Superior Yield of the New strategy of Enoxaparin, Revascularization, and GlYcoprotein IIb/IIIa inhibitors - SYNERGY


The goal of the trial is to evaluate the safety and efficacy of enoxaparin compared with unfractionated heparin (UFH) in high-risk patients with non-ST-segment elevation acute coronary syndromes (ACSs) treated with an early invasive strategy.


Treatment with enoxaparin will be associated with a reduction in death or nonfatal myocardial infarction (MI) at 30 days compared with UFH in high-risk patients with non-ST-segment elevation ACS treated with an early invasive strategy.

The primary analysis is for superiority of enoxaparin over UFH. However, if enoxaparin is not superior to UFH, an analysis will be performed to determine whether enoxaparin is noninferior to UFH for death or nonfatal MI.

Study Design

Study Design:

Patients Enrolled: 10,027
Mean Follow Up: One year
Mean Patient Age: Median age 68 years
Female: 34

Patient Populations:

Age ≥18 years; ischemic pain at rest lasting ≥10 minutes and occurring within 24 hours before enrollment; and at least two of the following: electrocardiographic changes, age ≥60 years, and abnormal cardiac markers within 24 hours before enrollment


Known or suspected to be pregnant; allergic to pork or pork products; contraindications to UFH or low molecular weight heparin; or recent (<48 hours) or planned spinal or epidural anesthesia or puncture, PCI within the past 24 hours, or thrombolytic therapy within the preceding 24 hours; ischemic stroke within the last year or any previous hemorrhagic stroke, tumor, or intracranial aneurysm; recent trauma or major surgery (including bypass surgery); active bleeding; impaired hemostasis caused by known international normalized ratio >1.5; a past or present bleeding disorder; thrombocytopenia; history of thrombocytopenia with GP IIb/IIIa inhibitor therapy, heparin, or enoxaparin; angina from a secondary cause; anemia; valvular disease; congenital heart disease; hypertrophic cardiomyopathy; restrictive or constrictive cardiomyopathy; thyrotoxicosis; other serious comorbidities; treatment within 30 days or planned use of other investigational agents or devices; previous enrollment in this trial; inability to give informed consent; contraindications to coronary angiography or PCI; and high likelihood of being unavailable for follow-up

Primary Endpoints:

Efficacy: Death or nonfatal MI at 30 days

Safety: Major bleeding and stroke Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA. 2004 Jul 7;292(1):45-54.

Secondary Endpoints:

Combined incidence of all-cause mortality, nonfatal MI, stroke, or recurrent ischemia requiring revascularization and individual components of the composite at 14 days and 30 days; the incidence of death or nonfatal MI at 14 days and six months; and mortality at one year

Drug/Procedures Used:

Patients will be randomized in an open-label manner to enoxaparin (subcutaneously 1 mg/kg every 12 hours) or UFH (bolus of 60 U/kg and initial infusion of 12 U/kg/h, activated partial thromboplastin time goal 1.5-2.0 times upper limit of normal). Randomized treatment was started immediately after enrollment and continued until the patient requires no further anticoagulation, or at least through angiography and percutaneous coronary intervention (PCI), if performed. Patients pretreated with antithrombotic therapy were not excluded from the trial.

Concomitant Medications:

Aspirin (162 mg to 325 mg). Glycoprotein (GP) IIb/IIIa inhibitors at the physician's discretion in patients at high risk and during PCI.

Principal Findings:

Catheterization was performed in 92% of patients in each treatment arm, with a median time from enrollment to angiography of 22 hours in the enoxaparin arm and 21 hours in the UFH arm. PCI was performed in 46% of patients in the enoxaparin arm and 47% in the UFH arm.

Medication use included aspirin (95% in each arm), beta-blockers (86% in each arm), clopidogrel (62% in the enoxaparin arm and 63% in the UFH arm), and GP IIb/IIIa inhibitors (56% and 58%, respectively). The majority of patients were treated with prerandomization antithrombotic therapy, with only 25% receiving no pretreatment.

The crossover rate was 8% overall, with more patients crossing from enoxaparin to UFH than the reverse. Patients enrolled in the trial were relatively high-risk, with 45% meeting all three high-risk criteria of age ≥60 years, elevated cardiac markers, or ST-segment changes.

The primary endpoint of death or nonfatal myocardial infarction (MI) at 30 days occurred in 14.0% in the enoxaparin arm and 14.5% in the UFH arm (hazard ratio [HR] 0.96, 95% confidence interval [CI] 0.87-1.06), which did not meet the superiority criteria (p=0.396), but did meet the prespecified noninferiority criteria (below the HR upper bound 95% CI of 1.1). There was no difference in mortality (3.2% vs. 3.1%, p=0.705) or infarction (11.7% vs. 12.7%, p=0.135).

In a subgroup analysis of patients not pretreated with anticoagulation therapy (n=2,440), the primary endpoint occurred in 12.6% in the enoxaparin group and 14.8% in the UFH group, while the event rates in patients who were pretreated but were subsequently randomized to the same therapy as pretreatment (n=6,138) were 13.3% versus 15.9%, respectively.

Major bleed per TIMI criteria was higher in the enoxaparin arm (9.1% vs. 7.6%, p=0.008), but there was no significant difference when using the GUSTO criteria (2.9% vs. 2.4%, p=0.106). There was also no difference in the transfusion rate (17.0% vs. 16.0%, p=0.155).

In a meta-analysis of the large-scale randomized trials of enoxaparin versus UFH (n=21,946), the frequency of death or MI at 30 days was significantly lower in the enoxaparin group (10.1% vs. 11.0%), but rates of TIMI major bleed were higher (4.8% vs. 4.1%).


Among high-risk patients with a non-ST elevation MI ACS treated with an invasive management strategy, use of enoxaparin was noninferior compared with use of UFH for death or MI at 30 days, but TIMI major bleeding was elevated with enoxaparin. Prior studies comparing enoxaparin with UFH have primarily included patients treated with a conservative rather than invasive management strategy, and the present trial is the first designed to evaluate the therapies in high-risk patients with an invasive management strategy.

An important subgroup analysis was identified: patients not pretreated with antithrombotic therapy or those patients who continued on the same therapy post-randomization. In these patients, enoxaparin was associated with a lower rate of death or MI. Examining these patients exclusively removes the possible interaction between receiving both therapies, suggesting that continual treatment with enoxaparin was beneficial over UFH.

The meta-analysis of nearly 22,000 patients, which included trials with a conservative and invasive management strategy, showed a significant benefit of enoxaparin over UFH in all patients and in the subgroup of patients not pretreated with antithrombotic therapy.


Ferguson JJ, Califf RM, Antman EM, et al., for the SYNERGY Trial Investigators. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA 2004;292:45-54.

Presented by Dr. Kenneth W. Mahaffey at the American College of Cardiology Annual Scientific Session, March 2004.

SYNERGY Executive Committee. Superior Yield of the New strategy of Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa inhibitors. The SYNERGY trial: study design and rationale. Am Heart J 2002;143:952-60.

Keywords: Myocardial Infarction, Acute Coronary Syndrome, Platelet Aggregation Inhibitors, Heparin, Ticlopidine, Fibrinolytic Agents, Platelet Membrane Glycoprotein IIb, Purinergic P2Y Receptor Antagonists, Percutaneous Coronary Intervention, Enoxaparin, Partial Thromboplastin Time, Catheterization, Confidence Intervals, Platelet Glycoprotein GPIIb-IIIa Complex

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