EBM Tools for Practice: Is There a Role for Aspirin in Prevention in 2022?

With recent guideline changes, it is common for clinicians to field questions regarding aspirin therapy. This article is intended to help clinicians apply an individualized and evidence-based approach to the appropriate use of aspirin in specific at-risk patient populations.

Aspirin’s Role in Secondary Prevention

Aspirin exerts antiplatelet activity through selective and irreversible acetylation of cyclooxygenase (COX), which inhibits its activity and the downstream production of prostaglandins and thromboxane A2 from arachidonic acid.¹ These pathways provide the antiplatelet² and proposed anti-inflammatory activities³ that give aspirin both its cardiovascular benefits as well as the bleeding risk associated with the inhibition of prostaglandin E2 and loss of its gastric protective effects.⁴ When considering aspirin therapy and its appropriate dosage, clinicians must weigh its atherosclerotic cardiovascular disease (ASCVD) benefits and bleeding risk.

Current guidelines recommend aspirin therapy for secondary prevention of ASCVD^5,6 and meta-analyses and clinical trials, such as the Antithrombotic Trialist Collaboration meta-analysis and the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial, support the use of low dose aspirin for these high-risk patients.^7,8 Recently, a 2021 open-label pragmatic study in patients with cardiovascular disease (CVD) comparing daily aspirin 325 mg to aspirin 81 mg found no significant difference in composite ASCVD outcomes (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.91 to 1.14) related to the dosing options.⁹ However, a recent meta-analysis by Aggarwal et al suggested that aspirin was inferior to P2Y12 inhibitors in secondary prevention of ASCVD. Importantly, results were consistent irrespective of the P2Y12 inhibitor used.¹⁰  As this evidence continues to support the use of low-dose aspirin or P2Y12 inhibition in secondary prevention, aspirin seems to be inferior to P2Y12 inhibitors. Moreover, newer evidence has brought changes to our primary prevention recommendations as well.

Evidence for Primary Prevention

Three large trials; Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus (ASCEND), Use of Aspirin to Reduce Risk of Initial Vascular Events in Patients at Moderate Risk of Cardiovascular Disease (ARRIVE), and Aspirin in Reducing Events in the Elderly (ASPREE), examining the effectiveness of aspirin for primary prevention were published in 2018. Despite improved composite cardiovascular outcomes in ARRIVE (HR 0.89; 95% CI 0.84-0.95), improved composite MI, CVA, TIA, death from vascular causes in ASCEND (HR 0.88; CI 0.79-0.97), and disability free survival in ASPREE (HR 1.14; CI 1.01-1.29), there was no decrease in non-fatal MI or non-fatal ischemic stroke in any of these trials. Further, all three trials showed a significantly increased risk of major bleeding.^11-13

In 2019, the American College of Cardiology revised its aspirin for primary prevention in the 2019 ACC/AHA Guideline for the Primary Prevention of Cardiovascular Disease. These guidelines recommend against the routine use of aspirin for primary prevention in patients older than 70 years of age or those at any age with an increased risk of bleeding (Class III: Harm, LOW B-R) and allows consideration of aspirin therapy in patients 40-70 with increased risk of ASCVD and without increased risk of bleeding (Class IIB, LOE A).¹⁴

In 2022 the United States Preventive Services Task Force (USPSTF) updated their recommendations for aspirin, along with a systematic review of the effectiveness of aspirin in reducing the risk of ASCVD events (myocardial infarction and stroke), cardiovascular mortality, and all-cause mortality in persons without a history of CVD.¹⁵ The recommendations examined the potential harms, particularly bleeding, associated with aspirin use and commissioned a microsimulation modeling study to assess the net balance of benefits and harms from aspirin use for primary prevention of CVD, stratified by age, sex, and ASCVD risk level. The USPSTF concluded with moderate certainty that aspirin use for the primary prevention of CVD events in adults aged 40 to 59 years who have a 10% or greater 10-year CVD risk has a small net benefit (Grade C – meaning offer or provide this service only if other considerations support the offering or providing the service in an individual patient) and indicated that persons who are not at increased risk for bleeding and are willing to take low-dose aspirin daily are more likely to benefit. However, it recommended (with moderate certainty) against initiating low-dose aspirin use for the primary prevention of CVD in adults 60 years or older. (Grade D recommendation – meaning ‘discourage the use’ of this intervention.)

