THE INCITING EVENT IN AN ACUTE

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1 CLINICAL CARDIOLOGY Use of Low-Molecular-Weight Heparins in the Management of Acute Coronary Artery Syndromes and Percutaneous Coronary Intervention Graham C. Wong, MD Robert P. Giugliano, MD, SM Elliott M. Antman, MD THE INCITING EVENT IN AN ACUTE coronary syndrome (ACS) typically involves disruption of a vulnerable atherosclerotic plaque with superimposed thrombosis, leading to varying degrees of occlusion of the culprit artery. 1-3 ST-elevation myocardial infarction (STEMI) is usually associated with complete thrombotic occlusion of the culprit artery, 4 while nonocclusive thrombus is the typical finding associated with unstable angina/ non ST-elevation myocardial infarction (UA/NSTEMI). 5,6 Tissue factor exposed following plaque rupture leads to activation of the coagulation cascade and generation of factor Xa (FIGURE 1). 7 Thrombin is formed, which leads to fibrin deposition, platelet activation, and ultimately the formation of a stable clot. 8 Given the central role of thrombin in the pathogenesis of ACSs, an antithrombotic agent is an important element in therapy, regardless of whether ST elevation is present. However, there are important limitations associated with unfractionated (currently the most commonly used antithrombotic agent), which has prompted a search for alternative compounds. 9 One promising class of agents is the low-molecular-weight s (LMWHs), which offer potential advantages in terms of clinical efficacy, safety, and ease of use in the setting of ACS. Context Low-molecular-weight s (LMWHs) possess several potential pharmacological advantages over unfractionated as an antithrombotic agent. Objective To systematically summarize the clinical data on the efficacy and safety of LMWHs compared with unfractionated across the spectrum of acute coronary syndromes (ACSs), and as an adjunct to percutaneous coronary intervention (PCI). Data Sources We searched MEDLINE for articles from 1990 to 2002 using the index terms, enoxaparin, dalteparin, nadroparin, tinzaparin, low molecular weight, myocardial infarction, unstable angina, coronary angiography, coronary angioplasty, thrombolytic therapy, reperfusion, and drug therapy, combination. Additional data sources included bibliographies of articles identified on MEDLINE, inquiry of experts and pharmaceutical companies, and data presented at recent national and international cardiology conferences. Study Selection We selected for review randomized trials comparing LMWHs against either unfractionated or placebo for treatment of ACS, as well as trials and registries examining clinical outcomes, pharmacokinetics, and/or phamacodynamics of LMWHs in the setting of PCI. Of 39 studies identified, 31 fulfilled criteria for analysis. Data Extraction Data quality was determined by publication in the peer-reviewed literature or presentation at an official cardiology society sponsored meeting. Data Synthesis The LMWHs are recommended by the American Heart Association and the American College of Cardiology for treatment of unstable angina/non ST-elevation myocardial infarction. Clinical trials have demonstrated similar safety with LMWHs compared with unfractionated in the setting of PCI and in conjunction with glycoprotein IIb/IIIa inhibitors. Finally, LMWHs show promise as an antithrombotic agent for the treatment of ST-elevation myocardial infarction. Conclusions The LMWHs could potentially replace unfractionated as the antithrombotic agent of choice across the spectrum of ACSs. In addition, they show promise as a safe and efficacious antithrombotic agent for PCI. However, further study is warranted to define the benefit of LMWHs in certain high-risk subgroups before their use can be universally recommended. JAMA. 2003;289: METHODS Studies for this review were identified using MEDLINE searches, reviewing reference lists, and conferring with experts and pharmaceutical companies. The medical subject headings used were, enoxaparin, dalteparin, nadroparin, tinzaparin, low molecular weight Author Affiliations: TIMI Study Group, Brigham and Women s Hospital, Boston, Mass. Financial Disclosures: Dr Giugliano has received honoraria from Aventis for educational programs. Dr Antman has received clinical research grants from Aventis. Corresponding Author and Reprints: Robert P. Giugliano, MD, SM, TIMI Study Group, 350 Longwood Ave, First Floor Offices, Boston, MA ( rgiugliano@partners.org). Clinical Cardiology Section Editor: Michael S. Lauer, MD, Contributing Editor American Medical Association. All rights reserved. (Reprinted) JAMA, January 15, 2003 Vol 289, No

2 Figure 1. Differential Effects of Unfractionated Heparin and Low-Molecular-Weight Heparin Factor IX + Activation Factor X Tissue Factor LMWH Antithrombin III UFH Factor VIIa Factor IXa + + Activation Prothrombin LMWH Tissue Factor Pathway Inhibitor + LMWH Antithrombin III - UFH Factor Xa Prothrombinase Complex + Fibrinogen Endothelial Cells Thrombin + Fibrin In acute coronary syndromes, thrombosis is typically initiated via exposure of tissue factor at the site of a disrupted plaque. The complex of tissue factor and Factor VIIa activates Factor X to Xa. Factor Xa subsequently participates in the prothrombinase complex (Factor Xa, Factor Va, Ca ++, and a phospholipid membrane, usually from an activated platelet). The tissue factor/viia complex also activates Factor IX to IXa, which helps maintain the thrombotic process. Both unfractionated (UFH) and low-molecular-weight s (LMWHs) act by complexing with antithrombin III. LMWHs have a relatively greater inhibitory effect on Factor Xa than on factor IIa (thrombin), such that the anti-xa:iia inhibitory ratio is greater than 1. This produces greater upstream inhibition of the coagulation cascade and relatively greater reduction of thrombin generation than when unfractionated is administered. Unfractionated has an anti-xa:iia inhibitory ratio of 1. While it is theoretically possible to achieve similar anti-xa activity with unfractionated as with LMWH, because of poor