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Frequently Asked Questions

When should aspirin be used for the primary prevention of cardiovascular disease?

Introduction
The United States Preventive Services Task Force (USPSTF) recently updated their recommendations on the use of aspirin (ASA) in the primary prevention of cardiovascular (CV) disease.¹ In these guidelines, primary prevention applies to any individual without a history of coronary heart disease (CHD) or stroke. Trials published since the 2002 guidelines include a single randomized controlled trial, a meta-analysis, and 2 subanalyses of randomized controlled trials.² The Task Force focused on 2 main questions when updating the guidelines; 1) When used as primary prevention, does ASA reduce coronary events, strokes, death from coronary events or stroke, or all-cause mortality in men and women? 2) When used as primary prevention, does ASA increase the risk of gastrointestinal (GI) bleeding or hemorrhagic strokes in men and women? Based on the Women’s Health Study and other trials, these 2 questions were evaluated independently based on gender.^2,3

Efficacy/Safety
The Women’s Health Study was the lone randomized controlled trial published since 2002 that evaluated the use of ASA in primary CV prevention.³ In this trial 39,876 healthy women 45 years of age or older were randomized to receive either ASA 100 mg every other day or placebo. Patients were to be followed for 10 years, and the primary endpoint was the incidence of a first CV event (nonfatal myocardial infarction, nonfatal stroke, or death from CV causes). Results showed no statistically significant differences in the primary endpoint for the 2 groups. When the endpoint measures were evaluated independently, the ASA group had a significantly reduced incidence of stroke (relative risk [RR], 0.83; 95% confidence interval [CI], 0.69 to 0.99). Nonfatal myocardial infarction, death from CV causes and all-cause mortality were not statistically significantly different between the 2 groups. The ASA group had a significantly higher incidence of serious GI bleeds compared to placebo (RR, 1.40; 95% CI, 1.07 to 1.83).³

A recent meta-analysis found that men tend to have fewer myocardial infarctions when taking ASA, while women experience fewer ischemic strokes.² Cardiovascular and all-cause mortality were not significantly influenced by ASA use. Major GI bleeds requiring transfusion occurred more frequently when taking ASA in both men (odds ratio [OR] 1.72; 95% CI, 1.35 to 2.20) and women (OR 1.68; 95% CI 1.13 to 2.52), and hemorrhagic stroke occurred significantly more often in men (OR 1.69; 95% CI, 1.04 to 2.73) but not in women.²

Various doses and schedules of aspirin therapy have been utilized in primary prevention trials. The guidelines suggest that lower doses (e.g. 75 mg/day) are as effective as higher doses and may cause less GI bleeding.¹ A recent post-hoc observational analysis evaluated the safety and efficacy of the various ASA doses used in the Clopidogrel for High Atherothrombotic Risk and Ischemic, Stabilization, Management, and Avoidance (CHARISMA) trial.⁴ CHARISMA was a double-blind, placebo-controlled, randomized trial that evaluated 15,595 patients with CV disease or multiple risk factors for CV disease. Patients were given ASA (75 to 162 mg/day) and were also randomized to receive clopidogrel (75 mg/day) or placebo. The primary clinical endpoint was the composite of myocardial infarction, stroke, or CV death, and the primary safety endpoint was the composite of severe or life-threatening bleeding. For the post-hoc analysis, daily doses utilized in the trial were classified as <100 mg/day, 100 mg/day, or >100 mg/day. The analysis demonstrated that both the efficacy and safety outcomes were independent of ASA dose. However, when given with clopidogrel, ASA doses >100 mg had a non-significant statistical trend toward reduced efficacy and increased bleeding. It was concluded that aspirin doses <100 mg may be optimal especially if given with clopidogrel.⁴

Decision-Making
Aspirin’s benefit in reducing CV events should be weighed against its risk to cause bleeding.¹ Risk factors for CV disease include age, diabetes mellitus (DM), total cholesterol, high-density-lipoprotein, blood pressure, and smoking. Assessing the benefit of using ASA in women centers on risk factors for cerebrovascular events and bleeding. Risk factors for cerebrovascular disease in women include age, hypertension, DM, smoking, atrial fibrillation, history of cerebrovascular events, and left ventricular hypertrophy.

