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Aspirin in the primary prevention of cardiovascular disease and cancer

Aspirin in the primary prevention of cardiovascular disease and cancer
Literature review current through: Jan 2024.
This topic last updated: Sep 13, 2023.

INTRODUCTION — Cardiovascular disease (CVD) and cancer are the leading causes of morbidity and mortality worldwide, representing 24 and 13 percent of all deaths, respectively [1,2]. Aspirin produces important reductions in CVD morbidity and mortality among survivors of a wide range of occlusive CVD events, including subsequent coronary heart disease, especially myocardial infarction (MI) and stroke. In secondary prevention, the absolute benefits on occlusive events are far greater than the absolute risks of major bleeding. In primary prevention, however, among apparently healthy people, the benefit-to-harm ratio is less clear.

Although the benefits of aspirin on CVD have been known for decades, more recent evidence from randomized trials has suggested a benefit on colorectal cancer. These findings may impact the threshold for the prescription of aspirin by health care professionals and the wishes of healthy people considering aspirin use.

This topic summarizes the evidence regarding the benefits and harms of aspirin for primary prevention of CVD and cancer. We believe the utilization of aspirin should be a shared decision between the health care professionals and their patients that carefully weighs all the absolute benefits against the absolute risks [3-5].

Discussion of the role of aspirin in secondary prevention of CVD is presented separately. The role of nonsteroidal antiinflammatory drugs (NSAIDs) and aspirin in the prevention of colorectal cancer (exclusive of CVD) is discussed separately as well. (See "NSAIDs (including aspirin): Role in prevention of colorectal cancer" and "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

MECHANISMS OF ACTION

Cardiovascular disease — Aspirin produces a clinically relevant antiplatelet effect by irreversibly acetylating the active site of cyclooxygenase-1 (COX-1), which is required for the production of thromboxane A2, a powerful promoter of aggregation. These findings are achieved by daily doses of 75 mg (and higher) or perhaps doses as low as 30 mg. Higher doses of aspirin also inhibit COX-2, which blocks prostaglandin production leading to analgesic and antipyretic effects. (See "NSAIDs: Therapeutic use and variability of response in adults", section on 'Dosing and duration' and "Platelet biology and mechanism of anti-platelet drugs" and "Mechanisms of acute coronary syndromes related to atherosclerosis".)

Cancer — Plausible biological mechanisms for anticancer effects of aspirin include induction of cell apoptosis as well as inhibition of cyclooxygenase-catalyzed prostaglandin production. In colorectal cancer, aspirin may also influence the PIK3CA pathway [6]. Prostaglandins are associated with tumor angiogenesis, cell proliferation, and inhibition of immune surveillance and apoptosis [7]. (See "The role of platelets in coronary heart disease" and "NSAIDs (including aspirin): Role in prevention of colorectal cancer".)

POSSIBLE BENEFITS — Based on multiple meta-analyses [8-12] and subsequent trials [13-17], a summary of possible benefits of aspirin on outcomes are outlined in the table (table 1). Key information in the table includes the last two columns that present the number of events in 1000 patients not receiving aspirin and the difference in those receiving aspirin. For example, in patients at low cardiovascular risk, 27 in 1000 patients (2.7 percent) not using aspirin will experience, over 10 years, a myocardial infarction (MI); this will be the case in five (0.5 percent) fewer receiving aspirin (their likelihood of infarction drops from 2.7 to 2.2 percent). The following presents a summary of the evidence in the table:

All-cause mortality or cardiovascular mortality – No impact, or a very small reduction (high-quality evidence)

Nonfatal myocardial infarction – Likely a reduction in nonfatal MI over 10 years (moderate-quality evidence)

Nonfatal stroke – Likely no reduction or a very small reduction in nonfatal stroke over 10 years (moderate-quality evidence)

Colon cancer incidence – Possible reduction in colon cancer incidence over long-term follow-up of 20 years (low-quality evidence)

Although meta-analyses, including a 2019 analysis that added the three large 2018 trials [13-17], have found a reduction in composite outcomes with aspirin, we feel that it is more informative to assess the potential benefits on individual outcomes independently, as outlined below [18].