bioavailability very high doses of unfractionated are required that would result in unacceptably high anti-iia levels and an increased risk of bleeding. Both unfractionated and LMWHs also inhibit coagulation through release of tissue factor pathway inhibitor (TFPI) from endothelial cells. However, unlike unfractionated, LMWHs do not cause TFPI depletion, which has been associated with a paradoxical prothrombotic state during anticoagulant therapy in the setting of acute coronary syndromes. + UFH, myocardial infarction, unstable angina, coronary angioplasty, thrombolytic therapy, reperfusion, and drug therapy, combination. In addition, relevant abstracts from the annual meetings of the American Heart Association (AHA), American College of Cardiology (ACC), and European Society of Cardiology were reviewed. We selected for review randomized clinical trials that compared a LMWH with either unfractionated or placebo for the treatment of STEMI and UA/NSTEMI. We also included nonrandomized trials and registries of LMWH that examined clinical outcomes, and/or pharmacokinetics and phamacodynamics in the setting of percutaneous coronary intervention (PCI). Data quality was determined by publication in a peerreviewed journal or presentation at an official cardiology society sponsored meeting. Of 39 studies identified, 31 fulfilled criteria for analysis. RESULTS Understanding of the pharmacological characteristics of LMWHs has evolved since previous reviews. 10,11 The LMWHs act more proximally on the coagulation cascade than unfractionated and more effectively inhibit thrombin generation (Figure 1). Increasing evidence also suggests that LMWHs may differ from unfractionated in other thrombin-dependent and thrombin-independent mechanisms (TABLE 1). These differences may explain the different pharmacological profiles of LMWH and unfractionated in the setting of ACSs and PCI. Although anti-xa monitoring is not commonly performed nor recommended in routine clinical practice, 12,13 it has been suggested that monitoring of LMWH activity may be of benefit in certain high-risk patient subgroups in which the optimal dose of LMWH has not been established. 14 These include patients at weight extremes, patients with renal insufficiency (prolongation of anti-xa activity), 15 and patients who are pregnant (lower than normal anti-xa activity for a given LMWH). 16 Non ST-Elevation ACSs (UA/NSTEMI) The LMWHs have been compared with unfractionated for the treatment of UA/NSTEMI in 4 large, prospective randomized trials Several meta-analyses comparing unfractionated with LMWH have already demonstrated the superiority of LMWH over placebo and the superiority of enoxaparin over unfractionated 21,22 (FIGURE 2). Key differences in clinical trial design, patient selection, and characteristics of the preparations make comparisons among LMWHs difficult. Only 1 trial has compared 2 LMWH preparations in the setting of UA/NSTEMI. The Enoxaparin Versus Tinzaparin (EVET) trial randomized 438 patients 332 JAMA, January 15, 2003 Vol 289, No. 3 (Reprinted) 2003 American Medical Association. All rights reserved.

3 Table 1. Limitations of Unfractionated Heparin Properties Thrombin-dependent properties Nonspecific protein binding 11,78 Short plasma half-life 10,11 Relative inability to inhibit clot-bound thrombin 30,82 Depletion of TFPI 83,84 Thrombin-independent properties Increased binding to platelets 87 Unfractionated Heparin Pharmacological Consequences Less drug binding to thrombin Sensitivity to inactivation by platelet factor 4 and histidine-rich glycoprotein Poor bioavailability with a single intravenous or subcutaneous dose Increased thrombin generation following clot lysis in presence of therapeutic levels of unfractionated Decreased attenuation of tissue factor/factor VIIa complex Increased immunogenicity Increased platelet activation and adhesion to endothelium Clinical Consequence Variable level of anticoagulation requiring monitoring of activated PTT Requires continuous intravenous infusion Rebound thrombosis during and following unfractionated treatment Potential Pharmacological Advantage of LMWH Over Unfractionated Heparin Less nonspecific protein binding 78,79 Long plasma half-life relative to unfractionated enables intermittent intravenous or subcutaneous injections without a concomitant infusion 80,81 Decreased new thrombin generation due to superior proximal Xa inhibition 29 Rebound hypercoaguability Relatively less TFPI depletion Increased potential for bleeding, HITTS, or thrombosis Relatively less platelet activation 87,90 and platelet-endothelial interactions 91 Inability to blunt increase of vwf in ACS 88,89 Elevations of vwf in ACS Increased potential for thrombosis Superior attenuation of the increase of vwf in ACS 88,89 Abbreviations: ACS, acute coronary syndrome; HITTS, -induced thrombocytopenia and thrombosis syndrome; LMWH, low-molecular-weight ; PTT, partial thromboplastin time; TFPI, tissue factor pathway inhibitor; vwf, von Willebrand factor. presenting with UA/NSTEMI to either enoxaparin (subcutaneous injection of 1 mg/kg ; n=220) or tinzaparin (subcutaneous injection of 175 IU/kg daily; n=318). 24 The composite primary end point (death, reinfarction, or recurrent angina) was lower with enoxaparin compared with tinzaparin at day 7 (12.3% vs 21.1%; P=.02). This difference, which persisted to 30 days, was driven almost entirely by a reduction in recurrent angina (at 7 days: 11.8% vs 19.3% [P=.03]; at 30 days: 17.3% vs 26.1% [P=.02]). Major bleeding was uncommon and not statistically different between the enoxaparin and tinzaparin groups (3.6% vs 3.2%). Figure 2. Effects of Low-Molecular-Weight Heparins in Unstable Angina on the Combined End Point of Death, Myocardial Infarction, and Recurrent Ischemia With or Without Revascularization LMWH Sample Preparation Size Day LMWH Better UFH Better FRIC 20 Dalteparin FRAXIS 17 Nadroparin ESSENCE 19 Enoxaparin TIMI 11B 18 Enoxaparin Odds Ratio (95% Confidence Interval) ESSENCE indicates Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events; FRAXIS, Fraxiparine in Ischaemic Syndrome; FRIC, Fragmin in Unstable Coronary Artery Disease; LMWH, low-molecularweight ; TIMI 11B, Thrombolysis in Myocardial Infarction; and UFH, unfractionated. Reproduced with permission. 