SYNERGY

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Ferguson JJ, et al. "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(1):45-54.
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Clinical Question

In patients with high risk UA/NSTEMI treated with an early invasive approach, does enoxaparin reduce all-cause death or nonfatal MI in the first 30 days when compared to unfractionated heparin?

Bottom Line

In patients with high risk non-ST-elevation acute coronary syndromes (NSTEACS) treated with an early invasive approach, enoxaparin is non-inferior to unfractionated heparin in reducing a primary composite endpoint of all-cause death or non-fatal MI.

Major Points

Enoxaparin is a low-molecular weight heparin (LMWH) that has shown superiority over unfractionated heparin (UFH) for the treatment of UA/NSTEMI in the ESSENCE trial (1997). This trial was performed in an era when early invasive therapy was not an established modality of standard care.

The 2004 Enoxaparin vs. Unfractionated Heparin in High-Risk Patients With Non-ST-Segment Elevation Acute Coronary Syndromes Managed With an Intended Early Invasive Strategy (SYNERGY) trial was a prospective, randomized, open-label, multicenter and international trial designed to assess a primary composite outcome of all-cause death or non-fatal MI at 30 days in a group of patients with high-risk NSTEACS treated with an early invasive approach. The trial randomized 10,027 patients to enoxaparin or UFH in addition to standard care. At 30 days, there was no significant difference in the primary composite end point of all-cause death or nonfatal MI in patients treated with enoxaparin or UFH (14% vs. 14.5%; 95% confidence interval 0.86-1.06). There was a statistically significant increase in TIMI (Thrombolysis in Myocardial Infarction) major bleeding (9.1% vs. 7.6%, P=0.008), but this was statistically nonsignificant when assessed by GUSTO (Global Utilization of Streptokinase and t-PA for Occluded Arteries) severe bleeding (2.7% vs. 2.2%, P=0.08) or the need for supportive transfusions (17% vs. 16%, P=0.16).

This trial suggests that enoxaparin can be used as a safe and effective alternative to UFH, but the margin of benefit is significantly reduced when used in a population of patients treated with an early invasive strategy. The benefits of convenient dosing must be balanced with an increased risk of bleeding.

Guidelines

AHA/ACC NSTE-ACS (2014)

  • Anticoagulation in addition to antiplatelet therapy is recommended for all patients with NSTE-ACS, regardless of initial treatment strategy
    • Enoxaparin 1mg/kg subcutaneous q12h (or 1mg/kg subcutaneous q24h for patients with CrCl<30mL/min) for the duration of hospitalization or until PCI is performed. Initial intravenous loading dose of 30mg.
    • UFH IV initial loading dose 60IU/kg (max. 4,000IU) with initial infusion 12IU/kg/h (max. 1,000IU/h) adjusted per aPTT to maintain therapeutic anticoagulation according to hospital protocol for 48h or until PCI performed.

Design

  • Prospective, randomized, open-label, multicenter, international trial
  • N=10,027
    • Enoxaparin (n=1,993)
    • UFH (n=4985)
    • Excluded due to randomization error (n=49)
  • Setting: 467 investigative centers from 12 different countries
  • Enrollment: August 2001 - December 2003
  • Follow-up: 30 days (primary outcome), 1 year (survival)
  • Analysis: Intention-to-treat
  • Primary outcome: Composite all-cause death or nonfatal MI at 30 days

Population

Inclusion Criteria

  • Ischemic symptoms lasting at least 10 minutes and occurring within 24h before enrollment, and with at least 2 of:
    • Age 60 or older
    • Troponin or creatine kinase elevation above upper limit of normal
    • ST segment changes on ECG

Exclusion Criteria

  • Known or suspected pregnancy
  • Contraindications to UFH or LMWH
  • Recent (<48h) or planned spinal or epidural anesthesia/puncture
  • PCI or thrombolytics within the preceding 24h
  • Increased risk of bleeding due to recent stroke or surgery
  • Elevated INR (>1.5)
  • Pas or present bleeding disorder
  • CrCl < 30mL/min

Baseline characteristics

  • Enoxaparin group
    • Median age: 68.0
    • Sex: 34% female
    • Race: 86.1% white, 6.2% black, 4.7% hispanic
    • Weight: 80kg
    • Kilip class: 87.2% class I, 10.2% class II, 2.1% class III, 0.5% class IV
    • Risk factors: 68.3% Hypertension, 28.5% Diabetes mellitus, 9.6% peripheral vascular disease, 58.3% hypercholesterolemia, 46.4% family history of CAD

Interventions

Outcomes

Criticisms

Funding

Further Reading