anti-platelet and anti-thrombotic approaches in patients undergoing percutaneous coronary...

Core Curriculum

Anti-Platelet and Anti-Thrombotic Approachesin Patients Undergoing Percutaneous

Coronary Intervention

Rajeev Garg,1 MD, Barry F. Uretsky,2* MD, and Eli I. Lev,3,4 MD

Over the past three decades, there has been a tremendous increase in the use of per-cutaneous coronary interventions (PCI) for the treatment of patients with atheroscler-otic coronary artery disease. However, PCI causes disruption of atherosclerotic plaqueand denudation of the endothelium, leading to stimulation of platelet aggregation andactivation of the coagulation cascade. Therefore, anti-platelet and anti-thromboticagents have a pivotal role as adjuncts before, during and after PCI, in order to mini-mize the risk of procedural ischemic complications, such as myocardial infarction,stent thrombosis, and various degrees of myonecrosis. The current article presents acomprehensive review of the evolution of current anti-platelet and anticoagulation regi-mens used in the setting of PCI. It starts with a summary of the current perspective ofthe coagulation process along with platelet activation and aggregation. The reviewthen focuses specifically on individual anti-platelet and anti-thrombotic drugs includingtheir mechanism of action and the scientific evidence which led to their use in PCI.Finally, we present summary recommendations from the AHA/ACC guidelines for indi-vidual anticoagulant and anti-platelet regimens given peri-PCI. ' 2007 Wiley-Liss, Inc.

Key words: percutaneous coronary intervention; anti-platelet therapy; anticoagulation

OVERVIEW OF VASCULAR THROMBOSIS

Nearly a century ago, Rudolf Virchow presented ahypothesis that three factors-vessel injury, alteredblood flow, and changes in blood coagulation-were re-sponsible for vascular thrombosis (Virchow’s triad).The primary condition affecting the actual compositionof this thrombus was the ‘‘nature’’ of blood flow [1].Arterial thrombosis results from a complex, well

orchestrated series of interactions between platelets,erythrocytes, and leukocytes intertwined with enzy-matic reactions of the coagulation system. Rupture ofan atheromatous plaque or endothelial denudation dur-ing angioplasty creates a nidus for platelet aggregationand thrombus formation, which may result in vesselocclusion and subsequent myocardial infarction (MI)or death [2].

Platelets

Platelets are cytoplasmic fragments, released into theblood from bone marrow megakaryocytes, with an av-erage circulating life span of 7–10 days [3]. The plate-let’s main function is to respond to endothelial dam-age, tethering to the site of injury or lesion to initiate

hemostasis. The platelet’s structure is such that thenegatively charged elements within its phospholipidmembrane provide a surface on which coagulationenzymes can function efficiently, whereas glycoproteinreceptors on the platelet surface act as points of attach-ment for both other platelets and various plasma com-ponents that are necessary for clot mass to grow [3,4].

1Division of Cardiology, University of Missouri, Columbia,Missouri2Department of Cardiology, Sparks Health System, Fort Smith,Arkansas3Division of Cardiology, University of Texas Medical Branch,Galveston, Texas4The Cardiology Department, The Methodist Hospital ResearchInstitute, The Methodist Hospital, Houston, Texas

*Correspondence to: Barry F. Uretsky, MD, Department of Cardiol-

ogy, Sparks Medical System, 1001 Towson Avenue, PO Box 17006,

Fort Smith, AR 72917-7006.

E-mail: [email protected]

Received 9 January 2007; Revision accepted 20 March 2007

DOI 10.1002/ccd.21204

Published online 24 August 2007 in Wiley InterScience (www.

interscience.wiley.com).

' 2007 Wiley-Liss, Inc.

Catheterization and Cardiovascular Interventions 70:388–406 (2007)

The role of platelets in arterial thrombosis is bestappreciated in the context of four important physio-logic steps: (1) adhesion, (2) activation, (3) aggrega-tion, and (4) support of coagulation.Platelet adhesion is defined as adherence of platelets

to sites of vessel-wall damage.Vascular intimal injury exposes thrombogenic suben-

dothelial collagen to circulating platelets, which adhereto the site of injury by means of von Willebrand factor(vWf)—A multimeric protein, synthesized by both en-dothelial cells and megakaryocytes, where it is storedin Weibel-Palade bodies and alpha granules, respec-tively. vWf binds platelets to the damaged vessel wallvia the glycoprotein (GP) Ib/IX/V receptor complex onthe platelet membrane [5]. Platelets can also directlybind to subendothelial collagen through other receptorsincluding the GP IV, GP VI, and GP Ia/IIa receptors;this interaction probably predominates at low shearrates [6,7].Platelet activation is defined as the process by which

a resting platelet changes shape and becomes an inte-gral part of clot formation. Platelet activating agonistsin blood (such as ADP, thromboxane A2, collagen,and thrombin), platelet granules, and extracellular ves-sel wall matrix bind to receptors on adherent platelets[8], leading to transmission of intra-cellular plateletactivating signals (Fig. 1). This event, in turn, causessecretion of prepackaged granules, synthesis of throm-boxane A2, and increased expression of GP IIb/IIIareceptors on the platelet surface. Additionally platelet

activation produces platelet membrane phospholipidreconfiguration, facilitating binding of key coagulationfactors such as factor Va and VIIIa [9]. The productsof the release reaction, namely granule constituentsand TXA2, mediate the final phase of platelet aggrega-tion [10].Platelet aggregation is defined as platelet binding to

each other to form a platelet ‘‘plug’’ as shown inFig. 2. Aggregation is primarily mediated by fibrinogen

Fig. 1. Mechanism of action of different anti-platelet and antithrombotic agents. (CourtesyDr. R. Hillman). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Fig. 2. Platelet activation followed by platelet aggregation.(Figure adapted with permission from Lippincott Williams andWilkins from Platelet glycoprotein IIb/IIIa antagonists. What arethe relevant issues concerning their pharmacology and clinicaluse? Scarborough RM, et al. Circulation 1999;100:437–444.)

Anti-Platelet and Anti-Thrombotic Therapy for PCI Patients 389

Catheterization and Cardiovascular Interventions DOI 10.1002/ccd.Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).

(and to a lesser extent, VWf) which acts as a bridgebetween the two GP IIb/IIIa receptors on neighboringplatelets as depicted in Fig. 2. The tripeptide RGDsequence (arginine–glycine–aspartic acid) of the fibri-nogen molecule is recognized by the GP receptor. GPIIb/IIIa receptor is the most abundant receptor on theplatelet surface (80,000 copies/quiescent platelet whichincreases to 100,000 copies on the surface of activatedplatelets) [11]. The GP IIb/IIIa receptor permits rapidformation of a network of fibrinogen bridges betweenplatelets leading to formation of a platelet plug at thesite of vascular injury [12]. The RGD sequence hasserved as the molecular basis for the structure of twoclinically used GP IIb/IIIa antagonists: tirofiban andeptifibatide [13]. The platelet plug is anchored and sta-bilized by the fibrin mesh that develops simultaneouslyfrom the coagulation cascade. Platelet aggregates pro-vide a surface for coagulation protease assembly,thrombin generation, and fibrin formation.Platelet support of coagulation occurs as follows:

Platelet activation by collagen and thrombin leads toredistribution of phosphatidylserine from the inner tothe outer surface of the platelet membrane and pro-vides a surface for factor Va and VIIIa binding(Fig. 3). Binding of these two cofactors is essential forthe conversion of prothrombin to thrombin by factor Xa,and factor X to Xa by factor IXa, respectively. Thus,the activated platelet surface plays an important role inthrombin generation, which in turn causes positive feed-back activation and recruitment of further platelets.