57 Combination of LMWH and Glycoprotein IIb/IIIa Inhibitors for the Initial Medical Management of ACSs The combination of enoxaparin and tirofiban resulted in a trend toward a greater proportion of patients achieving more than 70% inhibition of platelet aggregation compared with the combination of unfractionated and tirofiban in the Antithrombotic Combination Using Tirofiban and Enoxaparin (ACUTE I) trial (84% vs 65%), 25 suggesting a possible synergistic effect on platelet inhibition from LMWH and glycoprotein IIb/IIIa inhibitors. This combination has since been evaluated in 5 trials of initial medical therapy for UA/NSTEMI (TABLE 2 and TABLE 3). The major finding was that major hemorrhage occurred rarely in the LMWH and glycoprotein IIb/IIIa inhibitor arms (0.3%-1.8%). These rates compare favorably with the overall 2.4% rate of major bleeding calculated in a metaanalysis of glycoprotein IIb/IIIa inhibitors and unfractionated for the treatment of ACSs. 26 Furthermore, no increase in bleeding was noted among UA/NSTEMI patients who proceeded to PCI. Although not powered to detect differences in clinical events, rates of ischemic events in these trials were noted to be similar between the LMWH and unfractionated groups American Medical Association. All rights reserved. (Reprinted) JAMA, January 15, 2003 Vol 289, No

4 The combination of tirofiban and enoxaparin was studied in 1224 patients presenting with STEMI in the Treatment of Enoxaparin and Tirofiban in Acute Myocardial Infarction (TETAMI) trial. Patients ineligible for fibrinolysis were randomized in a 2 2 fashion to receive either enoxaparin (intravenous 30-mg bolus and subcutaneous injection of 1 mg/kg ) or unfractionated (intravenous 70 U/kg bolus and 15 U/kg per hour infusion) with or without tirofiban (intravenous 10-µg/kg bolus and 0.1-µg/kg per minute infusion) for 2 to 8 days. 27 There were no differences noted in the primary efficacy end point between either enoxaparin and unfractionated monotherapy groups (15.4% vs 17.3%) or between enoxaparin and unfractionated combination groups (16.1% vs 17.2%). Major bleeding was rare and not statistically different among all 4 groups. Duration of Therapy of LMWH in UA/NSTEMI Evidence suggests that the prothrombotic state associated with an ACS may persist for several months following the index event, providing a biologically plausible rationale for prolonged antithrombotic therapy in this setting. The LMWHs are attractive as longterm antithrombotic agents by virtue of their safety profile and ease of use, prompting several trials to evaluate their use in the outpatient setting following an acute coronary event ,31 Although the clinical benefit of inhospital LMWH therapy is maintained up to 1 year following the index event 32 (hazard ratio, 0.88; 95% confidence interval, ; P=.008 for the combined end point of death, MI, or urgent ), no additional benefit from use of LMWH beyond hospital discharge has been convincingly Table 2. Characteristics of s of Low-Molecular-Weight Heparin and Glycoprotein IIb/IIIa Inhibitor Combination for the Treatment of Unstable Angina/Non ST-Elevation MI LMWH Group Control Group * Subjects Drug Dose ACUTE II Enoxaparin Subcutaneous 1 mg/kg NICE Enoxaparin Subcutaneous 1 mg/kg GUSTO IV Dalteparin substudy Dalteparin Subcutaneous 120 IU/kg INTERACT Enoxaparin Subcutaneous 1 mg/kg Subjects Drug 210 Unfractionated Duration of Therapy Primary Efficacy Outcome 24 to 96 h Death, MI, urgent to 96 h Death, MI, urgent 4556 Unfractionated 366 Unfractionated PARAGON-B LMWH Not specified 2205 Unfractionated 5 to 7 d Death, MI 48 h 3 d Death, MI Death, MI, urgent Abbreviations: ACUTE II, second Antithrombotic Combination Using Tirofiban and Enoxaparin; GUSTO IV, Global Use of Strategies To Open Occluded Coronary Arteries; INTERACT, Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndromes Treatment; LMWH, low-molecular-weight ; MI, myocardial infarction; PARAGON, Platelet IIb/IIIa Antagonist for Reduction of Acute Coronary Syndrome Events in a Global Organization Network; ellipses indicate no control group. *Major bleeding definitions were TIMI Major for all trials, except PARAGON-B, which used intracranial hemorrhage or bleeding that caused hemodynamic compromise and required intervention. Of this number, 315 patients received abciximab for 24 hours and 331 received abciximab for 48 hours. Of this number, 2275 patients received abciximab for 24 hours and 2281 received abciximab for 48 hours. The type of LMWH was not mandated by protocol. Table 3. Clinical Efficacy and Major Non-CABG Bleeding in s Combining Low-Molecular-Weight Heparin and Glycoprotein IIb/IIIa Inhibitor Combination for the Treatment of Unstable Angina/Non ST-Elevation MI Treatment Effect, % Major Non-CABG Bleeding, % Timing of Efficacy Outcome LMWH Control Difference Timing of Safety Outcome LMWH Control Difference ACUTE II 66 In hospital d NICE d d 1.9* GUSTO IV Dalteparin substudy d d INTERACT d h (P =.03) PARAGON-B d d Abbreviations: ACUTE II, second Antithrombotic Combination Using Tirofiban and Enoxaparin; CABG, coronary artery bypass graft; GUSTO IV, Global Use of Strategies To Open Occluded Coronary Arteries; INTERACT, Integrilin and Enoxaprin Randomized Assessment of Acute Coronary Syndromes Treatment; LMWH, low-molecular-weight ; MI, myocardial infarction; PARAGON, Platelet IIb/IIIa Antagonist for Reduction of Acute Coronary Syndrome Events in a Global Organization Network; ellipses indicate no control group. *The LMWH values for major non-cabg bleeding are: 0.8 for abciximab; 2.6 for eptifibatide; and 1.7 for tirofiban. Analysis of all patients who completed treatment with enoxaparin and any glycoprotein IIb/IIIa inhibitor. Analysis performed with the abciximab 24-hour and 48-hour groups combined. 334 JAMA, January 15, 2003 Vol 289, No. 3 (Reprinted) 2003 American Medical Association. All rights reserved.

