11th October 2023, Dr Chee L Khoo
Aspirin is commonly used as an anti-platelet agent for the prevention of acute coronary syndromes and cerebrovascular accidents. Its role in secondary prevention is well established but its role in primary prevention remains very complicated and very debatable. There is no question that aspirin is definitely beneficial in reducing events especially in patients at high risk of cardiovascular events. Its usefulness has to be balanced against the adverse effects of bleeding. Now, these are major bleeding events which include major gastrointestinal bleeding requiring transfusions and occasionally, result in deaths. Perhaps, enteric-coated (EC) aspirin might mitigate against those risks. Does it, really?
Before we look at the safety aspect of enteric coated aspirin, we need to look at the efficacy of EC aspirin. If it causes less bleeding (if indeed it does!), then is it because it is less efficacious which may mean less CV protection?
Enteric coating of aspirin delays the breakdown of the tablet until it is in the higher pH of the duodenum. Several studies have proposed that the enteric coating reduces the bioavailability of aspirin due to reduced dissolution and absorption (1-3). Maree et al examined serum thromboxane B2 levels in 131 patients with stable CVD who were taking 75mg EC aspirin. 44% of patients who are prescribed low-dose EC aspirin for secondary prevention of cardiovascular events have persistent uninhibited platelet COX activity. Younger and heavier patients and those with a previous MI are most likely to have an inadequate response to treatment.
Haastrup et al performed a mini-review of trials which looked at the pharmacokinetics and anti-platelet effects of EC aspirin (2). Data from 7 clinical trials indicate that enteric coating can reduce the antiplatelet effect of aspirin compared to plain aspirin. This is thought to be possibly due to decreased bioavailability of aspirin caused by prolonged solvation and absorption of the enteric-coated formulations. They concluded that low-dose EC aspirin might not be bioequivalent to plain aspirin, entailing the risk of insufficient cardiovascular prophylaxis.
In 2021, the ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness) trial evaluated the effectiveness of high-dose (325 mg) vs low-dose (81 mg) daily aspirin in 15 076 patients with established atherosclerotic cardiovascular disease (4). The results of the trial showed no statistical significance between high- and low-dose aspirin on the primary composite end points of all-cause death, hospitalization for MI, or hospitalization for stroke,
Sleem et al recently performed a post-hoc secondary analysis 10 678 participants with atherosclerotic cardiovascular disease (ASCVD) from the above ADAPTABLE trial (5). They asked the question of whether EC aspirin reduce effectiveness or increase safety in patients with cardiovascular disease. The primary effectiveness end point was the cumulative incidence of the composite of myocardial infarction, stroke, or death from any cause, and the primary safety end point was major bleeding events (hospitalization for a bleeding event with use of a blood product or intracranial haemorrhage).
Of the 10 678 participants, 69% took EC aspirin while 31% took uncoated (plain) aspirin. They found that EC aspirin was not associated with significantly higher risk of myocardial infarction, stroke, or death or with lower bleeding risk compared with uncoated aspirin, regardless of dose.
While the recent study concluded that EC aspirin is just as effective in CVD prevention in patients with established CVD (secondary prevention), it also concluded that EC aspirin does not protect against the risk of bleeding inherent with aspirin intake. In patients with established CVD, we often don’t have the choice of whether aspirin is recommended or not. We have to be wary of the GI bleeding risk and monitor GI bleed closely.
In patients who hasn’t had a CVD (i.e. primary prevention), the recommendations from the recent USPSTF Recommendations on Aspirin Prophylaxis for Primary CV Prevention (April 2022) was well covered 12 months ago here on GPVoice. To recap, the guidelines does not recommend routine prevention with aspirin for anyone at all. 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 recent article suggest that EC aspirin doesn’t solve the bleeding problem. The situation becomes more complicated in those patients who may not have “established” cardiovascular disease but have evidence of “significant” coronary, cerebral or peripheral arterial disease as demonstrated on angiographic studies but has not had an event yet. These are patients who are at high risk of an event. Should they be on aspirin (EC or not)? As they say, medicine is not a science but an art.
References:
- Bhatt DL, Grosser T, Dong JF, et al. Enteric coating and aspirin nonresponsiveness in patients with type 2 diabetes mellitus. J Am Coll Cardiol. 2017;69(6):603-612.
- Haastrup PF, Grønlykke T, Jarbøl DE. Enteric coating can lead to reduced antiplatelet effect of low-dose acetylsalicylic acid. Basic Clin Pharmacol Toxicol. 2015;116(3):212-215
- Maree AO, Curtin RJ, Dooley M, Conroy RM, Crean P, Cox D, Fitzgerald DJ. Platelet response to low-dose enteric-coated aspirin in patients with stable cardiovascular disease. J Am Coll Cardiol. 2005 Oct 4;46(7):1258-63. doi: 10.1016/j.jacc.2005.06.058.
- Jones WS, Mulder H, Wruck LM, et al; ADAPTABLE Team. Comparative effectiveness of aspirin dosing in cardiovascular disease. N Engl J Med. 2021;384(21):1981-1990.
- 14. Sleem A, Effron MB, Stebbins A, et al. Effectiveness and Safety of Enteric-Coated vs Uncoated Aspirin in Patients With Cardiovascular Disease: A Secondary Analysis of the ADAPTABLE Randomized Clinical Trial. JAMA Cardiol. Published online October 04, 2023. doi:10.1001/jamacardio.2023.3364