Article Identification

Article Title: Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events (ESSENCE) Trial

Authors: Cohen M, Demers C, Gurfinkel EP, Turpie AG, Fromell GJ, Goodman S, Langer A, Califf RM, Fox KA, Premmereur J, Bigonzi F.

Journal Name, Year, Volume, Issue: New England Journal of Medicine, 1997, Volume 337, Issue 7.

Type of Study: Double-blind, randomized, placebo-controlled trial

DOI/PMID: PMID: 9250846, DOI: 10.1056/NEJM199708143370702

Quick Reference Summary

• Enoxaparin plus aspirin significantly reduced the incidence of death, myocardial infarction, or recurrent angina at both 14 days (16.6% vs. 19.8%, P = 0.019) and 30 days (19.8% vs. 23.3%, P = 0.016) compared to unfractionated heparin plus aspirin in patients with unstable coronary artery disease.
• While enoxaparin was more effective in reducing ischemic events, it was associated with a higher overall incidence of minor bleeding complications (18.4% vs. 14.2%, P = 0.001), primarily due to injection-site ecchymoses.

Core Clinical Question

In patients with unstable angina or non–Q-wave myocardial infarction (Population), does subcutaneous enoxaparin (Intervention) compared to intravenous unfractionated heparin (Comparison) reduce the incidence of death, myocardial infarction, or recurrent angina (Outcome)?

Background

Disease Overview:

Unstable coronary artery disease encompasses conditions like unstable angina and non–Q-wave myocardial infarction, characterized by recent onset angina at rest or evidence of ischemia.

Prior Data on the Topic:

• Antithrombotic therapy with heparin plus aspirin has been standard but has a substantial failure rate.
• Low-molecular-weight heparins (e.g., enoxaparin) have demonstrated advantages in predictable anticoagulation and ease of administration.

Current Standard of Care:

Intravenous unfractionated heparin plus oral aspirin for hospitalized patients with unstable angina or non–Q-wave myocardial infarction.

Knowledge Gaps Addressed by Study:

Efficacy and safety comparison between low-molecular-weight heparin (enoxaparin) and standard unfractionated heparin in reducing ischemic events.

Study Rationale:

Given the predictable anticoagulant effect and easier administration of low-molecular-weight heparins, the ESSENCE trial aimed to evaluate whether enoxaparin offers superior clinical outcomes over unfractionated heparin.

Methods Summary

Study Design:

Prospective, randomized, double-blind, parallel-group, multicenter trial.

Setting and Time Period:

Conducted from October 1994 to May 1996 across 176 centers in the United States, Canada, South America, and Europe.

Population Characteristics:

• 3171 patients with unstable angina or non–Q-wave myocardial infarction.
• Inclusion: ≥18 years old, recent onset angina at rest ≥10 minutes within 24 hours before randomization, evidence of underlying ischemic heart disease.
• Exclusion: Left bundle-branch block, pacemaker, persistent ST-segment elevation, established precipitating cause for angina, contraindications to anticoagulation, creatinine clearance <30 ml/min.

Inclusion/Exclusion Criteria:

As outlined above under Population Characteristics.

Intervention Details:

Enoxaparin: 1 mg/kg subcutaneously every 12 hours plus intravenous placebo.

Control/Comparison Group Details:

Unfractionated heparin: Intravenous bolus (usually 5000 units) followed by continuous infusion adjusted per activated partial-thromboplastin time plus subcutaneous placebo.

Primary and Secondary Outcomes:

• Primary: Composite of death, myocardial infarction, or recurrent angina at 14 days.
• Secondary: Composite endpoints at 48 hours and 30 days, incidence of major and minor hemorrhage.

Statistical Analysis Approach:

• Intention-to-treat principle using logistic regression adjusted for country.
• Kaplan–Meier for time-to-event analysis.

