01 270083 cvr1&4 · Factor Xa Inhibitors (Pentasaccharides) Clinical trials have shown the efficacy...

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UpdateAntithrombotics andThrombolytics for theTreatment of AcuteCoronary SyndromesGuest Editor/ChairmanGeno J. Merli, MD, FACP

Thomas Jefferson UniversityPhiladelphia, Pennsylvania

ChairmanDeepak L. Bhatt, MD, FACC, FSCAI, FESC

The Cleveland Clinic FoundationCleveland, Ohio

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UPDATE � Antithrombotics and Thrombolytics for the Treatment of Acute Coronary Syndromes 5

INTRODUCTIONThere has been remarkable progress in the development of new drugs for the treatment of coronary throm-

botic disorders during the past 3 decades. Advances in biotechnology and improved methods of synthesis haveyielded several new drugs that have been added to the standard agents for antithrombotic treatment (Table 1).Newer agents include the antithrombotics (low-molecular-weight heparins [LMWHs], direct thrombininhibitors, and factor Xa inhibitors); the antiplatelet drugs (adenosine diphosphate [ADP] antagonists and theglycoprotein [GP] IIb/IIIa receptor inhibitors); and the recombinant fibrinolytic agents. Use of these drugs incombination has become the standard of care in acute coronary syndromes (ACS). The term ACS is used tocover a group of clinical symptoms compatible with acute myocardial ischemia that result from coronary arterydiseases. These include unstable angina (UA) and the closely related non–ST-segment elevation myocardialinfarction (NSTEMI), which are associated with an increased risk of death and myocardial infarction (MI); andST-segment elevation myocardial infarction (STEMI), which requires immediate reperfusion therapy (throm-bolysis) or percutaneous coronary intervention (PCI).1–3 In fact, the American College of Cardiology/American Heart Association (ACC/AHA) 2002 guidelines recommend a combination of aspirin, a heparin, anda GP IIb/IIIa inhibitor as the most effective therapy in patients with UA/NSTEMI, including those who arescheduled to undergo PCI.1 Moreover, the 2004 American College of Chest Physicians (ACCP) guidelines rec-ommend the use of a fibrinolytic agent with adjunctive anticoagulant and antiplatelet agents depending on theclinical presentation.2

Geno J. Merli, MD, FACPThomas Jefferson UniversityPhiladelphia, Pennsylvania

Antithrombotics and Thrombolytics for theTreatment of Acute Coronary Syndromes

The effects of drugs given in combination cannot bepredicted reliably even when extensive data are availableon the individual clinical effects of each drug. Informa-tion on the mechanism of action, pharmacokinetics, andpharmacodynamics of medications may suggest combi-nations that could be beneficial, but clinical trials are nec-essary to determine if the combination therapy is effica-cious in a particular patient population. The dosage and timing of administration of these agents may have aneffect on the outcome as well. In the case of anticoagu-lants, antiplatelet agents, and thrombolytics in patients

with ACS, combination treatment may also increase the rate of adverse events, particularly bleeding. In recentyears, a number of combinations of anticoagulants,antiplatelet agents, and thrombolytics have been testedin clinical trials in patients with ACS, leading to changesin clinical practice and improvements in patient morbid-ity and mortality. This article will provide a review of the clinical trial data on various combinations of theseagents, focusing on the interactions between antithrom-botics and drugs that are frequently used in combinationwith them in the treatment of patients with ACS.

Table 1. Antithrombotic and Fibrinolytic Agents Used for Acute Coronary Syndromes

Anticoagulants Antiplatelet agents Fibrinolytic agents

• Unfractionated heparin • Aspirin • Streptokinase• Low-molecular-weight heparins • Adenosine diphosphate receptor blockers • Recombinant tissue plasminogen activator

(eg, enoxaparin, dalteparin) (eg, ticlopidine, clopidogrel) (eg, alteplase, reteplase, tenecteplase)• Direct thrombin inhibitors • Glycoprotein IIb/IIIa inhibitors

(eg, argatroban, bivalirudin, hirudin) (eg, abciximab, eptifibatide, tirofiban)

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OVERVIEW OF PHARMACOLOGYUFH

Unfractionated heparin (UFH) is a heterogeneousmixture of glycoaminoglycans of varying molecularsize, with a molecular weight ranging from 3000 to30,000 daltons (mean 15,000 daltons).4 UFH is anindirect anticoagulant that requires a plasma cofactor,antithrombin (AT). The heparin/AT complex inacti-vates thrombin factor IIa, and factors IXa, Xa, XIa,and XIIa. The binding of UFH to AT occurs primari-ly through a unique glucosamine unit contained with-in a pentasaccharide sequence.5 Additionally, UFHbinds to a number of plasma proteins, blood cells, andendothelial cells that modify its physiologic effect.4 Inan ex vivo study, Aggarwal et al found that, in thepresence of tirofiban, anticoagulation with therapeuticdoses of UFH significantly increased platelet reactivitycompared with either enoxaparin or bivalirudin.6

UFH may also induce immune-mediated platelet acti-vation, leading to heparin-induced thrombocytopenia(HIT) in addition to adverse effects on bone metabo-lism that may result in osteoporosis.4,7

Continuous IV infusion and SC injection are the 2 preferred routes of administration of UFH.4

However, plasma recovery of UFH is reduced when itis administered SC in low (eg, 5000 U q12h) or mod-erate (eg, 12,500 or 15,000 U q12h) doses. At doses>35,000 U over 24 hours, however, plasma recoveryis almost complete.

LMWHsDifferent and distinct LMWHs are formed by

depolymerization of UFH, depending on whichpatented procedure is used. LMWHs are relativelymore potent in the catalyzation of the inhibition offactor Xa by AT than in the inactivation of thrombin.Although there are individual differences, the meanmolecular weight of currently available LMWHsranges from 4000 to 5000 daltons.4 LMWHs do notonly exhibit physical and chemical heterogeneity butvariability in biologic actions, which are translatedinto differences in clinical effects as well.

The pharmacokinetic properties of LMWHs aresuperior to those of UFH. For example, bioavailabil-ity of SC bolus injections approaches 100% at lowdoses and peak anti-factor X activity occurs 3 to 5hours after SC injection, with a more predictable

dose-response compared with UFH. LMWHs arealso associated with a longer, non–dose-dependenthalf-life than UFH. Effective SC dosing of LMWHsprovides potential major clinical benefits includingthe potential for an earlier, more rapid treatment, theability to treat prehospitalization, and decreased med-ication errors, all of which are important for improvedclinical outcomes.2 Other theoretical advantages ofthe LMWHs over UFH include less protein andendothelial cell binding, and a more predictabledegree of anticoagulation without the need for closelaboratory monitoring. LMWHs are also less likely toactivate platelets, and are less likely to cause thrombo-cytopenia or osteopenia than UFH. These featuresalong with the body of evidence from clinical trialsfavor their use in ACS.1,8,9

Nevertheless, LMWHs have been associated withincreased rates of minor bleeding, which is generallycharacterized as cutaneous (at the injection site) andoral.1 Additionally, there has been some reservationabout the use of LMWHs in patients undergoinginvasive surgical procedures because of the longerhalf-life and the fact that the anticoagulation effect isnot easily reversed. However, clinical data are emerg-ing that support the use of LMWHs, especially enoxa-parin, in more invasive procedures.8,9

Factor Xa Inhibitors (Pentasaccharides)Clinical trials have shown the efficacy of pen-

tasaccharides for the prevention and treatment ofvenous thromboembolism and for the treatment ofarterial thrombosis.10 Fondaparinux is a syntheticanalog of the pentasaccharide sequence found inheparin and LMWHs that is responsible for bind-ing to AT.10 The fondaparinux/AT complex is astrong inhibitor of factor Xa. Fondaparinux sharesmany of the advantages of the LMWHs: it isadministered SC, requires no monitoring, and isless likely to cause thrombocytopenia or osteope-nia. It has excellent plasma availability and a longhalf-life. It also shares the disadvantage of notbeing easily reversed. It is approved for treatmentof acute deep vein thrombosis and pulmonaryembolism, as well as for venous thromboembolismprophylaxis in at-risk patients undergoing abdomi-nal surgery or any of several types of orthopedicsurgery.

6 UPDATE � Antithrombotics and Thrombolytics for the Treatment of Acute Coronary Syndromes

05_270083_merli 7/10/06 11:33 AM Page 6

Direct Thrombin InhibitorsThese agents specifically and directly block throm-

bin without the need for a cofactor such as AT.Hirudin, a 65-amino-acid polypeptide, binds directlyto thrombin receptors producing potent and pre-dictable anticoagulation.1 Hirudin is indicated foranticoagulation in patients with HIT and for the prophy-laxis of deep vein thrombosis in patients undergoinghip-replacement surgery.1 Hirudin may have somepotential advantages over UFH. It has the ability toinhibit clot-bound thrombin, it is not inhibited byactivated platelets, it does not require a cofactor, andit may provide a more stable anticoagulant response.2

Bivalirudin is a small 20 amino-acid peptide mod-eled after the hirudin molecule. It binds specificallyand reversibly to active thrombin in a bivalent fash-ion.1 Bivalirudin acts initially as a noncompetitivethrombin inhibitor and subsequently as a competitiveunivalent inhibitor, allowing complex, transient inhi-bition of thrombin. Unlike heparin, bivalirudininhibits free and unbound thrombin, thus inhibitingboth initiation and continuation of clot formation. Itdoes not induce platelet activation or aggregation,which is an additional advantage over heparin.11

However, the ACCP 2004 guidelines reserve use ofthe direct thrombin inhibitors to patients with knownor suspected HIT; the ACCP recommends the com-bination of hirudin with tissue plasminogen activator(t-PA) (Grade 1A) or bivalirudin with streptokinase(Grade 2A).2

Aspirin/Nonsteroidal Anti-inflammatory DrugsAspirin has been and remains the foundation of

antithrombotic treatment regimens in patients withACS. Aspirin irreversibly inhibits cyclo-oxygenase-1within platelets, preventing the formation of throm-boxane A2 and diminishing platelet formation.1 Asynergistic effect is observed when aspirin is com-bined with other agents. In the Second InternationalStudy of Infarct Survival (ISIS-2), streptokinase andaspirin both reduced mortality when compared withplacebo (25% vs 23%, respectively), while the combi-nation of aspirin with streptokinase reduced mortalityby 42% (8% vs 13.2%; P < 0.001) when comparedwith placebo.2

