Higher loading doses of clopidogrel — such as 600 mg or 900 mg — may be optimal, but trial results are needed.
Despite uncertainty regarding the appropriate dosage level, the ACC and AHA guidelines for treatment of ACS patients with clopidogrel are “on target” and generally support upstream use of the drug, according to Peter Berger, MD, associate chief research officer for clinical studies at the Geisinger Clinic
in Danville, Pa. Berger reviewed and discussed the guidelines regarding treatment with clopidogrel for ACS patients before and after PCI.

“A policy of nearly routine administration of clopidogrel benefits more patients than it harms,” Berger said. Routine administration of clopidogrel in ACS patients may also be associated with reduced overall costs, he said.

Berger cited several trials examining clopidogrel treatment, including the CURE trial, which examined
treatment with aspirin plus placebo or clopidogrel in patients with ACS. Patients treated with aspirin plus clopidogrel had lower rates of CV death, MI, and stroke.

Guidelines updated

The ACC/AHA guidelines for the use of clopidogrel in non-ST-elevation MI patients undergoing PCI were updated earlier this year.

In 2005, the ACC/AHA guidelines stated that a loading dose of 300 mg of clopidogrel administered at least 6 hours before the procedure had the highest level of evidence of efficacy.

The ACC/AHA’s updated guidelines this year state that uncertainty exists about optimum dosing of
clopidogrel. According to Berger, the new guidelines indicate that higher loading doses of clopidogrel — such as 600 mg or 900 mg — achieve more rapid and a higher absolute level of inhibition of aggregation. But the efficacy and safety of these doses have not been rigorously established,Berger said.

Nevertheless, the new guidelines recommend that “a loading dose of clopidogrel should be administered
before PCI is performed.”

The guidelines also state that when high-risk ACS patients are admitted, they should be treated
with aspirin, a beta-blocker, an anticoagulant, a GP IIb/IIIa inhibitor, and clopidogrel. Clopidogrel may
be deferred until a revascularization decision is made.

“The longer the interval between presentation and angiography, the greater the incremental benefit of upstream antiplatelet therapy,” Berger said. “However, clopidogrel treatment should be discontinued 5 to 7 days before elective CABG.”

Loading dose

Berger said some controversy remains about the appropriate loading dose of clopidogrel.

According to Berger, both the CREDO and the CLASSICS trials proved that a 300-mg dose of clopidogrel
at the time of PCI was not more effective than a 75-mg dose. The ARMYDA trial found that a 600-mg
dose of clopidogrel outperformed a 300-mg dose when given 4 to 8 hours
prior to PCI.

“A 600-mg dose inhibits aggregation more rapidly and with less variability,” Berger said. “A 600-
mg dose has been administered to thousands of patients in trials and practice; this dose appears safe and
well-tolerated.”

Berger said that until the results of the OASIS 7 trial are known, he recommends the 600-mg dose. OASIS 7 is an ongoing study examining the optimal dose for clopidogrel treatment.

For some high-risk patients – those with vascular disease, valvular disease, left main lesions, cerebrovascular disease, longstanding diabetes, and chronic kidney disease – upstream clopidogrel treatment may not be optimal, Berger said.