

●

Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes trial – In the Japanese Primary

Prevention of Atherosclerosis With Aspirin for Diabetes trial, aspirin was given at a dose of 81 to 100 mg

daily to patients with diabetes [46].

●

Prevention of Progression of Arterial Disease and Diabetes trial – In the Prevention of Progression of

Arterial Disease and Diabetes trial, aspirin was given at a dose of 100 mg daily to patients with diabetes

[45].

●

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of CVD is far more complex than that for secondary prevention. In secondary prevention, the randomized

evidence has far more stroke and CVD death end points and shows conclusive benefits on MI, stroke, and

CVD death. When aspirin is used for secondary prevention, the benefit of therapy (at least a 20 percent relative

risk reduction in a population whose 10-year risk is greater than 20 percent) almost always exceeds the

absolute risk (ranging from about 1 percent in young to about 4 percent in older individuals) of major

extracranial bleeding as well as the very serious but very rare risk of hemorrhagic stroke.

In primary prevention, the randomized evidence shows conclusive benefits on first MI, but the data on stroke

and CVD death remain inconclusive. In addition, the absolute risk reduction is far lower for primary prevention;in the primary prevention trials, the average absolute risk was less than 5 percent (a 20 percent relative risk

reduction in a patient with a 10-year risk of 5 percent is about 1 percent; a 10 percent relative risk reduction in a

patient with a 10-year risk of 5 percent is about 0.5 percent). Further, if one assumes that the risk of a bleeding

event is the same as described for secondary prevention, the benefits outweigh the risks only when the risk of

a cardiovascular event begins to exceed 6 to 10 percent in 10 years (table 2C).

In addition, however, age is a risk factor for bleeding as well as occlusion. Further, not all patients are at equal

risk for the development of major bleeding. Patients with a history of GI bleed, those on chronic nonsteroidal

antiinflammatory therapy, and those with GI symptoms attributable to (or history of) ulcer disease, gastritis, or

gastroesophageal reflux disease are at increased risk.

(See 'Bleeding risk' above and "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity",

section on 'Risk factors'.)

We suggest assessing the net benefit (reduction in coronary heart disease [CHD] events minus an increase in

the risk of major bleeding) of aspirin using the following guidelines from the United States Preventive Services

Task Force (USPSTF):

While the Framingham risk calculator has a large body of evidence to support its validity in risk stratification,

one cohort study suggested that measuring coronary artery calcification (CAC) may be a reasonable alternative

approach. (See "Diagnostic and prognostic implications of coronary artery calcification detected by computed

tomography", section on 'CAC and prognosis in asymptomatic patients'.) Using data from 4229 patients in the

Multi-Ethnic Study of Atherosclerosis (MESA), participants with CAC ≥100 had favorable risk-to-benefit

estimations for aspirin use and those with a score of zero were estimated to receive net harm [56]. At present,

we believe that further research is necessary to support the use of CAC scoring.

Some patients are at particularly high risk, such as those over age 40 with metabolic syndrome whose 10-year

risks of a first CHD event are 16 to 18 percent. As such, it may be prudent to consider aspirin as an adjunct to

statins for primary prevention. The decision should also be an individual clinical judgment that weighs the

magnitude of the absolute benefit on first MI against the magnitude of the absolute risk, chiefly major bleeding.

The individual patient's risk of a first cardiovascular event should be calculated. We suggest using a

calculator that uses a multivariable risk function derived from data in the Framingham Heart

Study (calculator 1 and calculator 2). (See "Estimation of cardiovascular risk in an individual patient

without known cardiovascular disease".)

●

The magnitude of the benefit and risk can be estimated from existing tables provided by the USPSTF

(table 2A-C).

●

Aspirin should be prescribed based on an individual clinical judgment when the magnitude of the absolute

benefit exceeds the magnitude of the absolute harm (table 2C). When the magnitude of benefit is similar

to that of risk, patient preference may be considered (USPSTF). For instance, an individual who feels that

the prevention of an MI or stroke is more important than the development of a GI bleed may state a clear

preference for aspirin use.

●

This general approach may not be useful in patients with risk factors for bleeding such as history of GI

bleeding or ulcers, nonsteroidal antiinflammatory drug use, or upper GI tract pain, as their risk of GIbleeding is much higher. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity",

section on 'Risk factors'.)

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We believe that any general guidelines for aspirin in primary prevention should include the results of ongoing

randomized trials of aspirin in moderate- to high-risk primary prevention subjects.