Sample Size Calculations:

The sample size calculations for the ESSENCE trial are not explicitly detailed in the article itself, but the trial included 3,171 patients randomized across two groups: 1,607 patients received enoxaparin, and 1,564 received unfractionated heparin.

Ethics and Funding Information:

• Approved by institutional review boards.
• Written informed consent obtained from all patients.
• Funded by Rhône-Poulenc Rorer, Collegeville, Pa.

Detailed Results

Participant Flow and Demographics:

• Enrollment: 3171 patients across 176 hospitals in 10 countries.
• Baseline Characteristics: No significant differences between treatment groups.
• Treatment Initiation: Within 12 hours of randomization in 96% of patients.
• Treatment Duration: Median of 2.6 days; therapy discontinued within 48 hours for 11.6% of patients.

Primary Outcome Results:

• 14 Days:
  • Enoxaparin: 16.6%
  • Unfractionated Heparin: 19.8%
  • Difference: Odds Ratio 0.80; 95% CI [0.67–0.96]; P = 0.019
• 30 Days:
  • Enoxaparin: 19.8%
  • Unfractionated Heparin: 23.3%
  • Difference: Odds Ratio 0.81; 95% CI [0.68–0.96]; P = 0.016

Secondary Outcome Results:

• Revascularization Procedures at 30 Days:
  • Enoxaparin: 27.0%
  • Unfractionated Heparin: 32.2%
  • Difference: P = 0.001
• Major Bleeding Complications at 30 Days:
  • Enoxaparin: 6.5%
  • Unfractionated Heparin: 7.0%
  • Not Significant
• Overall Bleeding:
  • Enoxaparin: 18.4%
  • Unfractionated Heparin: 14.2%
  • Difference: P = 0.001

Subgroup Analyses:

Significant efficacy of enoxaparin in patients >65 years, previous long-term aspirin use, previous percutaneous transluminal coronary angioplasty, echocardiographic changes at baseline, or ST-segment depression at baseline.

Adverse Events/Safety Data:

• Higher incidence of minor hemorrhagic events with enoxaparin, primarily injection-site ecchymosis.
• No verified cases of heparin-induced thrombocytopenia.

Results Tables

Outcome	Enoxaparin Group	Unfractionated Heparin Group	Difference (95% CI)	P-value
Composite Triple End Point at 14 Days	16.6%	19.8%	OR 0.80 (0.67–0.96)	0.019
Composite Triple End Point at 30 Days	19.8%	23.3%	OR 0.81 (0.68–0.96)	0.016
Revascularization at 30 Days	27.0%	32.2%	-	0.001
Overall Bleeding at 30 Days	18.4%	14.2%	-	0.001

Authors' Conclusions

• Primary Conclusions:
  • Enoxaparin plus aspirin is more effective than unfractionated heparin plus aspirin in reducing ischemic events in patients with unstable angina or non–Q-wave myocardial infarction during the early phase.
• Interpretation of Results:
  • The reduction in ischemic events was achieved without an increase in major bleeding, though minor bleeding was higher with enoxaparin.
• Clinical Implications:
  • Enoxaparin offers a superior antithrombotic strategy in the specified patient population, potentially improving clinical outcomes.
• Future Research Recommendations:
  • Further studies to explore long-term outcomes and optimal dosing strategies.

Literature Review

Previous Studies and Meta-Analyses:

