Acetylsalicylic Acid (Low Doses): What the Clinical Studies Show

Aspirin is one of the most studied drugs in cardiology. Over more than 40 years, the understanding of it has traveled from «a pill for everyone over 50» to a clearly defined group of patients for whom it is truly beneficial. Our editorial team traced which studies shaped the modern view and why the recommendations changed.

Early studies: from heart attack to prevention

A turning point was the ISIS-2 study, published in 1988. In it, more than 17,000 patients with suspected acute myocardial infarction received streptokinase, aspirin, both drugs, or placebo. Aspirin at a dose of 162.5 mg per day for a month reduced vascular mortality over five weeks by about a quarter, and in combination with streptokinase the effect was even greater.

The result of ISIS-2 was striking given the simplicity and availability of the drug. It cemented aspirin as the standard treatment for acute coronary syndrome, and this status persists to this day.

Almost simultaneously, primary prevention data appeared. In the Physicians’ Health Study (1989), American male physicians took aspirin every other day or placebo. The study was stopped early because of a substantial reduction in the incidence of first myocardial infarction in the aspirin group. At the same time, the effect on stroke and overall mortality was uncertain.

These early works formed the notion that aspirin is beneficial for practically all adults with cardiovascular risk. Only later did it become clear that the participant population, design, and background therapy of those years differed substantially from modern ones.

Secondary prevention: where the benefit is obvious

Secondary prevention concerns people who have already had a heart attack, ischemic stroke, transient ischemic attack, or other manifestations of atherosclerosis. A meta-analysis by the Antithrombotic Trialists’ Collaboration (2009), which combined individual participant data from randomized studies, showed that in this group aspirin reduced the incidence of major vascular events by about a fifth.

Since the baseline risk of a recurrent event in such patients is high, even a relative reduction of 20% means a significant absolute benefit. It substantially outweighs the increased risk of bleeding.

That is precisely why current guidelines from the European Society of Cardiology and American cardiology associations recommend low-dose aspirin for practically all patients with atherosclerotic cardiovascular disease in the absence of contraindications.

For secondary prevention other antiplatelet agents have also been studied, in particular P2Y12 receptor inhibitors, and their combination with aspirin. However, aspirin remains the base drug to which other agents are added depending on the clinical situation.

Primary prevention: the 2018 studies

In 2018, three large randomized studies were published that substantially changed the approach. ARRIVE included people with a moderate calculated cardiovascular risk without diabetes. Aspirin did not significantly reduce the incidence of cardiovascular events, although the incidence of bleeding rose.

ASCEND studied patients with diabetes mellitus without cardiovascular disease. Aspirin reduced the incidence of major vascular events, but increased the incidence of major bleeds to about the same degree, so the absolute benefit was balanced by harm.

ASPREE enrolled more than 19,000 people aged 70 and over (in some groups from 65) without cardiovascular disease. Aspirin did not reduce the incidence of cardiovascular events but increased the risk of major bleeding. In a separate publication of the same study, unexpectedly higher overall mortality was recorded in the aspirin group, mainly due to oncological causes; this result is interpreted with caution.

The shared conclusion of these studies is that in the era of statins, better blood-pressure control, and reduced smoking, the additional benefit of aspirin for people without established disease has become small, while the risk of bleeding has remained.

Cancer, preeclampsia, and other directions

Analyses by Rothwell and colleagues (2011) based on data from randomized aspirin studies conducted for the prevention of cardiovascular disease showed a reduction in mortality from certain cancers, especially colorectal, with long-term use and follow-up. These data stimulated interest in chemoprevention.

However, the ASPREE results in the elderly did not confirm an antitumor benefit, and aspirin is now not recommended for cancer prevention in the general population. Exceptions are certain groups with a high hereditary risk (for example, Lynch syndrome), where the decision is made individually.

In obstetrics, the ASPRE study (2017) showed that a low dose of aspirin in women at high risk of preterm preeclampsia reduced its incidence. This became the basis for recommendations on preeclampsia prevention in at-risk groups under a doctor’s supervision.

• Colorectal cancer: a signal of benefit in long-term analyses, but not confirmed in the elderly.
• Preeclampsia: proven benefit in high-risk women.
• Venous thromboembolism: aspirin has some effect but is inferior to anticoagulants.
• Cognitive health: no benefit for dementia was found in ASPREE.

How these data changed the recommendations

The ACC/AHA primary prevention guidelines (2019) indicated that aspirin should not be routinely prescribed to people over 70 or to those at increased risk of bleeding. For 40–70-year-olds at high risk of atherosclerosis it can be considered only in select cases.

The USPSTF recommendations (2022) moved in the same direction: do not start aspirin for primary prevention in people aged 60 and over, and for those aged 40–59 with a 10-year risk of 10% or more, make the decision individually.

In secondary prevention nothing substantially changed: aspirin remains the standard for people with atherosclerotic disease. The difference between the two scenarios became the key lesson: the same drug can be essential for some and superfluous for others.

For active people and athletes a simple conclusion follows from this: daily aspirin without diagnosed cardiovascular disease is generally not indicated, and the decision to take it should be based on an individual risk assessment by a doctor.

Editorial conclusions

The benefit of low-dose aspirin is convincingly proven in secondary prevention — in people who already have atherosclerotic disease.

The ARRIVE, ASCEND, and ASPREE studies showed that in primary prevention the benefit is small and often balanced by the risk of bleeding, which changed international recommendations.

The data on cancer prevention are mixed, whereas in obstetrics aspirin has a proven place for preventing preeclampsia in at-risk groups.

We also recommend reading our articles on the mechanism of action of low-dose aspirin, on its side effects and contraindications, and on why athletes discuss it.

References

1. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet. 1988;2(8607):349–360.
2. Steering Committee of the Physicians' Health Study Research Group. Final report on the aspirin component of the ongoing Physicians' Health Study. N Engl J Med. 1989;321(3):129–135.
3. Antithrombotic Trialists' (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373(9678):1849–1860.
4. Gaziano JM, Brotons C, Coppolecchia R, 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):1036–1046.
5. ASCEND Study Collaborative Group. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med. 2018;379(16):1529–1539.
6. McNeil JJ, Wolfe R, Woods RL, et al. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med. 2018;379(16):1509–1518.
7. Rothwell PM, Fowkes FG, Belch JF, et al. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet. 2011;377(9759):31–41.
8. US Preventive Services Task Force. Aspirin use to prevent cardiovascular disease: US Preventive Services Task Force recommendation statement. JAMA. 2022;327(16):1577–1584.