5 demonstrated among UA/NSTEMI patients. 17,18,31,33 In addition, an increase in bleeding with prolonged LMWH treatment has been noted. 17 Prolonged treatment with subcutaneous injections of dalteparin in Fragmin and Fast Revascularization During Instability in Coronary Artery Disease (FRISC II) did significantly lower the overall risk of death, MI, and at 30 days compared with placebo (3.1% vs 5.9%; P=.002). 33 However, this benefit was not sustained at 6 months. Because this difference was observed only in patients randomized to the conservative arm of FRISC II, 34 the investigators suggested that prolonged antithrombotic therapy may offer ben- Table 4. Characteristics of s Using LMWH in ST-Elevation Myocardial Infarction LMWH Group Subjects Dose and Duration Dalteparin FRAMI 94 * 247 Subcutaneous 150 IU/kg throughout hospitalization BIOMACS First dose: subcutaneous 100 IU/kg; second dose: 120 IU/kg at 12 h ASSENT PLUS IU/kg intravenous bolus and then subcutaneous 120 IU/kg for 4to7d Enoxparin ASENOX mg intravenous bolus and then subcutaneous 1 mg/kg for 2-3 d Baird et al mg intravenous bolus and then subcutaneous 40 mg three times daily for4d AMI-SK mg intravenous bolus and then subcutaneous 1 mg/kg for 3-8 d HART II mg intravenous bolus and then subcutaneous 1 mg/kg for 3 or more days ENTIRE-TIMI # 324 ±30-mg intravenous bolus and then subcutaneous 1 mg/kg during hospitalization (maximum of 8 d) ASSENT mg intravenous bolus and then subcutaneous 1 mg/kg during hospitalization (maximum of 7 d) ASSENT 3 PLUS Prehospital dose of 30-mg intravenous bolus and then subcutaneous 1 mg/kg (maximum 7 d) Subjects Control Group Drug Fibrinolytic Therapy Bleeding Definition 270 Placebo Streptokinase Any intracranial hemorrhage or bleeding requiring transfusion or surgical intervention 47 Placebo Streptokinase Composite 210 Unfractionated 158 Unfractionated 151 Unfractionated Tissue plasminogen activator Streptokinase Streptokinase, anistreplase, tissue plasminogen activator Composite 243 Placebo Streptokinase Composite 200 Unfractionated 159 Unfractionated 2035 Unfractionated 821 Unfractionated Tissue plasminogen activator Tenecteplase or half dose of tenecteplase with abciximab Tenecteplase Tenecteplase NA Bleeding requiring at least temporary cessation of study drug TIMI Major TIMI Major Any bleed requiring transfusion, intervention because of hemodynamic compromise, or both Any bleed requiring transfusion, intervention because of hemodynamic compromise, or both Abbreviations: AMI-SK, Acute Myocardial Infarction-Streptokinase; ASENOX, Accelerated Streptokinase and Enoxaparin; ASSENT, Assessment of the Safety and Efficacy of a New Thrombolytic; BIOMACS, Biochemical Markers in Acute Coronary Syndromes; ENTIRE-TIMI 23, Enoxaparin Antithrombin Therapy for ST-Elevation Thrombolysis in Myocardial Infarction; FRAMI, Fragmin in Acute Myocardial Infarction; HART II, second trial of Heparin and Aspirin Reperfusion Therapy; LMWH, low-molecular-weight ; NA, data not available. *Analysis restricted to 517 of 776 original patients with evaluable echocardiograms. Symptomatic decrease in hemoglobin of more than 20 g/l, need for transfusion, intracranial, intramuscular or joint bleed, treatment cessation due to bleeding or death from bleeding. Decrease in hemoglobin of more than 20 g/l in association with symptoms or 40 g/l regardless of symtoms, any intraocular, intraspinal, intracranial or retroperitoneal bleeding, and bleeding leading to death. Analysis of bleeding rates performed for patients on treatment. Accelerated regimen of 1.5 mu infused over 20 minutes. Death from bleeding, transfusion higher than2uofblood, higher than 3 g/dl (not associated with coronary artery bypass graft surgery), any intracerebral hemorrhage, intraocular or retroperitoneal bleeding, or any bleeding requiring surgical or percutaneous intervention. Major bleeding criteria: more than 5 g/dl drop in hemoglobin (or, when hemoglobin not available, a 15% drop in hematocrit); any intracranial hemorrhage or cardiac tamponade. #Pooled results of all patients treated with enoxaparin compared with all patients treated with unfractionated American Medical Association. All rights reserved. (Reprinted) JAMA, January 15, 2003 Vol 289, No

