The primary prevention of CVD for patients with diabetes

Antiplatelet therapy may not help primary prevention of CVD in diabetes, say Dr Nick Barwell and Dr Miles Fisher.

Mortality and morbidity in diabetes is predominantly a consequence of cardiovascular disease (CVD).

Cardiovascular death in patients with diabetes is elevated threefold compared with the general population.

Data from the Framingham study suggest that diabetes should be viewed as a CVD risk equivalent, with a risk that is similar to that conferred by a previous significant vascular event. The treatment of patients with diabetes should therefore focus not only on adequate glycaemic control, but also on cardiovascular risk identification and management.

Antiplatelet therapy is widely used as a preventative agent in CVD. Aspirin is the most commonly used antiplatelet agent and a substantial evidence base exists for its role in prevention of cardiovascular events.

It seems intuitive that if diabetic individuals are at an increased risk of cardiovascular events, it would be reasonable to try to diminish the risk by giving antiplatelet therapy to all diabetic patients. However, the evidence is not convincing.

Evidence of benefits

The Antiplatelet Trialists' Collaboration (ATC) has performed two meta-analyses of antiplatelet therapy.

In 1994 they demonstrated a significant reduction in vascular events (non-fatal MI, non-fatal stroke or vascular death) in diabetic patients with vascular disease treated with antiplatelet therapy.

The reduction was similar to that seen in other high-risk cohorts; for example, previous MI, TIA or stroke.

A second analysis of 1,365 diabetic patients whose sole vascular risk factor was diabetes (for example primary prevention) showed no benefit from antiplatelet therapy.

The larger ATC meta-analysis again showed no benefit where diabetes alone was the risk factor. It included data from the diabetic subgroup of the Hypertension Optimal Treatment (HOT) study, and Early Treatment Diabetic Retinopathy Study (ETDRS).

In the HOT study, aspirin 75mg reduced symptomatic MI in diabetic patients with hypertension, but total and cardiovascular mortality was not reduced.

MI reduction

In ETDRS, aspirin 650mg produced a reduction in symptomatic MI.

HOT and ETDRS therefore showed benefits only in terms of decreased symptomatic MI, but show no impact on reducing cardiovascular death in patients with diabetes.

The Primary Prevention Project (PPP) was designed to examine the impact of aspirin on vascular outcomes in subjects with at least one cardiovascular risk factor, but no history of a previous cardiovascular event.

In this general practice study population aspirin therapy caused a significant 44 per cent relative risk reduction in cardiovascular death, and a 23 per cent relative risk reduction in the incidence of all cardiovascular events.

Post-hoc analysis of the diabetic subgroup showed a non-significant reduction in the combined end-point of cardiovascular events (including cardiovascular death).

A number of trials have assessed the potential of novel antiplatelet agents either instead of, or in addition to aspirin therapy.

New antiplatelet agents

These trials have focused on secondary prevention and in some cases secondary prevention in high-risk subjects.

The Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial suggests an enhanced reduction in risk of major vascular events (including vascular death) with clopidogrel therapy.

The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial examined the role of clopidogrel therapy in addition to aspirin in those who presented with acute coronary syndrome.

Combination antiplatelet therapy produced a 20 per cent reduction in major cardiovascular events including cardiovascular death, MI and stroke.

Both CURE and CAPRIE assessed a diabetic subgroup. Both subgroups had a higher vascular event rate than non-diabetic patients. The CAPRIE diabetes subgroup analysis was underpowered to assess results with respect to the initial combined primary end point of cardiovascular death, non-fatal MI and non-fatal stroke.

The CURE investigators report a 2.5 per cent reduction in primary end point achievement in diabetic subjects on combined antiplatelet therapy but this did not achieve significance.

Ischaemic stroke

Finally, the Management of Atherothrombosis with Clopidogrel in High-risk patients (MATCH) trial assessed combined antiplatelet therapy in patients with ischaemic cerebrovascular disease, with a similar combined vascular end point to the previous studies.

Combined therapy in ischaemic stroke produced a relative risk reduction that was not statistically significant and was countered by a higher bleeding event rate in this population; 68 per cent of the MATCH population had diabetes and combined therapy in this group produced a slightly higher relative risk reduction than in the rest of the study population, but again this did not achieve statistical significance and was associated with increased bleeding.

Diabetic patients with a history of vascular events appear to derive at least as much benefit from antiplatelet therapy as non-diabetic patients.

However, antiplatelet therapy for primary prevention in diabetes remains to be proven. Given that there are interventions that reduce cardiovascular events for primary prevention in diabetes, aspirin therapy should be reserved for secondary prevention in diabetes, and combination antiplatelet therapy for diabetic patients with high-risk vascular events, excluding ischaemic stroke, and be instituted under specific conditions.

KEY POINTS
- Cardiovascular death in patients with diabetes is elevated threefold
compared with the general population.
- Antiplatelet therapy is widely used as a preventative agent in CVD.
- Aspirin is the most commonly used antiplatelet agent.
- Studies have shown no impact of aspirin on reducing cardiovascular
death in patients who suffer from diabetes.
- Combination antiplatelet therapy should be reserved for diabetic
patients who suffer with high-risk vascular events.

REFERENCES

- Haffner S M, Lehto S, Ronnemaa T, et al. Mortality from coronary heart disease in subjects with type-2 diabetes and in non-diabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339: 229-34.

- Kannel W B. Metabolic risk factors for coronary heart disease in women: perspective from the Framingham Study. Am Heart J 1987;114: 413-9.

- Altman R, Carreras L, Diaz R, Figueroa E et al. 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: 81-106.

- Anti-thrombotic 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.

- Hansson L, Lennart Zanchetti A, Alberto Carruthers S G, et al. Effects of intensive BP lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998; 351: 1,755-62.

- ETDRS investigators. Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report 14. Lancet 1992; 268(10): 1,292-1,300.

- Sacco M, Pellegrini Ff, Roncaglioni M C, et al on behalf of the PPP Collaborative Group. Primary Prevention of Cardiovascular Events With Low-Dose Aspirin and Vitamin E in type-2 Diabetic Patients. Results of the Primary Prevention Project (PPP). Diabetes Care 2003; 26: 3,264-72.

- CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1,329--39.

- The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromes without ST-segment Elevation. N Engl J Med 2001; 345: 494-502.

- Bhatt D L, Marso S P, Hirsch AT et al. Amplified Benefit of Clopidogrel Versus Aspirin in Patients With Diabetes Mellitus. Am J Cardiol 2002; 90: 625-28.

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