OVERVIEW OF COAGULATION

Fibrin formation on the ruptured plaque surface iscatalyzed by a cascade of complex biochemical reac-tions. The traditionally distinct ‘‘intrinsic’’ and ‘‘extrin-sic’’ coagulation pathways are now known to be inter-dependent. Recent observations have demonstrated thatcoagulation is predominantly initiated through the firstcomponent of the extrinsic pathway: tissue factor (TF).Some researchers have also proposed a shift from acascade to a cell-based model of coagulation com-prised of three stages: initiation, amplification, andpropagation occurring on surfaces on different cells[14].Initiating (or Extrinsic) Pathway: The main source

of TF is probably the plaque gruel and cellular plaqueconstituents, namely smooth muscle cells and lipid-laden macrophages. Activated monocytes on the plaquesurface shed microparticles into the circulating bloodand these TF-bearing microvesicles dock on activatedplatelets via a PSGL-1-P-selectin interaction, bringingTF in close proximity to the rest of the coagulation

factors present on the surface of activated platelets thatis factor Va and VIIIa, as described earlier [15,16].Extrinsic pathway coagulation is initiated by TF ex-

posure to circulating factor VIIa. The VIIa/TF complexrecruits factor X and IX and converts them into factorXa and IXa, respectively. Factor Xa converts pro-thrombin to thrombin. Thrombin is important in gener-ating activated factor Va, factor VIIIa, and factor XIIIaand activating nearby platelets. Thus, the TF/VIIa/Xapathway has been named the initiation phase of coagu-lation. By contrast, factor IXa generated by VIIa/TF isthe predominant pathway for generating a large quan-tity of thrombin and fibrin. The VIIa/TF/IXa pathwayhas been called the ‘‘propagation phase’’ of coagulation(Fig. 3) [17].Propagation of the thrombotic response occurs as the

process moves from the surface of TF- bearing cells tothe surface of activated platelets. Thrombin is releasedfrom the platelet surface and converts fibrinogen tofibrin, which is cross-linked by factor XIIIa, a transglu-taminase. The cross- linked fibrin forms a fibrillarstructure that enmeshes platelet aggregates forming aclot.

CONTROL OF COAGULATION

Coagulation is controlled by several naturally occur-ring molecules. Endothelial PGI2, ADPase, and carbonmonoxide are physiological platelet inhibitory media-tors. Other anticoagulant systems designed to limitfibrin accumulation can be divided into constitutiveand dynamically-induced. The main constitutive antico-

Fig. 3. Figure adapted with kind permission from SpringerScience and Business Media from Remodeling the bloodcoagulation cascade. Hoffman M. Journal of Thrombosis andThrobolysis 2003;16:17–20.

390 Garg et al.


agulant mechanisms are the antithrombin and the TFpathway inhibitor systems (Fig. 4). The main dynamicanticoagulant mechanism is the activated protein Csystem [18].Antithrombin (AT), previously denominated anti-

thrombin-III, a member of the serine protease inhibitorfamily synthesized by the liver, is usually found inplasma at relatively high concentrations and is knownto inactivate mainly factor Xa and thrombin (IIa).Binding of heparin to the pentasaccharide-recognitionsite of antithrombin causes a conformational change inantithrombin accelerating by 1,000-fold its interactionwith thrombin and activated factor X (factor Xa). Thechief difference between unfractionated heparin (UFH)and low-molecular-weight heparins (LMWHs) is intheir relative inhibitory activity against factor Xa andthrombin. Any pentasaccharide-containing heparinchain can inhibit the action of factor Xa simply bybinding to antithrombin and causing a conformationalchange. In contrast to inactivating thrombin, heparinmust bind to both antithrombin and thrombin, therebyforming a ternary complex. This complex can beformed only by pentasaccharide-containing heparinchains composed of at least 18 saccharide units.Whereas most of the chains of UFH are at least 18saccharide units long, fewer than half of those ofLMWHs are of sufficient length to bind to both antith-rombin and thrombin. Consequently, unlike UFH,which has equivalent activity against factor Xa and

thrombin, LMWHs have greater activity against factorXa.

Tissue Factor Pathway Inhibitor

Tissue Factor Pathway Inhibitor (TFPI) is synthe-sized by endothelial cells and is a plasma protease in-hibitor regulating the TF-induced extrinsic coagulationpathway by inhibiting both TF/VIIa complex and fac-tor Xa. TFPI can also be released by heparin from en-dothelial cells and this heparin-mediated TFPI releasemay play a role in the anticoagulant role of UFH andLMWH.

Protein C/Protein S/Thrombomodulin

In the presence of endothelial thrombomodulin,thrombin activates proteins C and S, which in turn,inactivate factor Va and VIIIa. Thrombomodulin thusserves an antithrombotic function both by binding andthereby removing thrombin from the circulation and bypromoting the generation of active protein C with itsanticoagulant properties.

Lysis of Fibrin Clots

Thrombin serves as a bridging molecule to signalthe activation of the fibrinolytic system, primarily byinducing production and release of tissue plasminogenactivator (tPA) from endothelial cells. Recent reportsindicate that when tPA and its substrate, plasminogen,bind to fibrin, tPA converts plasminogen to plasmin, a

Fig. 4. Schematic depiction of the coagulation system with its various inhibitors. (Figureadapted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc. from Arterialthrombosis for the interventional cardiologist: From adhesionmolecules and coagulation factorsto clinical therapeutics. Conde ID, Kleiman NS. Catheter Cardiovasc Interv 2003;60:236–246.)



potent protease that degrades fibrin step-wise into mul-tiple degradation products.

ANTI-THROMBOTIC THERAPY BEFORE,DURING, AND FOLLOWING PCI

Aspirin

Aspirin (ASA) exerts its antiplatelet effect by acety-lating a key serine moiety (serine 530) of cyclooxy-genase-1 (COX-1) and inactivating it, thus preventingthe formation of thromboxane A2 from arachidonicacid [19–23]. ASA has much weaker activity againstCOX-2. ASA’s effect is transient in endothelial cellsbecause ASA plasma half-life is short and the constitu-tive enzyme regenerates rapidly. In platelets, whichhave no nuclei and cannot resynthesize mRNA, thiseffect is irreversible and lasts during the platelet’s cir-culating lifespan.It is estimated that 25–30 million people in the

United States take ASA to prevent or treat atheroscler-otic vascular disease. The Antithrombotic Trialistsmeta-analysis [24] of randomized trials of antiplatelettherapy in more than 200,000 ASA-treated patients forprevention of death, MI, and stroke in high-riskpatients showed that ASA is associated with a reducedincidence of ischemic events in a wide array of athero-thrombotic diseases [24]. Among high-risk patients,ASA reduced the combined outcome of any seriousvascular events by about 25%, nonfatal MI by about33%, nonfatal stroke by 25%, and vascular mortalityby 16% with no apparent adverse effect on mortalityfrom other causes. ASA doses of 75–162 mg dailywere as effective as higher doses. The effect of doseslower than 75 mg daily was less certain. This largemeta-analysis confirmed that ASA is protective inmost types of patients with atherothrombotic diseasewho are at increased risk of cardiovascular eventsincluding patients with an acute MI, ischemic stroke,unstable or stable angina, previous MI or stroke, pe-ripheral arterial disease, or atrial fibrillation. The ISIS-2 trial (Second International Study of Infarct Survival)also showed that in the setting of an acute ST segmentelevation MI (STEMI), ASA alone reduced mortalityby 23% compared with placebo [25]. Studies of ASAin the PCI setting have shown a beneficial effect onshort term ischemic complications [26–30]. High-doseASA (990 mg/d) administered with dipyridamole (225mg/d) 24 hr before angioplasty and continued for 4–7months after PCI reduced the frequency of periproceduralMI compared with placebo (1.6 and 6.9%, respectively)[27]. The M-HEART II trial [28] randomized 752patients undergoing PTCA to receive either placebo,a specific thromboxane A2 receptor inhibitor or ASA

