For thousands of years, extracts from the bark of willow trees have been used for analgesic and antipyretic effects.¹ In the 19th century, German chemists changed history by adding an acetyl group to one of the tree bark compounds to make it more palatable. This acetyl group gave acetylsalicylic acid—aspirin—the unique ability to irreversibly acetylate serine in the active site of cyclo-oxygenase (COX), permanently blocking the action of this important enzyme used in prostaglandin synthesis. In some cells, this results in temporary analgesic, antipyretic, and anti-inflammatory effects until the cell regenerates new COX. In the platelet, it results in a more durable effect because, without a nucleus, platelets cannot replace the disabled COX-1.

The sustained antiplatelet effect of aspirin was elucidated by John Vane at a time when the role of platelets in acute atherothrombotic vascular events began to be appreciated. Reducing platelet activity has been an important therapeutic target and results in both the beneficial and harmful effects of aspirin, primarily reversal of thrombus formation and bleeding.

The antiplatelet effects of aspirin led to multiple trials testing its efficacy for the prevention of acute cardiovascular (CV) events and following vascular procedures. For example, in the ISIS-2 (International Study of Infarct Survival-2) trial,² 17,187 individuals admitted with an acute myocardial infarction (MI) were randomized to a streptokinase infusion over 1 hour, aspirin for 1 month, or placebo. Aspirin significantly reduced the risk of serious vascular events, including death. These benefits of aspirin were evident in just a few days, with little risk of bleeding in this short time. Similarly, in other trials following a vascular procedure such as stenting, aspirin clearly reduced the risk of events over and above any bleeding downsides, at least in the short term. For this reason, most guidelines for acute vascular events and following certain vascular procedures are in agreement that aspirin remains the mainstay of therapy for secondary prevention of CV events.

The next logical question, then, was whether aspirin could prevent a first vascular event. However, there are many challenges in conducting primary prevention trials. Event rates for a first CV event, even in a population considered at moderate risk of CV disease, are much lower than rates of secondary events. This is due in part to the challenges related to identifying CV risk and improvements in CV prevention related to smoking cessation, lifestyle changes, and other preventive therapies such as cholesterol-lowering agents. For this reason, study populations need to be much larger and the study durations much longer. Further, it is likely more motivating for patients to take a medication long term when they already have disease and are concerned about preventing the next event. For this reason, there are fewer trials in primary prevention, with some varied results.

The first trial to demonstrate that aspirin could prevent a primary CV event was the Physicians' Health Study.⁴ Meta-analysis showed that aspirin reduced the risk of first CV event by about 12%, which was not as dramatic as the 22% reduction seen in secondary prevention.⁵ When only the first 3 years of trials were included, the effect of aspirin on primary events was closer to that of secondary prevention, with an 18% reduction.⁶ The prevailing hypothesis is that participants did not continue to take aspirin in the later years of the study, leading to a lower protective benefit. One possibility for decreased aspirin use over time is the increased risk of bleeding events, which occur more frequently than CV events in populations without a prior CV event. Although not all bleeding events are severe, bruising and minor bleeding can be irritating and lead to self-discontinuation of aspirin. Furthermore, for some patients, the risk of a major bleed may outweigh the benefit of a potentially prevented event. As a result, current guidelines differ on the role of aspirin in primary prevention. The US Preventive Services Task Force recommends clinicians consider starting aspirin after weighing not only the impact of aspirin on primary vascular events and bleeding, but also the longer-term effects in reduction of risk of colorectal cancer and recommending aspirin based on a patient's risk of future vascular disease versus their bleeding events. All of this is also considered through the lens of personal preferences, age, and estimated remaining life expectancy.⁷

Three recently published trials have attempted to address the limitations of existing data for primary prevention. The ARRIVE (Aspirin to Reduce Risks of Initial Vascular Events) trial enrolled 12,456 participants at moderate risk of CV disease to aspirin 100 mg/d versus placebo.⁸ Participants were included if they were ≥55 (men) or ≥60 (women) and had a moderate risk of CV disease, defined as ≥3 CV risk factors (current smoker, dyslipidemia, hypertension, or a family history of CV disease). Individuals with diabetes were excluded. After a median 5 years of follow-up, the event rate was 1/3 of what had been anticipated, and there was no significant difference in the main outcome (composite of CV death, MI, unstable angina, stroke, or transient ischemic attack) with 269 (4.3%) in the aspirin arm versus 281 (4.5%) in the placebo group (hazard ratio 0.96; 95% confidence interval, 0.81-1.13; p = 0.60). Rates of serious adverse events were similar in both groups; however, the incidence of gastrointestinal bleeding was higher in the aspirin group compared with placebo (0.97% vs. 0.46%, p = 0.0007), although these were predominantly mild events. An important caveat of this trial is that although the goal had been to enroll individuals at moderate risk, the event rate reflects a low risk population. Additionally, there were substantial drop-out and drop-in rates. Results confined to those who adhered treatment assignment were consistent with previous trials.

The ASCEND (A Study of Cardiovascular Events in Diabetes) trial was undertaken to specifically examine the role of aspirin for primary prevention in those with diabetes, often considered a coronary artery disease equivalent.⁹ In total, 15,480 individuals were randomized to 100 mg of aspirin daily versus placebo. Over a mean follow-up of 7 years, those randomized to aspirin had a significant reduction in primary CV events (MI, stroke or transient ischemic attack, or all-cause mortality), 658 (8.5%) versus 743 (9.6%) (rate ratio 0.88; 95% confidence interval, 0.79-0.97, p = 0.01). Major bleeding events were more common in the aspirin arm (4.1% vs. 3.2%; p = 0.003) and were largely gastrointestinal bleeds.