The use of aspirin with UFH has raised some con-cerns. Although aspirin irreversibly binds cyclo-

oxygenase-1, a transient reversal of this effect occursin response to arachidonic acid during carotidendarterectomy or PCI in a small number of patients.This may be the result of the impact of UFH onendothelial cells causing platelet activation. The clini-cal significance of this observation is currentlyunknown.12

Additionally, in a post hoc analysis of 2 clinical tri-als, ESSENCE (Efficacy and Safety of SubcutaneousEnoxaparin in Non-Q-wave Coronary Events) andPRISM-PLUS (Platelet Receptor Inhibition inIschemic Syndrome Management in Patients Limitedby Unstable Signs and Symptoms), Lancaster et al13

observed that patients presenting with UA/NSTEMIwho have received prior aspirin therapy often fail ther-apy with UFH. Use of enoxaparin or the combinationof tirofiban with UFH was more effective than UFHalone in these patients. It was postulated that prioruse of aspirin may render thrombi less thrombin-dependent and more platelet-dependent. Recent find-ings with hirudin showed that agents with a strongAT effect tend to prevent thrombin-mediated plateletactivation. The fact that LMWHs have less effect onplatelet aggregation than UFH may explain theobservations in these studies.13

ADP AntagonistsThe ADP antagonists, ticlopidine and clopidogrel,

are antiplatelet agents with a mode of action that dif-fers from that of aspirin. These thienopyridine deriva-tives inhibit platelet aggregation induced by ADP.Combining these drugs with aspirin may have anadditive effect. As with other antithrombotic agentsused in combination, the use of clopidogrel andaspirin is associated with increased bleeding.14

Because of the delayed onset of action (several daysfor a complete antiplatelet effect), these drugs are notconsidered to be first-line agents in the acute settingand are indicated only for use in patients who areunable to tolerate aspirin. Clopidogrel is the preferredADP antagonist because of its slightly faster onset ofaction and potentially better adverse event profile.1

GP IIb/IIIa Inhibitors The platelet GP IIb/IIIa inhibitors (abciximab,

eptifibatide, tirofiban) block fibrinogen from bindingto the platelet GP IIb/IIIa receptors.1 Abciximab has


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been shown to reduce tissue-factor thrombin genera-tion, prothrombin, microparticle release, and muralthrombus formation.3 In vitro studies with GPIIb/IIIa inhibitors have shown dose-dependentdecreases in prothrombinase activity and thrombinactivity. When GP IIb/IIIa inhibitors are combinedwith heparins, thrombin generation is furtherreduced: the greatest reductions are seen in combina-tion with enoxaparin.3

The GP IIb/IIIa inhibitors and the AT agents tar-get different but complementary physiological mech-anisms. GP IIb/IIIa inhibitors prevent platelet aggre-gation and the formation of platelet-rich thrombi,which are the primary causes of ischemic complica-tions in non–ST-elevation ACS and PCI, while theAT agents inhibit the thrombin-mediated depositionof fibrin that stabilizes the platelet-rich thrombus. Ina crossover study in healthy subjects, UFH andLMWH showed similar effects on the pharmacokinet-ics and pharmacodynamics of eptifibatide. The inves-tigator concluded that LMWH can be substituted forUFH in combination with eptifibatide in NSTEMI.15

Fibrinolytic AgentsThe fibrinolytic agents include streptokinase and

the recombinant t-PAs. The differentiating character-istics of these agents are outlined in Table 2.2

The benefits of streptokinase infusion have beenknown for more than 40 years and set the stage forthe current use of fibrinolytic agents in STEMI. Overthe past decade, attention has been focused onimproving the potency, efficacy, and ease of adminis-tration of fibrinolytic agents.2 Streptokinase continuesto be widely used, but the t-PAs have proven to be

both effective and safe. Tenecteplase, a geneticallyengineered variant of alteplase, has become the newstandard for fibrinolytic therapy. It can be adminis-tered in a bolus and has been associated with lessbleeding. In the treatment of STEMI, standard treat-ment is a fibrinolytic agent combined with UFH,although major bleeding has been problematic. Theprimary predictors of bleeding with this combinationare prolongation of activated partial thromboplastintime (aPTT) and fibrinogen degradation. In vitrostudies have shown that alteplase or reteplase com-bined with UFH significantly prolonged aPTT com-pared with UFH alone, whereas tenecteplase is asso-ciated with attenuation of aPTT prolongation.Tenecteplase may interfere with the anticoagulationproperties of UFH because of its fibrin specificity andmay have a lesser effect on fibrinogen breakdownthan do the other t-PAs.16 In in vitro studies,tenecteplase combined with UFH resulted in short-ened aPTT compared with UFH alone. Further eval-uation of this interaction as well as the interaction oftenecteplase and LMWH is necessary.16

CLINICAL TRIALS WITH COMBINATION THERAPYUA/NSTEMI

UA is defined as angina pectoris or equivalentischemic discomfort with at least one of the followingcharacteristics of chest or arm discomfort: may occurat rest or with minimal exertion and lasting >10 min-utes, severe and of new onset (within the prior 4–6weeks), and/or crescendo pattern (more severe, pro-longed, or frequent than previously). The diagnosisof NSTEMI is established if a patient with clinical

Table 2. Characteristics of Fibrinolytic Agents2

Agent Source Fibrin Specific Mode of Action Half-life (minutes) Dosing

Streptokinase Group A Activator 1-hourstreptococci complex 18–23 infusion

Alteplase Recombinant, ++ Direct 3–8 Bolus,human t-PA 90-minute infusion

Reteplase Recombinant, + Direct 15–18 Double bolushuman mutant t-PA

Tenecteplase Recombinant +++ Direct 18–20 Single bolusplus mutation

t-PA = tissue plasminogen activator.Adapted with permission from Menon et al. Chest. 2004;126:549–575.

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features of UA develops signs of myocardial necrosis,evidenced by elevated cardiac biomarkers and with noor transient elevation of ST segment on the electro-cardiogram (ECG).

Treatment goals in UA/NSTEMI include modify-ing the disease process and slowing the progression tomore serious adverse cardiac events. A large body ofliterature and clinical experience support the use ofvarious combinations of AT and antiplatelet agents.The 2002 ACC/AHA guidelines recommend use ofboth UFH and LMWH depending on the clinicalpresentation.1 The guidelines recommend that allpatients with possible ACS be given aspirin. If ACS islikely or definite, patients should receive IV heparinor SC LMWH in addition to aspirin. When definiteACS is accompanied by continuing ischemia or thereare high-risk features, a GP IIb/IIIa inhibitor shouldbe given in addition to aspirin and heparin. A GPIIb/IIIa inhibitor is also recommended if an inter-vention is planned such as PCI or coronary arterybypass graft (CABG).

Combination Therapy With LMWHs or UFH Clinical studies in the 1980s demonstrated the

benefits of aspirin and UFH, alone and in combina-tion, compared with placebo in patients with ACS.For example, in the acute phase of UA, both aspirinand UFH reduced the incidence of MI, with a trendfavoring UFH. However, aspirin plus heparin was notsuperior to heparin alone and was associated withslightly more complications.17 Additional trials inves-tigated the potential advantages of combination ther-apy with aspirin and UFH over aspirin monotherapy.Consistent trends across each study favored combinedpharmacotherapy for its ability to reduce death or MI.Evidence has also emerged supporting the use ofUFH in combination with either aspirin alone or incombination with a GP IIb/IIIa inhibitor in higher-risk patients or those undergoing early PCI.1

Over the past decade, growing literature has sup-ported the use of LMWHs as a substitute for UFH inpatients with UA/NSTEMI, including high-riskpatients. Despite the advances in the acute manage-ment of patients with UA/NSTEMI, the risk offuture life-threatening ischemic events remains. Theaddition of the GP IIb/IIIa inhibitors to UFH-containing regimens has resulted in significant bene-

fits for those patients considered to be intermediateor high risk. Multiple studies have assessed the use ofLMWHs as an alternative to UFH in combinationwith GP IIb/IIIa inhibitors.

The GUSTO-IV (Global Utilization of Streptoki-nase and Tissue-plasminogen Activator for OccludedArteries) ACS study18 enrolled 7800 patients. Themajority received treatment with UFH and abciximab.In a subset of patients (n = 974) in which dalteparinwas substituted for UFH, transfusions, major andminor bleeding rates, and types of bleeding were notsignificantly different from those of the population asa whole. Combination with abciximab in bothheparin groups was associated with increased majorand minor bleeding. The increased number of minorbleeding incidents with LMWH was attributable tohematomas at injection sites. In combination withabciximab, lower doses of dalteparin are recommend-ed, especially in older patients and in women. Inpatients who had invasive procedures, between-groupbleeding rates were similar. Increased thrombocy-topenia was observed with the addition of abciximabin both treatment groups. There was no difference inefficacy between the dalteparin and UFH groups.18

The ACUTE (Antithrombotic Combination UsingTirofiban and Enoxaparin) II trial19 evaluatedtirofiban in combination with enoxaparin or UFH, ina blinded, randomized study. Of the 525 patientsevaluated, 210 patients received UFH and 315received enoxaparin. In general, there were very fewsignificant bleeding events. TIMI (Thrombolysis InMyocardial Infarction) major bleeding rates were0.3% for enoxaparin versus 1.0% for UFH; minorbleeding rates were 2.5% for enoxaparin versus 4.3%for UFH. Minor bleeding was mostly oral and atinjection sites. The cutaneous bleeding rate was high-er in the enoxaparin group. Death/MI rates weresimilar in the 2 groups. However, patients whoreceived enoxaparin had more favorable outcomeswith respect to refractory ischemia requiring revascu-larization and rehospitalization for UA.19

The INTERACT (Integrilin and EnoxaparinRandomized Assessment of Acute CoronarySyndrome Treatment) trial20 strongly favored anenoxaparin/eptifibatide combination compared withUFH/eptifibatide. High-risk patients (N = 746) wereevaluated in this randomized, open-label study. The