In compiling their recommendations, the USPSTF analyzed results from 13 randomized clinical trials involving 161,680 participants that reported on the benefits of aspirin use for the primary prevention of cardiovascular morbidity and mortality.¹⁶  Most trials used low-dose aspirin of 100 mg/d or less or aspirin every other day and included a balanced number of male and female participants along with a broad distribution of ages. For example, the mean age ranged from 53 years in the Physicians' Health Study¹⁷ and 74 years in the ASPREE trial.¹³

Applying Current Evidence into Practice  

The decision to use aspirin for primary prevention begins with an assessment of CVD risk and includes an evaluation of bleeding risk in the shared decision-making discussion with the patient.¹⁵ These discussions may be facilitated using evidence-based clinical decision support tools to calculate a patient’s individual ASCVD and bleeding risk.¹⁸ One such tool, the Aspirin Guide which is available at www.aspiringuide.com can be used to calculate the number needed to treat with aspirin to prevent one ASCVD event and the number needed to harm from one excess bleeding event.¹⁹ Though decision support tools such as this one may enhance shared decision-making discussions, limitations include a lack of direct validation studies for this practice in regard to patient outcomes. Newer considerations include an assessment for subclinical atherosclerosis using coronary artery calcium (CAC) scoring. The 2021 National Lipid Association Scientific Statement on CAC scoring to guide preventive strategies for ASCVD risk reduction states that therapy with aspirin 81 mg daily is reasonable for patients with a CAC score >100 who do not have bleeding-related contraindications to such therapy (Class IIA, LOE B-NR).²⁰ Clinicians should recognize the increased bleeding risk in older adults and recent guideline changes for this population.^14,15 Ultimately, an evidence-based approach to aspirin therapy for primary prevention requires an individualized approach that includes an assessment of ASCVD risk and bleeding risk, in the context of shared-decision making discussion.

In summary, low-dose aspirin has potential benefits in the primary prevention of ASCVD, but its use needs to take into account estimation of risk for ASCVD events, bleeding risk, and clinician-patient shared decision-making. Other event reduction approaches including statin therapy are effective, but aspirin has antiplatelet effects which may be important in high-risk patients.

Guidelines for Aspirin for Primary Prevention

a. Grade C Definition: The USPSTF recommends the service. There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial. Suggestion for practice: Offer or provide this service.¹⁵

b. Grade D Definition: The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits. Suggestion for practice: Discourage the use of this service.¹⁵

c. Class of Recommendation IIB is weak, usefulness or efficacy of treatment is less well established; Level of Evidence A is supported by data from multiple RCTs or a single, large RCT.¹⁴

d. Class of Recommendation III indicates evidence or agreement that the treatment is not useful or effective and may be harmful; Level of Evidence B-R is supported by moderate-quality evidence from 1 or more RCTs or meta-analysis of moderate quality RCTs.¹⁴

e. Class of Recommendation III indicates evidence or agreement that the treatment is not useful or effective and may be harmful; Level of Evidence C-LD is supported by randomized or nonrandomized observational or registry studies with limitations of design or execution, meta-analysis of such studies, or physiological or mechanistic studies in human subjects.¹⁴

f. Class of Recommendation IIa is reasonable and can be useful/effective/beneficial; Level of Evidence B-NR is supported by moderate-quality evidence from 1 or more well-designed, well-executed nonrandomized studies, observational studies, or registry studies or a meta-analysis of such studies.²⁰