All-cause mortality — In the aggregate, there is moderate-quality evidence for no more than a very small impact on mortality. Multiple meta-analyses performed before 2018 suggested a small relative risk reduction of the order of 6 to 8 percent, with confidence intervals bordering on no effect [8-10]. In two 2019 meta-analyses of primary prevention trials, the impact of aspirin on all-cause mortality included the possibility of both very small benefit and harm (risk ratio [RR] 0.98, 95% CI 0.93-1.02 in one analysis of 11 trials and hazard ratio [HR] 0.94, 95% CI 0.88-1.01 in one analysis of 13 trials) [18,19].

These 2019 meta-analyses included three large 2018 randomized trials that enrolled somewhat different populations [13-17]. One of these trials reported an effect consistent with earlier evidence suggesting a small relative risk reduction in mortality; a second suggested no effect, though with a confidence interval consistent with the prior evidence; and a third suggested an increase in mortality:

In the ASCEND trial, 15,480 patients with diabetes (94 percent with type 2 diabetes) but no evidence of cardiovascular disease (CVD) were randomly assigned to aspirin (100 mg daily) or placebo [13]. The majority of patients were taking statins and antihypertensive medication. Over 80 percent of patients were at low to moderate risk (less than 10 percent within five years) of a CVD event (see "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach", section on 'How to assess ASCVD risk'). The risk of death from any cause was 9.7 versus 10.2 percent, respectively (rate ratio 0.94, 95% CI 0.85-1.04) during a mean follow-up of 7.4 years [13].

In the ARRIVE trial, 12,546 moderate CVD risk patients (about 15 percent in 10 years) were randomly assigned to aspirin (100 mg daily) or placebo [17]. After a median follow-up of five years, the risk of any death was 2.55 and 2.57 percent, respectively (HR 0.99, 95% CI 0.80-1.24) [17].

In the ASPREE trial, 19,114 individuals 70 years or older were randomly assigned to aspirin (100 mg daily) or placebo [14-16]. After a median of 4.7 years of follow-up, the risk of death from any cause was 12.7 and 11.1 events per 1000 person-years, respectively (HR 1.14, 95% CI 1.01-1.29) [16]. (See 'Cancer-related mortality' below.)

Cardiovascular mortality — A 2016 meta-analysis of 11 trials that included individual patient level data among 118,445 adults who were randomly assigned to either aspirin (at doses between 50 and 500 mg daily) or placebo found no difference in the risk of cardiovascular mortality (relative risk 0.97, 95% CI 0.85 to 1.10) [10]. Three large subsequent trials produced results consistent with prior evidence; differences in vascular or cardiovascular death were very small, and consistent with chance (ASCEND [rate ratio 0.93, 95% CI 0.77-1.12], ARRIVE [HR 0.97, 95% CI 0.62-1.52], and ASPREE trial of patients 70 years of age or older [HR 0.97, 95% CI 0.71-1.33]) [13-17].

Myocardial infarction — The 2016 meta-analysis described above found a 22 percent reduction in nonfatal MI with aspirin use (relative risk 0.78, 95% CI 0.71-0.87) [10]. Although the point estimates in three subsequent trials suggest a less beneficial impact on nonfatal MI, the results have relatively wide confidence intervals, and are consistent with estimates from the 2016 meta-analysis: ASCEND (rate ratio 0.98, 95% CI 0.80-1.19), ARRIVE trial (HR 0.85, 95% CI 0.64-1.11), and ASPREE trial of patients 70 years of age or older (HR 0.93, 95% CI 0.76-1.15).

Stroke — The 2016 meta-analysis described above found no significant benefit on nonfatal stroke (relative risk 0.95, 95% CI 0.85-1.06) [10].

