Use of Low-Molecular-Weight Heparins in the Management of Acute Coronary Artery Syndromes and Percutaneous Coronary Intervention

CLINICAL CARDIOLOGY

Graham C. Wong, MD Context Low-molecular-weight heparins (LMWHs) possess several potential phar- Robert P. Giugliano, MD, SM macological advantages over unfractionated heparin as an antithrombotic agent. Elliott M. Antman, MD Objective To systematically summarize the clinical data on the efficacy and safety of LMWHs compared with unfractionated heparin across the spectrum of acute coro- HE INCITING EVENT IN AN ACUTE nary syndromes (ACSs), and as an adjunct to percutaneous coronary intervention (PCI). coronary syndrome (ACS) typi- Data Sources We searched MEDLINE for articles from 1990 to 2002 using the in- cally involves disruption of a dex terms heparin, enoxaparin, dalteparin, nadroparin, tinzaparin, low molecular weight vulnerable atherosclerotic heparin, myocardial infarction, unstable angina, coronary angiography, coronary an- Tplaque with superimposed thrombosis, gioplasty, thrombolytic therapy, reperfusion, and drug therapy, combination. Addi- leading to varying degrees of occlusion tional data sources included bibliographies of articles identified on MEDLINE, inquiry of the culprit artery.1-3 ST-elevation myo- of experts and pharmaceutical companies, and data presented at recent national and cardial infarction (STEMI) is usually as- international cardiology conferences. sociated with complete thrombotic oc- Study Selection We selected for review randomized trials comparing LMWHs against clusion of the culprit artery,4 while either unfractionated heparin or placebo for treatment of ACS, as well as trials and reg- nonocclusive thrombus is the typical istries examining clinical outcomes, pharmacokinetics, and/or phamacodynamics of LMWHs finding associated with unstable angina/ in the setting of PCI. Of 39 studies identified, 31 fulfilled criteria for analysis. non–ST-elevation myocardial infarc- Data Extraction Data quality was determined by publication in the peer-reviewed tion (UA/NSTEMI).5,6 Tissue factor ex- literature or presentation at an official cardiology society–sponsored meeting. posed following plaque rupture leads to Data Synthesis The LMWHs are recommended by the American Heart Associa- activation of the coagulation cascade and tion and the American College of Cardiology for treatment of unstable angina/non– generation of factor Xa (FIGURE 1).7 ST-elevation myocardial infarction. Clinical trials have demonstrated similar safety with Thrombin is formed, which leads to fi- LMWHs compared with unfractionated heparin in the setting of PCI and in conjunc- brin deposition, platelet activation, and tion with glycoprotein IIb/IIIa inhibitors. Finally, LMWHs show promise as an antithrombotic agent for the treatment of ST-elevation myocardial infarction. ultimately the formation of a stable clot.8 Given the central role of thrombin in Conclusions The LMWHs could potentially replace unfractionated heparin as the the pathogenesis of ACSs, an antithrom- antithrombotic agent of choice across the spectrum of ACSs. In addition, they show botic agent is an important element in 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 therapy, regardless of whether ST eleva- their use can be universally recommended. tion is present. However, there are im- JAMA. 2003;289:331-342 www.jama.com portant limitations associated with unfractionated heparin (currently the most commonly used antithrombotic agent), METHODS Author Affiliations: TIMI Study Group, Brigham and which has prompted a search for alter- Studies for this review were identified Women’s Hospital, Boston, Mass. 9 Financial Disclosures: Dr Giugliano has received hono- native compounds. One promising class using MEDLINE searches, reviewing ref- raria from Aventis for educational programs. Dr Antman of agents is the low-molecular-weight erence lists, and conferring with ex- has received clinical research grants from Aventis. Corresponding Author and Reprints: Robert P. heparins (LMWHs), which offer poten- perts and pharmaceutical companies. Giugliano, MD, SM, TIMI Study Group, 350 Long- tial advantages in terms of clinical effi- The medical subject headings used were wood Ave, First Floor Offices, Boston, MA 02115 (e-mail: [email protected]). cacy, safety, and ease of use in the set- heparin, enoxaparin, dalteparin, nadro- Clinical Cardiology Section Editor: Michael S. Lauer, ting of ACS. parin, tinzaparin, low molecular weight MD, Contributing Editor.

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reviewed journal or presentation at an Figure 1. Differential Effects of Unfractionated Heparin and Low-Molecular-Weight Heparin official cardiology society–sponsored meeting. Of 39 studies identified, 31 ful- Tissue Factor Tissue Factor filled criteria for analysis. - Pathway Inhibitor Factor VIIa RESULTS

Endothelial Cells Understanding of the pharmacological

+ + characteristics of LMWHs has evolved Factor IX Factor IXa 10,11 Activation since previous reviews. The LMWHs LMWH UFH act more proximally on the coagula- - + + tion cascade than unfractionated heparin and more effectively inhibit throm- Factor X Factor Xa Activation bin generation (Figure 1). Increasing evidence also suggests that LMWHs may LMWH differ from unfractionated heparin in other thrombin-dependent and thrombin-independent mechanisms (TABLE 1). Antithrombin III - These differences may explain the different pharmacological profiles of UFH LMWH and unfractionated heparin in Prothrombinase Complex the setting of ACSs and PCI. + Although anti-Xa monitoring is not Prothrombin Thrombin commonly performed nor recommended in routine clinical practice,12,13 it has been suggested that monitoring of LMWH LMWH activity may be of benefit in certain high-risk patient subgroups in Antithrombin III - which the optimal dose of LMWH has not been established.14 These include patients at weight extremes, patients with UFH + renal insufficiency (prolongation of Fibrinogen Fibrin anti-Xa activity),15 and patients who are pregnant (lower than normal anti-Xa ac- In acute coronary syndromes, thrombosis is typically initiated via exposure of tissue factor at the site of a dis- 16 rupted plaque. The complex of tissue factor and Factor VIIa activates Factor X to Xa. Factor Xa subsequently tivity for a given LMWH). 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 Non–ST-Elevation ACSs maintain the thrombotic process. Both unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs) act by complexing with antithrombin III. LMWHs have a relatively greater inhibitory effect on Factor Xa than (UA/NSTEMI) on factor IIa (thrombin), such that the anti-Xa:IIa inhibitory ratio is greater than 1. This produces greater up- The LMWHs have been compared with stream inhibition of the coagulation cascade and relatively greater reduction of thrombin generation than when unfractionated heparin is administered. Unfractionated heparin has an anti-Xa:IIa inhibitory ratio of 1. While unfractionated heparin for the treat- it is theoretically possible to achieve similar anti-Xa activity with unfractionated heparin as with LMWH, be- ment of UA/NSTEMI in 4 large, pro- cause of poor bioavailability very high doses of unfractionated heparin are required that would result in un- 17-20 acceptably high anti-IIa levels and an increased risk of bleeding. Both unfractionated heparin and LMWHs also spective randomized trials. Several inhibit coagulation through release of tissue factor pathway inhibitor (TFPI) from endothelial cells. However, meta-analyses comparing unfraction- unlike unfractionated heparin, LMWHs do not cause TFPI depletion, which has been associated with a para- ated heparin with LMWH have al- doxical prothrombotic state during anticoagulant therapy in the setting of acute coronary syndromes. ready demonstrated the superiority of LMWH over placebo21-23 and the supe- heparin, myocardial infarction, unstable als that compared a LMWH with either riority of enoxaparin over unfraction- angina, coronary angioplasty, thrombo- unfractionated heparin or placebo for the ated heparin21,22 (FIGURE 2). lytic therapy, reperfusion, and drug treatment of STEMI and UA/NSTEMI. Key differences in clinical trial de- therapy, combination. In addition, rel- We also included nonrandomized tri- sign, patient selection, and character- evant abstracts from the annual meet- als and registries of LMWH that exam- istics of the preparations make com- ings of the American Heart Association ined clinical outcomes, and/or pharma- parisons among LMWHs difficult. Only (AHA), American College of Cardiol- cokinetics and phamacodynamics in the 1 trial has compared 2 LMWH prepa- ogy (ACC), and European Society of setting of percutaneous coronary inter- rations in the setting of UA/NSTEMI. Cardiology were reviewed. We se- vention (PCI). Data quality was deter- The Enoxaparin Versus Tinzaparin lected for review randomized clinical tri- mined by publication in a peer- (EVET) trial randomized 438 patients