6 efit as a medical bridge to PCI in patients for whom invasive procedures are delayed. Benefit of LMWHs in High- Subgroups A statistically significant benefit of prolonged dalteparin treatment compared with placebo was demonstrated in the subgroup of patients in FRISC and FRISC II who presented with elevated baseline troponin-t levels. 35,36 Moreover, an analysis of Efficacy and Safety of Subcutaneous Enoxaparin in Unstable Angina and Non Q-Wave MI/Thrombolysis in MI (ESSENCE/ TIMI 11B) demonstrated that compared with unfractionated, enoxaparin blunted the increase in event rates associated with higher baseline risk, 37 and among those who underwent invasive therapy. 38 However, the effects of early mechanical may minimize any early differences attributable to prolonged antithrombotic therapy. 34 ST-Elevation Myocardial Infarction Necessity for Adjunctive Antithrombotic Therapy in Thrombolytic Regimens. The effectiveness of pharmacological reperfusion for STEMI depends on the balance between fibrinolytic and prothrombotic activity. Fibrinolysis enhances the prothrombotic state associated with STEMI by promoting the generation and release of thrombin following successful clot lysis, and activating the coagulation cascade, leading to further platelet activation Therefore, there is sound theoretical rationale to support the use of concurrent antithrombotic therapy to enhance the process of fibrinolysis in STEMI. Results of Randomized Clinical s of LMWH in STEMI. To date, 8 phase 2 trials and 2 large exploratory clinical trials have been completed that evaluate LMWH with fibrinolytic therapy in STEMI (TABLE 4 and TABLE 5). Infarct-related arterial patency following fibrinolysis has been evaluated in 3 trials with enoxaparin (Acute MI-Streptokinase [AMI-SK], 45 second trial of Heparin and Aspirin Reperfusion Therapy [HART II 46 ], and Enoxaparin Antithrombin Therapy for ST-Elevation Thrombolysis in MI [ENTIRE-TIMI ]) and 1 trial with dalteparin (second trial of Biochemical Markers in ACSs [BIOMACS II 48 ]). Use of adjunctive LMWH resulted in improved late coronary artery patency rates (3%-16% absolute improvement in TIMI 2 flow and TIMI 3 flow 49 ) and a tendency toward higher TIMI 3 flow rates (1%-17% absolute improvement ) compared with unfractionated (Table 5). Adjunctive LMWH may also be associated with improved tissue level perfusion following fibrinolysis assessed using ST-segment resolution and other noninvasive composite measurements of reperfusion seen with enoxaparin in the AMI-SK 45 and Accelerated Streptokinase and Enoxaparin (ASENOX 50 ) trials, respectively. Rates of other significant clinical events such late infarct-related arterial reocclu- Table 5. Clinical Efficacy and Major Bleeding in s of LMWH in ST-Elevation Myocardial Infarction Dalteparin FRAMI 94 Primary Efficacy Outcome Reduction in left ventricular thrombus and arterial thromboembolism Timing of Outcome LMWH Efficacy, % Major Bleeding, %* Control Difference LMWH Control Difference 9 d (P =.02) (P =.006) BIOMACS 48 TIMI 3 flow h ASSENT PLUS 49 TIMI 3 flow 4-7 d Enoxparin ASENOX 50 Mortality 30 d Reperfusion (noninvasive Not defined measurement ) Baird 51 Composite 3 mo (P =.04) AMI-SK 45 TIMI 3 flow 5-10 d (P =.01) HART II 46 Infarct-related artery patency 90 min ENTIRE-TIMI TIMI 3 flow 60 min ASSENT 3 95 Composite# 30 d (P.001) ASSENT 3 PLUS 52 Composite# 30 d (P =.08) Abbreviations: AMI-SK, Acute Myocardial Infarction-Streptokinase; ASENOX, Accelerated Streptokinase and Enoxaparin; ASSENT, Assessment of the Safety and Efficacy of a New Thrombolytic; BIOMACS, Biochemical Markers in Acute Coronary Syndromes; ENTIRE-TIMI 23, Enoxaparin Antithrombin Therapy for ST-Elevation Thrombolysis in Myocardial Infarction; FRAMI, Fragmin in Acute Myocardial Infarction; HART II, second trial of Heparin and Aspirin Reperfusion Therapy; LMWH, low molecular-weight. *See column 7 in Table 4 for definitions of major bleeding. Analysis restricted to 517 of 776 original patients with evaluable echocardiograms. Composite of rapid resolution of chest pain; rapid peak of creatine kinase within 9 hours of drug administration; and rapid resolution of ST elevation higher than 50%. End point of death, reinfarction, or rehospitalization. Lower bound of 95% confidence interval was 2%, fulfilling prespecified definition for noninferiority (lower bound of 95% confidence interval for noninferiority = 10%). Pooled analysis of all patients treated with unfractionated compared with all patients treated with enoxaparin. #End point of death, in-hospital reinfarction, and in-hospital refractory ischemia. 336 JAMA, January 15, 2003 Vol 289, No. 3 (Reprinted) 2003 American Medical Association. All rights reserved.

