Enoxaparin : A Review of its Pharmacology and Clinical Applications in the Prevention and Treatment of Thromboembolic Disorders.

SYNOPSIS: Enoxaparin (PK 10169) belongs to the group of low molecular weight heparins which have a greater bioavailability and longer half-life than unfractionated heparin, permitting less frequent subcutaneous administration. In well controlled trials in surgical venous thrombosis (DVT), enoxaparin has demonstrated prophylactic efficacy against venographically confirmed DVT at least equal to that observed with unfractionated heparin. Efficacy has also been demonstrated in patients at moderate risk and in limited investigations using 125I-fibrinogen scanning in nonsurgical patients at risk of DVT; in addition, enoxaparin appears to provide effective treatment of established DVT. In clinical studies, enoxaparin has also prevented coagulation of extracorporeal circulation, maintaining the patency of the circuit in patients undergoing haemodialysis. Thus, enoxaparin represents an effective alternative in the prophylaxis and treatment of thrombosis, with the convenience of less frequent administration than unfractionated heparin and the possible advantage of a lesser propensity for bleeding complications.

PHARMACODYNAMIC PROPERTIES: Enoxaparin, in common with other low molecular weight heparins, was developed in response to the observation of an apparently greater separation of its antithrombotic and haemorrhagic dose ranges, relative to unfractionated heparin; the experimental basis of this dissociation is at present incompletely understood. The low molecular weight heparins are pharmacologically distinct agents with different physicochemical properties and unique profiles. A number of their pharmacological properties have been determined to be directly proportional to their molecular weight, including affinity for antithrombin III, anti-factor Xa and anti-thrombin (anti-factor Ha) activities, and susceptibility to neutralisation by platelet factor 4 and other heparin binding proteins. Enoxaparin is prepared from heparin by benzylation followed by alkaline depolymerisation. The apparent mean molecular weight of enoxaparin, as determined by high performance liquid chromatography with ultraviolet detection, is 3.8kD. The anti-factor Xa activity of enoxaparin (units/mg) is less than that of unfractionated heparin. However, for equivalent anti-factor Xa activity, enoxaparin has up to 5 times less effect on thrombin. A ratio of 3.6 for amidolytic antifactor Xa activity to anti-thrombin activity in plasma has been reported for enoxaparin, with the value for unfractionated heparin defined as unity. In a modified stasis venous thrombosis model in the rabbit, the dose producing 50% effect (ED50) for in vivo antithrombotic activity of enoxaparin, after intravenous administration, was determined to be 58 vs 32 μg/kg for unfractionated heparin. A significantly smaller extent of blood loss with enoxaparin than with unfractionated heparin has been apparent in studies employing a rabbit ear model. Most in vitro and ex vivo studies in animal and human platelet rich plasma, primarily using collagen as inducer, indicate a somewhat lesser effect of enoxaparin to that of unfractionated heparin on platelet aggregation, and these observations provide the basis for one postulated mechanism of the apparently lesser haemorrhagic effect of enoxaparin relative to unfractionated heparin in animal models. The full clinical significance of these findings remains to be determined.

PHARMACOKINETICS: Enoxaparin is highly and predictably absorbed after subcutaneous administration. Studies in volunteers indicate that absorption of enoxaparin is linear within a subcutaneous dose range of 20 to 80mg. The absolute bioavailability of subcutaneous enoxaparin, in terms of anti-factor Xa activity, is estimated to be 9.1%, approximately 3 times higher than that of low dose unfractionated heparin. Estimates of the volume of distribution of enoxaparin in volunteers range between 5.2 and 9.3L. Enoxaparin does not appear to cross the placenta to any significant extent. While the available data are somewhat incomplete, the primary route of elimination of enoxaparin appears to be renal, in contrast with unfractionated heparin, for which additional saturable mechanisms of elimination are significant. Thus, enoxaparin appears to possess the advantage of dose-independent elimination. Total body clearance of enoxaparin in volunteers is rather low, published estimates ranging between 0.83 and 1.86 L/h. The terminal phase elimination half-life of enoxaparin, based on anti-factor Xa activity, has ranged between 3 and 6 hours following subcutaneous administration to volunteers. Although there are discordant findings in the literature, it appears that in the presence of chronic severe renal failure, enoxaparin total clearance may be halved and elimination half-life doubled.

