In Review Of Use In Stemi

ADIS DRUG EVALUATION

Drugs 2008; 68 (5): 691-710 0012-6667/08/0005-0691/$53.45/0 © 2008 Adis Data Information BV. All rights reserved.

Enoxaparin A Review of its Use in ST-Segment Elevation Myocardial Infarction Natalie J. Carter, Paul L. McCormack and Greg L. Plosker Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer Health, Conshohocken, Pennsylvania, USA Various sections of the manuscript reviewed by: E.M. Antman, Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts, USA; E.R. Bates, Institute of Medical/Cardiology, University of Michigan, Ann Arbor, Michigan, USA; R. Corbalan, Hospital Clinico de la Universidad Catolica de Chile, Piso, Chile; J. Lopez-Sendon, Cardiology Department, Hospital Universitario La Paz, Madrid, Spain; I.B.A. Menown, Craigavon Cardiac Centre, Craigavon Area Hospital, Craigavon, Northern Ireland; J.C. Nicolau, Heart Institute, University of S˜ao Paulo Medical School, S˜ao Paulo, Brazil; F. Van de Werf, Department of Cardiology, University of Leuven, Leuven, Belgium. Data Selection Sources: Medical literature published in any language since 1980 on ‘enoxaparin’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug. Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘enoxaparin’ and ‘ST-segment elevation myocardial infarction’, ‘ST-elevation myocardial infarction’ or ‘STEMI’. Searches were last updated 12 March 2008. Selection: Studies in patients with ST-segment elevation myocardial infarction who received enoxaparin. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included. Index terms: Enoxaparin, ST-segment elevation myocardial infarction, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

Contents Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694 2. Overview of Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694 2.1 Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694 2.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 695 3. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696 3.1 The ExTRACT-TIMI 25 Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696 3.1.1 Primary Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 697 3.1.2 Subgroup Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698 3.2 Other Randomized Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701 3.2.1 Clinical Efficacy versus Unfractionated Heparin (UFH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701 3.2.2 Angiographic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703 3.3 Meta-Analysis of All Randomized Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 704 4. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 704

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5. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 706 6. Place of Enoxaparin in the Management of Patients with ST-Segment Elevation Myocardial Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 706

Summary Abstract

Pharmacological Properties

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 (CLCR) 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

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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. Therapeutic Efficacy

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 CLCR 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 CLCR 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.

Tolerability

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.

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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.

1. Introduction The development of reperfusion strategies over the last three decades has resulted in considerable advances in the management of patients presenting with ST-segment elevation myocardial infarction (STEMI).[1,2] Despite there being a reduction in inhospital mortality levels over this time, there has been little improvement in the overall survival of patients with STEMI in the past decade, possibly reflecting in part the suboptimal improvement in coronary reperfusion, the recurrence of myocardial infarction (MI) and the bleeding complications, such as intracranial haemorrhage (ICH), that can occur as a result of fibrinolytic therapy.[1,3,4] As a result, STEMI remains a significant public health issue in all industrialized countries and is becoming more so in developing countries.[2] US estimates predict 565 000 first-time cases, and 300 000 recurrent cases, of MI annually.[5] It has also been estimated that the number of years of life lost due to an MI can be as many as 15 years, and that those patients with a history of previous STEMI have a sudden death rate that is 4- to 6-fold higher than that of the general population.[5] Therefore, there remains a need for new and improved treatment strategies for patients with STEMI. Current US[2,6] and European[7] guidelines recommend a multimodal approach for the treatment of STEMI that includes reperfusion (either medical or via subsequent percutaneous coronary intervention [PCI]), along with adjuvant antiplatelet and antithrombin agents. Despite there having been a number of advances with respect to the first two modalities in recent years, there has been relatively little progress in the development of new an-

tithrombin therapies, and unfractionated heparin (UFH) has long been the agent of choice.[2,6-8] However, UFH has a number of potential limitations, such as the difficulty in maintaining therapeutic plasma levels necessitating frequent monitoring and dose adjustment (section 6).[8,9] The use of enoxaparin (enoxaparin sodium; Lovenox®),1 a low-molecular-weight heparin (LMWH), has recently been studied in patients with STEMI[3,4,8-12] and may offer benefits over UFH as the adjuvant antithrombotic of choice in these patients. This article reviews the pharmacological properties, clinical efficacy and tolerability of subcutaneous enoxaparin in adult patients with STEMI. 2. Overview of Pharmacology Enoxaparin is an LMWH produced by controlled depolymerization of a benzyl ester of UFH using sodium hydroxide.[13] It has a variable size, with an average molecular weight of 4–5 kD.[13] The pharmacodynamic and pharmacokinetic properties of enoxaparin have been reviewed previously.[13-16] This section provides a brief overview of its major pharmacological properties. 2.1 Pharmacodynamics

Enoxaparin, like UFH, binds to and potentiates the action of antithrombin, which is an endogenous inhibitor of coagulation factors XIa, IXa, Xa and IIa (thrombin). Inhibition of these serine proteases inhibits the coagulation cascade and prevents formation of blood clots.[14] Enoxaparin has also been shown to cause the release of tissue factor pathway inhibitor (TFPI) and to inhibit the generation of factor VIIa.[16] While the interaction of enoxaparin

1 Other trade names include Clexane®, Decipar® and Klexane®. The use of trade names is for identification purposes only and does not imply endorsement. © 2008 Adis Data Information BV. All rights reserved.

Drugs 2008; 68 (5)

Enoxaparin: A Review

with the coagulation cascade is complex, inhibition of factors Xa (which converts prothrombin to thrombin) and IIa (which converts fibrinogen to fibrin) are central to its action.[13] As a result of its low molecular weight, enoxaparin has markedly lower anti-factor IIa activity than UFH, while its anti-factor Xa activity is not affected.[14] Therefore, enoxaparin has a higher ratio of anti-factor Xa to IIa activity (variously estimated between 3.6 : 1 and 14 : 1) than UFH (1 : 1).[13,16] A high ratio of anti-factor Xa to IIa activity has been linked to a lesser tendency to cause bleeding.[14] However, this has not been borne out in clinical studies (section 4). Although enoxaparin and UFH produce similar increases in free TFPI concentrations following single-dose administration, total TFPI activity is partially depleted after continuous, multiple-dose, subcutaneous administration of UFH, but not of enoxaparin.[14] The effects of enoxaparin on platelets (either platelet activation or inhibition of platelet aggregation) are less pronounced than those of UFH.[14,15] Although the lower propensity of enoxaparin to inhibit platelet aggregation suggests a lower tendency to cause bleeding, this has not been shown in clinical studies (section 4). Platelet factor 4, which is released by activated platelets, almost completely inactivates UFH, but has only minor effects on enoxaparin. The anti-factor Xa activity of enoxaparin is almost completely retained and the antifactor IIa activity is only partially reduced.[14] The reduced interaction with platelets may be responsible for the reduced incidence of heparin-induced thrombocytopenia observed with enoxaparin.[14] Furthermore, unlike UFH, enoxaparin does not promote platelet retention in fibrin clots.[14] Enoxaparin binds with lower affinity than UFH to endothelial cells, which may explain its higher bioavailability following subcutaneous administration. The lower propensity of enoxaparin than UFH to bind nonspecifically to a variety of plasma proteins may explain its lower variability in pharmacodynamic effects relative to UFH.[14] © 2008 Adis Data Information BV. All rights reserved.

