Pre Treatment with 600 mg of Clopidogrel does not Improve Outcomes in Stable PCI Patients: PRAGUE-8

C. Michael Gibson, M.S., M.D. September 3rd 2007

Vienna, Austria: While multiple studies such as PCI-CURE, CREDO, EPISTENT, and ESPIRIT have demonstrated benefits without a risk of bleeding following a loading dose of Clopidogrel before planned PCI in ACS patients, the results of PRAGUE-8 suggest no benefit of 600 mg of clopidogrel when administered before diagnostic angiograpy vs at the time of the PCI in stable angina patients. Despite no benefit, there was actually a hazard of increased bleeding associated with pre-angiography clopidogrel loading.

Extension of Recommendation Regarding Clopidogrel Loading From ACS Patients to Stable Angina Patients: Is It Justified?
While the ESC guidelines recommend pre-angiography clopidogrel loading in both ACS and stable angina patients, lead investigator Petr Widimsky was concerned that there was little data to support pre-angiography administration of 600 mg of clopidogrel in stable angina patients, and thus undertook the PRAGUE-8 trial to evaluate this question.

PRAGUE-8 Design
PRAGEU-8 was an open-label study in which patients were randomized on the day prior to angiography to one of two strategies:
 * 1) Pre-angiography clopidogrel administration > 6 hours prior to elective angiography (600 mg; n = 513) or
 * 2) Delayed clopidogrel administration in the catheterization lab if needed for PCI (600 mg; n = 515).

PRAGUE-8 Results
Because clopidogrel was administered and randomization occurred before the anatomy was defined on angiography, PCI was not planned and was performed in only 29% of patients. 12% of patients underwent CABG (generally more than a week following angiography). A large proportion of patients, 59%, were managed medically. This is different than a US practice pattern where many more patients may have undergone PCI.

Efficacy Results
The primary endpoint was death, periprocedural MI, stroke, TIA, or reintervention within 7 days. When all patients were included in the analysis, there was no difference between the treatment groups (0.8% in each arm). When the analysis was restricted to patients who underwent PCI, again there were no differences between clopidogrel administration pre-angiography (1.3%) vs at the time of PCI (2.2%)(p = NS).

When the risk of myonecrosis was examined separately, there was no difference in the frequency of post-procedural troponin elevation of >3 times the upper limit of normal between the two strategies (2.7% in the pre-angio clopidogrel group vs 3.0% among those treated at the time of PCI, p = NS). When this analysis was restricted to PCI patients, there was again no difference (8.6% vs 11.1%, respectively, p = NS).

Bleeding Results
While no difference was observed in efficacy, bleeding events were more frequent in patients administered clopidogrel pre-angiography (3.5% vs. 1.2%, p = 0.02). When the analysis was restricted to patients undergoing PCI, the difference was even more striking: 7.2% vs. 0.7%, p = 0.006.

Conclusions
Among patients with stable angina who are about to undergo elective angiography (the decision has not yet been made to perform PCI) a routine strategy of an early loading dose of 600 mg of clopidogrel more than 6 hours before angiography does not reduce the risk of death, MI, stroke, TIA, or reintervention within 7 days when compared with a more conservative approach of administering clopidogrel after the anatomy has been defined immediately before PCI. A pre angiography loading strategy is associated with a greater risk of bleeding, particularly if the patient undergoes PCI.

These data suggests that there is no benefit to clopidogrel loading in patients with stable angina who are about to undergo diagnostic cardiac catheterization.