Impact of age — The six large scale randomized trials of aspirin in primary prevention include over 90,000

subjects from age 40 to 89, but their average 10-year risk of a first CHD event is less than 5 percent. Further

randomized evidence is accumulating in several large scale randomized trials, in particular ARRIVE and

ASPREE, which target patients at moderate to high risk with an average risk of a f irst CHD event of 10 to 19

percent. Since risk of a first CHD event increases with age in men and women, these trials will include a

greater preponderance of older subjects. Such data should form a rational basis for guidelines for primaryprevention in moderate to high-risk men and women.

Impact of gender — The totality of randomized evidence suggests no differences in response to aspirin

between men and women [57]. A 2009 meta-analysis of the results from 22 trials of primary and secondary

prevention, including about 135,000 patients, showed no difference in the response to aspirin between men and

women [43]. A 2002 meta-analysis of the trials of secondary prevention came to a similar conclusion [ 12].

In the Women’s Health Study (WHS), aspirin showed a significant benefit on risk of a first stroke but not a first

MI [55]. Since 90 percent of the subjects were under 65, the predominant occlusive vascular event in such

women is stroke, not MI. In the 10 percent of women aged 65 and over who accrued 30 percent of the end

points, MI was far more common, and aspirin reduced the risk of a first MI to the same degree as in the

previous trials of primary prevention predominantly in men.

This hypothesis of possible gender differences had been formulated from a 2006 gender-specific meta-analysis

of randomized trials restricted to aspirin in the primary prevention of CVD suggested a gender difference [58].

In this meta-analysis of over 51,000 women, about 80 percent of women were from the WHS discussed above.

Aspirin was associated with a significant 12 percent reduction in the combined cardiovascular outcome of

nonfatal MI, nonfatal stroke, and cardiovascular mortality (odds ratio 0.88; 95% confidence interval 0.79-0.99),

attributable principally to a significant 33 percent MI reduction in men and 17 percent stroke reduction in

women.

Impact of diabetes — In the 2002 version of the National Cholesterol Education Program Adult Treatment

Panel III, diabetes was elevated from a major risk factor to a CHD risk equivalent [59]. The rationale for this

change derives, in part, from earlier observations that patients with diabetes have several-fold increased risks

of CHD, which are even greater in women than men. This issue is discussed in detail elsewhere. (See

"Overview of the risk equivalents and established risk factors for cardiovascular disease", section on 'Diabetes

mellitus'.)

With respect to the use of aspirin for the primary prevention of CVD among patients with diabetes but no other

risk factors, evidence of benefit is conflicting. Further randomized evidence is necessary and will emerge over

the next several years [60]. (See "Overview of medical care in adults with diabetes mellitus", section on

'Aspirin'.)

Based on the available evidence, a 2010 expert consensus document written jointly by the American Diabetes Association, American Heart Association, and the American College of Cardiology Foundation made the

following recommendations for the use of low-dose aspirin (75 to 162 mg daily) in adults with diabetes but no

history of CVD [61]:

These recommendations do not differ in substance from our recommendations for primary prevention. (See

'Summary and recommendations' below.)

The viewpoint of this consensus document, as well as the 2012 American College of Chest Physicians

Antithrombotic Therapy and Prevention of Thrombosis guideline on the Primary and secondary prevention of

cardiovascular disease, is that diabetes should be considered a risk factor, as opposed to a CHD equivalent

Aspirin may be considered for those whose 10-year risk of CVD events is greater than or equal to 10

percent and in whom the risk of bleeding is not increased.

●

A weaker recommendation, based on weak evidence, was made for patients whose 10-year risk of CVD

events is between 5 and 10 percent.

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[35].

The 2012 European Guidelines on Cardiovascular Disease Prevention in Clinical Practice make a strong

recommendation to not prescribe aspirin for patients with diabetes if CVD is not present [62].

Possible benefit for the prevention of cancer related events — The use of aspirin for primary prevention of

CVD as well as cancer is reviewed elsewhere. (See "Aspirin in the primary prevention of cardiovascular

disease and cancer".)

Recommendations of others — The 2009 USPSTF statement on the use of aspirin for the prevention of CVDmakes strong but separate recommendations for women and men, based on their interpretation of the above

trials [18,63]:

The 2012 American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis

guideline on the Primary and secondary prevention of cardiovascular disease makes a weak recommendation

for low-dose aspirin (as opposed to no aspirin) for primary prevention in all persons over the age of 50 years.The document acknowledges the importance of individual clinical judgement, which should include an

assessment of the absolute benefits and risks. (See "Estimation of cardiovascular risk in an individual patient

without known cardiovascular disease".)

In 2014, the United States Food and Drug Administration issued a statement, consistent with our position, that

any decision to use aspirin in primary prevention of CVD should be an individual clinical judgment between the

healthcare provider and each of his or her patients that weighs the absolute benefits on occlusion against the

absolute risks of bleeding [64]. Randomized trials of such subjects are ongoing and will provide direct data on

this issue.

