Aspirin: Its risks, benefits, and optimal use in preventing cardiovascular events
ABSTRACTAspirin has a well-established role in preventing adverse events in patients with known cardiovascular disease. However, its benefit in patients without a history of cardiovascular disease is not as clear, particularly in people with diabetes, in women, and in the elderly. Recent studies have provided insight into the risks of aspirin use, particularly bleeding, compared with its benefits in these subgroups.
KEY POINTS
- Aspirin is as beneficial in low doses (eg, 81 mg daily) as it is in standard doses (325 mg) and poses less risk of gastrointestinal bleeding, although the bleeding risk is still twice as high as without aspirin.
- Since the absolute reduction in heart attacks and strokes is less in primary prevention than in secondary prevention, the risk of bleeding may for some groups outweigh the benefit, and the decision to use aspirin must be more individualized.
- Whether to prescribe aspirin for primary prevention depends on the combination of the individual patient’s sex, age, and 10-year risk of myocardial infarction (in men) or of stroke (in women).
ASPIRIN IN PATIENTS WITH CORONARY ARTERY DISEASE
Randomized clinical trials have validated the benefits of aspirin in secondary prevention of cardiovascular events in patients who have had a myocardial infarction. Patients with coronary disease who withdraw from aspirin therapy or otherwise do not adhere to it have a risk of cardiovascular events three times higher than those who stay with it.17
Despite the strong data, however, several issues and questions remain about the use of aspirin for secondary prevention.
Bleeding risk must be considered, since gastrointestinal bleeding is associated with a higher risk of death and myocardial infarction in patients with cardiovascular disease.18 Many patients with coronary disease are on more than one antiplatelet or anticoagulant therapy for concomitant conditions such as atrial fibrillation or because they underwent a percutaneous intervention, which further increases the risk of bleeding.
This bleeding risk is reflected in changes in the most recent recommendations for aspirin dosing after percutaneous coronary intervention. Earlier guidelines advocated use of either 162 or 325 mg after the procedure. However, the most recent update (in 2011) now supports 81 mg for maintenance dosing after intervention.7
Patients with coronary disease but without prior myocardial infarction or intervention. Current guidelines recommend 75 to 162 mg of aspirin in all patients with coronary artery disease.6 However, this group is diverse and includes patients who have undergone percutaneous coronary intervention, patients with chronic stable angina, and patients with asymptomatic coronary artery disease found on imaging studies. The magnitude of benefit is not clear for those who have no symptoms or who have stable angina.
Most of the evidence supporting aspirin use in chronic angina came from a single trial in Sweden, in which 2,000 patients with chronic stable angina were given either 75 mg daily or placebo. Those who received aspirin had a 34% lower rate of myocardial infarction and sudden death.19
A substudy of the Physicians’ Health Study, with fewer patients, also noted a significant reduction in the rate of first myocardial infarction. The dose of aspirin in this study was 325 mg every other day.20
In the Women’s Health Initiative Observational Study, 70% of women with stable cardiovascular disease taking aspirin were taking 325 mg daily.21 This study demonstrated a significant reduction in the cardiovascular mortality rate, which supports current guidelines, and found no difference in outcomes with doses of 81 mg compared with 325 mg.21 This again corroborates that low-dose aspirin is preferential to standard-dose aspirin in women with cardiovascular disease.
These findings have not been validated in larger prospective trials. Thus, current guidelines for aspirin use may reflect extrapolation of aspirin benefit from higher-risk patients to lower-risk patients.
Nevertheless, although the debate continues, it has generally been accepted that in patients who are at high risk of vascular disease or who have had a myocardial infarction, the benefits of aspirin—a 20% relative reduction in vascular events22—clearly outweigh the risks.
ASPIRIN FOR PRIMARY PREVENTION
Assessing risk vs benefit is more complex when considering populations without known cardiovascular disease.