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Table 1. Limitations of Unfractionated Heparin Unfractionated Heparin Potential Pharmacological Pharmacological Advantage of LMWH Over Properties Consequences Clinical Consequence Unfractionated Heparin Thrombin-dependent properties Nonspecific protein binding11,78 Less drug binding to thrombin Variable level of anticoagulation Less nonspecific protein binding78,79 Sensitivity to inactivation by requiring monitoring of platelet factor 4 and activated PTT histidine-rich glycoprotein Short plasma half-life10,11 Poor bioavailability with a Requires continuous Long plasma half-life relative to single intravenous or intravenous infusion unfractionated heparin enables subcutaneous dose intermittent intravenous or subcutaneous injections without a concomitant infusion80,81 Relative inability to inhibit Increased thrombin Rebound thrombosis during Decreased new thrombin generation clot-bound thrombin30,82 generation following clot and following due to superior proximal Xa lysis in presence of unfractionated heparin inhibition29 therapeutic levels of treatment unfractionated heparin Depletion of TFPI83,84 Decreased attenuation of Rebound hypercoaguability Relatively less TFPI depletion84-86 tissue factor/factor VIIa complex Thrombin-independent properties Increased binding to platelets87 Increased immunogenicity Increased potential for Relatively less platelet activation87,90 Increased platelet activation bleeding, HITTS, or and platelet-endothelial and adhesion to thrombosis interactions91 endothelium Inability to blunt increase Elevations of vWF in ACS Increased potential for Superior attenuation of the increase of vWF in ACS88,89 thrombosis of vWF in ACS88,89 Abbreviations: ACS, acute coronary syndrome; HITTS, heparin-induced thrombocytopenia and thrombosis syndrome; LMWH, low-molecular-weight heparin; PTT, partial throm- boplastin time; TFPI, tissue factor pathway inhibitor; vWF, von Willebrand factor.

presenting with UA/NSTEMI to either enoxaparin (subcutaneous injection of 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 1 mg/kg twice daily; n=220) or tinza- Revascularization parin (subcutaneous injection of 175 IU/kg daily; n=318).24 The composite LMWH Sample Trial PreparationSize Day LMWH Better UFH Better primary end point (death, reinfarction, 20 or recurrent angina) was lower with FRIC Dalteparin 1482 6 enoxaparin compared with tinzaparin at FRAXIS17 Nadroparin 2357 14 day 7 (12.3% vs 21.1%; P=.02). This dif- ESSENCE19 Enoxaparin 3171 14 ference, which persisted to 30 days, was TIMI 11B18 Enoxaparin 3910 14

driven almost entirely by a reduction in 0.75 1.0 1.5 recurrent angina (at 7 days: 11.8% vs Odds Ratio (95% Confidence Interval) 19.3% [P=.03]; at 30 days: 17.3% vs ESSENCE indicates Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events; FRAXIS, 26.1% [P=.02]). Major bleeding was un- Fraxiparine in Ischaemic Syndrome; FRIC, Fragmin in Unstable Coronary Artery Disease; LMWH, low-molecular- common and not statistically different weight heparin; TIMI 11B, Thrombolysis in Myocardial Infarction; and UFH, unfractionated heparin. Repro- between the enoxaparin and tinzapa- duced with permission.57 rin groups (3.6% vs 3.2%). bination Using Tirofiban and Enoxa- vorably with the overall 2.4% rate of Combination of LMWH and parin (ACUTE I) trial (84% vs 65%),25 major bleeding calculated in a meta- Glycoprotein IIb/IIIa Inhibitors suggesting a possible synergistic effect analysis of glycoprotein IIb/IIIa inhibi- for the Initial Medical on platelet inhibition from LMWH and tors and unfractionated heparin for the Management of ACSs glycoprotein IIb/IIIa inhibitors. This treatment of ACSs.26 Furthermore, no The combination of enoxaparin and ti- combination has since been evaluated increase in bleeding was noted among rofiban resulted in a trend toward a in 5 trials of initial medical therapy for UA/NSTEMI patients who proceeded to greater proportion of patients achiev- UA/NSTEMI (TABLE 2 and TABLE 3). PCI. Although not powered to detect ing more than 70% inhibition of plate- The major finding was that major hem- differences in clinical events, rates of let aggregation compared with the com- orrhage occurred rarely in the LMWH ischemic events in these trials were bination of unfractionated heparin and and glycoprotein IIb/IIIa inhibitor arms noted to be similar between the LMWH tirofiban in the Antithrombotic Com- (0.3%-1.8%). These rates compare fa- and unfractionated heparin groups.

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The combination of tirofiban and mary efficacy end point between either antithrombotic therapy in this setting. enoxaparin was studied in 1224 pa- enoxaparin and unfractionated hepa- The LMWHs are attractive as long- tients presenting with STEMI in the rin monotherapy groups (15.4% vs term antithrombotic agents by virtue of Treatment of Enoxaparin and Tirofi- 17.3%) or between enoxaparin and un- their safety profile and ease of use, ban in Acute Myocardial Infarction fractionated heparin combination groups prompting several trials to evaluate their (TETAMI) trial. Patients ineligible for fi- (16.1% vs 17.2%). Major bleeding was use in the outpatient setting following brinolysis were randomized in a 2ϫ2 rare and not statistically different among an acute coronary event.18-20,31 fashion to receive either enoxaparin (in- all 4 groups. Although the clinical benefit of inhos- travenous 30-mg bolus and subcutane- pital LMWH therapy is maintained up ous injection of 1 mg/kg twice daily) or Duration of Therapy of LMWH to 1 year following the index event32 unfractionated heparin (intravenous 70 in UA/NSTEMI (hazard ratio, 0.88; 95% confidence in- U/kg bolus and 15 U/kg per hour infu- Evidence suggests that the prothrom- terval, 0.81-0.97; P=.008 for the com- sion) with or without tirofiban (intra- botic state associated with an ACS may bined end point of death, MI, or urgent venous 10-µg/kg bolus and 0.1-µg/kg per persist for several months following the revascularization), no additional ben- minute infusion) for 2 to 8 days.27 There index event,28-30 providing a biologi- efit from use of LMWH beyond hospi- were no differences noted in the pri- cally plausible rationale for prolonged tal discharge has been convincingly

Table 2. Characteristics of Trials 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

No. of No. of Duration of Primary Efficacy Trial* Subjects Drug Dose Subjects Drug Therapy Outcome ACUTE II66 315 Enoxaparin Subcutaneous 1 mg/kg 210 Unfractionated 24 to 96 h Death, MI, urgent twice daily heparin revascularization NICE 371 671 Enoxaparin Subcutaneous 1 mg/kg ...... 24 to 96 h Death, MI, urgent twice daily revascularization GUSTO IV 646† Dalteparin Subcutaneous 120 IU/kg 4556‡ Unfractionated 5 to 7 d Death, MI Dalteparin twice daily heparin substudy92 INTERACT93 380 Enoxaparin Subcutaneous 1 mg/kg 366 Unfractionated Ն48 h Death, MI twice daily heparin PARAGON-B69 411 LMWH§ Not specified 2205 Unfractionated Ն3 d Death, MI, urgent heparin revascularization 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 heparin; 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 Trials 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 Absolute Timing of Absolute Efficacy Risk Safety Risk Trial Outcome LMWH Control DifferenceOutcome LMWH Control Difference ACUTE II66 In hospital 9.2 9.0 0.2 30 d 0.3 1.0 −0.7 NICE 371 30 d 11.6† ...... 30 d 1.9* ...... GUSTO IV Dalteparin substudy92‡ 30 d 9.6 8.5 1.1 7 d 1.2 0.7 0.5 INTERACT93 30 d 10.1 11.8 −1.7 96 h 1.8 4.6 −2.8 (P = .03) PARAGON-B69 30 d 10.2 12.1 −1.9 30 d 1.5 1.6 −0.1 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 heparin; 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.

