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J Am Coll Cardiol, 2007; 50:1844-1851, doi:10.1016/j.jacc.2007.07.053 (Published online 22 October 2007).
© 2007 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: CLINICAL TRIAL

Safety, Tolerability, and Initial Efficacy of AZD6140, the First Reversible Oral Adenosine Diphosphate Receptor Antagonist, Compared With Clopidogrel, in Patients With Non–ST-Segment Elevation Acute Coronary Syndrome

Primary Results of the DISPERSE-2 Trial

Christopher P. Cannon, MD, FACC*,*, Steen Husted, MD{dagger},1, Robert A. Harrington, MD, FACC{ddagger},2, Benjamin M. Scirica, MD*, Håkan Emanuelsson, MD, PhD§,3, Gary Peters, MD||,4, Robert F. Storey, MD,5 for the DISPERSE-2 Investigators

* TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
{dagger} Århus University Hospital, Århus, Denmark
{ddagger} Duke Clinical Research Institute, Durham, North Carolina
§ AstraZeneca, Mölndal, Sweden
|| AstraZeneca, Wilmington, Delaware
University of Sheffield, Sheffield, United Kingdom.

Manuscript received May 18, 2007; revised manuscript received July 27, 2007, accepted July 30, 2007.

* Reprint requests and correspondence: Dr. Christopher P. Cannon, TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115. (Email: cpcannon{at}partners.org).

Objectives: Our goal was to compare the safety and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, with clopidogrel in patients with non–ST-segment elevation acute coronary syndromes (NSTE-ACS).

Background: AZD6140 achieves higher mean levels of platelet inhibition than clopidogrel in patients with stable coronary artery disease.

Methods: A total of 990 patients with NSTE-ACS, treated with aspirin and standard therapy for ACS, were randomized in a 1:1:1 double-blind fashion to receive either twice-daily AZD6140 90 mg, AZD6140 180 mg, or clopidogrel 300-mg loading dose plus 75 mg once daily for up to 12 weeks.

Results: The primary end point, the Kaplan-Meier rate of major or minor bleeding through 4 weeks, was 8.1% in the clopidogrel group, 9.8% in the AZD6140 90-mg group, and 8.0% in the AZD6140 180-mg group (p = 0.43 and p = 0.96, respectively, vs. clopidogrel); the major bleeding rates were 6.9%, 7.1%, and 5.1%, respectively (p = 0.91 and p = 0.35, respectively, vs. clopidogrel). Although not statistically significant, favorable trends were seen in the Kaplan-Meier rates of myocardial infarction (MI) over the entire study period (MI: 5.6%, 3.8%, and 2.5%, respectively; p = 0.41 and p = 0.06, respectively, vs. clopidogrel). In a post-hoc analysis of continuous electrocardiograms, mostly asymptomatic ventricular pauses >2.5 s were more common, especially in the AZD6140 180-mg group (4.3%, 5.5%, and 9.9%, respectively; p = 0.58 and p = 0.01, respectively, vs. clopidogrel).

Conclusions: This initial experience with AZD6140 in patients with ACS showed no difference in major bleeding but an increase in minor bleeding at the higher dose with encouraging results on the secondary end point of MI. This agent is currently being studied in a large outcomes trial in 18,000 patients with ACS.

Abbreviations and Acronyms
  ACS = acute coronary syndromes
  ADP = adenosine diphosphate
  CABG = coronary artery bypass grafting
  CI = confidence interval
  IQR = interquartile range
  NSTE-ACS = non–ST-segment acute coronary syndromes
  PCI = percutaneous coronary intervention




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