Aspirin for primary prevention of myocardial infarction and stroke: What have we learned after more than 40 years of trials?

Author: Huagui Li, MD, PhD, FACC

Statement：This is the author’s personal opinion only. It does not reflect the position of the author’s employer or the sponsor website.

Brief history of aspirin

Around 400 BC, Hippocrates referred the use of willow leaf tea for fever. Around year 1700, willow bark was found to have analgesic effect. It was later understood that the willow tree contained salicin which could be converted to salicyclic acid in the human body. It was salicyclic acid that produced the antipyretic and analgesic effect. In 1853, French chemist Charles Frédéric Gerhardt synthesized acetyl salicyclic acid. In 1899, German pharmaceutical company Bayer manufactured acetyl salicyclic acid and marketed it with the brand name of Aspirin. It was initially marketed as an agent for fever, pain and inflammation. Years later, Bayer lost its patent in many countries and aspirin somehow became a generic name. It was estimated that the global consumption of aspirin was about 44,000 tons in 2016!

British pharmacologist John Robert Vane discovered the mechanism of aspirin-induced inhibition of prostaglandins and thromboxanes and shared a Noble prize in physiology and medicine with Swedish biochemists Sune Bergstrom and Bengt I. Samuelsson in 1982.   Aspirin suppresses clot formation by inhibiting thromboxane synthesis in the platelets (through irreversible inactivation of the cyclooxygenase).

Prevention of recurrent myocardial infarction (MI) and improvement of survival in post MI patients was first reported in 1974. Since the FDA approval in 1985, aspirin has been widely used for secondary prevention in patients with past history of MI or confirmed diagnosis of coronary artery disease (CAD).

Almost around the same time of aspirin trials for secondary prevention, clinical trials of aspirin for primary prevention of MI and stroke in people without known CAD or stroke were started. Over the last 40 years, multiple large scale clinical trials with follow up to 10 years have been completed in people at different levels of risk for MI and stroke.

Are cardiologists less likely to have coronary artery disease (CAD)?

I have searched extensively but have not found a study that can answer this question. Our understanding of CAD is still quite primitive. It is generally believed that CAD is a multifactorial disease. The risk factors associated with CAD include genetic, biological (such as aging, hypertension, diabetes, hyperlipidemia) and environmental (such as smoking, pollution, mental stress). Some of these factors can be modified but others cannot. Unlike vaccination for some infectious diseases, primary prevention of a multifactorial disease such as CAD is far more complicated and much less effective. With our limited knowledge about of the etiology and mechanism of CAD, our ability to prevent the development of CAD is quite limited.

Cardiologists are trained to diagnose and treat cardiovascular diseases. Our daily work load only allows us limited time to read. Our critical reading of the original research papers is more focused on diagnosis and treatment than prevention. After someone has already had a confirmed diagnosis of CAD, most of us are well educated about secondary prevention. On the other hand, for primary prevention (in the absence of confirmed diagnosis of CAD), most of our information is second hand from text books, reviews, editorials, guidelines and conferences. Few of us conduct research in primary prevention and not many practicing cardiologists read primary prevention research papers critically. However, with the above limited background, we are frequently asked for and we do frequently offer advices about primary prevention. Until we have data to demonstrate that cardiologists are less likely to develop CAD or suffer MI, we should be humble enough to acknowledge the limitations of our advices.

There is at least one study that suggested the American physicians may have a more healthy life style than the others, which made them live about 1 year longer than the lawyers⁽¹⁾. Perhaps one component of this health advantage, regardless how small it is, is from primary prevention of diseases.

What caused the wide spread use of aspirin for primary prevention of MI and stroke?

Because most cases of MI and stroke are due to blood clot occlusion of the relevant arteries and aspirin can inhibit blood clot formation, it is natural to believe that aspirin may reduce the risk of MI and stroke in the general population as well as those at high risk for MI and stroke. Since the late 1970s, at least 13 large scale randomized trials have been completed. Another trial, ACCETPT-D is still ongoing.

The first primary prevention trial was the British Male Doctor trial and was started in 1978⁽²⁾. This placebo controlled open label trial randomized 3,429 male physicians to aspirin 500 mg daily and 1,710 physicians to the placebo. After a mean follow up of 6 years, not only there was no significant difference in the rates of MI and stroke between the two groups but there was also a higher risk of peptic ulcer in the aspirin than the placebo group.  However, two subsequent American trials reported different findings.

The Physicians Health Study initiated in 1982 was a randomized, double blind, placebo controlled trial⁽³⁾. In this trial, 11,037 physicians were randomized to aspirin 325 mg every other day, and the other 11,034 were randomized to the placebo. After a mean follow up of 60.2 months, there was a 44% relative risk reduction of MI in the aspirin group!  The actual rates of MI were 254.8/100,000 per year in the aspirin group and 439.7/100,000 per year in the placebo group, with p value <0.00001. That would translate into this: for every 1,000 physicians taking aspirin for 1 year, about 2 (1.9) MIs could be prevented.  In the same trial, there were more strokes numerically in the aspirin group (119/11,037) than the placebo group (98/11,034), although not statistically significant. In addition, the risk of major bleeding was significantly increased in the aspirin group (hazard ratio 1.32, 95% confidence interval 1.25-1.40, p<0.00001).