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demonstrated among UA/NSTEMI pa- and Fast Revascularization During In- ever, this benefit was not sustained at 6 tients.17,18,31,33 In addition, an increase in stability in Coronary Artery Disease months. Because this difference was ob- bleeding with prolonged LMWH treat- (FRISC II) did significantly lower the served only in patients randomized to ment has been noted.17 overall risk of death, MI, and revascu- the conservative arm of FRISC II,34 the Prolonged treatment with subcutane- larization at 30 days compared with pla- investigators suggested that prolonged ous injections of dalteparin in Fragmin cebo (3.1% vs 5.9%; P=.002).33 How- antithrombotic therapy may offer ben-

Table 4. Characteristics of Trials Using LMWH in ST-Elevation Myocardial Infarction LMWH Group Control Group

No. of No. of Trial Subjects Dose and Duration Subjects Drug Fibrinolytic Therapy Bleeding Definition Dalteparin FRAMI94* 247 Subcutaneous 150 IU/kg 270 Placebo Streptokinase Any intracranial twice daily throughout hemorrhage or hospitalization bleeding requiring transfusion or surgical intervention BIOMACS48 54 First dose: subcutaneous 47 Placebo Streptokinase Composite† 100 IU/kg; second dose: 120 IU/kg at 12 h ASSENT PLUS49 224 30 IU/kg intravenous bolus 210 Unfractionated Tissue plasminogen Composite‡ and then subcutaneous heparin activator 120 IU/kg twice daily for 4to7d Enoxparin ASENOX50 154 40-mg intravenous bolus and 158 Unfractionated Streptokinase§ NA then subcutaneous heparin 1 mg/kg twice daily for 2-3 d Baird et al51 149 40-mg intravenous bolus and 151 Unfractionated Streptokinase, Bleeding requiring at least then subcutaneous heparin anistreplase, tissue temporary cessation 40 mg three times daily plasminogen activator of study drug for4d AMI-SK45 253 30-mg intravenous bolus and 243 Placebo Streptokinase Composite࿣ then subcutaneous 1 mg/kg twice daily for 3-8 d HART II46 200 30-mg intravenous bolus and 200 Unfractionated Tissue plasminogen TIMI Major¶ then subcutaneous heparin activator 1 mg/kg twice daily for 3 or more days ENTIRE-TIMI 2347# 324 ±30-mg intravenous bolus 159 Unfractionated Tenecteplase or half dose TIMI Major¶ and then subcutaneous heparin of tenecteplase with 1 mg/kg twice daily abciximab during hospitalization (maximum of 8 d) ASSENT 395 2040 30-mg intravenous bolus and 2035 Unfractionated Tenecteplase Any bleed requiring then subcutaneous heparin transfusion, 1 mg/kg twice daily intervention because during hospitalization of hemodynamic (maximum of 7 d) compromise, or both ASSENT 3 PLUS52 818 Prehospital dose of 30-mg 821 Unfractionated Tenecteplase Any bleed requiring intravenous bolus and heparin transfusion, then subcutaneous intervention because 1 mg/kg twice daily of hemodynamic (maximum 7 d) 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 In- farction; FRAMI, Fragmin in Acute Myocardial Infarction; HART II, second trial of Heparin and Aspirin Reperfusion Therapy; LMWH, low-molecular-weight heparin; 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 Ͼ15% drop in hematocrit); any intracranial hemorrhage or cardiac tamponade. #Pooled results of all patients treated with enoxaparin compared with all patients treated with unfractionated heparin.

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efit as a medical bridge to PCI in pa- ST-Elevation Myocardial Infarction (Acute MI-Streptokinase [AMI-SK],45 tients for whom invasive procedures are Necessity for Adjunctive Antithrom- second trial of Heparin and Aspirin delayed. botic Therapy in Thrombolytic Regi- Reperfusion Therapy [HART II46], and mens. The effectiveness of pharmaco- Enoxaparin Antithrombin Therapy for Benefit of LMWHs logical reperfusion for STEMI depends ST-Elevation Thrombolysis in MI in High-Risk Subgroups on the balance between fibrinolytic and [ENTIRE-TIMI 2347]) and 1 trial with A statistically significant benefit of prothrombotic activity. Fibrinolysis dalteparin (second trial of Biochemical prolonged dalteparin treatment com- enhances the prothrombotic state asso- Markers in ACSs [BIOMACS II48]). Use pared with placebo was demonstrated ciated with STEMI by promoting the gen- of adjunctive LMWH resulted in im- in the subgroup of patients in FRISC eration and release of thrombin follow- proved late coronary artery patency rates and FRISC II who presented with ing successful clot lysis,39-41 and activating (3%-16% absolute improvement in TIMI elevated baseline troponin-T levels.35,36 the coagulation cascade, leading to fur- 2 flow45-47 and TIMI 3 flow49) and a ten- Moreover, an analysis of Efficacy and ther platelet activation.42-44 Therefore, dency toward higher TIMI 3 flow rates Safety of Subcutaneous Enoxaparin in there is sound theoretical rationale to (1%-17% absolute improvement45-49) Unstable Angina and Non–Q-Wave support the use of concurrent antithrom- compared with unfractionated heparin MI/Thrombolysis in MI (ESSENCE/ botic therapy to enhance the process of (Table 5). Adjunctive LMWH may also TIMI 11B) demonstrated that com- fibrinolysis in STEMI. be associated with improved tissue level pared with unfractionated heparin, Results of Randomized Clinical Tri- perfusion following fibrinolysis as- enoxaparin blunted the increase in als of LMWH in STEMI. To date, 8 sessed using ST-segment resolution and event rates associated with higher phase 2 trials and 2 large exploratory other noninvasive composite measure- baseline risk,37 and among those who clinical trials have been completed that ments of reperfusion seen with enoxa- underwent invasive therapy.38 How- evaluate LMWH with fibrinolytic parin in the AMI-SK45 and Accelerated ever, the effects of early mechanical therapy in STEMI (TABLE 4 and Streptokinase and Enoxaparin revascularization may minimize any TABLE 5). Infarct-related arterial pat- (ASENOX50) trials, respectively. Rates of early differences attributable to pro- ency following fibrinolysis has been other significant clinical events such longed antithrombotic therapy.34 evaluated in 3 trials with enoxaparin late infarct-related arterial reocclu-

Table 5. Clinical Efficacy and Major Bleeding in Trials of LMWH in ST-Elevation Myocardial Infarction Efficacy, % Major Bleeding, %*

Absolute Absolute Primary Efficacy Timing of Risk Risk Trial Outcome Outcome LMWH Control Difference LMWH Control Difference Dalteparin FRAMI94† Reduction in left 9 d 14.2 21.9 7.7 (P = .02) 2.9 0.3 2.6 (P = .006) ventricular thrombus and arterial thromboembolism BIOMACS48 TIMI 3 flow 20-28 h 68 51 17 3.7 0 3.7 ASSENT PLUS49 TIMI 3 flow 4-7 d 69.3 62.5 6.8 3.6 5.2 −1.6 Enoxparin ASENOX50 Mortality 30 d 7.1 8.2 −1.1 000 Reperfusion (noninvasive Not defined 79.8 75.9 3.9 measurement‡) Baird51 Composite§ 3 mo 26 36 −10 (P = .04) 2.7 4 −1.3 AMI-SK45 TIMI 3 flow 5-10 d 70 58 12 (P = .01) 4.8 2.8 2 HART II46 Infarct-related artery 90 min 80.1 75.1 5࿣ 3.6 3 0.6 patency ENTIRE-TIMI 2347¶ TIMI 3 flow 60 min 51 50 1 5.2 3.8 1.4 ASSENT 395 Composite# 30 d 11.4 15.4 −4 (PϽ.001) 3.0 2.2 0.8 ASSENT 3 PLUS52 Composite# 30 d 14.2 17.4 −3.2 (P = .08) 4.0 2.8 1.2 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 heparin. *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 heparin compared with all patients treated with enoxaparin. #End point of death, in-hospital reinfarction, and in-hospital refractory ischemia.

