Dr Éric Thorin, Ph. D.
Professeur titulaire, Département de Chirurgie, Université de Montréal. Chercheur au centre de recherche de l'Institut de cardiologie de Montréal.
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Dr Martin Juneau, M.D., FRCP
Cardiologue, directeur de l'Observatoire de la prévention de l'Institut de Cardiologie de Montréal. Professeur titulaire de clinique, Faculté de médecine de l'Université de Montréal. / Cardiologist and Director of Prevention Watch, Montreal Heart Institute. Clinical Professor, Faculty of Medicine, University of Montreal.
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- Despite recommendations, a recent study shows that 30% of healthy individuals aged 60 and over regularly take low-dose aspirin.
- Three large randomized, placebo-controlled trials published in 2018, including a total of 47,140 patients, demonstrated that aspirin not only provided no protection, but also promoted gastrointestinal bleeding and certain cancers.
- The use of low-dose aspirin for primary prevention should be discontinued.
One of the most persistent medical myths is that low-dose aspirin protects against cardiovascular disease in healthy older adults. This belief originated a long time ago. A Canadian study published in 1978 showed that in men who had suffered a stroke, high-dose aspirin (325 mg/day) could reduce the occurrence of a second stroke and death within the following 12 months by 48%. Aspirin’s protective effect is due to its antiplatelet action, that is, its ability to prevent platelets from being activated when an atherosclerotic plaque (calcified fatty plaque in the arteries) ruptures and also from aggregating to form a clot that could obstruct an artery. Aspirin blocks cyclooxygenase enzymes and thus the synthesis of prostaglandins, including thromboxane A2, which is a potent platelet pro-aggregant. The mechanism of action is therefore different from anticoagulants such as warfarin, heparin, or the newer oral anticoagulants (NOACs), which act by directly inhibiting specific coagulation factors (vitamin K-dependent coagulation factors, thrombin, or factor Xa). Some researchers suggested that if aspirin had beneficial effects in secondary prevention, why wouldn’t it also have beneficial effects in primary prevention? The seed was planted.
Twenty years later (1998), the results of the Hypertension Optimal Treatment (HOT) study in primary prevention were published: 18,790 patients with a mean age of 61.5 years, treated for hypertension, were either treated with low-dose aspirin (75 mg/day) or were not treated with low-dose aspirin. In this study, aspirin reduced the number of major cardiovascular events by an additional 15% (p=0.03), and more specifically, myocardial infarctions by 36% (p=0.002). Even though aspirin doubled (p<0.001) the risk of major gastrointestinal bleeding, this validated the idea that aspirin was beneficial in primary prevention; the seed had been planted. This is reflected in the 2002 medical guidelines, which recommend treating asymptomatic patients with a 10% or higher risk of developing coronary heart disease within the next 10 years with low-dose aspirin (75 to 160 mg/day).
Seven years later (2005), another large primary prevention study was published. It focused on 39,876 healthy women aged 45 and older, some treated with low-dose aspirin (100 mg every other day for 10 years) and others not. The study showed a non-significant 9% reduction in the risk of major cardiovascular events, but a 40% increase in the number of gastrointestinal bleeding episodes requiring blood transfusions. Overall, low-dose aspirin was therefore more harmful than beneficial. Yet the myth took hold when a sub-analysis of data collected from women aged 65 and over (4,097 patients, or 10% of the total) showed a 26% reduction in the risk of major cardiovascular events (p=0.008). This reduction in cardiovascular events was primarily due to a reduction in ischemic strokes (blocked cerebral artery, p<0.05) and myocardial infarctions (p=0.04). These results were consistent with those of the HOT study. However, since it was already known that men were at higher risk of cardiovascular disease than women, many clinicians quickly concluded that if aspirin was good for older women, it should be even better for men of the same age!
It was only in 2018, 13 years later, that three very large randomized clinical studies (see the table below) totalling 47,140 patients showed in a reproducible and irrefutable manner that the risk of bleeding was much greater than the cardiovascular benefit that low-dose aspirin (100 mg) could provide, both in women and men. And yet, the myth is still alive; a recent study reports that a very large number of people aged 60 and over (29.7%) without any cardiovascular pathology take aspirin for primary prevention, and that 5.2% did so without medical advice.
Randomized clinical trials with aspirin (100 mg/day) in primary prevention
| Study (Year); n | Inclusion criteria | First CV event | Major bleeding |
|---|---|---|---|
| ARRIVE (2018) 12,546 | Individuals at average risk (10–20%), without diabetes. Average age: 61 years. | Neutral, no beneficial effect. RR 0.96 (0.81–1.13), no difference in stroke and MI. | Significantly increased (111%). |
| ASCEND (2018) 15,480 | Type 2 diabetes without cardiovascular disease. Average age: 63 years. | 12% reduction of CV events | Increase of 29%. |
| ASPREE (2018) 19,114 | Healthy subjects (over 70 years old; minorities over 65 years old). Average age: 74 years. | Neutral, no beneficial effect. RR 0.95 (0.83–1.08). | Increase of 38% Mortality increased by 14% from all causes, including cancer. |
The ARRIVE study recruited 12,546 patients (30% women) with a mean age of 61 years and a moderate risk of developing cardiovascular disease in Europe (6 countries) and the United States. They were randomly assigned to receive either aspirin (100 mg/day, n=6270) or a placebo (n=6276) for an average of 5 years. The study demonstrates that aspirin has no effect in men or women over or under 65 years of age; it does not delay the onset of the first cardiovascular event, whether death, myocardial infarction, unstable angina, stroke, or transient ischemic attack. However, aspirin nearly doubled the incidence of gastrointestinal bleeding.
The British ASCEND study recruited 15,480 diabetic patients (37.5% women) without cardiovascular disease, with a mean age of 63. Like hypertension, diabetes is a major risk factor for cardiovascular disease. As in the previous study, patients were randomized into two groups: low-dose aspirin (100 mg/day, n=7740) or placebo (n=7740), with a mean follow-up of 7.4 years. According to the study authors’ conclusion, the 12% reduction in the number of major cardiovascular events was largely offset by a 29% increase in severe gastrointestinal bleeding.
Finally, the ASPREE study recruited 19,114 healthy patients (56.4% women) over the age of 70 in Australia and the United States, or over the age of 65 for Black and Hispanic patients in the United States. Of these patients, 9,525 received aspirin (100 mg/day) and 9,589 received a placebo; they were followed for an average of 4.7 years. During this period, a 14% higher mortality rate was reported in the aspirin group. This increase was primarily due to a 31% increase in cancer-related deaths.
It is therefore dangerous to treat individuals without cardiovascular disease with low doses of aspirin. Not only are there no benefits, but the risks outweigh the benefits. The only remaining indication for aspirin is secondary prevention in patients with a history of cardiovascular disease who are at high risk of recurrence.