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enoxaparin group had significantly lower rates ofmajor bleeding at 96 hours (1.8% vs 4.6%; P = 0.03),with no intracranial hemorrhage, but the rate ofminor bleeding was higher with enoxaparin (30.3% vs20.8%; P = 0.003). The enoxaparin group had a lowerrate of death or MI at 30 days compared with UFHand eptifibatide (5% vs 9%; P = 0.031). Lower rates ofischemia were observed in the enoxaparin group(14.3% vs 25.4%, P = 0.0002 for 48 hours, and 12.7%vs 25.9%, P < 0.0001 for 48–96 hours).20

The A to Z study showed that the use of enoxa-parin with tirofiban is a suitable alternative to UFHand tirofiban in high-risk patients.8 In this prospec-tive, randomized, open-label study of 3987 patientsthat compared tirofiban in combination with eitherenoxaparin or UFH, primary and secondary endpoints favored the enoxaparin group, except death,which occurred in only 1% of all patients. Rates werelow for any TIMI grade bleeding (enoxaparin 3% andUFH 2.2%). The incidence of major bleeding was0.9% with enoxaparin and 0.4% with UFH. Therewere no between-group differences in major bleeds inpatients who underwent early interventions. Thedesign of this study met prespecified criteria for non-inferiority, with a 1% absolute benefit and a 12% rela-tive benefit favoring the enoxaparin combination.8

ACUITY (Acute Catheterization and UrgentIntervention and Triage Strategy Trial)21 compared 3pharmacologic treatments for patients with UA orNSTEMI. All patients received aspirin and were ran-domized to receive: UFH or enoxaparin plus a GPIIb/IIIa inhibitor (n = 4603), bivalirudin with a GPIIb/IIIa inhibitor (n = 4604), or bivalirudin alone (n = 4612). Within 72 hours, 56.7% of the patientsunderwent PCI, 11.1% underwent surgical revascu-larization, and 32.5% received medical therapy.Bivalirudin treatment alone was found to be superiorto combination treatment with UFH or enoxaparinplus a GP IIb/IIIa inhibitor in major bleeding (3.0%vs 5.7%; P < 0.001) and in the composite net clinicalbenefit defined as a combination of the ischemic com-posite and major bleeding (10.1% vs 11.7%; P =0.015).21

The ISAR-REACT 2 (Intracoronary Stenting andAntithrombotic Regimen: Rapid Early Action forCoronary Treatment 2) trial22 evaluated 2022 high-risk ACS patients undergoing PCI who received a

high (600-mg) loading dose of clopidogrel 2 hoursprior to the procedure, along with 500-mg oral or IVaspirin. Patients were randomized to receive abcix-imab or placebo plus heparin to determine if treat-ment with the GP IIb/IIIa inhibitor abciximabwould reduce the composite end point of death, MI,or urgent target vessel revascularization at 30 days.The results showed that in patients who received pre-treatment with clopidogrel, the primary compositeend point of death, MI, or urgent target vessel revas-cularization due to myocardial ischemia within 30days was reduced in the abciximab group in compar-ison with the placebo group (8.9% vs 11.9%; relativerisk [RR] = 0.75; P = 0.03).22

Most trials evaluating the use of LMWHs haveexcluded patients with renal dysfunction, which is arisk factor for vascular disease and a predictor ofbleeding. Analyses of data from the Global Registryof Acute Coronary Events (GRACE) (N = 11,881)showed that LMWH is as effective as or superior toUFH in preventing ischemic events in patients withNSTEMI, even in those with renal dysfunction.23

Combination therapy with LMWH and a GPIIb/IIIa inhibitor seems to be better tolerated thanUFH plus a GP IIb/IIIa inhibitor, regardless of renalstatus. LMWH alone was associated with a lower riskof mortality compared with UFH alone (4.2% vs6.2%, P < 0.0001). LMWH alone resulted in fewermajor bleeding incidents than UFH (2.1% vs 3.3%, P = 0.0006). This benefit was found irrespective ofrenal status, but remained nonsignificant in patientswith severe renal dysfunction. There was a similarreduction in major bleeding with LMWH combinedwith a GP IIb/IIIa inhibitor compared with UFHand a GP IIb/IIIa inhibitor (4.3% vs 6.9%, P =0.0420). A similar but nonsignificant trend wasobserved in patients with renal dysfunction.23

Refer to Appendix 1 for a summary of trials inpatients with NSTEMI receiving combination therapy.

STEMIThe diagnosis of STEMI is established if a patient

develops clinical symptoms of myocardial necrosisand is evidenced by elevated serum cardiac biomark-ers and elevated ST-segment on the ECG.

In patients with STEMI, the goal is to achieve bothshort- and long-term arterial reperfusion to attenuate

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the progression of adverse cardiac events. Standardthrombolytic therapy includes aspirin, a fibrinolyticagent, heparin, and, increasingly, a GP IIb/IIIainhibitor. UFH continues to be the standardantithrombin, despite its potential therapeutic disad-vantages. UFH interferes with thrombin activity butit does not inhibit the production of thrombin, whichmay lead to subsequent thrombotic events. Agentsthat act earlier in the coagulation cascade may beassociated with a lower risk for thrombosis.24 LMWHpotentially offers a more stable and predictable anti-coagulant effect, simple bolus administration, andgreater inhibition of thrombin generation. Otheradvantages of LMWH include a greater capacity torelease tissue factor pathway inhibitor, a lowerpropensity to promote activation and aggregation ofplatelets, and potential antiplatelet effects via a higherdegree of suppression of von Willebrand factor.24

Fibrinolytic Agents With UFH or LMWHAlthough UFH has been the standard of care, the

evidence for combining UFH with fibrinolytic agentsis strong for t-PA (alteplase), but less strong withstreptokinase. Despite the benefits seen with IVUFH, the increase in major bleeding and intracranialhemorrhage led to reduced doses of UFH in theGUSTO IIb and TIMI 9B studies.2

The HART II (Second Trial of Heparin andAspirin Reperfusion Therapy), AMI-SK, andASSENT-3 (Assessment of the Safety and Efficacy ofa New Thrombolytic Regimen) trials showed thatcoronary patency rates are improved with enoxaparinand that enoxaparin may also be related to improvedtissue-level profusion. In regimens that include thespecific fibrinolytic agents (t-PAs) studies have shownUFH and aspirin to improve coronary patency. Inpatients receiving the fibrinolytic agent streptokinase,UFH is not recommended.24–26

In the HART II study,24 all patients (N = 400)received aspirin and recombinant alteplase and wererandomly assigned to receive either enoxaparin orUFH. Enoxaparin was at least as effective as UFH inrestoring patency. Enoxaparin also trended towardshigher rates of recanalization and lower rates of reoc-clusion. Adverse events were similar in both groups.24

The AMI-SK study25 assessed 496 patients withSTEMI treated with aspirin and streptokinase and

randomized to receive either placebo or enoxaparin asadjunctive therapy. The enoxaparin group did betterthan the placebo group with early reperfusion andreduced risk of reocclusion. By day 30 there weremore hemorrhages in the enoxaparin group, but thedifference was not statistically significant.25

In the large, open-label, randomized ASSENT-3trial26 (N = 6095), patients received full-dosetenecteplase plus enoxaparin; half-dose tenecteplaseand weight-adjusted low-dose UFH, plus an infusionof abciximab; or full-dose tenecteplase and weight-adjusted low-dose UFH. Adjunctive therapy witheither enoxaparin or abciximab resulted in greaterimprovement in coronary complications than withheparin. Based on the efficacy and safety results,tenecteplase plus enoxaparin was the most effectivecombination.26

In the ENTIRE-TIMI 23 open-label study,27

patients were randomized to receive standard reperfu-sion therapy (full-dose tenecteplase) or combinationtherapy (half-dose tenecteplase plus abciximab), andeither UFH or enoxaparin. Results indicate similarearly reperfusion with both enoxaparin and UFH,with enoxaparin showing benefit over UFH withrespect to ischemic events through 30 days, with sim-ilar risk for major bleeding. When the combination ofhalf-dose tenecteplase plus abciximab was comparedwith full-dose tenecteplase at 60 minutes, similarreperfusion rates were observed and at 180 minutesthere was a trend towards more complete ST-segmentresolution, regardless of AT agent.27

In the NRMI (National Registry of MyocardialInfarction) STEMI registry,28 2482 patients receivinga GP IIb/IIIa inhibitor and LMWH were comparedwith 34,838 patients treated with UFH. Major bleed-ing occurred in 4% of LMWH-treated patients versus4.2% of those treated with UFH, with a trend towardsfewer recurrences of acute MI in the LMWHgroup.28

The results of the ASSENT-PLUS trial29 under-scored the need for continuous assessment ofLMWH. In this open-label, randomized study per-formed in the prehospitalization setting, there was anincrease in the rate of major hemorrhage and intracra-nial hemorrhage with enoxaparin versus UFH inpatients treated with t-PA for STEMI before hospitalarrival. However, almost all cases of hemorrhage


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occurred in patients >75 years old.29 As a result of thisstudy, the dose of enoxaparin was then adjusted in thepivotal ExTRACT (Enoxaparin and ThrombolysisReperfusion for Acute Myocardial InfarctionTreatment)-TIMI 25 trial to 0.75 mg/kg SC BID inpatients 75 years or older.30

ExTRACT-TIMI 2530,31 was a randomized, con-trolled, double-blind trial comparing UFH withenoxaparin as adjunctive therapy in fibrinolytic treat-ment of STEMI. Patients with planned fibrinolytictreatment were randomized to receive UFH for 48hours (n = 10,223) or enoxaparin 30 mg IV bolusplus 1 mg/kg SC BID for the duration of the indexhospitalization (n = 10,256). Patients aged 75 yearsor older received no IV bolus and the SC dose wasreduced to 0.75 mg/kg BID. The IV loading dosewas omitted and a 25% reduction in the maintenancedose of enoxaparin was selected for patients whodeveloped or were discovered to have renal impair-ment (creatinine clearance ≤30 mL/min). There wasa significant 33% reduction in the RR of MI and a26% reduction in the need for urgent revasculariza-tion at 30 days in the enoxaparin group. Death or MIat 30 days occurred in 9.9% of the patients in theenoxaparin group, compared with 12.0% of thepatients in the UFH group (RR reduction = 17%, P <0.001). The rate of intracranial hemorrhage was thesame in both treatment groups, but major bleeding at30 days was increased in the enoxaparin group com-pared with UFH (1.4% vs 2.1%; RR = 53%; P <0.001). The results demonstrated that in patientsreceiving fibrinolysis for STEMI for 48 hours, treat-ment with enoxaparin through the index hospitaliza-tion was superior when compared with UFH.31

