|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
|Main C, Palmer S, Griffin S, Jones L, Orton V, Sculpher M, Henderson R, Sudlow C, Hawkins N, Riemsma R
This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn.
The study examined the use of 12-month clopidogrel in combination with aspirin for the prevention of morbidity and mortality associated with non-ST-segment elevation acute coronary syndrome (ACS). The combined therapy was compared with standard therapy including aspirin. Three alternative strategies (representing treatment with clopidogrel over a 1-, 3- or 6-month duration) were also considered.
The study population comprised a hypothetical cohort of patients with non-ST-segment elevation ACS
The setting was secondary care. The economic study was carried out in the UK.
Dates to which data relate
The clinical data were derived from studies published between 1988 and 2003. The resource use data were mainly taken from a study published in 2002. A 2001/02 price base was used.
A probabilistic decision model was constructed to determine the cost-effectiveness of clopidogrel in comparison with standard care in a hypothetical cohort of eligible patients. A lifetime horizon (i.e. 40 years) was chosen. The model consisted of two parts: a short-term element standard decision tree (with a 12-month time horizon) and a long-term model (which extrapolated a patient's lifetime costs and benefits conditional on surviving the first 12-month period). After 12 months, survived patients might or might not have experienced a myocardial infarction (MI). A Markov process with annual cycles was used in the long-term analysis. The model was adapted from another published decision model (Main et al. 2004, see 'Other Publications of Related Interest' below for bibliographic details).
Study designs and other criteria for inclusion in the review
The clinical data used in the analysis were treatment effectiveness, rates of adverse events, death rates and rates of revascularisation procedures. The long-term risk of cardiovascular events was also considered.
Sources searched to identify primary studies
Treatment effect for clopidogrel plus aspirin versus aspirin alone (relative risk) was derived from a high-quality, randomised, double-blind, placebo-controlled trial (i.e. the CURE study). Adverse events associated with the two treatments were derived from five published systematic reviews. In the decision model, the baseline probabilities of events were derived from an observational cohort registry of 1,046 patients admitted to 56 UK hospitals and followed for 6 months. Supplementary data were also obtained from an audit of ACS patients identified at a large UK cardiac centre (Leeds). The long-term risk of cardiovascular events was taken from the Nottingham Heart Attack Register.
Methods used to derive estimates of effectiveness
A systematic review of the literature was carried out to obtain effectiveness data. The search methods and inclusion and exclusion criteria were reported in detail. Only randomised clinical trials (RCTs) were included. The quality of the primary studies was assessed using a published checklist and widely used criteria. Manufacturers' submissions to NICE were also considered as potential sources of data. Only clinical data based on head-to-head comparisons of the two strategies under analysis were considered (only one clinical trial). Other data were combined on the basis of meta-analyses. The data for baseline probabilities of events were chosen to reflect the UK context.
Measure of benefits used in the economic analysis
The summary benefit measure used was the quality-adjusted life-years (QALYs). These were estimated using the decision analysis model. Utility weights were derived from the original model from which the current one was adapted. The benefits were discounted at an annual rate of 1.5%.
The analysis was carried out from the perspective of the NHS. It included the costs of the medications under study, hospital stay (in different wards), the treatment of adverse events, surgical procedures and diagnostic tests. The unit costs and the quantities of resources used were presented separately for all items. The resource use data were derived from the two UK studies (for the two parts of the decision model, short-term and long-term), while the drug costs came from undiscounted prices from the British National Formulary. Other costs were based on either a published study or were from NHS Trusts. Discounting was relevant, as the long-term costs were evaluated, and an annual discount rate of 6% was used. In the base-case analysis, 2001/02 prices were used.
Statistical analysis of costs
The costs and quantities were treated stochastically and probabilistic distributions were attributed to resource use.
Productivity costs were not included in the analysis.
Second-order Monte Carlo simulations were performed to reflect the overall uncertainty in the model parameters. The results of the analysis were presented using cost-effectiveness acceptability curves, which were reported for different thresholds of willingness-to-pay. One-way sensitivity analyses were also carried out on key areas of uncertainty such as time horizon, baseline data, risk stratification, alternative utility estimates and cost estimates, and alternative discount rates.
Estimated benefits used in the economic analysis
The lifetime QALYs were 8.2795 with clopidogrel and 8.2022 with the standard therapy.
The expected lifetime costs per patient were £12,695 with clopidogrel and £12,225 with the standard treatment.
Synthesis of costs and benefits
Incremental cost-utility ratios were calculated in order to combine the costs and benefits of the alternative strategies.
In the base-case scenario, the incremental cost per QALY gained with clopidogrel over usual treatment was £6,078. Acceptability curves showed that the probability for clopidogrel being cost-effective over standard care was 0.68 at a willingness-to-pay value of £10,000 per QALY, 0.79 at £30,000 per QALY, and 0.81 at £50,000 per QALY.