Results from the large, randomized trials published subsequently are similar: Aspirin did not significantly reduce the risk of nonfatal presumed ischemic stroke in ASCEND (rate ratio 0.88, 95% CI 0.73-1.06) or ARRIVE, (HR 1.12). In the ASPREE trial of patients 70 years of age or older, the risk of fatal or nonfatal ischemic stroke was similar (HR 0.89, 95% CI 0.71-1.11). Although differing in point estimates, all three trials have relatively wide confidence intervals and results are completely consistent with estimates from the 2016 meta-analysis.

It is possible that the finding of a neutral effect of aspirin on total stroke may represent a small increase in hemorrhagic stroke and a small decrease in ischemic stroke.

Cancer — Long-term follow-up data from some trials of aspirin in the treatment and prevention of CVD have provided an opportunity to explore possible benefits on cancer incidence and mortality.

Colorectal cancer — Aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) inhibit colorectal carcinogenesis, and may influence metastases, and related mortality. However, in the absence of another indication for aspirin use, we do not use aspirin to prevent the development of colorectal cancer in the general population. The potential benefit from aspirin in patients at high risk for colorectal cancer is discussed elsewhere. (See "NSAIDs (including aspirin): Role in prevention of colorectal cancer".)

Incidence — Evidence from individual patient data in randomized trials utilized in a meta-analysis with long-term follow-up suggests that aspirin decreases colorectal cancer incidence, but this finding begins to emerge only after 10 years of follow-up [20]. The extent to which participants in either the intervention or control groups used aspirin following the study intervention period is uncertain.

The US Preventive Services Task Force (USPSTF) conducted a meta-analysis of four randomized controlled trials [21-24] and reported no effect of aspirin on colorectal cancer incidence over a follow-up spanning 0 to 12 years (RR 0.99, 95% CI 0.85-1.15) [25]. Data were available for longer-term post-treatment follow-up for three of these studies (British Medical Doctor study [24], Women's Health Study [26], United Kingdom TIA study [median treatment duration range 4.4 to 10.1 years] [23]). The meta-analyses showed that aspirin use in these studies was associated with a lower long-term risk (10 to 19 years) of colorectal cancer (RR 0.60, 95% CI 0.47-0.76).

Subsequently, in the ASCEND trial with mean follow-up of 7.4 years, there was no significant difference between the aspirin and placebo groups in the incidence of gastrointestinal tract cancer (2 percent in both groups) [13]. (See 'All-cause mortality' above.)

In the ARRIVE trial with mean follow-up of five years, the rate of colon cancer was 0.22 in the aspirin group and 0.10 percent in the placebo group [17]. (See 'All-cause mortality' above.)

However, a randomized trial that demonstrated a reduction in the incidence of polyps with aspirin use provides indirect evidence for an impact of aspirin on colon cancer incidence [27].

Mortality — Although there is some evidence that long-term use of aspirin may be associated with a lower colorectal cancer mortality, it comes from post hoc analyses that have not been confirmed in appropriately designed randomized controlled trials and are not consistent with results from shorter follow-ups.

In a 2010 systematic review, utilizing long-term follow-up data from four randomized controlled trials, aspirin was associated with a 34 percent reduced long-term risk of colorectal cancer mortality (HR 0.66, 95% CI 0.51-0.85) [28].

A subsequent meta-analysis published in 2011 reported data from randomized trials comparing aspirin with no aspirin (trials of patients without [and with] established vascular disease) [29]. Individual patient data (23,535 patients) were available from seven of the eight trials.

Aspirin was associated with a possible but nonsignificant 22 percent reduction in colorectal cancer mortality during zero to five years follow-up (HR 0.78, 95% CI 0.39-1.56), but there was a 59 percent reduction of borderline significance for follow-up of ≥5 years (HR 0.41, 95% CI 0.17-1.00).

Three of the trials conducted in the United Kingdom continued to collect mortality data up to 20 years. In these trials, aspirin was associated with a significant 40 percent reduction in risk of death from colorectal cancer over this period (HR 0.60, 95% CI 0.45-0.81). In the first 10 years of follow-up, there was a possible but nonsignificant 21 percent reduction (HR 0.79, 95% CI 0.49-1.26), but a significant reduction was found from 10 to 20 years (HR 0.51, 95% CI 0.35-0.74).

