Dr Alan Begg reviews the POPADAD trial results along with other evidence for the use of aspirin in patients with diabetes

It is accepted that patients with diabetes are at a higher cardiovascular (CV) risk than those without; however, confusion still remains over the degree of this risk compared with that in patients who do not have diabetes but have had a previous CV event. There is also conflicting evidence as to whether preventive treatment with aspirin can mitigate this CV risk in diabetes patients.

Risk of cardiovascular events in patients with diabetes

In 1998, Haffner et al published a study with the aim of quantifying the level of CV risk in patients with diabetes based on data from a Finnish population.1 The 7-year incidence of myocardial infarction (MI) among 1373 patients without diabetes was compared with the incidence of MI among 1059 patients with diabetes. The authors concluded that patients with diabetes have an equivalent risk of an MI as those without diabetes who have had a previous MI, and this supports the aggressive treatment of risk factors in both of these groups of patients.

However, different conclusions were obtained by Evans et al who performed:2

  • a cross-sectional study of patients aged 45–64 years comparing 1155 patients with type 2 diabetes with 1347 patients without diabetes who had an MI (in the preceding 8 years)
  • a cohort study of 3477 patients of all ages with newly diagnosed type 2 diabetes compared with 7414 patients who had just had a MI.2

The conclusion from these studies was that patients with type 2 diabetes were at a lower risk of CV outcomes than patients with established coronary heart disease (CHD).2 The authors also pointed out that one weakness of the Haffner study was the lack of power to distinguish differences between the two groups. Moreover, patient selection was not random: the patients represented the 80% of eligible subjects who attended a clinic visit for the study.2

Antiplatelet therapy in patients with diabetes

In 1994, the Antiplatelet Trialists’ Collaboration published an overview of the randomised trials involving antiplatelet therapy: this revealed a significant benefit from this treatment in patients with diabetes and atherosclerotic disease,3 which included a reduction of subsequent non-fatal MI, non-fatal strokes, or vascular deaths after an initial event. This reduction was similar to that seen in other groups of patients with a previous vascular event. However, based on data from seven trials, no benefit in the use of antiplatelet therapy for primary prevention of CV events in diabetes was observed.3 A subsequent meta-analysis in 2002 from the Antithrombotic Trialists’ Collaboration (using data from a total of 4961 patients with diabetes in nine trials), showed that antiplatelet therapy was associated with a non-significant 7% proportional reduction in serious vascular events in patients with diabetes.4

Despite the lack of evidence, the NICE guideline update on The management of type 2 diabetes recommends offering low-dose aspirin, 75 mg daily, to patients with diabetes who are aged:5

  • ?50 years whose blood pressure is <145/90 mmHg
  • <50 years if there are other significant CV risk factors (e.g. metabolic syndrome, a strong early family history of cardiovascular disease [CVD], smoking, hypertension, extant CVD, microalbuminuria).


The benefits of giving aspirin to patients with diabetes has again been raised by the recent publication of the Prevention Of Progression of Arterial Disease And Diabetes (POPADAD) trial.6 This study recruited 1276 patients who were aged over 40 years and who had type 1 or type 2 diabetes and an ankle brachial pressure index (ABPI) of 0.99 or less (with the lower than normal ABPI being used as an indicator of asymptomatic peripheral arterial disease). Patients were divided to receive either: aspirin and placebo; antioxidant capsule and aspirin; antioxidant capsule and placebo; or double placebo. The trial was designed as a 2x2 factorial placebo-controlled trial and there were two hierarchical composite primary end points of death from CHD or stroke, non-fatal MI or stroke, or critical limb ischaemia plus above ankle amputation; and death from CHD or stroke.