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Enoxaparin appears to inhibit bone formation to a much lesser extent than UFH, indicating a lower propensity to produce osteoporotic effects.[14] Enoxaparin has also been shown to differ from UFH in that it reduces the release of von Willebrand factor, which mediates platelet adhesion to exposed subendothelium and, thereby, protects patients with acute coronary syndromes.[14] 2.2 Pharmacokinetics

The pharmacokinetics of enoxaparin are based on anti-factor Xa activity, rather than direct detection of the molecular species, and have predominantly been determined using the 100 mg/mL formulation. Following subcutaneous administration, enoxaparin demonstrates high bioavailability (≈100%).[17] The pharmacokinetics of subcutaneous enoxaparin are linear over the normal therapeutic dosage range and steady state is normally achieved by the second day of treatment.[13,17] Single-dose pharmacokinetics of enoxaparin are a good indicator of the steady-state activity levels. Peak plasma antifactor Xa activity (Amax) generally occurs 3–5 hours after single-dose subcutaneous administration.[17] The mean Amax values in healthy volunteers receiving single-dose subcutaneous enoxaparin 20 and 40 mg were 0.16 and 0.38 IU/mL, while the Amax following subcutaneous enoxaparin 1.5 mg/kg once daily for 5 days was 1.37 IU/mL and the steady-state area under the plasma activity-time curve (AUC) was 14.26 IU • h/mL.[17] Following a 30 mg intravenous bolus, immediately followed by 1 mg/kg subcutaneously, then 1 mg/kg subcutaneously every 12 hours, the initial Amax was 1.16 IU/mL and the average exposure was 84% of steady-state levels.[17] The apparent volume of distribution of enoxaparin has been reported to be between 4.3 and 9.3 L.[13,15-17] Enoxaparin is predominantly metabolized in the liver by desulfation or depolymerization to lower molecular weight species with substantial loss of biological activity and is eliminated renally.[17] After intravenous administration of radiolabelled enoxaparin, 40% of the radioactivity and 8–20% of the anti-factor Xa activity were recovered in the urine Drugs 2008; 68 (5)

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within 24 hours.[17] The total body clearance of intravenous enoxaparin is 26 mL/min, while the apparent clearance of subcutaneous enoxaparin is about 15 mL/min.[17] The elimination half-life of enoxaparin is ≈4.5 hours after a single subcutaneous dose and ≈7 hours at steady state; however, substantial anti-factor Xa activity remains in plasma for ≈12 hours after the administration of subcutaneous enoxaparin 40 mg once daily.[17] The clearance of anti-factor Xa activity at steady state declines with increasing renal dysfunction, necessitating dosage reduction in patients with severe renal impairment (creatinine clearance [CLCR] <30 mL/min) [section 5].[17] The maximum plasma activity and clearance of subcutaneous enoxaparin in elderly subjects were similar to those in young subjects. The AUC at steady state (day 10) in elderly subjects was ≈15% higher than the AUC on day 1.[17] The pharmacokinetics of weight-adjusted dosages of enoxaparin at steady state were generally similar in obese and non-obese volunteers, but with a non-weight-adjusted single subcutaneous 40 mg dose, the exposure to enoxaparin was 52% higher in low-weight women (<45 kg) and 27% higher in lowweight men (<57 kg) than in normal-weight volunteers.[17] 3. Therapeutic Efficacy The efficacy of enoxaparin in patients with STEMI has been evaluated in several fully published, randomized, multicentre, phase III clinical trials (see table I for acronyms).[3,4,8-12] The majority of data in this section are from a large, randomized, double-blind, double-dummy, parallel-group, multicentre, phase III trial, known as the ExTRACTTIMI 25 study. Overall results of this study are available in one main article (section 3.1)[10] and a further seven articles[18-24] report data from pre-specified subgroup analyses (section 3.1.1). Additional ExTRACT-TIMI 25 trial data are from an abstract reporting 1-year results,[25] as well as from the manufacturer’s prescribing information.[17] Supplementary data from six other randomized trials are also discussed (section 3.2),[3,4,8,9,11,12] as © 2008 Adis Data Information BV. All rights reserved.

Table I. Enoxaparin clinical trial acronyms AMI-SK

Acute Myocardial Infarction-StreptoKinase

ASSENT-3 and ASSENT-3 PLUS

ASsessment of the Safety and Efficacy of a New Thrombolytic regimen

ENTIRE-TIMI 23

ENoxaparin and TNK-tPA with or without GP IIb/IIIa Inhibitor as REperfusion strategy in ST-elevation myocardial infarctionThrombolysis In Myocardial Infarction

ExTRACT-TIMI 25 Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction TreatmentThrombolysis in Myocardial Infarction HART II

Heparin and Aspirin Reperfusion Therapy

well as results of a large meta-analysis of randomized trials in patients with STEMI who received either enoxaparin or UFH (section 3.3).[26] Patients eligible for these trials were ≥18 years,[3,4,8-11] had symptoms of ischaemia that lasted for ≥30 minutes[8,9,12] and occurred ≤6[3,4,8,10] to 12[11] hours prior to randomization, had ST-segment elevation of ≥0.1 mV in two or more limb leads,[3,4,8-10] ≥0.2 mV in two or more contiguous precordial leads,[3,4,8-10] or ≥1 mm in two or more contiguous leads,[12] or a left bundle branch block.[3,4,10] In one study, patients with a left bundle branch block on ECG were excluded from the trial.[8] In the ExTRACT-TIMI 25 trial,[10] patients were eligible for inclusion only if they had planned reperfusion with streptokinase, tenecteplase, alteplase or reteplase. Patients were excluded from the trials if they had a cardiovascular, haematological or other disorder, or had received prior or concomitant pharmacological therapy that would place them at an unacceptable risk of serious bleeding from the administration of a fibrinolytic agent.[3,4,8,10,11] Patients with known renal insufficiency (serum creatinine >2.5 mg/dL for men and >2.0 mg/dL for women)[3,4,8,10,11] or other serious medical illness[10] were also excluded. 3.1 The ExTRACT-TIMI 25 Study

In addition to fibrinolytic therapy, patients were randomized 1 : 1 to receive enoxaparin 30 mg as an initial intravenous bolus, followed within 15 minutes by a 1 mg/kg subcutaneous dose that was repeated every 12 hours (maximum dose for first two subcutaneous dosages was 100 mg) for 8 days or Drugs 2008; 68 (5)

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until hospital discharge (whichever occurred earlier), or UFH 60 U/kg (up to a maximum of 4000 U) as an initial intravenous bolus, followed by an intravenous infusion of 12 U/kg/h (up to a maximum of 1000 U/h) for at least 48 hours.[10] To minimize the risk of enoxaparin accumulation in patients aged ≥75 years, the 12-hourly subcutaneous dosages of enoxaparin were reduced from 1 to 0.75 mg/kg and the initial 30 mg intravenous bolus was omitted in this age group.[10] The dose was also reduced to 1 mg/kg every 24 hours in patients of any age who had an estimated CLCR of <30 mL/min.[10] Study medication was administered between 15 minutes prior to, and 30 minutes following, the commencement of fibrinolytic therapy.[10] All patients received aspirin (acetylsalicylic acid) or an alternative antiplatelet agent.[10] The primary efficacy endpoint was the composite of all-cause mortality and nonfatal recurrent MI in the first 30 days following randomization.[10] The main secondary endpoint was the composite of 30-day all-cause mortality, nonfatal recurrent MI and recurrent myocardial ischaemia leading to urgent revascularization.[10] Other endpoints included the individual components of the primary and secondary endpoints, as well as three combined efficacysafety endpoints that were designed to give an indi-

cation of the net clinical benefit of enoxaparin relative to UFH.[10] A total of 20 506 patients were randomized in the ExTRACT-TIMI 25 study and 20 479 were included in the intention-to-treat population.[10] Baseline characteristics were similar between the enoxaparin (n = 10 256) and UFH (n = 10 223) groups. The mean treatment duration was 6.6 days for enoxaparin recipients and 2.2 days for UFH recipients.[17] 3.1.1 Primary Analysis

At day 30, the combined incidence of all-cause mortality plus nonfatal recurrent MI (primary endpoint), and all-cause mortality plus nonfatal recurrent MI plus urgent revascularization (secondary endpoint), was significantly lower in patients who received enoxaparin than in those who received UFH (both p < 0.001; table II).[10] When each component of these endpoints was analysed separately, a significant difference was seen between enoxaparin and UFH for the endpoints of nonfatal recurrent MI and urgent revascularization (both p < 0.001), but not for the endpoint of all-cause mortality (table II).[10] In addition, enoxaparin was superior to UFH with respect to net clinical benefit, as evidenced by the lower incidence of the three pre-specified combined

Table II. Efficacy of enoxaparin (ENO) as an adjunct to fibrinolytic therapy in ST-segment elevation myocardial infarction: results of the randomized, double-blind ExTRACT-TIMI 25 study.[10] See text for trial design and dosage details Study endpoint

Incidence 30 d after randomization (% of pts)

Relative risk

ENO (n = 10 256)

UFH (n = 10 223)

(95% CI)

9.9*

12.0

0.83 (0.77, 0.90)

11.7*

14.5

0.81 (0.75, 0.87)

Primary efficacy endpoint Death or nonfatal reMI Secondary efficacy endpoint Death, nonfatal reMI or urgent revascularization Other efficacy endpoints Death

6.9

7.5

0.92 (0.84, 1.02)

Nonfatal reMI

3.0*

4.5

0.67 (0.58, 0.77)

Urgent revascularization

2.1*

2.8

0.74 (0.62, 0.88)

Net-clinical-benefit endpoints Death, nonfatal reMI or nonfatal disabling stroke

10.1*

12.3

0.82 (0.76, 0.89)

Death, nonfatal reMI or nonfatal major bleeding

11.0*

12.8

0.86 (0.80, 0.93)

Death, nonfatal reMI or nonfatal ICH 10.1* 12.2 0.83 (0.77, 0.90) ICH = intracranial haemorrhage; reMI = recurrent myocardial infarction; UFH = unfractionated heparin; * p < 0.001 vs UFH.

