Low-dose Aspirin therapy - Do the benefits outweigh the risks for people with type 2 diabetes?

Stuart T. Haines, Pharm.D., FCCP, FASHP, FAPhA
October, 2009

The dogma that nearly every patient with diabetes should take low-dose aspirin to prevent cardiovascular events is being seriously questioned. Indeed, until recently, the ADA Standards of Care recommended that all patients with type 1 or 2 diabetes over the age of 40 should take aspirin 75-162mg per day. This recommendation was purportedly based on grade "A" evidence. But in 2009 the recommendation, while unchanged, was based on grade "C"evidence. What's going on here?

The recommendations to use low-dose aspirin for the primary prevention of cardiovascular events in people with diabetes has been based largely on two randomized controlled trials - the Physicians' Health Study (PHS 1989)¹ and the Hypertension Optimal Treatment (HOT) trial (HOT 1998).² Both demonstrated the beneficial effects of aspirin by substantially reducing the risk of myocardial infarction. These studies enrolled patients with and without diabetes - so the evidence is derived from sub-group analyses. People with type 2 diabetes stand to gain the most from aspirin therapy. After all, their risk of myocardial infarction and stroke is at least a magnitude of two greater than people without diabetes. And we know, unequivocally, that the use of aspirin in patients following an acute cardiovascular event (e.g. ischemic stroke or acute coronary syndrome) substantially reduces the likelihood of future events. So, it all made logical sense.

But in two recently published clinical trials - the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD 2008) ³ study and the Prevention of Progression of Arterial Disease and Diabetes (POPADAD 2008)⁴ study - aspirin therapy failed to provide significant protection against CV events in people with diabetes. Both studies enrolled patients with diabetes exclusively. The JPAD study enrolled only patients with type 2 diabetes who were age 30 or greater who DID NOT have evidence of cardiovascular disease at baseline. Thus, JPAD is truly a primary prevention study. POPADAD enrolled patients with either type 1 or 2 diabetes who were 40 years of age and older with asymptomatic peripheral arterial disease at baseline. While participants could not have symptomatic cardiovascular disease, POPADAD enrolled patients with evidence of atherosclerosis at baseline. Therefore, subjects who participated in POPADAD were at substantially greater risk of cardiovascular events when compared to those in JPAD. Patients in both studies were randomly assigned to take low-dose aspirin (81 - 100mg daily) or a placebo. POPADAD also randomized subject to take antioxidants every day using a 2 X 2 factorial design. Patients in both studies had the diagnosis of diabetes for a mean of 6 - 7 years. Confounders that might alter cardiovascular risk, such as the use of statins, ACE inhibitors, or beta-blockers, blood pressure, serum lipids, and smoking status were similar among the treatment groups in both studies. The mean duration of follow-up was 4.3 (JPAD) or 6.7 (POPADAD) years.

The results in both studies failed to provide any compelling evidence to support the use of aspirin therapy in people with diabetes (see Table 1). Why? Why did aspirin fail to protect against cardiovascular events in these studies but did so in previous trials? One explanation is the potential interplay between aspirin therapy and other CVD risk-reduction strategies commonly employed today. JPAD and POPADAD were conducted during a time when aggressive management of diabetes (e.g. glycemia, blood pressure, and lipids) was the standard of care. Less aggressive targets and less effective drugs were used in years past. Thus the benefits observed with aspirin in the past may have been mitigated by other interventions routinely used today.

Another explanation - the underlying assumptions about risk were wrong. Indeed, the JPAD population was at relatively low risk for CV events - the 10-year risk of a major cardiovascular event in the placebo group was on the order of 10-15% and the risk of MI was <5%. Among patients at low to moderate risk of CVD, the use of aspirin for primary prevention has been a long-standing debate. The recently published meta-analysis by the Antithrombotic Trialists' (ATT) Collaborative⁵ suggests that many factors need to be considered - including age, sex, 10-year CVD risk, quality of life, and risk of adverse events - and only select subsets of patients would benefit from aspirin therapy for primary prevention (ATT 2009). ⁵ Thus, it's not surprising that aspirin failed to confer a significant benefit in JPAD.

Perhaps genetic variables may have influenced the outcome. One could argue that differences in the pathophysiology of type 2 diabetes in the Japanese versus other populations as well as potential differences in the pharmacodynamics and pharmacokinetics of aspirin might explain why aspirin didn't work in this study.

Such arguments, however, can't explain the results seen in POPADAD - where the 10-year CV event rate was > 20%. Further, the trial was conducted in Scotland where participants are, arguably, genetically similar to participants in the Physician's Health Study and HOT trial. True, POPADAD was a relatively small study - so it's perhaps underpowered to detect a meaningful reduction in CV events. But looking at the data there doesn't seem to be even a trend in favor of aspirin for any outcome other than non-fatal stroke. Perhaps the dose of aspirin was too low? In the Physician's Health Study patients took aspirin 325mg every other day, not 81 - 100mg daily. Moreover, there are some data that support the contention that patients with diabetes are less responsive to aspirin (Watala 2005). ⁶ Any conjectures are simply hypotheses.

So, for now, low-dose aspirin remains a "standard of care" for people with diabetes over the age of 40 according to most clinical practice guidelines. I believe it's prudent to offer aspirin therapy to patients with diabetes who are over the age of 50 and have at least one other CV risk factor and who are at low risk for GI bleeds - but that recommendation is on shaky ground. Stay tuned.

^a Composite Endpoint: JPAD = sudden death; death from coronary, cerebrovascular, and aortic causes; nonfatal acute myocardial infarction; unstable angina; newly developed exertional angina; nonfatal ischemic and hemorrhagic stroke; transient ischemic attack; or nonfatal aortic and peripheral vascular disease; POPADAD = death from myocardial infarction or stroke; non-fatal myocardial infarction or stroke; or above the ankle amputation for critical limb ischemia.

^b p = 0.0037 Aspirin versus Placebo (JPAD only)

References

1. The 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.
   
   
2. Hansson L 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 ;351:1755-62.
   
   
3. Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial Investigators. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA. 2008 Nov 12;300(18):2134-41.
   
   
4. Prevention of Progression of Arterial Disease and Diabetes Study Group; Diabetes Registry Group; Royal College of Physicians Edinburgh. 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. doi: 10.1136/bmj.a1840.
   
   
5. Antithrombotic Trialists' (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomized trials. Lancet 2009; 373: 1849-60.
   
   
6. Watala C, Pluta J, Golanski J et al. Increased protein glycation in diabetes mellitus is associated with decreased aspirin-mediated protein acetylation and reduced sensitivity of blood platelets to aspirin. J Mol Med 2005; 83: 148-58.