Aspirin for primary prevention of cardiovascular events?

Dr Martin Juneau, M.D., FRCPCardiologue et Directeur de la prévention, Institut de Cardiologie de Montréal. Professeur titulaire de clinique, Faculté de médecine de l'Université de Montréal. / Cardiologist and Director of Prevention, Montreal Heart Institute. Clinical Professor, Faculty of Medicine, University of Montreal.7 September 2018

Updated on January 24, 2019

It is well established that aspirin is beneficial in secondary prevention, that is, for patients who have already suffered a myocardial infarction or stroke or who have a condition such as angina, acute coronary syndrome, or myocardial ischemia, and for those who have undergone coronary artery bypass grafting or coronary angioplasty. It has been suggested that aspirin may also be beneficial in primary prevention, i.e., to prevent cardiovascular events in those who have never had one, but are at risk. For the last few decades, aspirin has been used at low doses to prevent myocardial infarction and stroke; however, a recent study indicates that this drug does not prevent a first heart attack or stroke in people with moderate cardiovascular risk. In another study, this time of people with type 2 diabetes, taking aspirin modestly reduced the risk of cardiovascular events, but increased the risk of serious bleeding.

Primary prevention in people at moderate risk
Low-dose aspirin (100 mg/day) does not prevent a first heart attack or stroke in people at moderate risk of developing cardiovascular disease according to the ARRIVE study (Aspirin to Reduce Risk of Initial Vascular Events), published in The Lancet in August 2018. Aspirin has been tested in primary prevention over an average of 5 years, with 12,546 people living in the United Kingdom, Poland, Germany, Italy, Ireland, Spain and the USA. During these years, participants who took 100 mg of aspirin daily did not have significantly fewer vascular events than those who took a placebo . There were fewer vascular events than expected in this study, suggesting that participants had low cardiovascular risk rather than moderate risk. Gastrointestinal bleeding, which was mostly mild, was significantly higher in the aspirin group than in the placebo group .

The authors of the ARRIVE study conclude that “The use of aspirin remains a decision that should involve a thoughtful discussion between a clinician and a patient, given the need to weigh cardiovascular and possible cancer prevention benefits against the bleeding risks, patient preferences, cost, and other factors. The ARRIVE data must be interpreted and used in the context of other studies, which have tended to show a reduction primarily in myocardial infarction, with less of an effect on total stroke (including both ischaemic and haemorrhagic stroke).”

Primary prevention in people with diabetes
Aspirin has been tested for primary prevention in 15,480 people with type 2 diabetes, who are therefore at increased risk of developing or dying from cardiovascular disease. During the seven years of the randomized study, people who took 100 mg of aspirin daily had significantly fewer serious vascular events than those who took a placebo . In contrast, major bleeding was greater in the aspirin group than in the placebo group . There was no significant difference between the group that took aspirin and the placebo group for gastrointestinal cancer incidence or any type of cancer . The authors of this study conclude that the benefits of aspirin for people with diabetes are largely outweighed by the risk of bleeding.

Aspirin for prevention in the elderly
The effects of daily low-dose aspirin were evaluated specifically in the elderly in the ASPREE study (Aspirin in Reducing Events in the Elderly), the results of which were published as three articles in the New England Journal Of Medicine (see here, here, and here). The study enlisted 19,114 Australians and Americans aged 70 or older who did not have cardiovascular disease, dementia, or physical disability. Participants were randomly assigned to take a 100 mg enteric-coated aspirin or placebo tablet daily for 5 years. The primary endpoint was a composite endpoint including death, dementia, and persistent physical disability. Secondary endpoints included severe bleeding and cardiovascular disease (nonfatal myocardial infarction, fatal coronary heart disease, fatal or nonfatal stroke, hospitalization for heart failure).

Aspirin did not prolong disability-free survival in the elderly and did not decrease the risk of cardiovascular disease, but it increased the rate of serious bleeding compared with placebo. The composite rate of mortality, dementia, and persistent physical disability was 21.5 and 21.2 events per 1,000 person-years in the group who took aspirin and in the placebo group, respectively. The rates of cardiovascular events were 10.7 and 11.3 events per 1,000 person-years in the aspirin group and the placebo group, respectively. The rate of serious bleeding was significantly higher (P <0.001) in the aspirin group (8.6 events per 1,000 person-years) than in the placebo group (6.2 events per 1,000 person-years). Finally, the all-cause mortality rate was higher in the aspirin group than in the placebo group, a result mainly attributable to deaths from cancer. Since an increase in mortality has not been observed in previous studies on aspirin used for prevention, this unexpected result should be interpreted with caution according to the authors.

Systematic review and meta-analysis
A synthesis of 13 randomized controlled trials of aspirin for primary prevention of cardiovascular disease, including the 3 major trials in 2018, was published in January 2019 in JAMA. All studies included 164,225 participants aged 53 to 74 and a follow-up of 1,050,511 person-years. This meta-analysis confirms that aspirin is associated with a decreased risk of cardiovascular events (cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke) and an increased risk of major bleeding. Aspirin was associated with an 11% reduction in relative risk (absolute risk reduction of 0.38%) of cardiovascular events and a 43% greater relative risk of major bleeding (absolute risk increase of 0.47%). As a result, 265 people will need to be treated with aspirin for 5 years to prevent a cardiovascular event, but one in 210 treated people will experience major bleeding. Because of the unfavourable benefit-to-disadvantage ratio, the European guidelines do not recommend taking aspirin until cardiovascular disease occurs (secondary prevention), i.e., at a time when the benefits outweigh the risks of adverse effects. On the other hand, the US Preventive Services Task Force (USPSTF) recommends improving the benefit-harm ratio for aspirin in primary prevention by estimating the risks of cardiovascular events and bleeding for each patient, considering the potential longer-term benefits of aspirin for the prevention of colorectal cancer, and carefully discussing with patients the balance between the risks of vascular and haemorrhagic events.