1. Exeter Drugs Update
Aspirin in the primary prevention of cardiovascular disease in people
with diabetes
Richard Haynes1
Louise Bowman1
Kenneth Macleod2
1
Clinical Research Fellow, Clinical Trial Service Unit, University of Oxford
2
Associate Dean & Reader in Medicine, Peninsula College of Medicine &
Dentistry and Consultant Physician (Diabetes & Endocrinology)
Royal Devon & Exeter NHS Foundation Trust

2. The prevalence of diabetes mellitus is increasing and it affects over two
million people in the UK alone. Patients with diabetes (either type 1 or type 2)
are at increased risk of mortality compared to age- and gender-matched
patients without diabetes and about two-thirds of deaths can be attributed to
vascular causes.1, 2 However, surveys of people with diabetes show that the
large majority do not yet have manifest vascular disease3, 4 and it is therefore
logical to focus on strategies that could prevent the development of
symptomatic vascular disease in these people.
Aspirin has well-proven benefits in the secondary prevention of cardiovascular
disease. Meta-analyses of antiplatelet trials (mostly involving aspirin) showed
a reduction in subsequent vascular events of around one-quarter and the
benefits appear to be similar whether or not such patients also had diabetes.5,
6
These meta-analyses also found an approximately 60% increase in the risk
of major bleeding (defined as bleeding which was fatal or required
transfusion) with antiplatelet therapy, but this risk is far outweighed by the
benefits in patients at high risk of vascular disease i.e. those with known
vascular disease. Consequently most people with diabetes and known
vascular disease receive antiplatelet therapy.
It remains unclear, however, whether patients with diabetes without a history
of vascular disease are at sufficient risk of vascular disease for the benefits of
aspirin to outweigh the risks. Until recently, the main randomised evidence on
the effects of aspirin in such patients came from a meta-analysis of 9 trials
involving almost 5000 patients which indicates a much smaller proportional

3. reduction in cardiovascular events than has been found in the secondary
prevention setting (just 7% compared with about 20-25%).6 Even in aggregate
these studies involved relatively few events and the confidence interval for the
estimated effect is wide, ranging from a 23% risk reduction to an 8% hazard.
Guidelines are inconsistent on the recommendation to use aspirin because of
the lack of clear evidence.7 This uncertainty has been reinforced by two recent
trials.
The Prevention of Progression of Arterial Disease And Diabetes (POPADAD)
study randomised 1276 people with diabetes to receive aspirin 100 mg daily
or placebo.8 All participants had an ankle-brachial pressure index <1.0 but
were asymptomatic and the primary outcome was death from coronary
disease or stroke, non-fatal myocardial infarction or stroke, or amputation
above the ankle for critical limb ischaemia. Participants were followed for a
median of 6.7 years but only 233 primary events were reported (annual event
rate 2.7% per annum, well below the 8% the sample size was predicated on).
The study was therefore underpowered to detect a plausible treatment effect
which was reflected in the wide confidence interval of the main result: hazard
ratio 0.98 (95% CI 0.76 – 1.26). The results of POPADAD are consistent with
anything from a 24% risk reduction with aspirin to a 26% increased risk.
More recently the Japanese Primary prevention of atherosclerosis with Aspirin
for Diabetes (JPAD) study reported its results.9 JPAD randomised 2539
patients with type 2 diabetes to receive aspirin 100 mg daily or open control
(placebo arms are not allowed in Japan). There were only 154 atherosclerotic

4. events in this study: 68 (5.4%) in the aspirin group and 86 (6.7%) in the
control group with a hazard ratio of 0.80 (95% CI 0.58 – 1.10). Again, JPAD
was not large enough to be definitive and, as the accompanying editorial
states, the use of aspirin in the primary prevention of vascular disease in
people with diabetes remains on open question.10
Currently less than half of people with diabetes are taking aspirin: if it is
effective then reliable trial data will help increase this and help prevent
thousands of vascular events in the UK alone each year. Conversely if it is not
safe then hundreds of bleeding episodes could be prevented. GPs deciding
whether or not to treat with aspirin can consider a third option: help to resolve
the current uncertainty by inviting their patients into a large ongoing trial.
ASCEND (A Study of Cardiovascular Events iN Diabetes) is a randomised
placebo-controlled trial of aspirin (and omega-3 fatty acids in a 2x2 factorial
design) in this setting which plans to randomise 10,000 patients with diabetes.
By more than doubling the available data, ASCEND should help to clarify this
important question. It has already recruited nearly 5000 patients and
interested GPs can help identify and invite patients (with the support of the
local Diabetes and Primary Care Research Networks). Further details can be
found on the study website (www.ctsu.ox.ac.uk/ascend), by e-mailing
ascend@ctsu.ox.ac.uk or calling (Freefone) 0800 585323.

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with diabetes: estimates from the Third National Health and Nutrition
Examination Survey. Diabetes Care 2001;24:197-201.
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5. Collaborative overview of randomised trials of antiplatelet therapy--I:
Prevention of death, myocardial infarction, and stroke by prolonged
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Collaboration. BMJ 1994;308:81-106.
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for prevention of death, myocardial infarction, and stroke in high risk patients.
BMJ 2002;324:71-86.
7. Nicolucci A, De Berardis G, Sacco M, Tognoni G. AHA/ADA vs.
ESC/EASD recommendations on aspirin as a primary prevention strategy in
people with diabetes: how the same data generate divergent conclusions. Eur
Heart J 2007;28:1925-7.
8. 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-.
9. Ogawa H, Nakayama M, Morimoto T, et al. Low-Dose Aspirin for
Primary Prevention of Atherosclerotic Events in Patients With Type 2
Diabetes: A Randomized Controlled Trial. JAMA 2008.
10. Nicolucci A. Aspirin for primary prevention of cardiovascular events in
diabetes: still an open question. JAMA 2008;300:2180-1.