OASIS-6 (Organization for the Assessment ofStrategies for Ischemic Syndromes) is another recenttrial that analyzed the STEMI patient population.32

This trial evaluated fondaparinux versus standardapproaches to antithrombotic therapy in patients withSTEMI in preventing the primary and composite endpoints of death or reinfarction at 30 days. OASIS-6was a randomized, double-blind, controlled trial inpatients with STEMI comparing fondaparinux to acontrol group consisting of patients receiving UFHor placebo. The 12,092 patients with STEMI wererandomized to receive fondaparinux 2.5 mg oncedaily for up to 8 days (n = 6036) or control (n =

6056), which consisted of UFH bolus injection of 60IU/kg followed by an infusion of 12 IU/kg/h for 24to 48 hours followed by placebo for up to 8 days orplacebo in patients for whom heparin was not indicat-ed. The primary end point was decreased in the fon-daparinux group compared with the control group(9.7% vs 11.2%; hazard ratio [HR] = 0.86; P =0.008). The reduction in the primary end point at 30days in the fondaparinux group was driven by com-parison with the placebo group. There was no differ-ence in the primary efficacy end point when patientswho received fondaparinux were compared withthose who received UFH (8.3% vs 8.7%; HR = 0.96;P = NS). Fondaparinux was superior to placebo inreducing death or MI at 30 days in patients withSTEMI.32 Essentially, the results of OASIS-6 shouldbe interpreted cautiously and are in favor of fonda-parinux versus placebo but not fondaparinux versusUFH. It does not appear that the dose of fondaparin-ux tested in OASIS-6 is adequate for primary PCI inpatients with STEMI.

The current ACCP recommendation for patientsaged <75 years with preserved renal function (creati-nine levels <2.5 mg/dL in male patients and <2.0mg/dL in female patients) is enoxaparin (30-mgbolus IV followed by 1 mg/kg SC q12h) withtenecteplase up to 7 days (Grade 2B).2

Refer to Appendix 2 for a summary of trials inpatients with STEMI receiving combination therapy.

PCIDespite innovations in techniques, use of stents,

and newer, more effective, and safer antiplateletagents, optimal antithrombotic treatment regimensfor PCI need to be further elucidated. Published lit-erature supports the use of low-dose UFH with a GPIIb/IIIa inhibitor in ACS patients during PCI. Thereis also a growing body of evidence validating LMWHsas adjunctive therapy for PCI.33

Khosla et al34 found encouraging safety and effica-cy results in a prospective study of enoxaparin andeptifibatide in 56 patients undergoing PCI. Majorbleeding occurred in 1 of 56 patients (2%); there wereno vascular complications in this small study.34

An earlier pilot study35 showed similar favorableresults with dalteparin and abciximab. The combina-tion of dalteparin with abciximab was studied in


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107 patients randomized to receive 40 or 60 IU/kgof dalteparin IV. The higher dose of dalteparin pro-vided greater efficacy and a more consistentantithrombotic effect with no apparent increase inbleeding rates.35

An observational study33 with a lower dose ofenoxaparin (0.5 mg/kg) in 242 patients (26%received concomitant abciximab) found very lowrates of bleeding and ischemic complications withenoxaparin. The prespecified anticoagulant effect(target anti-Xa >0.5 IU) was achieved in mostpatients. Similar anticoagulation and safety wereobserved irrespective of advanced age, renal dysfunc-tion, body weight, or the use of eptifibatide. Noenoxaparin dose adjustments were needed in combi-nation with eptifibatide.33

Another small (N = 75) observational study36

found encouraging results with the 0.5 mg/kg IVdose of enoxaparin combined with abciximab, eptifib-atide, or tirofiban in a population of 67 outpatientswith positive stress test results and 8 inpatients withrecent ACS. No major bleeding or adverse cardiacevents occurred through 30 days posthospitalization,and the minor TIMI bleeding rate was <2%. Thesebenefits were seen even in patients with high-risklesions and multivessel interventions, the majoritywith stents (87%).36

Two parallel-group, prospective studies, NICE(National Investigators Collaborating on Enoxaparin)1 and 4,37 evaluated the use of LMWH in patientsundergoing elective PCI. NICE 1 evaluated enoxa-parin (1 mg/kg) alone in 828 patients and NICE 4evaluated a reduced dose of enoxaparin (0.75mg/kg) with the standard dose of abciximab in 818patients. NICE 4 was the first large-scale trial thatevaluated enoxaparin and abciximab during PCI.Enoxaparin, used alone or in combination, providedsafe and effective anticoagulation during PCI. In bothstudies bleeding events were infrequent.37

Comparative, randomized studies with standardtherapies further confirm the efficacy of LMWH as analternative to UFH during PCI. Galeote et al38 com-pared abciximab with enoxaparin or UFH as adjuvanttherapy during percutaneous transluminal coronaryangioplasty in a prospective, randomized, nonblindedstudy (N = 99). They concluded that adjuvant treat-ment with enoxaparin and abciximab during PCI was

safe and associated with a low incidence of adverseevents. There was a trend towards less major bleedingand less of an increase in creatinine kinase with enoxa-parin compared with UFH.38

Another randomized study39 (N = 162) comparedenoxaparin, enoxaparin plus abciximab, and UFH asadjunctive therapy during PCI. All patients receivedaspirin and ticlopidine for 3 days prior to PCI. Nomajor cardiac events occurred in any of the treatmentgroups. There was a similar low rate of major orminor bleeding events. Both enoxaparin groups hadless of an increase in necrosis markers post-PCI and areduced number of ischemic events compared withUFH.39

The NICE 3 observational study9 was initiated toassess the safety and efficacy of enoxaparin combinedwith GP IIb/IIIa inhibitors in higher-risk patients,including those who go on to PCI.9 Of the 707patients enrolled, 671 were treated with enoxaparin,and 628 of these patients also received a GP IIb/IIIainhibitor. Of the 286 patients who underwent PCI,283 also received a GP IIb/IIIa inhibitor. The com-bination of enoxaparin and a GP IIb/IIIa inhibitorwas associated with a low incidence of bleeding. Theoverall 30-day incidence of non-CABG-related bleed-ing was 1.9%, which is consistent with an estimatedhistorical rate of 2%. Major and non-CABG-relatedbleeding occurred in a small percentage of patientswho underwent PCI. Death occurred at hospital dis-charge in 1.0% of patients, and 1.6% at 30 days; MIoccurred in 3.5% and 5.1% of patients, respectively;and urgent revascularization occurred in 2.7% and6.8%, respectively. The investigators concluded thatthe combination of enoxaparin and a GP IIb/IIIainhibitor was safe, even in patients undergoing subse-quent PCI.9

The SYNERGY (Superior Yield of the NewStrategy of Enoxaparin, Revascularization andGlycoprotein IIb/IIIa Inhibitors) trial40 comparedenoxaparin with UFH in patients at high risk forischemic events. This was a prospective, randomized,open-label, multicenter study in 10,027 patientsintended for PCI. A majority of patients (92%)enrolled in this study underwent PCI. Use of GPIIb/IIIa inhibitors was not mandated. Results fromthis study did not show either superiority or inferior-ity with enoxaparin compared with UFH. The primary


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end point, death or nonfatal MI by 30 days, occurredin 14.0% and 14.5% of patients, with enoxaparin andUFH, respectively. Bleeding was moderately in-creased in the enoxaparin group, with no significantdifferences with respect to transfusions or intracranialhemorrhage.40

The ASPIRE (Arixtra Study in PercutaneousCoronary Intervention: A Randomized Evaluation)trial41 was a pilot study in a total of 350 patients,comparing fondaparinux and UFH with and withoutGP IIb/IIIa inhibitors. Patients undergoing PCI wererandomized to receive UFH (n = 117), 2.5 mg fonda-parinux IV (n = 118), or 5 mg fondaparinux IV (n =115). The randomization was stratified depending onwhether GP IIb/IIIa inhibitors were planned. Efficacyand safety were similar in the fondaparinux and UFHgroups. There were no significant differences in out-comes between those who received GP IIb/IIIainhibitors and those who did not. This suggests thatfondaparinux may be substituted for UFH in PCI.41

The STEEPLE (Safety and Efficacy of GP IIb/IIIaInhibitors With Intravenous Enoxaparin in PatientsUndergoing Elective Percutaneous CoronaryIntervention) trial42 evaluated 3528 patients under-going a nonemergent PCI. Patients were randomizedto 0.5 or 0.75 mg/kg enoxaparin IV or UFH regi-men adjusted by activated clotting time. Patientsgiven enoxaparin experienced a 57% reduction inmajor bleeding compared with UFH (P < 0.01). Thecomposite ischemic end points were similar. Therewas an increase in bleeding when GP IIb/IIIainhibitors were used (10.3% vs 5.0% without GPIIb/IIIa inhibitors; P < 0.001), as well as ischemicevents (8.1% vs 5.2%, P < 0.001). Multivariate analy-sis showed that the use of GP IIb/IIIa inhibitors wasindependently correlated with bleeding (odds ratio[OR] = 2.3 [1.7–3.0]; P < 0.0001), but not withischemic events, regardless of the anticoagulant used.The study indicates that enoxaparin may be a suitablealternative to UFH for patients undergoing electivePCI. The use of GP IIb/IIIa inhibitors with enoxa-parin or UFH was associated with an increase inbleeding.42 More clinical studies should be performedto draw any solid conclusions.

Refer to Appendix 3 for a summary of trials inpatients undergoing PCI and receiving combinationtherapy.

SUMMARYIn selecting treatment for patients with ACS, clini-

cians must depend on the results of clinical trials. Thereis no other way to predict with certitude whether acombination of drugs will be beneficial or whether therisk of adverse events will outweigh the benefits of treat-ment. Fortunately, more combinations of agents arebeing tested in well-designed trials, providing a base ofevidence to support decisions in clinical practice.