In the ASPREE trial over a mean follow-up of five years, the number of colorectal cancer deaths was higher in the aspirin group (0.8 versus 0.5 deaths per 1000 person years; HR 1.77, 95% CI 1.02-3.06) [16].

A more detailed review of aspirin and other NSAIDs on reducing risk of colorectal adenomas and cancer, depending on dose and duration of therapy, is discussed elsewhere. (See "NSAIDs (including aspirin): Role in prevention of colorectal cancer".)

Other cancers — Evidence from the entire body of literature provides very limited support for incidence reductions in cancers other than colorectal, or for mortality reductions in any cancer. Evidence in support of reductions in non-colon cancer risk and mortality comes from a restricted set of studies from a single investigative team. The failure of other meta-analysis from a wider selection of studies to provide any support leaves us skeptical about possible benefits of aspirin for non-colon cancer outcomes.

Incidence — The evidence for a beneficial effect of aspirin on cancer incidence is inconsistent.

A 2012 meta-analysis of individual patient-level data from six trials of aspirin versus no aspirin that followed patients for up to 20 years reported that daily aspirin use reduced the incidence of all cancers by 12 percent during up to 10 years of follow-up (HR 0.88, 95% CI 0.80-0.98) [20]. The benefit became apparent at four years of follow-up and was independent of age, sex, and smoking status. In analysis of longer durations of five years or greater, aspirin was associated with a 30 percent reduction in all cancers (HR 0.70, 95% CI 0.56-0.88).

A 2019 meta-analysis focusing on cancer outcomes included a wider range of trials (16 trials, 104,018 patients) failed to demonstrate any effect on cancer incidence (RR 0.98; 95% CI 0.92-1.04) [30]. However, mean follow-up was only 5.5 years.

In the ASPREE trial, conducted among older adults, there was no meaningful difference in incident cancers between the daily low-dose aspirin and placebo groups (HR 1.04, 95% CI 0.95-1.14) after a median of 4.7 years follow-up [31]. However, the aspirin group did have a greater risk of incident cancer that had metastasized (HR 1.19, 95% CI 1.00-1.43) or was stage 4 at diagnosis (HR 1.22, 95% CI 1.02-1.45).

Cancer-related mortality — The evidence for a beneficial effect of aspirin on cancer-related mortality is inconsistent, although benefit, when reported, occurs only with duration of five years or greater.

In a 2012 meta-analysis of 51 randomized trials, in which data on cancer-related mortality were available from 34 (n = 69,224), aspirin reduced overall cancer-related mortality by 15 percent compared with no aspirin (odds ratio [OR] 0.85, 95% CI 0.76-0.96) [20]. When stratified by follow-up duration (<3 years, 3 to 4.9 years, ≥5 years), only patients followed for >5 years demonstrated a benefit (OR 0.63, 95% CI 0.49-0.82).

In the 2019 meta-analysis of trials comparing aspirin with placebo focusing on cancer outcomes noted above, aspirin did not reduce cancer-related mortality (risk ratio [RR] 0.99, 95% CI 0.87-1.12) [30].

In the ASPREE trial, those randomized to aspirin had a higher risk of death for cancers that presented at stages 3 (HR 2.11, 95% CI 1.03-4.33) or 4 (HR 1.31, 95% CI 1.04-1.64) compared with placebo [31].

Dementia or disability — The primary endpoint of the ASPREE trial was a composite of death, dementia, or persistent physical disability. The rate of this composite endpoint was similar in both groups at a median of 4.7 years of follow-up (21.5 versus 21.2, respectively) [14].

POTENTIAL RISKS

Bleeding

Major bleeding —The primary adverse effect of aspirin is major bleeding, typically defined as bleeding from the gastrointestinal tract or other sites that requires hospitalization and/or transfusion, as well as the extremely rare but catastrophic intracranial bleeding.

