The role of aspirin in the primary prevention of atherosclerotic cardiovascular disease

Primary prevention of atherosclerotic cardiovascular disease (ACD) is defined as the administration of drugs to people who do not have confirmed cardiovascular disease (myocardial infarction, acute coronary syndrome, chronic coronary artery disease, stroke or transient ischaemic attack and peripheral vascular disease). Secondary prevention of CHD is considered to be the administration of drugs to people with confirmed CHD.

Aspirin administration in the secondary prevention of AKN has shown significant benefit and is the cornerstone of antithrombotic therapy. Aspirin administration in the primary prevention of CHD has not been established and there are recent conflicting data. However, for different reasons, millions of people in the world take a small daily dose of aspirin (80-100 mg).

In this review we will examine the data from the most recent studies, as well as the European Heart Association and American Heart Association (AHA/ACC) guidelines for aspirin administration in the primary prevention of CHD.

Recently, three large studies were published on the efficacy and safety of low-dose aspirin as primary prevention in non-diabetic patients with multiple risk factors (ARRIVE study), in diabetic patients (ASCEND study) and in elderly patients (ASPREE study). The new 2019 guidelines for the use of aspirin in primary prevention took these studies into account.

Specifically, the ARRIVE study was a double-blind, randomised, multicentre trial involving 12,546 men aged 55 years and over and women aged 60 years and over, who had three or more risk factors. Patients were randomized to receive 100 mg of enterosoluble aspirin or placebo daily. The study investigated the following primary endpoints: the likelihood of cardiovascular death, myocardial infarction and vascular stroke (VTE) or transient ischaemic attack. In terms of safety, endpoints were bleeding episodes and other adverse events. The median follow-up time was 60 months. Primary endpoints occurred in 4.29% of subjects in the aspirin group and 4.48% of subjects in the placebo group, i.e. there was no statistically significant difference between the two groups. However, as expected, more gastrointestinal bleeding occurred in the aspirin group. In conclusion, the ARRIVE study did not show aspirin to be of benefit to intermediate-risk individuals in primary prevention.

The second ASCEND study was a randomised trial in 15,480 people aged over 40 years with a mean age of 63 years with diabetes mellitus (DM) who received 100 mg of enterosoluble aspirin or placebo, without known cardiovascular disease. The primary endpoints of the study were: vascular death, myocardial infarction and MI or transient ischemic attack. In terms of safety, intracranial bleeding, gastrointestinal bleeding and ocular bleeding were examined. Secondarily, the occurrence of gastrointestinal cancer was also studied. The results showed that in the people given aspirin there were significantly fewer episodes of cardiovascular disease (8.5% versus 9.6%), a statistically significant difference, but they had more bleeding (4.1% versus 3.2%). As for cancer, it occurred with the same frequency in the two groups. Therefore, this study showed that in patients with DM, aspirin reduces the risk of cardiovascular disease, but unfortunately significantly increases the risk of major bleeding.

The ASPREE study was a randomized double-blind study involving 19,114 people aged 70 years or older for whites or 65 years or older for people of black race or Hispanic origin with no previous cardiovascular disease or symptoms of cardiovascular disease, dementia or disability. The average follow-up time was 4.7 years. Results were similar for both the aspirin and placebo groups. In terms of bleeding, in the aspirin group there were statistically more brain bleeds and bleeds from the gastrointestinal tract. Also an interesting finding, for the first time, was the increased cancer mortality in the aspirin group. Therefore, the ASPREE study showed that low-dose aspirin in healthy older people did not have a beneficial effect.

The European Society of Cardiology in its 2019 guidelines does not generally recommend the use of aspirin in primary prevention. In patients with DM and a high or very high risk of CHD, aspirin can be given only if there are no definite contraindications.

The 2019 guidelines of the American Heart Association recommend that aspirin should not be given routinely in the primary prevention of CHD because it has no beneficial effect.

In particular, it is important not to administer it to patients with a history of gastrointestinal bleeding or peptic ulcer, thrombocytopenia, coagulation disorders, chronic kidney disease, age > 70 years and concomitant administration of anti-inflammatory drugs, steroids and anticoagulants.

Therefore, according to the guidelines of the European and US Heart Societies and the findings of the three recent large studies discussed above, aspirin should not be given for primary prevention in people under 40 and over 70 years of age, in people who have an increased risk of bleeding or who are taking anticoagulants, antiplatelets, nonsteroidal anti-inflammatory drugs and steroids. Aspirin administration in primary prevention is discussed in people aged 40-70 years of very high cardiovascular risk, i.e. when they are smokers, people with a burdened family history of coronary artery disease, unregulated arterial hypertension and hypercholesterolaemia. A special category is diabetic patients, in whom aspirin administration has been shown to be useful in preventing cardiovascular events, but at the cost of causing more severe bleeding. Therefore, according to the results of the ASCEND study, in diabetic patients with a very high risk of cardiovascular disease, despite the increased risk of bleeding, aspirin can be administered prophylactically, after detailed discussion with the patient and with his/her agreement, particularly if the risk of bleeding is low.

Finally, there is another category of patients who have an increased risk of coronary artery disease and present findings of advanced atherosclerosis, detected by CT coronary angiography, vascular ultrasound or have an increased calcium index in the coronary vessels. In this group of patients, who are considered high-risk, aspirin is recommended for primary prevention when they do not have an increased risk of bleeding. In case these patients have an increased risk of bleeding, co-administration of PPI drugs is recommended.

However, in our contact with these patients about the potential benefits and risks of aspirin administration, it should be emphasised in particular and in as simple and convincing a way as possible that avoiding or modifying other risk factors, such as smoking, blood pressure control, management of hypercholesterolaemia, control of DM, obesity, proper diet and daily exercise, offer much greater benefit in the effort to prevent cardiovascular disease.

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