Enoxaparin

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Abstract
Enoxaparin (enoxaparin sodium) is a low molecular weight derivative of un-fractionated heparin which has been evaluated for the treatment and prevention of thromboembolic disease. Since a previous review in Drugs, well controlled clinical trials have confirmed the effectiveness of enoxaparin as prophylaxis in patients with a high risk for deep venous thrombosis (DVT), i.e. those undergoing hip or knee replacement surgery. Enoxaparin 30mg twice daily, initiated postoperatively, offers an overall balance of prophylactic efficacy and haemorrhagic tolerability which is superior to that of unfractionated heparin. In comparative clinical trials, this dosage demonstrated either improved efficacy and a similar haemorrhagic profile, or a similar degree of efficacy with a lower rate of haemorrhagic events, compared with unfractionated heparin 5000IU 3 times daily. Limited data indicate that an enoxaparin regimen of 40mg once daily, starting preoperatively, is more effective than unfractionated heparin in patients undergoing hip replacement and has a comparable haemorrhagic profile. In patients with a moderate risk for DVT, enoxaparin is similar to unfractionated heparin in both efficacy and haemorrhagic profile, while preliminary investigations have demonstrated the utility of enoxaparin in the prevention of DVT in elderly, nonsurgical patients. Enoxaparin may also be useful for the treatment of existing DVT and as an anticoagulant in haemodialysis. Thus, enoxaparin is an effective form of prophylaxis f or thromboembolic disease in moderate to high risk surgical situations. Recent evidence for improved efficacy, together with a similar incidence of haemorrhagic complications in most situations, may lead to enoxaparin being preferred to unfractionated heparin for the routine prevention of DVT after high risk surgery. Although detailed comparisons with other low molecular weight heparins and antithrombotic agents are required before its relative clinical utility can be fully assessed, enoxaparin is likely to play a significant role in the prophylaxis of thromboembolic disorders. Enoxaparin is a low molecular weight heparin (average molecular weight 4 to 5kD) which is produced from benzylated unfractionated heparin by alkaline depolymerisation. The principal pharmacological properties of enoxaparin include binding affinity for anti-thrombin III, anti-factor Xa activity and anti-factor IIa (anti-thrombin) activity. However, as a consequence of distinct structure-activity relationships common to all heparin molecules, the relative contributions of these properties to the overall activity of enoxaparin are significantly different from those of unfractionated heparin and other low molecular weight heparins. Enoxaparin has been reported to have a lower anti-factor IIa activity than anti-factor Xa activity, and for an equivalent level of anti-factor Xa activity it has approximately 5 times less anti-factor IIa activity than unfractionated heparin. Enoxaparin appears to inhibit thrombin directly but also inhibits the generation of thrombin by the prothrombinase enzyme complex; the relative clinical importance of these different activities remains to be fully determined. The significance of peripheral effects involving enoxaparin, such as resistance to inhibition by platelet factor 4, effects on platelets, release of tissue factor pathway inhibitor, and nonspecific binding to plasma proteins, also remains unclear. Data from several animal models suggest that enoxaparin has a more favourable haemorrhagic profile than unfractionated heparin, and this is supported by limited information from healthy human volunteers. Enoxaparin has an anti-factor Xa bioavailability after subcutaneous administration which is significantly greater than that of unfractionated heparin (91 vs 29%) and exhibits a linear dose-response relationship over a range of clinical doses. The volume of distribution of enoxaparin is estimated to be between approximately 5 and 9L, and the drug does not appear to cross the placenta to any significant extent. Elimination is believed to occur primarily by a nonsaturable renal mechanism, although the available data are contradictory. Following single dose subcutaneous administration to healthy volunteers, enoxaparin has an elimination half-life of between 3 and 5 hours and total body clearance of 0.8 to 1.9 L/h. Clinical trials conducted since the previous review in Drugs have confirmed the efficacy of enoxaparin in the prophylaxis of DVT after total hip or knee replacement surgery, both of which are high risk contexts for DVT. The rates of DVT were significantly lower with enoxaparin 30mg twice daily than with un-fractionated heparin 5000IU 3 times daily (5 to 25% vs 12 to 34%) and warfarin (37 vs 50%) when all treatments were initiated postoperatively. In comparisons with