7 sion 45,46,49 and recurrent ischemia 47,48,51 were reduced with LMWH compared with unfractionated. Finally, similar bleeding rates were found with LMWH compared with unfractionated in the majority of completed trials (Table 5). However, preliminary results presented at the AHA 2002 Scientific Sessions from the third Assessment of the Safety and Efficacy of a New Thrombolytic PLUS (ASSENT 3 PLUS) underscore the need for continued evaluation of the safety of LMWH as an adjunct to fibrinolysis. 52 Among 1639 patients with STEMI receiving tenecteplase and either enoxaparin or unfractionated in a prehospital setting, higher rates of both major bleeding (4.0% vs 2.8%) and intracranial hemorrhage (2.2% vs 1.0%; P=.05) were seen in the enoxaparin group compared with the unfractionated group. There was a significant interaction between patient age and risk of bleeding because almost all cases of intracerebral hemorrhage were confined to patients older than 75 years. This safety concern of enoxaparin among elderly patients will be addressed in the ongoing (ExTRACT- TIMI 25) trial. This double-blind, parallel group trial is randomizing approximately fibrinolysiseligible STEMI patients in a 1:1 fashion to receive either adjunctive unfractionated (intravenous 60- IU/kg bolus and 12-IU/kg infusion per hour) or enoxaparin (intravenous 30-mg bolus and a subcutaneous injection of 1 mg/kg ). Of note, patients older than 75 years will not receive the intravenous bolus of enoxaparin and will receive only 75% of the subcutaneous injection dose. The primary end point is a composite of allcause mortality and nonfatal reinfarction within 30 days of randomization. Low-Molecular-Weight Heparin and PCI The issue of LMWH treatment in combination with PCI is becoming increasingly relevant given the results of several studies demonstrating the superiority of an invasive approach for the management of both UA/NSTEMI 34,53 and STEMI. 54 Compared with the large amount of literature evaluating LMWHs for the medical management of UA/NSTEMI, there are fewer data evaluating LMWHs in the invasive setting. Accordingly, while the ACC, AHA, European Society of Cardiology, and the American College of Chest Physicians have all acknowledged the safety and potential pharmacological advantages of LMWH over unfractionated, none of these organizations have endorsed the use of LMWH as the preferred antithrombotic agent in the invasive management of UA/NSTEMI. Nevertheless, data suggest that LMWH monotherapy is safe and efficacious in the setting of elective and urgent PCI (TABLE 6 and TABLE 7). In addition, several trials have also demonstrated the safety and efficacy using LMWH in combination with a glycoprotein IIb/IIIa inhibitor (TABLE 8 and TABLE 9). Unfractionated retains several attractive properties compared with LMWH in the invasive setting, including low cost, complete reversibility with Table 6. Characteristics of s Using Low-Molecular-Weight Heparin Alone in PCI* Study Population Subjects REDUCE 64 Elective PCI 306 Reviparin 7000-U intravenous bolus and infusion Rabah et al 65 Elective PCI 30 Enoxaparin 1 mg/kg intravenous for 1 dose Choussat et al 73 Elective PCI 242 Enoxaparin 0.5 mg/kg intravenous for 1 dose PEPCI 72 Elective PCI 40 Enoxaparin 1 mg/kg subcutaneous NICE 1 68 Elective or urgent PCI 828 Enoxaparin 1 mg/kg intravenous for 1 dose Colletetal 67 ESSENCE/ TIMI 11B 38 FRISC II (Invasive) 34 Unstable angina/ non ST-segment elevation MI Unstable angina/ non ST-segment elevation MI Unstable angina/ non ST-segment elevation MI LMWH Group Drug or Control Group Timing of PCI Relative to Last LMWH Preparation Dose and Duration Subjects Drug Dose 132 Enoxaparin 1 mg/kg subcutaneous 431 Enoxaparin 1 mg/kg subcutaneous and ±30-mg intravenous bolus 1222 Dalteparin 120 IU/kg subcutaneous (open label 5 d) 306 Unfractionated 30 Unfractionated Immediately Supplemental Periprocedural Anticoagulant U intravenously within a 24-h period and 3500 U subcutaneously daily for 28 d Immediately Immediately h 0.3 mg/kg intravenously Immediately h Unfractionated At physician s discretion after initial 24 h Unfractionated at discretion of investigator h pre-pci NA Abbreviations: ESSENCE/TIMI, Efficacy and Safety of Subcutaneous Enoxaparin in Unstable Angina and Non-Q-Wave MI/Thrombolysis in Myocardial Infarction; FRISC, Fragmin and Fast Revascularization During Instability in Coronary Artery Disease; LMWH, low molecular-weight ; MI, myocardial infarction; NA, data not available; PCI, percutaneous coronary intervention; PEPCI, Pharmacokinetic Study of Enoxaparin in Patients Undergoing Coronary Intervention; REDUCE, Reduction of Restenosis After PTCA, Early Administration of Reviparin in a Double-Blind Unfractionated Heparin and Placebo-Controlled Evaluation; ellipses indicate no control group. *Event rates for the efficacy and safety end points are summarized in Table 7. Sixteen patients received concomitant eptifibatide and 6 patients received concomitant abciximab. Analysis is for all 40 patients who received enoxaparin and underwent PCI. Major bleeding to 43 days. Analysis restricted to patients who underwent PCI in hospital. Efficacy end point evaluated following PCI American Medical Association. All rights reserved. (Reprinted) JAMA, January 15, 2003 Vol 289, No

