Low Molecular Weight Heparin for Unstable Coronary Syndromes

Abstract & Commentary

Synopsis: In patients with unstable angina or non-Q-wave myocardial infarction, short-term enoxaparin reduced the incidence of subsequent ischemic events and revascularization in the first 30 days and at one year.

Source: Goodman SG, et al. J Am Coll Cardiol 2000;36:693-698.

Aspirin plus heparin therapy is standard evidence-based therapy for unstable angina/non-Q-wave myocardial infarction (MI) patients admitted to the hospital. Recent studies have suggested that low molecular weight heparin (LMWH) may be superior to unfractionated heparin in the short term, but little long-term data are available. Thus, Goodman and colleagues reported on the one-year results of the Efficacy and Safety of Subantaneous Enoxaprin in Non-Q-wave Coronary Events (ESSENCE) study. They studied 3171 patients from 176 centers worldwide who had angina decubitus for less than 24 hours and evidence of coronary artery disease, but not acute Q-wave MI. The patients were randomized to enoxaparin 1 mg/kg, 12 hour SQ or unfractionated heparin 5000 U bolus followed by a continuous infusion adjusted by the activated clotting time (ACT). Aspirin was given also and heparin was continued for 48 hours—eight days (median 2.6 days). The 14-and-30 day results have already been reported.1 This report details the one year follow-up results in 2915 (92%) survivors not lost to follow-up. The primary end point of the study was death, MI, or recurrent angina requiring hospitalization or revascularization. The percent achieving this end point is shown in the Table. The secondary end points of death or MI were not statistically significant despite a trend toward lower rates with enoxaparin. However, the rates of subsequent cardiac catheterization and revascularization were significantly lower on enoxaparin.

Goodman et al concluded that in patients with unstable angina or non-Q-wave MI, short-term enoxaparin reduced the incidence of subsequent ischemic events and revascularization in the first 30 days and at one year.

Comment by Michael H. Crawford, MD

Despite the success of heparin plus aspirin therapy, significant numbers of patients with acute coronary syndromes have recurrent ischemic events or require revascularization. This has stimulated interest in other approaches to these patients. Initial short-term studies with the LMWH suggested that ischemic end points were less for up to 45 days but may wane after that. Other studies showed no benefits vs. unfractionated heparin of two LMWHs, nadroparin and dalparin. Thus, the ESSENCE study is of interest because it used enoxaparin, the agent with only positive reports and the most wide usage in the United States. Also, economic studies have shown that enoxaparin is cost-effective for the treatment of unstable angina. The benefits of enoxaparin were seen by 48 hours and persisted at 14, 30, and 360 days following a median treatment period of 2.6 days. The major reason for the persistent effect was the reduction in need for subsequent revascularization.

It is not clear why studies with the other two LMWH were negative, especially since one used a long-term administration protocol. However, these agents have different pharmacodynamics, which may partly explain the disparity. Also, the effects of LMWH in this clinical setting are not profound. Therefore, some of these studies may have been underpowered to detect a difference. In addition to these positive results with regard to ischemic events vs. infractionated heparin, there are several other advantages to LMWH: They are weight dosed without needing ACTs because of their predictable pharmacokinetics; they have less interactions with platelets; and heparin-induced thrombocytopenia is less frequent. A proposal for the care of unstable coronary syndromes is as follows: aspirin for all patients; LMWH for 48-72 hours for those admitted; IIb/IIIa blockers and catheterrization/revascularization for high-risk patients (ST changes, serum markers elevated, rest pain). This proposal has not been tested yet but makes some sense based upon available data.

Table-Frequency of the Primary End Point on the Two Treatments in ESSENCE
14 d 30 d 1 y
Enoxaparin 16.6% 19.8 32.0
IV heparin 19.8 23.3 35.7
P value P < 0.02 P < 0.02 P = 0.02

Reference

1. Cohen M, et al. N Engl J Med 1997;337:447-452.