Trial Design
The SYNERGY trial: Study design and rationale,☆☆,,★★

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Abstract

Background Enoxaparin was shown to be superior to unfractionated heparin in the patients with non-ST-segment elevation acute coronary syndromes (ACS) in the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events study and the Thrombolysis In Myocardial Infarction (TIMI) 11B trial. However, enoxaparin has had limited acceptance in clinical practice, in part because of the contemporary management of these patients, which includes glycoprotein IIb/IIIa inhibition and the use of early invasive management strategies. Study Design The Superior Yield of the New strategy of Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa inhibitors (SYNERGY) trial is an 8000-patient, prospective, randomized, open-label, multicenter investigation of enoxaparin compared with unfractionated heparin in patients at high risk with non-ST-segment elevation ACS treated with an early invasive strategy. The primary efficacy end point is death or nonfatal myocardial infarction 30 days after enrollment. Implications The SYNERGY trial is the largest study currently planned for the acute therapy of patients with non-ST-segment elevation ACS and the first large trial since the publication of the revised American College of Cardiology/American Heart Association guidelines for the management of these patients. In addition to evaluating the potential superiority of enoxaparin over unfractionated heparin, this investigation will provide important observations of current treatment strategies in patients with ACS. (Am Heart J 2002;143:952-60.)

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).

. Trial design.

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.

. Patient follow-up.

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.

Table IIIA. Overall 30-day death/MI rates in recent ACS trials

Empty CellPURSUIT3(%)PRISM Plus18(%)PRISM29(%)PARAGON B8(%)GUSTO IV ACS30(%)
Death/MI15.010.3

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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    Supported by AVENTIS Pharmaceutical Products, Inc, Bridgewater, NJ.

    ☆☆

    Guest Editor for this manuscript was David A. Vorchheimer, MD, Mount Sinai Medical Center, New York, NY.

    Reprint requests: Kenneth W. Mahaffey, MD, Assistant Professor of Medicine, PO Box 17969, Duke Clinical Research Institute, Durham, NC 27715.

    ★★

    E-mail: [email protected]

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