Aspirin is the mainstay of antithrombotic regimensin patients with ACS. UFH is still commonly used inUA/NSTEMI and STEMI. However, because of itsmechanism and pharmacodynamic/pharmacokineticprofile, it is not always the ideal agent—monitoringand dose adjustments are required, its use is not recom-mended with streptokinase, and there is an increasedrisk for bleeding. Evidence from clinical trials clearlysupports the substitution of UFH with LMWH,because of the physiologic effects of LMWH and itspharmacokinetic and pharmacodynamic profile.

Successful outcomes in clinical studies have easedconcerns about potential adverse bleeding events anddifficulties in reversing the antithrombotic effects ofLMWH. Most of the clinical trial data is based onenoxaparin and, as a result, the ACCP 2004 recom-mendations for LMWH with fibrinolytics are specificfor enoxaparin. Because of successes in treating pa-tients in the acute setting, current studies are focusedon early use of antithrombotic agents in the prehospi-talization setting to further improve outcomes.

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42. Steinhubl S, White H, King S, et al. Safety and efficacy of

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GUSTO-IV1

Objective: Investigate the safety and efficacyof abciximab + UFH vs LMWH (dalteparin)in ACSDrugs: Abciximab, UFH, dalteparin; allpatients received aspirin Patient Population: 7800

ACUTE II2

Objective: Estimate the incidence of bleed-ing complications and collect data on clinicalefficacy of tirofiban + enoxaparin + aspirin Drugs: Tirofiban, enoxaparin, UFH; allpatients received aspirin.Patient Population: 525

INTERACT3

Objective: Determine the rates of majorhemorrhage and ischemia in GP IIb/IIIainhibitor-treated patients receiving enoxa-parin vs UFHDrugs: Eptifibatide, enoxaparin, UFH; allpatients received aspirinPatient Population: 746

A to Z Trial4

Objective: Phase A: Assess efficacy and safe-ty of enoxaparin compared with UFH inpatients with non–ST-segment elevationACS receiving concomitant tirofiban andaspirinDrugs: Tirofiban, enoxaparin, UFH; allpatients received aspirinPatient Population: 3987

Patients were randomized to receive abcix-imab for 24 hours or 48 hours, or placebo ina double-blind, double-dummy fashion. Inthe dalteparin substudy patients received 5 days of SC dalteparin instead of a 48-hourinfusion of UFH. All patients receivedaspirin.

Patients were randomized to receive tirofibanwith either SC enoxaparin (1 mg/kg q12h)or aPTT-adjusted IV UFH (1.5–2.5 timescontrol) in a 2:3 double-blind, double-dummy fashion. Therapy was administeredfor 24–96 hours. Bleeding incidences wereassessed until 24 hours after trial therapy wasdiscontinued; other clinical outcomes wereassessed for as long as 30 days.

All patients received eptifibatide and aspirinand were randomized to receive, in an open-label manner, either SC enoxaparin (1 mg/kgq12h) for 48 hours or aPTT-adjusted UFHinfusion (1.5–2 times control) for 48 hours.

Phase A of the A to Z study was a multicen-ter, prospective, open-label, randomizednoninferiority trial to compare SC enoxa-parin (1 mg/kg q12h) with weight-adjustedUFH infusion in patients receiving tirofibanand aspirin.

Addition of abciximab to UFH or LMWHand aspirin as primary treatment of ACS isnot associated with any significant reductionin cardiac events but a doubled risk of bleed-ing compared with placebo. In the dal-teparin cohort, major and minor bleedingoccurred in 5.0% of patients in the abcix-imab groups compared with 1.8% of patientsin the placebo group (P < 0.05). In theUFH cohort the difference between theabciximab and placebo groups was similar(3.8% vs 1.8%, P < 0.001). At 30 days therewere no significant differences in the rate ofdeath or MI, either in the dalteparin (abcix-imab 9.6% vs placebo 11.3%: OR: 0.85; 95%CI: 0.58–1.25) or in the UFH cohort (8.5%vs 7.6%; OR: 1.12; CI: 0.95–1.34). The com-bination of abciximab with dalteparin seemsas safe as abciximab plus UFH, although nui-sance bleedings are more common.

Incidence of total TIMI bleeding events was4.8% in the tirofiban/UFH group vs 3.5% inthe tirofiban/enoxaparin group (OR: 1.4;95% CI: 0.6–3.4). The incidence of anybleeding event was 34.3% vs 54.6%, respec-tively. Most bleeds were cutaneous.Although not powered to compare ischemicend points, refractory ischemia requiringurgent intervention (4.3% vs 0.6%, P = 0.01)and rehospitalization for unstable angina(7.1% vs 1.6%, P = 0.002) were observedmore frequently in the tirofiban/UFHgroup compared with the tirofiban/enoxa-parin group.

Major non-coronary artery bypass surgery-related bleeding at 96 hours (primary safetyoutcome) was significantly lower amongenoxaparin-treated patients than amongheparin-treated patients (1.8% vs 4.6%, P =0.03). Minor bleeding was more frequent inthe enoxaparin group (30.3% vs 20.8%, P =0.003). Less ischemia as detected by contin-uous ECG evaluation (primary efficacy out-come) was seen in the enoxaparin groupduring the initial (14.3% vs 25.4%, P =0.002) and subsequent (12.7% vs 25.9%, P <0.0001) 48-hour monitoring periods. Therate of death or MI at 30 days was signifi-cantly lower in the enoxaparin group (5% vs9%, P = 0.031).

A total of 169 (8.4%) of 2018 patients ran-domized to receive enoxaparin experienceddeath, MI, or refractory ischemia at 7 dayscompared with 184 (9.4%) of 1952 patientsrandomized to receive UFH (HR: 0.88; 95%CI: 0.71–1.08). This met the prespecifiedcriterion for noninferiority. Rates for anyTIMI grade bleeding were low (3.0% forenoxaparin and 2.2% for UFH; P = 0.13).


Appendix 1. Summary of Clinical Trials in Patients With NSTEMI Receiving Combination Therapy

Trial Methods Results/Conclusions

continued

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ACUITY5

Objective: Determine if bivalirudin com-pared with UFH or LMWH in combinationwith GP IIb/IIIa inhibitors was moreeffectiveDrugs: UFH, enoxaparin, GP IIb/IIIainhibitor, bivalirudin; all patients receivedaspirinPatient Population: 13,819

ISAR-REACT 26

Objective: Determine if abciximab is associ-ated with clinical benefit in high-risk patientswith ACS undergoing PCI after pretreat-ment with clopidogrelDrugs: Heparin, abciximab, placebo; allpatients received clopidogrel and aspirinPatient Population: 2022

Prospective, randomized comparison of 3treatments for patients with unstable anginaor NSTEMI.

Patients were randomly assigned to receiveabciximab plus UFH or placebo plus UFHin a double-blind, placebo-controlled man-ner. The primary end point was a compositeof death, MI, or urgent target vessel revascu-larization occurring within 30 days afterrandomization.

For the intent-to-treat population, the com-bination of bivalirudin and GP IIb/IIIainhibitor was noninferior to UFH/enoxa-parin and GP IIb/IIIa inhibitor for all pri-mary end points. Bivalirudin alone was supe-rior to the combination of UFH/enoxaparinand GP IIb/IIIa inhibitor in major bleeding(3.0% vs 5.7%; P < 0.001 for superiority).The primary net clinical benefit was signifi-cantly improved in the bivalirudin-alonegroup compared with the UFH/enoxaparinplus GP IIb/IIIa group (10.1% vs 11.7%; P = 0.015 for superiority).

The primary end point was reached in 90patients (8.9%) assigned to abciximab vs 120(11.9%) assigned to placebo for a 25%reduction in risk with abciximab (RR: 0.75;95% CI: 0.58–0.97; P = 0.03). Amongpatients with an elevated troponin level, theincidence of ischemic events was significant-ly lower in the abciximab group (67/513patients [13.1%]) compared with the place-bo group (98/536 patients [18.3%]) (RR:0.71; 95% CI: 0.54–0.95; P = 0.02) (P = 0.7for interaction).

NSTEMI = non–ST-elevation myocardial infarction; UFH = unfractionated heparin; LMWH = low-molecular-weight heparin; ACS =acute coronary syndrome; MI = myocardial infarction; OR = odds ratio; CI = confidence interval; aPTT = activated partial thromboplas-tin time; GP = glycoprotein; ECG = electrocardiogram; HR = hazard ratio; PCI = percutaneous coronary intervention; RR = relative risk.

Appendix 1. Continued


References 1. James S, Armstrong P, Califf R, et al. Safety and efficacy

of abciximab combined with dalteparin in treatment of

acute coronary syndromes. Eur Heart J. 2002;23:1538–

1545.

2. Cohen M, Theroux P, Borzak S, et al, on behalf of the

ACUTE II Investigators. Randomized double-blind safety

study of enoxaparin versus unfractionated heparin in

patients with non–ST-segment elevation acute coronary

syndromes treated with tirofiban and aspirin: The ACUTE

II study. Am Heart J. 2002;144:470–477.

3. Goodman SG, Fitchett D, Armstrong PW, et al, for the

Integrilin and Enoxaparin Randomized Assessment of

Acute Coronary Syndrome Treatment (INTERACT) Trial

Investigators. Randomized evaluation of the safety and

efficacy of enoxaparin versus unfractionated heparin in

high-risk patients with non–ST-segment elevation acute

coronary syndromes receiving the glycoprotein IIb/IIIa

inhibitor eptifibatide. Circulation. 2003;107:238–244.

4. Blazing MA, de Lemos JA, White HD, et al, for the A to Z

Investigators. Safety and efficacy of enoxaparin vs unfrac-

tionated heparin in patients with non–ST-segment elevation

acute coronary syndromes who receive tirofiban and aspirin:

A randomized controlled trial. JAMA. 2004;292:55–64.

5. Stone GW, for the ACUITY Investigators. Acute

Catheterization and Urgent Intervention and Triage

Strategy Trial (ACUITY). Prospective, randomized com-

parison of heparin plus IIb/IIIa inhibition and bivalirudin

with or without IIb/IIIa inhibition in patients with acute

coronary syndromes. Presented at: American College of

Cardiology; March 11–14, 2006; Atlanta, Ga.