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sion45,46,49 and recurrent ischemia47,48,51 This safety concern of enoxaparin management of both UA/NSTEMI34,53 were reduced with LMWH compared among elderly patients will be ad- and STEMI.54 Compared with the large with unfractionated heparin. Finally, dressed in the ongoing (ExTRACT- amount of literature evaluating LMWHs similar bleeding rates were found with TIMI 25) trial. This double-blind, par- for the medical management of LMWH compared with unfractionated allel group trial is randomizing UA/NSTEMI, there are fewer data evalu- heparin in the majority of completed tri- approximately 21000 fibrinolysis- ating LMWHs in the invasive setting. als (Table 5). eligible STEMI patients in a 1:1 fash- Accordingly, while the ACC, AHA, Euro- However, preliminary results pre- ion to receive either adjunctive unfrac- pean Society of Cardiology, and the sented at the AHA 2002 Scientific Ses- tionated heparin (intravenous 60- American College of Chest Physicians sions from the third Assessment of the IU/kg bolus and 12-IU/kg infusion per have all acknowledged the safety and Safety and Efficacy of a New Throm- hour) or enoxaparin (intravenous potential pharmacological advantages of bolytic PLUS (ASSENT 3 PLUS) un- 30-mg bolus and a subcutaneous in- LMWH over unfractionated hepa- derscore the need for continued evalu- jection of 1 mg/kg twice daily). Of note, rin,55-57 none of these organizations have ation of the safety of LMWH as an patients older than 75 years will not re- endorsed the use of LMWH as the pre- adjunct to fibrinolysis.52 Among 1639 ceive the intravenous bolus of enoxa- ferred antithrombotic agent in the inva- patients with STEMI receiving te- parin and will receive only 75% of the sive management of UA/NSTEMI. Nev- necteplase and either enoxaparin or un- subcutaneous injection dose. The pri- ertheless, data suggest that LMWH fractionated heparin in a prehospital mary end point is a composite of all- monotherapy is safe and efficacious in setting, higher rates of both major cause mortality and nonfatal reinfarc- the setting of elective and urgent PCI bleeding (4.0% vs 2.8%) and intracra- tion within 30 days of randomization. (TABLE 6 and TABLE 7). In addition, sev- nial hemorrhage (2.2% vs 1.0%; P=.05) eral trials have also demonstrated the were seen in the enoxaparin group com- Low-Molecular-Weight Heparin safety and efficacy using LMWH in compared with the unfractionated heparin and PCI bination with a glycoprotein IIb/IIIa group. There was a significant interac- The issue of LMWH treatment in com- inhibitor (TABLE 8 and TABLE 9). tion between patient age and risk of bination with PCI is becoming increas- Unfractionated heparin retains sev- bleeding because almost all cases of in- ingly relevant given the results of eral attractive properties compared with tracerebral hemorrhage were con- several studies demonstrating the supe- LMWH in the invasive setting, includ- fined to patients older than 75 years. riority of an invasive approach for the ing low cost, complete reversibility with

Table 6. Characteristics of Trials Using Low-Molecular-Weight Heparin Alone in PCI* LMWH Group Control Group Timing of PCI Relative to Supplemental No. of Drug or No. of Last LMWH Periprocedural Trial Study Population Subjects Preparation Dose and Duration Subjects Drug Dose Anticoagulant REDUCE64 Elective PCI 306 Reviparin 7000-U intravenous 306 Unfractionated Immediately 10 500 U intravenously bolus and infusion heparin within a 24-h period and 3500 U subcutaneously daily for 28 d Rabah et al65 Elective PCI 30 Enoxaparin 1 mg/kg intravenous 30 Unfractionated Immediately 0 for 1 dose heparin Choussat et al73 Elective PCI 242 Enoxaparin 0.5 mg/kg intravenous ...... Immediately 0 for 1 dose PEPCI72† Elective PCI 40 Enoxaparin 1 mg/kg subcutaneous ...... 8-12 h 0.3 mg/kg twice daily intravenously NICE 168 Elective or urgent PCI 828 Enoxaparin 1 mg/kg intravenous ...... Immediately 0 for 1 dose Colletetal67 Unstable angina/ 132 Enoxaparin 1 mg/kg subcutaneous ...... 4-8h 0 non−ST-segment twice daily elevation MI ESSENCE/ Unstable angina/ 431 Enoxaparin 1 mg/kg subcutaneous 493 Unfractionated At physician’s Unfractionated heparin TIMI 11B38‡ non−ST-segment twice daily heparin discretion at discretion of elevation MI and ±30-mg after initial investigator intravenous bolus 24 h FRISC II Unstable angina/ 1222 Dalteparin 120 IU/kg subcutaneous ...... Յ12 h pre-PCI NA (Invasive)34 non−ST-segment twice daily (open elevation MI label Ն5d) 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 heparin; 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.

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protamine, and the availability of an eas- during invasive cardiac procedures has adopted. The currently accepted thera- ily interpretable and standardized point- not been prospectively defined. peutic activity of LMWH in PCI (anti- of-care test (activated clotting time).58 Since LMWH does not appreciably Xa, Ͼ0.5-1.8 IU/mL) is based primar- In contrast, protamine is able to fully re- affect either the activated partial throm- ily on clinical data from the deep venous verse the effect of LMWH on throm- boplastin time or activated clotting time, thrombosis literature60 and dose- bin, but only 60% of its anti-Xa activ- clinical trials have focused on the ranging studies in UA/NSTEMI.61 In ity.59 It remains controversial whether anti-Xa activity as a surrogate to as- TIMI 11A, enoxaparin administered as routine monitoring of anticoagulation is sess the level of anticoagulation. Al- an intravenous 30-mg bolus followed needed with LMWH in the catheteriza- though now commercially available, by a subcutaneous injection of 1 mg/kg tion laboratory.12,13,60 Moreover, the op- routine monitoring of anticoagulation twice daily generated trough anti-Xa timal level of anticoagulation for LMWH with LMWH has not been universally activity of 0.5 IU/mL and peak activity

Table 7. Major Bleeding and Event Rates of Trials Using Low-Molecular-Weight Heparin Alone in PCI* Event Rate, % Major Bleeding, %

Absolute Absolute Primary Timing of Risk Risk Trial Efficacy Outcome Outcome LMWH Control Difference LMWH Control Difference REDUCE64 Death, MI, or Within 30 wk 33.3 32 1.3 2.3 2.6 −0.3 revascularization Rabah et al65 TIMI 3 flow Post-PCI 97 93 4 3.3 0 3.3 Ischemic complications Within 30 d 0 10 −10 Choussat et al73 Death, MI, or urgent Within 30 d 2.5 ...... 0.4 ...... revascularization PEPCI72† Death, MI, or urgent Within 30 d 5.4 ...... 0 ...... revascularization NICE 168 Death, MI, or urgent Within 30 d 7.7 ...... 1.1 ...... revascularization Collet et al67 Death or MI Within 30 d 3.0 ...... 0.8 ...... ESSENCE/TIMI 11B38‡ Death or MI Within 43 d 3.3 5.9 −2.6 (P = .06) 5.4 6.2 −0.8 FRISC II(Invasive)34 Death or MI Within 6 mo 9.4 ...... 1.6 ...... 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 heparin; MI, myocardial infarction; PEPCI, Pharmacokinetic Study of Enoxa- parin 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 Trials of Low-Molecular-Weight Heparin in Combination With Glycoprotein IIb/IIIa Inhibitors in PCI* LMWH Group Timing of PCI Control Group Glycoprotein Relative to No. of Drug or IIb/ Last LMWH No. of Trial Study Population Subjects Preparation Dose and Duration IIIa Inhibitor Dose† Subjects Drug NICE 468 Elective or urgent PCI 818 Enoxaparin 0.75 mg/kg intravenous Abciximab Immediately ...... for 1 dose Kereiakes et al70 Elective or urgent PCI 103 Dalteparin 40 IU/kg intravenous Abciximab Immediately ...... for 1 dose; 60 IU/kg intravenously for 1 dose CRUISE77 Elective or urgent PCI 129 Enoxaparin 0.75 mg/kg intravenous Eptifibatide Immediately 132 Unfractionated for 1 dose heparin NICE 371‡ Unstable angina/ 283 Enoxaparin 1 mg/kg subcutaneous Tirofiban, At physician’s ...... non−ST-segment twice daily eptifibatide, discretion elevation MI or abciximab Abbreviations: ACUTE, Antithrombotic Combination Using Tirofiban and Enoxaparin; LMWH, low-molecular-weight heparin; 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.