References

1. Roth GJ, Majerus PW. The Mechanism of the Effect of Aspirin on Human Platelets. I. Acetylation of a particulate fraction protein. J Clin Invest. 1975;56(3):624-632. doi:10.1172/JCI108132
2. Schrör K. Aspirin and Platelets: The Antiplatelet Action of Aspirin and Its Role in Thrombosis Treatment and Prophylaxis. Semin Thromb Hemost. 1997;23(4):349-356. doi:10.1055/s-2007-996108
3. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, Aspirin, and the Risk of Cardiovascular Disease in Apparently Healthy Men [published correction appears in N Engl J Med 1997 Jul 31;337(5):356]. N Engl J Med. 1997;336(14):973-979. doi:10.1056/NEJM199704033361401
4. Roderick PJ, Wilkes HC, Meade TW. The Gastrointestinal Toxicity of Aspirin: An Overview of Randomised Controlled Trials. Br J Clin Pharmacol. 1993;35(3):219-226. doi:10.1111/j.1365-2125.1993.tb05689.x)
5. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients with Stable Ischemic Heart Disease: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and th. J Am Coll Cardiol. 2012;60(24):e44-e164. doi:10.1016/j.jacc.2012.07.013
6. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC Guidelines for the Diagnosis and Management of Chronic Coronary Syndromes. Eur Heart J. 2020;41(3):407-477. doi:10.1093/eurheartj/ehz425
7. Antithrombotic Trialists' Collaboration. Collaborative Meta-analysis of Randomised Trials of Antiplatelet Therapy for Prevention of Death, Myocardial Infarction, and Stroke in High Risk Patients [published correction appears in BMJ 2002 Jan 19;324(7330):141]. BMJ. 2002;324(7329):71-86.
8. Peters RJG, Mehta SR, Fox KAA, et al. Effects of Aspirin Dose When Used Alone or in Combination with Clopidogrel in Patients with Acute Coronary Syndromes: Observations from the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Study. Circulation. 2003;108(14):1682-1687. doi:10.1161/01.CIR.0000091201.39590.CB
9. Jones WS, Mulder H, Wruck LM, et al. Comparative Effectiveness of Aspirin Dosing in Cardiovascular Disease. N Engl J Med. 2021;384(21):1981-1990. doi:10.1056/NEJMoa2102137
10. Aggarwal D, Bhatia K, Chunawala ZS, et al. P2Y12 inhibitor Versus Aspirin Monotherapy for Secondary Prevention of Cardiovascular Events: Meta-analysis of Randomized Trials. Eur Heart J Open. 2022;2(2):oeac019. Published 2022 Mar 21. doi:10.1093/ehjopen/oeac019
11. 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 (London, England). 2018;392(10152):1036-1046. doi:10.1016/S0140-6736(18)31924-X
12. Bowman L, Mafham M, Wallendszus K, et al. Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus. N Engl J Med. 2018;379(16):1529-1539. doi:10.1056/NEJMoa1804988
13. 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(16):1509-1518. doi:10.1056/NEJMoa1805819
14. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease:  Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;74(10):1376-1414. doi:10.1016/j.jacc.2019.03.009
15. Davidson KW, Barry MJ, Mangione CM, Cabana M, Chelmow D, Coker TR, Davis EM, Donahue KE, Jaén CR, Krist AH, et al. Aspirin Use to Prevent Cardiovascular Disease: US Preventive Services Task Force Recommendation Statement. Jama. 2022;327:1577-1584. doi: 10.1001/jama.2022.4983
16. Guirguis-Blake JM, Evans CV, Perdue LA, Bean SI, Senger CA. Aspirin Use to Prevent Cardiovascular Disease and Colorectal Cancer: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2022;327:1585-1597. doi: 10.1001/jama.2022.3337
17. Final Report on the Aspirin Component of the Ongoing Physicians' Health Study. N Engl J Med. 1989;321:129-135. doi: 10.1056/nejm198907203210301
18. Mora S, Ames JM, Manson JE.  Low-dose Aspirin in the Primary Prevention of Cardiovascular Disease: Shared Decision Making in Clinical Practice. JAMA. 2016;316(7):709-710. doi:10.1001/jama.2016.8362
19. Aspirin Guide. Modified April 22, 2022. Accessed August 18, 2022. http://www.aspiringuide.com/nav/1
20. Orringer CE, Blaha MJ, Blankstein R, et al. The National Lipid Association Scientific Statement on Coronary Artery Calcium Scoring to Guide Preventive Strategies for ASCVD Risk Reduction. J Clin Lipidol. 2021;15(1):33-60. doi:10.1016/j.jacl.2020.12.005

Disclosures: 

Dr. Michael Cheshire has no financial relationships to disclose. 

Dr. Robert Block has no financial relationships to disclose.