6. Kastrati A, Mehilli J, Neumann F-J, et al, for the

Intracoronary Stenting and Antithrombotic Regimen: Rapid

Early Action for Coronary Treatment 2 (ISAR-REACT 2)

Trial Investigators. Abciximab in patients with acute coro-

nary syndromes undergoing percutaneous coronary inter-

vention after clopidogrel pretreatment: The ISAR-REACT

2 randomized trial. JAMA. 2006;295:1531–1538.

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HART II1

Objective: Demonstrate noninferiority ofenoxaparin vs UFH in efficacy measured bythe 90-minute TIMI 2 and 3 reperfusionwith alteplaseDrugs: Enoxaparin, UFH, alteplase; allpatients received aspirinPatient Population: 400

AMI-SK2

Objective: Determine if addition of enoxa-parin to streptokinase improves early andsustained coronary patency and clinical out-come in patients with evolving MI Drugs: Enoxaparin, streptokinase, aspirin,placeboPatient Population: 496

ASSENT-33

Objective: Compare efficacy and safety oftenecteplase plus enoxaparin or abciximab,with that of tenecteplase plus weight-adjustedUFH in patients with acute MI Drugs: Tenecteplase, enoxaparin, UFH,abciximab Patient Population: 6095

After enrollment, all patients received aspirinand underwent thrombolysis with alteplasewith the accelerated infusion regimen.Patients allocated to enoxaparin received 30-mg IV bolus followed by 1 mg/kg SC q12h.Patients in the UFH group received an ini-tial IV bolus (4000 U for those weighing upto 67 kg; 5000 U for patients weighing >67kg), followed by an infusion of 15 U/kg perhour for at least 3 days, adjusted to achieve atarget aPTT of 2–2.5 times control.Coronary angiography was performed 90minutes after the initial bolus alteplase doseand repeated for reocclusion assessment after5–7 days.

All patients were treated with IV streptoki-nase and aspirin. In a double-blind fashion,patients were randomized to receive eitherenoxaparin (n = 253) IV bolus (30 mg) andthen SC injections (1 mg/kg q12h) orplacebo (n = 243) for 3–8 days. The medianduration of treatment in both groups was 5days.

Patients were randomly assigned to 1 of 3regimens: full-dose tenecteplase and enoxa-parin for a maximum of 7 days (enoxaparingroup; n = 2040), half-dose tenecteplasewith weight-adjusted low-dose UFH and a12-hour infusion of abciximab (abciximabgroup; n = 2017), or full-dose tenecteplasewith weight-adjusted UFH for 48 hours(UFH group; n = 2038). The primary endpoints were the composites of 30-day mor-tality, in-hospital reinfarction, or in-hospitalrefractory ischemia (efficacy end point), andthe above end point plus in-hospital intracra-nial hemorrhage or in-hospital major bleed-ing complications (efficacy plus safety endpoint). Analysis was by intention to treat.

Patency rates (TIMI grades 2 and 3) of theinfarct-related artery 90 minutes after start oftherapy were 80.1% in patients treated withenoxaparin compared with 75.1% in the UFHgroup. The noninferiority of enoxaparinwhen compared with UFH was confirmedper protocol. A total of 259 patients withTIMI 2 or 3 flow on the initial angiogramand with an assessable angiogram at follow-upwere assessed for reocclusion. Reocclusion,defined as deterioration from TIMI grade 2or 3 at 90 minutes to grade 0 or 1 at follow-up, occurred in 5.9% and 9.8% of patients inthe enoxaparin and UFH groups, respective-ly. Reocclusion of TIMI grade 3 arteriesoccurred in 3.1% and 9.1% of enoxaparin- andUFH-treated patients (P = 0.12).

ST-segment resolution at 90 minutes and180 minutes measured by ECG wasimproved in patients receiving enoxaparin.Complete, partial, and no ST-segment reso-lution at 180 minutes was observed in36.3%, 44.4%, and 19.2% in the enoxaparingroup vs 25.4%, 43.5%, and 31.6% in theplacebo group, respectively (P = 0.014).Assessment of the primary end pointrevealed improved TIMI-3 flow with enoxa-parin vs placebo (70.3% vs 57.8%, P = 0.01).Combined TIMI-2 and -3 flow was alsoimproved (87.6% vs 71.7%, P = 0.001), aswas TIMI frame count (P = 0.003). Thetriple clinical end point of death, reinfarc-tion, and recurrent angina at 30 days wasreduced with enoxaparin (13.4% vs 21.0%, P = 0.03). By day 30, more major hemor-rhages occurred in the enoxaparin group vsthe placebo group (4.8% vs 2.5%, P = 0.2).

There were significantly fewer efficacy endpoints in the enoxaparin and abciximabgroups than in the UFH group: 233/2037(11.4%) vs 315/2038 (15.4%; RR: 0.74[95% CI: 0.63–0.87], P = 0.0002) forenoxaparin, and 223/2017 (11.1%) vs315/2038 (15.4%; RR: 0.72 [95% CI:0.61–0.84], P < 0.0001) for abciximab. Thesame was true for the efficacy plus safety endpoint: 280/2037 (13.7%) vs 347/2036(17.0%; RR: 0.81 [95% CI: 0.70–0.93], P =0.0037) for enoxaparin, and 287/2016(14.2%) vs 347/2036 (17.0%; RR: 0.84[95% CI: 0.72–0.96], P = 0.01416) forabciximab. The tenecteplase plus enoxaparinor abciximab regimens reduced the frequen-cy of ischemic complications of an acute MI.Tenecteplase plus enoxaparin seems to be anattractive alternative reperfusion regimenthat warrants further study.

Appendix 2. Summary of Clinical Trials in Patients With STEMI Receiving Combination Therapy WithFibrinolytic Agents


continued

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ENTIRE-TIMI 234

Objective: Evaluate enoxaparin and full-dose tenecteplase and half-dose tenecteplaseplus abciximab Drugs: Tenecteplase, abciximab, UFH,enoxaparin; all patients received aspirinPatient Population: 483

ASSENT-3 PLUS5

Objective: Study the feasibility and treat-ment delays and compare efficacy and safetyof the 2 antithrombin cotherapies withtenecteplase in the prehospital settingDrugs: Tenecteplase, enoxaparin, UFH Patient Population: 1639

ExTRACT-TIMI 256,7

Objective: Test if enoxaparin, when com-pared with UFH, reduces the composite endpoint of all-cause mortality and nonfatal MIwithin 30 days after randomization inpatients with STEMI who receive fibrinolyt-ic therapyDrugs: Fibrinolytic therapy with streptoki-nase, alteplase, tenecteplase, or reteplase,enoxaparin, UFH; all patients receivedaspirin Patient Population: 20,506

In this open-label study, patients were ran-domized to receive either standard reperfu-sion (full-dose tenecteplase) or combinationtherapy (half-dose tenecteplase plus abcix-imab) and to either a control group usingUFH or enoxaparin. To provide a concur-rent control group while obtaining moreinformation regarding the experimentalenoxaparin regimens, randomization ratiosof either 1:2 or 1:3 were used (UFH:enoxaparin).

In the prehospital setting, patients withSTEMI were randomly assigned to receivetenecteplase and either enoxaparin IV bolusof 30 mg followed by 1 mg/kg SC BID fora maximum of 7 days or weight-adjustedUFH for 48 hours. The median delay fromsymptom onset to tenecteplase administra-tion was 115 minutes.

Using a double-blind, double-dummydesign, patients with STEMI who werescheduled to undergo fibrinolysis were ran-domized to receive either enoxaparinthroughout the index hospitalization orweight-based UFH for at least 48 hours. Forpatients <75 years of age, enoxaparin (ormatching placebo) was to be given as a fixed30-mg IV bolus followed 15 minutes laterby an SC injection of 1.0 mg/kg q12h. Forpatients ≥75 years of age, the IV bolus waseliminated and the SC dose was reduced to0.75 mg/kg q12h. In patients with a creati-nine clearance of <30 mL/min, the dose wasmodified to 1.0 mg/kg q24h. The primaryefficacy end point was death or nonfatalrecurrent MI through 30 days.

With full-dose tenecteplase and UFH therate of TIMI 3 flow at 60 minutes was 52%and was 48%–51% with enoxaparin. Usingcombination therapy the rate of TIMI 3 flowat 60 minutes was 48% with UFH and47%–58% with enoxaparin. The rate of TIMI3 flow among all UFH patients was 50% andwas 51% among all enoxaparin patients.Through 30 days, death/MI occurred in thefull-dose tenecteplase group in 15.9% ofpatients with UFH and 4.4% with enoxa-parin (P = 0.005). In the combination ther-apy group, the rates were 6.5% with UFHand 5.5% with enoxaparin. The rate of majorhemorrhage with full-dose tenecteplase was2.4% with UFH and 1.9% with enoxaparin;with combination therapy it was 5.2% withUFH and 8.5% with enoxaparin.

The primary efficacy end point (the compos-ite of 30-day mortality or in-hospital rein-farction or in-hospital refractory ischemia)tended to be lower with enoxaparin com-pared with UFH (14.2% vs 17.4%, P =0.080), and there was a smaller, nonsignifi-cant trend for the primary efficacy and safe-ty end point (18.3% vs 20.3%, P = 0.297).There were reductions in in-hospital rein-farction (3.5% vs 5.8%, P = 0.028) andrefractory ischemia (4.4% vs 6.5%, P =0.067) but increases in total stroke (2.9% vs1.3%, P = 0.026) and intracranial hemor-rhage (2.20% vs 0.97%, P = 0.047). Theincrease in stroke and intracranial hemor-rhage was seen in patients >75 years of age.The combination of tenecteplase withenoxaparin reduced early ischemic events,but lower doses of enoxaparin need to betested in elderly patients.

