ESSENCE

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Cohen M, et al. "A Comparison of Low-Molecular-Weight Heparin with Unfractionated Heparin for Unstable Coronary Artery Disease". The New England Journal of Medicine. 1997. 337(7):447-452.
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Clinical Question

In patients with UA/NSTEMI, does enoxaparin reduce rates of death, MI, or recurrent angina at 14 days when compared to unfractionated heparin?

Bottom Line

Enoxaparin reduces the composite endpoint of death, MI, or recurrent angina at 14 days when compared to unfractionated heparin in the treatment of UA/NSTEMI.

Major Points

The efficacy of unfractionated heparin (UFH) in UA/NSTEMI was first demonstrated in the ATACS trial (1994).[1] Low-molecular weight heparin (LMWH) has the advantage of once- and twice-daily subcutaneous dosing and more predictable therapeutic effects.[2] Thus, investigators wished to compare LMWH to UFH in UA/NSTEMI.

The 1997 Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events (ESSENCE) trial randomized 3,171 patients with UA/NSTEMI to UFH or enoxaparin in addition to standard care. At 14 days, enoxaparin outperformed UFH for the composite endpoint of death, MI, or recurrent angina (16.6% vs. 19.8%) with a NNT of 31, mostly driven by a reduction in recurrent angina.[3] There was no difference in major bleeding between the groups though enoxaparin was associated with a higher rate of minor bleeding. Finally, the enoxaparin group had a lower rate of revascularization (27.0% vs. 32.2%).

The subsequent SYNERGY trial[4] (2004) studied enoxaparin vs. UFH in patients with NSTEMI when combined with the newer GP IIb/IIIa inhibitors. It demonstrated that enoxaparin was non-inferior but not superior to UFH in a similar outcome to ESSENCE.

Guidelines

ACCF/AHA NSTE-ACS (2014, adapted)[5]

  • Regardless of initial treatment strategy, all patients with definite NSTE-ACS should be treated with antiplatelet therapy and an anticoagulation strategy:
    • Enoxaparin 1 mg/kg sub-q q12h or 1 mg/kg if creatinine <30 mL/min (class I, level A) or fondaparinux 2.5 mg sub-q daily (class I, level B) for duration of hospitalization or until PCI
      • Loading dose is enoxaparin 30 mg IVx1
      • Use UFH or bivalrudin (anti-IIa-active) during PCI while on fondaparinux to prevent against catheter thrombosis (class I, level B)
    • If early invasive strategy, can give bivalrudin 0.10 mg/kg loading dose then 0.25 mg/kg/hour until angiography or PCI with provisional GP IIb/IIIa inhibitor use in the setting of dual anti-platelet therapy
    • UFH IV with loading dose 60 units/kg (maximum 4,000 units) and continuous infusion of 12 units/kg/hr (maximum 1000 units/hour) adjusted to target PTT for 48 hours or until PCI is performed (class I, level B)

Design

  • Multicenter, randomized, double-blind trial
  • N=3,171
    • Enoxaparin (n=1,607)
    • UFH (n=1,564)
  • Setting: 176 centers in the US, Canada, S. America, and Europe
  • Enrollment: 1994-1996
  • Follow-up: 14 days (primary outcome) and 30 days (secondary outcome)
  • Analysis: Intention-to-treat
  • Primary outcome: Death, MI, or recurrent angina

Population

Inclusion Criteria

  • Age ≥18 years with ≥10 minutes of angina at rest in the prior 24 hours and ≥1 of the following:
    • ST depression ≥0.1 mV, transient ST elevation, or T-wave changes in ≥2 contiguous leads
    • Prior MI or revascularization
    • Testing indicative of ischemic heart disease

Exclusion Criteria

  • Pregnancy
  • LBBB
  • Pacemaker
  • Persistent ST elevation
  • Angina with a precipitating cause
  • Contraindications to AC
  • Creatinine clearance <30 mL/min

Baseline Characteristics

From the enoxaparin group.