Bleeding most commonly occurs in the gastrointestinal (GI) tract and is rarely fatal [32]. Bleeding also occurs at other sites, with intracranial bleeding (hemorrhage) being the rarest but the most serious (with a 50 percent case fatality ratio).

Overall, aspirin confers a 50 percent increase in the relative risk of major nonfatal extracranial bleeding over 10 years. As an example, a 2016 meta-analysis of the use of aspirin for primary prevention found that the use of low dose aspirin (≤100 mg daily or every other day) increased the risk of major GI hemorrhage (OR 1.58; 95% CI 1.29-1.95; 1.39 excess events per 1000 person-years) [33].

In a 2019 meta-analysis of 134,446 participants, which included the ASCEND, ARRIVE, and ASPREE trials, low-dose aspirin use (≤100 mg daily) increased the risk of intracranial hemorrhage (RR 1.37, 95% CI 1.13-1.66; 2 excess intracranial hemorrhages per 1000 persons), compared with placebo [34]. The greatest risk was for subdural or extradural hemorrhage (RR 1.53, 95% CI 1.08-2.18).

However, the absolute risk increase in young, healthy individuals is low. This is illustrated in a table that presents the absolute bleeding risks with and without aspirin (table 1).

Patient characteristics that may increase the risk of major bleeding include increasing age, male sex, diabetes, chronic kidney disease, smoking, hypertension, and obesity [33,35]. If a patient has an episode of major bleeding while taking aspirin for primary prevention, the patient and clinician should weigh the risk of recurrent bleeding with the potential benefits of long-term use. (See 'Assessing benefits and risks' below.)

Issues related to the primary prevention of gastrointestinal toxicity from nonsteroidal antiinflammatory drugs (NSAIDs) are discussed in detail elsewhere. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity", section on 'Prevention strategies'.)

Minor bleeding and anemia — Daily low-dose aspirin use may also increase rates of anemia and iron deficiency, particularly in older individuals. The magnitude of the potential risk and the role for monitoring for anemia to detect occult bleeding in patients taking daily aspirin is discussed separately. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Overview of screening considerations'.)

Aspirin sensitivity — A very small minority of patients are unable to tolerate aspirin because of hypersensitivity, which most often presents with respiratory symptoms, including rhinitis or asthma and, less frequently, urticaria/angioedema (7 to 20 per 10,000 treated) [36-38]. With some forms of aspirin sensitivity, cross-reactions with other NSAIDs can occur. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions".)

In such circumstances, clinicians may consider aspirin desensitization or clopidogrel. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Desensitization' and "Introduction of aspirin to patients with aspirin hypersensitivity requiring cardiovascular interventions", section on 'Our approach'.)

DOSING — The potential benefits on cardiovascular disease (CVD) events from long-term aspirin therapy are achieved with doses in the range of 75 to 100 mg daily, but the data for cancer benefit are not entirely consistent.

The potential relationship between dose, body weight, and outcomes is discussed separately. (See "Nonresponse and resistance to aspirin", section on 'Body weight'.)

Prevention of cardiovascular disease events — The subgroup analyses from the 2002 Antithrombotic Trialists Collaboration meta-analyses provide [39] direct and indirect comparisons of different daily doses of aspirin (500 to 1500 mg versus 160 to 325 mg versus 75 to 160 mg versus <75 mg) in patients with preexisting vascular disease at high risk for future events. In these analyses, aspirin appears to be equally effective for the prevention of vascular events at doses between 75 and 325 mg daily. Aspirin in doses from 75 to 325 mg daily produce similar benefits on CVD events to doses in excess of 1300 mg but with far fewer side effects.

Prevention of cancer events — Most observational cohort studies suggest a preventive effect on development of adenomas and/or colorectal cancer that increases with increasing number of aspirin doses per week [40,41]. (See "NSAIDs (including aspirin): Role in prevention of colorectal cancer", section on 'Aspirin trials'.)