The primary end point occurred in 12.0% ofpatients in the UFH group and 9.9% ofthose in the enoxaparin group (17% reduc-tion in relative risk, P < 0.001). Nonfatalreinfarction occurred in 4.5% of the patientsreceiving UFH and 3.0% of those receivingenoxaparin (33% reduction in RR, P < 0.001);7.5% of patients given UFH died, as did6.9% of those given enoxaparin (P = 0.11).The composite of death, nonfatal reinfarc-tion, or urgent revascularization occurred in14.5% of patients given UFH and 11.7% ofthose given enoxaparin (P < 0.001); majorbleeding occurred in 1.4% and 2.1%, respec-tively (P < 0.001). The composite of death,nonfatal reinfarction, or nonfatal intracranialhemorrhage (a measure of net clinical benefit)occurred in 12.2% of patients given UFH and10.1% of those given enoxaparin (P < 0.001).



continued

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STEMI = ST-elevation myocardial infarction; UFH = unfractionated heparin; aPTT = activated partial thromboplastin time; MI = myocardialinfarction; ECG = electrocardiogram; RR = relative risk; CI = confidence interval; HR = hazard ratio; PCI = percutaneous coronary intervention.

OASIS-68

Objective: Evaluate the effect of fondaparin-ux when initiated early and given for up to 8days vs usual care (placebo in those in whomUFH is not indicated [stratum 1] or UFHfor up to 48 hours followed by placebo forup to 8 days [stratum 2]) in patients withSTEMIDrugs: Fondaparinux, UFH, placeboPatient Population: 12,092

Randomized, double-blind comparison offondaparinux 2.5 mg once daily or controlfor up to 8 days in patients with STEMI.From day 3 through day 9, all patientsreceived either fondaparinux or placeboaccording to the original randomized assign-ment. Composite of death or reinfarction at30 days (primary) with secondary assess-ments at 9 days and at final follow-up (3 or6 months).

Death or reinfarction at 30 days was signifi-cantly reduced from 677 (11.2%) of 6056patients in the control group to 585 (9.7%)of 6036 patients in the fondaparinux group(HR: 0.86; 95% CI: 0.77–0.96; P = 0.008;absolute risk reduction: 1.5%; 95% CI:0.4%–2.6%). These benefits were observed at9 days (537 [8.9%] placebo vs 444 [7.4%]fondaparinux; HR: 0.83; 95% CI: 0.73–0.94; P = 0.003), and at study end (857[14.8%] placebo vs 756 [13.4%] fondaparin-ux; HR: 0.88; 95% CI: 0.79–0.97; P =0.008). Mortality was significantly reducedthroughout the study. There was no hetero-geneity of the effects of fondaparinux in the2 strata by planned UFH use. There was nobenefit in patients undergoing primary PCI.In patients in stratum 2, fondaparinux wassuperior to UFH in preventing death orreinfarction at 30 days (HR: 0.82; 95% CI:0.66–1.02; P = 0.08) and at study end (HR:0.77; 95% CI: 0.64–0.93; P = 0.008).Significant benefits were observed in thosereceiving thrombolytic therapy (HR: 0.79; P = 0.003) and those not receiving anyreperfusion therapy (HR: 0.80; P = 0.03).There was a tendency to fewer severe bleeds(79 for placebo vs 61 for fondaparinux; P =0.13), with significantly fewer cardiac tam-ponade (48 vs 28; P = 0.02) with fonda-parinux at 9 days. In patients with STEMI,particularly those not undergoing primaryPCI, fondaparinux significantly reducedmortality and reinfarction without increas-ing bleeding and strokes.

References 1. Ross AM, Molhoek P, Lundergan C, et al. Randomized com-

parison of enoxaparin, a low-molecular-weight heparin, withunfractionated heparin adjunctive to recombinant tissueplasminogen activator thrombolysis and aspirin: Second trialof Heparin and Aspirin Reperfusion Therapy (HART II).Circulation. 2001;104:648–652.

2. Simoons ML, Krzeminska-Pakula M, Alonso A, et al, for theAMI-SK Investigators. Improved reperfusion and clinicaloutcome with enoxaparin as an adjunct to streptokinasethrombolysis in acute myocardial infarction: The AMI-SKstudy. Eur Heart J. 2002;23:1282–1290.

3. The Assessment of the Safety and Efficacy of a NewThrombolytic Regimen (ASSENT)-3 Investigators. Efficacyand safety of tenecteplase in combination with enoxaparin,abciximab, or unfractionated heparin: The ASSENT-3 ran-domised trial in acute myocardial infarction. Lancet.2001;358:605–613.

4. Antman EM, Louwerenburg HW, Baars HF, et al, for theENTIRE-TIMI 23 Investigators. Enoxaparin as adjunctiveantithrombin therapy for ST-elevation myocardial infarction:Results of the ENTIRE-Thrombolysis in MyocardialInfarction (TIMI) 23 Trial. Circulation. 2002;105:1642–1649.

5. Wallentin L, Goldstein P, Armstrong PW, et al. Efficacy andsafety of tenecteplase in combination with the low-molecular-weight heparin enoxaparin or unfractionated heparin in theprehospital setting: The Assessment of the Safety andEfficacy of a New Thrombolytic Regimen (ASSENT)-3PLUS randomized trial in acute myocardial infarction.Circulation. 2003;108:135–142.

6. Antman EM, Morrow DA, McCabe CH, et al, for theExTRACT-TIMI 25 Investigators. Enoxaparin versusunfractionated heparin as antithrombin therapy in patientsreceiving fibrinolysis for ST-elevation myocardial infarction:Design and rationale for the Enoxaparin and ThrombolysisReperfusion for Acute Myocardial Infarction Treatment-Thrombolysis In Myocardial Infarction study 25(ExTRACT-TIMI 25). Am Heart J. 2005;149:217–226.

7. Antman EM, Morrow DA, McCabe CH, et al, for theExTRACT-TIMI 25 Investigators. Enoxaparin versusunfractionated heparin with fibrinolysis for ST-elevationmyocardial infarction. N Engl J Med. 2006;354:1477–1488.

8. The OASIS-6 Trial Group. Effects of fondaparinux on mor-tality and reinfarction in patients with acute ST-segment ele-vation myocardial infarction: The OASIS-6 randomizedtrial. JAMA. 2006;295:1519–1530.

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Khosla et al1

Objective: Evaluate the safety and efficacyof coadministration of IV enoxaparin andeptifibatide during nonemergent coronaryand peripheral vascular interventionDrugs: Enoxaparin, eptifibatide, aspirin,clopidogrel Patient Population: 56

Kereiakes et al2

Objective: Assess anticoagulant effect andclinical safety for multiple dose regimens ofdalteparin administered either SC beforePCI or IV at the time of PCI in combinationwith abciximab initiated at the time of theprocedureDrugs: Abciximab, dalteparin, clopidogrel;all patients received aspirin

Patient Population: 107

Choussat et al3

Objective: Examine low-dose IV enoxaparinin elective PCI and its applicability to anunselected population regardless of age,weight, renal function, or use of GPIIb/IIIa inhibitorsDrugs: Enoxaparin, eptifibatide Patient Population: 242

Carnendran et al4

Objective: Observe the safety and efficacy ofa lower dose of IV enoxaparin (0.5 mg/kg)in conjunction with any GP IIb/IIIainhibitorDrugs: Enoxaparin, GP IIb/IIIa inhibitor,aspirin, clopidogrel Patient Population: 75

All patients were pretreated with 325 mgaspirin daily for at least 3 days before theprocedure. At the beginning of the proce-dure, 0.75 mg/kg enoxaparin and a 180-µg/kg bolus of eptifibatide were adminis-tered IV. An IV infusion of eptifibatide at adose of 2 µg/kg per minute was initiated. At10 minutes after bolus administration ofeptifibatide, a platelet aggregation study wasdone to assess platelet inhibition and achieveplatelet inhibition of ≥94%. If the plateletinhibition was <90%, a second bolus of 180µg/kg of eptifibatide was administered.Eptifibatide was continued for a mean of 17± 6 hours postprocedure. All patientsreceived 75 mg clopidogrel orally for 4weeks postprocedure.

Patients without prior SC dalteparin therapyor >12 hours after an SC dose were random-ly allocated in a blinded fashion to receiveeither 40 (n = 27) or 60 (n = 28) IU/kg dal-teparin IV at the time of PCI. After observ-ing thrombus during PCI, the blind wasbroken and all subsequent patients received60 IU/kg (no randomization). All patientsreceived oral aspirin before PCI and dailythereafter. Oral clopidogrel was initiatedafter coronary stent deployment.

Consecutive patients undergoing PCI weretreated with a single IV bolus of enoxaparin(0.5 mg/kg), and 26% of patients (n = 64)also received eptifibatide. Sheaths wereremoved immediately after the procedure inpatients treated with enoxaparin only, and 4hours after the procedure in those also treat-ed with eptifibatide.

Eligible PCI patients received 0.5 mg/kg IVenoxaparin and a GP IIb/IIIa inhibitor.None received anticoagulation 24 hoursprior to PCI; all received preproceduralaspirin, postprocedural deployment of theAngio-Seal, and clopidogrel therapy.

The procedural success rate was 99% (92/93procedures), the acute clinical success ratewas 98% (54/55 patients), the major complication rate was 2% (1/56 patients),and the vascular complication rate was 2% (1/56 patients). The use of IV enoxaparin inconjunction with IV eptifibatide duringnonemergent coronary and peripheral vascu-lar intervention is safe and effective andeliminates the need for routine measurementof ACT during the procedure.

Patients who received 60 IU/kg of dal-teparin IV had a lower incidence of proce-dural thrombosis (0% vs 11.1%, P < 0.01),more consistent antithrombotic effect (anti-factor Xa activity), and a similar incidence ofmajor bleeding (3.7% vs 2.6%) comparedwith patients who received 40 IU/kg of IVdalteparin. Dalteparin appears to be safe andeffective when administered in conjunctionwith abciximab for PCI.

A peak anti-Xa >0.5 IU/mL was obtained in97.5% of the population, and 94.6% ofpatients had their peak anti-Xa level in thepredefined target range of 0.5 to 1.5IU/mL. Advanced age, renal failure, beingoverweight, and eptifibatide use did notalter the anticoagulation profile. At 1-monthfollow-up, 6 patients (2.5%) had died, had anMI, or had undergone an urgent revascular-ization; all the patients had an anti-Xa level>0.5 IU/mL during PCI. Patients withoutan ischemic event and without a CK increase,but with a detectable troponin release in thenext 24 hours of PCI (>2 µg/mL, n = 21),had similar anti-Xa levels as those withouttroponin elevation. There were 1 major and3 minor bleeding events that were not asso-ciated with anti-Xa overshoot. Low-doseenoxaparin appears to be safe and effectiveand does not require dose adjustment whenused with eptifibatide.