8 protamine, and the availability of an easily interpretable and standardized pointof-care test (activated clotting time). 58 In contrast, protamine is able to fully reverse the effect of LMWH on thrombin, but only 60% of its anti-xa activity. 59 It remains controversial whether routine monitoring of anticoagulation is needed with LMWH in the catheterization laboratory. 12,13,60 Moreover, the optimal level of anticoagulation for LMWH during invasive cardiac procedures has not been prospectively defined. Since LMWH does not appreciably affect either the activated partial thromboplastin time or activated clotting time, clinical trials have focused on the anti-xa activity as a surrogate to assess the level of anticoagulation. Although now commercially available, routine monitoring of anticoagulation with LMWH has not been universally adopted. The currently accepted therapeutic activity of LMWH in PCI (anti- Xa, IU/mL) is based primarily on clinical data from the deep venous thrombosis literature 60 and doseranging studies in UA/NSTEMI. 61 In TIMI 11A, enoxaparin administered as an intravenous 30-mg bolus followed by a subcutaneous injection of 1 mg/kg generated trough anti-xa activity of 0.5 IU/mL and peak activity Table 7. Major Bleeding and Event Rates of s Using Low-Molecular-Weight Heparin Alone in PCI* REDUCE 64 Primary Efficacy Outcome Death, MI, or Timing of Outcome LMWH Event Rate, % Major Bleeding, % Control Difference LMWH Control Difference Within 30 wk Rabah et al 65 TIMI 3 flow Post-PCI Ischemic complications Within 30 d Choussat et al 73 Death, MI, or urgent Within 30 d PEPCI 72 Death, MI, or urgent Within 30 d NICE 1 68 Death, MI, or urgent Within 30 d Collet et al 67 Death or MI Within 30 d ESSENCE/TIMI 11B 38 Death or MI Within 43 d (P =.06) FRISC II(Invasive) 34 Death or MI Within 6 mo Abbreviations: ESSENCE/TIMI, Efficacy and Safety Subcutaneous Enoxaparin in Unstable Angina and Non-Q-Wave MI/Thrombolysis in Myocardial Infarction; FRISC II, second Fragmin and Fast Revascularization During Instability in Coronary Artery Disease; LMWH, low-molecular-weight ; MI, myocardial infarction; PEPCI, Pharmacokinetic Study of Enoxaparin in Patients Undergoing Coronary Intervention; PCI, percutaneous coronary intervention; REDUCE, Reduction of Restenosis After PTCA, Early Administration of Reviparin in a Double-Blind Unfractionated Heparin and Placebo-Controlled Evaluation; ellipses indicate no control group. *Characteristics of trials are listed in Table 6. Sixteen patients received concomitant eptifibatide and 6 patients received concomitant abciximab. Analysis is for all 40 patients who received enoxaparin and underwent PCI. Analysis restricted to patients who underwent PCI in hospital. The use and type of LMWH was not mandated by protocol and its use was per physician preference. Analysis restricted to patients who received LMWH alone during PCI. Table 8. Characteristics of s of Low-Molecular-Weight Heparin in Combination With Glycoprotein IIb/IIIa Inhibitors in PCI* Study Population Subjects Drug or Preparation LMWH Group Dose and Duration NICE 4 68 Elective or urgent PCI 818 Enoxaparin 0.75 mg/kg intravenous for 1 dose Kereiakes et al 70 Elective or urgent PCI 103 Dalteparin 40 IU/kg intravenous for 1 dose; 60 IU/kg intravenously for 1 dose CRUISE 77 Elective or urgent PCI 129 Enoxaparin 0.75 mg/kg intravenous for 1 dose NICE 3 71 Unstable angina/ non ST-segment elevation MI 283 Enoxaparin 1 mg/kg subcutaneous Glycoprotein IIb/ IIIa Inhibitor Timing of PCI Relative to Last LMWH Dose Subjects Control Group Drug Abciximab Immediately Abciximab Immediately Eptifibatide Immediately 132 Unfractionated Tirofiban, eptifibatide, or abciximab At physician s discretion Abbreviations: ACUTE, Antithrombotic Combination Using Tirofiban and Enoxaparin; LMWH, low-molecular-weight ; MI, myocardial infarction; PCI, percutaneous coronary intervention; ellipses indicate no control group. *Event rates for clinical efficacy and safety end points for these trials are in Table 9. No loading dose was given prior to PCI except for in the NICE 3 trial in which a 0.3-mg intravenous dose was given if PCI was more than 8 hours after last subcutaneous dose. No supplemental anticoagulation was performed in any of these trials. Analysis restricted to patients undergoing PCI who were treated with both enoxaparin and a glycoprotein IIb/IIIa inhibitor and with 30-day follow-up data available. Three of 43 patients treated with enoxaparin alone also had PCI. Analysis restricted to patients undergoing PCI treated with both an LMWH and lamifiban. 338 JAMA, January 15, 2003 Vol 289, No. 3 (Reprinted) 2003 American Medical Association. All rights reserved.

9 of 1.1 IU/mL, with a low rate (2.7%) of major hemorrhage among patients undergoing PCI. 61 Several trials have demonstrated that reliable levels of anti-xa activity consistently greater than the 0.5 IU/mL threshold may be obtained using various doses of LMWH when administered several days or immediately before PCI (TABLE 10). From the available data, 2 strategies have emerged guiding the use of LMWH (with or without concomitant glycoprotein IIb/IIIa inhibition) for PCI. First, unfractionated has been substituted for LMWH prior to angiography and coronary intervention if the last LMWH dose was given more than 8 to 12 hours before the procedure. 34,38,62,63 Second, a number of pilot trials have evaluated the use of LMWH as the sole anticoagulant throughout angiography and intervention without changing to unfractionated. 25,64-73 However, these 2 strategies have not been directly compared. With the limited data available, both approaches appear to be safe and efficacious, with bleeding and clinical event rates similar to historical controls (Table 7 and Table 9). Ongoing large trials (ie, A to Z, 74 SYNERGY 75 ) will yield additional information on the safety and efficacy of enoxaparin and glycoprotein IIb/IIIa inhibition in the PCI setting. Current Recommendations and Observations From Clinical s Unstable Angina/Non ST-Elevation MI. Based on the available evidence, the Table 9. Clinical Efficacy and Major Bleeding in s of LMWH in Combination With Glycoprotein IIb/IIIa Inhibitors in PCI* Event Rate, % Major Bleeding, % Difference LMWH Control Difference Primary Efficacy Outcome Timing of Outcome LMWH Control NICE 4 68 Death, MI, urgent Within 30 d Kereiakes 70 Death, MI, urgent In hospital CRUISE 77 Death, MI, urgent Within 48 h NICE 3 71 Death, MI, recurrent ischemia Within 30 d Abbreviations: ACUTE, Antithrombotic Combination Using Tirofiban and Enoxaparin; LMWH, low-molecular-weight ; MI, myocardial infarction; PCI, percutaneous coronary intervention; ellipses indicate no control group. *Characteristics of trials are listed in Table 8. Data observed with 40 IU/kg intravenous dose of dalteparin. Data observed with 60 IU/kg intravenous dose of dalteparin. Analysis restricted to patients undergoing PCI who were treated with both enoxaparin and a glycoprotein IIb/IIIa inhibitor and with 30-day follow-up data available. Three of 43 patients treated with enoxaparin alone also had PCI. Pooled analysis of all glycoprotein IIb/IIIa inhibitors in combination with enoxaparin.reated with both a LMWH and lamifiban. Table 10. Anticoagulant Profiles of LMWH in Elective and Urgent PCI Study Population Subjects Drug or Preparation Dose and Duration PEPCI 72 Elective PCI 47 Enoxaparin 1 mg/kg subcutaneous 8-12 h and 0.3 mg/kg intravenous bolus immediately preprocedure NICE 1 68 Elective or urgent PCI 828 Enoxaparin Single 1 mg/kg intravenous bolus dose immediately preprocedure Collet et al 67 Kereiakes et al 70 Unstable angina/ non ST-segment elevation MI Unstable angina/ non ST-segment elevation MI 293 Enoxaparin 1 mg/kg subcutaneous for 48 h; last dose given within 4 to 8hofPCI 107 Dalteparin 120 IU/kg subcutaneously and if procedure was 8 h since last dose then an additional 40 or 60 IU/kg intravenously Choussat et al 73 Elective PCI 242 Enoxaparin Single 0.5 mg/kg intravenous bolus dose immediately preprocedure Definition of Adequate Anticoagulation IU/mL Anti-Xa activity None stated 0.5 IU/mL Anti-Xa activity 0.6 IU/mL Anti-Xa activity 0.5 IU/mL Anti-Xa activity Patients Meeting Definition at Time of Angiography, % Abbreviations: LMWH, low-molecular-weight ; MI, myocardial infarction; NA, data not available; PCI, percutaneous coronary intervention; PEPCI, Pharmacokinetic Study of Enoxaparin in Patients Undergoing Coronary Intervention. *Although no definition of adequate anticoagulation levels were stated, the mean anti-xa level among patients who received enoxaparin was 2.1 ± 0.7 IU/mL within 5 minutes of intravenous injection. Three of 27 patients assigned to the 40 IU/kg dalteparin group had angiographically evident thrombus; this arm was subsequently dropped in favor of the 60 IU/kg intravenous dose. More patients in the 40 IU/kg intravenous group were under the prespecified 0.6 IU/mL anti-xa threshold than the 60 IU/kg intravenous dalteparin group. 96 NA* 98 NA American Medical Association. All rights reserved. (Reprinted) JAMA, January 15, 2003 Vol 289, No

10 2002 ACC and AHA guidelines list the use of either LMWH or unfractionated as a class I recommendation for the treatment of UA/NSTEMI (level of evidence, A). 57 In addition, use of enoxaparin is preferred over unfractionated (class IIA; level of evidence, A), except if coronary artery bypass graft surgery is anticipated within 24 hours. 57 ST-Elevation MI. Completed trials of adjunctive LMWH compared with either placebo or unfractionated in the setting of STEMI have demonstrated lower rates of late ischemic events and improved rates of late coronary artery patency. The increased bleeding seen with prehospital enoxaparin in ASSENT-3 PLUS requires further study and possible dose modification in elderly patients, although it appears LMWHs are safe among patients younger than 75 years. Ex- TRACT-TIMI 25, ADVANCE-MI, and FINESSE will be able to provide more definitive data regarding the utility of enoxaparin in modern reperfusion regimens in all age groups. Percutaneous Coronary Intervention Although an expert consensus statement has been published with recommendations of LMWH in the setting of PCI, 60 the most recent guidelines from the ACC and AHA do not discuss the use of LMWH as the sole anticoagulant in the setting of PCI. 76 Moreover, the optimal level of anticoagulation has not been prospectively validated, although similar efficacy and safety outcomes with LMWH compared with unfractionated (with and without concomitant glycoprotein IIb/IIIa inhibitors) have been shown with a target anti-xa level of higher than 0.5 IU/mL. Low-molecular-weight may be used as the sole anticoagulant during PCI. Dalteparin should be given at a dose of 120 IU/kg subcutaneously provided PCI is performed within 8 hours. 34 If PCI is to be performed more than 8 to 12 hours following the last subcutaneous injection dose, patients should be given an additional 60-IU/kg intravenous bolus of dalteparin. 70 Enoxaparin may be given subcutaneously at a dose of 1 mg/kg without the need for further supplementation if PCI is performed within 8 hours. 38,67,68 An additional 0.3-mg/kg intravenous bolus should be given if PCI is performed between 8 and 12 hours after the last subcutaneous dose. 71,72 Subcutaneous enoxaparin should be reduced for patients with severe renal insufficiency (creatinine clearance 30 ml/min [ ml/s]). A single 0.5-mg/kg intravenous dose of enoxaparin without further subcutaneous dosing may be safe and efficacious in the setting of moderate-to-severe renal failure. 73 Alternatively, unfractionated may be substituted for enoxaparin if PCI is to be performed more than 8 to 12 hours following the last subcutaneous dose of enoxaparin. 38 Low-molecular-weight can also be used in conjunction with glycoprotein IIb/IIIa inhibitors. Data from several clinical trials suggest that the combination of enoxaparin with various glycoprotein IIb/IIIa inhibitors 66,68,69,77 and dalteparin with abciximab 70 are safe in the setting of PCI. More definitive information will be forthcoming about the combination of enoxaparin and glycoprotein IIb/IIIa inhibitors during PCI. 74,75 CONCLUSIONS The use of LMWH has been established as a first-line choice in the treatment of UA/NSTEMI, and increasing evidence suggests that it may supplant unfractionated as an anticoagulant in the setting of PCI and STEMI. 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All rights reserved. (Reprinted) JAMA, January 15, 2003 Vol 289, No