9th September 2022, Dr Chee L Khoo
While aspirin does provide a modest benefit in reducing nonfatal MI and nonfatal stroke events, low dose aspirin has little or no effect on cardiovascular disease mortality or all-cause mortality in patients who have not had cardiovascular disease (1). In 2016, the US Preventive Services Task Force (USPSTF) concluded that the beneficial effect of aspirin for the primary prevention of CVD was modest and occurred at doses of 100 mg or less per day (2). Older adults achieved a greater relative MI benefit than younger adults. For the first time in 2016, low-dose aspirin for primary prevention of CVD was recommended for individuals aged 50-59 years with a 10% ten-year cardiovascular risk. There has been a very recent and significant change in recommendations in the latest guidance from the USPSTF.
The History
The USPSTF issued its very first recommendation in 1989 to “consider” aspirin prophylaxis for primary prevention of CVD (3). It updated its position in 1996 when it “reconsidered” the evidence and concluded that the balance of harms and benefits was too close to justify a general recommendation (4).
In 2002, with more data from more clinical trials, it upgraded its recommendations by recommending strongly that clinicians discuss aspirin chemo-prevention with people at increased risk for coronary disease and suggested that decisions be informed by risk calculators and tables with estimated benefits and harms (5).
In 2009, the USPSTF not only strongly recommended aspirin prophylaxis but encouraged specifically for a broad range of adults (men aged 45-79 years; women aged 55-79 years) according to estimated 10-year risk for myocardial infarction, stroke, and gastrointestinal bleeding (6).
As we can see, the 2016 recommendations come after a long tortuous trajectory with significant updates over the last 25 years. The recommendations for aspirin prophylaxis for primary prevention seemed stronger with each iteration. This is not unusual as guidelines and recommendations are dynamic and change as more data become available. Strangely enough, on the back of 11 clinical trials since 2016, the newest recommendations that came out in April this year seems to have taken the opposite direction. The pendulum has swung back.
USPSTF Recommendations on Aspirin Prophylaxis for Primary CV Prevention April 2022
The 2022 guideline does not recommend routine prevention with aspirin for anyone at all (7). For those between 40–59-year-old with a 10 year CVD risk >10%, the decision to initiate low-dose aspirin use for the primary prevention of CVD should be an individual one. The quoted evidence indicates that the net benefit of aspirin use in this group (40-59 yo) is small. The USPSTF recommends against initiating low-dose aspirin use for the primary prevention of CVD in adults 60 years or older. (D recommendation).
This sounds like a much softer recommendation than the recommendations in 2016. Between 2016 guidelines and the current guidelines, three notable large studies reported which significantly affect the change in direction of the current guidelines.
The ARRIVE study randomised 12546 participants aged >55 years old with multiple risk factors (except diabetes) to either aspirin or placebo (8). The participants’ 10-year CV risk was 17%. Over a median follow up period of 60 months, they found no evidence of cardiovascular benefit and a small statistically significant increase in gastrointestinal bleeding.
In the ASPREE study, 19114 US and Australian participants > 70 years old who did not have cardiovascular disease were randomised to 100mg aspirin or placebo (9). After a median duration of 4.7 years, low dose aspirin in older healthy adults resulted in a significantly higher risk of major haemorrhage (38% increase) and did not result in a significantly lower risk of cardiovascular disease than placebo.
Diabetes is associated with an increased in cardiovascular disease. For a little while, diabetes was thought to be equivalent to having a pre-existing CVD and aspirin was recommended in primary prevention of CVD. In the ASCEND study, 15480 participants who did not have existing CVD but had diabetes were randomised to receive 100mg aspirin or placebo (10). After a median follow-up of 7.4 years, aspirin use prevented serious vascular events in persons who had diabetes and no evident cardiovascular disease at trial entry (12% reduction, p = 0.01), but it also caused major bleeding events (29% increase, p = 0.003). The absolute benefits were largely counterbalanced by the bleeding hazard.
The latest recommendations provide guidance on initiating aspirin. What about those already on aspirin? The authors of the guidelines did indicate that “for patients who have initiated aspirin use… it may be reasonable to consider stopping aspirin use around age 75 years” (7).
For patients 40-59 years old, the decision to start aspirin therapy is heavily dependent on 10-year risk for cardiovascular events, as estimated in the widely used calculator associated with the American College of Cardiology and American Heart Association (ACC/AHA)(11). Perhaps, a coronary artery calcium (CAC) score might assist further.
So, here we are. Pendulum has swung back. Paradoxically, persons who are not at increased risk for bleeding and are willing to take low-dose aspirin daily are more likely to benefit. See, the older you are, the higher your bleeding risk but yet that is the group that are more likely to be prescribed aspirin for primary CVD prevention and least likely to benefit. You have to have a pretty good reason to initiate aspirin for primary prevention. It should initiate a conversation with the patient about the pros and cons of initiating aspirin for primary prevention.
References:
1. Guirguis-Blake JM, Evans CV, Senger CA, O’Connor EA, Whitlock EP. Aspirin for the Primary Prevention of Cardiovascular Events: A Systematic Evidence Review for the U.S. Preventive Services Task Force. Ann Intern Med. 2016 Jun 21;164(12):804-13. doi: 10.7326/M15-2113. Epub 2016 Apr 12. PMID: 27064410.
2. Bibbins-Domingo K; US Preventive Services Task Force. Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2016;164(12):836-845. doi:10.7326/M16-0577
3. US Preventive Services Task Force. Guide to Clinical Preventive Services. Williams and Wilkins; 1989:381-384.
4. US Preventive Services Task Force. Aspirin use to prevent cardiovascular disease and colorectal cancer: preventive medication. Published 1996. Accessed August 28, 2022. https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/aspirin-prophylaxis-myocardial-infarction-preventive-medication-1996
5. US Preventive Services Task Force. Aspirin for the primary prevention of cardiovascular events: recommendation and rationale. Ann Intern Med. 2002;136(2):157-160. doi:10.7326/0003-4819-136-2-200201150-00015
6. US Preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;150(6):396-404. doi:10.7326/0003-4819-150-6-200903170-00008
7. 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. Published April 26, 2022. doi:10.1001/jama.2022.3337
8. Gaziano JM, Brotons C, Coppolecchia R, et al; ARRIVE Executive Committee. 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(10152):1036-1046. doi:10.1016/S0140-6736(18)31924-XPubMedGoogle ScholarCrossref
9. McNeil JJ, Wolfe R, Woods RL, et al; ASPREE Investigator Group. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med. 2018;379(16):1509-1518. doi:10.1056/NEJMoa1805819PubMedGoogle ScholarCrossref
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(16):1529-1539. doi:10.1056/NEJMoa1804988
11. Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2935-2959. doi:10.1016/j.jacc.2013.11.005