Our approach — The approach summarized below takes into account only the prevention of CVD events. Asmentioned at the beginning of the section, there is reported evidence that a decision to prescribe aspirin may

need to take into account the primary prevention of cancer. This approach is discussed in detail separately.

(See "Aspirin in the primary prevention of cardiovascular disease and cancer".)

The data for the use of aspirin in primary prevention of cardiovascular disease have far more uncertainties than

for secondary prevention. We believe that healthcare providers should make individual clinical judgments about

the use of aspirin for primary prevention in those apparently healthy men and women whose absolute benefit on

reducing cardiovascular events will outweigh their risks of major bleeding. (See 'Primary prevention of CVD'

above.)

At present, judgments about prescribing long-term aspirin therapy for apparently healthy individuals atintermediate cardiovascular risk should continue to be made on a case-by-case basis. Such decisions should

be based on individual clinical judgments between the healthcare provider and each of his or her patients. The

decision should involve the absolute risk of an important vascular event as well as the absolute risk of a major

extracranial bleed. (See 'Efficacy' above and 'Estimating the benefit to risk ratio' above.)

The following points may be considered decision making:

In women aged 55 to 79 years, when the potential benefit of a reduction in ischemic stroke outweighs the

risk of an increase in gastrointestinal hemorrhage.

●

In men aged 45 to 79, when the potential benefit from a reduction in the rate of MI outweighs the risk of

an increase in GI hemorrhage.

●

For low-risk patients (ie, men and women whose 10-year risk of a first CHD event is less than 10

percent), the absolute benefit on occlusive vascular events may be less than the absolute risk of major

bleeding.

●

For moderate risk patients (ie, men and women whose 10-year absolute risk of a first CHD event is 10 to19 percent), the randomized data on benefits and risks are sparse, so clinical decision-making should be

made on an individual basis for those men and women in whom the benefits of aspirin to prevent a first

MI are likely to exceed their risk of major extra-cranial bleeding. In these patients, it should also be noted

that aggressive risk-preventative strategies, including the use of statins, will reduce both MI and

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UNDERUTILIZATION OF ASPIRIN — Despite the established benefit of aspirin in patients with a wide range

of prior occlusive vascular diseases, its use remains suboptimal. In addition, aspirin remains an underutilized

treatment for acute myocardial infarction (MI). In a national registry of more than 1000 larger United States

hospitals, only 77 percent of acute MI patients received aspirin in 1993 [65]. Similar findings were noted in a

1992 to 1993 study of patients 65 years of age and older: Only 61 percent were receiving aspirin within two

days of hospitalization [66]. Increasing the use of aspirin to virtually all acute MI patients would save an

additional 5000 to 10,000 lives in the United States each year [67].

Aspirin utilization in patients with an acute MI in the United States appears to be improving over time. This was

illustrated in a report in which a cohort of Medicare patients hospitalized with acute MI (both ST elevation and

non-ST elevation MI) between 1994 and 1995 (over 230,000 patients) was compared with a cohort hospitalizedbetween 1998 and 1999 (over 35,000 patients) [68]. The use of several recommended therapies increased over

time, including early aspirin (76 to 83 percent) and aspirin at discharge (77 to 83 percent).

While 60 to 84 percent of patients in the United States hospitalized for unstable angina or an MI receive

aspirin, it is less frequently used in outpatients with coronary artery disease or diabetes [69-71]. One study of

10,942 visits to cardiologists or primary care physicians by patients with coronary disease found that for the

period of 1993 to 1996, aspirin use was 26 percent [ 70]. Aspirin use was more frequently reported by

cardiologists than internists, family practitioners, or general practitioners (37 versus 20, 18, and 11 percent,

respectively).

ANTICOAGULATED PATIENTS — Despite the evidence presented above, which shows that aspirin reducesthe rate of adverse cardiovascular events in most patients with established disease and many at high risk, the

addition of aspirin (or other antiplatelet agent) to warfarin in patients with an indication for the latter has not

been shown to improve outcomes. This section will outline the rationale for not recommending aspirin for

anticoagulated patients who would otherwise seem to benefit.

Patients who potentially could benefit from both antiplatelet and anticoagulant therapy are common. For

example, it is estimated that between 5 and 10 percent of patients scheduled for percutaneous coronary

intervention are taking oral anticoagulation. (See "Atrial fibrillation: Anticoagulant therapy to prevent

embolization" and "Triple antithrombotic therapy in patients with cardiovascular disease", section on

'Introduction'.)

For patients with cardiovascular disease who must be anticoagulated, it is important to know 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 to

warfarin alone. (See "Triple antithrombotic therapy in patients with cardiovascular disease", section on 'Rates'.)