These observational data are consistent with some, but not all, randomized data that daily, as opposed to every second day, aspirin is required for prevention of colorectal and possibly other cancers [23].

Reducing risk of bleeding — Available evidence suggests that, for primary prevention, aspirin doses of ≤100 mg per day should be used to minimize risk of bleeding. In indirect comparisons in the meta-analysis conducted by the 2002 Antithrombotic Trialists' Collaboration, there were no significant differences in risk of major extracranial bleeding across dose of aspirin from 75 to 325 mg daily [39]. By contrast, a number of observational studies, which are prone to confounding by indication, have suggested a potential relationship between increased aspirin doses and bleeding. In a systematic review of >190,000 patients enrolled in 31 studies, aspirin dosage greater than 200 mg daily was associated with an approximate 30 percent increase in major bleeding compared with lower doses [42]. The investigators also reported an increase in nonmajor bleeding in patients receiving 100 to 200 mg of aspirin daily compared with patients taking less than 100 mg daily.

ASSESSING BENEFITS AND RISKS — The decision regarding aspirin for primary prevention among healthy patients should be individualized based on patient preference after discussion of the potential benefits and risks (table 1). Practitioners and patients should have frank and open discussions and these discussions should include patient values and preferences regarding cardiovascular disease (CVD), colorectal cancer, and major bleeding [43].

While numerous tools are available to estimate benefits and risks of disease, they all have limitations. None of these tools provides a risk-to-benefit calculation that takes into account all the risk factors for CVD events or the combined risk of cardiovascular events, colon cancer, and major bleeding with daily use. In addition, many calculators may not include major risk factors such as family history of early CVD or cancer as well as obesity or physical inactivity [44]. (See "Cardiovascular disease risk assessment for primary prevention: Risk calculators".)

Level of risk — The anticipated absolute effects of taking low-dose aspirin for 10 years compared with no aspirin in the primary prevention of CVD and cancer is shown for populations at different levels of risk for CVD and different risk levels for cancer. Patients without prior CVD or cancer will fall into one of three broad groups:

Low-risk individuals – Our judgment is that for most low-risk patients, the absolute benefits are insufficient to warrant use of long-term daily aspirin. For example, consider aspirin use for 10 years in 1000 patients at age 40 with low Framingham risk score (estimated 10-year cardiovascular risk of <3 percent) and low risk of colorectal cancer (<3 percent); one could expect five fewer myocardial infarctions (MIs), four more major bleeds, and seven fewer colorectal cancers with aspirin use. This also means that over 980 individuals taking aspirin for 10 years will potentially see no benefit or risk.

Intermediate-risk individuals – A different benefit-to-risk ratio emerges for patients at intermediate risk of CVD and malignancy: 1000 patients at age 60 years and a risk of CVD events of 10 to 20 percent over 10 years and at average risk of any malignancy (approximately 12 percent). Aspirin use over a 10-year period would be expected to result in 17 fewer MIs, 16 more major extracranial bleeding events, and 13 fewer cases of colorectal cancer over a 20-year follow-up. Individual patient values and preferences should play significantly into decision-making in this group. (See 'Individualizing decisions' below.)

High-risk individuals – Some patients are at particularly high risk of CVD, such as those whose 10-year risks of a first coronary heart disease event are greater than 20 percent. These are typically individuals over the age of 40 years who have multiple CVD risk factors. In addition, individuals with familial hypercholesterolemia are at very high risk for premature CVD (see "Familial hypercholesterolemia in adults: Overview", section on 'Prognosis'). This group includes individuals who are more likely to benefit from long-term daily aspirin, although the absolute benefit remains small and potential risks present.

Importance of age — Although numerous trials have reported subgroup analyses for the benefit and harm of low-dose aspirin, results have been inconsistent. However, the risk/benefit ratio of aspirin for primary prevention appears to be less favorable among older adults.

