Role of Enoxaparin in the Invasive Management of the ACS Patient

Compared to unfractionated heparin (UFH), enoxaparin has many advantages in the management of acute coronary syndromes (ACS). Rapidly and reliably absorbed after subcutaneous administration, enoxaparin has pharmacodynamic and pharmacokinetic profiles that are much more predictable than UFH, leading to prompt and consistent levels of anticoagulation and no need for routine monitoring.^1,2 In addition, unlike unfractionated heparin, enoxaparin is resistant to platelet factor 4 (PF4) inhibition, is associated with less heparin-induced thrombocytopenia, does not activate platelets, preferentially inhibits factor Xa production, augments tissue-factor pathway inhibitor, and attenuates Von Willebrand factor release. As a result of these favorable characteristics, two large randomized trials, ESSENCE and TIMI-11b, demonstrated a 15–20% reduction in ischemic events in patients with ACS treated with enoxaparin compared to UFH.^3,4 Consequently the most recent ACC/AHA guidelines have suggested that enoxaparin is preferable to UFH as an anticoagulant in patients with unstable angina and non-ST elevation MI unless CABG is planned within 24 hours (Class IIa recommendation).⁵ In acute ST elevation MI, two recent studies have suggested the combination of enoxaparin plus thrombolytic is associated with at least comparable efficacy and potentially less bleeding, particularly in the non-elderly.^6,7 Despite large trials suggesting its superiority in the medical management of ACS, enoxaparin has not been embraced as the preferred anti-coagulant in many medical centers. Major barriers to its use include its incompletely defined efficacy and safety in the setting of coronary intervention and the lack of an easily available way to monitor its activity during percutaneous intervention (PCI). Furthermore, questions about the safety of combination therapy with glycoprotein IIb/IIIa antagonists exist. In addition, there is uncertainty as to what the optimal dosing regimen is in the setting of an early invasive approach, especially when patients are not at steady state, having received only one or two subcutaneous doses. Although the safety and efficacy of enoxaparin compared to unfractionated heparin in PCI has not been adequately studied in a randomized controlled manner, multiple registries and observational studies provide insight into its use. The NICE (North American Investigators Collaborating on Enoxaparin) studies examined enoxaparin in patients undergoing percutaneous coronary intervention in three registries. In NICE 1, 1 mg/kg of enoxaparin was administered intravenously followed by routine intervention.⁸ NICE-3 was a real-world trial of upstream subcutaneous enoxaparin, followed by coronary stenting in conjunction with IIb/IIIa inhibition (predominantly small molecule IIb/IIIa inhibitors utilized).⁹ Finally, NICE 4 examined full-dose abciximab plus intravenous enoxaparin 0.75 mg/kg in patients undergoing elective stenting.¹⁰ The efficacy and safety (bleeding) noted in these studies using enoxaparin was favorable compared to historical controls in which UFH was utilized. In the TIMI-11b/ESSENCE (TESSMA–PCI) meta analysis, the subgroup of patients undergoing PCI in these predominantly medical trials was studied. In those undergoing “in-hospital” PCI, there was a marked reduction in the combined endpoint of death, MI and nonfatal MI at one-year follow-up in the enoxaparin group compared to those receiving UFH (6% versus 12%; p = 0.003).¹¹ Collet and colleagues reported the results of intervention in 451 patients given 1 mg/kg subcutaneous enoxaparin for at least 48 hours, followed by invasive evaluation within eight hours of the last subcutaneous dose. There were no in-hospital abrupt closures. In the PCI group, the 30-day mortality was 3.0% and the 30–day major bleeding was 1.3%.¹² Choussat et al. studied 241 patients undergoing PCI who received only 0.5 mg/kg of IV enoxaparin prior to intervention; 64 of the patients received concomitant eptifibatide.¹³ For those receiving only enoxaparin, sheaths were removed immediately. At one-month follow-up, only 2.5% had died, had a myocardial infarction, or had undergone urgent intervention. Nearly 95% of patients had anti-Xa activity within the pre-specified target range of 0.5 to 1.5 IU/ml. There was one major bleed and three minor bleeding events. Although these favorable results were obtained without measuring anticoagulant activity to guide therapy, a bedside point-of-service measure of enoxaparin activity would be helpful, particularly when there are uncertainties about if and when drug was given and in those circumstances when fewer than three doses of subcutaneous enoxaparin have been administered and steady-state has not been achieved. The ENOX system (Pharmanetics, Morrisville, North Carolina) is a rapid point-of-service measurement of enoxaparin acitivity. The ENOX time in seconds correlates with enoxaparin-specific anti-Xa activity. Results from the Evaluating Enoxaparin Clotting Times (ELECT) trial provide important information about the use of this assay.¹⁴ In this study of 445 patients undergoing PCI with enoxaparin, ischemic events were infrequent (in-hospital death, myocardial infarction, and urgent TVR in 5.4%) and major or minor bleeding was noted in only 1.2%. There was a linear correlation between bleeding and ENOX time, and it was recommended that sheath pull after PCI was safe with an ENOX time 15 The safety profile of enoxaparin was comparable (major hemorrhage 0.3% versus 1.0%), and 30–day mortality (2.5% versus 1.9%) and MI (6.7% versus 7.1%) was equivalent. A significant reduction in refractory ischemia (0.6% versus 4.3%; 0 = 0.001) and rehospitalization for unstable angina (1.6% versus 7.1%, p = 0.002) were observed in the enoxaparin group. In the largest trial to date of combination therapy, the Integralin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment (INTERACT) trial randomized 746 patients with high-risk non-ST segment ACS on integralin to either UFH or enoxaparin.¹⁶ After 48 hours, patients were eligible to undergo revascularization if indicated. The enoxaparin group had significantly fewer major non-coronary bypass bleeds (1.8% versus 4.6%, p = 0.03) and experienced less recurrent ischemia detected by continuous ST segment monitoring during the initial 48 hours of monitoring (14.3% versus 25.4%, p = 0.0002). Death or MI was significantly lower in the enoxaparin group (5% versus 9%, p = 0.031). Lee and colleagues in the current report, contribute further insights into the use of enoxaparin in the setting of real-world combination therapy and evaluation.¹⁷

See Lee, et al. on pages 46–51

In this pilot trial, a combination of IIb/IIIa inhibitors, subcutaneous enoxaparin, and early invasive evaluation was evaluated in 49 patients with ACS. Twenty-three of the patients underwent PCI, with enoxaparin and IIb/IIIa inhibitors being the procedural anti-thrombotics. At thirty days, the primary composite endpoint of death, MI or urgent TVR occurred in 8%. There were no deaths. One patient received a transfusion. No other adverse events were noted. These event rates were comparable to those from the pooled EPILOG/EPISTENT database. Anti-Xa levels were therapeutic in the majority undergoing intervention within eight hours of the last dose of enoxaparin, whereas only 40% were therapeutic when the last dose was between eight and twelve hours, suggesting that these patients require an additional IV bolus. Although this pilot study by Lee et al provides further evidence that enoxaparin use in combination with 2b/3a inhibition and early invasive evaluation is well tolerated, safe, and efficacious, further data are certainly required before this becomes the standard of care. A number of large randomized studies, including the Superior Yield of the New Strategy of Enoxaparin, Revascularization, Glycoprotein IIb/IIIa Inhibitor (SYNERGY) trial will be particularly helpful. These trials, as well as studies of low-dose therapy during PCI, will allow clinicians to further define the role of enoxaparin as an integral component in the management of the ACS patient both before and during invasive evaluation and treatment.