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efficacy-safety endpoints in enoxaparin recipients than in UFH recipients (table II).[10] At 1 year following randomization into the ExTRACT-TIMI 25 trial, the incidence of the primary endpoint and the net-clinical-benefit endpoint of allcause mortality, nonfatal recurrent MI or nonfatal disabling stroke remained significantly lower in patients who had received enoxaparin than in those who had received UFH (15.8% vs 17.0%, p < 0.01; 16.0% vs 17.3%, p = 0.007).[25] When the components of the primary endpoint were analysed separately, the incidence of nonfatal recurrent MI remained significantly lower in enoxaparin recipients than in UFH recipients (5.7% vs 6.7%, p < 0.001), and no statistical difference had emerged between the incidence of all-cause mortality in enoxaparin and UFH recipients (10.5% vs 10.6%).[25] The incidence of urgent revascularisation at 1 year was not reported.[25] 3.1.2 Subgroup Analyses Renal dysfunction

Because of the potential for enoxaparin to accumulate in patients with renal dysfunction (section 2.2), patients with known poor renal function were excluded from the ExTRACT-TIMI 25 trial, and those with a degree of renal dysfunction received reduced dosages of enoxaparin (see section 3.1). In a subgroup analysis, the effect of enoxaparin was stratified according to the estimated baseline CLCR of patients.[21] Baseline characteristics between the strata varied greatly, with patients in each lower stratum being older (p < 0.001) with a higher incidence of hypertension, diabetes mellitus, previous MI and a higher baseline mortality risk (higher thrombolysis in myocardial infarction [TIMI] risk score) [all p < 0.001] than patients in the strata above.[21] In those patients with severe renal dysfunction, there was no significant difference in the incidence of the primary endpoint between patients who received enoxaparin and those who received UFH.[21] However, a significant difference in favour of enoxaparin appeared as renal function improved (table III). © 2008 Adis Data Information BV. All rights reserved.

Similarly, there was no statistical difference in the incidence of the net-clinical-benefit endpoint of all-cause mortality, nonfatal recurrent MI or nonfatal major bleeding between enoxaparin and UFH recipients who had a CLCR of <30 mL/min (34.9% vs 37.7%) or 30–60 mL/min (21.3% vs 20.6%), but there was a statistically significant difference in favour of enoxaparin for this endpoint in those with a CLCR of >60–90 mL/min (10.7% vs 13.0%, p < 0.01) or >90 mL/min (5.7% vs 7.9%, p < 0.001).[21] Type of Lytic Therapy

In this subgroup analysis,[18] data were analysed according to the type of fibrinolytic therapy that patients received: fibrin-specific lytic (alteplase, reteplase or tenecteplase; n = 16 283) or streptokinase (n = 4139). The type of fibrinolytic therapy administered was not a randomized procedure, but occurred at the physician’s discretion. Patients who received streptokinase were older (p < 0.001) and had a higher incidence of diabetes (p = 0.008) than those who received fibrin-specific lytics; other baseline characteristics were similar between the two groups.[18] The incidence of the primary endpoint was significantly lower in patients who received a fibrinspecific lytic and enoxaparin than in those who received a fibrin-specific lytic and UFH; however, there was no significant difference between these two groups in those patients who received streptokinase as their lytic therapy (table III).[18] The benefits of enoxaparin over UFH for the prevention of the primary endpoint translated into a number of patients who need to be treated (NNT) to prevent one event of 48 and 67 for the fibrin-specific lytic cohort and the streptokinase cohort, respectively.[18] When data from each fibrin-specific lytic was analysed separately, the difference in the incidence of the primary endpoint between enoxaparin and UFH recipients was significant in patients who received alteplase (10.1% vs 12.2%, p < 0.001; n = 5605 and 5570) and reteplase (8.4% vs 11.4%, p = 0.05; n = 561 in both groups), but not for those who received tenecteplase (9.4% vs 11.5%; n = 1976 and 2010); however, the study was not Drugs 2008; 68 (5)

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699

Table III. Efficacy of enoxaparin (ENO) in patients (pts) with ST-segment myocardial infarction (MI): primary endpoint results of prespecified comparative subgroup analyses[18,20-24] of the randomized, double-blind ExTRACT-TIMI 25 trial.[10] See text for trial design and dosage details Comparative subgroup

Stratification factor

30-Day all-cause mortality or nonfatal recurrent MI (% of pts) ENO [no. of pts]

UFH [no. of pts]

CLCR <30 mL/min

33.0 [106]

37.7 [106]

CLCR 30–60 mL/min

19.4 [1813]

19.4 [1858]

analysis Fox et al.[21]

CLCR >60–90 mL/min

9.6* [3583]

CLCR >90 mL/min

5.1** [3739]

7.3 [3723]

10.7** [2272]

13.8 [2404]

Gibson et al.[19]

Underwent PCIa

Giraldez et al.[18]

Received fibrin-specific lytic

Mega et al.[24] Sabatine et al.[20] Scirica et al.[22]

White et al.[23]

9.8** [8142]

12.1 [3620]

12.0 [8141]

Received streptokinase

10.2 [2083]

11.8 [2056]

Women

15.4* [2415]

18.3 [2368]

Men (15 696)b

8.2**

Clopidogrel

7.3 [1083]

7.8 [1090]

No clopidogrel

9.9c [6528]

12.0 [6390]

Complete STRd

4.4** [575]

10.1

9.9 [525]

Partial STRd

14.2 [422]

12.5 [408]

No STRd

16.2 [167]

15.9 [201]

Aged <75 y Aged ≥75 y

7.9*** [9015] 24.8 [1241]

a

Corresponding values for pts who did not undergo PCI are not available.

b

Total no. of men in study; no. in each treatment arm not specified.

9.9 [8932] 26.3 [1291]

c

No p-value available for this result; adjusted odds ratio = 0.79 (95% CI 0.70, 0.90).

d

On ECG at 180 mins after fibrinolytic therapy. Initial ECG was conducted at onset of fibrinolytic therapy.

CLCR = creatinine clearance; PCI = percutaneous coronary intervention; STR = ST-segment resolution; UFH = unfractionated heparin; * p < 0.01, ** p ≤ 0.001, *** p < 0.0001 vs UFH.

powered to detect differences between the subgroups.[18] Similar to the primary endpoint data, there was also a significantly lower incidence of all-cause mortality, nonfatal recurrent MI or urgent revascularization (secondary endpoint) with enoxaparin than with UFH in patients who received fibrinspecific lytics (11.6% vs 14.4%, p < 0.001).[18] This difference was seen in those who received alteplase (11.3% vs 14.0%, p < 0.001) and tenecteplase (12.5% vs 15.7%, p = 0.05), but not in those who received reteplase (11.1% vs 14.4%, p = 0.07).[18] However, unlike primary endpoint data, the incidence of the secondary endpoint was significantly lower in streptokinase recipients who received enoxaparin than in those who received UFH (12.2% vs 14.5%, p = 0.01).[18] In addition, the incidence of the net-clinicalbenefit endpoint of all-cause mortality, nonfatal recurrent MI or nonfatal major bleeding was signifi© 2008 Adis Data Information BV. All rights reserved.

cantly lower in fibrin-specific lytic recipients who received adjuvant enoxaparin than in those who received UFH (10.8% vs 12.7%, p < 0.001).[18] The difference between these two groups of patients in the streptokinase cohort was not significant (11.8% vs 13.0%).[18] Sex of Patient

