Medication reduces risk of heart attack and cardiovascular death before and after angioplasty

September 04, 2005

Use of the antiplatelet drug clopidogrel before a coronary angioplasty reduced the risk of cardiovascular death, heart attack or stroke within 30 days following the procedure, according to an article in the September 14 issue of JAMA.

Dual antiplatelet therapy following percutaneous coronary intervention (PCI; procedures such as angioplasty in which a catheter-guided balloon is used to open a narrowed coronary artery, often accompanied by placement of a stent in the artery), using a combination of a drugs such as ticlopidine or clopidogrel along with aspirin, helps reduce platelet activation and thrombotic and ischemic complications, according to background information in the article. However, the optimal timing of the initiation of clopidogrel has been debated. The benefit of clopidogrel pretreatment started hours to days before PCI compared with treatment given at the time of PCI in high-risk patients with acute coronary syndromes remains incompletely defined, and current guidelines do not universally recommend pretreatment.

Marc S. Sabatine, M.D., M.P.H., of Brigham and Women's Hospital and Harvard Medical School, Boston, and colleagues conducted a study to determine if clopidogrel pretreatment hours to days before PCI is superior to clopidogrel treatment initiated at the time of PCI in preventing major adverse cardiovascular events in patients undergoing PCI after initial pharmacological therapy for ST-segment elevation myocardial infarction (STEMI; a severe heart attack with specific type of findings on an electrocardiogram).

The PCI-Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY) study included an analysis of 1,863 patients undergoing PCI after mandated angiography in CLARITY-Thrombolysis in Myocardial Infarction (TIMI) 28, a randomized, double-blind, clinical trial of clopidogrel vs. placebo in patients receiving fibrinolytics (medication for dissolving blood clots) for STEMI. Patients were enrolled at 319 sites in 23 countries from February 2003 through October 2004. Patients received aspirin and were randomized to receive either clopidogrel (300 mg loading dose [a comparatively large dose given at the beginning of treatment to start getting the effect of a drug more quickly], then 75 mg once daily) or placebo initiated with fibrinolysis and given until coronary angiography, which was performed 2 to 8 days after initiation of the 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 PCI, the study medication (clopidogrel or placebo) that patients were randomized to when they first presented to the hospital became the pretreatment before their PCI.

The researchers found that pretreatment with clopidogrel significantly reduced by 46 percent the odds of cardiovascular death, heart attack, or stroke following PCI (34 events [3.6 percent] vs. 58 events [6.2 percent]. Pretreatment with clopidogrel also reduced the odds by 38 percent of heart attack or stroke prior to PCI (37 [4.0 percent] vs. 58 [6.2 percent]. Overall, pretreatment with clopidogrel resulted in a 41 percent reduction in the odds of cardiovascular death, heart attack, or stroke from randomization through 30 days (70 [7.5 percent] vs. 112 [12.0 percent].There was no significant excess in the rates of TIMI 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 [MIs; heart attacks] 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 write.

"The significant reduction in adverse cardiovascular events before PCI suggests that a strategy of clopidogrel pretreatment should be initiated as soon as possible. Accordingly, even if clopidogrel is not given at presentation, once the decision is made to proceed with angiography, and hence possible PCI, initiation of pretreatment will maximize the benefit," the researchers write.
-end-
(JAMA. 2005; 294:1224-1232. Available pre-embargo to the media at www.jamamedia.org.)

Editor's Note: The parent trial, CLARITY-TIMI 28, was supported by the pharmaceutical partnership of Sanofi-Aventis and Bristol-Myers Squibb. Dr. Sabatine is the recipient of a grant from the National Heart, Lung, and Blood Institute. For financial disclosures of the authors, please see the JAMA article.

Editorial: Clopidogrel for Percutaneous Coronary Revascularization - Time for More Pretreatment, Retreatment, or Both?

In an accompanying editorial, David J. Moliterno, M.D., and Steven R. Steinhubl, M.D., of the University of Kentucky, Lexington, comment on the findings by Sabatine et al.

"... 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 ìmol/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 (i.e., repeat loading dose) at the time of PCI," they conclude.

(JAMA. 2005; 294:1271-1273. Available pre-embargo to the media at www.jamamedia.org.)

Editor's Note: Dr. Moliterno has received past honoraria for speaking for Sanofi-Synthelabo Inc. and Bristol-Meyers Squibb. Dr. Steinhubl has served as a consultant for Sanofi-Aventis, The Medicines Company, and AstraZeneca.

The JAMA Network Journals

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