(325 mg daily), started within 6 hr before PTCA and con-tinued for 6 months. There was a significant reduction inpostprocedural MIs with ASA compared to placebo; theMI rate was 1.2% versus 5.7% at 6 months. On the basisof this trial, and on the overwhelming evidence of thebenefit of long-term ASA in patients with atherotrom-botic diseases, chronic use of ASA is recommended in allpatients post-PCI.Most studies examining ASA administration before

and following PCI were performed at least 15–20years ago [26–30]. Because these studies demonstratedthe benefit of ASA with PCI, recent trials of antith-rombotic treatment during and following PCI (e.g.,thienopyridines, GP IIb/IIIa inhibitors and directthrombin inhibitors) were performed with ASA as the‘‘background’’ treatment in all patients.Oral ASA exerts its platelet inhibitory effect within

60 min. This effect lasts for up to 7 days (the lifespanof the platelet) [31]. Low-dose ASA (75–162 mgdaily) appears to be an effective antiplatelet regimenfor long-term use, but in acute settings an initial load-ing dose of 300–325 mg ASA should probably beused. Although the minimum effective ASA dosageduring PCI has not been clearly established, forpatients who have not received chronic ASA therapy,an empiric ASA dose (300–325 mg) given at least2 hr and preferably 24 hr before PCI is recommended[32–36].When ASA is administered with other antiplatelet

agents or with anticoagulants, it is reasonable to use adaily dose of 75–162 mg (rather than 325 mg) to mini-mize bleeding complications. This strategy is supportedby a post-hoc data analysis from the CURE trial [37]showing that in acute coronary syndrome (ACS)patients, adding clopidogrel to ASA is beneficialregardless of ASA dose, with bleeding risks increasingwith higher ASA doses, with or without clopidogrel,without an increase in efficacy. In addition, a meta-analysis of 31 randomized trials has shown that fewermajor bleeding events, particularly gastrointestinal,occur with ASA doses of �200 mg [38] supportingthe use of lower doses (75–162 mg) for chronictherapy.ASA hypersensitivity may be manifested as acute

asthma, urticaria, angioedema, or as a systemic ana-phylactoid reaction [39]. The thienopyridine deriva-tives ticlopidine and clopidogrel have been used rou-tinely as alternative agents in ASA-sensitive patientsduring coronary angioplasty. In addition, ASA desen-sitization can be performed safely in selected patients[40,41]. However, large-scale prospective trials arewarranted to further define the safety of acetylsalicylicacid desensitization therapy in patients with coexistentCAD [41].

392 Garg et al.


Recommendations (as per the AHA/ACC/SCAI

2005 PCI guidelines) [42].

Class I

1. Patients already taking daily chronic ASA therapyshould take 75–325 mg prior to PCI (level of evi-dence: A).

2. Patients not already taking chronic ASA therapyshould be given 300–325 mg at least 2 hr and pref-erably 24 hr prior to PCI (level of evidence: C).

3. After PCI, in patients without ASA resistance,allergy, or increased bleeding risk, 325 mg dailyshould be given for at least 1 month after bare-metalstent (BMS), 3 months after sirolimus-eluting stent,and 6 months after paclitaxel-eluting stent implanta-tion, after which daily ASA use should be continuedindefinitely at a dose of 75–162 mg (level of evi-dence: B).

Thienopyridine Derivatives

The thienopyridines clopidogrel and ticlopidine in-

hibit the purinergic adenosine diphosphate (ADP) re-

ceptor P2Y12. ADP activates platelets through two G-

protein coupled receptors: P2Y1 and P2Y12 (Fig. 5)

[8,43]. Stimulation of the P2Y1 receptor results in pla-

telet conformational change and weak transient platelet

aggregation while activation of P2Y12 leads to sus-

tained platelet aggregation [43]. Inhibition of the ADP

receptor by thienopyridines leads to attenuation of pla-

telet aggregation in response to ADP released from

activated platelets [44,45].

Ticlopidine compared with clopidogrel has a worseside effect profile including life-threatening granulocy-topenia (1%) and thrombotic thrombocytopenic purpura(0.01%). Furthermore, ticlopidine requires twice-dailydosing while clopidogrel may be administered oncedaily. Ticlopidine administration also requires whiteblood cell count monitoring because of the risk of gra-nulocytopenia. Clopidogrel very rarely causes throm-botic thrombocytopenic purpura [46,47].ASA and thienopyridine derivatives have comple-

mentary mechanisms of action and the combinationinhibits platelet aggregation to a greater extent than ei-ther agent alone [48]. ASA and clopidogrel have beencompared in the CAPRIE (Clopidogrel vs. ASA inPatients at Risk of Ischemic Events) trial [49], arandomized, blinded comparison of the relative effi-cacy of clopidogrel (75 mg once daily) versus ASA(325 mg once daily) in reducing the risk of the com-posite outcome of ischemic stroke, MI, or vasculardeath in 19,185 patients with atherosclerotic vasculardisease (recent ischemic stroke or MI, or symptomaticperipheral arterial disease). This trial showed a 9% rel-ative risk reduction (RRR) favoring clopidogrel andrevealed that the overall safety profile of clopidogrel issimilar to that of medium-dose ASA.ASA and a thienopyridine in patients undergoing

coronary stent placement. Combined antiplatelet ther-apy with ASA and a thienopyridine has been found tobe the most effective therapeutic regimen for preven-tion of ischemic complications after coronary stentplacement [49–52]. This combination has been com-pared to anticoagulation treatment in several relativelysmall trials. The ISAR (Intracoronary Stenting andAntithrombotic Regimen) trial evaluated 517 high-riskpatients undergoing urgent or elective placement ofBMS and randomized to ASA (100 mg bid) plus ticlo-pidine (250 mg bid) or ASA, intravenous UFH andphenprocoumon after stent placement [50]. The pri-mary end-point of cardiac death, MI, CABG, or repeatPCI occurred in 1.5% of patients assigned to dual anti-platelet therapy and 6.2% of those assigned to anticoa-gulant therapy (relative risk 0.25) [50].The STARS (Stent Anticoagulation Restenosis Study

investigators) trial [51] evaluated the efficacy of ASA(325 mg daily), the combination of ASA (325 mgdaily) plus ticlopidine (500 mg daily for 1 month), andASA (325 mg daily) plus warfarin on ischemic endpoints at 30 days in 1,653 low-risk patients undergoingBMS placement. This trial demonstrated a reduction inadverse events in patients who received ASA andticlopidine. The primary 30-day composite end pointof death, target lesion revascularization, subacutethrombosis, or MI was 3.6% in patients assigned toASA only, 2.7% in ASA plus warfarin, and 0.5% in

Fig. 5. Platelet Purinergic Receptors. (Figure adapted withpermission from Elsevier from Platelet purinergic receptors.Kunapuli SP, et al. Curr Opin Pharmacology 2003;3:175–180.)[Color figure can be viewed in the online issue, which is avail-able at www.interscience.wiley.com.]



