Health Technology Assessment 2004; Vol 8: number 40
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C Main,1* S Palmer,2 S Griffin,2 L Jones,1 V Orton,1 M Sculpher,2 R Henderson,3 C Sudlow,4 N Hawkins2 and R Riemsma1
for Reviews and Dissemination, University of York, UK
2 Centre for Health Economics, University of York, UK
3 Nottingham City Hospital, UK
4 University of Edinburgh, UK
* Corresponding author
Most of the mortality and morbidity associated with non-ST-segment elevation acute coronary syndromes (ACS) arises from disruption of atheromatous plaques, followed by platelet aggregation and thrombus formation. Aspirin is the most commonly prescribed antiplatelet agent, which is known to reduce the risk of fatal and non-fatal myocardial infarction in patients with unstable angina. Clopidogrel, a different antiplatelet agent, inhibits platelet aggregation induced by adenosine diphosphate, thereby reducing ischaemic events. Combining clopidogrel with aspirin may therefore have an additive effect as each acts via a different inhibitory pathway.
To review systematically the clinical effectiveness and the cost-effectiveness of clopidogrel used in combination with standard therapy including aspirin, compared with standard therapy alone for the treatment of non-ST-segment elevation ACS.
A systematic review of the literature and an economic evaluation were undertaken.
Eleven electronic databases were searched from inception to April 2003 for the clinical effectiveness and cost-effectiveness sections. In addition, the manufacturers submissions to the National Institute for Clinical Excellence were reviewed.
Studies were included if they fulfilled the following criteria:
Both data extraction and quality assessment were undertaken by one reviewer and independently checked by a second reviewer, with any disagreements being resolved through discussion. The quality of RCTs was assessed according to criteria based on NHS CRD Report No. 4, and the quality of systematic reviews was assessed according to the guidelines for the Database of Reviews of Effect (DARE) criteria. The quality of economic evaluations was assessed according to a checklist updated from one developed by Drummond and colleagues.
The clinical effectiveness and cost-effectiveness of clopidogrel in combination with standard therapy compared with standard therapy alone were synthesised through a narrative review with full tabulation of the results of the included studies. In the economic evaluations, a cost-effectiveness model was constructed using the best available evidence to determine cost-effectiveness in a UK setting.
One RCT (the CURE trial) was included in the review of the clinical effectiveness of clopidogrel in combination with aspirin. The study was a randomised, double-blind, placebo-controlled trial of high quality. A further five systematic reviews of varying quality examined the adverse events associated with long-term aspirin use. The results of the trial showed that clopidogrel in addition to aspirin was significantly more effective than placebo plus aspirin in patients with non-ST-segment elevation ACS for the composite outcome of death from cardiovascular causes, non-fatal myocardial infarction or stroke over the 9-month treatment period. However, clopidogrel was associated with a significantly higher number of episodes of both major and minor bleeding. The results from the systematic reviews that assessed the adverse events associated with long-term aspirin use showed that aspirin was associated with a significantly higher incidence of haemorrhagic stroke, extracranial haemorrhage and gastrointestinal haemorrhage compared with placebo.
The systematic literature search identified only one study that met the criteria for inclusion in the cost-effectiveness review. A separate cost-effectiveness model and accompanying report were submitted by the manufacturers (Sanofi-Synthelabo Ltd and Bristol-Myers Squibb).
Of the cost-effectiveness evidence reviewed, only the manufacturers submission was considered relevant from the perspective of the NHS. The review of this evidence highlighted potential limitations within the submission in its use of data and in the model structure used. These limitations led to the development of a new model with the aim of providing a more reliable estimate of the cost-effectiveness from the perspective of the UK NHS. This model indicated that clopidogrel appears cost-effective compared with standard care alone in patients with non-ST-elevation ACS as long as the NHS is willing to pay £6078 per quality-adjusted life-year (QALY). The results were most sensitive to the inclusion of additional strategies which assessed alternative treatment durations with clopidogrel. Although treatment with clopidogrel for 12 months remained cost-effective for the overall cohort, provisional findings indicate that the shorter treatment durations may be more cost-effective in patients at low risk.
The results of the CURE trial indicate that clopidogrel in combination with aspirin was significantly more effective than placebo combined with aspirin in a wide range of patients with ACS. This benefit was largely related to a reduction in Q-wave myocardial infarction. There was no statistically significant benefit in relation to mortality. The trial data suggested that a substantial part of the benefit derived from clopidogrel is achieved by 3 months, with a further small benefit over the remaining 9 months of chronic treatment.
The results from the base-case model suggest that treatment with clopidogrel as an adjunct to standard therapy (including aspirin) for 12 months, compared with standard therapy alone, is cost-effective in non-ST elevation ACS patients as long as the health service is willing to pay £6078 per additional QALY. However, although treatment with clopidogrel for 12 months remained cost-effective for the overall cohort, provisional findings indicate that the shorter treatment durations may be more cost-effective in patients at low risk.
To estimate the exact length of time that clopidogrel in addition to standard therapy should be prescribed for patients with non-ST-segment ACS would require a prospective trial that randomised patients to various durations of therapy. This would accurately assess whether a rebound phenomenon occurs in patients if clopidogrel were stopped after 3 months of treatment.
Main C, Palmer S, Griffin S, Jones L, Orton V, Sculpher M, et al. Clopidogrel used in combination with aspirin compared with aspirin alone in the treatment of non-ST-segment-elevation acute coronary syndromes: a systematic review and economic evaluation. Health Technol Assess2004;8(40).
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Reports are published in the HTA monograph series if (1) they have resulted from work commissioned for the HTA Programme, and (2) they are of a sufficiently high scientific quality as assessed by the referees and editors.
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The research reported in this monograph was commissioned and funded by the HTA Programme on behalf of NICE as project number 02/24/02. The authors have been wholly responsible for all data collection, analysis and interpretation and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.
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Editor-in-Chief: Professor Tom Walley
Series Editors: Dr Peter Davidson, Professor John Gabbay, Dr Chris Hyde, Dr Ruairidh Milne, Dr Rob Riemsma and Dr Ken Stein
Managing Editors: Sally Bailey and Caroline Ciupek
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