Assessment of the Treatment Effect of Enoxaparin for Unstable Angina/Non-Q-Wave Myocardial Infarction - TIMI 11B-ESSENCE Meta-Analysis
TIMI 11B and ESSENCE were Phase III trials designed to test the efficacy of enoxaparin versus unfractionated heparin in patients with unstable angina/non-ST elevation myocardial infarction (MI). This prospectively planned meta-analysis was designed to provide more statistically robust estimates of the treatment effects of enoxaparin with regard to efficacy and safety.
Compared to unfractionated heparin, treatment with enoxaparin would be associated with lower odds of death and nonfatal MI in a pooled analysis from both trials.
Patients Enrolled: 7,081
Mean Follow Up: 43 days
Both trials required rest angina within 24 hours with either ST-segment deviation, elevated cardiac markers, or history of coronary artery disease (later dropped from TIMI 11B).
Planned revascularization ≤24 hours (TIMI 11B), correctable cause of angina, or contraindications to anticoagulation
Odds of death/nonfatal MI
Odds of death/nonfatal MI/urgent revascularization, odds of all-cause death, and odds of major hemorrhage
• Enoxaparin: 30 mg intravenous (IV) bolus followed by 1.0 mg/kg sc every 12 hours while in-hospital and then reduced during outpatient phase with median duration of treatment 4.6 days.
• Heparin: 70 U/kg bolus followed by infusion adjusted to 1.5-2.5 x control with median duration 3.0 days
• Enoxaparin: no IV bolus, 1.0 mg/kg sc every 12 hours with median duration of treatment 2.6 days.
• Heparin: 5000 U bolus followed by infusion adjusted to 1.5-2.5 x control with median duration 2.6 days
The meta-analysis included results from 7,081 patients (3,910 in TIMI 11B and 3,171 in ESSENCE). There was no heterogeneity in efficacy endpoints between the two trials. The incidence of death/nonfatal MI was approximately 20% lower in patients receiving enoxaparin at all time points, with statistical significance observed after eight days and persisting through later follow-up (at eight days, odds ratio [OR] 0.77, p=0.02, for enoxaparin compared to unfractionated heparin).
The absolute difference between groups was 1.2% at eight days (5.3% unfractionated heparin vs. 4.1% enoxaparin), and 1.8% at 43 days (8.6% unfractionated heparin vs. 7.1% enoxaparin). There was a similar effect seen with death/nonfatal MI/urgent revascularization, and pooled overall mortality trended lower in the enoxaparin group, but did not reach statistical significance. The rates of major hemorrhage were similar between groups, but minor bleeding was significantly increased in the enoxaparin pooled group (OR 2.38, p<0.0001).
In a pooled analysis of TIMI 11B and ESSENCE, treatment with enoxaparin was associated with an approximately 20% reduction in death/nonfatal MI and no difference in major hemorrhage compared with treatment with unfractionated heparin in patients with unstable angina/non-ST elevation MI, with a significant increase in minor hemorrhage. Because TIMI 11B and ESSENCE were not individually powered to detect differences in endpoints such as death or death/nonfatal MI, this meta-analysis was prospectively planned.
In both trials, rates of revascularization were low (approximately 30% in ESSENCE, and planned revascularization within 24 hours was an exclusion criterion in TIMI 11B), making it somewhat difficult to apply these results directly to patients treated with an early invasive strategy for unstable angina/non-ST elevation MI. The ongoing SYNERGY trial will evaluate treatment with enoxaparin compared with unfractionated heparin in patients treated with an early invasive strategy.
Antman EM, Cohen M, Radley D, et al. Assessment of the treatment effect of enoxaparin for unstable angina/non-Q-wave myocardial infarction. TIMI 11B-ESSENCE meta-analysis. Circulation 1999;100:1602-8.
Keywords: Odds Ratio, Coronary Artery Disease, Myocardial Infarction, Follow-Up Studies, Enoxaparin, Myocardial Revascularization, Heparin
< Back to Listings