• FRISC Study5:
  • Evaluated dalteparin plus aspirin vs. aspirin alone in acute coronary syndromes without ST-segment elevation.
  • Found a 48% relative-risk reduction in composite end points during the first six days.
  • Reference: European Heart Journal, 1996, Volume 17, Issue 10.
• Neri Serneri et al.25:
  • Compared subcutaneous unfractionated heparin with intravenous unfractionated heparin.
  • Observed equivalent beneficial effects in ischemic event reduction.
  • Reference: American Heart Journal, 1995, Volume 130, Issue 5.
• Gurfinkel et al.14:
  • First to compare low-molecular-weight heparin and aspirin directly with standard unfractionated heparin and aspirin.
  • Reported significant reductions in recurrent angina, silent ischemia, revascularization, and minor bleeding with low-molecular-weight heparin.
  • Reference: Journal of the American College of Cardiology, 1997, Volume 29, Issue 6.
• FRIC Study26:
  • Compared dalteparin plus aspirin with unfractionated heparin plus aspirin in acute non–Q-wave coronary syndromes.
  • Found no difference in efficacy or hemorrhage rates during the hospital phase.
  • Reference: European Heart Journal, 1998, Volume 19, Issue 6.

Contrasting Methodological Quality:

• ESSENCE vs. FRIC:
  • ESSENCE used enoxaparin with a higher anti–factor Xa to anti–factor IIa ratio compared to dalteparin in FRIC.
  • Differences in study therapy duration and anticoagulant profiles affected outcomes.

Comparisons with Guidelines:

• Current Guidelines:
  • Standard antithrombotic therapy involves unfractionated heparin plus aspirin.
  • Emerging evidence supports low-molecular-weight heparins as effective alternatives.

  This Trial's Contribution:

  • ESSENCE Trial:
    • Demonstrated sustained efficacy of enoxaparin over unfractionated heparin up to 30 days.
    • Provided evidence supporting the use of enoxaparin in reducing ischemic events without increasing major bleeding.

Critical Analysis

A. Strengths:

• Methodological Strengths:
  • Large sample size (3171 patients) enhancing statistical power.
  • Double-blind, placebo-controlled design minimizing bias.
  • Multicenter international setting increases generalizability.
• Internal Validity Considerations:
  • Randomization effectively balanced baseline characteristics.
  • Independent end-point committee verification reducing assessment bias.
• External Validity Considerations:
  • Diverse patient population across multiple continents enhances applicability to various clinical settings.

B. Limitations:

• Study Design Limitations:
  • Lack of detailed information on sample size calculations.
• Potential Biases:
  • Absence of blinded treatment allocations information might introduce performance bias.
• Generalizability Issues:
  • Results may not apply to populations excluded from the study, such as those with severe renal impairment.
• Statistical Limitations:
  • Secondary endpoints (e.g., death or myocardial infarction) did not reach statistical significance.
• Missing Data Handling:
  • Limited information on how missing data were addressed beyond intention-to-treat analysis.

C. Literature Context

• Direct Comparisons to Previous Studies:
  • ESSENCE showed significant benefits of enoxaparin, aligning with some studies like Gurfinkel et al., but differing from FRIC which showed no difference.
• Positioning Within Existing Evidence:
  • Confirms the potential superiority of low-molecular-weight heparin in certain acute coronary settings.
• References to Current Guidelines:
  • Supports evolving guidelines incorporating low-molecular-weight heparins as viable alternatives.
• Identified Knowledge Gaps:
  • Necessitates exploration of long-term outcomes and broader patient populations.
• Ongoing Research:
  • Encourages further trials comparing various antithrombotic agents in similar settings.
• Systematic Reviews or Meta-Analyses Referenced:
  • Not explicitly mentioned within the provided text.
• Geographic or Population Differences Noted:
  • Conducted across multiple countries, suggesting applicability across different healthcare systems.

Clinical Application

• Enoxaparin can be considered a more effective alternative to unfractionated heparin for reducing ischemic events in patients with unstable angina or non–Q-wave myocardial infarction, particularly in older patients and those with specific risk factors.
• Clinicians should weigh the benefits of reduced ischemic events against the increased risk of minor bleeding when implementing enoxaparin in practice.

How To Use This Info In Practice

Practitioners should consider adopting enoxaparin plus aspirin therapy over unfractionated heparin plus aspirin for appropriate patients with unstable coronary artery disease to improve clinical outcomes while monitoring for minor bleeding complications.