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of 1.1 IU/mL, with a low rate (2.7%) of fractionated heparin has been substi- safe and efficacious, with bleeding and major hemorrhage among patients un- tuted for LMWH prior to angiography clinical event rates similar to historical dergoing PCI.61 Several trials have dem- and coronary intervention if the last controls (Table 7 and Table 9). Ongo- onstrated that reliable levels of anti-Xa LMWH dose was given more than 8 to ing large trials (ie, A to Z,74 SYNERGY75) activity consistently greater than the 0.5 12 hours before the procedure.34,38,62,63 will yield additional information on the IU/mL threshold may be obtained us- Second, a number of pilot trials have safety and efficacy of enoxaparin and gly- ing various doses of LMWH when ad- evaluated the use of LMWH as the sole coprotein IIb/IIIa inhibition in the PCI ministered several days or immedi- anticoagulant throughout angiography setting. ately before PCI (TABLE 10). and intervention without changing to From the available data, 2 strategies unfractionated heparin.25,64-73 How- Current Recommendations and have emerged guiding the use of LMWH ever, these 2 strategies have not been di- Observations From Clinical Trials (with or without concomitant glycopro- rectly compared. With the limited data Unstable Angina/Non–ST-Elevation tein IIb/IIIa inhibition) for PCI. First, un- available, both approaches appear to be MI. Based on the available evidence, the

Table 9. Clinical Efficacy and Major Bleeding in Trials of LMWH in Combination With Glycoprotein IIb/IIIa Inhibitors in PCI* Event Rate, % Major Bleeding, %

Absolute Absolute Timing of Risk Risk Trial Primary Efficacy Outcome Outcome LMWH Control Difference LMWH Control Difference NICE 468 Death, MI, urgent revascularization Within 30 d 6.8 ...... 0.4 ...... Kereiakes70 Death, MI, urgent revascularization In hospital 11.1† ...... 3.7† ...... 17.1‡ ...... 2.6‡ ...... CRUISE77 Death, MI, urgent revascularization Within 48 h 8.5 7.6 0.9 2.5 1.6 0.9 NICE 371§ Death, MI, recurrent ischemia Within 30 d 11.3࿣ ...... 1.4࿣ ...... Abbreviations: ACUTE, Antithrombotic Combination Using Tirofiban and Enoxaparin; LMWH, low-molecular-weight heparin; 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 Definition of Patients Meeting No. of Drug or Adequate Definition at Time Trial Study Population Subjects Preparation Dose and Duration Anticoagulation of Angiography, % PEPCI72 Elective PCI 47 Enoxaparin 1 mg/kg subcutaneous 0.6-1.8 IU/mL 96 8-12 h and 0.3 mg/kg Anti-Xa activity intravenous bolus immediately preprocedure NICE 168 Elective or urgent PCI 828 Enoxaparin Single 1 mg/kg intravenous None stated NA* bolus dose immediately preprocedure Collet et al67 Unstable angina/ 293 Enoxaparin 1 mg/kg subcutaneous Ͼ0.5 IU/mL Anti-Xa 98 non–ST-segment twice daily for 48 h; last activity elevation MI dose given within 4 to 8hofPCI Kereiakes et al70 Unstable angina/ 107 Dalteparin 120 IU/kg subcutaneously Ͼ0.6 IU/mL Anti-Xa NA† non–ST-segment and if procedure was activity elevation MI Ն8 h since last dose then an additional 40 or 60 IU/kg intravenously Choussat et al73 Elective PCI 242 Enoxaparin Single 0.5 mg/kg Ͼ0.5 IU/mL Anti-Xa 98 intravenous bolus activity dose immediately preprocedure Abbreviations: LMWH, low-molecular-weight heparin; 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.

