Intended for healthcare professionals

Rapid response to:


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 doi: (Published 16 October 2008) Cite this as: BMJ 2008;337:a1840

Rapid Response:

Aspirin for Priamary Prevention in Diabetes

Dear Editor

26 October 2008

The excellent study by Belch et al (BMJ 2008;337:a1840) suggests that
aspirin is not universally indicated for primary prevention of vascular
events in diabetic patients. Biologically, there is no difference in the
action of antiplatelet drugs for primary or secondary prevention – the
major difference is in the event rate and therefore the power of study
needed to show benefit. Arguably, the patients in the study had
atherosclerotic disease and were therefore secondary prevention patients.
With baseline risk factors (smoking, blood pressure, cholesterol) as
presented, many patients in this study would have been above the 1.5% per
year risk threshold where benefit of aspirin outweighs risk. 1 The event
rate documented was considerably short of that predicted, and this may
have been due to increased use of statins and other cardioprotective drugs
during the study – no data are given for this. Benefits of aspirin in high
-risk patients are significant, 2 but less than those projected for
statins. 3

Increased risk of haemorrhagic events is an inevitable consequence of
deriving benefit from the antiplatelet effects of aspirin. There was no
increased risk of dyspeptic symptoms or gastrointestinal haemorrhage with
aspirin in Belch’s study in spite of the fact that the numbers and length
of follow-up were sufficient to expect adverse effects to be detected. 4
Compliance and aspirin resistance are two factors not addressed in the
study, but which could affect response. At least a quarter of patients
treated with aspirin may be resistant, and this translates into decreased
protection from cardiovascular events. 5 Because of increased platelet
reactivity, aspirin resistance appears to be even more common in diabetic
patients and may be overcome by increasing the dose or prescribing an
additional antiplatelet drug. 6 Presumably, aspirin-resistant patients,
while not benefiting from treatment, are also not susceptible to
haemorrhagic side effects.

Diabetic patients are at high risk of macrovascular complications,
but trials must take account of the interaction between drugs and changing
clinical practice. Although aspirin is cheap and safe, it is not always
effective. The time may have come to consider monitoring platelet function
in patients with aspirin – as other forms of anticoagulation are
monitored. Aggregrometry is simple and cheap, but requires
standardisation. Current evidence does not allow us to preclude an effect
of aspirin in primary prevention of vascular events in diabetes, but
neither does it support universal prescription of aspirin despite the very
high risk experienced by diabetic patients.

Conflicts of Interest:

The authors have no conflicts of interest to declare


1. Sanmuganathan PS, Ghahramani P, Jackson PR, Wallis EJ, Ramsay LE.
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(3):265-71.
2. Antithrombotic Trialists C. Collaborative meta-analysis of randomised
trials of antiplatelet therapy for prevention of death, myocardial
infarction, and stroke in high risk patients. BMJ 2002;324(7329):71-86.
3. Cholesterol Treatment Trialists C, Kearney PM, Blackwell L, Collins R,
Keech A, Simes J, et al. Efficacy of cholesterol-lowering therapy in
18,686 people with diabetes in 14 randomised trials of statins: a meta-
analysis. Lancet 2008;371(9607):117-25.
4. Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term
use of aspirin: meta-analysis. BMJ 2000;321(7270):1183-7.
5. Krasopoulos G, Brister SJ, Beattie WS, Buchanan MR. Aspirin
"resistance" and risk of cardiovascular morbidity: systematic review and
meta-analysis. BMJ 2008;336(7637):195-8.
6. Duzenli MA, Ozdemir K, Aygul N, Soylu A, Tokac M. Comparison of
increased aspirin dose versus combined aspirin plus clopidogrel therapy in
patients with diabetes mellitus and coronary heart disease and impaired
antiplatelet response to low-dose aspirin. American Journal of
Cardiology 2008;102(4):396-400.

Competing interests:
None declared

Competing interests: No competing interests

26 October 2008
Richard L. Kennedy
Professor of Medicine
Usman H. Malabu
James Cook University, Douglas, Queensland QLD 4814, Australia