ASA plus ticlopidine. (P ¼ 0.001 for the comparisonof all three groups).The MATTIS (Multicenter Aspirin and Ticlopidine

Trial after Intracoronary Stenting) [52] trial randomized350 high-risk patients undergoing coronary stenting andto either ASA (250 mg daily) and ticlopidine (500 mg/d) or ASA 250 mg/d and oral anticoagulation (targetedat an INR ratio of 2.5:3). The primary composite endpoint defined as the occurrence of cardiovascular death,MI, or repeat revascularization at 30 days occurred in5.6% of patients receiving ASA þ ticlopidine versus11% of patients on ASA þ oral anticoagulation (RRRof 1.9; 95% CI, 0.9 to 4.1; P ¼ 0.07). These studiesconfirmed that the combination of ASA plus a thieno-pyridine is superior to the combination of ASA plus oralanticoagulant or ASA alone in the reduction of ischemicevents following coronary stenting.Choice of thienopyridine: ticlopidine versus clopi-

dogrel. In two randomized trials which compared theadministration of ticlopidine versus clopidogrel inpatients following coronary stenting, the two drugs hadsimilar efficacy in reducing ischemic complications,but clopidogrel was associated with fewer side effects[53,54]. The CLASSICS (The Clopidogrel AspirinStent International Cooperative Study) [53] trialrandomized 1,020 patients who underwent stenting toclopidogrel (300 mg loading dose followed by 75 mg/d) plus ASA (325 mg/d) or clopidogrel (75 mg/d with-out a loading dose) and ASA or to ticlopidine (500mg/d) and ASA. Overall rates of major adverse cardiacevents (cardiac death, MI, target lesion revasculariza-tion) were low and similar between treatment groups;however, clopidogrel administration was associatedwith fewer side effects. A similar result was obtainedin another randomized comparison between the twodrugs after placement of coronary stents [53].Clopidogrel prior to and following PCI. In early

randomized trials demonstrating benefit of ticlopidinein the setting of PCI, the drug was started immediatelyafter PCI completion. In the CURE (Clopidogrel inUnstable angina to prevent Recurrent Events) trial, theeffect of clopidogrel in addition to ASA was tested in12,562 patients with non-ST-elevation ACS with eitherpositive biomarkers of myocardial injury or new ECGchanges [32]. Patients were randomized to receive animmediate 300-mg loading dose of clopidogrel in theemergency room followed by 75 mg a day for 1 yearor matching placebo. The primary end point of MI,stroke, and cardiovascular death at 1 year wasdecreased by 20% in the patients who received clopi-dogrel. The most pronounced benefit was observed inMI reduction, with the largest reduction of 40% for Q-wave MI. The effect of pretreatment with clopidogrelcompared with treatment at the time of PCI was eval-

uated in a sub-study of the CURE trial the PCI CUREstudy [35]. The PCI-CURE study examined 2,658patients undergoing PCI who were randomly assignedto clopidogrel or placebo. Patients were pretreated withASA and the study drug for an average of 6 daysbefore PCI. Following PCI, 80% of patients in bothgroups received open-label clopidogrel for 4 weeks, af-ter which the study drug was restarted for a mean of8 months. The primary end point of cardiovasculardeath, MI, or urgent target-lesion revascularizationwithin 30 days occurred in 4.5% of patients in the clopi-dogrel group compared with 6.4% in the placebo group(relative risk 0.70 [95% CI 0.50–0.97], P ¼ 0.03).Long-term clopidogrel administration conferred addi-tional reduction in cardiovascular death, MI, or any re-vascularization. Overall there was a 31% reduction incardiovascular death and MI with clopidogrel treatment.Subsequently, the benefits of pretreatment and long-

term treatment with clopidogrel after PCI were testedin the CREDO trial (Clopidogrel for the Reduction ofEvents During Observation) [34] a randomized, dou-ble-blind, trial of early and sustained dual oral antipla-telet therapy after PCI [34]. In this trial 2,116 patientsundergoing PCI were randomized to receive either a300 mg loading dose of clopidogrel 3–24 hr beforePCI or placebo. All patients thereafter received clopi-dogrel 75 mg daily through day 28. Following the firstmonth patients in the loading dose group received clo-pidogrel and those in the control group received pla-cebo for 12 months. All patients received ASA(325 mg daily through day 28 and 81–325 mg dailythereafter). At 1 year clopidogrel use was associatedwith a 27% RRR in the combined risk of death, MI,or stroke. In a subgroup analysis, the patients whoreceived clopidogrel pretreatment at least 6 hr beforePCI had a RRR of 39% for the combined endpoint.This trial, therefore, suggests that clopidogrel pretreat-ment when given at least 6 hr prior to PCI, as well aslong-term clopidogrel therapy following PCI (for 1year) significantly reduces the risk of adverse ischemicevents. Additional support for pretreatment with clopi-dogrel has been found in the PCI-CLARITY [ThePCI-Clopidogrel as Adjunctive Reperfusion Therapy(CLARITY)] study [33]. In a substudy of theCLARITY trial, which included patients with ST seg-ment elevation MI (STEMI) treated with fibrinolysisand subsequent angiography, patients undergoing PCI2–8 days after receiving a 300 mg loading dose of clo-pidogrel (administered with the fibrinolysis), hadreduced incidence of CV death or ischemic complica-tions when compared with those who received 300 mgclopidogrel immediately prior to PCI [33]. [7.5% vs.12.0%; adjusted OR, 0.59 (95% CI, 0.43–0.81]; P ¼0.001].

394 Garg et al.


A loading 600 mg dose provides a more rapid andpronounced early in vitro antiplatelet effect than 300mg [55–58]. In these studies, platelet reactivity wasgenerally assessed by platelet aggregation and markersof platelet activation. With administration of a 900 mgloading dose (compared with 600 mg), no further sup-pression of platelet aggregation was observed [55]. Inthe ARMYDA-2 trial [59] (Antiplatelet therapy for theReduction of Myocardial Damage during Angioplasty)255 patients undergoing PCI were randomized to a600- or 300-mg loading dose 4–8 hr before PCI. Theprimary end point of death, MI or target-vessel revas-cularization at 30 days after the procedure occurred in4% of patients in the 600 mg versus 12% in the300 mg loading dose group (P ¼ 0.041). Reduction inendpoints was mainly attributed to a decrease in peri-procedural MI as defined as CK MB above the upperlimit of normal. This study had relatively low-riskpatients, small sample size and only few patientsreceived GP IIb/IIIa inhibitors. Therefore, the resultsneed to be interpreted with caution. Although a loadingdose of 600 mg clopidogrel does appear to have poten-tial advantages over 300 mg [55–58], the currentAHA/ACC recommendation remains 300 mg.Duration of thienopyridine therapy after stent

placement. Recent concern has been raised over thepotential for late stent thrombosis (after 30 days) asso-ciated with drug eluting stents (DES), possibly relatedto delayed reendothelialization following DES implan-tation [60,61]. A meta-analysis of 10 randomized stud-ies comparing DES and BMS which included 5,030patients (2,602 were allocated to DES and 2,428 toBMS) showed a similar incidence of stent thrombosisin patients who received DES (0.58%) and those whoreceived BMS (0.54%) (odds ratio: 1.05; 95% CI:0.51–2.15; P ¼ 1.0) [62]. In a Korean study of 1,911consecutive patients with DES implantation (sirolimus-eluting stents in 1,545 patients and paclitaxel-elutingstents in 366 patients) stent thrombosis occurred in0.8% of the patients (during median follow-up of 19.4months), similar to the rate previously observed forBMS. However, the incidence of late stent thrombosis(during median follow up of 6.1 months) was 0.6%.The predictors of stent thrombosis were prematureantiplatelet therapy interruption, primary stenting inacute MI, and total stent length [63]. A Europeanstudy reported an early stent thrombosis rate of 1.0%and the incidence of angiographically proven late stentthrombosis of 0.35% among 2,006 patients treated witheither sirolimus-eluting stents (n ¼ 1,017) or pacli-taxel-eluting stents (n ¼ 989) [64]. The variables asso-ciated with stent thrombosis were cessation of clopi-dogrel therapy and angiographic parameters such asbifurcation lesions [65].

