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Washington, DC - Administration of clopidogrel before elective PCI, on top of standard aspirin therapy, can help prevent thrombotic complications over the course of the following monthbut only if the pretreatment lasts for at least 6 hours, suggests a randomized study.
No single recommended clopidogrel pretreatment time is used at elective PCI, a common practice that is based on retrospective and observational studies, according to Dr Steven R Steinhubl (University of North Carolina, Chapel Hill). The 28-day results of the Clopidogrel for Reduction of Events During Observation (CREDO) trial, which he presented here at the annual Transcatheter Cardiovascular Therapeutics meeting, suggest that the timing of pretreatment makes a difference. CREDO, he said, is the first randomized trial to show this. "If you use a 300-mg [clopidogrel] loading dose, to receive its full effect [its administration] must be greater than 6 hours before the intervention."
The CREDO findings build on those of PCI-CURE, a prospective substudy of the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial.1 In CURE, which randomized 12562 patients with ACS to receive long-term clopidogrel or placebo with aspirin, active therapy was associated with an 18.4% drop in the composite 1-year rate of cardiovascular death, nonfatal MI, or stroke (p<0.001). PCI-CURE consisted of the 2658 CURE patients who underwent PCI at the physicians' discretion. Those who received clopidogrel before PCI showed a 36% lower rate of cardiovascular death, MI, or urgent target vessel revascularization (TVR).
PCI-CURE, said Steinhubl, confirmed the benefit of clopidogrel pretreatment in an ACS population without defining the optimal pretreatment time. Pretreatment lasted a median of 10 days in PCI-CURE, which was conducted mostly outside the US, where early invasive therapy is common for patients presenting with ACS. "The 28-day results of CREDO are consistent with those of PCI-CURE and expand those findings to a much more stable population."
An effective pretreatment duration defined
In CREDO, 2116 patients were randomized to receive a 300-mg clopidogrel bolus or placebo on top of 325-mg aspirin, 3 to 24 hours before intervention (median 9 hours). This 1-month CREDO analysis excludes the 15% of patients who went on to bypass surgery or medical therapy instead of PCI.
At PCI, all patients started on 75-mg clopidogrel and 325-mg aspirin daily for 28 days. Physicians were allowed at randomization to prespecify the use of GP IIb/IIIa inhibitors, usually abciximab, in up to 20% of patients; the IIb/IIIa inhibitors could also be used in anyone for bailout as necessary.
Patients who received active pretreatment continued in a blinded fashion on 75-mg clopidogrel plus aspirin out to 1 year, while the other group discontinued clopidogrel but were maintained on aspirin, for a total treatment time of 1 year.
Overall, clopidogrel-pretreated patients showed a nonsignificant 18.5% relative reduction in the primary end point. Nor was there a significant outcome difference among those pretreated <6 hours. But those who were pretreated beyond 6 hours, said Steinhubl, "achieved a nearly 40% reduction in the end point of death, MI, or urgent target vessel revascularization."
Clopidogrel pretreatment benefited only when it lasted more than 6 hours|
28-day death, MI, or urgent TVR (%) |
Actively pretreated group (n=903) |
No pretreatment (n=917) |
RR* reduction |
p |
| Overall | 6.8 | 8.3 | 18.5 | 0.23 |
| <6 hours pretreatment | 7.9 | 7.0 | -13.4 | 0.56 |
| 6-24 hours pretreatment | 5.8 | 9.4 | 38.6 | 0.05 |
GP IIb/IIIa inhibition with clopidogrel pretreatment?
It has been unclear "whether there is benefit or potentially even harm to adding a GP IIb/IIIa receptor antagonist on top of a clopidogrel loading dose," said Steinhubl in an interview with heartwire. "I think the the results show absolutely that there is an added benefit."
Patients who didn't receive GP IIb/IIIa inhibitors were, appropriately, "very low risk with a low event rate and showed a minimal trend toward benefit with the addition of the clopidogrel loading dose," said Steinhubl. But those who received GP IIb/IIIa inhibitors benefited with "a very consistent and very strong relative reduction in clinical events, regardless of whether [they were given] as bailout or were prespecified." The combination proved safe, as well: together the antithrombotics did not significantly influence the rate of major bleeding events.
The trial's 1-year results, which will be based on intention-to-treat, are slated for presentation at the American Heart Association scientific sessions this November, according to Steinhubl. "The most crucial question we have yet to answer is whether the long-term risk of thrombotic events...following percutaneous intervention can be safely diminished by maintaining combination therapy with clopidogrel and aspirin."