As a subgroup, women were older, were more likely to have hypertension, diabetes or prior angina pectoris, were at a higher baseline mortality risk (TIMI risk score >3), experienced a longer delay from symptom onset to fibrinolytic therapy, were less likely to be prescribed antiplatelet agents, βadrenergic antagonists or HMG-CoA reductase inhibitors (statins), and underwent significantly fewer cardiac procedures (all p < 0.001).[24] The incidence of the primary endpoint was significantly lower in the subgroups of women and men receiving enoxaparin than in the corresponding subgroups receiving UFH (table III). The relative risk Drugs 2008; 68 (5)

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reduction (RRR) in women and men was 16% and 19%, and the absolute risk difference (ARD) was 2.9% and 1.9%.[24] Women and men had a similar relative benefit (both RRR 14%) with enoxaparin over UFH for the net-clinical-benefit endpoint of all-cause mortality, nonfatal recurrent MI or nonfatal major bleeding (incidence in women 16.4% vs 19.0%; men 9.3% vs 10.9%).[24] Because of their higher baseline risk, women received a numerically greater absolute benefit than men with enoxaparin relative to UFH (ARD 2.6% vs 1.6%) and this translated into a NNT to prevent one episode of the net-clinical-benefit endpoint of 38 for women and 63 for men.[24] Clopidogrel Use

In patients who received a fibrinolytic and aspirin on presentation, and who did not undergo PCI during the index hospital stay, 2173 also received clopidogrel and 12 918 did not.[20] The decision to commence clopidogrel treatment was not a randomized procedure, but occurred at the discretion of the treating physician. Whilst treatment was similar between the two groups, clopidogrel recipients were younger (p < 0.001), were more likely to be male (p < 0.001), have hyperlipidaemia (p = 0.008) or diabetes (p < 0.001) and have had previous PCI (p < 0.001), but less likely to be Caucasian (p < 0.001), have prior angina pectoris (p < 0.001) or a previous MI (p = 0.025).[20] In this subgroup analysis,[20] enoxaparin was significantly more effective than UFH in decreasing the incidence of the primary endpoint in patients who did not receive clopidogrel, but not in those who received clopidogrel (table III). ST-Segment Elevation Resolution

ECGs were obtained in 3208 patients at the onset of fibrinolytic therapy (baseline ECG) and then again at 180 minutes after the administration of fibrinolytic therapy.[22] Of the 2298 patients who had ECGs that were valid for calculation of STsegment elevation resolution, baseline characteristics were similar between those who received enoxaparin and those who received UFH.[22] When compared with UFH, enoxaparin significantly reduced the incidence of the primary endpoint © 2008 Adis Data Information BV. All rights reserved.

in patients with complete ST-segment elevation resolution at 180 minutes following fibrinolytic therapy, but not in those with partial or no ST-segment elevation resolution (table III).[22] These results suggest that enoxaparin acts to prevent the reocclusion of the vessel after successful reperfusion with fibrinolytic therapy.[22] Age of Patient

In a previous study,[3] enoxaparin was associated with an increased risk of bleeding in elderly patients.[23] Because of this, patients ≥75 years of age received reduced dosages of enoxaparin in the ExTRACT-TIMI 25 trial (see section 3.1). Baseline characteristics varied considerably between patients who were aged ≥75 years (n = 2532) and those who were aged <75 years (17 947).[23] In particular, patients aged ≥75 years were significantly (p < 0.001) more likely to have hypertension, diabetes, prior MI or angina pectoris, have been receiving long-term aspirin therapy, or have a greater baseline mortality risk (assessed by Killip class, TIMI risk score and TIMI risk index) than their younger counterparts. In addition, patients aged ≥75 years were significantly (p < 0.001) less likely to receive aspirin, clopidogrel, β-adrenergic antagonists and statins during the index hospital stay.[23] Baseline characteristics were similar between the enoxaparin and UFH treatment arms of each subgroup.[23] The incidence of the primary endpoint was significantly lower in enoxaparin than UFH recipients in the subgroup of patients aged <75 years, but not in the subgroup of those aged ≥75 years (table III).[23] The ARD was 1.5% and 2.0% for ≥75-year olds and <75-year olds, respectively, and was in favour of enoxaparin. This corresponded to a NNT to prevent one primary endpoint event of 67 in patients aged ≥75 and 50 in those aged <75 years.[23] A statistical difference was reported between enoxaparin and UFH recipients who were aged <75 years (9.7% vs 12.4%, p < 0.001), but not between the two groups in patients ≥75 years (26.0% vs 28.4%, p = 0.18) for the secondary endpoint of all-cause mortality, nonfatal recurrent MI and urgent revascularization.[23] This corresponded with an ARD in favour of enoxaparin of 2.7% in Drugs 2008; 68 (5)

Enoxaparin: A Review

patients aged <75 years and 2.4% in those aged ≥75 years, with NNT to prevent one secondary endpoint event of 37 and 42, respectively.[23] Similarly, a statistical difference favouring enoxaparin over UFH was seen for the net-clinical-benefit endpoint of all-cause mortality, nonfatal recurrent MI or nonfatal major bleeding in patients <75 years of age (9.0% vs 10.7%, p < 0.001), but not in those aged ≥75 years (25.8% vs 27.3%).[23] Percutaneous Coronary Intervention

All patients who subsequently underwent PCI during their index hospital stay were continued on their double-blind study medication for antithrombotic support.[19] In those patients whose last subcutaneous dosage of enoxaparin had been administered >8 hours prior to PCI, an additional intravenous bolus of enoxaparin (or matched placebo) of 0.3 mg/kg was administered; those who had received their last dose of study medication <8 hours previously did not receive this additional dose. UFH (or matched placebo) was dosed according to the activated partial thromboplastin time (aPTT).[19] If PCI occurred after day 8 or hospital discharge, all patients received antithrombotic support with openlabel UFH. Significant differences in baseline characteristics of patients who did and did not undergo PCI by day 30 were identified in this subgroup analysis and a propensity score was calculated to adjust for the differences.[19] In the subgroup of patients who underwent PCI by day 30, the combined incidence of the primary endpoint was 10.7% in enoxaparin recipients compared with 13.8% in UFH recipients (p = 0.001).[19] In addition, PCI was performed less frequently in patients in the enoxaparin group than in those in the UFH group (22.8% vs 24.2%, p = 0.027) and was delayed longer in enoxaparin recipients than in UFH recipients (121.7 vs 109.2 hours, p = 0.006).[19] Moreover, enoxaparin was also superior to UFH for the net-clinical-benefit endpoint of all-cause mortality, nonfatal MI or nonfatal major bleeding with the incidence being 11.5% in enoxaparin recipients compared with 14.8% in UFH recipients (p < 0.001).[19] © 2008 Adis Data Information BV. All rights reserved.

701

3.2 Other Randomized Studies

A number of earlier randomized studies have also compared the efficacy of enoxaparin with that of UFH or placebo. Efficacy was established using clinical[3,4,12] and/or angiographic[8,9,11] endpoints; data in this section are discussed according to the nature (clinical or angiographic) of the primary endpoint. 3.2.1 Clinical Efficacy versus Unfractionated Heparin (UFH)

The clinical efficacy of enoxaparin compared with UFH was established in two pivotal (ASSENT-3[4] and ASSENT-3 PLUS[3]) randomized trials. A total of 6095 patients were enrolled in the ASSENT-3 trial and 5989 patients received fibrinolytic therapy with tenecteplase and were randomized to receive enoxaparin, full-dose UFH or low-dose UFH plus abciximab.[4] Enoxaparin was administered as an intravenous bolus of 30 mg, followed by a 1 mg/kg subcutaneous dose that was repeated every 12 hours until hospital discharge or revascularization for a maximum of 7 days; the first two subcutaneous dosages were not to exceed 100 mg. Full-dose UFH was administered as an intravenous bolus of 60 U/kg (up to a maximum of 4000 U) followed by a 12 U/kg/h infusion (up to a maximum of 1000 U/h) for ≥48 hours; the infusion dosage was adjusted according to the aPTT. In the third group, low-dose UFH was administered as an intravenous bolus of 40 U/kg (up to a maximum of 3000 U), followed by a 7 U/kg/h infusion (up to a maximum of 800 U/h) adjusted as per aPTT for ≥48 hours, and patients received abciximab as a 0.25 mg/kg bolus, followed by a 0.125 µg/kg/min infusion (up to a maximum of 10 µg/min) for 12 hours.[4] Half-dose tenecteplase was administered to patients in the abciximab treatment arm, whereas all other patients received full-dose tenecteplase. All patients in the study received aspirin. As an extension of the ASSENT-3 trial,[4] the ASSENT-3 PLUS[3] trial was performed to assess the efficacy of enoxaparin versus UFH when administered in conjunction with tenecteplase in the prehospital (patient’s home or ambulance) setting. DosDrugs 2008; 68 (5)