The other sensitivity analyses showed that reducing the time horizon of the model to 5 years led to a higher incremental cost per QALY gained (£14,844).
An interesting result of the sub-group analysis was that, in low-risk patients, short-term clopidogrel (given for 1, 3 or 6 months) was highly cost-effective. Changes in other model inputs did not substantially alter the results of the base-case analysis.
The authors concluded that, from the perspective of the UK health service, clopidogrel added to aspirin was a cost-effective treatment for patients with non-ST-segment elevation acute coronary syndrome (ACS). Shorter treatment durations for clopidogrel might be more cost-effective in patients at low risk.
CRD COMMENTARY - Selection of comparators
The rationale for the choice of the comparator was clear. Aspirin represented the 'gold' standard of care for the long-term treatment and secondary prevention of ischaemic vascular events in the authors' context. Alternative treatment durations were also considered. You should decide whether standard therapy including aspirin represents a valid comparator in your own setting.
Validity of estimate of measure of effectiveness
Extensive information about the approach and methods of the literature review was provided. The results of the literature review were reported extensively. The authors described search criteria, inclusion and exclusion criteria, the methods used to determine the quality of the primary sources, and the data extraction strategies. Overall, only high-quality studies were sought, although this resulted in only one effectiveness study being found from which to determine the treatment effect. Data on toxicity were derived from systematic reviews, which represent a valid source and combination of estimates. Interestingly, the authors used UK sources to obtain baseline probabilities of events on the basis of observational studies, and then applied the treatment relative risk from the main clinical trial. This represents an appropriate and typical approach to ensuring that the baseline data are representative of the context of the analysis.
Validity of estimate of measure of benefit
The use of QALYs as the summary benefit measure was appropriate since they capture the impact of the interventions on both quality of life and survival, which are relevant dimensions of health for patients with ACS. The benefits were appropriately discounted and the impact of alternative discounting rates was investigated in the sensitivity analysis. The approach used to derive the utility weights was reported.
Validity of estimate of costs
The analysis of the costs was consistent with the authors' stated perspective. Extensive details of the unit costs, quantities of resources used, price year, sources of data, and assumptions made were reported. This enhances the robustness of the economic analysis and the possibility of replicating the analysis in other settings and time periods. Alternative values were considered in the sensitivity analyses in order to take into account variability surrounding the cost estimates. Statistical analyses of the costs and quantities were performed.
The authors compared their findings with those from the manufacturers' submissions and highlighted the reasons for any discrepancies. However, despite some methodological differences, similar results were generally achieved. Comments and justifications for the assumptions made in the extrapolation to a lifetime horizon were made. The issue of the generalisability of the study results to other settings was not explicitly addressed since the model was UK-centred. However, the wide use of sensitivity analysis and the clear description of the methodology of the study improve the external validity of the economic evaluation. The study generally demonstrated high standards, both in terms of the methodology adopted and in the description of the results.
Implications of the study
The study results support the use of clopidogrel added to aspirin for the prevention of morbidity and mortality in patients with non-ST-segment elevation ACS. The authors pointed out that future studies should evaluate the impact of various durations of therapy on the cost-effectiveness of clopidogrel.
Source of funding
Research commissioned and funded by the Health Technology Assessment (HTA) Programme, on behalf of NICE, project number 02/24/02.
Main C, Palmer S, Griffin S, Jones L, Orton V, Sculpher M, Henderson R, Sudlow C, Hawkins N, Riemsma R. 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 Technology Assessment 2004; 8(40): 1-156
Other publications of related interest
Because readers are likely to encounter and assess individual publications, NHS EED abstracts reflect the original publication as it is written, as a stand-alone paper. Where NHS EED abstractors are able to identify positively that a publication is significantly linked to or informed by other publications, these will be referenced in the text of the abstract and their bibliographic details recorded here for information.
Main C, Palmer S, Griffin S, 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 Assess 2004;8(40).
Gaspoz JM, Coxson PG, Goldman PA, et al. Cost-effectiveness of aspirin, clopidogrel, or both for secondary prevention of coronary heart disease. N Engl J Med 2003;348:560-1.
Yusuf S, Zhao F, Mehta S, et al. 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.
Subject indexing assigned by NLM
Acute Disease; Aspirin /economics /therapeutic use; Coronary Disease /diagnosis /drug therapy /economics; Cost-Benefit Analysis; Drug Therapy, Combination; Electrocardiography; Humans; Platelet Aggregation Inhibitors /economics /therapeutic use; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Ticlopidine /analogs & Treatment Outcome; derivatives /economics /therapeutic use
Date bibliographic record published
Date abstract record published