A total of 116 of 638 primary events occurred in the aspirin groups, compared with 117 of 638 in the no aspirin groups: hazard ratio = 0.98; 95% confidence interval (CI) 0.76–1.26.6 There were 43 deaths from CHD or stroke in the aspirin groups compared with 35 deaths in the no aspirin groups: hazard ratio = 1.23; 95% CI 0.79–1.93.6

In the POPADAD study it was assumed that patients with diabetes and a reduced ABPI would be at higher risk. The trial did, however, use a higher cut-off point of 0.99 for ABPI compared with the usual 0.90, on the basis that calcification in the vessels of people with diabetes can produce normal or high values for the ABPI even in the presence of arterial disease. A subsequent sub-group analysis showed no difference in the effect of aspirin between those with an ABPI <0.90 and those with an ABPI of between 0.91 and 0.99.6 The results from the POPADAD study do not support the use of either aspirin or antioxidants in the primary prevention of CV events and mortality in people with diabetes. Moreover, this study adds to the increasing evidence for the lack of benefit of antioxidants in the prevention of vascular disease.

Benefits versus the risks of aspirin in patients with diabetes

In view of the conflicting evidence on the benefits of aspirin in patients with diabetes without established CVD, should GPs continue to prescribe aspirin therapy to these patients regardless of their level of risk? In a meta-analysis of 65,987 patients, the risk of gastrointestinal (GI) haemorrhage increased by a factor of 1.68 for those on aspirin. It was concluded that, even at low dose, long-term aspirin therapy carries a risk of GI haemorrhage, with a number needed to harm per year of 248.7

The haemorrhagic problems associated with aspirin are not limited to the GI tract; intracerebral bleeds are another recognised problem. Although much less common than a GI haemorrhage, the clinical outcome is potentially far more serious. One meta-analysis of four randomised trials for aspirin for primary prevention attempted to determine the benefit and harm of aspirin treatment.8 It concluded that in patients with a 20% CVD risk over 10 years the overall benefit appeared acceptable—53 patients need to be treated in order to prevent an MI without a cerebral or major haemorrhage. This only applies to high-risk patients where the benefit of aspirin has been proven in clinical trials (i.e. those without diabetes but with a 10 year CVD risk ?20%).

The safety aspects of giving aspirin to a patient with high blood pressure are also unclear. In the thrombosis prevention trial there was an 8% increase in all CV events from aspirin when the systolic blood pressure exceeded 145 mmHg.9


The dilemma that GPs now face is whether to continue aspirin therapy in those patients with diabetes who have not suffered a CV event, in line with the recommendations from the NICE guideline.5 It would seem logical to discuss the continuation of treatment with each individual patient, and also not to commence any of these patients on aspirin until a definitive answer is available. This should be provided by the randomised ASCEND (A Study of Cardiovascular Events iN Diabetes) trial, which aims to recruit a minimum of 10,000 patients with either type 1 or type 2 diabetes who do not have known vascular disease.10 Patients in this trial will be randomly allocated to take 100 mg aspirin daily versus placebo with the trial also studying the possible benefits of omega-3 fatty acids and olive oil in this group of patients.10 Until these results are published, GPs should continue to consider on an individual basis whether to prescribe aspirin to patients with diabetes without a previous CV event.

  1. Haffner S, Lehto S, Rönnemaa T et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339 (4): 229–234.
  2. Evans J, Wang J, Morris A. Comparison of cardiovascular risk between patients with type 2 diabetes and those who had had a myocardial infarction: cross sectional and cohort studies BMJ 2002; 324 (7343): 939–942.
  3. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy—I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308 (6921): 81–106.
  4. Antithrombotic Trialists’ Collaboration. 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.
  5. National Institute for Health and Care Excellence. Type 2 diabetes: the management of type 2 diabetes (update). Clinical Guideline 66. London: NICE, 2008. Available at: www.nice.org.uk/Guidance/CG66
  6. Belch J, MacCuish A, Campbell I 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; 337: a1840.
  7. Derry S, Loke Y. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ 2000; 321 (7270): 1183–1187.
  8. Sanmuganathan P, Ghahramani P, Jackson P 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 (3): 265–271.
  9. Meade T, Brennan P. Determination of who may derive most benefit from aspirin in primary prevention: subgroup results from a randomised controlled trial. BMJ 2000; 321 (7252): 13–17.
  10. ASCEND (A Study of Cardiovascular Events in Diabetes) trial website. Available at: www.ctsu.ox.ac.uk/ascend/ (accessed 23 January 2009).G