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CLINICAL RESEARCH: ACUTE MI AND ANTIPLATELET THERAPY

Role of Clopidogrel Loading Dose in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Angioplasty

Results From the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) Trial

George Dangas, MD, PhD^_*,,_*, Roxana Mehran, MD^_*,, Giulio Guagliumi, MD, Adriano Caixeta, MD, PhD^_*,, Bernhard Witzenbichler, MD, Jiro Aoki, MD, PhD^_*,, Jan Z. Peruga, MD^||, Bruce R. Brodie, MD^¶, Dariusz Dudek, MD^#, Ran Kornowski, MD^_**, LeRoy E. Rabbani, MD^_*, Helen Parise, ScD^_*,, Gregg W. Stone, MD^_*, for the HORIZONS-AMI Trial Investigators

^_* Columbia University Medical Center, New York, New York
Cardiovascular Research Foundation, New York, New York
Ospedali Riuniti di Bergamo, Bergamo, Italy
Charité Universitätsmedizin Campus Benjamin Franklin, Berlin, Germany
^|| Department of Cardiology Medical University in Lodz Bieganski Hospital, Lodz, Poland
^¶ LeBauer Cardiovascular Research Foundation and Moses Cone Hospital, Greensboro, North Carolina
^# Jagiellonian University, Krakow, Poland
^_** Rabin Medical Center, Petach Tikva, Israel

Manuscript received February 20, 2009; revised manuscript received May 19, 2009, accepted June 1, 2009.

^_* Reprint requests and correspondence: Dr. George Dangas, Onassis Heart Center, Athens, Greece, Columbia University Medical Center, Cardiovascular Research Foundation, 111 East 59th Street, 11th Floor, New York, New York 10022 (Email: gdangas{at}crf.org).

Objectives: Our aim was to determine whether a 600-mg loading dose of clopidogrel compared with 300 mg results in improved clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI).

Background: A 600-mg loading dose of clopidogrel compared with 300 mg provides more rapid and potent inhibition of platelet activation.

Methods: In the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial, 3,602 patients with STEMI undergoing primary PCI were randomized to bivalirudin (n = 1,800) or unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor (n = 1,802). Randomization was stratified by thienopyridine loading dose, which was determined before random assignment.

Results: Patients in the 600-mg (n = 2,158) compared with the 300-mg (n = 1,153) clopidogrel loading dose group had significantly lower 30-day unadjusted rates of mortality (1.9% vs. 3.1%, p = 0.03), reinfarction (1.3% vs. 2.3%, p = 0.02), and definite or probable stent thrombosis (1.7% vs. 2.8%, p = 0.04), without higher bleeding rates. Compared with unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor, bivalirudin monotherapy resulted in similar reductions in net adverse cardiac event rates within the 300-mg (15.2% vs. 12.3%) and 600-mg (10.4% vs. 7.3%) clopidogrel loading dose subgroups (p_interaction = 0.41). By multivariable analysis, a 600-mg clopidogrel loading dose was an independent predictor of lower rates of 30-day major adverse cardiac events (hazard ratio: 0.72 [95% confidence interval: 0.53 to 0.98], p = 0.04).

Conclusions: In patients with STEMI undergoing primary PCI with contemporary anticoagulation regimens, a 600-mg loading dose of clopidogrel may safely reduce 30-day ischemic adverse event rates compared with a 300-mg loading dose. (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction [HORIZONS-AMI]; NCT00433966 [ClinicalTrials.gov] )

Key Words: myocardial infarction • angioplasty • stent • anticoagulants

Abbreviations and Acronyms   ACS = acute coronary syndromes   CABG = coronary artery bypass grafting   GPI = glycoprotein IIb/IIIa inhibitor   MACE = major adverse cardiovascular events   MI = myocardial infarction   NACE = net adverse clinical events   PCI = percutaneous coronary intervention   STEMI = ST-segment elevation myocardial infarction   UFH = unfractionated heparin

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