Despite the pathologic evidence for delayed arterialhealing following DES implantation [66], current pub-lished large single-centered studies and meta-analyses,do not indicate a significant difference in early (�30days) stent thrombosis rates between DES and BMS[62,67]. The exact risk of late stent thrombosis follow-ing DES implantation is dependent on the duration ofdual antiplatelet treatment and requires further investi-gation. However, given this potential risk, clopidogrelshould probably be continued for at least 12 months inpatients who are not at high risk of bleeding and possi-bly even indefinitely [34].AHA/ACC/SCAI recommendations [42]

Class I

4. A loading dose of clopidogrel of 300 mg should beadministered (level of evidence: A) at least 6 hrbefore the procedure (level of evidence:B).

5. In patients who have undergone PCI, clopidogrel 75mg daily should be given at least 1 month afterBMS implantation (unless patient is at increasedrisk of bleeding; then it should be given for a mini-mum of 2 weeks), 3 months after SES implantationand 6 months after PES implantation, and ideally upto 12 months in patients who are not at high risk ofbleeding (level of evidence: B).

Class IIa

1. If clopidogrel is given at the time of PCI, supple-mentation with GP IIb/IIIa receptor antagonists canbe beneficial to facilitate earlier platelet inhibitionthan with clopidogrel alone (level of evidence: B).

2. For patients with an absolute contraindication toASA, it is reasonable to give a 300 mg loading doseof clopidogrel, administered at least 6 hr beforePCI, and or GP IIb/IIIa antagonist, administered atthe time of PCI (level of evidence: C).

3. When a loading dose of clopidogrel is administered,a regimen of greater than 300 mg is reasonable toachieve higher levels of antiplatelet activity morerapidly, but the efficacy and safety compared with a300 mg loading dose are less established (level ofevidence: C).

4. It is reasonable that patients undergoing brachyther-apy be given daily clopidogrel 75 mg indefinitelyand ASA 75–325 mg indefinitely unless there is sig-nificant risk for bleeding (level of evidence: C).

Other oral antiplatelet agents. Cilostazol, whichselectively inhibits 3050-cyclic nucleotide phosphodies-terase III, has antiplatelet and vasodilating effects andalso inhibits vascular smooth muscle cell proliferation



in vitro. Several studies [68–72] have evaluated cilos-tazol for prevention of restenosis after coronary stent-ing and have yielded conflicting results. Although ini-tial small studies suggested that cilostazol reducesrestenosis, [68–71] the largest study failed to demon-strate a benefit of cilostazol [72].The addition of dipyridamole to ASA provides little

incremental benefit over ASA alone for the preventionof early complications after PCIs [29].

Glycoprotein IIb/IIIa Receptor Inhibitors

The platelet receptor glycoprotein (GP) IIb/IIIaserves as the ‘‘final common pathway’’ for plateletaggregation and is a principal determinant of arterialthrombus formation. Inhibition of the GP IIb/IIIa re-ceptor profoundly alters platelet hemostatic functionand prevents thrombus growth.Currently there are three FDA-approved intravenous

inhibitors of the GP IIb-IIIa receptor: abciximab, eptifi-batide and tirofiban. Abciximab is a chimeric (murine/human) monoclonal antibody (c7E3 Fab) which bindsnonspecifically to the GPIIb/IIIa receptor. Eptifibatideis a cyclic heptapeptide that competitively and selec-tively binds to the GP IIb/IIIa receptor. Tirofiban is anonpeptide derivative of tyrosine that also binds to GPIIb/IIIa receptor in a selective and competitive fashion.The latter two small molecule inhibitors are associatedwith lower rates of thrombocytopenia compared withabciximab (1.1–1.9% vs. 2.5–6%, respectively) [73]. Itshould be noted that on readministration of abciximab,the rate of occurrence of thrombocytopenia is the sameas for the primary exposure but the severity appears tobe greater [74].Administration of GP IIb/IIIa inhibitors during and

after PCI is associated with a 35–50% reduction inadverse clinical events following the procedure[75,76]. Meta-analyses have also suggested a mortalitybenefit in the setting of PCI (Fig. 6) [76].Abciximab. Abciximab was first studied clinically

in the EPIC trial (Evaluation of 7E3 for the Preventionof Ischemic Complications) [77], which included 2,099high-risk patients undergoing balloon angioplasty withdiscretionary stenting. All patients received ASA and anon-weight-adjusted UFH bolus (10,000–12,000 IU)prior to PCI and were randomized to placebo, abcixi-mab bolus only (0.25 mg/kg), or identical abciximabfollowed by a 12 hr infusion (10 mcg/min). Comparedwith placebo, the bolus plus infusion regimen wasassociated with a reduction in the frequency of the 30day end point, a composite of death, nonfatal MI, needfor repeat revascularization, or procedural failure(12.8% vs. 8.3%, respectively; P ¼ 0.008). However,major bleeding complications were twice as frequentin patients receiving abciximab (7% in placebo vs.

14% in bolus þ infusion group; P ¼ 0.001). Theincreased major bleeding rate was partly attributed tothe large heparin dose administered with abciximab.Therefore, the EPILOG trial (The Evaluation of PTCAto Improve Long-Term Outcome by Abciximab GPIIb/IIIa Blockade) [78] tested a strategy of abciximabwith a lower UFH dose. EPILOG included 2,792 low-risk PCI patients who received ASA and weight-adjusted UFH [100 IU/kg with target activated clottingtime (ACT) of 300 sec] plus placebo, the same UFHdose plus abciximab, or lower dose UFH (70 IU/kgwith minimum ACT target of 200 sec) plus abciximab.Compared with placebo, the 30-day end point, a com-posite of death, MI, or urgent revascularization, wassignificantly lower in patients treated with abciximabplus lower-dose or standard-dose UFH (11.7% in pla-cebo vs. 5.2% in abciximab plus lower-dose UFH; haz-ard ratio, 0.43; 95% CI, 0.30–0.60; P < 0.001). Theneed for transfusion was 3.9% in patients receiving thestandard UFH dose plus placebo, whereas it was 3.3%

Fig. 6. Meta-analysis of survival with platelet glycoproteinIIb/IIIa antagonists for percutaneous coronary interventionsevaluating 30 day mortality in a standard meta-analysis (PanelA) and a cumulative meta-analysis (Panel B) from Kong DF,et al. AM J Cardiol 2003;92:651–655. (Figure adapted with per-mission from Elsevier.)

396 Garg et al.


and 1.9% in the abciximab-treated patients receivingstandard-dose or low-dose UFH, respectively (3.9% vs.1.9%; P ¼ 0.013 and 3.9% vs. 3.3%; P ¼ 0.46). Onthe basis of these results, a lower dose UFH regimen(70 mcg/kg) has become the standard of care.The Evaluation of Platelet IIb-IIIa Inhibitor for

Stenting (EPISTENT) [79] tested abciximab with coro-nary stenting. In this trial, 2,399 PCI patients wererandomized to stenting plus placebo, stenting plusabciximab, or balloon angioplasty plus abciximab. Theprimary 30 day end point, a combination of death, MIor need for urgent revascularization occurred in 10.8%of the stent plus placebo group, 5.3% in the stent plusabciximab group(hazard ratio 0.48 [95% CI 0.33–0.69]P < 0.001), and 6.9% in the balloon angioplasty plusabciximab group (0.63 [0.45–0.88] P ¼ 0.007).No significant differences in bleeding complications

were noted among the various treatment groups. Thesethree large trials showed that treatment with abciximaband UFH (abciximab given during and after the proce-dure) was superior to UFH alone in the reduction ofmajor adverse cardiac events following PCI.A different therapeutic strategy was tested in the

randomized double-blind CAPTURE trial (Chimericc7E3 Antiplatelet Therapy in Unstable angina Refrac-tory to standard treatment) [80] in which abciximab orplacebo was given 24 hr prior to and after PCI inpatients with refractory unstable angina. MI rate waslower in the abciximab than the placebo group before(0.6% vs 2.1%; P ¼ 0.029) as well as after the PCI(2.6% vs. 5.5%; P ¼ 0.009). Further, the rate of death,MI or urgent intervention within 30 days after PCIwas lower in the abciximab group (11.3% vs. 15.9%;P ¼ 0.012). Patients who benefited the most fromtreatment with abciximab were those with elevated tro-ponin levels [81].Abciximab in the setting of PCI for acute MI.