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2002 ACC and AHA guidelines list the lus of dalteparin.70 Enoxaparin may be Critical revision of the manuscript for important in- tellectual content: Wong, Giugliano, Antman. use of either LMWH or unfractionated given subcutaneously at a dose of 1 Statistical expertise: Giugliano. heparin as a class I recommendation for mg/kg twice daily without the need for Administrative, technical, or material support: Antman. the treatment of UA/NSTEMI (level of further supplementation if PCI is per- Study supervision: Giugliano, Antman. evidence, A).57 In addition, use of enoxa- formed within 8 hours.38,67,68 An addi- parin is preferred over unfractionated tional 0.3-mg/kg intravenous bolus REFERENCES heparin (class IIA; level of evidence, A), should be given if PCI is performed be- 1. Ambrose JA. Plaque disruption and the acute coro- except if coronary artery bypass graft sur- tween 8 and 12 hours after the last sub- nary syndromes of unstable angina and myocardial infarction: if the substrate is similar, why is the clinical 57 71,72 gery is anticipated within 24 hours. cutaneous dose. Subcutaneous presentation different? J Am Coll Cardiol. 1992;19: ST-Elevation MI. Completed trials of enoxaparin should be reduced for pa- 1653-1658. 2. Ambrose JA, Weinrauch M. Thrombosis in ische- adjunctive LMWH compared with ei- tients with severe renal insufficiency mic heart disease. Arch Intern Med. 1996;156:1382- ther placebo or unfractionated hepa- (creatinine clearance Ͻ30 mL/min 1394. Ͻ 3. Libby P. Current concepts of the pathogenesis of rin in the setting of STEMI have dem- [ 0.501 mL/s]). A single 0.5-mg/kg in- the acute coronary syndromes. Circulation. 2001; onstrated lower rates of late ischemic travenous dose of enoxaparin without 104:365-372. 4. DeWood MA, Spores J, Notske R, et al. Preva- events and improved rates of late coro- further subcutaneous dosing may be lence of total coronary occlusion during the early hours nary artery patency. The increased safe and efficacious in the setting of of transmural myocardial infarction. N Engl J Med. bleeding seen with prehospital enoxa- moderate-to-severe renal failure.73 Al- 1980;303:897-902. 5. Davies MJ, Thomas A. Plaque fissuring—the cause parin in ASSENT-3 PLUS requires fur- ternatively, unfractionated heparin may of acute myocardial infarction, sudden ischemic death, ther study and possible dose modifica- be substituted for enoxaparin if PCI is and crescendo angina. Br Heart J. 1985;53:363-373. 6. Davies MJ, Thomas AC, Knapman PA, Hangart- tion in elderly patients, although it to be performed more than 8 to 12 ner JR. Intramyocardial platelet aggregation in pa- appears LMWHs are safe among pa- hours following the last subcutaneous tients with unstable angina suffering sudden ische- 38 mic cardiac death. Circulation. 1986;73:418-427. tients younger than 75 years. Ex- dose of enoxaparin. 7. Ardissino D, Merlini PA, Arlens R, et al. Tissue fac- TRACT-TIMI 25, ADVANCE-MI, and Low-molecular-weight heparin can tor in human coronary atherosclerotic plaques. Clin FINESSE will be able to provide more also be used in conjunction with gly- Chim Acta. 2000;291:235-240. 8. Weitz JI. Activation of blood coagulation by plaque definitive data regarding the utility of coprotein IIb/IIIa inhibitors. Data from rupture: mechanisms and prevention. Am J Cardiol. enoxaparin in modern reperfusion regi- several clinical trials suggest that the 1995;75:18B-22B. 9. Antman EM. The search for replacements for un- mens in all age groups. combination of enoxaparin with fractionated heparin. Circulation. 2001;103:2310- various glycoprotein IIb/IIIa inhibi- 2314. Percutaneous Coronary 66,68,69,77 10. Harenberg J. Pharmacology of low molecular tors and dalteparin with abcix- weight heparins. Semin Thromb Hemost. 1990;16 Intervention imab70 are safe in the setting of PCI. (suppl):12-18. 11. Weitz JI. Low-molecular-weight heparins. N Engl Although an expert consensus state- More definitive information will be J Med. 1997;337:688-698. ment has been published with recom- forthcoming about the combination of 12. Boneu B. Low molecular weight heparin therapy: mendations of LMWH in the setting of enoxaparin and glycoprotein IIb/IIIa in- is monitoring needed? Thromb Haemost. 1994;72: 60 74,75 330-334. PCI, the most recent guidelines from hibitors during PCI. 13. Abbate R, Gori AM, Farsi A, Attanasio M, Pepe the ACC and AHA do not discuss the use G. Monitoring of low-molecular-weight heparins in car- CONCLUSIONS diovascular disease. Am J Cardiol. 1998;82:33L-36L. of LMWH as the sole anticoagulant in 14. Duplaga BA, Rivers CW, Nutescu E. Dosing and the setting of PCI.76 Moreover, the op- The use of LMWH has been estab- monitoring of low-molecular-weight heparins in spe- cial populations. Pharmacotherapy. 2001;21:218- timal level of anticoagulation has not lished as a first-line choice in the treat- 234. been prospectively validated, although ment of UA/NSTEMI, and increasing 15. Bastani B, Gonzalez E. Prolonged anti-factor Xa level similar efficacy and safety outcomes with evidence suggests that it may sup- in a patient with moderate renal insufficiency receiving enoxaparin. Am J Nephrol. 2002;22:403-404. LMWH compared with unfractionated plant unfractionated heparin as an an- 16. Casele HL, Laifer SA, Woelkers DA, Venkatara- heparin (with and without concomi- ticoagulant in the setting of PCI and manan R. Changes in the pharmacokinetics of the low-molecular-weight heparin enoxaparin sodium tant glycoprotein IIb/IIIa inhibitors) have STEMI. However, more clinical data re- during pregnancy. Am J Obstet Gynecol. 1999;181: been shown with a target anti-Xa level garding the safety of these agents in el- 1113-1117. 17. The FRAXIS Investigators. Comparison of two of higher than 0.5 IU/mL. derly patients and in combination with treatment durations (6 days and 14 days) of a low mo- Low-molecular-weight heparin may potent platelet inhibitors such as lecular weight heparin with a 6-day treatment of unfractionated heparin in the initial management of un- be used as the sole anticoagulant dur- thienopyridines and glycoprotein IIb/ stable angina or non-Q wave myocardial infarction: ing PCI. Dalteparin should be given at IIIa inhibitors are needed before their FRAXIS (FRAxiparine in Ischaemic Syndrome). Eur Heart a dose of 120 IU/kg subcutaneously routine adoption in the setting of J. 1999;20:1553-1562. 18. Antman EM, McCabe CH, Gurfinkel EP, et al. twice daily provided PCI is performed STEMI and PCI. Enoxaparin prevents death and cardiac ischemic events within 8 hours.34 If PCI is to be per- in unstable angina/non–Q-wave myocardial infarc- Author Contributions: Study concept and design: tion: results of the thrombolysis in myocardial infarc- formed more than 8 to 12 hours fol- Wong, Giugliano, Antman. tion (TIMI) 11B trial. Circulation. 1999;100:1593- lowing the last subcutaneous injec- Acquisition of data: Wong, Giugliano, Antman. 1601. Analysis and interpretation of data: Wong, Giugliano, 19. Cohen M, Demers C, Gurfinkel EP, et al. A com- tion dose, patients should be given an Antman. parison of low-molecular-weight heparin with unfrac- additional 60-IU/kg intravenous bo- Drafting of the manuscript: Wong, Giugliano, Antman. tionated heparin for unstable coronary artery dis-