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Table IV. Clinical efficacy of enoxaparin (ENO) in patients (pts) with ST-segment elevation myocardial infarction (MI): results of randomized, multicentre, phase III trials[3,4,12] comparing the efficacy of ENO with that of unfractionated heparin (UFH). See text for trial design and dosage details. The primary endpoint was the 30[3,4] or 90[12] day composite of mortality (all-cause[3,4] or cardiac only[12]), nonfatal recurrent MI (reMI) or refractory ischaemia Trial

Treatment

No. of pts

Incidence (% of pts) death, nonfatal reMI or refractory ischaemia

death

nonfatal reMI

refractory ischaemia

Efficacy at 30 d ASSENT-3 Investigators (ASSENT-3 trial)

[4]

ENO UFH

2040 2038

11.4**a 15.4

a

2.7**a,b

6.0

a

4.6***a,b 6.5a

4.2

6.6

2.2**

3.2***a,b

Wallentin et al.[3]

ENO

818

14.2

7.5

3.5*a

4.4a

(ASSENT-3 PLUS trial)

UFH

821

17.4

6.0

5.8a

6.5a

ENO

149

25.5*c,d

6.0c

14.8

4.7d

36.4c,d

10.6c

19.9

6.0d

UFH + ABC

2017

11.1***

a

5.4

a ,b

Efficacy at 90 d Baird et al.[12] a

UFH 151 Includes only those pts with in-hospital events.

b

It was unclear from the source article as to whether p-value referred to ENO vs UFH and/or UFH + ABC vs UFH for this parameter.

c

Incidence of cardiac death only.

d

Includes only those pts who were re-admitted as a result of unstable angina pectoris.

ABC = abciximab; * p < 0.05, ** p < 0.001, *** p ≤ 0.0001 vs UFH.

ages were identical to those administered in the ASSENT-3 trial.[3,4] In the ASSENT-3 trial, the incidences of the primary endpoint and two of its three components were significantly lower in the patient groups that received enoxaparin or low-dose UFH plus abciximab than in those that received UFH (table IV).[4] In addition, patients who received adjuvant therapy with either enoxaparin or low-dose UFH plus abciximab had a lower incidence of the efficacy-safety endpoint of death, in-hospital nonfatal recurrent MI, refractory ischaemia, ICH or major bleeding than those who received UFH (13.7% and 14.2% vs 17.0%, p = 0.0037 and 0.0142, respectively).[4] Despite there not being a significant difference in the incidence of the primary endpoint between enoxaparin recipients and UFH recipients in the ASSENT-3 PLUS trial, when each component of the primary endpoint was analysed separately, a significant difference in favour of enoxaparin was seen for in-hospital recurrent MI (table IV).[3] There was also no significant difference in the incidence of the efficacy-safety endpoint of 30-day death, in-hospital nonfatal recurrent MI, in-hospital refractory ischaemia, in-hospital ICH or in-hospital major bleeding © 2008 Adis Data Information BV. All rights reserved.

(excluding ICH) between those who received enoxaparin and those who received UFH (18.3% vs 20.3%).[3] Results of the ASSENT-3 and ASSENT-3 PLUS trials are supported by those of a smaller randomized trial (Baird et al.)[12] In this trial, patients received fibrinolytic therapy and were then randomized prospectively to receive enoxaparin (initial intravenous bolus of 40 mg followed by a 40 mg subcutaneous dose every 8 hours) or UFH (initial intravenous bolus of 5000 U followed by an infusion of 30 000 U/24 h adjusted as per aPTT) for 4 days in conjunction with other standard therapy, including aspirin (24% were already taking aspirin on admission), which was administered only after the study period was over.[12] In the study by Baird et al.,[12] enoxaparin was significantly more effective than UFH in lowering the rates of the composite primary endpoint of death, nonfatal recurrent MI and readmission with unstable angina pectoris (table IV).[12] Univariate predictors of the occurrence of a recurrent cardiac event after administration of enoxaparin compared with UFH included left ventricular failure (28% vs 46%, p = 0.01), hypertension (27% vs 43%, p = 0.01) and Drugs 2008; 68 (5)

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a family history of heart disease (26% vs 37%, p = 0.033).[12] 3.2.2 Angiographic Efficacy Compared with UFH

The angiographic efficacy of enoxaparin has been compared with that of UFH in two randomized trials (HART II[9] and ENTIRE-TIMI 23[8]), one of which was also a noninferiority trial.[9] In HART II, patients received aspirin and alteplase and were randomized to receive adjuvant enoxaparin (intravenous 30 mg bolus followed by 1 mg/kg subcutaneously every 12 hours) or UFH (intravenous weightdependent bolus of 4000 or 5000 U followed by an infusion of 15 U/kg/h [adjusted according to aPTT]) for at least 3 days.[9] An angiogram was performed 90 minutes after the initial bolus of alteplase was administered and again 5–7 days later. A total of 380 patients had assessable angiograms and 259 with TIMI grade 2 or 3 flow on initial angiogram were eligible for follow-up angiography.[9] Patients in the ENTIRE-TIMI 23 trial were randomized to receive either standard reperfusion with full-dose tenecteplase or combination therapy with half-dose tenecteplase plus abciximab.[8] In addition, patients were also randomized to receive enoxaparin (intravenous 30 mg bolus followed by two dose-ranging subcutaneous injections 12 hours apart and then a fixed 1 mg/kg subcutaneous dose every

12 hours for the duration of hospital stay up to a maximum of 8 days) or UFH (with standard reperfusion [intravenous bolus of 60 U/kg followed by an infusion of 12 U/kg/h for ≥36 hours] or with combination therapy [intravenous bolus of 40 U/kg followed by an infusion of 7 U/kg/h for ≥36 hours]) at a ratio of either 2 : 1 or 3 : 1.[8] Angiography was performed 60 minutes after initiation of fibrinolytic therapy. Of the 483 patients who were treated, 415 had an angiogram at 60 minutes that was assessable. The noninferiority of the efficacy of enoxaparin to UFH (determined by the TIMI 2 and 3 reperfusion rates at 90 minutes in all randomized patients with a technically adequate coronary angiogram) in patients with STEMI was verified in the HART II trial with the between-group difference being within the limits for noninferiority (–10%) and nearing that of superiority (lower limit of 95% CI –2.1%).[9] Results pertaining to the incidence of the primary and secondary endpoints of the HART II study are shown in table V. In the ENTIRE-TIMI 23 trial, there was no statistically significant difference in the incidence of the primary endpoint between enoxaparin and UFH recipients; pooled primary endpoint results are shown in table V.[8] When data were stratified according to the receipt of standard or combination reperfusion, the rate of TIMI 3 flow (primary endpoint) was 50%

Table V. Angiographic efficacy of enoxaparin (ENO) in patients (pts) with ST-segment elevation myocardial infarction: results of randomized, multicentre phase III trials comparing the efficacy of ENO with that of unfractionated heparin (UFH) or placebo (PL).[8,9,11] See text for trial design and dosage details Trial

Comparator

Incidence (% of pts) primary endpoint

secondary endpoint

Antman et al.[8] (ENTIRE-TIMI 23 trial)

ENO vs UFH (evaluable n = 275 and 140)

TIMI grade 3 flow at 60 min in infarct-related artery: 50.9 vs 77.5

TIMI grade 2 or 3 flow at 60 min in infarct-related artery on initial angiogram: 77.5 vs 75.0

Ross et al.[9] (HART II trial)

ENO vs UFH (total evaluable for primary and secondary endpoints n = 380 and 259; no. of evaluable pts in each treatment group not specified)

TIMI grade 2 or 3 flow at 90 min in Reocclusion rates (defined as the infarct-related artery on initial deterioration from TIMI grade 2 or angiogram: 80.1 vs 75.1 3 flow at 90 min to grade 0 or 1 at follow-up) on repeat angiogram in pts with TIMI grade 2 or 3 flow on initial (90 min) angiogram: 5.9 vs 9.8

Simoons et al.[11] (AMI-SK trial)

ENO vs PL (evaluable n = 389; no. of evaluable pts in each treatment group not specified) TIMI = thrombolysis in myocardial infarction.

