The benefits of low-dose aspirin in the prevention of cardiovascular events have been investigated since the 1970s following studies that finally elucidated the pharmacodynamics of aspirin, including inhibition of platelet aggregation. In 1974, a team led by Dr. A L Cochrane (of Cochrane database fame) was one of the first to conduct a randomised trial looking at the efficacy of daily aspirin in secondary prevention of mortality post-MI (myocardial infarction). Since then, a wealth of evidence has been amassed supporting the benefits of aspirin in secondary prevention of CVD (cardiovascular disease), which significantly outweigh the risks in the vast majority of cases. The story of primary prevention of CVD, however, is far less compelling and continues to be debated and scrutinised today. Last year three large trials were published, which reviewed the benefits/risks of low-dose aspirin in different patient populations.
In August of 2018, the Lancet published the results of a randomised, double-blind, placebo-controlled, multi-centre clinical trial, known as ARRIVE. This interventional trial was funded by Bayer – the company that invented aspirin over 100 years ago. The trial spanned a period of roughly ten years and included over 12,500 participants aged 55 years and over (mean age = 63.9 years) with relatively low risk of developing CVD. The results of the trial failed to show any significant benefit of aspirin in reducing cardiovascular events or all-cause mortality, however, participants in the aspirin arm were twice as likely to experience a major bleeding event (HR 2.11).
A few years prior to the start date of the ARRIVE trial, Oxford University set up a randomized 2×2 factorial study of aspirin (and omega-3 fatty acid supplementation) vs placebo for primary prevention in people with diabetes (type 1 and 2). Although this trial remains active, preliminary results of the trial were published in the New England Journal of Medicine (NEJM) in October 2018. This is a larger scale study with almost 15,500 participants enrolled. The participants are predominantly Caucasian (62.6% male, mean age = 63.2 years) with a much higher CVD risk (~60% moderate or high risk). As expected, this trial managed to detect benefits of aspirin – recording an absolute risk reduction of “serious vascular events” of 1.1% (8.5% vs 9.6%). However, this of course came at a price of an increased absolute risk of major bleeding of 0.9% (4.1% vs 3.2%). The authors of the trial have noted the extra bleeding events are predominantly gastrointestinal and other extra-cranial bleeds. The ASCEND trial, therefore, illustrates a measurable benefit to low-dose aspirin in this relatively high-risk population, but that it is not clearly outweighed by the risk of bleeding.
At the end of 2009, a couple of years after the ARRIVE trial began, an Australian-US trial was set up to investigate the efficacy of low-dose aspirin in the elderly – ASPREE. Although the ASPREE trial was pulled before its scheduled completion date due to unacceptable risk to the participants, the trial continues to be active in following up with patients and analysing results (ASPREE-XT). In similar fashion to the ASCEND trial, results from ASPREE were published in the NEJM in October 2018. This was the largest of the three trials and included over 19,000 participants aged 65 years or older (most participants were over 75 years old). Not only did this trial fail to show any significant benefits of low-dose aspirin, but aspirin was found to be increasing the risk of all-cause mortality (5.9% vs 5.2%). Although the risk of major bleeding was higher in the aspirin arm (3.8% vs 2.8%), the increase in mortality was not caused by bleeding as expected, rather, it was predominantly caused by an increase in cancer-related death – a risk that was increasing with time from randomisation. This led to the trial being ceased in 2017.
The researchers have advised that these results be interpreted with caution for two main reasons:
- Previous studies have not found an association with cancer or have reported protective effects of aspirin in relation to cancer;
- Participants in the study had a much lower incidence of cancer and all-cause mortality compared to the general population (most likely due to the selection of a relatively healthy elderly population secondary to the exclusion criteria of the study).
These three large-scale trials warn against the use of aspirin for primary prevention of CVD in those with low-moderate risk. Individuals with moderate-high risk would seem to have the most to gain from using low-dose aspirin in this way. However, the risks associated with therapy should be discussed and weighed against the likely benefits.
- Elwood PC, Cochrane AL, Burr ML, Sweetnam PM, Williams G, Welsby E, Hughes SJ, et al. A randomized controlled trial of acetyl salicylic acid in the secondary prevention of mortality from myocardial infarction. Br Med J. 1974; 1(5905): 436–40.
- Gaziano JM, Brotons C, Coppolecchia R, Cricelli C, Darius H, Gorelick PB, 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(10152): 1036-46.
- McNeil JJ, Nelson MR, Woods RL, Lockery JE, Wolfe R, et al. for the ASPREE Investigator Group. Effect of aspirin on all-cause mortality in the healthy elderly. N Engl J Med. 2018; 379:1519-28.
- The ASCEND Study Collaborative Group. Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus. N Engl J Med 2018; 379:1529-1539