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Monday, March 19, 2012

Who Should Take Aspirin for Prevention?

The answer is not entirely straightforward.  Aspirin has been shown to reduce the risk of cardiovascular disease, including heart attack and stroke. Aspirin inhibits the function of platelets, the blood cell line responsible for clot formation.  When a heart attack or stroke occur the cholesterol plaque that lines an artery ruptures and platelets aggregate, resulting in a cascade that results in acute occlusion of a blood vessel.  Patients who are treated with aspirin are less likely to clot.  However, the effects of aspirin are not entirely benign. With its platelet inhibition it also confers a higher risk of bleeding—in particular gastrointestinal bleeding and hemorrhagic stroke, which also may be life threatening.
Clinical trials have looked at aspirin intake, cardiovascular outcomes, and bleeding risk. Aspirin for acute cardiovascular events and for “secondary prevention” (prevention after the diagnosis of coronary artery disease or cerebrovascular disease has been established) is undisputed.  Trials suggest that the benefits of therapy outweigh the risks of bleeding. 

However, whether or not aspirin should be prescribed for “primary prevention” (prevention in a person who is disease-free) is more ambiguous.  In 2009 a meta-analysis of existing study data looking at this question was published in Lancet.  The analysis found that aspirin reduced the risk of non-fatal myocardial infarction by one fifth, but that aspirin therapy also significantly increased risk of major gastrointestinal and extracranial bleeding and did not improve overall mortality.  In 2009 the US Preventive Services Task Force (USPSTF) reviewed the existing data and concluded that while aspirin reduces the risk of myocardial infarction in men and ischemic stroke in women, it increases the risk of major extracranial bleeding.  The USPSTF recommended that the decision to use aspirin therapy for the purpose of primary prevention should take into account an individualized assessment of cardiovascular risk and also bleeding risk. Patients with higher cardiovascular risk may benefit most from therapy.  
Patients considering aspirin therapy for primary prevention should assess their cardiovascular risk profile with their personal physician. The Framingham Risk Calculator is a recommended tool for estimating one’s ten year risk of having a major cardiovascular event.   However, Framingham may not be as useful for women as it is for men, and some recommend use of the Reynolds Risk Calculator. The Reynolds Calculator incorporates the inflammatory marker hs-crp into its calculation of ten year risk.
In a similar vein, in 2010 the American Diabetes Association, the American Heart Association, and the American College of Cardiology issued a joint statement revising their recommendations for use of aspirin for thepurpose of primary prevention amongst diabetic patients.  In contrast to old guidelines, the new recommendations do not advise that all diabetics over age 40 receive aspirin therapy.  Rather, they advise aspirin therapy for primary prevention in male diabetics under 50 and female diabetics under 60 only if one additional cardiac risk factor is present (hypertension, high cholesterol, smoking, family history, microalbuminuria) The new recommendation is based in part on a subgroup analyses of diabetic patients in the meta-analysis of the Antithrombotic Trialists’ Collaboration showing  that diabetic patients benefited less from aspirin therapy than non-diabetics. In addition, several smaller studies conducted specifically on diabetics and looking at primary prevention failed to demonstrate a significant benefit of aspirin therapy in those without diagnosed cardiovascular disease.  Further study is ongoing to research the issue of primary prevention of cardiovascular disease with aspirin in diabetic patients.  For now the therapy is recommended for diabetics who are determined to be intermediate to high risk (Framingham risk of 10% or higher).
Who is most likely to suffer a complication related to daily use of aspirin? Risk factors for gastrointestinal bleeding with aspirin therapy have been identified:
  • Non-steroid anti-inflammatory (NSAID) use (in particular, high dose NSAID use)
  • Chronic steroid use
  • Prior history of peptic ulcer disease (PUD)
  • Advanced age (>60-65 years old)
  • GERD or dyspepsia (less risk than PUD)
  • Concomitant use of another anti-coagulant
Treatment with a proton pump inhibitor, or the prostaglandin E analog misoprostol, can reduce one’s risk of gastrointestinal bleeding from NSAIDS.  By contrast, H2 blockers are not effective in this regard.  In addition, using enteric coated aspirin does not reduce its gastrointestinal toxicity.  It is unclear what dose of aspirin is best for primary prevention, but most recommend low dose aspirin (81-162mg), which appears to be equal in efficacy to higher doses (though it has not been demonstrated to be safer).

It’s interesting to me that simultaneous with a growing emphasis on incorporating population-based strategies into healthcare delivery we are also becoming increasingly aware of the importance of identifying personalized risk factors in order to best counsel individual patients on medical care and prevention.  Aspirin therapy for primary prevention is an example of how a one-size-fits-all population-based strategy is hard to apply.  We have seen similar recent trends with mammography screening recommendations, using PSA for prostate cancer screening, and will likely soon be hearing more about using a personalized approach to recommending statins for the purpose of primary prevention of cardiovascular disease (given recent associations between statin use and reversible cognitive complaints and diabetes). How population medicine, its associated quality reporting, and pay-for-performance on the one hand, and personalized medicine on the other, are reconciled in medical practice will be a challenge to be dealt on the level of policy, practice, and reimbursement in years to come.