Aspirin for primary prevention of cardiovascular disease and predicting risk of first cardiovascular event

The benefit of aspirin in reducing cardiovascular (CV) events or mortality in those patients with known CV disease (secondary prevention) is well established.  However, the benefit of aspirin in those without CV disease (primary prevention) is less clear.  Various organizations have differing opinions and recommendations regarding who, if anyone, should receive aspirin in this capacity, and their recommendations are summarized further below.  To go straight to the current recommendations, skip down to 'Current Recommendations'.

Meta-analysis data

Much of the rationale for the recommendations from the organizations below comes from two meta-analyses.  The first was the 2009 Antithrombotic Trialists’ Collaboration’s meta-analysis that included 95,000 patients in the primary prevention group.¹  With regards to the effect of long-term aspirin versus placebo, the following was found:

• Serious vascular events were reduced with aspirin (0.51% vs 0.57% per year, p=0.0001), which was mostly due to a reduction in…
• Nonfatal MI (0.18% vs 0.23% per year, p<0.0001)

No difference for aspirin versus placebo with regards to:

• Stroke (0.20% vs 0.21% per year, p=0.4)
• Hemorrhagic stroke (0.04% vs 0.03% per year, p=0.05)
• Other stroke (0.16% vs 0.18% per year, p=0.08)
• Vascular mortality (0.19% vs 0.19% per year, p=0.07)

And there was an increase in the aspirin group in:

• Gastrointestinal and extracranial bleeds (0.1% vs 0.07% per year, p<0.0001)

A more recent meta-analysis was published in 2012 (after the most recent guidelines were already out).  This study included the 95,000 patients above plus >5000 additional patients and came to similar conclusions. ² 

• Aspirin significantly reduced CV events, primarily driven by a reduction in nonfatal MI, with a number needed to treat of 120
• No significant difference in CV death or cancer mortality
• A significant increase in nontrivial bleeding, with a number needed to harm of 73
• Of note, these authors recommend not to use aspirin for primary prophylaxis because its benefit largely lies only by reducing nonfatal MIs (but not CV death) and is offset by clinically important bleeding events. (NNT is greater than NNH)

Current recommendations

2012 Joint European Society of Cardiology guidelines: ³

• Aspirin or clopidogrel “cannot be recommended in individuals without cardiovascular or cerebrovascular disease due to the increased risk of major bleeding” and this included those patients who also had diabetes. 

This contrasts with the 2012 ACCP CHEST guidelines: ⁴

• Aspirin 75-100 mg is recommended daily to patients aged ≥50 years old without symptomatic CV disease.  They acknowledge the debate largely rests with the issue that the small reduction in certain endpoints may or may not be offset by the increased risk of bleeding. 

The USPSTF (is currently updating their recommendations from 2009 which) currently states: ⁵

• Aspirin is recommended for men aged 45-79 and women aged 55-79 years old
• Evidence is insufficient for men and women ≥80 years old
• Evidence is against the use of aspirin in men <45 or women <55 years old

Request for FDA approval for primary prevention

Bayer submitted a petition to the FDA to amend the labeling of aspirin to include the use of 75-325 mg for the primary prevention of a first MI in patients with a CHD risk ≥10% in 10 years or patients where a positive benefit-risk is assessed by their provider.  In 2014, this petition for this new labeling was denied by the FDA. ⁶  So the current approved indications for aspirin remain to be:

• Secondary prevention of vascular disease in those with CVA, MI, or angina
• Revascularization procedures
• Rheumatologic disease

Weighing the risk of CHD

Since atherosclerosis is not an all-or-none phenomenon and exists along a spectrum of risk, several risk stratification tools have been developed to try to quantify this risk.  A systematic review identified >1900 titles about cardiovascular risk assessment.7  The idea behind stratifying patients' cardiovascular risk is that theoretically, the higher risk patients would then be those who would benefit more from aspirin.  However, numerous studies have shown that the main risk factors for coronary disease are also the risk factors for bleeding.  For example, age, diabetes, smoking, hypertension and BMI are all associated with bleeding.1  

The following table lists three of the more commonly referenced risk stratification tools, the outcomes they look at, a note or two about them, and a link where to find them.

Risk assessment tool	Outcome (all for 10-year risk prediction)	Note
Framingham CHD	Composite coronary event (MI + coronary death)	White population From the 1970s-80s, so may overestimate risk Available where: PDF file through this link
ACC/AHA Task Force - (Atherosclerotic Cardiovascular disease – ASCVD event)	Composite (nonfatal MI + CHD death + fatal/nonfatal stroke)	Calculator used in the 2013 cholesterol guidelines Nonhispanic blacks and whites Better than Framingham because it includes CVAs Available where: Through browser or downloadable app for the iPhone and Google Play through this link
European Society of Cardiology SCORE	Fatal atherosclerotic event	Roughly a 3x difference between ESC’s score (death only) and the two scores above that also include nonfatal events also (so 5% ESC risk is roughly 10-25% ASCVD risk depending on age and other factors) Available where: Chart of SBP vs Tchol with different charts for smokers and by gender (no chart for America) through this link

Take home points:

• Organizations have conflicting recommendations on the role of aspirin in primary prevention of CV disease
• Aspirin's benefit-risk difference is controversial and (if it exists at all) is slim either way
• As the 10-year risk of CV events increases, so does the risk of bleeding
• Do not underestimate the risk of bleeding from low dose daily aspirin in the context of primary prevention
• NNT = 120
• NNH = 73

References:

1.  Antithrombotic Trialists’ (ATT) Collaboration.  Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.  Lancet  2009;373:2849-60.

2.  Seshasai SR, Wijesuriya S, Sivakumaran R, et al.  Effect of aspirin on vascular and nonvascular outcomes.  Arch Intern Med  2012;172(3):209-216.

3.  Perk J, De Backer G, Gohlke H, et al.  European Guidelines on cardiovascular disease prevention in clinical practice (version 2012).  Atherosclerosis  2012;223(1):1-68.

4.  Vandvik PO, Lincoff AM, Gore JM, et al.  Primary and secondary prevention of cardiovascular disease: Antithrombotic therapy and prevention of thrombosis, 9^th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.  CHEST  2012;141(2 Suppl):e637S-68S.

5.  U.S. Preventive Services Task Force.  Aspirin for the prevention of cardiovascular disease: Preventive medication.  March 2009.  Available at: http://www.uspreventiveservicestaskforce.org/uspstf/uspsasmi.htm  Accessed January, 2015.

6.  U.S. Food and Drug Administration.  Use of aspirin for primary prevention of heart attack and stroke.  May 2014.  Available at: http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm390574.htm Accessed January, 2015.
7.  Ferket BS, Colkesen EB, Visser JJ, et al.  Systematic review of guidelines on cardiovascular risk assessment:  Which recommendations should clinicians follow for a cardiovascular health check?  Aarch Intern Med  2010;170(1):27-40.

photo by Damian Gadal