Applied Evidence

Aspirin for primary prevention: USPSTF recommendations for CVD and colorectal cancer

J Fam Pract. 2019 April;68(3):146-151

Author(s):

Patient age, baseline cardiovascular disease risk, bleeding risk, and personal preference regarding aspirin use are key to decision making. A clinical decision tool can help.

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PRACTICE RECOMMENDATIONS

› Consider aspirin for patients 50 to 59 years of age who have a 10-year cardiovascular disease (CVD) risk of ≥ 10% and low bleeding risk. C

› Discuss prophylactic aspirin (using a shared decision-making model) with patients 60 to 69 years of age who have a 10-year CVD risk of ≥ 10% and low bleeding risk. C

› Avoid using aspirin for primary prevention in patients ≥ 70 years of age. B

Strength of recommendation (SOR)

A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

References

1. FDA. Use of aspirin for primary prevention of heart attack and stroke. https://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm390574.htm. Accessed March 22, 2019.

2. Guirguis-Blake JM, Evans CV, Senger CA, et al. Aspirin for the primary prevention of cardiovascular events: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2016;164:804-813.

3. Whitlock EP, Burda BU, Williams SB, et al. Bleeding risks with aspirin use for primary prevention in adults: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2016;164:826-835.

4. Chubak J, Whitlock EP, Williams SB, et al. Aspirin for the prevention of cancer incidence and mortality: systematic evidence reviews for the U.S. Preventive Services Task Force. Ann Intern Med. 2016;164:814-825.

5. Dehmer SP, Maciosek MV, Flottemesch TJ, et al. Aspirin for the primary prevention of cardiovascular disease and colorectal cancer: a decision analysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2016;164:777-786.

6. Bibbins-Domingo K. Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2016;164:836-845.

7. Baigent C, Blackwell L, Colins R, et al; Antithrombotic Trialists (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participation data from randomised trials. Lancet. 2009:373:1849-1860.

8. Ikeda Y, Shimada K, Teramoto T, et al. Low-dose aspirin for primary prevention of cardiovascular events in Japanese patients 60 years or older with atherosclerotic risk factors: a randomized clinical trial. JAMA. 2014;312:2510-2520.

9. Rothwell PM, Cook NR, Gaziano JM, et al. Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: analysis of individual patient data from randomised trials. Lancet. 2018;392:387-399.

10. Bowman L, Mafham M, Wallendszus K, et al; ASCEND Study Collaborative Group. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med. 2018;379:1529-1539.

11. McNeil JJ, Wolfe R, Woods RL, et al. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med. 2018;379:1509-1518.

12. Gaziano JM, Brotons C, Coppolecchia R, et al. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial. Lancet. 2018;392:1036-1046.

13. Kune GA, Kune S, Watson LF. Colorectal cancer risk, chronic illness, operations, and medications: case control results from Melbourne Colorectal Cancer Study. Cancer Res. 1988;48:4399-4404.

14. Sutcliffe P, Connock M, Gurung T, et al. Aspirin for prophylactic use in the primary prevention of cardiovascular disease and cancer: a systematic review and overview of reviews. Health Technol Assess. 2013;17:1-253.

15. Burn J, Gerdes AM, Macrae F, et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet. 2011;378:2081-2087.

16. Gamba CA, Swetter SM, Stefanick ML, et al. Aspirin is associated with lower melanoma risk among postmenopausal Caucasian women: the Women’s Health Initiative. Cancer. 2013;119:1562-1569.

17. Trabert B, Ness RB, Lo-Ciganic WH, et al. Aspirin, nonaspirin nonsteroidal anti-inflammatory drug, and acetaminophen use and risk of invasive epithelial ovarian cancer: a pooled analysis in the Ovarian Cancer Association Consortium. J Natl Cancer Inst. 2014;106:djt431.

18. Risch H, Lu L, Streicher SA, et al. Aspirin use and reduced risk of pancreatic cancer. Cancer Epidemiol Biomarkers Prev. 2016;26:68-74.

19. McNeil JJ, Nelson MR, Woods RL, et al. Effect of aspirin on all-cause mortality in the healthy elderly. N Engl J Med. 2018;379:1519-1528.

20. Hernández-Díaz S, Rodríguez LA. Incidence of serious upper gastrointestinal bleeding/perforation in the general population: review of epidemiologic studies. J Clin Epidemiol. 2002;55:157-163.

21. Guirguis-Blake JM, Evans CV, Senger CA, et al. Aspirin for the primary prevention of cardiovascular events: a systematic evidence review for the U.S. Preventive Services Task Force. Evidence Synthesis no 131. Rockville, MD: Agency for Healthcare Research and Quality; 2015. https://www.ncbi.nlm.nih.gov/books/NBK321623/. Accessed March 22, 2019.

22. De Berardis G, Lucisano G, D’Ettorre A, et al. Association of aspirin use with major bleeding in patients with and without diabetes. JAMA. 2012;307:2286-2294.

23. Thorat MA, Cuzick J. Prophylactic use of aspirin: systematic review of harms and approaches to mitigation in the general population. Eur J Epidemiol. 2015;30:5-18.

24. Hernández-Díaz S, García Rodríguez LA. Cardioprotective aspirin users and their excess risk of upper gastrointestinal complications. BMC Med. 2006;4:22.

25. Huang ES, Strate LL, Ho WW, et al. Long term use of aspirin and the risk of gastrointestinal bleeding. Am J Med. 2011:124;426-433.

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27. NIH. Aspirin dosing: a patient-centric trial assessing benefits and long-term effectiveness (ADAPTABLE). https://clinicaltrials.gov/ct2/show/NCT02697916. Accessed March 22, 2019.

