Prevention of progression of arterial disease and diabetes (POPADAD) trial

A meta-analysis of four randomised controlled trials of aspirin as primary prophylaxis against cardiovascular events showed that although aspirin decreased the risk of myocardial infarction it did not reduce total mortality and might increase the risk of stroke and of major bleeding (1). This study the use of aspirin in diabetic patients with an ankle brachial pressure index of <=0.99 to see whether there was evidence for the use of aspirin in this population reducing cardiovascular risk.

• objective of the study:
  • to determine whether aspirin and antioxidant therapy, combined or alone, are more effective than placebo in reducing the development of cardiovascular events in patients with diabetes mellitus and asymptomatic peripheral arterial disease
• study design
  • multicentre, randomised, double blind, 2x2 factorial, placebo controlled trial
    • 1276 adults aged 40 or more with type 1 or type 2 diabetes and an ankle brachial pressure index of 0.99 or less but no symptomatic cardiovascular disease
      • the number recruited into the study resulted in a 73% power to detect a 25% relative reduction in event rate and 89% power to detect a 30% reduction in event rate if only one treatment was effective
  • inteventions
    • daily, 100 mg aspirin tablet plus antioxidant capsule (n=320), aspirin tablet plus placebo capsule (n=318), placebo tablet plus antioxidant capsule (n=320), or placebo tablet plus placebo capsule (n=318)
  • main outcome measures
    • two hierarchical composite primary end points of death from coronary heart disease or stroke, non-fatal myocardial infarction or stroke, or amputation above the ankle for critical limb ischaemia; and death from coronary heart disease or stroke
    • main secondary end points were all cause mortality, non-fatal myocardial infarction, and occurrence of other vascular events, including stroke, transient ischaemic attack, coronary or peripheral arterial bypass surgery, coronary or peripheral arterial angioplasty, development of angina, claudication, or critical limb ischaemia
• study results
  • median length of follow-up for randomised participants was 6.7 years and for those with a final follow-up in 2006 follow-up ranged from 4.5 to 8.6 years. A total of 8127 patient years of follow-up were completed
  • no evidence was found of any interaction between aspirin and antioxidant
  • overall, 116 of 638 primary events occurred in the aspirin groups compared with 117 of 638 in the no aspirin groups (18.2% v 18.3%): hazard ratio 0.98 (95% confidence interval 0.76 to 1.26)
    • forty three deaths from coronary heart disease or stroke occurred in the aspirin groups compared with 35 in the no aspirin groups (6.7% v 5.5%): 1.23 (0.79 to 1.93)
  • among the antioxidant groups 117 of 640 (18.3%) primary events occurred compared with 116 of 636 (18.2%) in the no antioxidant groups (1.03, 0.79 to 1.33)
    • forty two (6.6%) deaths from coronary heart disease or stroke occurred in the antioxidant groups compared with 36 (5.7%) in the no antioxidant groups (1.21, 0.78 to 1.89)
• study authors concluded that:
  • this trial does not provide evidence to support the use of aspirin or antioxidants in primary prevention of cardiovascular events and mortality in the population with diabetes studied
  • antioxidants showed no benefit on cardiovascular events in this population

Reference:

• 1. Sanmuganathan PS et al. Aspirin for primary prevention of coronary heart disease: safety and absolute benefit related to coronary risk derived from meta-analysis of randomised trials. Heart 2001;85:265-71
• 2. Belch J et al. 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 16;337:a1840