  • Demographics: Age 63 years, male 67.1%
  • Baseline health data: Weight 79 kg
  • Past cardiac history: Cardiac catheterization with ≥50% stenosis 43.7%, positive exercise-tolerance test 25.0%, MI 45%, CABG: 19.7%, PCA: 21.5%
  • CV risk factors: Family history 42.1%, active smoker 24.8%, HTN 53.3%, HLD 44.8%, DM 22.4%
  • EKG changes: ST elevation 7.1%, ST depression 22.3%, TWI 38.8%

Interventions

  • Randomization to one of two groups
    • Enoxaparin 1 mg/kg subcutaneously q12h plus IV placebo
    • UFH IV bolus then aPTT-titrated infusion plus subcutaneous placebo
  • Both groups received aspirin 100-325 mg by mouth daily
  • Continuation of intervention for 2-8 days with cessation at hospital discharge, new MI, revascularization, or death

Outcomes

Comparisons are UFH vs. enoxaparin.

Primary Outcome

Death, MI, or recurrent angina at 14 days
19.8% vs. 16.6% (OR 0.80; 95% CI 0.67-0.96; P=0.02: NNT=31)
Death: 2.3% vs. 2.2% (OR 0.98; 95% CI 0.61-1.56; P=0.92)
MI: 4.5% vs. 3.2% (OR 0.70; 95% CI 0.48-1.01; P=0.06)
Recurrent angina: 15.5% vs. 12.9% (OR 0.80; 95% Ci 0.65-0.98; P=0.03)

Secondary Outcomes

Death, MI, or recurrent angina at 2 days
7.4% vs. 6.2% (OR 0.83; 95% CI 0.62-1.09; P=0.18)
Death: 0.4% vs. 0.5% (OR 1.12; 95% CI 0.40-3.23; P=0.83)
MI: 0.9% vs. 0.7% (OR 0.76; 95% CI 0.34-1.69; P=0.50)
Recurrent angina: 6.3% vs. 5.2% (OR 0.80; 95% CI 0.60-1.09; P=NS)
Death, MI, or recurrent angina at 30 days
23.3% vs. 19.8% (OR 0.81; 95% CI 0.68-0.96; P=0.02; NNT=29)
Death: 3.6% vs. 2.9% (OR 0.79; 95% CI 0.53-1.18; P=0.25)
MI: 5.2% vs. 3.9% (OR 0.74; 95% CI 0.52-1.03; P=0.08)
Recurrent angina: 18.0% vs. 15.7% (OR 0.85; 95% CI 0.70-1.02; P=0.08)
Revascularization at 30 days
32.2% vs. 27.0% (P=0.001; NNT=19)
CABG: 13.7% vs. 12.3% (P=0.25)
PCI: 18.7% vs. 14.7% (P=0.002; NNT=25)

Adverse Events

Hemorrhage
Major: 7.0% vs. 6.5% (P=0.57)
Minor: 7.2% vs. 11.9% (P<0.001; NNH=21)
Stroke
0.5% vs. 0.4%
Hemorrhagic: 1 vs. 0 (P=NS)
Non-hemorrhagic: 0.4% vs. 0.4% (P=NS)
TIA
0.5% vs. 0.1% (no statistics given)
>50% drop in platelets
3.7% vs. 2.5% (P=0.08)

Criticisms

  • The UFH normogram was not weight-based and may have favored enoxaparin[2]
  • Significant variability in length of treatment[2]
  • Reagents for aPTT likely varied and influenced consistent dosing of the UFH[6]

Funding

Rhône-Poulenc Rorer Corporation (now Sanofi-Aventis) the makers of Lovenox (enoxaparin).

Further Reading

  1. Cohen M, et al. "Combination antithrombotic therapy in unstable angina and non-Q-wave infarction in nonprior aspirin users: primary end points analysis from the ATACS trial." Circulation. 1994;89:81-88.
  2. 2.0 2.1 2.2 Concurrent editorial
  3. Kaul S, Shah PK. "Low molecular weight heparin in acute coronary syndrome: evidence for superior or equivalent efficacy compared with unfractionated heparin?" Journal of the American College of Cardiology 2000;35(7):1699-1712.
  4. 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.
  5. Amsterdam EA, et al. "2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes." Journal of the American College of Cardiology. 2014;epublished 2014-09-23. Accessed 2014-09-24.
  6. Letters to the editor