In the ASPREE trial, the only trial enrolling only patients age 70 and above, there was no clear effect of aspirin in primary prevention of MI, stroke, or cardiovascular mortality [15]. Furthermore, among patients treated with aspirin, the rate of major hemorrhage was higher compared with placebo (8.6 events per 1000 person-years versus 6.2; hazard ratio [HR] 1.38 95% CI 1.18-1.62). (See 'Possible benefits' above.)

The US Preventive Services Task Force (USPSTF) performed a microsimulation model to assess the magnitude of net benefit of low-dose aspirin use stratified by age and cardiovascular risk [45]. Their data suggest that aspirin initiation provides a modest net benefit in life-years in those aged 40 to 59 years with 10 percent or higher 10-year cardiovascular risk. In older patients, the impact varied according to age, sex, and cardiovascular risk. However, aspirin resulted in a loss of life years in men and woman aged 70 to 79.

Individualizing decisions — After assessing the patients' risk for CVD and cancer, clinicians should then discuss potential benefits and risks as discussed above and the anticipated effects on each individual outcome. Individual patients will place different values on each outcome, particularly when considering a long-term therapy with low absolute benefit and potential for risk. Some may determine that the absolute net benefit of aspirin therapy is not of sufficient magnitude to warrant the inconvenience of long-term daily medication use.

Factors to be considered in this discussion include the following:

Recommendations may differ depending on the degree of cardiovascular risk, with more potential cardiovascular benefit of aspirin in patients at greater cardiovascular risk. It is very likely, however, that bleeding risk also increases with increasing cardiac risk, limiting the gradient in net benefit across cardiovascular risk.

Use of concomitant medications known to increase bleeding risk associated with aspirin (anticoagulants, nonsteroidal antiinflammatory drugs [NSAIDs]) will reduce the net benefit associated with aspirin use.

Individualized clinical assessment of patient risk for colorectal malignancy based on family history and prior medical history (eg, colonic polyps) should be considered (see "Screening for colorectal cancer: Strategies in patients at average risk" and "Screening for colorectal cancer in patients with a family history of colorectal cancer or advanced polyp"). Calculators for estimated risk of colorectal cancer (eg, National Cancer Institute [NCI] Colorectal Cancer Risk Predictor Tool) may help in making this determination. Such a history may increase the possible absolute benefit of aspirin use.

Assessing the value a patient places on preventing a specific outcome relative to others is important. For example, patients may place greater value on avoiding vascular events or colon cancer versus increasing risk of bleeding.

OUR APPROACH — The decision to prescribe aspirin should be made on an individual (patient-by-patient) basis through a process of shared decision making by the patient and health care provider after assessment of the benefit-to-risk profile of the patient. Based on the evidence presented above, the major potential benefit of long-term aspirin appears to be a reduction in the risk of myocardial infarction (MI) among a small number of individuals (see 'Possible benefits' above). This potential benefit needs to be balanced with the small number of individuals at increased risk for bleeding. (See 'Potential risks' above.)

For patients who receive aspirin for primary prevention, we recommend a dose of 75 to 100 mg daily. Some experts may prescribe higher daily doses for prevention of colorectal cancer.

Many tools are available to calculate the risk of a cardiovascular event. None of these provides a risk-to-benefit calculation that takes into account risk of cardiovascular events, risk of the development of colorectal cancer, and risk of major bleeding with daily aspirin. We sometimes use one of these to help patients in decision-making (calculator 1 and calculator 2) [46]. These tools are discussed separately. (See "Cardiovascular disease risk assessment for primary prevention: Risk calculators".)

For all patients, whether low or high risk, the absolute benefit on MI approximated the absolute increase in the risk of major bleeding. Most patients will also want to consider the potential but small benefits on development of colorectal cancer and on total mortality. Whatever the level of cardiovascular risk, patients considering primary prophylaxis may reasonably choose to use or not use aspirin.

Some individuals age 40 years or greater at high risk for developing cardiovascular disease (CVD) and without excess bleeding risks may conclude that the benefits of aspirin at a dose of 75 to 100 mg daily for the prevention CVD events, colorectal cancer incidence, and overall mortality outweigh the risks [47]. We aim to individualize patient decisions regarding aspirin use in light of existing guidelines and patient preferences. However, we suggest not initiating aspirin for primary prevention in patients over the age of 70. Patients already taking aspirin for primary prevention should re-discuss potential risks and benefits with their clinician upon reaching age 70.