© 2008 Adis Data Information BV. All rights reserved.

TIMI grade 3 flow on day 8 angiogram: 70.3 vs 57.9; p = 0.01

TIMI grade 2 or 3 flow on day 8 angiogram: 87.6 vs 71.7; p = 0.001

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in enoxaparin recipients compared with 52% in UFH recipients who received full-dose tenecteplase, and 52% and 48% in those who received half-dose tenecteplase and abciximab.[8] In addition, the incidence of the composite clinical endpoint of death or nonfatal recurrent MI in patients who received fulldose tenecteplase plus either enoxaparin or UFH was 4.4% vs 15.9% (p = 0.005) with corresponding values being 5.5% and 6.5% (p-value not reported) in patients who received half-dose tenecteplase plus abciximab; the overall incidence of death or nonfatal recurrent MI was 4.9% and 11.3% in enoxaparin and UFH recipients, respectively (p = 0.01).[8] Compared with Placebo

The angiographic efficacy of enoxaparin was compared with that of placebo in a randomized trial (AMI-SK).[11] All patients in the AMI-SK study received streptokinase and aspirin, and were randomly assigned to either enoxaparin (intravenous 30 mg bolus followed by 1 mg/kg [maximum of 100 mg for first two subcutaneous injections] subcutaneously every 12 hours for ≥3 days up to angiography or day 8) or placebo.[11] Study drug was given at the same time as, or within 1 hour of, streptokinase. Compared with patients who received placebo, significantly more enoxaparin recipients had a TIMI flow of grade 3 (primary endpoint), or grade 2 or 3 (secondary endpoint), in the infarct-related artery on day 8 angiography [table V].[11] In addition, enoxaparin recipients also had a lower incidence of the composite clinical endpoint of death, recurrent MI or refractory ischaemia than UFH recipients (13.4% vs 21.0%, p = 0.03); however, there was no statistically significant between-group difference when each of the clinical endpoint components were analysed separately.[11] 3.3 Meta-Analysis of All Randomized Studies

Data from patients with STEMI who received either enoxaparin or UFH in randomized trials have been collated in a meta-analysis.[26] Aside from the AMI-SK study,[11] all the trials discussed in sections 3.1 and 3.2[3,4,8-10,12] were included in this metaanalysis.[26] The primary endpoint of the meta-analysis was net clinical events, which was a composite © 2008 Adis Data Information BV. All rights reserved.

of mortality, non-fatal recurrent MI or non-fatal major bleeding at 30 days, or the closest timepoint to 30 days.[26] A total of 27 131 patients with STEMI received enoxaparin or UFH in these trials.[26] The incidence of the primary endpoint was significantly lower in enoxaparin recipients than in UFH recipients according to the meta-analysis (11.1% vs 12.9%, p = 0.018).[26] When the largest trial (ExTRACT-TIMI 25) was excluded from the analysis, the incidence of the primary endpoint was 11.5% in enoxaparin recipients compared with 13.2% in UFH recipients; however this difference was no longer significant (p = 0.09).[26] When each component of the primary endpoint was analysed separately, the incidences of non-fatal recurrent MI and non-fatal major bleeding were significantly lower in enoxaparin recipients than in UFH recipients (3.4% vs 5.1% and 2.6% vs 1.8%, respectively; p < 0.001 for both); however, there was no significant between-group difference in the incidence of mortality (6.6% and 7.1%).[26] 4. Tolerability As expected, bleeding complications were the most frequently occurring adverse events associated with enoxaparin use in clinical trials.[3,4,8-12] Given that tolerability data were generally similar among all the trials discussed in section 3,[3,4,8-12] this section focuses on tolerability data from the largest trial (ExTRACT-TIMI 25; section 3.1)[10] including a number of its subgroup analyses.[18-24] Supporting data are from the manufacturer’s prescribing information.[17] In addition, pivotal tolerability data in patients >75 years of age from the ASSENT-3[4] trial are also presented. Minor bleeding (defined by the TIMI Haemorrhage Criteria[27] as a spontaneous onset of gross haematuria, haemoptysis or haematemesis, or a drop in haemoglobin of >3 g/dL, but ≤5 g/dL, with bleeding from a known site) accounted for the majority of haemorrhagic adverse events at day 30 in the ExTRACT-TIMI 25 trial and occurred in 2.6% of patients with STEMI who received enoxaparin compared with 1.8% of those who received UFH (p < 0.001; table VI).[10] When data from this trial Drugs 2008; 68 (5)

Enoxaparin: A Review

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Table VI. Tolerability of enoxaparin (ENO) as an adjunct to fibrinolytic therapy in patients (pts) with ST-segment elevation myocardial infarction: bleeding complications in the ExTRACT-TIMI 25 trial[10,21,23] at day 30 unless otherwise specified. See text for trial design and dosage details Stratification factor

Treatment regimen

Bleeding complications (% of pts)

(no. of pts)

TIMI major bleed (including ICH)

TIMI minor bleed

ICH

ENO (10 176)

1.4

1.6

0.7

UFH (10 151)

1.0**

1.2*

0.6

ENO (10 176)

2.1

2.6

0.8

UFH (10 151)

1.4***

1.8***

0.7

ENO (106)

5.7

7.6

1.9

UFH (106)

2.8

3.7

0.9

CLCR 30–60 mL/min

ENO (1813)

3.5

5.0

1.2

UFH (1858)

1.9**

3.6*

1.2

CLCR >61–90 mL/min

ENO (3583)

2.3

2.3

1.2

UFH (3620)

1.6*

1.6*

0.9

CLCR >90 mL/min

ENO (3739)

1.2

1.6

0.3

UFH (3723)

0.8

1.2

0.2

Aged <75 y

ENO

1.9

(n = 17 947)a

UFH

1.1****

0.5

Aged ≥75 y

ENO

3.3

1.6

Overall At 48 h At 30 d

Stratified according to baseline creatinine clearance (CLCR) CLCR <30 mL/min

Stratified according to pt age

(n = 2532)a a

UFH 2.9 Total no. of pts aged <75 years (17 947) or aged ≥75 years (2532); no. of pts in each treatment arm not specified.

0.7

1.7

ICH = intracranial haemorrhage; TIMI = thrombolysis in myocardial infarction; UFH = unfractionated heparin; * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001 vs ENO.

were stratified according to pre-specified subgroup analyses (section 3.1.1), minor bleeding was reported in 1.6–7.6% of enoxaparin recipients and 1.2–3.7% of UFH recipients.[10,18-24] The highest incidence of events in enoxaparin recipients was reported in the subgroup of patients with a CLCR of <30 mL/min (7.6%)[21] and that consisting of women (4.4%);[24] the corresponding incidences in patients in these two subgroups who received UFH were 3.7% (between-group difference not statistically significant)[21] and 2.9% (p = 0.006 vs enoxaparin).[24] The incidence of major bleeds in the ExTRACTTIMI 25 trial (defined by the TIMI Haemorrhage Criteria[27] as an ICH, cardiac tamponade or drop in haemoglobin of >5 g/dL with or without an identified site of bleeding) at day 30 was 2.1% in enoxaparin recipients and 1.4% in UFH recipients (p < 0.001; table VI).[10] Taking into account stratifi© 2008 Adis Data Information BV. All rights reserved.

cation factors, major bleeds at 30 days occurred at a rate of 1.2–5.7% in patients who received enoxaparin compared with 0.8–2.9% in those who received UFH.[10,18-24] The highest incidence of events in enoxaparin recipients was reported in patients aged ≥75 years (3.3%),[23] and those with a CLCR of <30 mL/min (5.7%) or 30–60 mL/min (3.5%);[21] corresponding values for UFH recipients in these subgroups were 2.9% (between-group difference not significant),[23] 2.8% (between-group difference not significant) and 1.9% (p < 0.01 vs enoxaparin).[21] ICH alone occurred at a similar rate in enoxaparin and UFH recipients 0.8% vs 0.7%; table VI).[10] In the ASSENT-3 PLUS trial,[3] the incidences of total stroke (2.9% vs 1.3%, p = 0.026) and inhospital ICH (2.2% vs 1.0%, p = 0.047) were significantly higher in enoxaparin recipients than in UFH recipients. This difference was attributed to the sigDrugs 2008; 68 (5)

