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- Ibbotson, T. & Goa, K.L. Drugs (2002) 62: 1407. doi:10.2165/00003495-200262090-00017
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Enoxaparin (enoxaparin sodium) is a low molecular weight heparin (LMWH) indicated for use in the treatment of ischaemic complications of unstable angina and non-Q wave myocardial infarction (MI). Unfractionated heparin (UFH) has for many years represented the standard in anticoagulant therapy for patients with acute coronary syndromes; however, recent studies suggest that enoxaparin is also a viable option for anticoagulant therapy in these patients.
The ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q wave Coronary Events) and the TIMI 11B (Thrombolysis in Myocardial Infarction) studies reported that twice daily enoxaparin was significantly more effective than a continuous infusion of UFH in reducing the composite triple endpoint of death, MI, or recurrent angina or urgent revascularisation. Follow-up of both patient populations showed continued benefit associated with enoxaparin. Enoxaparin has been compared with tinzaparin in the treatment of unstable coronary artery disease using a nonblind study design. There was no difference between treatment groups in the therapeutic endpoints.
Three nonblind studies have also compared the effects of enoxaparin and UFH in patients receiving thrombolytic therapy following acute MI. The HART II (Heparin and Aspirin Reperfusion Therapy), the ASSENT 3 (Assessment of the Safety and Efficacy of a New Thrombolytic Regimen) and the ENTIRE-TIMI23 (Enoxaparin and Tenecteplase with or without glycoprotein IIb/IIIa Inhibitor as Reperfusion strategy in ST Elevation MI — Thrombolysis in Myocardial Infarction) studies have revealed that enoxaparin in combination with alteplase or tenecteplase is at least equivalent (HART II and ENTIRE-TIMI 23), and possibly superior (ASSENT 3) to UFH.
Enoxaparin is administered as a twice-daily subcutaneous injection. In contrast, UFH is administered as an intravenous infusion which requires routine monitoring of the activated partial thromboplastin time to ensure adequate levels of anticoagulation are maintained. During the acute phase of the the ESSENCE and TIMI 11B studies, the incidence of major bleeding was similar in patients receiving enoxaparin to that in patients receiving UFH. In contrast, the rates of minor bleeding were higher in patients receiving enoxaparin than in those receiving UFH throughout these studies.
Conclusions: Data from the ESSENCE, TIMI 11B and ASSENT 3 studies have prompted calls for those LMWHs which have been shown to be superior to UFH, to be considered as first choice treatment for anticoagulation in unstable coronary syndromes. To date, these suggestions are not reflected in current guidelines which consider UFH and LMWHs equally. Irrespective, the clinical data reported in this review support the use of enoxaparin in the treatment of acute coronary syndromes. These data suggest that enoxaparin shows certain clinical and practical advantages over standard treatment with UFH and represents an important development in the treatment of acute coronary syndromes.
Overview of Pharmacology
Enoxaparin (enoxaparin sodium) is produced through depolymerisation of unfractionated heparin (UFH) and consists of polysaccharide chains with an average molecular weight of about 4 to 5kD. The primary anticoagulant effect of enoxaparin is mediated via a conformational interaction with antithrombin III which, in turn, inactivates procoagulatory serine proteases. Thus, the indirect consequence of enoxaparin is inhibition of the conversion of prothrombin to thrombin, thus reducing the thrombin-mediated conversion of fibrinogen to fibrin and preventing the formation of clots.
In pharmacodynamic studies, enoxaparin inhibited thrombus formation but had only minor effects on platelet activation. Enoxaparin had little effect on platelets in vivo [in patients with unstable angina (UA)] and ex vivo (from volunteers), whereas UFH activated platelets in vivo and enhanced platelet aggregability ex vivo. However, other clinical evidence suggests that UFH is a more potent inhibitor of platelet aggregation than enoxaparin. Enoxaparin also inhibits platelet prothrombinase activity and tissue factor-mediated prothrombinase assembly in blood samples taken from patients receiving enoxaparin for the treatment of UA/non-ST-segment elevation myocardial infarction (MI). Plasma samples taken from these patients 1 and 30 hours after initiation of enoxaparin treatment indicated that the drug inhibited tissue factor-mediated prothrombinase assembly by 31.2 and 11.3%, respectively, and platelet prothrombinase activity by 27.5 and 21.9%, respectively.
