The effect of different treatment durations of clopidogrel in patients with non-ST-segment elevation acute coronary syndromes: a systematic review and value of information analysis.

OBJECTIVE: To update the previous systematic review of the use of clopidogrel in combination with aspirin for patients with non-ST-elevation acute coronary syndrome (NSTE-ACS), investigating the optimal duration of treatment and effects of withdrawal from treatment.

DATA SOURCES: Ten electronic databases and internet resources were searched from 2003 to February 2007, including MEDLINE, MEDLINE In-Process, EMBASE, BIOSIS, CENTRAL and CINAHL.

REVIEW METHODS: Randomised controlled trials (RCTs) of clopidogrel plus aspirin compared with aspirin alone were used to evaluate clinical effectiveness and safety. Inclusion criteria included any comparator trial for duration of treatment studies, and any study design conducted in patients with NSTE-ACS, percutaneous coronary intervention (PCI), stroke, peripheral artery disease (PAD) or ST-elevation myocardial infarction (STEMI) for evidence of rebound on withdrawal of treatment. The existing model was updated to provide a more robust approach to evaluating the cost-effectiveness of alternative durations of clopidogrel and to assess the potential value of further research using value of information approaches.

RESULTS: Two RCTs were included for the review of clinical effectiveness and safety. The only RCTs identified that evaluated different durations of clopidogrel treatments were conducted in patients with stroke, PAD, STEMI or PCI. Two small RCTs and one uncontrolled retrospective cohort study were identified for the review of rebound after thienopyridine withdrawal in patients with medically-treated NSTE-ACS. On broadening the criteria, five RCTs, two observational cohorts, nine case series and 33 case reports were identified in patients post-PCI, and two case series and two case reports were identified in patients with stroke, PAD or STEMI. The CURE trial reported that the proportion of patients experiencing cardiovascular death, myocardial infarction or stroke was lower in the clopidogrel group at 30 days [relative risk (RR) 0.79; 95% confidence interval (CI) 0.67-0.92] and from 30 days to 12 months (RR 0.82; 95% CI 0.70-0.95). Clopidogrel seems to be effective in reducing adverse cardiovascular events in patients with NSTE-ACS at intermediate and high risk of ischaemic events, and appears to increase the risk of bleeding when compared with aspirin in patients with intermediate risk of ischaemic events. In terms of the cost-effectiveness of alternative durations of clopidogrel, the updated model reinforced the conclusions from the earlier analysis, i.e. a policy of 12 months of clopidogrel for patients with NSTE-ACS appears to be cost-effective in both 'average' patients and higher-risk patients. The incremental cost-effectiveness (ICER) of 12 months' duration ranged from 13,380 pounds to 20,661 pounds per additional quality-adjusted life-year (QALY) across the different scenarios. For lower-risk patients, treatment beyond 3 months does not appear to be cost-effective. The ICER of 12 months' treatment with clopidogrel varied between 49,436 pounds and 58,691 pounds per QALY. Estimates of expected value of perfect information (EVPI) were higher for the combined analysis and for analysis of high-risk patients alone (between 48.69 million pounds and 108.4 million pounds at a threshold of 30,000 pounds per QALY). At a threshold of 20,000 pounds-30,000 pounds per QALY, total EVPI ranged between 3.27 million pounds and 20.38 million pounds in the lower-risk group.

CONCLUSIONS: The review was limited by the lack of available data. There is considerable variation in the costs of uncertainty surrounding the different scenarios and populations considered. The validity of these may also be less reliable in the higher-risk groups owing to changes in clinical practice. An adequately powered, well-conducted RCT that directly compares different durations of clopidogrel treatment in patients with NSTE-ACS would ideally be required to provide more robust evidence in relation to the impact of clopidogrel withdrawal.