|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 review found that clopidogrel in combination with standard therapy was significantly more effective than aspirin alone for the treatment of acute coronary syndromes. Overall, this was a well-conducted review and the authors' conclusions are supported by the evidence presented.
To review the clinical and cost-effectiveness of clopidogrel in combination with standard therapy compared with standard therapy alone for the treatment of non-ST-segment-elevation acute coronary syndromes (ACS).
The authors searched 11 electronic databases, including MEDLINE, EMBASE, Inside Conferences and the Cochrane Library, all from inception to April 2003; a detailed search strategy was given in an appendix to the review. This was supplemented by a review of manufacturers' submissions to the National Institute for Clinical Excellence.
Study designs of evaluations included in the review
In order to establish the clinical effectiveness of clopidogrel, randomised controlled trials (RCTs) were the only studies eligible for inclusion in the review. In order to evaluate adverse events for combined therapy, RCTs and post-marketing surveillance studies were eligible for inclusion. Systematic reviews and meta-analyses were used to confirm the safety profile for aspirin.
Specific interventions included in the review
Studies that compared clopidogrel used in combination with standard therapy (including aspirin) with standard therapy alone were eligible for inclusion in the review.
Participants included in the review
Studies of participants with unstable angina or non-ST-segment elevation myocardial infarction (MI) were eligible for inclusion in the review.
Outcomes assessed in the review
Studies were included if they reported any of the following outcomes: cardiovascular death, nonfatal MI, stroke, refractory ischaemia, severe ischaemia, heart failure, revascularisation, unstable angina, other vascular events, death, bleeding complications, other adverse events, quality of life and costs.
How were decisions on the relevance of primary studies made?
Two reviewers independently screened the titles and abstracts of all potentially relevant studies identified by the searches. Full papers of studies deemed to be potentially eligible by either reviewer were sought. One reviewer assessed the full papers for inclusion and a second reviewer checked for accuracy. Any disagreements were resolved through consensus, with a third reviewer consulted if necessary.
Assessment of study quality
The quality of the included studies was assessed according to criteria based on CRD Report 4, which were detailed in the review. One reviewer checked the quality of the included studies and a second reviewer independently checked for accuracy. Any disagreements were resolved through consensus, with a third reviewer consulted if necessary.
One reviewer extracted the data and a second reviewer independently checked for accuracy. Any disagreements were resolved through consensus, with a third reviewer consulted if necessary.
Methods of synthesis
How were the studies combined?
Only one RCT that fulfilled the inclusion criteria was identified.
How were differences between studies investigated?
Only one RCT that fulfilled the inclusion criteria was identified.
Results of the review
One RCT, with a total of 12,652 patients, fulfilled the inclusion criteria of the review.
Only one RCT was eligible for inclusion in this review. This was a high-quality, double-blind, placebo-controlled trial that included patients with ACS without ST-segment elevation. This study evaluated the efficacy and safety of the early and longer term use of clopidogrel. The intervention in this study was 75 mg/day clopidogrel plus 75 to 325 mg/day aspirin versus placebo plus 75 to 325 mg/day aspirin.
The primary outcome of this trial was composite, comprising of death from cardiovascular events, nonfatal MI or stroke over the 9-month treatment period. The results showed that clopidogrel in addition to aspirin was significantly more effective than placebo plus aspirin for this outcome, with a relative risk (RR) of 0.80 (95% confidence interval, CI: 0.72, 0.90). The second primary outcome was the rate of deaths from cardiovascular causes, nonfatal MI, stroke or refractory ischaemia. The results showed that clopidogrel plus aspirin was also significantly more effective than placebo plus aspirin for this outcome, with an RR of 0.86 (95% CI: 0.79, 0.94).
Patients receiving clopidogrel had significant benefits in comparison with those receiving placebo with regards to the secondary outcomes: incidence of severe ischaemia, recurrence of angina and reduced rates of radiological evidence of heart failure. Clopidogrel was associated with a significantly higher incidence of major and minor bleeding compared with the placebo group: the RRs were 1.38 (95% CI: 1.13, 1.67) and 2.12 (95% CI: 1.75, 2.56) for major and minor bleeding, respectively. Further subgroup analyses for the trial were given in the report.
Yes. A cost-effectiveness study showed that clopidogrel plus aspirin treatment for 12 months was cost-effective for non-ST elevation ACS if the provider was willing to pay £6,078 per quality-adjusted life-year gained.
The results of the one trial eligible for inclusion in this review indicated that clopidogrel in addition to aspirin was significantly more effective than placebo plus aspirin in a wide range of patients with ACS.
The review addressed a specific question and had clear inclusion criteria. Several relevant electronic databases were searched and a detailed search strategy was given in an appendix. Foreign language studies do not appear to have been eligible for inclusion in the review, which introduces the possibility of language bias. Screening for study inclusion and the data extraction were carried out in duplicate, thus reducing the chance of reviewer bias or error. A detailed description of the one study that was eligible for inclusion in the review was provided alongside a quality assessment.
Overall, this was a well-conducted review and the authors' conclusions follow from the evidence presented: one large, high-quality RCT.
Implications of the review for practice and research
Practice: The authors did not state any implications for practice.
Research: The authors stated that a prospective trial randomising patients to various durations of treatment is required to assess the temporal affects of clopidogrel. However, such a trial would need to be much larger than the trial included in this review for it to be sufficiently powered to detect significant differences.
NHS R&D Health Technology Assessment (HTA) Programme, 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
Subject indexing assigned by NLM
Acute Disease; Aspirin /economics /therapeutic use; Coronary Disease /diagnosis /drug therapy /economics; Cost-Benefit Analysis; Drug Therapy, Combination; Electrocardiography; Platelet Aggregation Inhibitors /economics /therapeutic use; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Ticlopidine /analogs & derivatives /economics /therapeutic use; Treatment Outcome
Database entry date
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.