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).
Statins may dilute the benefit of aspirin
The use of statins has been increasing, and this trend may have played a role in the marginal benefit of aspirin therapy in these recent studies. In the Japanese trial, approximately 25% of the patients were known to be using a statin; the percentage of statin use was not reported specifically in POPADAD, but both of these studies were published in 2008, when the proportion of diabetic patients taking a statin would be expected to be higher than in earlier primary prevention trials, which were performed primarily in the 1990s. Thus, the beneficial effects of statins may have somewhat diluted the risk reduction attributable to aspirin.
Trials under way in patients with diabetes
The evolving and somewhat conflicting guidelines highlight the need for further study in patients with diabetes. To address this area, two trials are in progress: the Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D) and A Study of Cardiovascular Events in Diabetes (ASCEND).41,42
ACCEPT-D is testing low-dose aspirin (100 mg daily) in diabetic patients who are also on simvastatin. This study also includes prespecified subgroups stratified by sex, age, and baseline lipid levels.
The ASCEND trial will use the same aspirin dose as ACCEPT-D, with a target enrollment of 10,000 patients with diabetes without known vascular disease.
More frequent dosing for people with diabetes?
Although not supported by current guidelines, recent work has suggested that people with diabetes may need more-frequent dosing of aspirin.43 This topic warrants further investigation.
Aspirin as primary prevention in elderly patients
The incidence of cardiovascular events increases with age37—but so does the incidence of gastrointestinal bleeding.44 Upper gastrointestinal bleeding is especially worrisome in the elderly, in whom the estimated case-fatality rate is high.12 Assessment of risk and benefit is particularly important in patients over age 65 without known coronary disease.
Uncertainty about aspirin use in this population is reflected in the most recent US Preventive Services Task Force guidelines, which do not advocate either for or against regular aspirin use for primary prevention in those over the age of 80.
Data on this topic from clinical trials are limited. The Antithrombotic Trialists’ Collaboration (2009) found that although age is associated with a risk of major coronary events similar to that of other traditional risk factors such as diabetes, hypertension, and tobacco use, older age is also associated with the highest risk of major extracranial bleeding.22
Because of the lack of data in this population, several studies are currently under way. The Aspirin in Reducing Events in the Elderly (ASPREE) trial is studying 100 mg daily in nondiabetic patients without known cardiovascular disease who are age 70 and older.45 An additional trial will study patients age 60 to 85 with concurrent diagnoses of hypertension, hyperlipidemia, or diabetes and will test the same aspirin dose as in ASPREE.46 These trials should provide further insight into the safety and efficacy of aspirin for primary prevention in the elderly.
FUTURE DIRECTIONS
Aspirin remains a cornerstone of therapy in patients with cardiovascular disease and in secondary prevention of adverse cardiovascular events, but its role in primary prevention remains under scrutiny. Recommendations have evolved to reflect emerging data in special populations, and an algorithm based on Framingham risk assessment in men for myocardial infarction and ischemic stroke assessment in women for assessing appropriateness of aspirin therapy based on currently available guidelines is presented in Figure 1.6,8,47–49 Targeted studies have advanced our understanding of aspirin use in women, and future studies in people with diabetes and in the elderly should provide further insight into the role of aspirin for primary prevention in these specific groups as well.
Additionally, the range of doses used in clinical studies has propagated the general misperception that higher doses of aspirin are more efficacious. Future studies should continue to use lower doses of aspirin to minimize bleeding risk with an added focus on re-examining its net benefit in the modern era of increasing statin use, which may reduce the absolute risk reduction attributable to aspirin.
One particular area of debate is whether enteric coating can result in functional aspirin resistance. Grosser et al50 found that sustained aspirin resistance was rare, and “pseudoresistance” was related to the use of a single enteric-coated aspirin instead of immediate-release aspirin in people who had not been taking aspirin up to then. This complements an earlier study, which found that enteric-coated aspirin had an appropriate effect when given for 7 days.51 Therefore, for patients who have not been taking aspirin, the first dose should always be immediate-release, not enteric coated.
SHOULD OUR PATIENT RECEIVE ASPIRIN?
The patient we described at the beginning of this article has several risk factors—hypertension, dyslipidemia, left ventricular hypertrophy, and smoking—but no known cardiovascular disease as yet. Her risk of an adverse cardiovascular event appears moderate. However, her 10-year risk of stroke by the Framingham risk calculation is 10%, which would qualify her for aspirin for primary prevention. Of particular note is that the significance of left ventricular hypertrophy as a risk factor for stroke in women is higher than in men and in our case accounts for half of this patient’s risk.
We should explain to the patient that the anticipated benefits of aspirin for stroke prevention outweigh bleeding risks, and thus aspirin therapy would be recommended. However, with her elevated LDL-cholesterol, she may benefit from a statin, which could lessen the relative risk reduction from additional aspirin use.