Only a few studies have specifically evaluated the use of aspirin for primary prevention (Table 3).23–31 The initial trials were in male physicians in the United Kingdom and the United States in the late 1980s and had somewhat conflicting results. A British study did not find a significant reduction in myocardial infarction,23 but the US Physician’s Health Study study did: the relative risk was 0.56 (95% confidence interval 0.45–0.70, P < .00001).24 The US study had more than four times the number of participants, used different dosing (325 mg every other day compared with 500 or 300 mg daily in the British study), and had a higher rate of compliance.
Several studies over the next decade demonstrated variable but significant reductions in cardiovascular events as well.25–27
A meta-analysis of primary prevention trials of aspirin was published in 2009.22 Although the relative risk reduction was similar in primary and secondary prevention, the absolute risk reduction in primary prevention was not nearly as great as in secondary prevention.
These findings are somewhat difficult to interpret, as the component trials included a wide spectrum of patients, ranging from healthy people with no symptoms and no known risk factors to those with limited risk factors. The trials were also performed over several decades during which primary prevention strategies were evolving. Additionally, most of the participants were middle-aged, nondiabetic men, so the results may not necessarily apply to people with diabetes, to women, or to the elderly. Thus, the pooled data in favor of aspirin for primary prevention may not be as broadly applicable to the general population as was once thought.
Aspirin for primary prevention in women
Guidelines for aspirin use in primary prevention were initially thought to be equally applicable to both sexes. However, concerns about the relatively low number of women participating in the studies and the possible mechanistic differences in aspirin efficacy in men vs women prompted further study.
A meta-analysis of randomized controlled trials found that aspirin was associated with a 12% relative reduction in the incidence of cardiovascular events in women and 14% in men. On the other hand, for stroke, the relative risk reduction was 17% in women, while men had no benefit.32
Most of the women in this meta-analysis were participants in the Women’s Health Study, and they were at low baseline risk.28 Although only about 10% of patients in this study were over age 65, this older group accounted for most of the benefit: these older women had a 26% risk reduction in major adverse cardiovascular events and 30% reduction in stroke.
Thus, for women, aspirin seems to become effective for primary prevention at an older age than in men, and the guidelines have been changed accordingly (Figure 1).
More women should be taking aspirin than actually are. For example, Rivera et al33 found that only 41% of eligible women were receiving aspirin for primary prevention and 48% of eligible women were receiving it for secondary prevention.
People with diabetes
People with diabetes without overt cardiovascular disease are at higher risk of cardiovascular events than age- and sex-matched controls.34 On the other hand, people with diabetes may be more prone to aspirin resistance and may not derive as much cardiovascular benefit from aspirin.
Early primary prevention studies included few people with diabetes. Subsequent meta-analyses of trials that used a wide range of aspirin doses found a relative risk reduction of 9%, which was not statistically significant.9,35,36
But there is some evidence that people with diabetes, with37 and without22 coronary disease, may be at higher inherent risk of bleeding than people without diabetes. Although aspirin may not necessarily increase the risk of bleeding in diabetic patients, recent data suggest no benefit in terms of a reduction in vascular events.38
The balance of risk vs benefit for aspirin in this special population is not clear, although some argue that these patients should be treated somewhere on the spectrum of risk between primary and secondary prevention.
The US Preventive Services Task Force did not differentiate between people with or without diabetes in its 2009 guidelines for aspirin for primary prevention.8 However, the debate is reflected in a change in 2010 American College of Cardiology/American Diabetes Association guidelines regarding aspirin use in people with diabetes without known cardiovascular disease.39 As opposed to earlier recommendations from these organizations in favor of aspirin for all people with diabetes regardless of 10-year risk, current recommendations advise low-dose aspirin (81–162 mg) for diabetic patients without known vascular disease who have a greater than 10% risk of a cardiovascular event and are not at increased risk of bleeding.
These changes were based on the findings of two trials: the Prevention and Progression of Arterial Disease and Diabetes Trial (POPADAD) and the Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) study. These did not show a statistically significant benefit in prevention of cardiovascular events with aspirin.29,30
After the new guidelines came out, a meta-analysis further bolstered its recommendations. 40 In seven randomized clinical trials in 11,000 patients, the relative risk reduction was 9% with aspirin, which did not reach statistical significance.
