Q. What is the cost to treat a patient with clopidogrel for 1 year?

A. The price of clopidogrel varies depending on the country and the region. In the United States, clopidogrel costs approximately $3USD per day. Treatment for one year would therefore be in the range of $1095USD.

Q. How many patients in the study developed thrombotic thrombocytopenic purpura syndrome?

A. There were no reported cases of TTP in CURE. There were 28 patients with reported thrombocytopenia in the placebo group versus 26 patients in the clopidogrel group

Q. Would you recommend treatment for greater than 1 year with clopidogrel following an episode of ACS?

A. Patients in CURE were treated for a minimum of 3 months or a maximum of 1 year (with a mean duration of 9 months) post randomization. Therefore CURE does not provide data on patients who were treated for greater than 1 year post ACS. The benefits of clopidogrel were observed early, i.e. within the first 30 days and from the period greater than 30 days after randomization to the end of follow up. There was incremental benefit in treating patients with clopidogrel longer than 30 days after randomization. Whether treating patients longer than 1 year would add further benefit was not within the objectives of the CURE Study. The decision to continue therapy longer than 1 year will be left to the discretion of individual clinicians. One reasonable approach might be to continue therapy in those patients who are considered moderate to high risk of having a future cardiovascular event.

Q. Should patients who have suffered an acute myocardial infarction be treated with clopidogrel long-term to prevent further cardiac events?

A. Patients with suspected myocardial infarction without ST segment elevation were eligible for the CURE Study and accounted for approximately 25% of the patients enrolled. There was a significant reduction in the primary outcome of CV death, MI or stroke with clopidogrel compared to placebo in this group of patients. The question of whether patients with acute myocardial infarction with ST segment elevation who are candidates for reperfusion therapy will benefit from clopidogrel was not an objective of the CURE trial. Other studies such as the CCS-2 Study will help clarify the role of clopidogrel in this group of patients.

Q. Why were the event rates so low such that the sample size had to be increased and what are the implications for generalisability of these results?

A. The Steering Committee took the decision to increase the sample size and tighten the inclusion criteria (all pts must have ECG evidence of ischemia and/or already elevated cardiac enzymes or markers (troponin) to at least 2x the upper limit of normal at inclusion) when the overall event rate at ~2,000 pts randomized was lower than expected. As we later learned, some of this was due to the treatment effect in the clopidogrel arm but the steering committee could not have known this at the time. As per the study protocol, the sample size calculations were based on overall event rates and were adjusted to project 1250-1500 events.

Q. What about total death and total MI + death?

A. We would not expect clopidogrel to have an effect on non-CV death. We did analyze non CV death and there was no difference.

Q. Is there a plan to do cost-effectiveness evaluations?

A. Yes

Q. Was there a differential effect in aspirin naive and aspirin treated patients?

A. The results were similar in both subsets. Clopidogrel benefitted those who were previously taking aspirin as well as those who were not on aspirin at the time of randomization.

Q. Was efficacy evaluated according to aspirin dose?

A. The results indicated a consistent benefit of clopidogrel whether or not people were on a low dose of aspirin, such as 80mg/day, on about 160mg/day, or on higher doses of 325mg/day. However, the absolute bleeding rates increased with increasing doses of aspirin, and therefore it may be prudent to use lower doses of aspirin with clopidogrel.

Q. Most studies show more benefit in high risk groups and less benefit in low risk groups. CURE seems to have about a 20% risk reduction in all groups. How do you explain this?

A. In fact, I don't think most of the pharmacological intervention studies show that benefits are greater in higher risk patients, at least in terms of relative risk reductions. The only acceptions are surgical interventions or PTCA. With surgical interventions we do know that in patients with left main disease, the benefit is greater than in those with 3 vessel disease, which in tern is greater in those with 1 and 2 vessel disease. Similarly, PTCA in acute MI or in unstable angina, provides greatest relative risk reductions in the high risk patients. However, for pharmacological therapies, including anti-platelet therapies, anti-coagulant etc., the relative risk reductions appears to be the same across most risk groups. However, the absolute benefit will therefore be larger in the high risk subgroups. Similar results are observed in CURE with clopidogrel.

Q. How will CURE impact on management of ACS in a) the pre-hospital setting, and, b) the emergency room?

A. CURE indicates that clopidogrel should certainly be started as early as possible when patients present to hospital. We did not evaluate it in the pre-hospital setting, but given how easy it is to use, and it's relative safety, I would recommend that in patients with unstable angina, future studies should evaluate it's role in the pre-hospital setting. Perhaps even studies of acute myocardial infarction may wish to evaluate it in the pre-hospital setting.




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