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nificantly (p = 0.01) greater incidences of these endpoints (total stroke 9.4% vs 2.3%; ICH 6.7% vs 0.8%) in the predefined subgroup of patients >75 years of age.[3] Because of this finding, patients ≥75 years of age in the ExTRACT-TIMI 25 trial received reduced dosages of enoxaparin (section 3.1 and 3.1.1). In addition, patients with some degree of renal dysfunction have been shown to be at an increased risk of bleeding with enoxaparin use in previous studies;[17] as a result, patients in this subgroup received reduced dosages of enoxaparin in the ExTRACT-TIMI 25 trial (section 3.1). However, despite this adjustment, the risk of major or minor bleeding increased by ≈50% with each increase in CLCR of 30 mL/min in both enoxaparin and UFH recipients in a subgroup analysis,[21] in which data were stratified according to baseline CLCR (table VI). In addition, even a modest degree of renal dysfunction was associated with an increased risk of major or minor bleeding irrespective of enoxaparin or UFH use in this subgroup analysis (table VI). In general, enoxaparin has been associated with local reactions, such as mild local irritation, pain, haematoma, ecchymosis and erythema.[17] In addition, fully reversible elevations in ALT or AST levels to ≥3-fold that of normal have been reported in up to 5.9% and 6.1% of patients who received enoxaparin in clinical trials.[17] Such laboratory abnormalities have also been reported in healthy volunteers and patients receiving heparin or other LMWHs in clinical trials.[17] 5. Dosage and Administration Enoxaparin is approved by the US FDA for use in patients with STEMI. Although not currently approved for this indication in other countries, an application has been filed for approval in Europe. In the US, enoxaparin is indicated for the treatment of medically managed patients with acute STEMI and in those with STEMI who undergo subsequent PCI.[17] The recommended dosage in this indication in patients <75 years of age is an initial 30 mg intravenous bolus plus a 1 mg/kg subcutaneous dosage followed by 1 mg/kg subcutaneously © 2008 Adis Data Information BV. All rights reserved.

every 12 hours with adjuvant aspirin; in patients of this age group with severe renal impairment (CLCR <30 mL/min), the recommended dosage is an initial 30 mg intravenous bolus plus a 1 mg/kg subcutaneous bolus followed by 1 mg/kg subcutaneously once daily.[17] In patients ≥75 years of age, it is recommended that 0.75 mg/kg of enoxaparin is administered subcutaneously every 12 hours, with the notable exclusion of the initial intravenous bolus; those in this age group with severe renal impairment have a recommended dosage of 1 mg/kg subcutaneously once daily.[17] In patients who subsequently undergo PCI, an additional 0.3 mg/kg intravenous bolus of enoxaparin should be administered to patients whose last dosage of enoxaparin was administered >8 hours prior to balloon inflation; in those whose last dosage was administered <8 hours prior to balloon inflation, no additional dosage is required.[17] Local prescribing information should be consulted for additional information, including dosage and administration, contraindications, warnings and precautions, adverse reactions, drug interactions and use in special populations. 6. Place of Enoxaparin in the Management of Patients with ST-Segment Elevation Myocardial Infarction Time to reperfusion is one of the major determinants of mortality in patients with STEMI; therefore, treatment of STEMI centres on achieving early and persistent reperfusion of the infarct-related artery.[1,3,22] Although there is increasing interest in a catheter-based approach to reperfusion,[8] fibrinolytic therapy remains the leading reperfusion strategy around the globe in patients with STEMI.[18] Following fibrinolytic therapy, there is potential for reocclusion of the infarct-related artery when thrombin, which was previously bound up in clots, is exposed and released; this, in turn, may activate the coagulation cascade.[12,28] Therefore, adjuvant antiplatelet and antithrombin therapies also play an important role in medical reperfusion.[28] Drugs 2008; 68 (5)

Enoxaparin: A Review

The choice of reperfusion strategy is dependent upon availability and timing, as well as the perceived benefit versus risk for each individual patient.[2,7] Current US[2,6] and European[7] guidelines recommend PCI if a skilled laboratory with surgical backup is available and medical contact-to-balloon or door-to-balloon time is <90 minutes,[2,6,7] the patient is in cardiogenic shock or otherwise at high risk,[2,6,7] fibrinolytic therapy is contraindicated,[2,6,7] the patient is presenting >3 hours after the onset of symptoms[2,6] or the diagnosis of STEMI is unclear.[2,6] Fibrinolytic therapy, on the other hand, is the preferred method of reperfusion in the US[2,6] if patients present within 3 hours of the onset of symptoms and a delay to mechanical reperfusion is expected, mechanical reperfusion is not an option or there is a delay to mechanical reperfusion as a result of prolonged transport, the door-to-balloon minus door-to-needle time of >1 hour, or there is a medical contact-to-balloon or door-to-balloon time of >90 minutes. In Europe,[7] fibrinolytic therapy is preferred when PCI cannot be performed within 90 minutes after first medical contact by an experienced team. However, a more fibrin-specific agent, such as tenecteplase or alteplase, is preferred in patients who present >4 hours after the onset of symptoms.[7] A number of fibrinolytic agents are approved for use in patients with STEMI in the US and Europe, but the specific choice of agent is dependent upon the individual assessment of benefit and risk, as well as the likelihood of complications and cost.[2,6,7] Adjuvant therapy with aspirin and/or clopidogrel, and other myocardial protective agents such as βadrenergic antagonists and angiotensin-converting enzyme inhibitors, is also strongly recommended for use in patients presenting with STEMI.[2,6,7] UFH is recommended in US[2,6] and European[7] guidelines for use in patients undergoing PCI or surgical revascularization,[2,6] and in those undergoing medical reperfusion with alteplase, reteplase or tenecteplase.[2,6,7] In the US,[2,6] UFH is recommended in patients receiving nonselective fibrinolytic agents if they are at high risk of developing systemic © 2008 Adis Data Information BV. All rights reserved.

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emboli and, in Europe,[7] UFH is optional in patients who are receiving nonselective fibrinolytic agents, such as streptokinase. Unfortunately, UFH has many potential limitations, including the need for frequent monitoring and dose adjustment, the need for antithrombin as a cofactor, a non-specific plasma protein binding that results in an unpredictable anticoagulant response, an inability to inhibit fibrinbound thrombin or platelet-bound factor Xa, neutralization by platelet factor 4, activation of platelets and a rebound increase in thrombogenicity after cessation of the infusion.[29] Compared with UFH, LMWHs may offer several advantages when administered to patients with STEMI. Such advantages include the following: (i) a simpler administration route; (ii) a high bioavailability and minimal plasma binding leading to more reliable anticoagulant effects, thereby eliminating the need for therapeutic monitoring; (iii) a greater capacity to release TFPI, a higher anti-factor Xa : IIa ratio and a lower propensity to inhibit platelet aggregation, leading to a lesser tendency to cause bleeding; (iv) less inhibition by platelet factor 4; (v) potential antiplatelet effects via higher degrees of suppression of von Willebrand factor; and (vi) a lesser propensity to cause osteoporosis (section 2.1). A recent meta-analysis[30] of randomized trials comparing LMWHs with UFH demonstrated reductions in the rate of recurrent MI and death of ≈25% and ≈10% with LMWHs relative to placebo; compared with UFH, LMWHs reduced the rate of recurrent MI by ≈ 50%. However, whilst all LMWHs are similar, they all differ in their physical and pharmacological properties and, therefore, may differ in relative clinical efficacies.[14] In light of the limitations of UFH, and the promising results demonstrated in the recent trials of enoxaparin, a recent focused update[6] of the US treatment guidelines[2] now also recommends enoxaparin as an alternative to UFH in patients with STEMI. Despite the increased risk of bleeding associated with enoxaparin use, a summary of trial observations presented in the updated US guidelines[6] suggests that enoxaparin may be superior to UFH in Drugs 2008; 68 (5)