The pharmacokinetics of enoxaparin are based on measurement of antifactor Xa activity. Following subcutaneous administration, the bioavailability of enoxaparin is 92% and time to reach peak plasma antifactor Xa activity is 3 to 5 hours. There is a linear dose relationship for antifactor Xa activity and the area under the antifactor Xa activity-time curve over the dose range 20 to 80mg. Elimination half-life (t½) of enoxaparin is 4.5 hours, and elimination is via the kidneys and independent of dosage. In patients with end-stage renal disease t½ is prolonged to 8.2 hours and apparent total body clearance is 0.0114 L/h/kg. In obese but otherwise healthy volunteers, the maximum amount of the drug in the body was 15% higher and t½was 9% longer than that in healthy volunteers. These differences were attributed to the weight-adjusted dosage used in this study.
In Patients with Non- ST Segment Elevation Acute Coronary Syndromes
The ESSENCE study (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q wave Coronary Events) was a double-blind, double-dummy, placebo-controlled study performed in patients who had experienced angina at rest or with non-Q wave MI. 3171 patients were randomised to receive subcutaneous enoxaparin (n = 1607; 1 mg/kg every 12 hours) or UFH (n = 1564) as an intravenous bolus (usually 5000IU) followed by a continuous infusion at a dose that was adjusted according to the activated partial thromboplastin time (aPTT) for 2 to 8 days. All patients also received 100 to 325mg of oral aspirin daily. The primary outcome of this study (a composite triple endpoint of death, MI or recurrent angina after 14 days) was significantly lower in patients receiving enoxaparin than in those receiving UFH (16.6 vs 19.8%, p = 0.019).
A retrospective 1 -year follow-up of the ESSENCE study was performed using the same composite triple endpoint of death, MI or recurrent angina as the primary endpoint in 2915 patients. The incidence of the composite triple endpoint at 1 year was significantly lower in patients who received enoxaparin than in patients who received UFH (32.0 vs 35.7%, p = 0.022). The secondary composite double endpoint of death or MI was not significantly different between treatment groups; however, patients who received enoxaparin showed significantly lower rates of cardiac catheterisation (55.8 vs 59.4%, p = 0.036) and coronary revascularisation (35.9 vs 41.2%, p = 0.002) than patients receiving UFH.
The TIMI 11B study (Thrombolysis In Myocardial Infarction) examined the effects of an extended course of enoxaparin compared with UFH for prevention of death and cardiac ischaemic events in patients with UA/non-Q wave MI. It was a double-blind study comprising acute and outpatient phases. During the acute phase, patients were randomised to treatment with UFH (intravenous bolus of 70 IU/kg and an initial infusion of 15 IU/kg/h; n = 1957) or enoxaparin (intravenous bolus of 30mg followed by subcutaneous injections of 1 mg/kg every 12 hours; n = 1953) for between 3 and 8 days. All patients also received aspirin (100 to 325 mg/day). During the outpatient phase patients received either subcutaneous enoxaparin (40mg) or placebo every 12 hours for a further 35 days after hospital discharge. The primary efficacy measure (a composite endpoint of mortality, recurrent MI or urgent revascularisation measured at day 8) was significantly different between treatment groups (enoxaparin 12.4 vs UFH 14.5%, p = 0.048). When the components of the triple endpoint were considered individually, the rates of MI at day 8 were significantly lower in the enoxaparin treatment group than in the UFH treatment group (3.4 vs 4.8%, p = 0.028). Death, urgent revascularisation and the composite double endpoint of death/Ml did not differ between treatment groups at day 8. Similar numbers of patients from each treatment group progressed to the outpatient phase of the study (enoxaparin n = 1179, UFH n = 1185). The incidence of the primary endpoint was 17.3% in patients receiving enoxaparin and 19.7% in patients receiving placebo at day 43.
In the ESCAPEU study (Efficacy, Safety, Cost and Platelet Aggregation Effects of Enoxaparin and Unfractionated Heparin), patients with UA were randomised to nonblind treatment with either enoxaparin (n = 51) or UFH (n = 42) for at least 72 hours. After 7 days of therapy, the composite risk of death, MI, revascularisation or recurrent angina (the primary endpoint) was significantly lower in patients receiving enoxaparin than in patients receiving UFH (37% vs 62%, p = 0.04); however, there was no statistical difference between the treatment groups when each of the endpoints were considered individually.
