What is the role of aspirin in primary prevention — preventing the first cardiovascular event in our patients? This has been an area of changing recommendations leading to considerable uncertainty among practitioners.

Aspirin is an effective antiplatelet agent that acts by inhibiting cyclooxygenase-1 (COX-1) which leads to reduced levels of thromboxane A2, a potent promoter of platelet aggregation. It is therefore widely used in high-risk individuals to prevent myocardial infarction and stroke. It may also reduce the risk of colorectal cancer. However, aspirin use is not without risks — the reduced platelet action increases the risk of gastrointestinal bleeding and hemorrhagic strokes. When aspirin is used for secondary prevention — to reduce the risk of recurrent myocardial infarction or ischemic stroke in patients with established cardiovascular disease — the risk of a recurrent cardiovascular event is so high that the benefits of aspirin greatly outweigh the risks.

But what about aspirin in primary prevention? Many patients who present with myocardial infarction or ischemic stroke have no previous history of cardiovascular disease but may have been at high risk for such disease due to risk factors such as type 2 diabetes.

NEJM Knowledge+ Internal Medicine Board Review includes the following question on this very topic; we have heard from many learners that they are uncertain about the current recommendations.

The Case & Question

A 44-year-old man with hypertension, hyperlipidemia, obesity, type 2 diabetes, and paroxysmal atrial fibrillation presents for a new-patient visit. He feels well and has no complaints. His current medications include metformin 1000 mg twice daily, metoprolol extended-release 75 mg once daily, lisinopril 20 mg once daily, simvastatin 20 mg once daily, and aspirin 325 mg daily. He has no history of stroke or ischemic heart disease.

His blood pressure is 128/80 mm Hg. His pulse is irregularly irregular, but his examination is otherwise unremarkable.

An electrocardiogram reveals atrial fibrillation with a ventricular rate of 88 beats per minute.

His calculated 10-year risk for atherosclerotic cardiovascular disease is 4.9%.

Which one of the following long-term antithrombotic approaches is most appropriate for this patient?

The Choices

  1. Stop aspirin and start warfarin, with a target international normalized ratio of 2.0 to 3.0
  2. Reduce aspirin to 81 mg daily and start clopidogrel 75 mg daily
  3. Stop aspirin and start clopidogrel 75 mg daily
  4. Continue aspirin 325 mg daily
  5. Reduce aspirin to 81 mg daily and start warfarin, with a target international normalized ratio of 2.0 to 3.0

The Correct Answer

  1. Stop aspirin and start warfarin, with a target international normalized ratio of 2.0 to 3.0

Learner Feedback and Our Response

At NEJM Knowledge+, we update content regularly based on our proactive review of new studies, on changes in guidelines and drug labels, and — most of all — on comments from our learners. Learners can challenge a question and comment on any question, answer choice, or feedback that they think is misleading, incorrect, or unclear — and we take those challenges very seriously.

The above question is our most challenged question. Most people agree on the need for warfarin given the patient’s elevated risk for thromboembolism, but we are frequently challenged on our recommendation to not prescribe aspirin for this patient. Many learners feel that diabetes is such an important risk factor for cardiovascular disease that the patient should take aspirin 81 mg along with the warfarin (answer option E).

The justification is usually that diabetes is a “cardiovascular disease equivalent.” This concept arose after the publication in 1998 of an analysis of a cohort of almost 2500 individuals with or without diabetes or a history of myocardial infarction. The study found that diabetic subjects without a history of myocardial infarction were at the same risk of death from coronary heart disease as nondiabetic subjects with a history of myocardial infarction.

Figure 1. Kaplan–Meier Estimates of the Probability of Death from Coronary Heart Disease in 1059 Subjects with Type 2 Diabetes and 1378 Nondiabetic Subjects with and without Prior Myocardial Infarction. MI denotes myocardial infarction. I bars indicate 95 percent confidence intervals.

Source: Haffner et al. Mortality from Coronary Heart Disease in Subjects with Type 2 Diabetes and in Nondiabetic Subjects with and without Prior Myocardial Infarction. N Engl J Med 1998 Jul 23;339:229-34.

This led to a change in practice, whereby many practitioners recommended that all their diabetic patients take aspirin, just like all their patients with established atherosclerotic cardiovascular disease.

Since this initial analysis, more data has been published that has challenged the view of diabetes as a cardiovascular disease equivalent. An observational study of over 4500 individuals showed that the incidence of fatal myocardial infarction in diabetic patients only started approaching the incidence in those with previous coronary heart disease when the diabetic patients had at least another 5 cardiovascular risk factors.

In fact, this analysis found that the 10-year incidence of coronary heart disease in diabetic patients with only one to two additional risk factors was only 1.4 times higher than that of nondiabetic individuals. (For more details, see the article “Coronary Heart Disease Risk Equivalence in Diabetes Depends on Concomitant Risk Factors” in Diabetes Care.)

Based on this and other data, a diagnosis of diabetes is no longer considered a “cardiovascular disease equivalent” and is not an automatic reason to initiate aspirin therapy. In fact, the reduction in cardiovascular events with aspirin therapy is around 12% both for high-risk diabetic patients and nondiabetic patients (See this study in the Lancet for more details). Therefore, aspirin can be considered in higher-risk patients.

The current recommendation from the American Diabetes Association is as follows: “Consider aspirin therapy (75–162 mg/day) as a primary prevention strategy in those with type 1 or type 2 diabetes who are at increased cardiovascular risk. This includes most men and women with diabetes aged ≥50 years who have at least one additional major risk factor (family history of premature atherosclerotic cardiovascular disease, hypertension, dyslipidemia, smoking, or albuminuria) and are not at increased risk of bleeding.” For patients who are at low risk of ASCVD, such as most patients younger than 50 years of age, the risk of adverse effects of aspirin outweigh their use. The USPSTF also does not consider diabetes a cardiovascular disease equivalent. It recommends using risk calculators (such as the ACC/AHA risk calculator), which take diabetes into account, to determine the appropriateness of aspirin. The USPSTF recommends considering prescribing aspirin in those aged 50 to 69 with a 10-year risk of cardiovascular disease that exceeds 10%; there is insufficient evidence for people outside of this age bracket.

Therefore, this patient should not have been prescribed aspirin in the first place. Even if aspirin were indicated, the dose that he was taking was too high, because the recommended dose for cardiovascular disease reduction is 75 to 162 mg daily. At this point, he is about to initiate warfarin for his atrial fibrillation; concomitant use of anticoagulants and antiplatelet agents increases the risk of severe bleeding complications dramatically and should therefore further dissuade the provider from starting aspirin in a low-risk patient.

Of course, all other cardiovascular risk factors should be addressed as appropriate, including smoking cessation if applicable, blood-pressure control, statin therapy if indicated, and lifestyle interventions such as weight loss, increased physical activity, and medical nutrition therapy.

Learning from Your Challenges

Many of the challenges that we receive lead to a question being updated or even (occasionally) retired. However, in this case we have chosen to keep the question unchanged. As evidence in medicine changes, the correct answers of yesteryear become the incorrect answers of today. Incorporating new evidence into practice takes time; the goal of learning tools such as NEJM Knowledge+ is to speed up the process of putting new evidence into practice. Hopefully, the lessons learned from this question will allow learners to provide the most evidence-based care for their patients.

Ole-Petter Riksfjord Hamnvik, MB, BCh, BAO, MMSc is an endocrinologist at Brigham and Women’s Hospital; Program Director, Endocrinology Fellowship and Assistant Program Director, IM residency, at BWH; and Senior Consulting Education Editor, NEJM Knowledge+.