The Women’s Health Study, a double blind, placebo controlled study, was started in 1992 and randomized women without history of CAD or stroke (mostly nurses, age ≥45) to aspirin 100 mg every other day (19,934) and the placebo (19,942)⁽⁴⁾. Unlike the Physicians Health Study, after a mean follow up of 10.1 years, there was no significant difference in the incidences of MI between the two groups.  On the other hand, there was a significantly lower rate of stroke in the aspirin than the placebo group (221/19,934 vs 266/19,942, hazard ratio 0.83, 95% confidence interval 0.69–0.99, p = 0.04). How significant is this difference? For every 400 women taking aspirin for 10 years, 1 stroke could be prevented! In addition, there was an increased risk of gastrointestinal bleeding (hazard ratio 1.40; 95% confidence interval, 1.07 to 1.83; P=0.02) and a non-significant increase of hemorrhagic stroke.

It was these two Americans trials that served as the major trigger for the widespread use of aspirin in primary prevention in the whole world for the last 20-30 years.

Primary prevention trials in the high risk population

Most individuals in the above 3 trials were relatively healthy. There have been at least 9 primary prevention trials that were conducted in the high risk population. The risk factors among these subjects included hypertension, hyperlipidemia, diabetes, asymptomatic peripheral artery disease, smoking and family history of early CAD^(5-13).  These trials were conducted in Europe, USA, Australia and Asia. Of the 9 trials, 5 trials claimed possible benefit for prevention of cardiovascular events from aspirin^(5,6,11-13) and the other 4 did not^(7-10). Of the 5 trials that claimed possible benefit from aspirin, none of them demonstrated statistically significant difference of MI or stroke between aspirin and placebo!

Primary prevention trial in the elderly

The elderly population is known to have an increased risk of MI and stroke and is considered a natural high risk population. Because of the high risk status, there was a strong belief for the elderly to benefit from aspirin for primary prevention. The ASPREE trial published in 2018 surprised many people⁽¹⁵⁾. This double blind, placebo controlled trial randomized the healthy elderly (age >65-70 years) to aspirin 100 mg daily (n=9,525) and the placebo (n=9,589). After a mean follow up of 4.7 years, the aspirin group not only did not have a reduced risk of MI or stroke but also had a significantly increased risk of major bleeding and mortality.

Almost all aspirin primary prevention trials observed an increased risk of bleeding with aspirin. None of the trials ever showed any mortality benefit.

Problems in the evaluation of aspirin primary prevention trial results

One of the problems in the data analysis of aspirin primary prevention trials is the use of composite primary end points. In addition to MI and stroke, some “soft” end points such unstable angina, transient ischemic attack, peripheral artery disease, revascularization or hospitalization for cardiovascular events were included as the primary end points in many trials. Some of the “soft” components could be affected by bias even for double blind trials. The advantages of using the composite end points include small sample size requirement, shortened research time and reduced cost for both the researchers and pharmaceutical companies. After all, if taking aspirin is mainly for prevention of MI and stroke, why not just focus on MI and stroke only? If the use of MI and stroke only would have required a very large and long-term trial, why not to pursue such a trial? If such a large trial is too expensive or infeasible to conduct, that by itself would demonstrate the lack of apparent clinical benefit from taking aspirin. The use of composite end points is good for the researchers and drug companies but is not so for a patient to make a decision.

The other problem is meta-analysis. Meta analysis is useful to reveal a statistically significant effect when it is not feasible to conduct large scale trials or large trials are not available. Meta analysis is known to have multiple limitations. It does not matter how great a method is used in a meta analysis, it cannot correct the error or bias in the original trial. Inclusion or exclusion of statistically insignificant studies that did not contain numerical values, along with publication bias, results in unfair treatment of all available studies. Most importantly, the authors’ preoccupation or intention is known to create the agenda-driven bias. This is well demonstrated by the fact that different meta analyses by using the same original trials may come up with different conclusions. In fact, the data quality of a meta analysis is lower than that of a well-designed randomized trial. Unfortunately, meta analysis is widely used as a publication generator. There are far more meta analysis papers in the literature than the number of aspirin primary prevention trials! Even worse, meta-analysis papers have been the major source of references in the many current guidelines.

In the era of evidence-based medicine, the strongest evidence should come from more than one well-designed, large, randomized, double blind, and placebo-controlled trials that consistently demonstrate similar and statistically significant results. For whatever reason, majority of the drugs and medical devices have been approved by the FDA after only one randomized trial. When different trials with the above described good quality cannot produce similar results, it clearly shows non-reproducibility. It makes no sense to perform a meta analysis in such cases. When many large scale and well designed trials have not been able to show consistent results, it is clear:  aspirin has no apparent benefit for the primary prevention of MI or stroke!

The different opinions about aspirin for primary prevention

For more than 40 years, the prevailing opinions about aspirin for primary prevention among the medical professionals can be described as: curious, confident, and doubtful.