The first step in supporting a recommendation to not add aspirin to warfarin is to demonstrate that

anticoagulant therapy lowers the rate of ischemic heart disease events in patients not taking aspirin. The

following two studies are relevant:

occlusive stroke with little hazard. An informed clinical decision should include whether to use aspirin as

an adjunct, not alternative to other therapeutic lifestyle changes and pharmacologic measures.

We believe that individual clinical judgement should be considered for those subjects whose 10-year risk

of a first event is 10 percent or greater while awaiting the results of the ongoing randomized trials directly

testing this hypothesis.

●

Available data suggest that daily doses of aspirin between 75 and 325 mg are equally safe and effective.

(See 'Efficacy' above and 'Primary prevention of CVD' above.)

●

A 2003 meta-analysis identified three trials of nearly 1000 patients with established cardiovascular

disease that compared moderate intensity warfarin therapy (international normalized ratio [INR] 2 to 3) to

placebo [72]. (See "Chronic anticoagulation after acute coronary syndromes", section on 'Randomized

trials'.) Anticoagulation was associated with a non-significant 16 percent (95% confidence interval [CI] -11

to 37) reduction in the risk of cardiovascular death, myocardial infarction (MI), or stroke. In 13 trials (8140

patients) that compared high-intensity warfarin (INR >2.8) to placebo, warfarin significantly reduced the

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The second step is to show that anticoagulant plus aspirin is not significantly better than warfarin alone, given

the known increase in major bleeding associated with the concomitant use of both agents:

Based on limited evidence, we do not recommend routinely adding aspirin (or other antiplatelet agent) to

warfarin (or other anticoagulant) to reduce the risk of ischemic cardiovascular disease events in patients with or at high risk for cardiovascular disease. There is no convincing evidence of benefit and the risk of major

bleeding with combined therapy is higher. This recommendation is consistent with that made in the 2012

American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis guideline on

Antithrombotic therapy for atrial f ibrillation [74].

The use of dual antiplatelet therapy (aspirin plus a platelet P2Y receptor blocker) plus oral anticoagulant in

patients with recent acute coronary syndrome or stent placement is discussed in detail elsewhere. (See

"Chronic anticoagulation after acute coronary syndromes", section on 'Patients with indications for chronic

anticoagulation' and "Triple antithrombotic therapy in patients with cardiovascular disease", section on 'TOAT

versus other therapies'.)

Some of our authors and reviewers are comfortable continuing aspirin and anticoagulant therapy, especially in

patients with prior MI or less than a year after stenting if there have been no significant bleeding episodes and

the risk of future bleeding is low. (See "Therapeutic use of warfarin and other vitamin K antagonists", section

on 'Major risk factors'.)

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 5 to 6

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 10 to 12 grade reading level and are best for patients who want in-depthinformation 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

rate of this outcome compared to placebo (2.3 versus 30.3 percent).

The Thrombosis Prevention trial (not included in the meta-analysis) randomly assigned nearly 5000 men

(without cardiovascular disease but at high risk) in a 2x2 factorial design to either to low-dose aspirin (75

mg daily) or placebo and to low-dose warfarin (INR target of 1.5) or placebo [52]. (See 'Individual trials'

above.) Low dose warfarin significantly reduced the rate of ischemic heart disease events compared to

placebo (10.3 versus 13.3 percent). An important limitation of this study is the low INR achieved.

●

In the meta-analysis discussed above, three trials (over 3000 patients) compared moderate to high

intensity warfarin (INR >2) plus aspirin to warfarin alone. Combined therapy was associated with a non-

significant lowering of the rate of cardiovascular death, MI, and stroke (12.5 versus 14.3 percent,

respectively; odd ratio 0.86, 95% CI 0.70-1.06). The results of this analysis should be interpreted with

some caution, as the achieved INR target was somewhat lower than that felt to be ideal (2.5).

●

In the Thrombosis Prevention trial discussed above, combination warfarin plus aspirin reduced the rate of

ischemic heart disease (8.7 versus 10.3 percent), but the statistical significance was not reported.

●

The SPORTIF trials (III and IV) evaluated the relative efficacy of warfarin (INR 2 to 3) to ximelagatran inpatients with atrial fibrillation and included a high percentage of patients with stable cardiovascular

disease or at high risk. (See "Atrial fibrillation: Anticoagulant therapy to prevent embolization", section on

'Clinical use of anticoagulants'.)

A post-hoc analysis compared outcomes in the 14 percent of patients who received aspirin to those who

did not [73]. The rate of MI with aspirin plus warfarin (0.6 percent per year) was not significantly different

from that with warfarin alone (1.0 percent per year). In addition, combination therapy was associated with

a significant increase in the risk of major bleeding compared to warfarin alone (3.9 versus 2.3 percent).

●

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