The guidelines emphasize that providers should talk to all potential candidates about the potential risks and benefits of using ASA to prevent CV disease, especially when the risks/benefits are closely matched.¹ The decision to start or avoid ASA should be one that is based on shared decision making between the patient and the provider. If started on ASA, patients should be educated on the signs and symptoms of GI bleeding (e.g. bright red blood per rectum, dark stools, vomiting blood, syncope, and lightheadedness).

Recommendations
Aspirin should not be used in individuals who would confer minimal CV benefit (e.g. < 45 years of age for men and <55 years of age for women) or who are at a high risk for GI bleeding.¹ The risk of cerebrovascular and/or CV events in patients 80 years or older is high. Bleeding risk in this population is also quite high. People over 80 years of age without other risk factors for GI bleeding and who have the greatest chance to overcome a GI bleed (e.g. normal hemoglobin, normal kidney function, etc) would be the best candidates for ASA therapy in this age group. Educating patients on the risks and benefits of ASA therapy and involving them in the decision-making process is recommended.¹

Age and 10-year CV risk should be considered when determining the potential benefits of myocardial infarctions prevented in men and ischemic strokes prevented in women.¹ These potential benefits should be weighed against the risk of GI hemorrhage. The risk level at which the number of CV disease events prevented exceeds the risk of GI bleeding is summarized in the table below. Ten-year CV risk assessment calculators for men and women can be found online at http://healthlink.mcw.edu/article/923521437.html or http://www.westernstroke.org/index.php.

Risk Level at Which CV Disease Events Prevented Exceeds GI Harms
Men		Women
Age	10-year CV Risk	Age	10-year Stroke Risk
45-59 years	≥4%	55-59 years	≥3%
60-69 years	≥9%	60-69 years	≥8%
70-79 years	≥12%	70-79 years	≥11%

Assumes adults are not taking non-steroidal anti-inflammatory drugs (NSAIDs) and do not have upper GI pain or a history of GI ulcers

Based on the information summarized above, the following are the USPSTF recommendations for using ASA for the primary prevention of CV events.¹

Summary of USPSTF Recommendations on When to Use ASA for Primary CV Prevention

Men 45 to 79 years of age when the benefit of reducing CV events outweighs the risk of GI bleeding (Grade A)
Women 55 to 79 years of age when the benefit of reducing ischemic strokes outweighs the risk of GI bleeding (Grade A)
Do not use for CV prophylaxis in women less than 55 years of age or men less than 45 years of age. (Grade D)
There is insufficient evidence to make recommendations in men and women 80 years of age or older. (I statement)

Definitions of the USPSTF Grades are as follows: Grade A – the USPSTF recommends this as there is high certainty that the net benefit is substantial; Grade B – the USPSTF recommends this as there is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial; Grade C – the USPSTF recommends against routinely providing this and there is moderate or high certainty that the net benefit is small; Grade D – the USPSTF recommends against this as there moderate to high certainty that the service has no benefit or that harms outweigh benefits; I statement – the USPSTF concludes that current evidence is insufficient to assess benefits and risks.¹

Other societies have also made recommendations on the use of ASA in certain populations.¹ The American Diabetes Association (ADA) in conjunction with the American Heart Association (AHA) recommend low-dose ASA (75 to 162 mg/day) in patients with diabetes who are 40 years of age or older with at least 1 additional risk factor for CV disease. The AHA along with the American Stroke Association recommend against the use of ASA for the prevention of stroke in men. ASA prophylaxis for cerebrovascular prevention can be used in women for whom the benefit is felt to outweigh the risk. For CV prevention these same associations recommend using ASA when the benefits are felt to outweigh the risks.¹

Summary
Evidence demonstrates that ASA reduces the risk of myocardial infarction in men and ischemic stroke in women, but also significantly increases the risk of GI bleeding. The mutual decision between a patient and a provider to start ASA therapy for primary CV prevention should be based on the patient’s baseline CV risk and the risk of GI bleeding.

References

U.S. Preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;150(6):396-404.
Wolff T, Miller T, Ko S. Aspirin for the primary prevention of cardiovascular events: an update of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2009;150(6):405-410.
Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005;352(13):1293-1304.
Steinhubl SR, Bhatt DL, Brennan DM, et al. Aspirin to prevent cardiovascular disease: the association of aspirin dose and clopidogrel with thrombosis and bleeding. Ann Intern Med. 2009;150(6):379-386.

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