Use of clopidogrel before coronary angioplasty significantly reduces 30-day risk of cardiovascular mortality as well as morbidity from myocardial infarction and stroke, according to a presentation made at the 2005 European Society of Cardiology meeting and published online simultaneously by the Journal of the American Medical Association.

Although the value of antiplatelet therapy following percutaneous coronary intervention has been established, the optimal timing of initiation of clopidogrel has been debated. The benefit of clopidogrel pretreatment started hours to days before procedures compared with treatment given at the time of the procedure in high-risk patients with acute coronary syndromes remains incompletely defined, and current guidelines do not universally recommend pretreatment.

Marc S. Sabatine, MD, MPH, of Brigham and Women's Hospital and Harvard Medical School, Boston, and his American colleagues conducted a study to determine if clopidogrel pretreatment that was started hours to days before angioplasty was superior to clopidogrel initiated at the time of the procedure.

Outcome measures were prevention of major adverse cardiovascular events in patients undergoing angioplasty after initial pharmacological therapy for ST-segment elevation myocardial infarction (ST-elevation MI).

The Percutaneous Coronary Intervention-Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY) study included an analysis of 1,863 patients undergoing angioplasty after mandated angiography in the CLARITY-Thrombolysis in Myocardial Infarction (TIMI) 28 trial, a randomized, double-blind, clinical trial of clopidogrel versus placebo in patients receiving fibrinolytics for ST-elevation MI.
Patients were enrolled at 319 sites in 23 countries from February 2003 through October 2004. Patients received aspirin and were randomized to clopidogrel (300 mg loading dose followed by 75 mg once daily) or placebo initiated with fibrinolysis and given until coronary angiography, which was performed 2 to 8 days after initiation of study drug.

For patients undergoing coronary artery stenting, it was recommended that open-label clopidogrel (including a loading dose) be administered after the diagnostic angiogram. Thus, for patients who ultimately underwent angioplasty, the study medication (clopidogrel or placebo) to which patients were randomized when they first presented to the hospital became their pretreatment drug.

Pretreatment with clopidogrel caused a 46-percent reduction in the 30-day risk of cardiovascular death, myocardial infarction, or stroke (34 events [3.6 percent] vs. 58 events [6.2 percent]. Pretreatment with clopidogrel also caused a 38-percent reduction of pre-procedure myocardial infarction or stroke (37 [4.0 percent] vs. 58 [6.2 percent].

Overall, pretreatment with clopidogrel resulted in a 41-percent reduction in the 30-day risk of cardiovascular death, myocardial infarction, or stroke starting from time of randomization (70 [7.5 percent] vs. 112 [12.0 percent]. There was no significant excess in the rates of TIMI-associated major or minor bleeding (18 [2.0 percent] vs. 17 [1.9 percent].

"In terms of implications of PCI-CLARITY for clinical practice, for every 100 patients undergoing PCI in whom a strategy of clopidogrel pretreatment is adopted, approximately 2 myocardial infarctions would be prevented before PCI and an additional 2 cardiovascular deaths, MIs, or strokes would be prevented after PCI to 30 days. Overall, only 23 patients would need to be pretreated with clopidogrel to prevent 1 cardiovascular death, MI, or stroke. This benefit with pretreatment is achieved when compared with the current practice in which patients receive a loading dose of clopidogrel at the time of PCI and a maintenance dose thereafter. Thus in 100 patients, 4 major cardiovascular events can be avoided simply by the use of 1 to 3 doses of clopidogrel before PCI," the authors wrote.

In an accompanying editorial, David J. Moliterno, MD, and Steven R. Steinhubl, MD, of the University of Kentucky, Lexington, commented on the findings:

"... like any study, PCI-CLARITY has limitations, particularly since PCI was not randomized. The trial excluded many patient groups known to be at particularly high risk for death, reinfarction, or major bleeding events such as patients older than 75 years, those with prior coronary artery bypass graft surgery, prior intracranial hemorrhage or non-hemorrhagic stroke, or with a creatinine level higher than 2.5 mg/dL (221 μmol/L). While the investigators carefully performed propensity analysis to correct for selection bias for undergoing PCI, it is possible that residual confounding factors were present. For example, undiscerned factors may exist that explain why patients receiving a GpIIb/IIIa inhibitor [an antiplatelet drug] had event rates higher than patients not receiving GpIIb/IIIa inhibitors or why one fourth of patients did not receive open-label clopidogrel loading at the time of PCI."

"Despite these limitations, PCI-CLARITY provides important data, and application of the study findings seems straightforward-patients receiving thrombolytic therapy for STEMI should also receive a 300-mg loading dose of clopidogrel followed by 75 mg daily. Additionally, clinicians should consider giving 600 mg of clopidogrel as a loading dose, even though this approach has not been formally tested with thrombolytic therapy. So far, no safety concerns have emerged with 600- or 900-mg loading doses. Finally, all patients not receiving a loading dose within several days of angiography should be considered for clopidogrel retreatment (repeat loading dose) at the time of PCI," they concluded.