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J Am Coll Cardiol, 2007; 50:1852-1856, doi:10.1016/j.jacc.2007.07.058 (Published online 22 October 2007).
© 2007 by the American College of Cardiology Foundation
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CLINICAL RESEARCH

Inhibition of Platelet Aggregation by AZD6140, A Reversible Oral P2Y12 Receptor Antagonist, Compared With Clopidogrel in Patients With Acute Coronary Syndromes

Robert F. Storey, MD*,*, Steen Husted, MD{dagger}, Robert A. Harrington, MD, FACC{ddagger}, Stanley Heptinstall, PhD§, Robert G. Wilcox, MD§, Gary Peters, MD||, Mark Wickens, BSc, Håkan Emanuelsson, MD, PhD#, Paul Gurbel, MD, FACC**, Peer Grande, MD{dagger}{dagger} and Christopher P. Cannon, MD, FACC{ddagger}{ddagger}

* Cardiovascular Research Unit, University of Sheffield, Sheffield, United Kingdom
{dagger} Department of Medicine and Cardiology, Århus University Hospital, Århus, Denmark
{ddagger} Division of Cardiovascular Medicine, Duke Clinical Research Institute, Durham, North Carolina
§ Cardiovascular Medicine, University of Nottingham, Nottingham, United Kingdom
|| AstraZeneca R&D, Wilmington, Delaware
AstraZeneca R&D, Charnwood, United Kingdom
# AstraZeneca R&D, Mölndal, Sweden
** Sinai Center for Thrombosis Research, Baltimore, Maryland
{dagger}{dagger} Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
{ddagger}{ddagger} TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts

Manuscript received May 18, 2007; revised manuscript received July 19, 2007, accepted July 24, 2007.

* Reprint requests and correspondence: Dr. Robert F. Storey, Cardiovascular Research Unit, School of Medicine and Biomedical Sciences, Beech Hill Road, Sheffield S10 2RX, United Kingdom. (Email: r.f.storey{at}sheffield.ac.uk).

Objectives: In a substudy of DISPERSE (Dose confIrmation Study assessing anti-Platelet Effects of AZD6140 vs. clopidogRel in non–ST-segment Elevation myocardial infarction)-2, we compared the antiplatelet effects of AZD6140 and clopidogrel and assessed the effects of AZD6140 in clopidogrel-pretreated patients.

Background: Clopidogrel, in combination with aspirin, reduces cardiovascular events in patients with acute coronary syndromes (ACS). However, patients with poor inhibition of platelet aggregation with clopidogrel may be less well protected. AZD6140 is a reversible oral P2Y12 receptor antagonist that has been studied in ACS patients in comparison with clopidogrel (DISPERSE-2 study).

Methods: Patients were randomized to receive either AZD6140 90 mg twice a day, AZD6140 180 mg twice a day, or clopidogrel 75 mg once a day for up to 12 weeks in a double-blind, double-dummy design. One-half the patients allocated AZD6140 received a 270-mg loading dose. Patients randomized to receive clopidogrel were given a 300-mg loading dose unless they had already been treated with clopidogrel. Adenosine diphosphate-induced platelet aggregation was assessed by optical aggregometry on day 1 and at 4-week intervals.

Results: AZD6140 inhibited platelet aggregation in a dose-dependent fashion and both doses achieved greater levels of inhibition than clopidogrel (e.g., 4 weeks, 4-h postdose [mean (±SD)]: clopidogrel 64% [±22%], AZD6140 90 mg 79% [±22%], AZD6140 180 mg 95% [±8%]. AZD6140 also produced further suppression of platelet aggregation in patients previously treated with clopidogrel.

Conclusions: AZD6140 exhibited greater mean inhibition of platelet aggregation than a standard regimen of clopidogrel in ACS patients. In addition, AZD6140 further suppressed platelet aggregation in clopidogrel pretreated patients. (Substudy of DISPERSE-2; http://www.clinicaltrials.gov/ct/show/NCT00391872 [ClinicalTrials.gov] ; NCT00391872)

Abbreviations and Acronyms
  ACS = acute coronary syndromes
  ADP = adenosine diphosphate
  bid = twice-daily administration
  qd = once-daily administration




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