Editorials: Controversies in Family Medicine
Appropriate Aspirin Use for Primary Prevention of Cardiovascular Disease
Am Fam Physician. 2011 Jun 15;83(12):1380-1386.
This is one in a series of pro/con editorials discussing controversial issues in family medicine.
Cardiovascular disease (CVD) is the leading cause of death in adults, accounting for one out of every 2.8 deaths in the United States.1 Daily use of low-dose (75 to 325 mg) aspirin as a secondary preventive measure reduces all-cause mortality by 18 percent, and subsequent myocardial infarctions by 30 percent in persons with known CVD.2,3 Aspirin use prevents CVD by inhibiting cyclooxygenase, which blocks the formation of thromboxane A2 and thus disrupts platelet aggregation and prevents vasoconstriction.4 The American Heart Association recommends that daily aspirin be used indefinitely in all patients with known CVD, unless contraindicated, for secondary prevention.5
There is interest in and controversy over daily use of aspirin for primary prevention of CVD in persons who have yet to demonstrate clinical evidence of CVD. Several major randomized clinical trials and subsequent meta-analyses involving more than 96,000 participants have demonstrated that daily aspirin use in persons at moderate to high risk of CVD can reduce the risk of a first-time CVD event by at least 28 percent.6,7 However, recent studies have questioned whether the benefits of daily aspirin for primary cardioprevention outweigh the risks of gastrointestinal (GI) and intracerebral hemorrhage.8,9 In addition, a recent randomized controlled trial involving 39,876 relatively healthy women 45 years and older suggested that daily aspirin therapy may not decrease the risk of acute myocardial infarction in women, although there was a 17 percent decreased risk of stroke.10 Currently, two large, international randomized controlled trials (n > 10,000) are investigating the benefit of daily aspirin therapy for primary cardioprevention in select populations: the ASCEND trial (a study of cardiovascular events in diabetes) and the ASPREE trial (aspirin in reducing events in the elderly). Results from these trials should be available within the next five years.
After critically analyzing the evidence of potential benefits and harms of aspirin therapy, the U.S. Preventive Services Task Force (USPSTF) reaffirmed and clarified its position in 2009, concluding that aspirin is effective for primary CVD prevention.11 Aspirin should be recommended when benefits outweigh risks. The USPSTF found good evidence that aspirin use decreases myocardial infarctions in men 45 to 79 years of age, and strokes in women 55 to 79 years of age who are at increased risk of, but have not yet experienced, these events. Compared with its 2002 recommendation,6 the USPSTF's 2009 recommendation differentiates CVD risk by age group and sex, complicating physicians' task of determining patients' CVD risk. Physicians must now consider the 10-year myocardial infarction risk for men and 10-year stroke risk for women.
Aspirin therapy should be considered in men with a 10-year CVD risk of at least 4 percent in those 45 to 59 years of age, 9 percent in those 60 to 69 years of age, and 12 percent in those 70 to 79 years of age. Aspirin therapy should be considered in women with a 10-year stroke risk of at least 3 percent in those 50 to 59 years of age, 8 percent in those 60 to 69 years of age, and 11 percent in those 70 to 79 years of age. Several online calculators are available to help physicians determine these risks (Table 1). To assist physicians in better identifying patients who potentially would benefit from aspirin therapy, the American College of Preventive Medicine is studying the use of a patient-friendly decision table.
Table 1. Online Cardiovascular Risk Calculators
Online Cardiovascular Risk Calculators
10-year cardiovascular risk
American Heart Association calculator
Framingham risk calculator
Mayo Clinic heart disease risk calculator
Medical College of Wisconsin coronary heart disease risk calculator
MDCalc.com cardiac risk score
10-year stroke risk
Reynolds Risk Score
Web site: http://www.reynoldsriskscore.org
Stroke Education Ltd risk calculator
UCLA Stroke Center stroke risk calculator
Web site: http://stroke.ucla.edu/#calculaterisk
When advising aspirin use, the USPSTF recommends considering the risk of GI bleeding. The most widely recognized adverse effect of aspirin therapy is a modestly increased risk of GI bleeding; 769 persons need to be treated with aspirin to cause one additional major bleeding episode annually.12 Aspirin-induced GI toxicity appears to be dose-dependent; higher aspirin doses increase the risk of bleeding.13 It appears that in most persons, low-dose aspirin (81 mg) is best. Increasing the dose to 325 mg does not increase the effectiveness, but does increase the risk of GI bleeding.14
Aspirin for primary cardioprevention should be avoided in persons who have had a GI or cerebral bleeding episode, and in those who are at risk of bleeding problems (e.g., bleeding disorder, severe liver disease, thrombocytopenia, concomitant anticoagulant therapy). For persons with an aspirin- induced bleeding ulcer, aspirin use in combination with a proton pump inhibitor may be safely restarted after the ulcer has healed.15 A randomized controlled trial found that in those taking low-dose aspirin who had GI bleeding, continuous aspirin therapy may increase the risk of recurrent GI bleeding, but potentially reduces cardiovascular and cerebrovascular mortality rates.16 Eradication of Helicobacter pylori decreases the risk of recurrent GI bleeding in those taking low-dose aspirin.15 Enteric-coated or buffered aspirin does not decrease the risk of GI toxicity.17 A list of absolute and relative contraindications to aspirin therapy is presented in Table 2.