RECOMMENDATIONS OF OTHERS — Recommendations regarding the daily use of low-dose aspirin vary from guideline to guideline. The following represent recommendations from societal guideline organizations:

The 2019 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on the primary prevention of cardiovascular disease (CVD) recommend that low dose aspirin (75 to 100 mg orally daily) may be considered among adults 40 to 70 years of age who are at higher risk of CVD but not at increased risk of bleeding [48]. However, they recommend that low-dose aspirin should not be given on a routine basis for primary prevention of CVD among adults over 70 years of age, or among adults of any age who are at increased risk of bleeding.

The 2022 US Preventive Services Task Force (USPSTF) statement on the use of aspirin for the primary prevention of CVD and colorectal cancer makes recommendations for adults aged 40 years or older without known heart disease and without increased bleeding risk [49].

The decision to initiate low-dose aspirin for individuals aged 40 to 59 years of age without known heart disease who have a 10 percent or greater 10-year risk of CVD risk should be individualized and the potential benefit is small. Risk was calculated using the ACC/AHA cardiovascular risk calculator [44,50].

Among adults 60 years or older without known heart disease, initiating low-dose aspirin for the primary prevention of CVD is not recommended.

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.)

Basics topics (see "Patient education: Aspirin to prevent heart attacks and cancer (The Basics)")

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

SUMMARY AND RECOMMENDATIONS

Possible benefits – Although aspirin produces important reductions in cardiovascular disease (CVD) mortality and morbidity among survivors of a wide range of atherosclerotic cardiovascular events (secondary prevention), the benefits and harms are closely balanced in apparently healthy people (primary prevention). In patients without prior CVD events, aspirin decreases the risk of nonfatal myocardial infarction (MI) but increases the risk of major bleeding. Aspirin possibly reduces the risk of colorectal cancer over long-term follow-up (with >10 years of treatment). (See 'Cancer' above and 'Bleeding' above and 'Possible benefits' above.)

Individualizing decisions – Factors to be considered in the discussion regarding aspirin use for primary prevention include assessment of the individual's risk for each outcome (cardiovascular events, colorectal cancer, bleeding, and total mortality), assessment of the relative value the individual places on preventing specific outcomes, assessment of the patient's response to aspirin (eg, any prior bleeding issues) and their attitude to inconvenience of long-term daily therapy, and value placed on immediate increase in risk of bleeding versus delayed potential benefit on CVD and cancer. (See 'Individualizing decisions' above.)

Dosing – The potential benefits on CVD events from long-term aspirin therapy are achieved with doses in the range of 75 to 100 mg daily. (See 'Dosing' above.)

Benefits and risks – In some adults, the benefits of aspirin for primary prevention may exceed the harms (principally bleeding), while in others the harms may exceed the benefits. For most patients, the benefits and harms are likely to be closely balanced. The absolute benefits of daily aspirin in most low-risk subjects are likely insufficient to warrant use of long-term daily aspirin, while a different benefit-to-risk ratio emerges for patients at intermediate risk of CVD and malignancy and those at high risk. The decision regarding aspirin for primary prevention must involve a discussion between patients and their clinicians. (See 'Possible benefits' above.)

Individuals age 40 years or greater who are not averse to using medication, more worried about preventing MI, less worried about bleeding, and optimistic about a possible reduction in colon cancer incidence will be inclined to use aspirin; those with the opposite perspectives will be disinclined. This table provides a succinct summary of the key evidence that may aid the discussion (table 1).

For patients over the age of 70, we suggest not initiating aspirin for primary prevention (Grade 2C). (See 'Assessing benefits and risks' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff thank Dr. Charles H. Hennekens for his past contributions as an author to prior versions of this topic review.

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Topic 16291 Version 66.0

References

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