Mechanisms for aspirin resistance may involve an inability of aspirin to partially or completely inhibit the cyclo-oxygenase-1 (COX-1) enzyme leading to thromboxane A2 production, or factors independent of the COX-1 pathway such as elevated levels of C-reactive protein.27 COX-1-related factors include aspirin nonadherence, reduced aspirin bioavailability, competitive inhibition by NSAIDs, inadequate aspirin dosage, genetic COX-1 polymorphisms, and increased platelet turnover.27,28 A subgroup analysis of the Physicians’ Health Study29 suggests that nonadherence with aspirin therapy or concomitant NSAID use negated the benefit of aspirin. In a small cohort study (n=18), patients who took ibuprofen or naproxen and aspirin did not demonstrate inhibition of platelet aggregation and had a 72% rate of recurrent ischemic events despite aspirin therapy.30
Until clinical trials can demonstrate benefit and cost effectiveness of empiric laboratory testing for aspirin resistance in patients without a history of CVD, emphasize adherence to the prescribed antiplatelet therapy and warn against concomitant NSAID use for patients at risk for CHD events.
Aspirin for patients with diabetes: Only when CVD risk is high
In 2010, the ADA revised its clinical practice recommendations to reflect the results of 2 studies that questioned the value of aspirin for primary prevention of CVD events in patients with diabetes.3 Instead of a global statement to use low-dose aspirin, the ADA guideline now recommends its use only in patients with diabetes who have a 10-year risk >10%. This includes men over the age of 50 and women over the age of 60, with at least one major risk factor in addition to diabetes. The studies driving this change were the Prevention of Progression of Arterial Disease and Diabetes (POPADAD)31 and the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD).32
The POPADAD study enrolled 1276 patients over the age of 40 with type 1 or type 2 diabetes who also had asymptomatic peripheral arterial disease but without symptomatic CHD. Participants were randomized to take aspirin 100 mg daily or placebo (POPADAD also included a study of antioxidants vs placebo). The participants had diabetes for a mean of 6.3 years. The study had 2 primary composite end points: death from CHD or stroke, nonfatal MI or stroke, or amputation above the ankle for critical ischemia; and death from CHD or stroke. The aspirin and placebo groups were similar at baseline in terms of demographic characteristics and use of statins, beta-blockers, and angiotensin-converting enzyme (ACE) inhibitors among other treatments. The composite end point of death from CHD or stroke was similar in the 2 groups. Nonfatal MI and nonfatal stroke were also similar in the 2 groups.31
The JPAD study enrolled individuals with type 2 diabetes who were over the age of 30 and had no evidence of CVD. Participants were randomized to receive either 81 mg aspirin or placebo daily. The composite end point was sudden death; death from CHD, stroke, or aortic causes; nonfatal MI; nonfatal stroke; unstable angina; transient ischemic attack; or nonfatal peripheral vascular disease. The 2 groups were similar in terms of the composite end point, nonfatal MI, and nonfatal stroke. The risk of death from MI and stroke was lower in the aspirin group.32
The authors of a 2010 consensus report from the ADA, the AHA, and the American College of Cardiology (ACC) evaluated the findings of individual placebo-controlled aspirin studies as well as those included in prior meta-analyses.33 They also conducted a separate meta-analysis, which indicated that aspirin decreased the risk of CHD in patients with diabetes by 9% (RR=0.91; 95% CI, 0.79-1.05), but the reduction was not statistically significant. If the findings of the Early Treatment of Diabetic Retinopathy Study, which included some individuals with prior CVD events, had been excluded from this meta-analysis, the risk reduction due to aspirin would have been smaller.
Results of this meta-analysis are mitigated by certain factors. The 9 studies analyzed were published between 1989 and 2008, and the use of drugs such as statins, beta-blockers, and ACE inhibitors increased over this 20-year period. Also, the age of study participants at enrollment varied, as did the presence of subclinical CVD. The rates of CHD in the placebo groups of the studies also varied significantly.
Accounting for differences between the sexes
A person’s sex in part determines the importance of certain CV risk factors, the prevalence of CV and related comorbid diseases, and the frequency of adverse drug effects. Women with diabetes have a 50% increased relative risk of CVD than men with diabetes, in part because they are often older and have more risk factors.34