Medication Reduces Risk Of Heart Attack And Cardiovascular Death Before And After Angioplasty

Dual antiplatelet therapy following percutaneous coronary intervention(PCI; procedures such as angioplasty in which a catheter-guided balloonis used to open a narrowed coronary artery, often accompanied byplacement of a stent in the artery), using a combination of a drugssuch as ticlopidine or clopidogrel along with aspirin, helps reduceplatelet activation and thrombotic and ischemic complications,according to background information in the article. However, theoptimal timing of the initiation of clopidogrel has been debated. Thebenefit of clopidogrel pretreatment started hours to days before PCIcompared with treatment given at the time of PCI in high-risk patientswith acute coronary syndromes remains incompletely defined, and currentguidelines do not universally recommend pretreatment.

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

The PCI-Clopidogrel as Adjunctive Reperfusion Therapy(CLARITY) study included an analysis of 1,863 patients undergoing PCIafter mandated angiography in CLARITY-Thrombolysis in MyocardialInfarction (TIMI) 28, a randomized, double-blind, clinical trial ofclopidogrel vs. placebo in patients receiving fibrinolytics (medicationfor dissolving blood clots) for STEMI. Patients were enrolled at 319sites in 23 countries from February 2003 through October 2004. Patientsreceived aspirin and were randomized to receive either clopidogrel (300mg loading dose [a comparatively large dose given at the beginning oftreatment to start getting the effect of a drug more quickly], then 75mg once daily) or placebo initiated with fibrinolysis and given untilcoronary angiography, which was performed 2 to 8 days after initiationof the study drug. For patients undergoing coronary artery stenting, itwas recommended that open-label clopidogrel (including a loading dose)be administered after the diagnostic angiogram. Thus, for patients whoultimately underwent PCI, the study medication (clopidogrel or placebo)that patients were randomized to when they first presented to thehospital became the pretreatment before their PCI.

The researchers found that pretreatment with clopidogrelsignificantly reduced by 46 percent the odds of cardiovascular death,heart attack, or stroke following PCI (34 events [3.6 percent] vs. 58events [6.2 percent]. Pretreatment with clopidogrel also reduced theodds by 38 percent of heart attack or stroke prior to PCI (37 [4.0percent] vs. 58 [6.2 percent]. Overall, pretreatment with clopidogrelresulted in a 41 percent reduction in the odds of cardiovascular death,heart attack, or stroke from randomization through 30 days (70 [7.5percent] vs. 112 [12.0 percent].There was no significant excess in therates of TIMI major or minor bleeding (18 [2.0 percent] vs. 17 [1.9percent].

"In terms of implications of PCI-CLARITY for clinical practice,for every 100 patients undergoing PCI in whom a strategy of clopidogrelpretreatment is adopted, approximately 2 myocardial infarctions [MIs;heart attacks] would be prevented before PCI and an additional 2cardiovascular deaths, MIs, or strokes would be prevented after PCI to30 days. Overall, only 23 patients would need to be pretreated withclopidogrel to prevent 1 cardiovascular death, MI, or stroke. Thisbenefit with pretreatment is achieved when compared with the currentpractice in which patients receive a loading dose of clopidogrel at thetime of PCI and a maintenance dose thereafter. Thus in 100 patients, 4major cardiovascular events can be avoided simply by the use of 1 to 3doses of clopidogrel before PCI," the authors write.

"The significant reduction in adverse cardiovascular eventsbefore PCI suggests that a strategy of clopidogrel pretreatment shouldbe initiated as soon as possible. Accordingly, even if clopidogrel isnot given at presentation, once the decision is made to proceed withangiography, and hence possible PCI, initiation of pretreatment willmaximize the benefit," the researchers write.

(JAMA. 2005; 294:1224-1232. Available pre-embargo to the media at www.jamamedia.org.)

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