Administration of abciximab in the setting of PCI foracute MI has been examined in several trials withmixed results. In the ADMIRAL (The Abciximabbefore Direct Angioplasty and Stenting in MyocardialInfarction Regarding Acute and Long-term Follow-up)[82] trial, a relatively small sample of 300 patientswere randomized to receive either abciximab plusstenting or placebo plus stenting for the treatment ofSTEMI. The trial demonstrated that prehospital abcixi-mab administration led to improved coronary patency,left ventricular function, and clinical outcomes—;mainly reinfarction and recurrent ischemia. After 3years, using an intention-to-treat analysis, the outcomeof all-cause mortality occurred in 9.1% of abciximab-treated patients compared with 12.2% of placebopatients with absolute and RRRs of 3.1 and 25%,respectively (P ¼ 0.36) [83]. In the CADILLAC trial

(Controlled Abciximab and Device Investigation toLower Late Angioplasty Complications) [84] 2,082patients with acute STEMI were randomly assigned toundergo balloon angioplasty alone, balloon angioplastyplus abciximab therapy, BMS alone, or BMS plusabciximab therapy. At 6 months, the primary endpoint—a composite of death, reinfarction, disablingstroke, and ischemia-driven target vessel revasculariza-tion- had occurred in 20.0% after balloon angioplastyalone, 16.5% balloon angioplasty plus abciximab,11.5% after BMS alone, and 10.2% after BMS plusabciximab (P < 0.001). Endpoint rates were drivenmainly by revascularization; there were no significantdifferences between the groups in the rates of death,stroke or reinfarction. It appeared that both groupstreated with stents (with or without abciximab) had sim-ilar outcomes. A possible difference between the benefitassociated with abciximab in the ADMIRAL andCADILLAC trials is that abciximab administration wasinitiated earlier (before PCI) in the ADMIRAL trial.An additional randomized trial [85] compared pri-

mary infarct-related artery BMS stenting with or with-out abciximab with STEMI. Four hundred patients wererandomized to stenting alone or stenting plus abcixi-mab. The primary end point—a composite of death,reinfarction, target vessel revascularization and stroke atone month— was lower in the stent plus abciximabthan the stent only group (4.5 and 10.5%, respectively,P ¼ 0.023). Infarct size, as assessed by one-monthtechnetium-99m sestamibi scintigraphy, revealed smallerinfarcts in the abciximab group. Taken together, thesetrials suggest that abcixmab may have an important roleas adjunctive treatment of patients undergoing PCI foracute STEMI. It should be noted that there are onlylimited data about administration of the other approvedGP IIb/IIIa inhibitors in the setting of acute MI.Abcixmab in low- versus high-risk patients. Con-

trary to the important role of abciximab (and GP IIb/IIIa inhibitors in general) in high-risk patients under-going PCI, recent evidence suggests that its role maybe limited in low-risk patients. The ISAR-REACT trialrandomized abciximab versus placebo in 2,159 low-risk PCI patients pretreated with high-dose clopidogrel(600 mg orally given 2 hr before the procedure) [86]with all patients receiving ASA and UFH. At 30 days,there was no difference in outcomes. The study mayhave been limited by a relatively small sample size fora low-risk population [86]. In contrast, a similar studydesign yielded different results in high-risk patients asshown in the ISAR-REACT 2 trial (abciximab inpatients with acute coronary syndromes undergoingPCI after clopidogrel pretreatment) [87]. In this trial,2,022 patients with ACS undergoing PCI were random-ized to UFH and either abciximab or placebo. All



patients received ASA and clopidogrel 600 mg at least2 hr prior to the procedure. Abciximab reduced therisk of adverse events in patients with troponin eleva-tion to 13.1% versus 18.3% in the placebo group. (RRof 0.71; 95% CI, 0.54–0.95; P ¼ 0.02). Therefore, inhigh-risk but not low-risk patients undergoing PCI,abciximab appears to be beneficial even after preload-ing with clopidogrel.Abciximab in patient with ACS managed conser-

vatively. Abciximab was tested in the GUSTO-IV trial[88] in patient with ACS who were not undergoingearly revascularization. In this, trial 7,800 ACSpatients were randomized to either placebo, abciximabbolus plus 24 hr infusion or abciximab bolus plus48 hr infusion. No significant benefit was observed fortreatment with abciximab compared with placebo,while an increased bleeding risk occurred in the abcix-imab group. Therefore, based on this large trial, abcixi-mab is not recommended in patients with ACS, unlessthe patient is going for PCI.Eptifbatide. The IMPACT-II [89] trial (The Integre-

lin to Minimize Platelet Aggregation and CoronaryThrombosis) randomized 4,010 PCI patients to treat-ment with placebo or one of two eptifibatide dosages(135 mcg/kg bolus followed by an infusion of0.5 mcg/kg/min for 20–24 hr or the same eptifibatidebolus followed by an infusion of 0.75 mcg/kg/min for20–24 hr). The primary end point, a 30-day compositeof death, MI, unplanned CABG surgery or repeat PCI,or stenting for abrupt closure occurred in 11.4% ofpatients in the placebo group compared with 9.2% inthe 135/0.5 eptifibatide group (P ¼ 0.063) and 9.9% inthe eptifibatide 135/0.75 group (P ¼ 0.22), withoutsignificant differences between the eptifibatide groups.The doses used in the IMPACT-II trial were likelyinsufficient to provide adequate platelet GP IIb-IIIa in-hibition. A higher dose was subsequently used in thePURSUIT trial [Platelet IIb/IIIa in Unstable Angina:Receptor Suppression Using Integrilin Therapy [90]], alarge ACS trial with about 1/3 of the 10,948 patientsundergoing PCI and randomized to placebo or one oftwo doses of eptifibatide: 180 mcg/kg bolus plus 1.3mcg/kg/min infusion (180/1.3) or 180 mcg/kg bolusplus 2.0 mcg/kg/min infusion (180/2.0). Patients receiv-ing 180/2.0 mcg infusion had a lower frequency of 30-day death or MI compared with placebo (14.2% versus15.7%; P ¼ 0.04). In patients undergoing early (<72hr) PCI, 30-day composite events occurred less often inpatients receiving 180/2.0 mcg eptifibatide (11.6% vs.16.7% in placebo-treated patients; P ¼ 0.01) [90].The ESPRIT [91] (The Enhanced Suppression of the

Platelet IIb/IIIa Receptor with Integrelin Therapy) trialevaluated a higher dose eptifibatide regimen specifi-cally in patients undergoing PCI. Eptifibatide was

given in two boluses (each 180 mcg/kg administered10 min apart, followed by an infusion of 2.0 mcg/kg/min for 18–24 hr) and was compared to placebo in alarge randomized study of 2,064 patients undergoingcoronary stenting. The primary end point, a compositeof death, MI or urgent TVR at 30 days was lower inthe eptifibatide than the placebo group (6.8% vs.10.5%, respectively; P ¼ 0.0034). Differences weremaintained through 1 year after the procedure [92].Major bleeding was infrequent, but occurred more of-ten with eptifibatide than with placebo (1.3 and 0.4%,respectively; P ¼ 0.027) [91,93]. The ESPRIT protocolhas become the standard for eptifibatide dosing duringPCI.Tirofiban. The RESTORE (Randomized Efficacy