Enoxaparin and tinzaparin have been compared in the treatment of unstable coronary artery disease in a nonblind study (Enoxaparin Versus Tinzaparin in the management of unstable coronary artery disease; EVET). Patients with UA or non-Q wave MI were randomised to receive either subcutaneous enoxaparin (100 IU/kg twice daily; n = 220) or tinzaparin (175 IU/kg once daily; n = 218) for 7 days. There was no statistical difference between treatment groups in three out of four primary study endpoints (death, MI and refractory angina) at 7 days; however, UA was experienced less frequently by patients receiving enoxaparin than by those receiving tinzaparin (10.9 vs 18.8%, p = 0.029). Revascularisation at day 30 was significantly less frequent in patients receiving enoxaparin than in those receiving tinzaparin (16.4 vs 26.1%, p = 0.019).
Combined with Thrombolytic Therapy in Patients with Persistent ST Segment Elevation Acute Coronary Syndromes
The HART II (Heparin and Aspirin Reperfusion Therapy) study was a non-blind randomised study that compared enoxaparin and UFH given as adjunctive treatment with alteplase in patients undergoing reperfusion therapy for acute MI (n = 380 evaluable). All patients received alteplase and aspirin, and were then randomised to treatment with either enoxaparin or UFH. The primary endpoint of the study was 90-minute TIMI 2 and 3 reperfusion rates in all randomly assigned patients; the study was powered to demonstrate noninferiority of enoxaparin versus intravenous UFH. Patency rates (TIMI grades 2 and 3) of the infarct-related artery 90 minutes after the start of therapy were 80.1% in patients treated with enoxaparin compared with 75.1 % in the UFH group. The lower limit of the 95% confidence interval was −2.1% (criterion for noninferiority = −10%). At follow-up after 5 to 7 days, reocclusion occurred in 5.9% of patients in the enoxaparin group and 9.8% of patients in the UFH group. Reocclusion of TIMI grade 3 arteries occurred in 3.1% of enoxaparin-treated patients and 9.1% of UFH-treated patients.
The ASSENT 3 study (Assessment of the Safety and Efficacy of a New Thrombolytic regimen) compared the efficacy of enoxaparin plus tenecteplase (n = 2040), with UFH plus tenecteplase (n = 2038) and with UFH plus tenecteplase plus a glycoprotein IIb/IIIa antagonist abciximab (n = 2017), for the treatment of acute MI. The rates of the primary efficacy endpoint (a composite of 30-day mortality, in-hospital reinfarction or in-hospital refractory ischaemia) were significantly greater (p = 0.0001) in patients receiving tenecteplase in combination with UFH than in the other two treatment groups (tenecteplase plus UFH 15.4% vs tenecteplase plus enoxaparin 11.4% vs tenecteplase plus abciximab plus UFH 11.1%). The individual parameters of in-hospital reinfarction (4.2 vs 2.1 vs 2.2% respectively) and in-hospital refractory ischaemia (6.5 vs 4.6 vs 3.2%, respectively)also occurred with a significantly greater frequency (p < 0.0009) in the tenecteplase plus UFH treatment group than in the tenecteplase plus enoxaparin, or the tenecteplase plus abciximab plus UFH treatment groups.
The ENTIRE-TIMI 23 study (Enoxaparin and Tenecteplase with or without glycoprotein Ilb/IIIa Inhibitor as Reperfusion strategy in ST Elevation MI — Thrombolysis in Myocardial Infarction) compared the use of enoxaparin and UFH in patients on standard reperfusion therapy (full dose tenecteplase) and in patients receiving combination reperfusion therapy (reduced dose tenecteplase and abciximab). The primary study endpoint (TIMI 3 flow rates in the infract related artery at 60 minutes) did not differ significantly between treatment groups. When considering combination and standard therapy together the pooled rate of TIMI 3 flow was 50% in patients receiving UFH and 51% in patients receiving enoxaparin. Amongst patients receiving standard reperfusion therapy, the composite clinical endpoint of death/MI was 15.9% in patients receiving UFH and 4.4% in patients receiving enoxaparin. The rates of death/Ml were similar for patients receiving enoxaparin and those receiving UFH in the combination therapy group (enoxaparin = 5.5% vs UFH = 6.5%). When considered together, the pooled rate of death/MI was significantly higher in patients receiving UFH compared with those receiving enoxaparin (11.3 vs 4.9%, p = 0.001).
