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Enoxaparin for Acute Coronary Syndromes
Payel Patel, Pharm.D. Student, Rubina Sunderji, Pharm.D., FCSHP

August 2000 Drug & Therapeutics Newsletter
(C) 2000, CSU-Pharmaceutical Sciences
Vancouver Hospital & Health Sciences Centre

Introduction

Acute coronary syndromes (ACS) include both unstable angina and non-Q wave myocardial infarction (MI).1 ACS are the result of atherosclerotic plaque rupture and exposure of thrombogenic material resulting in the activation of the coagulation system and platelet pathway.2,3 Traditional standard therapy has therefore included both aspirin and unfractionated heparin (UFH). Recent clinical trials indicate that low molecular weight heparins (LMWH) provide a therapeutic alternative to UFH in the treatment of ACS.

Enoxaparin is one of four LMWHs available in Canada. It has recently been added to the VHHSC formulary for the treatment of ACS. Compared to UFH, LMWHs are better absorbed after subcutaneous (SC) administration, have reduced protein binding, a longer half-life (3-6 hours compared to 60-90 minutes for UFH), and a more predictable anticoagulant response.4,5 LMWH has greater affinity for inhibiting factor Xa versus thrombin, although the importance of this difference is unclear.6,7 Both the predictable anticoagulant response and long half-life of the LMWH allows for once or twice daily SC injections at fixed or weight-adjusted doses.8 Since LMWHs do not affect the activated partial thromboplastin time (aPTT), routine laboratory monitoring is unnecessary.7 An antifactor Xa assay is available but due to the lack of a clinically defined therapeutic range and cost of the assay, antifactor Xa assays are not routinely performed. LMWHs also have decreased interactions with platelets, which could account for the reduced microvascular bleeding and lower incidence of heparin-induced thrombocytopenia (HIT).6,8 Recent clinical trials indicate that the risk of major bleeding secondary to LMWH treatment is similar to UFH9-11; however, minor bleeding complications have been higher with LMWHs.10,11

Comparative Studies of LMWH and UFH in ACS

There are no studies directly comparing tinzaparin to UFH for ACS and a comparative trial of dalteparin to UFH showed no difference in outcomes12.

One small study13 comparing nadroparin to UFH for ACS showed superior benefits with this LMWH although a subsequent larger comparative trial14 showed no difference between the treatments. Two large studies11,15 evaluating enoxaparin demonstrated superior outcomes compared to UFH. Although a recent meta-analysis of studies comparing various LMWHs to UFH for ACS suggested a lack of difference between the treatments16, some evidence suggests that enoxaparin should still be the preferred agent for this indication.

The Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group (ESSENCE) was a prospective, double blind, parallel group trial that enrolled 3,171 patients with unstable angina or non-Q-wave MI within 24 hours of onset of chest pain.11 Patients were randomized to receive enoxaparin (1mg/kg of body weight SC every 12 hours) or UFH (IV bolus 5000 units followed by a continuous infusion at a dose adjusted according to the aPTT) for at least 48 hours and up to 8 days. The primary endpoint was the composite of death, nonfatal MI, or recurrent angina at 14 days. Compared to UFH, the absolute risk reduction (ARR) for enoxaparin was 3.2% (p=0.02). This translates to a number needed to treat (NNT) with enoxaparin of 32 patients for a minimum of 48 hours (maximum 8 days) in order to avoid one event. There were no differences in the individual endpoints of death or myocardial infarction and the majority of the

benefit was accounted for by a reduction in recurrent angina. The benefit in the primary endpoint observed with enoxaparin was sustained at 30 days and at one year.17 There was no difference between the groups in major bleeding complications. However, there was an absolute risk increase (ARI) in minor bleeding events with enoxaparin of 4.7% (p<0.001). The majority of these episodes involved injection site ecchymoses. A criticism of the ESSENCE trial was that the investigators did not use a weight-adjusted UFH nomogram; rather they relied on a fixed dosing system. The clinical significance of weight-adjusted nomograms has yet to be established in patients with angina despite their proven advantage in the treatment of venous thromboembolism.18,19

The Thrombolysis in Myocardial Infarction (TIMI) 11B study group compared enoxaparin (1 mg/kg SC every 12 hours) against weight-adjusted UFH in 3,910 patients with ACS presenting within 24 hours of onset of chest pain.15 This double-blind, randomized trial was divided in two phases to assess the efficacy of enoxaparin in acute (3 to 8 days) and chronic (additional 35 days after discharge) treatment of ACS. After the acute phase, patients who were initially randomized to the UFH arm were treated with placebo injections, while those who received enoxaparin continued to receive a reduced weight-adjusted LMWH regimen of 40-60 mg SC every 12 hours. The primary endpoint was a composite of death, non-fatal MI, or severe recurrent ischemia requiring urgent revascularization at 8 days. This endpoint was also assessed at 43 days to determine if prolonged enoxaparin therapy is of additional benefit. Acute treatment was associated with an ARR of 2.1% in the primary endpoint in favour of enoxaparin (NNT = 48, p = 0.048). A significant difference was also recorded in the individual endpoint of MI. The authors noted that the initial benefit in the composite endpoint was maintained at 43 days and that there was no further reduction in events with continued enoxaparin treatment in the chronic phase. Major bleeding was not different between the groups during the acute phase but was higher with enoxaparin during the chronic phase (ARI 1.4%, p=0.021). Again, enoxaparin was associated with significantly more minor bleeding in both phases.

Economic Implications

Treatment with enoxaparin is associated with a higher drug acquisition cost than UFH. For a 70kg individual, a 5 day course of treatment costs $140 for enoxaparin and approximately $30 for UFH. However, the lack of need for aPTT monitoring and potential for reduction in event rates is reported to result in a more favorable economic outcome. Two Canadian cost-effectiveness analyses have been published to assess the economic impact of using enoxaparin for ACS. O’Brien et al performed an economic analysis based on the one-year follow up data from the ESSENCE study.20 They focused their analysis on the 1,259 Canadian participants (~40% of the study population) enrolled in the trial. Hospital resources were costed with the use of data from a teaching hospital in southern Ontario. The authors found that at one year, the reduced risk and costs of revascularization offset the increased acquisition costs of enoxaparin and resulted in a cost saving per patient of $1485 (95% confidence interval $-93 to $3167; p = 0.06). Balen et al also concluded from their pharmacoeconomic analysis that enoxaparin is the dominant strategy compared to UFH for ACS.21

Conclusions

The current available literature supports the use of enoxaparin in the management of ACS. The recommended dosage is enoxaparin 1 mg/kg SC twice daily for a minimum of 48 hours and a maximum of 8 days. Data from clinical trials and Canadian pharmacoeconomic analyses have shown enoxaparin to be more effective and less costly than UFH for ACS. Additional benefits of enoxaparin include the lack of need for aPTT monitoring and a lower incidence of HIT than UFH. A complete blood count is recommended at baseline and twice weekly for the duration of therapy to monitor for bleeding and thrombocytopenia.

References

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  17. Eikelboom JW et al. Unfractionated heparin and low-moelcular-weight heparin in acute coronary syndrome without ST elevagtion: a meta-analysis. Lancet 2000;355:1936-42.

  18. Goodman S et al. One year follow-up of the ESSENCE trial (enoxaparin vs. heparin in unstable angina/non-Q-wave MI): sustained clinical benefit [abstract]. Can J Cardiol 1998;14:122F.

  19. Raschke R et al. The weight based heparin nomogram compared with a “standard care” nomogram: a randomized controlled trial. Ann Intern Med 1993;119:874-881.

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