Table 2. Contraindications to Aspirin Therapy
Contraindications to Aspirin Therapy
Active peptic ulcer
Aspirin allergy or intolerance
Bleeding disorders (e.g., hemophilia, von Willebrand disease)
History of recent gastrointestinal bleeding
History of recent intracranial bleeding
Severe liver disease
Age younger than 21 years (increased risk of Reye syndrome)
Concurrent use of anticoagulation therapy
Concurrent use of nonsteroidal anti-inflammatory drugs
Poorly controlled hypertension (risk of intracranial bleeding)
As with any medication, the key to aspirin therapy for CVD prevention is appropriate use. A study evaluating 24 clinical preventive services considered effective by the USPSTF found that advising at-risk adults to consider taking daily aspirin was the most cost-effective preventive measure available for physicians.18 If 90 percent of those who should be taking aspirin were doing so, it is estimated that an additional 45,000 lives would be saved each year. Despite this benefit, less than one-half of those who should be taking aspirin regularly are actually taking it.19 Although not reported, there are also persons taking daily aspirin for primary cardioprevention in whom the benefit is negligible or the risk is high. These persons should be cautioned against this practice until the benefit outweighs the risk.
The factor most strongly associated with appropriate aspirin use is a conversation between the patient and physician.20 The National Committee for Quality Assurance has proposed that health plans measure their members' use of aspirin, as well as the extent to which physicians discuss aspirin use with their patients. Determining patients' CVD risk and discussing appropriate aspirin use with them should be a priority for all family physicians.
1. Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics—2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee [published corrections appear in Circulation. 2010;122(1):e9, and Circulation. 2007;115(5)e172]. Circulation. 2007;115(5):e69–e171.
2. Collaborative overview of randomised trials of anti-platelet therapy—I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration [published correction appears in BMJ. 1994;308(6943):1540]. BMJ. 1994;308(6921):81–106.
3. Weisman SM, Graham DY. Evaluation of the benefits and risks of low-dose aspirin in the secondary prevention of cardiovascular and cerebrovascular events. Arch Intern Med. 2002;162(19):2197–2202.
4. Awtry EH, Loscalzo J. Aspirin. Circulation. 2000;101(10):1206–1218.
5. Smith SC Jr, Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update endorsed by the National Heart, Lung, and Blood Institute. J Am Coll Cardiol. 2006;47(10):2130–2139.
6. Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;136(2):161–172.
7. Bartolucci AA, Howard G. Meta-analysis of data from the six primary prevention trials of cardiovascular events using aspirin. Am J Cardiol. 2006;98(6):746–750.
8. Antithrombotic Trialists' (ATT) Collaboration, Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from ran-domised trials. Lancet. 2009;373(9678):1849–1860.
9. De Berardis G, Sacco M, Strippoli GF, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials [published correction appears in BMJ. 2010; 340:c374]. BMJ. 2009;339:b4531.
10. 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.
11. 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.
12. McQuaid KR, Laine L. Systematic review and meta-analysis of adverse events of low-dose aspirin and clopidogrel in randomized controlled trials. Am J Med. 2006;119(8):624–638.
13. Patrono C, Coller B, FitzGerald GA, Hirsh J, Roth G. Platelet-active drugs: the relationships among dose, effectiveness, and side effects: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 suppl):234S–264S.
14. Campbell CL, Smyth S, Montalescot G, Steinhubl SR. Aspirin dose for the prevention of cardiovascular disease: a systematic review. JAMA. 2007;297(18):2018–2024.
15. Chan FK, Chung SC, Suen BY, et al. Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen. N Engl J Med. 2001;344(13):967–973.
16. Sung JJ, Lau JY, Ching JY, et al. Continuation of low-dose aspirin therapy in peptic ulcer bleeding: a randomized trial. Ann Intern Med. 2010;152(1):1–9.
17. Kelly JP, Kaufman DW, Jurgelon JM, Sheehan J, Koff RS, Shapiro S. Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product. Lancet. 1996;348(9039):1413–1416.
18. Maciosek MV, Coffield AB, Edwards NM, Flottemesch TJ, Goodman MJ, Solberg LI. Priorities among effective clinical preventive services: results of a systematic review and analysis. Am J Prev Med. 2006;31(1):52–61.
19. Ajani UA, Ford ES, Greenland KJ, Giles WH, Mokdad AH. Aspirin use among U.S. adults: Behavioral Risk Factor Surveillance System. Am J Prev Med. 2006;30(1):74–77.
20. Pignone M, Anderson GK, Binns K, Tilson HH, Weisman SM. Aspirin use among adults aged 40 and older in the United States: results of a national survey. Am J Prev Med. 2007;32(5):403–407.
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