This Article Figures Only Full Text Full Text (PDF) View Online Appendix View CVN Interview View Cardiosource Slide Set Correction (v50,p2196) All Versions of this Article: j.jacc.2007.07.053v1 50/19/1844    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (65) Citing Articles via Google Scholar Google Scholar Articles by Cannon, C. P. Search for Related Content PubMed Articles by Cannon, C. P.

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^,1, Robert A. Harrington, MD, FACC^,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
Århus University Hospital, Århus, Denmark
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

This article has been cited by other articles:

				L. Wallentin, R. C. Becker, A. Budaj, C. P. Cannon, H. Emanuelsson, C. Held, J. Horrow, S. Husted, S. James, H. Katus, et al. Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes N. Engl. J. Med., September 10, 2009; 361(11): 1045 - 1057. [Abstract] [Full Text] [PDF]

				M. P. Bonaca, P. G. Steg, L. J. Feldman, J. F. Canales, J. J. Ferguson, L. Wallentin, R. M. Califf, R. A. Harrington, and R. P. Giugliano Antithrombotics in acute coronary syndromes. J. Am. Coll. Cardiol., September 8, 2009; 54(11): 969 - 984. [Abstract] [Full Text] [PDF]

				D. R. Holmes Jr, D. J. Kereiakes, N. S. Kleiman, D. J. Moliterno, G. Patti, and C. L. Grines Combining Antiplatelet and Anticoagulant Therapies. J. Am. Coll. Cardiol., July 7, 2009; 54(2): 95 - 109. [Abstract] [Full Text] [PDF]

				S. Subherwal, R. G. Bach, A. Y. Chen, B. F. Gage, S. V. Rao, L. K. Newby, T. Y. Wang, W. B. Gibler, E. M. Ohman, M. T. Roe, et al. Baseline Risk of Major Bleeding in Non-ST-Segment-Elevation Myocardial Infarction: The CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) Bleeding Score Circulation, April 14, 2009; 119(14): 1873 - 1882. [Abstract] [Full Text] [PDF]

				M. S. SABATINE Novel antiplatelet strategies in acute coronary syndromes Cleveland Clinic Journal of Medicine, April 1, 2009; 76(Suppl_1): S8 - S15. [Abstract] [Full Text] [PDF]

				S. S. Smyth, D. S. Woulfe, J. I. Weitz, C. Gachet, P. B. Conley, S. G. Goodman, M. T. Roe, A. Kuliopulos, D. J. Moliterno, P. A. French, et al. G-Protein-Coupled Receptors as Signaling Targets for Antiplatelet Therapy Arterioscler Thromb Vasc Biol, April 1, 2009; 29(4): 449 - 457. [Abstract] [Full Text] [PDF]

				M. Cohen Expanding the Recognition and Assessment of Bleeding Events Associated With Antiplatelet Therapy in Primary Care Mayo Clin. Proc., February 1, 2009; 84(2): 149 - 160. [Abstract] [Full Text] [PDF]

				A. Colombo and R. T. Gerber Should dual antiplatelet therapy after drug-eluting stents be continued for more than 1 year?: Dual Antiplatelet Therapy After Drug-Eluting Stents Should Not Be Continued for More Than 1 Year and Preferably Indefinitely Circ Cardiovasc Interv, December 1, 2008; 1(3): 226 - 232. [Full Text] [PDF]

				G. De Luca Adjunctive antithrombotic therapy during primary percutaneous coronary intervention Eur. Heart J. Suppl., December 1, 2008; 10(suppl_J): J2 - J14. [Abstract] [Full Text] [PDF]

				M. Cattaneo Advances in antiplatelet therapy: overview of new P2Y12 receptor antagonists in development Eur. Heart J. Suppl., November 1, 2008; 10(suppl_I): I33 - I37. [Abstract] [Full Text] [PDF]

				R. P. Giugliano and E. Braunwald The Year in Non-ST-Segment Elevation Acute Coronary Syndrome J. Am. Coll. Cardiol., September 23, 2008; 52(13): 1095 - 1103. [Full Text] [PDF]

				L. T. Newsome, R. S. Weller, J. C. Gerancher, M. A. Kutcher, and R. L. Royster Coronary Artery Stents: II. Perioperative Considerations and Management Anesth. Analg., August 1, 2008; 107(2): 570 - 590. [Abstract] [Full Text] [PDF]

				M. J. Price New antiplatelet therapies in development Am. J. Health Syst. Pharm., July 1, 2008; 65(13_Supplement_5): S11 - S15. [Abstract] [Full Text] [PDF]

				R. F. Storey New developments in antiplatelet therapy Eur. Heart J. Suppl., May 1, 2008; 10(suppl_D): D30 - D37. [Abstract] [Full Text] [PDF]

				J.J.J. van Giezen Optimizing platelet inhibition Eur. Heart J. Suppl., May 1, 2008; 10(suppl_D): D23 - D29. [Abstract] [Full Text] [PDF]

				D. J. Kereiakes and P. A. Gurbel Peri-Procedural Platelet Function and Platelet Inhibition in Percutaneous Coronary Intervention J. Am. Coll. Cardiol. Intv., April 1, 2008; 1(2): 111 - 121. [Abstract] [Full Text] [PDF]

				A. N. DeMaria, J. J. Bax, O. Ben-Yehuda, P. Clopton, G. K. Feld, G. S. Ginsburg, B. H. Greenberg, J. D. Knoke, W. Y.W. Lew, J. A.C. Lima, et al. Highlights of the year in JACC 2007. J. Am. Coll. Cardiol., January 29, 2008; 51(4): 490 - 512. [Full Text] [PDF]

				R. F. Storey Variability of response to antiplatelet therapy Eur. Heart J. Suppl., January 1, 2008; 10(suppl_A): A21 - A27. [Abstract] [Full Text] [PDF]

				R. F. Storey, S. Husted, R. A. Harrington, S. Heptinstall, R. G. Wilcox, G. Peters, M. Wickens, H. Emanuelsson, P. Gurbel, P. Grande, et al. Inhibition of Platelet Aggregation by AZD6140, A Reversible Oral P2Y12 Receptor Antagonist, Compared With Clopidogrel in Patients With Acute Coronary Syndromes J. Am. Coll. Cardiol., November 6, 2007; 50(19): 1852 - 1856. [Abstract] [Full Text] [PDF]