As with other LMWHs and UFH, haemorrhagic complications are the adverse events occurring most often during enoxaparin treatment. Mainly these are minor and are related to injection site reactions. Major bleeding (defined as death, transfusion of at least two units of blood, a fall in haemoglobin of ≥30 g/L, or a retroperitoneal, intracranial or intraocular haemorrhage) in several trials (ESSENCE, TIMI 11B, ASSENT 3) was experienced by up to 7% of patients with unstable coronary artery disease treated with enoxaparin or UFH. In contrast, minor bleeding was significantly more common with enoxaparin than with UFH as shown in the 3 largest trials (ESSENCE, TIMI 11B and ASSENT 3).
In Patients with Non- ST Segment Elevation Acute Coronary Syndromes
In the ESSENCE and TIMI 11B (acute phase) studies there was no significant difference in the incidence of major haemorrhagic events between patients receiving enoxaparin and patients receiving UFH. However, during the outpatient phase of the TIMI 11B study, significantly higher rates of major haemorrhage were reported by patients in the enoxaparin treatment group compared with patients in the UFH treatment group who were receiving placebo (2.9 vs 1.5%, p < 0.05). Significantly more total haemorrhagic complications were reported by patients receiving enoxaparin compared with patients receiving UFH in the ESSENCE study. Also, in the TIMI 11B study, the rates of minor haemorrhage were significantly higher in patients receiving enoxaparin compared with patients receiving UFH at all timepoints.
A comparison of enoxaparin with tinzaparin (EVET) has been conducted in patients with unstable coronary artery disease. Apreliminary account of this study has suggested that bleeding complication rates were similar in both treatment groups; however, further information awaits the full publication of this study.
Combined with Thrombolytic Therapy in Patients with ST Segment Elevation Acute Coronary Syndromes
In the HARTII study, major haemorrhage was defined with the use of the TIMI criteria: a fall in haemoglobin levels ≥ 5 g/dl, intracranial haemorrhage or cardiac tamponade. There was no difference between treatment groups (enoxaparin vs UFH both in combination with alteplase) in this study with respect to tolerability endpoints such as intracranial haemorrhage (1 vs 1%), in-hospital TIMI major haemorrhage (3.6% vs 3.0%) and mortality rate at day 30 (4.5 vs 5.0%).
In the ASSENT 3 study, a combined primary efficacy plus tolerability endpoint was defined as the primary efficacy endpoint combined with in-hospital intracranial haemorrhage or in-hospital major bleeding other than intracranial bleeding. Patients receiving tenecteplase and UFH experienced significantly higher rates (p = 0.0081) in the primary efficacy and tolerability endpoint than those receiving tenecteplase and enoxaparin, or UFH and abciximab (17.0, 13.8 and 14.2%, respectively). Major bleeding other than intracranial haemorrhage occurred less frequently (p = 0.0005) in patients receiving tenecteplase plus UFH than in the other two treatment groups (2.2, 3.0 and 4.3%, respectively). Conversely, rates of minor bleeding were significantly higher (p < 0.0001) in patients receiving tenecteplase in combination with UFH and abciximab than in those receiving tenecteplase plus UFH or tenecteplase plus enoxaparin (35.3, 18.7 and 22.6%, respectively).
In the ENTIRE-TIMI 23 study, there was no significant difference in the rates of major haemorrhage between patients on standard reperfusion therapy (full dose tenecteplase) receiving enoxaparin and those receiving UFH (1.9 vs 2.4%). The rates of major haemorrhage were generally higher in patients undergoing combination reperfusion therapy (reduced dose tenecteplase and abciximab). In this group, 5.2% of patients receiving UFH, and 8.5% of those receiving enoxaparin experienced major haemorrhage.
Dosage and Administration
Enoxaparin is indicated for use in the treatment of non-ST segment elevation acute coronary syndromes, when concurrently used with aspirin. The recommended dose of enoxaparin is 1 mg/kg given as a subcutaneous injection every 12 hours in conjunction with oral aspirin therapy (100 to 325mg once daily). Treatment should be administered for a minimum of 2 days and should continue until clinical stabilisation has been achieved.