Study of Tirofiban Outcomes and Restenosis) trial [94]enrolled 2,319 patients undergoing PCI within 72 hr ofan ACS. Patients were randomized to tirofiban (bolus of10 mcg/kg followed by an infusion of 0.15 mcg/kg/minfor 36 hr) or placebo. The primary 30-day endpoint, acomposite of death, MI, revascularization for recurrentischemia, or stenting for abrupt closure, was only mod-estly and nonsignificantly reduced from 12.2% in theplacebo group to 10.3% in the tirofiban group. (16%relative reduction, P ¼ 0.160). Major bleeding, includ-ing transfusion, was somewhat higher with tirofiban(3.7% placebo, 5.3% tirofiban; P ¼ 0.096). It has beensuggested that the tirofiban dose used may have been tolow to achieve adequate platelet inhibition. However, todate, large randomized PCI trials with a higher dose oftirofiban have not been published to support this hy-pothesis. A greater clinical benefit with tirofiban wasobserved in the PRISM-PLUS study on ACS patients[95] with 30.5% of all patients undergoing PCI between49–96 hr after randomization. This trial randomized1,915 ACS patients to 48–108 hr treatment with UFHplus tirofiban (0.4 mcg/kg/min for 30 min, followed byan infusion of 0.1 mcg/kg/min) or UFH alone. Thecomposite end point of death, MI, or refractory ische-mia was reduced significantly in the UFH plus tirofibangroup compared with the UFH alone group at 7 days(12.9% vs. 17.9%; P ¼ 0.004), at 30 days (18.5% vs.22.3%, P ¼ 0.03) and at 6 months (27.7% vs. 32.1%,P ¼ 0.02). In the subgroup, who underwent PCI, thecomposite end point was reduced from 15.3% in thepatients who were treated with UFH alone to 8.8% inthe tirofiban plus UFH group (risk ratio, 0.55; 95% con-fidence interval, 0.32–0.94) [95].Use of GP IIb-IIIa inhibitors in ACS patients

prior to PCI. Intravenous GP IIb/IIIa inhibitors havealso been tested extensively in the setting of ACS[such as PURSUIT and PRISM PLUS trials [85,95]].Their main benefit appears to be in high-risk patientsand those planned for routine catheterization followed

398 Garg et al.


by possible PCI. The TIMI risk score has been used toidentify ACS patients at moderate to high-risk forrecurrent ischemic events [96–98]. These patients ben-efit from early GPIIb/IIIa inhibitors administration androutine PCI [96–98].Several trials that assessed the optimal therapeutic

strategy for ACS patients (early invasive vs. selectiveinvasive) have employed early GP IIb/IIIa treatment inboth treatment arms. In the TACTICS-TIMI 18 trial(Treat Angina with Aggrastat and Determine Cost ofTherapy with Invasive or Conservative Strategy) [99],2,220 ACS patients were treated with ASA, UFH, andtirofiban. Patients were randomized to an early inva-sive strategy (cardiac catheterization and possible re-vascularization within 4–48 hr) or a conservative strat-egy. With tirofiban pretreatment in both groups andfrequent use of coronary stents, the 6-month primaryend point, a composite of death, nonfatal MI and reho-spitalization, was 15.9% with the early invasive strat-egy and 19.4% with the conservative strategy.On the basis of the trials assessing ACS patients,

eptifibatide or tirofiban are recommended in moderateto high risk patients with ACS. Abciximab is not rec-ommended in this setting unless the coronary anatomyis known and PCI is planned within 24 hr (as was per-formed in the CAPTURE trial).AHA/ACC/SCAI recommendations [42]

Class I

1. In patients with ACS undergoing PCI without clopi-dogrel administration, a GP IIb/IIIa inhibitor (abcix-imab, eptifibatide, or tirofiban) should be adminis-tered (level of evidence: A).

Class IIa

1. In patients with ACS undergoing PCI taking clopi-dogrel, it is reasonable to administer a GP IIb/IIIainhibitor (abciximab, eptifibatide, or tirofiban) (levelof evidence: B).

2. In patients with STEMI undergoing PCI, it is rea-sonable to administer abciximab as early as possible(level of evidence: B).

3. In patients undergoing elective PCI with stent place-ment, it is reasonable to administer a GP IIb/IIIa in-hibitor (Fabciximab, eptifibatide, or tirofiban) (levelof evidence: B).

Indirect Anti-thrombins—UFH or LMWH

UFH. UFH is still the most commonly used anticoa-gulant during PCI world-wide. ‘‘Point-of-care’’ ACTmonitoring in the cardiac catheterization laboratoryfacilitates UFH dose titration during PCI [97]; ACT ispreferable to aPTT because the required level of anti-

coagulation is beyond the range that can be measuredaccurately by aPTT [101]. On the basis of retrospectiveanalyses [102–104], UFH in doses of 60–100 IU/kg anda target ACT between 250 and 300 sec are advocatedin the absence of adjunctive GP IIb/IIIa inhibition. Incontrast, a target ACT between 200–250 sec is advo-cated when UFH is administered in conjunction with aGP IIb-IIIa inhibitor. Routine UFH use after successfulPCI is no longer used because randomized studies[105,106] have shown that prolonged UFH infusions donot reduce ischemic complications, and are associatedwith a higher bleeding rate at the catheter access site.UFH does not appear to reduce the risk of restenosis af-ter balloon angioplasty [105,107].AHA/ACC/SCAI recommendations [42]

Class I

1. UFH should be administered to patients undergoingPCI (level of Evidence: C).

LMWH. Subcutaneous LMWH is an alternative toUFH for treatment of ACS patients. LMWH has sev-eral advantages over UFH: (1) more predictable anti-coagulant effect with a higher ratio of anti-factor Xato anti-factor IIa activity, (2) improved bioavailability,(3) no requirement for monitoring of anticoagulation,(4) not affected by platelet factor 4 secreted by acti-vated platelets, and (5) has a lower incidence of hepa-rin-induced thrombocytopenia. In addition severalACS trials have indicated that the LMWH enoxaparinhas a clinical advantage over UFH [108,109] althoughthis was not confirmed in the large SYNERGY trial[110,111]. Empiric dosing algorithms have been devel-oped for patients previously treated with LMWH [112].If the last enoxaparin dose is administered <8 hr beforePCI, no additional enoxaparin is used. When the lastenoxparin dose is administered 8–12 hr before PCI, a0.3 mg/kg IV enoxaparin bolus is advocated at the timeof PCI; whereas if the last enoxaparin dose is adminis-tered >12 hr before PCI, conventional anticoagulationtherapy is advocated. IV enoxaparin has been evaluatedas the primary anticoagulant during PCI, administered indoses of 0.5–1.0 mg/kg [113]. Enoxaparin appears to besafe when used in combination with tirofiban [114] oreptifibatide [115] during PCI. Short term LMWH admin-istration does not significantly reduce the rate of earlyischemic events [116].The routine administration of enoxaparin during PCI

has been evaluated in the STEEPLE trial [117] whichrandomized 3,528 patients with one of two doses of IVenoxaparin (0.5 or 0.75 mg/kg) or IV UFH with GPIIb/IIIa inhibition use at the operator’s discretion; theenoxaparin 0.5-mg/kg arm was discontinued early basedon a difference in all-cause mortality between the three



treatment groups. At study completion there were nosignificant differences in ischemic endpoints betweenthe two remaining arms (death, MI, and urgent targetvessel revascularization), but the rate of major bleedingwas significantly lower in the enoxaparin group. Thesefindings suggest that enoxaparin may be a reasonablealternative anticoagulant to UFH during PCI.ACC/AHA/SCAI guidelines [42]

Class IIa

1. LMWH is a reasonable alternative to UFH inpatients with UA/NSTEMI undergoing PCI. (levelof evidence: B)

Class IIb1. LMWH may be considered as an alternative to

UFH in STEMI patients undergoing PCI (level ofevidence: B).