The ASPREE (Aspirin in Reducing Events in the Elderly) trial was designed to specifically address the role of aspirin for primary prevention in older adults.^10-12 In total, 19,114 healthy older adults were randomized to 100 mg aspirin daily versus placebo. Individuals with dementia were excluded. The primary endpoint was a composite of all-cause death, dementia, or physical disability. The study was stopped early after a median of 4.7 years of follow-up. There was no significant difference in the primary composite outcome of death, dementia, or persistent physical disability (21.5 vs. 21.2 events per 1000 person-years). The results for major CV events in those randomized to aspirin versus placebo while underpowered were consistent with previous studies (7.8 vs. 8.8 per 1000 person-years) (hazard ratio 0.89; 95% confidence interval, 0.77-1.03). Rates of bleeding were higher in the aspirin group (8.6 vs. 6.2 events per 1000 person-years; p < 0.001), with the majority being gastrointestinal bleeds. Fatal bleeding rates were not significantly different, although there was a significantly higher rate of intracranial bleeding in those on aspirin. Also of concern in ASPREE was an increased rate of all-cause mortality in the aspirin group (5.9% vs. 5.2%; p < 0.05) that was attributed to the increased risk of cancer seen in those assigned to aspirin (3.1% vs. 2.3%; p < 0.05). These findings are counter to previously published data, and the interpretation is unclear.

A recently published meta-analysis that combines these new trials with 10 previous primary prevention trials includes data from a total of 164,225 participants over 1 million person years of follow-up and demonstrates that the estimated risk and benefits of aspirin for primary prevention are not materially altered. The risk of CV disease was lowered by 11%, and the number needed to treat was 265. Bleeding risk was increased 43%, with a number needed to harm of 210. There was no overall effect on total cancer during the trials. This finding is also consistent with previous studies that did not see much of an effect on total cancer until much longer follow-up.¹³ There was a nonsignificant 6% reduction in total mortality, which is consistent with what would be anticipated given the 11% reduction in CV disease events. The effects tended to be the same for individuals with diabetes.

Taken together with previous trial data, the three recently published trials clarify that the best estimates for the impact of aspirin on prevention primary CV disease events and bleeding have not materially changed. The recent trials add important information among older individuals, those with diabetes, and those with multiple risk factors. Additionally, this meta-analysis demonstrates that the vascular and bleeding estimates support an individualized approach advocated by the US Preventive Services Task Force guidelines.

This personalized approach is dependent on our ability to accurately estimate the risk of future events. We have seen that CV disease risk calculators tend to overestimate risk in populations where CV risk is falling, as it is in the United States and Europe. CV risk is not static. When patients stop smoking, better control their lipids and blood pressure, and adopt healthier lifestyles, their future risk is lowered. Other guidelines such as those for lipid and blood pressure management also advocate the use of risk estimation in tailoring therapy. Perhaps new genetic and artificial-intelligence-derived risk estimators will refine our ability to assess risk. The calculus is complicated in weighing the immediate effects of aspirin in CV disease and bleeding and longer-term effects on colorectal cancer, but it is likely to yield higher-risk primary prevention patients. This assessment should always involve a discussion with a health care provider.

In summary, new trial data, incorporated into a meta-analysis that includes decades of trial experience, demonstrate a general consistency of the role of aspirin for primary prevention of CV events. When applying these results to an individual patient, we must consider all the things we can do for patients to lower risk. In places of the world where risk is rising or where other preventive strategies such as statins are less available, aspirin, a low-cost intervention, may play an important preventive role. After 120 years, aspirin remains an important medication in the acute treatment of vascular events, after certain procedures, in secondary prevention, and in primary prevention in the right patients.

References

1. Gaziano JM, Greenland P. When should aspirin be used for prevention of cardiovascular events? JAMA 2014;312:2503-4.
2. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet 1988;2:349-60.
3. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86.
4. 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 1989:321:129-35.
5. Antithrombotic Trialists' (ATT) Collaboration, Baigent C, Blackwell L, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009;373:1849-60.
6. Rothwell PM, Wilson M, Elwin CE, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 2010;376:1741-50.
7. Bibbins-Domingo K; U.S. Preventive Services Task Force. Aspirin Use for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 2016;164:836-45.
8. 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;392:1036-46.
9. ASCEND Study Collaborative Group, Bowman L, Mafham M, et al. Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus. N Engl J Med 2018;379:1529-39.
10. 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;379:1509-18.
11. McNeil JJ, Nelson MR, Woods RL, et al. Effect of Aspirin on All-Cause Mortality in the Healthy Elderly. N Engl J Med 2018;379:1519-28.
12. McNeil JJ, Woods RL, Nelson MR, et al. Effect of Aspirin on Disability-free Survival in the Healthy Elderly. N Engl J Med 2018;379:1499-1508.
13. Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 2011;377:31-41.

Clinical Topics: Acute Coronary Syndromes, Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Novel Agents, Statins, Hypertension, Smoking, Sleep Apnea

Keywords: Aspirin, Analgesics, Angina, Unstable, Antipyretics, Blood Platelets, Blood Pressure, Cardiovascular Diseases, Calculi, Catalytic Domain, Confidence Intervals, Cholesterol, Colorectal Neoplasms, Coronary Artery Disease, Dyslipidemias, Diabetes Mellitus, Dementia, Health Personnel, Hemorrhage, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Follow-Up Studies, Hypertension, Ischemic Attack, Transient, Life Expectancy, Lipids, Life Style, Myocardial Infarction, Primary Prevention, Secondary Prevention, Prostaglandin-Endoperoxide Synthases, Prostaglandins, Risk Factors, Salix, Smoking Cessation, Smoking, Streptokinase, Stroke, Thrombosis, Acute Coronary Syndrome

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