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patients with STEMI receiving fibrinolytic therapy, and may also be used as a sole antithrombin agent to support PCI after fibrinolysis. Enoxaparin may be administered regardless of patient age, providing serum creatinine levels are <2.5 mg/dL in men and <2.0 mg/dL in women.[6] Based upon the results of the OASIS-6 (Organization for the Assessment of Strategies for Ischemic Syndromes) trial,[31] fondaparinux sodium (henceforth fondaparinux), a synthetic, sulfated pentasaccharide, selective factor Xa inhibitor, is now also recommended alongside UFH and enoxaparin in the updated US guidelines[6] for use in patients with STEMI (providing serum creatinine level is <3.0 mg/dL), particularly in those receiving fibrinolytic therapy; however, fondaparinux does not appear to be superior to control therapy (UFH/placebo) in patients undergoing primary PCI, and additional anticoagulant support is also required when patients receiving fondaparinux undergo PCI following fibrinolysis.[6] Reviparin sodium, another LMWH, has also demonstrated promising efficacy results in the CREATE (Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment Evaluation) trial[32] according to the updated guidelines.[6] Although this agent is approved for use as an antithrombotic agent in some European countries, it is not currently approved in the US. No one anticoagulant agent is recommended over another in the treatment of patients with STEMI in the updated US guidelines.[6] Although there have been no direct head-to-head comparative trials between enoxaparin and other LMWHs in patients with STEMI, no other LMWH has been evaluated as extensively as enoxaparin in this patient population. Moreover, enoxaparin has demonstrated clear benefits over UFH in several well designed randomized trials and a large metaanalysis (section 3). In comparative studies in patients with STEMI receiving fibrinolytic therapy, adjunctive therapy with enoxaparin was associated with better efficacy than UFH (section 3). The pivotal ExTRACT-TIMI 25 trial reported a significantly greater reduction in the combined 30-day incidence of all-cause mor© 2008 Adis Data Information BV. All rights reserved.

Carter et al.

tality and nonfatal MI (primary endpoint) as well as the combined 30-day incidence of all-cause mortality, nonfatal recurrent MI and urgent revascularization (secondary endpoint) in patients receiving enoxaparin than in those receiving UFH (section 3.1). Furthermore, the difference between the two groups for the primary endpoint remained significant at the 1-year follow-up. In addition, a significantly lower incidence of three pre-specified combined efficacy-safety endpoints was reported in enoxaparin than UFH recipients in this study. The FDA approval of enoxaparin in patients with medically managed STEMI, or STEMI with subsequent PCI, is based upon these results. However, the use of enoxaparin in patients with STEMI undergoing primary PCI has not yet been adequately studied. The findings of the ExTRACT-TIMI 25 trial are supported by subgroup analyses of the trial (section 3.1.1), as well as earlier randomized, double-blind, phase III trials comparing enoxaparin with UFH or placebo (section 3.2). As expected, bleeding complications were the most frequently occurring adverse events associated with enoxaparin use in clinical trials (section 4). Minor bleeding accounted for the majority of events and occurred with a significantly higher incidence in enoxaparin than UFH recipients in the ExTRACTTIMI 25 trial. The incidence of major bleeds was also higher in enoxaparin recipients than in UFH recipients in this trial. However, ICH occurred at a similar incidence in the two groups. Despite there being a significantly higher incidence of bleeding episodes reported in enoxaparin recipients than in UFH recipients in the ExTRACTTIMI 25 trial, enoxaparin remained superior to UFH in terms of the combined efficacy-safety endpoints (section 3.1). Previous studies have shown an increased number of bleeding events with antithrombin (including enoxaparin) use in elderly patients and in those with renal dysfunction, and for this reason, patients in these subgroups in the ExTRACT-TIMI 25 trial received reduced dosages of enoxaparin (section 3.1). Despite this adjustment, even a modest degree of renal dysfunction was associated with an inDrugs 2008; 68 (5)

Enoxaparin: A Review

creased risk of major or minor bleeding irrespective of enoxaparin or UFH use (table VI). An assessment of risk versus benefit is therefore important when deciding upon a regimen for the treatment of STEMI in these patient groups. In conclusion, enoxaparin was significantly more effective than UFH in patients presenting with STEMI in terms of 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. 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 compared with UFH. Data from several earlier randomized, multicentre, phase III trials support these results.

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9.

10.

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Disclosure The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

References 1. Hahn SA, Chandler C. Diagnosis and management of ST elevation myocardial infarction: a review of the recent literature and practice guidelines. Mt Sinai J Med 2006 Jan; 73 (1): 469-81 2. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). Circulation 2004 Aug 3; 110 (5): 588-636 3. Wallentin L, Goldstein P, Armstrong PW, et al. Efficacy and safety of tenecteplase in combination with the low-molecularweight heparin enoxaparin or unfractionated heparin in the prehospital setting: the asssessment of the safety and efficacy of a new thrombolytic regimen (ASSENT)-3 PLUS randomized trial in acute myocardial infarction. Circulation 2003 Jul 15; 108 (2): 135-42 4. ASSENT-3 investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated

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20. Sabatine MS, Morrow DA, Dalby A, et al. Efficacy and safety of enoxaparin versus unfractionated heparin in patients with STsegment elevation myocardial infarction also treated with clopidogrel. J Am Coll Cardiol 2007 Jun 12; 49 (23): 2256-63 21. Fox KAA, Antman EM, Montalescot G, et al. The impact of renal dysfunction on outcomes in the ExTRACT-TIMI 25 trial. J Am Coll Cardiol 2007 Jun 12; 49 (23): 2249-55 22. Scirica BM, Morrow DA, Sadowski Z, et al. A strategy of using enoxaparin as adjunctive antithrombin therapy reduces death and recurrent myocardial infarction in patients who achieve early ST-segment resolution after fibrinolytic therapy: the ExTRACT-TIMI 25 ECG study. Eur Heart J 2007 Jun; 28 (17): 2070-6 23. White HD, Braunwald E, Murphy SA, et al. Enoxaparin vs. unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction in elderly and younger patients: results from ExTRACT-TIMI 25. Eur Heart J 2007 May; 28 (9): 1066-71 24. Mega JL, Morrow DA, Ostor E, et al. Outcomes and optimal antithrombotic therapy in women undergoing fibrinolysis for ST-elevation myocardial infarction. Circulation 2007 Jun 5; 115 (22): 2822-8 25. Morrow D, Wallentin L. Enoxaparin versus unfractionated heparin for STEMI: one year results from ExTRACT-TIMI 25 (abstract plus slide presentation) [online]. Available from URL: http://www.escardio.org/knowledge/congresses/CongressReports/2007/hl-ctu/1027-morrow-wallentin-ctu1.htm [Accessed 2007 Sep 10] 26. Murphy SA, Gibson CM, Morrow DA, et al. Efficacy and safety of the low-molecular weight haparin enoxaparin compared with unfractionated heparin across the acute coronary syndrome spectrum: a meta-analysis. Eur Heart J 2007 Sep; 28 (17): 2077-86

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27. Classification of hemorrhagic events according to TIMI criteria [online]. Available from URL: http://www.aggrastat.com.sa/ secure/keystudies/timi_criteria/timi_criteria.html [Accessed 2007 Oct 12] 28. Cohen M. Low-molecular-weight heparin in patients with acute ST-segment elevation myocardial infarction. Am Heart Hosp J 2005; 3 (2): 82-7 29. Bates ER. New anticoagulant options for ST-elevation myocardial infarction and unstable angina pectoris/non-ST-elevation myocardial infarction. Curr Cardiol Rep 2007 Jul; 9 (4): 289-97 30. Eikelboom JW, Quinlan DJ, Mehta SR, et al. Unfractionated and low-molecular-weight heparin as adjuncts to thrombolysis in aspirin-treated patients with ST-elevation acute myocardial infarction: a meta-analysis of the randomized trials. Circulation 2005 Dec; 112 (25): 3855-67 31. The OASIS-6 Trial Group. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction. JAMA 2006 Apr 5; 295 (13): 1519-30 32. The CREATE Trial Group Investigators. Effects of reviparin, a low-molecular-weight heparin, on mortality, reinfarction, and strokes in patients with acute myocardial infarction presenting with ST-segment elevation. JAMA 2005 Jan 26; 293 (4): 427-36

Correspondence: Natalie J. Carter, Wolters Kluwer Health | Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore 0754, Auckland, New Zealand. E-mail: [email protected]

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