CLINICAL EFFICACY: In total hip replacement surgery, a model of high risk for postoperative DVT, and other orthopaedic surgery, the incidence of total venographically confirmed DVT following administration of subcutaneous enoxaparin at a dosage of 40mg once daily, initiated 12 hours preoper-atively (8 hours preoperatively in a single study), has ranged from 6.5 to 12.5%; with a regimen of 30mg twice daily initiated postoperatively, the range was 6.0 to 19.5%. These figures compare with rates for placebo of between 51 and 65%, for unfractionated heparin of between 23 and 25%, and for dextran 70 of 22% in these studies. Similarly, rates of proximal DVT of between 4.0 and 7.5% for enoxaparin 40mg once daily ('preoperative' regimen), 5.4 and 6.0% for enoxaparin 30mg twice daily ('postoperative' regimen), 23% for placebo, and between 7 and 19% for unfractionated heparin were observed. A 10mg once daily regimen was found to be minimally effective, with rates of total DVT of 31%, and of proximal DVT of 15%, being observed. Studies have variously used regimens initiating enoxaparin prophylaxis either pre-or postoperatively, as well as regimens in which a small perioperative single dose was administered, with a subsequent higher-dose 'maintenance' regimen. The different administration regimens reflect differences in clinical practice in Europe and North America. A large-scale postmarketing study in 8738 patients undergoing general surgery treated with enoxaparin 20mg once daily for 7 days evinced an incidence of total DVT, albeit identified by clinical signs only, of 0.16%. Other studies using the same dosage reported a similar rate of total DVT detected by [125I]-fibrinogen scanning (2.8 to 3.8%) to that seen with unfractionated heparin 5000U 3 times daily (2.7 to 7.6%) or enoxaparin 40 or 60mg once daily (2.8 and 2.9%, respectively). Enoxaparin prophylaxis at a dosage of 60mg once daily was also effective in preventing DVT (detected by [125I]-fibrinogen scanning) in medical patients in one placebo-controlled study. In investigations in patients with venographically-confirmed recent DVT, treatment with subcutaneous enoxaparin (dosages up to 2 mg/kg/day) has produced significant reductions in venographic scores, without significant haemorrhagic complications. Enoxaparin (dosage around 1 mg/kg) has been usefully employed in preventing coagulation of the dialysis circuit in patients undergoing haemodialysis, without the occurrence of haemorrhagic episodes. In a pilot study enoxaparin provided effective anticoagulant treatment in one small series of patients with heparin-induced thrombocytopenia.

TOLERABILITY: Data from clinical trials appear to indicate a lesser potential for haemorrhagic complications with enoxaparin than with unfractionated heparin. While it is not certain that sample sizes were sufficiently large to detect a significant difference, in placebo-controlled trials in orthopaedic surgery, the incidence of bleeding episodes following postoperative enoxaparin administration (2 to 6.1%) was similar to that observed with placebo (0 to 7.7%). In a large-scale postmarketing survey in general surgery, excessive bleeding considered related to enoxaparin therapy (20mg once daily) was observed in 0.6% of patients. However, the findings from other trials in general surgery indicate that some degree of dose-dependence in the rate of bleeding complications may be observed. Ecchymoses may develop at the site of injection of enoxaparin, but their incidence is likely to be considerably less than with unfractionated heparin because of a reduced frequency of administration. There are at present no reports from clinical studies of thrombocytopenia occurring in patients receiving enoxaparin; however, the possibility of its occurrence with enoxaparin and other low molecular weight heparins cannot be excluded, and the potential risk remains to be quantified in relation to the substantial risk apparent for unfractionated heparin.

DOSAGE AND ADMINISTRATION: In prevention of postoperative DVT in patients undergoing orthopaedic surgery, subcutaneous enoxaparin doses of 40mg once daily (from 12 hours preoperatively) are employed in Europe, while a dosage of 30mg twice daily (from 12 to 24 hours postoperatively) has been used in North America; in general surgery and in 'moderate risk' patients dosages of 20mg once daily have also been employed. Enoxaparin 2 mg/kg/day is effective in the treatment of established DVT, while 1 mg/kg appears to be effective in preventing coagulation of the extracorporeal circuit in patients undergoing haemodialysis. For daily dosages higher than 60mg, the elimination of enoxaparin may be prolonged in patients with severe renal dysfunction; however, an appropriate nomogram for dosage reduction has not yet been devised.