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29. ADA. Standards of medical care in diabetes – 2017. Diabetes Care. 2017;40(suppl 1). http://care.diabetesjournals.org/content/diacare/suppl/2016/12/15/40.Supplement_1.DC1/DC_40_S1_final.pdf. Accessed March 22, 2019.

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Which patients are likely to benefit from using aspirin for primary prevention? In this article, we review the evidence to date, summarized for primary care settings in guidelines issued by the US Preventive Services Task Force (USPSTF). We supplement this summary with a rundown of the risks associated with aspirin use. And then we wrap up by identifying a clinical decision tool that is available to help make personalized decisions in a busy clinic setting, where determining an individual’s potential cardiovascular benefits and bleeding risk can be challenging.

The “roadmap” from the guidelines. In 2014, after performing a review of the literature, the US Food and Drug Administration recommended against the routine use of aspirin for primary prevention of cardiovascular disease (CVD).¹ In 2016, the USPSTF published 4 separate systematic reviews along with a decision analysis using a microsimulation model, which informed their position statement on aspirin for primary prevention.^2-6 These USPSTF reviews and recommendations incorporated both CVD and colorectal cancer (CRC) benefits with the bleeding risks from aspirin. Generally, for individuals 50 to 59 years old, the benefits are deemed to outweigh the harms; shared decision making is advised with those 60 to 69 years of age. For patients younger than 50 or 70 and older, evidence is inconclusive.

The benefits of primary prevention with aspirin

Cardiovascular disease

The Antithrombotic Trialists’ (ATT) Collaboration was one of the first meta-analyses that addressed the benefit-to-harm balance and called into question the routine use of aspirin for primary prevention.⁷ The USPSTF systematic review included the studies from the ATT Collaboration as well as trials performed after its publication, bringing the total number of eligible randomized controlled trials reviewed to 11.²

The benefit of aspirin for primary prevention of nonfatal myocardial infarction (MI) has been shown in multiple randomized controlled trials. The USPSTF systematic review showed a statistically significant relative risk reduction of 17% in patients taking low-dose aspirin (≤ 100 mg; relative risk [RR] = 0.83; confidence interval [95% CI], 0.74-0.94), although the heterogeneity of the studies was high. The same low dose of aspirin showed a statistically significant reduction in nonfatal stroke (RR = 0.86; 95% CI, 0.76-0.98), although the same benefit was not observed when all doses of aspirin were included. Cardiovascular disease mortality and all-cause mortality were not statistically different for patients taking low-dose aspirin when compared with placebo (RR = 0.97; 95% CI, 0.85-1.10 for CVD mortality; RR = 0.95; 95% CI, 0.89-1.01 for all-cause mortality).²

One study of more than 14,000 older (≥ 60 years) Japanese patients showed a statistically significant reduction in nonfatal MI (hazard ratio [HR] = 0.53; 95% CI, 0.31-0.91, P = .02) and nonfatal strokes (HR = 0.57; 95% CI, 0.32-0.99; P = .04). The study was stopped early because at 5 years of follow-up there was no statistically significant difference in a composite primary outcome, which included death from cardiovascular causes, nonfatal MI, and nonfatal stroke (HR = 0.94; 95% CI, 0.77-1.15; P = .54).⁸

Preventive benefits of aspirin outweigh risks for those 50-59 years of age who have a 10-year cardiovascular disease risk of ≥ 10%.

Several recent landmark studies have called into question the benefit of aspirin for cardiovascular primary prevention, especially in obese individuals, patients with diabetes, and the elderly. A meta-analysis of 10 trials showed that the effectiveness of aspirin doses between 75 mg and 100 mg for primary prevention decreased as weight increased; patients weighing 70 kg or more received no benefit.⁹ The ASCEND (A Study of Cardiovascular Events in Diabetes) trial included more than 15,000 patients with diabetes but no cardiovascular disease. Patients randomized to receive the low-dose aspirin did have fewer serious vascular events (incidence rate ratio [IRR] = 0.88; 95% CI, 0.79-0.97; P = .01), but they also had high risk of major bleeding events (IRR = 1.29; 95% CI, 1.09-1.52; P = .003).¹⁰ The ASPREE (Aspirin in Reducing Events in the Elderly) trial included more than 19,000 patients ages 70 years and older with no cardiovascular disease and compared low-dose aspirin to placebo. There was no statistically significant cardiovascular benefit, although there was an increase of major hemorrhage (HR = 1.38; 95% CI, 1.18-1.62; P < .001).¹¹ The ARRIVE (A Randomized Trial of Induction Versus Expectant Management) trial included 12,546 moderate atherosclerotic CVD (ASCVD) risk patients. Although a per-protocol analysis showed a decrease in rates of fatal and nonfatal MI (HR = 0.53; 95% CI, 0.36-0.79; P = .0014), the more reliable intention-to-treat analysis showed no improvement for any outcomes.¹²

Colorectal cancer

The literature base on prevention of cancer has been growing rapidly. However, the deluge of findings over the past 2 decades of trials and analyses has also introduced ambiguity and, often, conflicting results. The first journal article suggesting aspirin for primary prevention of cancer, published in 1988, was a case-control study wherein a population with CRC was matched to controls to look for potential protective factors.¹³ The most notable finding was the CRC risk reduction for those taking aspirin or aspirin-containing medications. Since then numerous studies and analyses have explored aspirin’s potential in primary prevention of many types of cancer, with overall unclear findings as denoted in the 2016 USPSTF systemic reviews and recommendations.

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