Enoxaparin

Enoxaparin (enoxaparin sodium; Lovenox®) is a low-molecular-weight heparin (LMWH) that has recently been approved by the US FDA for use in patients with medically managed ST-segment myocardial infarction (STEMI), or STEMI with subsequent percutaneous coronary intervention (PCI). It binds to and potentiates the action of antithrombin, and inhibits coagulation factors XIa, IXa, Xa and IIa (thrombin), thereby preventing formation of blood clots. Unfractionated heparin (UFH) has long been regarded as the antithrombotic agent of choice in the adjunctive treatment of patients with STEMI. However, compared with UFH, enoxaparin has many advantages in terms of its pharmacodynamic profile and, potentially, also its efficacy.

Enoxaparin was significantly more effective than UFH in patients presenting with STEMI who underwent fibrinolytic therapy in terms of the 30-day combined incidence of all-cause mortality plus recurrent nonfatal myocardial infarction (MI) [primary endpoint], and all-cause mortality plus recurrent nonfatal MI plus urgent revascularization (secondary endpoint) in the ExTRACT-TIMI 25 trial. The significant difference in the incidence of the composite primary endpoint between these two groups was maintained at the 1-year follow-up. Although bleeding was reported more frequently with enoxaparin than with UFH in the ExTRACT-TIMI 25 trial, enoxaparin was associated with a net clinical benefit relative to UFH. Patients in this trial received enoxaparin as an initial 30 mg intravenous bolus, followed by 1 mg/kg subcutaneously within 15 minutes and then every 12 hours for up to 8 days; the first two subcutaneous dosages were not to exceed 100 mg. Patients ≥75 years of age did not receive the initial bolus of enoxaparin and the 12-hourly dosages were reduced to 0.75 mg/kg; the dose was also reduced to 1 mg/kg every 24 hours in patients of any age who had an estimated creatinine clearance (CL_CR) of <30 mL/min. Data from several earlier randomized, multicentre, phase III trials support these results.

Enoxaparin is an LMWH of a variable size, with an average molecular weight of 4–5 kD. It prevents the formation of blood clots by binding to antithrombin and potentiating its action, as well as by inhibiting coagulation factors XIa, IXa, Xa and IIa (thrombin). The pharmacodynamic profiles of LMWHs, such as enoxaparin, have many advantages when compared with that of UFH. Advantages include minimal plasma binding, leading to more reliable anticoagulant effects (thereby eliminating the need for therapeutic monitoring), a greater capacity to release tissue factor pathway inhibitor, a higher anti-factor Xa: IIa ratio, a lower propensity to inhibit platelet aggregation, less inhibition by platelet factor 4, potential antiplatelet effects via higher degrees of suppression of von Willebrand factor and a lesser propensity to cause heparin-induced thrombocytopenia and osteoporosis.

Following subcutaneous administration, enoxaparin demonstrates high bioavailability and has a linear pharmacokinetic profile over the normal therapeutic dose range. The pharmacokinetics of enoxaparin are based on anti-factor Xa activity. Following administration of subcutaneous enoxaparin 1.5 mg/kg once daily for 5 days, the mean peak plasma anti-factor Xa activity was 1.37 IU/mL and the steady-state area under the plasma activity-time curve was 14.26 IU · h/mL; the apparent volume of distribution has been reported as 4.3–9.3 L.

Enoxaparin is predominantly metabolized by the liver and is eliminated renally. The clearance of anti-factor Xa activity at steady state has been shown to decline with increasing renal dysfunction and hence, the dosage of enoxaparin must be reduced in patients with severe renal impairment (CLcr <30 mL/min). The pharmacokinetics of a non-weight-adjusted single subcutaneous 40-mg dose of enoxaparin differ depending upon the weight of the patient.

In patients with STEMI who received fibrinolytic therapy, enoxaparin was significantly more effective than UFH in reducing the 30-day combined incidence of all-cause mortality plus recurrent nonfatal MI (primary endpoint), and all-cause mortality plus recurrent nonfatal MI plus urgent revascularization (secondary endpoint) in the ExTRACT-TIMI 25 trial. Moreover, the significant difference between the two groups at the primary endpoint was still evident 1 year later. In addition, enoxaparin was superior to UFH as adjunctive therapy in patients with STEMI in terms of the incidence of three combined efficacy-safety endpoints. When data was stratified according to baseline CL_CR levels, there was no difference in the incidence of the primary endpoint between enoxaparin and UFH recipients in those with severe renal dysfunction, but a difference in favour of enoxaparin emerged as renal function improved. The incidence of the primary endpoint was lower in fibrin-specific lytic recipients who received enoxaparin than UFH; however, there was no statistically significant difference between the two groups in those who received streptokinase as their lytic therapy. In those patients who underwent PCI, the incidence of the primary endpoint was significantly lower in enoxaparin than UFH recipients, and fewer patients receiving enoxaparin than UFH underwent PCI.

In this randomized, double-blind, double-dummy, parallel-group, multicentre, phase III trial, enoxaparin was administered as an initial 30 mg intravenous bolus, followed by 1 mg/kg subcutaneously within 15 minutes and then every 12 hours for up to 8 days; the first two subcutaneous dosages were not to exceed 100 mg. Patients ≥75 years of age did not receive the initial bolus of enoxaparin and the 12-hourly dosages were reduced to 0.75 mg/kg; the dose was also reduced to 1 mg/kg every 24 hours if patients of any age had an estimated CL_CR of <30 mL/ min. Efficacy outcomes from this study have been supported by the results of several earlier randomized, double-blind, phase III trials that compared enoxaparin with UFH or placebo, and established both its clinical and angiographic efficacy.

As expected, bleeding complications were the most frequently occurring adverse events associated with enoxaparin use in clinical trials. Minor bleeding accounted for the majority of events and occurred at a significantly greater incidence in enoxaparin recipients than in UFH recipients in the ExTRACT-TIMI 25 trial. The incidence of major bleeds also occurred at a higher incidence in enoxaparin recipients than in UFH recipients in this trial. However, intracranial haemorrhage occurred at a similar incidence in the two groups.

Other adverse effects associated with enoxaparin use include local reactions, such as mild local irritation, pain, haematoma, ecchymosis and erythema. In addition, fully reversible elevations in AST or ALT levels have been reported in patients receiving enoxaparin; these laboratory abnormalities have also been seen in patients receiving heparin and other LMWHs in clinical trials.