Fondaparinux. Fondaparinux is a recently intro-duced pentasaccharide that irreversibly inhibits acti-vated factor Xa with greater specificity than UFH orLMWH. It is an indirect thrombin inhibitor likeLMWH but does not interact with platelet factor 4,and thus does not induce thrombocytopenia. The activ-ity of fondaparinux does not need to be monitored andit can be administered on a daily basis as it has a half-life of 15 hr. In addition, administration of factor VIIacan reverse its effect. In ACS patients without ST seg-ment elevation, fondaparinux at doses ranging from2.5 to 12 mg daily has demonstrated efficacy equal toenoxaparin in the prevention of major cardiac events(death, MI, need for revascularization) [118]. At adose of 2.5 mg/day, fondaparinux has obtained evensuperior results than enoxaparin (27% vs. 35.7%) withthe same endpoint [118]. However, these patients didnot undergo routine cardiac catheterization.In the OASIS-6 trial (Organization for the Assess-

ment of Strategies for Ischemic Syndromes) trial [119],fondaparinux (2.5 mg daily) was compared with stand-ard antithrombotic therapy in 12,092 patients withSTEMI. The composite endpoint of death or reinfarc-tion at 30 days was significantly reduced from 11.2%in the control group to 9.7% in the fondaparinuxgroup, with a tendency toward fewer severe bleeds.However, there was no benefit in the patients whounderwent primary PCI in this trial. Therefore, the roleof fondaparinux in the PCI setting is still unclear.

Direct Thrombin Inhibitors

Three direct thrombin inhibitors, hirudin, bivalirudin,and argatroban, have been evaluated as alternatives toheparin during PCI [120–124].

Hirudin. The HELVETICA trial [124] examined1,141 patients with unstable angina undergoing PCI(treated with ASA) and randomized to UFH or twodifferent doses of hirudin. Hirudin reduced early ische-mic events which occurred in 11.0, 7.9, and 5.6% ofpatients in the respective groups (UFH group, IV hiru-din, and IV plus sc hirudin); (P ¼ 0.023). However,the primary outcome of event-free survival at 7 monthswas similar in all three arms; event-free survival was67.3% in the group receiving UFH, 63.5% in the groupreceiving intravenous hirudin, and 68.0% in the groupreceiving both intravenous and subcutaneous hirudin(P ¼ 0.61).Argatroban. Argatroban has been studied in patients

with heparin-induced thrombocytopenia (HIT) under-going PCI [123]. Patients with HIT were treated withargatroban and compared with historical control sub-jects with HIT [125]. The incidence of the primaryend point, a composite of all-cause death, all-causeamputation, or new thrombosis was reduced signifi-cantly in argatroban-treated patients versus the histori-cal control subjects with HIT. Therefore, argatrobanmay be considered an alternative anti-thrombotic treat-ment during PCI for patients with HIT.Bivalirudin. Of the available direct thrombin inhib-

itors, bivalirudin has been studied the most exten-sively during PCI. The Bivalirudin Angioplasty Study[126] randomized 4,098 patients undergoing balloonangioplasty (without stents or GP IIb/IIIa receptorblockers) for unstable angina or post-MI angina to ei-ther UFH or bivalirudin (1 mg/kg bolus followed by a4 hr infusion at a rate of 2.5 mg/kg/h and a 14–20 hrinfusion at a rate of 0.2 mg/kg/hr). UFH patientsreceived a high-dose UFH bolus (175 IU/kg bolus fol-lowed by a 15 IU/kg/hr infusion for 18–24 hr). Theprimary end point of death, MI and need for emer-gency CABG surgery in the two groups was similar.The rate of major bleeding was lower in the bivaliru-din group (3.8% vs. 9.8%; P < 0.001). An intention-to-treat reanalysis of the data from this study using acontemporary composite end point of death, MI, orrepeat revascularization [127] demonstrated eventrates at 7 days of 6.2% in the bivalirudin, and 7.9%in the UFH group (P ¼ 0.032). These differences per-sisted at 90 and 180 days. The CACHET (Comparisonof Abciximab Complications with Hirulog for Ische-mic Events Trial) pilot study [122] confirmed thesafety of combining a GP IIb/IIIa blocker and bivalir-udin in elective coronary stenting. The subsequentRandomized Evaluation in PCI Linking Angiomax toreduced Clinical Events (REPLACE)-2 assessed biva-lirudin in the setting of PCI [121]. REPLACE-2randomized 6,010 patients with stable or unstable an-gina undergoing PCI to receive IV bivalirudin (0.75

400 Garg et al.


mg/kg bolus followed by an infusion of 1.75 mg/kg/hfor the duration of the PCI) with provisional GP IIb/IIIa inhibitor or UFH (65 IU/kg bolus) plus a GP IIb/IIIa inhibitor (either abciximab or eptifibatide). Of thepatients randomized to receive bivalirudin, 7.2%required provisional GP IIb/IIIa inhibitor treatment. Inthis trial, the primary end point included major bleed-ing (typically a ‘safety’ endpoint) as well as the‘‘classic’’ ischemic end points of death, MI or urgentrepeat revascularization. At 30 days bivalirudin withprovisional GP IIb/IIIa blockade was statistically notinferior (9.2%) to UFH plus planned GP IIb-IIIablockade (10.0%) in terms of suppression of the acuteischemic end points and bivalirudin was associatedwith less major bleeding. These results were main-tained at 6 months follow up [128]. Given the lowerrate of bleeding complications, bivalirudin may beparticularly useful for patients at high risk of bleed-ing, such as the elderly or those with renal insuffi-ciency.The Acute Catheterization and Urgent Intervention

Triage Strategy (ACUITY) trial, which studied higherrisk patients [129], was a large randomized trialwhich compared heparin þ GP IIb/IIIa inhibitor, biva-lirudin þ GP IIb/IIIa inhibitor, and bivalirudin alonein 13,819 patients with moderate- or high-risk acutecoronary syndromes undergoing an early invasivestrategy. Bivalirudin þ GP IIb/IIIa inhibitor, as com-pared with heparin þ GP IIb/IIIa inhibitor, was asso-ciated with noninferior 30-day rates of the compositeischemic end point (7.7% and 7.3%, respectively) andmajor bleeding (5.3% and 5.7%). Bivalirudin alonecompared with heparin þ GP IIb/IIIa inhibitor, wasassociated with a noninferior rate of the composite is-chemic end point (7.8% and 7.3%, respectively) andsignificantly reduced rates of major bleeding (3.0%vs. 5.7%; P < 0.001) [130]. However, in a prespeci-fied subgroup analysis patients assigned to bivalirudinalone who were not pretreated with clopidogrel had asignificant increase in ischemic events as comparedwith those treated with a GP IIb/IIIa inhibitor [130].The ACUITY trial, therefore, supports the use ofbivalirudin as a substitute for heparin þ GP IIb/IIIainhibitors in patients with acute coronary syndromeswho undergo early invasive management, in particularif they are pretreated with clopidogrel. The trial’sfindings have not been incorporated yet in the guide-lines.AHA/ACC/SCAI guidelines [42]

Class I

1. For patients with heparin-induced thrombocytopenia,it is recommended that bivalirudin or argatroban beused to replace heparin (level of evidence: B).

Class IIa1. It is reasonable to use bivalirudin as an alternative

to UFH and GP IIb/IIIa antagonists in low-riskpatients undergoing elective PCI. (Level of Evi-dence: B).

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