TIMI minor bleeding was 1.3%; there wereno TIMI major bleeding events or majoradverse cardiac events during in-hospital stayor at 30-day follow-up. IV enoxaparinappeared safe and effective during PCI whengiven at a low dose in conjunction with GP IIb/IIIa inhibitor and Angio-Seal.

Appendix 3. Summary of Clinical Trials in Patients Undergoing PCI and Receiving Combination Therapy


continued

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NICE 1 and NICE 45

Objective: Evaluate the safety and utility ofspecific dose regimens for enoxaparin bothwith and without concomitant abciximabduring PCI Drugs: Enoxaparin, abciximab, ticlopidine,clopidogrel; all patients received aspirin

Patient Population: 828 in NICE 1 and818 in NICE 4

Galeote et al6

Objective: Evaluate the safety of combinedenoxaparin and abciximab compared withstandard therapy using UFH and abciximab Drugs: Abciximab, enoxaparin, UFH, ticlopidine Patient Population: 99

Dudek et al7

Objective: Assess the efficacy and safety ofcombined abciximab and enoxaparin vsenoxaparin administration during PTCA ofcomplex (B2 or C) lesions Drugs: Enoxaparin, abciximab, UFH; allpatients were pretreated for 3 days withaspirin and ticlopidinePatient Population: 162

NICE-38

Objective: Examine the safety and efficacyof combined use of enoxaparin and 1 of the3 commercially available GP IIb/IIIainhibitors in patients with ACS, and deter-mine the feasibility and safety of bringingpatients who had already received SC enoxa-parin to the catheterization laboratory forcoronary intervention, if necessary, withoutthe supplemental use of UFH Drugs: Enoxaparin, abciximab, tirofiban,eptifibatide, clopidogrel; all patients receivedaspirinPatient Population: 671

Patients in NICE 1 received enoxaparin 1.0 mg/kg IV at PCI.Patients in NICE 4 received enoxaparin 0.75 mg/kg IV in combination with standard-dose abciximab IV immediately precedingPCI.

Patients with coronary stent deploymentalso received either oral ticlopidine or clo-pidogrel for 30 days.

Before beginning the procedure, all patientsreceived a loading dose of IV aspirin (500mg). The patients randomly received an IVbolus of enoxaparin (0.75 mg/kg) or UFH(70 U/kg). All patients received an IV bolusof abciximab (0.25 mg/kg) followed by a12-hour IV infusion. All patients received500 mg of oral ticlopidine at the end of theprocedure.

Patients were randomized to 1 of 3 groups:UFH (n = 50) adjusted to ACT >300 sec-onds, enoxaparin (n = 58; IV 1 mg/kg), andReoEnox (n = 54) receiving enoxaparin (IV0.75 mg/kg) followed by abciximab (IVbolus 0.25 mg/kg and 0.125 µg/kg/min12-hour infusion). Serial CK, CK-myocardialbound (0, 8, 16, 24, 48 h) and cardiac tro-ponin T and troponin I (0, 24, 48 h) wereobtained after PTCA.

Of 671 patients, 628 (93.6%) received com-bined therapy with enoxaparin and a GPIIb/IIIa inhibitor, while 43 patients (6.4%)received enoxaparin alone. There was nospecific protocol regarding the exact timingof PCI after enrollment. Of the 286 patientsundergoing PCI, 100 (35%) received sup-plemental IV enoxaparin, and 224 (78%)received at least 1 dose of clopidogrel beforePCI. There were 59 patients (21%) whoreceived a GP IIb/IIIa inhibitor only at thetime of PCI, with infusions continued afterthe procedure.

Bleeding events and ischemic outcomeswere assessed in-hospital and 30 days afterPCI and were infrequent with either phar-macologic regimen. Enoxaparin with orwithout abciximab provided safe and effec-tive anticoagulation during PCI.

There was less major bleeding in the enoxa-parin group (2%) than in the UFH group(8.2%) but the difference was not statistical-ly significant. There were no significant dif-ferences in the frequency of in-hospital clin-ical events. There was a lower increase inaPTT at 5 hours in the enoxaparin vs UFHgroup (P = 0.02). It was impossible toremove the introducer in 7 of the UFH grouppatients due to aPTT >60 seconds as opposedto 1 patient in the enoxaparin group.Postprocedural CK elevation occurred in8.0% of the enoxaparin group and in 6.1% ofthe UFH group (P = NS). No thrombocy-topenia was observed in either group.Enoxaparin/abciximab was safe and associat-ed with a low incidence of major bleeding andmajor ischemic in-hospital events.

There were no major cardiac events (death,large MI, re-PTCA, CABG) in any group,but the biochemical markers were distinct.Despite standard therapies (aspirin + UFH +ticlopidine), there was a relatively highoccurrence of peri-PTCA myocardial dam-age. The use of enoxaparin reduced thenumber of ischemic events and the combina-tion of enoxaparin and abciximab appearssafe. There was no additional benefit ofabciximab against myocardial damage inpatients with ticlopidine pretreatment andapplication of enoxaparin during PTCA.

The primary end point of non-CABG majorbleeding in patients who received enoxaparinand GP IIb/IIIa treatment was reached by12 of 628 patients, or 1.9% (95% CI:0.8%–3.0%). The cumulative 30-day inci-dence of major bleeding was 8.3%. Patientswho underwent PCI accounted for a minor-ity of the total number of patients whodeveloped major bleeding (6/52) and non-CABG major bleeding (4/12). Patientsundergoing PCI can be safely managed withenoxaparin and a GP IIb/IIIa inhibitor.



continued

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SYNERGY9

Objective: Compare the outcomes ofpatients treated with enoxaparin vs UFHand define the role of enoxaparin in patientswith non–ST-segment elevation ACS at highrisk for ischemic cardiac complications man-aged with an early invasive approach Drugs: Enoxaparin, UFHPatient Population: 10,027

ASPIRE10

Objective: Determine safety and feasibilityof fondaparinux in the PCI setting Drugs: UFH, fondaparinux, GP IIb/IIIainhibitorPatient Population: 350

STEEPLE11

Objective: Compare the efficacy and safetyof a GP IIb/IIIa inhibitor used as an adjunctto UFH or enoxaparin Drugs: Enoxaparin, UFH, GP IIb/IIIainhibitorPatient Population: 3528

Patients were randomized to receive eitherweight-adjusted IV UFH to aPTT of1.5–2.0 times normal or SC enoxaparin 1mg/kg q12h. The primary efficacy outcomewas the composite clinical end point of all-cause death or nonfatal MI during the first30 days after randomization. The primarysafety end point was major bleeding orstroke.

Patients undergoing PCI were randomizedin a blinded manner to receive UFH, 2.5 mgfondaparinux IV, or 5.0 mg fondaparinuxIV. Randomization was stratified for plannedor no planned use of GP IIb/IIIa inhibitors.The primary safety outcome was total bleed-ing, which was a combination of major andminor bleeding events.

Randomization was stratified by the physi-cian’s choice of GP IIb/IIIa inhibitor use.The primary efficacy end point was the com-posite of death, nonfatal MI, and urgent tar-get vessel revascularization. Non–CABG-related bleeding was the primary safety endpoint.

The primary end point occurred in 14.0%(696/4993) of patients assigned to enoxa-parin and 14.5% (722/4985) of patientsassigned to UFH (OR: 0.96; 95% CI:0.86–1.06). No differences in the ischemicevents during PCI were observed betweenenoxaparin and UFH groups, respectively,including similar rates of abrupt closure(31/2321 [1.3%] vs 40/2364 [1.7%]),threatened abrupt closure (25/2321 [1.1%]vs 24/2363 [1.0%]), unsuccessful PCI(81/2281 [3.6%] vs 79/2328 [3.4%]), oremergency CABG surgery (6/2323 [0.3%]vs 8/2363 [0.3%]). More bleeding wasobserved with enoxaparin, with a statisticallysignificant increase in TIMI major bleeding(9.1% vs 7.6%, P = 0.008) but nonsignificantexcess in GUSTO severe bleeding (2.7% vs2.2%, P = 0.08) and transfusions (17.0% vs16.0%, P = 0.16). Enoxaparin is a safe andeffective alternative to UFH.

The incidence of total bleeding was 7.7% inthe UFH group and 6.4% in the combinedfondaparinux groups (HR: 0.81; 95% CI:0.35–1.84; P = 0.61). Bleeding was lesscommon in the 2.5-mg fondaparinux groupcompared with the 5-mg fondaparinuxgroup (3.4% vs 9.6%, P = 0.06). The com-posite efficacy outcome of all-cause mortali-ty, MI, urgent revascularization, or need fora bailout GP IIb/IIIa inhibitor was 6.0% inthe UFH group and 6.0% in the fondaparin-ux group, with no significant difference inefficacy among the fondaparinux doses com-pared with UFH. Coagulation marker analy-sis at 6 and 12 hours after PCI demonstrat-ed that fondaparinux was superior to UFHin inducing a sustained reduction in markersof thrombin generation, as measured by pro-thrombin fragment F1.2 (P = 0.02).Fondaparinux was comparable to UFH forclinical safety and efficacy outcomes.

Patients given enoxaparin experienced a 57%reduction in major bleeding compared withUFH (P < 0.01). The composite ischemicend points were similar. When GP IIb/IIIainhibitors were used, bleeding increased(10.3% with vs 5.0% without GP IIb/IIIainhibitors, P < 0.001), as did ischemic events(8.1% vs 5.2%, P < 0.001). Multivariateanalysis showed that use of GP IIb/IIIainhibitors was independently correlated withbleeding (OR: 2.3 [1.7–3.0]; P < 0.001),but not with ischemic events, regardless ofthe anticoagulant choice. Enoxaparin can bea suitable alternative to UFH for patientsundergoing elective PCI.



PCI = percutaneous coronary intervention; ACT = activated clotting time; GP = glycoprotein; MI = myocardial infarction; CK = creatinekinase; UFH = unfractionated heparin; aPTT = activated partial thromboplastin time; PTCA = percutaneous transluminal coronary angio-plasty; CABG = coronary artery bypass graft; ACS = acute coronary syndrome; CI = confidence interval; OR = odds ratio; HR = hazard ratio.

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