Dr Alan Begg discusses the recommendations from NICE on the prevention of occlusive vascular events
Recently published NICE guidance on the use of clopidogrel and modified release (MR) dipyridamole in the prevention of occlusive vascular events has generated much debate. One comment was that the guidance was ‘not supported by adequate evidence from clinical trials’.1 Another criticised NICE for having treated each manifestation of occlusive vascular events separately and for failing to provide practical guidance for doctors.
The appraisal was not intended to be a systematically developed guideline on the treatment of occlusive vascular disease. It examines the clinical- and cost-effectiveness of the two antiplatelet preparations and considers evidence from the CAPRIE and ESPS 2 trials.2,3
Of the two, clopidogrel is licensed for use in patients following MI and in established peripheral arterial disease. In this respect, the guidance is clear and in line with previous guidelines: it recommends clopidogrel alone for patients who are intolerant of low-dose aspirin. This recommendation applies to patients with a true hypersensitivity to aspirin as well as those with a history of severe dyspepsia caused by a low dose of the drug.
Following ischaemic stroke or transient ischaemic attack (TIA), the guidance recommends, on the basis of a cost-effectiveness model, a combination of MR dipyridamole and low-dose aspirin for 2 years. This should be followed by standard care, including life-long aspirin for which there is little evidence.
In the ESPS 2 trial, patients were followed up for 2 years. The trial dose of aspirin of 25 mg twice daily was, however, below the current standard dose of 75 mg daily. One meta-analysis, which included 24 other trials not using the MR preparation, showed only a non-significant reduction in serious vascular events when adding dipyridamole to low-dose aspirin.4 However, another reported that dipyridamole is effective in reducing the risk of a subsequent stroke.5
It is generally accepted that atherothrombosis is a single disease process occurring in different vascular beds and manifesting as different clinical events or symptoms. However, ischaemic stroke may be of mixed cause, either large- or small-vessel disease or cardioembolic. Different manifestations of occlusive vascular disease occurring in the same patient is a well documented phenomenon, and the recruitment profile of patients in the CAPRIE trial is commonly used to illustrate the point. However, MI patients tend to have a recurrent MI and stroke patients in the first 5 years tend to have another stroke.
So has the guidance clarified which antiplatelet therapy to use in day-to-day clinical practice? Following a coronary event or in established peripheral arterial disease, the choice is clear. After an ischaemic stroke or TIA, patients are likely to be treated with a combination of low-dose aspirin and MR dipyridamole for at least 2 years, but there is no evidence for continuing MR dipyridamole beyond this. Clopidogrel is licensed for patients following an ischaemic stroke and can be considered in those who cannot tolerate aspirin.
In patients with occlusive vascular disease across different vascular beds, the whole clinical picture should be considered. The choice and combination of therapy depends on other indications, such as acute coronary syndrome, contraindications and the licensed indications of the drugs as well as the individual’s risk of future vascular events.
Clopidogrel and modified release dipyridamole in the prevention of occlusive vascular events, Technology Appraisal 90, can be downloaded from the NICE website: www.nice.org.uk
- Mayor S. NICE guidance to prevent strokes and heart attacks lacks evidence. Br Med J 2005; 330: 1286.
- A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996; 348: 1329-39.
- Diener HC, Cunha L, Forbes C et al. European Stroke Prevention Study. 2.Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143: 1-13.
- 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. Br Med J 2002 324: 71-86.
- Leonardi-Bee J, Bath PM, Bousser MG et al; Dipyridamole in Stroke Collaboration (DISC). Dipyridamole for preventing recurrent ischemic stroke and other vascular events: a meta-analysis of individual patient data from randomized controlled trials. Stroke 2005; 36: 162-8. Epub 2004 Nov 29.