unfractionated heparin published to date, enoxaparin 30mg twice daily, initiated postoperatively, yielded either lower rates of DVT and a similar degree of haemorrhagic complications, or comparable prophylactic efficacy with a superior haemorrhagic profile. A preoperatively initiated dosage of enoxaparin 40mg once daily has produced improved efficacy with respect to unfractionated heparin, with a similar rate of bleeding events, although data supporting these results would be useful. Clinical comparisons with other antithrombotic agents in a high risk setting are somewhat limited; while enoxaparin appears superior to warfarin or dextran-70, comparative findings with other low molecular weight heparins are only now beginning to emerge, and this is an important area for further investigation. Enoxaparin was similar in efficacy to unfractionated heparin in clinical trials involving patients with a moderate risk for DVT. The rates of DVT in these studies were 0.5 to 8% for enoxaparin compared with 1 to 7.6% for unfractionated heparin. Enoxaparin 20mg once daily, initiated preoperatively, was used in all investigations and produced a similar incidence of bleeding complications to unfractionated heparin. In a study of 9919 patients undergoing general surgery, the overall incidence of DVT with this enoxaparin dosage was 0.1%. Pulmonary embolism was observed in 0.24% of the patients in this trial and was also generally rare (0 to 0.18%) in the few comparative clinical studies which provided such details. Previous indications of a role for enoxaparin in the treatment of existing DVT are supported by more recently published findings. For treatment of acute DVT, enoxaparin 1 mg/kg twice daily was more effective than unfractionated heparin in reducing thrombus size. After acute treatment with full-dose unfractionated heparin, prevention of recurrent thromboembolism after 3 months was similar with enoxaparin 40mg once daily or oral warfarin. The relative efficacy of the 2 drugs over a longer period remains to be fully determined. Enoxaparin appears to be effective in preventing coagulation during haemo-dialysis and as prophylaxis for arterial thrombosis. However, definitive clinical information on the relative efficacy of enoxaparin compared with other agents has yet to be published in these indications. The most common and potentially serious adverse event with enoxaparin is haemorrhage. Minor bleeding events occurred in 7.1 % and major bleeding events occurred in 4.4% of 407 patients who received enoxaparin 30mg twice daily or 40mg once daily postoperatively in a well controlled dose-ranging study. Excessive bleeding occurred in 3.3% of 9919 patients who had undergone general surgery and who received enoxaparin 20mg once daily. An improved haemor-rhagic profile for enoxaparin compared with unfractionated heparin was suggested by limited data available at the time of the previous review in Drugs, but most subsequent studies have reported similar incidences of haemorrhagic complications for the 2 drugs. In comparative trials, the rate of major bleeding events with enoxaparin was 0.4 to 4% while the rate of minor bleeding was 0.4 to 28%, compared with 0 to 5.7% and 1.8 to 23.4% for the same events, respectively, in patients receiving other anticoagulants. Adverse skin reactions have been documented with enoxaparin but appear to be relatively rare. Moderate thrombocytopenia has been reported infrequently, occurring in <2.5% of patients receiving enoxaparin in a small number of clinical trials. Pooled US clinical trial data yielded a total incidence of 22% for non-haemorrhagic adverse events with enoxaparin, compared with 25% for unfractionated heparin. Rates for specific non-haemorrhagic adverse events such as confusion and nausea were 2 to 4% with enoxaparin and 1 to 7% with unfractionated heparin. Subcutaneous enoxaparin 30mg twice daily, initiated postoperatively, has been used in the US for the prevention of DVT after high risk surgery. In Europe, a preoperatively initiated regimen of 40mg once daily has been favoured. For moderate risk surgical procedures, subcutaneous enoxaparin 20mg once daily, initiated preoperatively, is the preferred doasage. Treatment duration is usually 7 to 14 days for both high and moderate risk situations and there is usually no need for daily monitoring. Dosage optimisation studies are required before definitive dosage recommendations regarding the use of enoxaparin in the treatment of existing DVT and in the prevention of clotting in the haemodialysis circuit can be made. Elimination of enoxaparin may be reduced in patients with chronic renal failure but no recommendations for dosage adjustment have been made. Combined use of low molecular weight heparins and the nonsteroidal analgesic ketorolac may cause potentiation of haemostatic effects and caution is advised.

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