Can ASA help prevent vascular events in DM?
Platelets may be to blame for a less than clear benefit
by Megha Poddar, MD and Ally P.H. Prebtani, MD
Vol.20, No.03, April 2012

Diabetes increases morbidity and mortality from cardiovascular disease (CVD) by 2-4 times that of the general population.1 More than 70% of deaths in patients with diabetes are due to macrovascular complications.2 With the growing incidence of diabetes and increasing amount of government spending on prevention,2 targeted trials within this population have become a hot topic. Various trials have suggested a benefit of anti-platelet agents for primary prevention of vascular disease for high-risk patients with no established disease in the general population. However, the results are varied for aspirin use in patients with diabetes. These patients may have altered platelet function causing them to behave differently.

The effect of ASA for primary prevention of vascular disease in high- and low-risk groups has been comprehensively studied. The American Diabetes Association/American Heart Association group led by Pignone M, et al collated 9 large trials in a meta-analysis including high- and low-risk cardiovascular (CV) patients and those with diabetes.3 They showed a 9% reduction in CV endpoints including fatal and non fatal MI; however, it did not reach statistical significance (RR 0.91, [0.79-1.05]) (Figure 1).3 In general, the results of the collaboration meta-analysis demonstrated a moderate reduction in CV events (about 10%) in patients with high CV risk.3,5

The trials

Trials that specifically targeted diabetic individuals included in the meta-analysis are comprised of The Japanese Primary Prevention of Atherosclerosis with ASA for Diabetes (JPAD), The Early Treatment of Diabetic Retinopathy Study (ETDRS), and The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial. Unfortunately, these studies had low event rates and were often underpowered causing ongoing difficulties in concluding the true benefit of ASA in diabetes.

The JPAD study is a prospective randomized control trial that included 2,539 type 2 diabetes patients.5 Of the 154 events, 68 (13.6 per 1,000 person-years) were in the ASA group and 86 (17.0 per 1,000 person-years) were in the non-ASA group, yielding a non-significant hazard ratio of 0.8 ([CI] 0.58-1.10).3 The event rates were below target and the study was underpowered to determine the true effect of its endpoints. The result of this study concludes that ASA, as primary prevention in type 2 diabetes does not yield a statistically significant reduction in cardiovascular, cerebrovascular or peripheral vascular disease. The POPADAD trial is a randomized, double-blind trial that enrolled 1,276 patients.4 The number of primary events in the ASA group included 116/638 compared to 117/638 (HR of 0.98 [CI] 0.76-1.26]), which wasn’t statistically significant.4 Between the two groups neither primary nor secondary endpoints reached statistical significance.4

A further meta-analysis by the Antithrombotic Trialists’ Collaboration reviewed 287 studies and included 135,000 high-risk CV patients.6 The main outcome was serious vascular events including nonfatal MI, stroke and vascular death, of which the combined outcome of any serious event was reduced by 12% (RR 0.88, [CI] 0.82-0.94)6 in the ASA group. Within this meta-analysis 4,961 patients with diabetes were included and the results showed a non significant odds risk reduction of 7% in patients with diabetes (15.7 vs 16.7 [OR 7% (8)]).6

Figure 1

Diabetes... Aspirin and Diabetes Mellitus Figure 1.jpg

Frank evaluation

Upon evaluating these trials, ASA may not have a clear benefit for primary prevention of CVD in diabetes as seen in the general population. This may be due to differences in platelet function and activity. Patients with diabetes have accelerated atherosclerosis and variations in their platelet function including increased platelet activation and thrombosis, aggregation and turnover.2,7 These physiological changes create a pro-coagulable state and may alter the effectiveness of ASA.7 Additionally, higher dosing strategy has been proposed by some to overcome these changes. Interestingly, the ETDRS and Primany Prevention Project (PPP) trials reviewed in the meta-analysis used higher doses of ASA and still fell short in overall outcome reduction.2

Secondary prevention (in patients with known CAD) has a well-established benefit in the general population and continues to be recommended in diabetes. It’s important to identify high-risk candidates (see Table 1) for prevention of CVD with lifestyle management and antiplatelet use based on the guidelines.2 This would include ASA in people with stable CVD (or clopidogrel in those unable to tolerate ASA), and ACE inhibitors or ARBs for high-risk individuals.2 The decision to use ASA for primary prevention in the low-risk patient group and in patients with diabetes should be made on an individual basis with more emphasis placed on statin therapy, smoking cessation, blood pressure control and healthy lifestyle interventions to improve global vascular health.

The bottom line

Diabetes itself is a strong player in increasing CV risk; an emphasis should be placed on adequate management of other risk factors including hypertension, hypercholesterolemia, smoking and obesity. The evidence shows no clear strong benefit of ASA for primary prevention of CVD in diabetic patients; however, it’s still recommended for secondary prevention and in high-risk groups. Further trials are required to understand the true long-term effect of ASA in this population.

References

  1. Haffner SM: Coronary heart disease in patients with diabetes. NEJM 2000;342:1040-2.
  2. Canadian Diabetes Association 2008 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. September 2008; Volume 32.
  3. American Diabetes Association, American Heart Association, American College of Cardiology Foundation, Michael Pignone, Mark J. Alberts, et al. Aspirin for Primary Prevention of Cardiovascular Events in People With Diabetes. J Am Coll Cardiol 2010;55;2878-86.
  4. Belch, Jill et al. BMJ 2008;337:a1840 doi:10.1136.
  5. Ogawa H, Nakayama M, et al. JAMA 2008;300:2180-1.
  6. Antithrombotic Trialists’ Collaboration Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients; Antithrombotic Trialists’ Collaboration. BMJ 2002;324:71.
  7. Aaron I. Vinik, et al. Diabetes Care 2001:24:1476-85.

Megha Poddar, MD, is a senior medical resident at McMaster University.

Ally P.H. Prebtani, MD, FRCPC, is Associate Professor of Medicine and Program Director of the Endocrinology & Metabolism Residency Training Program at McMaster University in Hamilton, ON. He is also Director of the Internal Medicine International Health Program at McMaster University.

Table 1: People with diabetes considered at high risk of a CV event
  • Men aged = 45 years and women aged = 50 years
  • Men aged = 45 years and women aged = 50 years with = 1 of the following:
    • macrovascular disease (MI or ischemia, CAD, PAD, stroke, transient ischemic attack, cerebrovascular disease, evidence of silent MI or ischemia or PAD)
    • microvascular disease (especially nephropathy or retinopathy)
    • multiple additinal risk factors, especially with a family history of premature coronary or cerebrovascular disease in a first-degree relative
    • extreme level of a single factor (e.g. LDL-C > 5.0 mmol/L, systolic BP > 180 mm Hg)
    • duration of diabetes > 15 years with age > 30 years

BP=blood pressure; CAD=coronary artery disease; CV=cardiovascular; LDL-C=low-density lipoprotein cholesterol; MI=myocardial infarction; PAD=peripheral arterial disease

Adapted from Canadian Diabetes Association 2008 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. September 2008; Volume 32.

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