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CLINICAL RESEARCH: CLINICAL TRIAL

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^_*,1,_*, Steen Husted, MD^,1, Robert A. Harrington, MD, FACC^,1, Stanley Heptinstall, PhD^,1, Robert G. Wilcox, MD^,1, Gary Peters, MD^||,2, Mark Wickens, BSc^¶,2, Håkan Emanuelsson, MD, PhD^#,2, Paul Gurbel, MD, FACC^_**,1, Peer Grande, MD and Christopher P. Cannon, MD, FACC^,1

^_* Cardiovascular Research Unit, University of Sheffield, Sheffield, United Kingdom
Department of Medicine and Cardiology, Århus University Hospital, Århus, Denmark
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
Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
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.

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

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