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ease: Efficacy and Safety of Subcutaneous Enoxaparin 36. Lindahl B, Diderholm E, Lagerqvist B, Venge P, Wal- American Heart Association 75th Scientific Sessions; in Non-Q-Wave Coronary Events Study Group. N Engl lentin L. Mechanisms behind the prognostic value of tro- November 17-20; 2002; Chicago, Ill. J Med. 1997;337:447-452. ponin T in unstable coronary artery disease: a FRISC II 53. Cannon CP, Weintraub WS, Demopoulos LA, et 20. Klein W, Buchwald A, Hillis SE, et al. Compari- substudy. J Am Coll Cardiol. 2001;38:979-986. al. Comparison of early invasive and conservative strat- son of low-molecular-weight heparin with unfraction- 37. Antman EM, Cohen M, Bernink PJ, et al. The TIMI egies in patients with unstable coronary syndromes ated heparin acutely and with placebo for 6 weeks in risk score for unstable angina/non–ST-elevation MI: treated with the glycoprotein IIb/IIIa inhibitor tirofi- the management of unstable coronary artery dis- a method for prognostication and therapeutic deci- ban. N Engl J Med. 2001;344:1879-1887. ease: Fragmin in Unstable Coronary Artery Disease sion making. JAMA. 2000;284:835-842. 54. Zijlstra F, Hoorntje JC, de Boer MJ, et al. Long- Study (FRIC). Circulation. 1997;96:61-68. 38. Fox K, Antman E, Cohen M, Bigonzi F. Compari- term benefit of primary angioplasty as compared with 21. Antman EM, Cohen M, Radley D, et al. Assess- son of enoxaparin versus unfractionated heparin in pa- thrombolytic therapy for acute myocardial infarc- ment of the treatment effect of enoxaparin for un- tients with unstable angina pectoris/non-ST- tion. N Engl J Med. 1999;341:1413-1419. stable angina/non–Q-wave myocardial infarction: TIMI segment elevation acute myocardial infarction having 55. Bertrand ME, Simoons M, Fox KA. Management 11B-ESSENCE meta-analysis. Circulation. 1999;100: subsequent percutaneous coronary intervention. Am of acute coronary syndromes: acute coronary syn- 1602-1608. J Cardiol. 2002;90:477-482. dromes without persistent ST segment elevation; rec- 22. Kaul S, Shah PK. Low molecular weight heparin 39. Seitz R, Pelzer H, Immel A. Prothrombin activa- ommendations of the Task Force of the European So- in acute coronary syndrome: evidence for superior or tion by thrombolytic agents. Fibrinolysis. 1993;7:109- ciety of Cardiology. Eur Heart J. 2000;21:1406-1432. equivalent efficacy compared with unfractionated hep- 115. 56. Cairns JA, Theroux P, Lewis HD Jr, Ezekowitz M, arin? J Am Coll Cardiol. 2000;35:1699-1712. 40. Eisenberg PR, Sherman L, Rich M, et al. Impor- Meade TW. Antithrombotic agents in coronary ar- 23. Eikelboom JW, Anand SS, Malmberg K, Weitz JI, tance of continued activation of thrombin reflected tery disease. Chest. 2001;119(1 suppl):228S-252S. Ginsberg JS, Yusuf S. Unfractionated heparin and low- by fibrinopeptide A to the efficacy of thrombolysis. 57. Braunwald E, Antman EM, Beasley JW, et al. ACC/ molecular-weight heparin in acute coronary syn- J Am Coll Cardiol. 1986;7:1255-1262. AHA 2002 guideline update for the management of drome without ST elevation: a meta-analysis. Lan- 41. Eisenberg PR, Sherman LA, Jaffe AS. Paradoxic patients with unstable angina and non-ST-segment cet. 2000;355:1936-1942. elevation of fibrinopeptide A after streptokinase: evi- elevation myocardial infarction: a report of the Ameri- 24. Michalis LK, Katsouras C, Papamichael N, et al. dence for continued thrombosis despite intense fibri- can College of Cardiology/American Heart Associa- Enoxaparin versus tinzaparin in non-ST-segment el- nolysis. J Am Coll Cardiol. 1987;10:527-529. tion Task Force on Practice Guidelines (Committee of evation acute coronary syndromes: the EVET trial. Am 42. Fitzgerald DJ, Catella F, Roy L, FitzGerald GA. the Management of Patients With Unstable Angina). Heart J. In press. Marked platelet activation in vivo after intravenous Available at: http://www.acc.org/clinical/guidelines 25. Cohen M, Theroux P, Weber S, et al. Combina- streptokinase in patients with acute myocardial in- /unstable/unstable.pdf. Accessed November 29, 2002. tion therapy with tirofiban and enoxaparin in acute coro- farction. Circulation. 1988;77:142-150. 58. Melandri G, Branzi A, Traini AM, Semprini F, Cervi nary syndromes. Int J Cardiol. 1999;71:273-281. 43. Coulter SA, Cannon CP, Ault KA, et al. High lev- V, Magnani B. On the value of the activated clotting 26. Boersma E, Harrington RA, Moliterno DJ, et al. els of platelet inhibition with abciximab despite height- time for monitoring heparin therapy in acute coro- Platelet glycoprotein IIb/IIIa inhibitors in acute coro- ened platelet activation and aggregation during throm- nary syndromes. Am J Cardiol. 1993;71:469-471. nary syndromes: a meta-analysis of all major ran- bolysis for acute myocardial infarction: results from TIMI 59. Gram J, Mercker S, Bruhn HD. Does protamine domised clinical trials. Lancet. 2002;359:189-198. (Thrombolysis in Myocardial Infarction) 14. Circula- chloride neutralize low molecular weight heparin suf- 27. Cohen M. The Treatment with Enoxaparin and tion. 2000;101:2690-2695. ficiently? Thromb Res. 1988;52:353-359. Tirofiban in Acute Myocardial Infarction (TETAMI) 44. Kerins DM, Roy L, FitzGerald GA, Fitzgerald DJ. 60. Kereiakes DJ, Montalescot G, Antman EM, et al. Study. Paper presented at: American Heart Associa- Platelet and vascular function during coronary throm- Low-molecular-weight heparin therapy for non-ST- tion 75th Scientific Sessions; November 17-20, 2002; bolysis with tissue-type plasminogen activator. Cir- elevation acute coronary syndromes and during per- Chicago, Ill. culation. 1989;80:1718-1725. cutaneous coronary intervention: an expert consen- 28. Merlini PA, Bauer KA, Oltrona L, et al. Persistent 45. Simoons M, Krzeminska-Pakula M, Alonso A, et sus. Am Heart J. 2002;144:615-624. activation of coagulation mechanism in unstable an- al. Improved reperfusion and clinical outcome with 61. The Thrombolysis in Myocardial Infarction (TIMI) gina and myocardial infarction. Circulation. 1994;90: enoxaparin as an adjunct to streptokinase thromboly- 11A Trial Investigators. Dose-ranging trial of enoxa- 61-68. sis in acute myocardial infarction: the AMI-SK study. parin for unstable angina: results of TIMI 11A. JAm 29. Ernofsson M, Strekerud F, Toss H, Abildgaard U, Eur Heart J. 2002;23:1282. Coll Cardiol. 1997;29:1474-1482. Wallentin L. Low molecular weight heparin reduces 46. Ross AM, Molhoek P, Lundergan C, et al. Ran- 62. Goodman S, Cohen M, Bigonzi F. Randomized the generation and activity of thrombin in unstable domized comparison of enoxaparin, a low-molecular- trial of low molecular weight heparin (enoxaparin) ver- coronary artery disease. Thromb Haemost. 1998;79: weight heparin, with unfractionated heparin adjunc- sus unfractionated heparin for unstable coronary ar- 491-494. tive to recombinant tissue plasminogen activator tery disease: one-year results of the ESSENCE Study: 30. Merlini PA, Ardissino D, Rosenberg RD, et al. In thrombolysis and aspirin: second trial of Heparin and Efficacy and Safety of Subcutaneous Enoxaparin in vivo thrombin generation and activity during and af- Aspirin Reperfusion Therapy (HART II). Circulation. Non-Q Wave Coronary Events. J Am Coll Cardiol. ter intravenous infusion of heparin or recombinant hi- 2001;104:648-652. 2000;36:693-698. rudin in patients with unstable angina pectoris. Arte- 47. Antman EM, Louwerenburg HW, Baars HF, et al. 63. Bassand JP. Low molecular weight heparin in pa- rioscler Thromb Vasc Biol. 2000;20:2162-2166. Enoxaparin as adjunctive antithrombin therapy for ST- tients undergoing interventional therapy: the ANGIO- 31. The FRISC Study Group. Low-molecular-weight elevation myocardial infarction: results of the ENTIRE- FRAX study [in German]. Paper presented at: XXIInd heparin during instability in coronary artery disease: Frag- Thrombolysis in Myocardial Infarction (TIMI) 23 Trial. Congress of the European Society of Cardiology; Au- min During Instability in Coronary Artery Disease (FRISC) Circulation. 2002;105:1642-1649. gust 26-30, 2000; Amsterdam, the Netherlands. Study Group. Lancet. 1996;347:561-568. 48. Frostfeldt G, Ahlberg G, Gustafsson G, et al. Low 64. Karsch KR, Preisack MB, Baildon R, et al. Low mo- 32. Antman EM, Cohen M, McCabe C, Goodman SG, molecular weight heparin (dalteparin) as adjuvant treat- lecular weight heparin (reviparin) in percutaneous trans- Murphy SA, Braunwald E. Enoxaparin is superior to ment of thrombolysis in acute myocardial infarc- luminal coronary angioplasty: results of a random- unfractionated heparin for preventing clinical events tion—a pilot study: Biochemical Markers in Acute Coro- ized, double-blind, unfractionated heparin and placebo- at 1-year follow-up of TIMI 11B and ESSENCE. Eur nary Syndromes (BIOMACS II). J Am Coll Cardiol. controlled, multicenter trial (REDUCE trial): Reduction Heart J. 2002;23:308-314. 1999;33:627-633. of Restenosis After PTCA, Early Administration of Re- 33. The FRISC II Investigators. Long-term low- 49. Wallentin L, Dellborg DM, Lindahl B, Nilsson T, viparin in a Double-Blind Unfractionated Heparin and molecular-mass heparin in unstable coronary-artery Pehrsson K, Swahn E. The low-molecular-weight hep- Placebo-Controlled Evaluation. J Am Coll Cardiol. disease: FRISC II prospective randomised multicentre arin dalteparin as adjuvant therapy in acute myocar- 1996;28:1437-1443. study. Lancet. 1999;354:701-707. dial infarction: the ASSENT PLUS study. Clin Cardiol. 65. Rabah MM, Premmereur J, Graham M, et al. Use- 34. The FRISC II Investigators. Invasive compared with 2001;24(3 suppl):I12-I14. fulness of intravenous enoxaparin for percutaneous non-invasive treatment in unstable coronary-artery dis- 50. Tatu-Chitoiu G, Tatu-Chitoiu A, Bumbu A, et al. coronary intervention in stable angina pectoris. Am J ease: FRISC II prospective randomised multicentre Accelerated streptokinase and enoxaparine: a new Cardiol. 1999;84:1391-1395. study: Fragmin and Fast Revascularisation During In- thrombolytic regimen in acute myocardial infarction 66. Cohen M, Theroux P, Borzak S, et al. Random- stability in Coronary Artery Disease Investigators. Lan- (the ASENOX study) [abstract]. Eur Heart J. 2000;21 ized double-blind safety study of enoxaparin versus cet. 1999;354:708-715. (suppl):177. unfractionated heparin in patients with non-ST- 35. Lindahl B, Venge P, Wallentin L. Troponin T iden- 51. Baird SH, Menown IB, McBride SJ, Trouton TG, segment elevation acute coronary syndromes treated tifies patients with unstable coronary artery disease Wilson C. Randomized comparison of enoxaparin with with tirofiban and aspirin: the ACUTE II study: the An- who benefit from long-term antithrombotic protec- unfractionated heparin following fibrinolytic therapy tithrombotic Combination Using Tirofiban and Enoxa- tion: Fragmin in Unstable Coronary Artery Disease for acute myocardial infarction. Eur Heart J. 2002;23: parin. Am Heart J. 2002;144:470-477. (FRISC) Study Group. J Am Coll Cardiol. 1997;29: 627-632. 67. Collet JP, Montalescot G, Lison L, et al. Percuta- 43-48. 52. Wallentin L. ASSENT 3 PLUS. Paper presented at: neous coronary intervention after subcutaneous enoxa-

