A 57-year-old woman with no history of cardiovascular disease comes to the clinic for her annual evaluation. She does not have diabetes mellitus, but she does have hypertension and chronic osteoarthritis, currently treated with acetaminophen. Additionally, she admits to active tobacco use. Her systolic blood pressure is 130 mm Hg on therapy with hydrochlorothiazide. Her electrocardiogram demonstrates left ventricular hypertrophy. Her low-density lipoprotein (LDL) cholesterol level is 140 mg/dL, and her high-density lipoprotein (HDL) cholesterol level is 50 mg/dL. Should this patient be started on aspirin therapy?
Acetylsalicylic acid (aspirin) is an analgesic, antipyretic, and anti-inflammatory agent, but its more prominent use today is as an antithrombotic agent to treat or prevent cardiovascular events. Its antithrombotic properties are due to its effects on the enzyme cyclooxygenase. However, cyclooxygenase is also involved in regulation of the gastric mucosa, and so aspirin increases the risk of gastrointestinal bleeding.
Approximately 50 million people take aspirin on a daily basis to treat or prevent cardiovascular disease.1 Of these, at least half are taking more than 100 mg per day,2 reflecting the general belief that, for aspirin dosage, “more is better”—which is not true.
Additionally, recommendations about the use of aspirin were based on studies that included relatively few members of several important subgroups, such as people with diabetes without known cardiovascular disease, women, and the elderly, and thus may not reflect appropriate indications and dosages for these groups.
Here, we examine the literature, outline an individualized approach to aspirin therapy, and highlight areas for future study.
HISTORY OF ASPIRIN USE IN CARDIOVASCULAR DISEASE
- 1700s—Willow bark is used as an analgesic.
- 1897—Synthetic aspirin is developed as an antipyretic and anti-inflammatory agent.
- 1974—First landmark trial of aspirin for secondary prevention of myocardial infarction.3
- 1982—Nobel Prize awarded for discovery of aspirin mechanism.
- 1985—US Food and Drug Administration approves aspirin for the treatment and secondary prevention of acute myocardial infarction.
- 1998—The Second International Study of Infarct Survival (ISIS-2) finds that giving aspirin to patients with myocardial infarction within 24 hours of presentation leads to a significant reduction in vascular deaths.4
Aspirin now carries a class I indication for all patients with suspected myocardial infarction. Since there are an estimated 600,000 new coronary events and 325,000 recurrent ischemic events per year in the United States,5 the need for aspirin will continue to remain great. It is also approved to prevent and treat stroke and in patients with unstable angina.
However, questions continue to emerge about aspirin’s dosing and appropriate use in specific populations. The initial prevention trials used a wide range of doses and, as mentioned, included few women, few people with diabetes, and few elderly people. The uncertainties are especially pertinent for patients without known vascular disease, in whom the absolute risk reduction is much less, making the assessment of bleeding risk particularly important. Furthermore, the absolute risk-to-benefit assessment may be different in certain populations.
Guidelines on the use of aspirin to prevent cardiovascular disease (Table 1)6–10 have evolved to take into account these possible disparities, and studies are taking place to further investigate aspirin use in these groups.
ASPIRIN AND GASTROINTESTINAL BLEEDING
Aspirin’s association with bleeding, particularly gastrointestinal bleeding, was recognized early as a use-limiting side effect. With or without aspirin, gastrointestinal bleeding is a common cause of morbidity and death, with an incidence of approximately 100 per 100,000 bleeding episodes in adults per year for upper gastrointestinal bleeding and 20 to 30 per 100,000 per year for lower gastrointestinal bleeding.11,12
The standard dosage (ie, 325 mg/day) is associated with a significantly higher risk of gastrointestinal bleeding (including fatal bleeds) than is 75 mg.13 However, even with lower doses, the risk of gastrointestinal bleeding is estimated to be twice as high as with no aspirin.14
And here is the irony: studies have shown that higher doses of aspirin offer no advantage in preventing thrombotic events compared with lower doses.15 For example, the Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Organization to Assess Strategies for Ischemic Stroke Syndromes study reported a higher rate of gastrointestinal bleeding with standard-dose aspirin therapy than with low-dose aspirin, with no additional cardiovascular benefit with the higher dose.16
Furthermore, several other risk factors increase the risk of gastrointestinal bleeding with aspirin use (Table 2). These risk factors are common in the general population but were not necessarily represented in participants in clinical trials. Thus, estimates of risk based on trial data most likely underestimate actual risk in the general population, and therefore, the individual patient’s risk of gastrointestinal bleeding, based on these and other factors, needs to be taken into consideration.