Although everyone insists that he/she is following the principles of evidence-based medicine, the recommendations based on the same evidence could be completely different. For example, the 2012 European Society of Cardiology guidelines recommended against aspirin for primary prevention, with III classification (harmful)⁽¹⁵⁾. In contrast, the 2012 American College of Chest Physicians recommended that healthy individuals 50 years or older may take aspirin 75-100 mg daily, with IIb classification (may be beneficial)⁽¹⁶⁾.

A few years ago, pharmaceutical company Bayer submitted an application for expanding the indication of aspirin for primary prevention. After the FDA reviewed the available evidence, not only the application was rejected but also the FDA issued the following warning in 2014: “The FDA has reviewed the available data and does not believe the evidence supports the general use of aspirin for primary prevention of a heart attack or stroke. In fact, there are serious risks associated with the use of aspirin, including increased risk of bleeding in the stomach and brain, in situations where the benefit of aspirin for primary prevention has not been established.” https://www.fda.gov/drugs/drug-information-consumers/use-aspirin-primary-prevention-heart-attack-and-stroke

The FDA warning was criticized by many cardiologists. Many physicians continued to recommend aspirin to their patients for the sole purpose of primary prevention.

Interestingly, the United States Preventive Services Task Force, an organization different from the FDA but also under the administration of the U.S. Department of Health and Human Services, did not pay much attention to the FDA warning. Two years after the FDA warning, USPSTF still recommended aspirin for primary prevention under certain conditions. This recommendation still remains on the current website of USPSTF.

The 2019 ACC/AHA guidelines for primary prevention of cardiovascular disease still has not given up on aspirin for primary prevention. The key points of the 2019 guidelines included this statement: “Aspirin should be used infrequently in the routine primary prevention of ASCVD because of lack of net benefit.”

My questions are:

What is considered infrequent?

When there is a lack of net benefit, why would you still recommend aspirin?

After aspirin has been tested in patients with diabetes, hypertension, mild peripheral arterial disease and hyperlipidemia and was found to have no apparent benefit consistently, who are those “at higher ASCD risk”? Is there any study that showed a higher number of risk factors conferring more benefit from aspirin?

Who are not at increased bleeding risk? Is there a study that can identify or accurately predict who is not at increased bleeding risk?

Up to today, some expert may still insist that whether to take aspirin or not should be based on the benefit and risk ratio assessment and patient’s preference. May I ask: “After spending more than 40 years of research, when the medical community cannot agree among themselves, how can a patient have a preference?”

What have we learned?

When the benefit/risk ratio assessment is to be discussed, a prerequisite condition is that there is a confirmed benefit. Regardless of how small of the benefit is, the debate may be only a matter of statistical versus clinical significance. In the case of aspirin for primary prevention, the finding of benefit is simply not reproducible from different well-designed trials whereas the increased risk of bleeding is quite consistent. If you are really serious about going by the trial evidence regardless of the clinical significance, maybe the male American physicians or female American nurses in this whole world are the only ones who may benefit from taking aspirin for primary prevention.

My professional philosophy is this: whatever I recommend to my patients, it should also be applicable to me or my family members. For this reason, I have always paid close attention to the use of aspirin for primary prevention. In the remote past, I did recommend aspirin to my patients and certain family members who did not have history of CAD or stroke. Later on, however, as I continued to read published results of more clinical trials, I changed my mind. Since 2009, I have stopped recommending aspirin for primary prevention to my patients. I also have kept telling my nurses and other staff members (except for physicians who would not listen to me anyway) that they should not take aspirin for primary prevention of MI or stroke.

References：

1. Frank E, et al. Am J Prev Med 2000;19:155.
2. British Male Doctor Study. Peto R, et al. Br Med J (Clin Res) 1988;296:313.
3. Physicians Health Study. N Eng J Med 1989;31:129.
4. Women’s Health Study. Ridker PM, et al. N Eng J Med 2005;352:1293.
5. TPT (Thrombosis Prevention Trial). Lancet 1998;351:233.
6. PPP (The Primary Prevention Project). Lancet  2001;357:89.
7. JPPA (The Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes Trial). Ogawa H, et a. JAMA 2008;300:2134.
8. PPAD (Prevention of Progression of Arterial Disease in Diabetes). Belch J, et al. B M J . 2008;337;a1840.
9. AAA (Aspirin for Asymptomatic Atherosclerosis trial). Fowkes FGR, et al. JAMA 2010;303:841.
10. JPP (Japanese Primary Prevention Project). Ikeda Y, et al. JAMA 2014;312:2510.
11. ASCEND trial. N Eng J Med 2018;379:1529.
12. ARRIVE trial. Gaziano JM, et al.  Lancet 2018;392:1036.
13. HOT trial. Hansson L, et al. Lancet 1988;351:1755.
14. Aspirin in Reducing Events in the Elderly trial. McNeill JJ, et al. N Eng J Med 2018;379:1509.  McNeil JJ, et al. N Eng J Med 2018;379:1519。
15. Perk J, et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice  constituted by representatives of nine societies and by invited experts). Eur Heart J 2012;33:1635–701.
16. Vandvik PO, et al. Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th edition: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e637S–68S.