FDA Shuts the Door on Aspirin in Primary Prevention

Dr Sharon Mulvagh, Director of the Women's Heart Clinic at Mayo Clinic; Dr Francisco Lopez, Director of Preventive Cardiology at Mayo Clinic. Selected by Pietro Cazzola

AspirinIn May, the US Food and Drug Administration (FDA) issued a public health advisory [1] announcing that an evidence review showed no support for the general use of aspirin for primary prevention of myocardial infarction or stroke. Coincident with that, the agency informed Bayer HealthCare that it had rejected its application to allow for the marketing of aspirin for primary prevention of heart attacks.[2] The agency stated that the current evidence for primary prevention of heart attacks was not strong enough to outweigh the bleeding risks.

What are your thoughts on this? What is the evidence base?

Francisco Lopez-Jimenez, MD: It was very interesting to see the FDA issue that statement when the American Heart Association (AHA), the American College of Cardiology, and every other major medical organization have endorsed the use of aspirin for primary prevention.
Unfortunately, we did not see the evidence upon which that decision was based, but when we review the evidence of all the clinical trials testing this question, I can see where the FDA is coming from and also why they issued this recommendation. There is an important message for clinicians that we can share.
The evidence supporting the use of aspirin for primary prevention comes primarily from 3 major clinical trials, but 9 clinical trials[3-11] have tested that question. The summary of the evidence is that aspirin can, indeed, prevent myocardial infarction. The benefit seems to be modest, and aspirin has no effect on total mortality or cardiovascular mortality.
In women, however, the benefit seems to be limited to stroke,[11] and the risk for bleeding, particularly gastrointestinal bleeding, is also real and almost matches, 1 for 1, the cardiovascular events that aspirin is intended to prevent. That is why this issue is controversial and why the benefit or risk is going to be a source of major discussion.

Dr Mulvagh: It's a real conundrum. Every day, we face the question with our patients, whether they should have aspirin. They ask us this. They have been very confused by the media releases during the past month. How do you deal with this in your office? There is this evidence base. There is a meta-analysis.[12] We have major trials, and the bottom line is that there is no convincing evidence for reduction of cardiovascular death or overall death. The reduction in nonfatal myocardial infaction occurs at the expense of the increased risk for bleeding. We have to individualize treatment. How do you do this with your patients?

Dr Lopez-Jimenez: I try to assess the patient who doesn't need aspirin. That is generally the young person with no risk factors who has a very healthy lifestyle, and the risk for cardiovascular events is so low that aspirin is clearly not justified. That is the very first step that I take.
After that, I identify the patient who might benefit and review the evidence and highlight the modest but real benefit of preventing myocardial infarction. I also review the evidence showing that there is no major effect on mortality or cardiovascular mortality.
I try to exercise shared decision making with the patient so he or she is part of the discussion. If the patient wants to take an aspirin every day for X number of years to get a modest benefit, then that is the patient's decision, and I think that's fine.
I also assess the risk for gastrointestinal problems. If the patient has a history of ulcers, particularly bleeding from the gastrointestinal tract in the past few years, I am more hesitant to start aspirin.
In patients who have tolerated aspirin in the past and qualify for its use, I don't stop the aspirin. It's a decision between the risk for bleeding and the potential benefit the patient might derive.

Dr Mulvagh: If a patient has significant risk factors—diabetes, hypertension, hyperlipidemia, obesity—and if the patient's overall risk score on the AHA pooled cohort score exceeds a certain threshold (eg, 7.5% or 10%) how would you approach it? Do you tell the patient that given a certain risk, we know that there may be some benefit, but there is also a significant risk for bleeding?

Dr Lopez-Jimenez: I base my decision in part on the global risk score; however, one of the issues that led the FDA to release that statement was the fact that there are 3 recent clinical trials that showed no benefit in patients with diabetes and/or peripheral vascular disease.[3-5] Therefore, using only single risk markers doesn't seem to help much. It is perhaps the patient who has several other risk factors, not just diabetes, and the one who has very minimal or is at very low risk for bleeding.
This issue just brought some additional discussion to the table, and we probably need more evidence to have more conclusive and clear guidance in when and how to use aspirin.

Dr Mulvagh: It's a very good point. Several trials are going on now looking at the prospective use of aspirin in primary prevention.
You have made the decision with your patient that the benefits outweigh any risk for bleeding. The big question is: What is the dose? The trials are all over the map. What do you recommend to your patients for primary prevention?

Dr Lopez-Jimenez: For some reason we became fixated on the 81-mg dose, even though the doses tested in clinical trials ranged from 75 mg to 500 mg daily. I go for the minimum dose that can block the effect of the platelets, and at the same time, is the safest with respect to bleeding risk—81 mg. There is no evidence showing that higher doses are better. The HOT trial used 75 mg daily, and that has been perhaps the most significant study across all patient groups that shows some benefit.[6]

Dr Mulvagh: That is a very important point because patients are quite confused. It's easy to get the "baby-aspirin size," so that is the simple approach. You would recommend one baby aspirin daily, if the risks justify it for cardiovascular disease risk?

Dr Lopez-Jimenez: Yes.

Dr Mulvagh: It's important to emphasize that this is for primary prevention. In patients who already have a diagnosis of heart disease, that is secondary prevention, and they all should be on aspirin unless there are significant contraindications. Would you agree with that?

Dr Lopez-Jimenez: Absolutely. Patients must be very careful not to mix those messages. People who have a history of myocardial infarction, of any sort of atherosclerotic cardiovascular disease, should definitely be on aspirin—no question about that.

Dr Mulvagh: And even though we think of primary prevention and secondary prevention as being very different, there is really is a continuum and that is the tricky part. We need prospective trials to sort those issues out.
It's worth mentioning that cardiovascular lifestyle prevention—standard behaviors that we recommend, including appropriate diet and physical activity—are free with respect to risk. We must always emphasize that to our patients. For those who are confused about aspirin, we can be very supportive and very strongly recommend optimal lifestyle behaviors.

Dr Lopez-Jimenez: Absolutely. Aspirin is not a substitute for exercise and nutrition.

  1. US Food and Drug Administration. Use of aspirin for primary prevention of heart attack and stroke. May 2, 2014. Available here.

  2. US Food and Drug Administration. Citizen's petition denial response from FDA to Bayer Healthcare [letter]. May 2, 2014. Available here

  3. Ogawa H, Nakayama M, Morimoto T, et al. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: A randomized controlled trial. JAMA 2008; 300:2134-2141. Article

  4. Belch J, MacCuish A, Campbell I, et al. The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial: Factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ 2008; 337:a1840. Article

  5. Fowkes FG, Price JF, Stewart MC, et al. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial. JAMA 2010; 303:841-848. Article

  6. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998; 351:1755-1762. Summary

  7. Peto R, Gray R, Collins R, et al. Randomised trial of prophylactic daily aspirin in British male doctors. Br Med J(Clin Res Ed) 1988; 296:313-316. Article

  8. The Medical Research Council's General Practice Research Framework. Thrombosis prevention trial: Randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. Lancet 1998; 351:233-241. Summary

  9. De Gaetano G, Collaborative Group of the Primary Prevention Project. Low-dose aspirin and vitamin E in people at cardiovascular risk: A randomised trial in general practice. Lancet 2001; 357:89-95. Summary

  10. 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;321:129-135. Article

  11. Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005; 352:1293-1304. Article

  12. Sutcliffe P, Connock M, Gurung T, et al. Aspirin in primary prevention of cardiovascular disease and cancer: A systematic review of the balance of evidence from reviews of randomized trials. PLoS One 2013; 8:e81970.Article