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parin pretreatment in patients with unstable angina comitant therapy with eptifibatide and enoxaparin in tissue factor pathway inhibitor and antithrombin. pectoris. Circulation. 2001;103:658-663. patients undergoing percutaneous coronary interven- Thromb Res. 2000;100:413-417. 68. Kereiakes DJ, Grines C, Fry E, et al. Enoxaparin tion—results of the CRUISE study. J Am Coll Car- 87. Cella G, Girolami A, Sasahara AA. Platelet acti- and abciximab adjunctive pharmacotherapy during per- diol. In press. vation with unfractionated heparin at therapeutic con- cutaneous coronary intervention. J Invasive Cardiol. 78. Barzu T, Molho P, Tobelem G, Petitou M, Caen centrations and comparison with low-molecular- 2001;13:272-278. J. Binding and endocytosis of heparin by human en- weight heparin and with a direct thrombin inhibitor. 69. Mukherjee D, Mahaffey KW, Moliterno DJ, et al. dothelial cells in culture. Biochim Biophys Acta. 1985; Circulation. 1999;99:3323. Promise of combined low-molecular-weight heparin 845:196-203. 88. Montalescot G, Philippe F, Ankri A, et al. Early in- and platelet glycoprotein IIb/IIIa inhibition: results from 79. Young E, Wells P, Holloway S, Weitz J, Hirsh J. crease of von Willebrand factor predicts adverse out- Platelet IIb/IIIa Antagonist for the Reduction of Acute Ex-vivo and in-vitro evidence that low molecular weight come in unstable coronary artery disease: beneficial coronary syndrome events in a Global Organization heparins exhibit less binding to plasma proteins than effects of enoxaparin: French Investigators of the Network B (PARAGON B). Am Heart J. 2002;144: unfractionated heparin. Thromb Haemost. 1994;71: ESSENCE Trial. Circulation. 1998;98:294-299. 995-1002. 300-304. 89. Morrow DA, Rifai N, Bigonzi F, et al. Enoxaparin 70. Kereiakes DJ, Kleiman NS, Fry E, et al. Dalteparin 80. Bara L, Billaud E, Gramond G, Kher A, Samama attenuates the rise in Von wilebrand factor in pain combination with abciximab during percutaneous M. Comparative pharmacokinetics of a low molecu- tients with ST-segment elevation myocardial infarc- coronary intervention. Am Heart J. 2001;141:348- lar weight heparin (PK 10169) and unfractionated hep- tion treated with fibrinolysis: results from ENTIRE- 352. arin after intravenous and subcutaneous administra- TIMI 23. Eur Heart J. 2002;23(suppl):506. 71. Ferguson JJ. The use of enoxaparin and IIb/IIIa tion. Thromb Res. 1985;39:631-636. 90. Xiao Z, Theroux P. Platelet activation with un- antagonists in acute coronary syndromes; including 81. Bara L, Bloch MF, Zitoun D, et al. Comparative fractionated heparin at therapeutic concentrations and PCI: final results of the NICE 3 study. J Am Coll Car- effects of enoxaparin and unfractionated heparin in comparisons with a low-molecular-weight heparin and diol. 2001;37(suppl A):365A. healthy volunteers on prothrombin consumption in with a direct thrombin inhibitor. Circulation. 1998; 72. Martin JL, Fry ET, Serano A. Pharmacokinetic study whole blood during coagulation, and release of tis- 97:251-256. of enoxaparin in patients undergoing coronary inter- sue factor pathway inhibitor. Thromb Res. 1993;69: 91. Serra A, Esteve J, Reverter JC, Lozano M, Escolar vention after treatment with subcutaneous enoxapa- 443-452. G, Ordinas A. Differential effect of a low-molecular- rin in acute coroanry syndromes: the PEPCI Study [ab- 82. Merlini PA, Bauer KA, Oltrona L, et al. Thrombin weight heparin (dalteparin) and unfractionated hepa- stract]. Eur Heart J. 2001;22(suppl):14. generation and activity during thrombolysis and con- rin on platelet interaction with the subendothelium un- 73. Choussat R, Montalescot G, Collet JP, et al. A comitant heparin therapy in patients with acute myo- der flow conditions. Thromb Res. 1997;87:405-410. unique, low dose of intravenous enoxaparin in elec- cardial infarction. J Am Coll Cardiol. 1995;25:203- 92. James S, Armstrong P, Califf R, et al. Safety and tive percutaneous coronary intervention. J Am Coll 209. efficacy of abciximab combined with dalteparin in treat- Cardiol. 2002;40:1943-1950. 83. Sandset PM, Bendz B, Hansen JB. Physiological ment of acute coronary syndromes. Eur Heart J. 2002; 74. Blazing MA, De Lemos JA, Dyke CK, Califf RM, function of tissue factor pathway inhibitor and inter- 23:1538-1545. Bilheimer D, Braunwald E. The A-to-Z Trial: methods action with heparins. Haemostasis. 2000;30(suppl 2): 93. Goodman S. Integrilin and Enoxaparin Random- and rationale for a single trial investigating combined 48-56. ized Assessment of Acute Coronary Syndromes Treat- use of low-molecular-weight heparin with the glyco- 84. Hansen JB, Sandset PM. Differential effects of low ment (INTERACT). Paper presented at: American Col- protein IIb/IIIa inhibitor tirofiban and defining the ef- molecular weight heparin and unfractionated hepa- lege of Cardiology 51st Annual Scientific Session; March ficacy of early aggressive simvastatin therapy. Am Heart rin on circulating levels of antithrombin and tissue fac- 17-20, 2002; Atlanta, Ga. J. 2001;142:211-217. tor pathway inhibitor (TFPI): a possible mechanism for 94. Kontny F, Dale J, Abildgaard U, Pedersen TR. Ran- 75. The SYNERGY Executive Committee. The SYN- difference in therapeutic efficacy. Thromb Res. 1998; domized trial of low molecular weight heparin (daltepa- ERGY trial: study design and rationale. Am Heart J. 91:177-181. rin) in prevention of left ventricular thrombus forma- 2002;143:952-960. 85. Hansen JB, Sandset PM, Huseby KR, et al. Differ- tion and arterial embolism after acute anterior 76. Smith SC Jr, Dove JT, Jacobs AK, et al. ACC/ ential effect of unfractionated heparin and low molecu- myocardial infarction: the Fragmin in Acute Myocar- AHA guidelines for percutaneous coronary interven- lar weight heparin on intravascular tissue factor path- dial Infarction (FRAMI) Study. J Am Coll Cardiol. 1997; tion: a report of the American College of Cardiology/ way inhibitor: evidence for a difference in antithrombotic 30:962-969. American Heart Association Task Force on Practice action. Br J Haematol. 1998;101:638-646. 95. The ASSENT 3 Investigators. Efficacy and safety Guidelines (committee to revise the 1993 guidelines 86. Hansen JB, Naalsund T, Sandset PM, Svensson B. of tenecteplase in combination with enoxaparin, ab- for percutaneous transluminal coronary angioplasty). Rebound activation of coagulation after treatment with ciximab, or unfractionated heparin: the ASSENT-3 ran- J Am Coll Cardiol. 2001;37:2215-2239. unfractionated heparin and not with low molecular domised trial in acute myocardial infarction. Lancet. 77. Bhatt DL, Lee BI, Casterella PJ, et al. Safety of con- weight heparin is associated with partial depletion of 2001;358:605-613.

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