Trial DesignThe SYNERGY trial: Study design and rationale☆,☆☆,★,★★
Section snippets
Study objectives
This prospective, randomized, open-label, multicenter trial will evaluate the efficacy and safety of enoxaparin versus UFH when administered with established therapy, including GP IIb/IIIa inhibitors and aspirin in patients at high risk who present with unstable angina or non-ST-segment elevation myocardial infarction (NSTEMI) and are to be managed with an early invasive treatment strategy (Figure 1).
Enoxaparin and unfractionated heparin
Enoxaparin or UFH will be given immediately after enrollment according to the randomly assigned treatment. Treatment will continue until the patient requires no further anticoagulation and will continue at least through angiography and PCI, if performed.
Intravenous UFH will be given according to a weight-adjusted nomogram (bolus of 60 U/kg and initial infusion of 12 U/kg/h).5 Enoxaparin will be given subcutaneously at a dose of 1 mg/kg every 12 hours. Many physicians have concerns regarding the
Aspirin/clopidogrel
Aspirin should be administered to all patients at enrollment and then daily at a dose of 162 mg to 325 mg. For patients with an allergy or contraindication to aspirin, clopidogrel (75 mg) should be given at enrollment, then 75 mg/day. The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial26 results were not available before completion of the study protocol. The decision to implement dual antiplatelet therapy in initial medical treatment will be left to physician discretion.
GP IIb/IIIa inhibitors
Study procedures and follow-up
A detailed study flow sheet is shown in Appendix B, and a study time line is shown in Figure 2.Clinical events, procedures, adverse events, and concomitant medications will be collected during the baseline hospitalization and for patients with rehospitalization during the first 30 days after enrollment. For 30-day follow-up, the patient will visit the clinic. Contact will also be made at 180 days after enrollment for collection of key cardiac events, and at 1 year to determine
Sample size justification
The goal is to enroll patients at high risk with a planned early (during baseline hospitalization) invasive treatment strategy. Death and/or MI rates at 30 days have varied in recent ACS trials (Table IIIA) because of differences in patient populations, MI definitions, type of clinical event adjudication, and quantity of cardiac marker data collection.Empty Cell PURSUIT3(%) PRISM Plus18(%) PRISM29(%) PARAGON B8(%) GUSTO IV ACS30(%) Death/MI 15.0 10.3
Steering and executive committees
The Steering Committee (see Appendix C for list of members) is composed of 2 chairs and members from the academic and clinical communities and the sponsor. The Committee will provide scientific direction and input, address policy issues regarding the protocol, and will meet periodically to assess the trial's progress.
The Executive Committee will represent a subset of senior leaders from the Steering Committee, including a representative from the sponsor. The Executive Committee will be
Discussion
Over the past decade, advances in the understanding of the pathophysiology of the acute coronary syndromes have been realized. In addition, multiple large clinical trials have demonstrated the benefits of new therapies in this patient population, including the role of GP IIb/IIIa inhibition30 and aggressive invasive treatment strategies.3, 4 Despite these advances, patients with ACS continue to have substantial morbidity and mortality.
The SYNERGY trial is the largest trial planned for the acute
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Trends in clinical trials of non-ST-segment elevation acute coronary syndromes over 15 years
2013, International Journal of CardiologyPrognostic significance of bleeding location and severity among patients with acute coronary syndromes
2013, JACC: Cardiovascular InterventionsComparison of the prognosis of spontaneous and percutaneous coronary intervention-related myocardial infarction
2012, Journal of the American College of CardiologyCitation Excerpt :Patients enrolled in the EARLY-ACS (Early Glycoprotein IIb/IIIa Inhibition in Non–ST-Segment Elevation Acute Coronary Syndrome) trial and the SYNERGY (Superior Yield of the New strategy of Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa inhibitors) trial (n = 19,433) were considered for analysis (11–14).
Standardized endpoint definitions for transcatheter aortic valve implantation clinical trials: A consensus report from the valve academic research consortium
2011, Journal of the American College of CardiologyCitation Excerpt :Bleeding is a critical safety endpoint in evaluating contemporary pharmacological agents and interventional devices (36–44). Valve Academic Research Consortium carefully reviewed several literature sources including: 1) landmark clinical trials assessing the effects of anti-thrombotic medications in stable and acute coronary syndromes (45–59); 2) a report by the Control of Anticoagulation Subcommittee of the International Society on Thrombosis and Haemostasis (60); and 3) surgery guidelines after cardiac valve procedures (12). The definition of clinically meaningful bleeding was guided by the following principles: 1) the definition must be based on objective criteria, including an obvious source of bleeding or number of transfusions; 2) serious or meaningful bleeding must result in death, be life-threatening, be proven to be associated with increased long-term mortality, cause chronic sequellae, or consume major health-care resources.
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Supported by AVENTIS Pharmaceutical Products, Inc, Bridgewater, NJ.
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Guest Editor for this manuscript was David A. Vorchheimer, MD, Mount Sinai Medical Center, New York, NY.
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Reprint requests: Kenneth W. Mahaffey, MD, Assistant Professor of Medicine, PO Box 17969, Duke Clinical Research Institute, Durham, NC 27715.
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E-mail: [email protected]