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nticoagulation Strategies for Patientsndergoing Percutaneous Coronary

ntervention: Unfractionated Heparin,ow-Molecular-Weight Heparins, andirect Thrombin Inhibitors

pyros Kokolis, Erdal Cavusoglu, Luther T. Clark, and Jonathan D. Marmur

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ow-molecular-weight heparins and direct throm-in inhibitors are emerging as alternative antico-gulants to unfractionated heparin in patients un-ergoing percutaneous coronary intervention (PCI).his paper reviews the pharmacologic properties ofhese newer antithrombotic agents and evaluateshe clinical data demonstrating their use in patientsndergoing PCI.

2004 Elsevier Inc. All rights reserved.

n recent years, an increasing number of antico-agulants have become available as alternatives

o unfractionated heparin (UFH) for treatment ofatients with acute coronary syndromes (ACS)nd for percutaneous coronary interventionPCI). Although UFH has served as the primarynticoagulant for nearly 50 years, it has severalell-established limitations1 (Table 1). From theerspective of an interventional cardiologist, per-aps the most significant of these limitations is thebility of UFH to activate platelets. In part to com-ensate for these limitations, a number of newherapies and strategies have been implemented inhe treatment of ACS (e.g., glycoprotein IIb/IIIantagonists, thienopyridines, stents).

From the State University of New York, Health Scienceenter at Brooklyn, Brooklyn, NY.Address reprint requests to Jonathan D. Marmur, MD,

ACC, State University of New York, Health Scienceenter at Brooklyn, 450 Clarkson Ave, Brooklyn, NY1203; E-mail: [email protected]/$ - see front matter© 2004 Elsevier Inc. All rights reserved.

cdoi:10.1016/j.pcad.2004.02.002

06 Progress in Cardiovascula

An alternative strategy to deal with the prob-ems associated with UFH is to substitute thisgent with antithrombins such as the low-molec-lar-weight heparins (LMWHs) and direct throm-in inhibitors (DTIs). The purpose of this reviews to examine the mechanisms of action, phar-

acologic properties and clinical uses for UFH,MWHs, and DTIs.

Indirect Thrombin Inhibitors

eparin

eparin is a large polymer, averaging approxi-ately 15,000 daltons in size, which contains neg-

tively charged sulfate and carboxylic acid groupshe effects of heparin can be rapidly reversed withrotamine, a basic molecule.2 UFH is a heteroge-eous preparation of heparin molecules ranging

n size from about 5,000 to 40,000 daltons, andypically extracted from porcine intestine or bo-ine lung.3 UFH is administered parenterally (in-ravenously [IV] or subcutaneously [SQ]) and ex-rts its therapeutic effect by indirectly inhibitingoagulation factor IIa (thrombin), a critical medi-tor in clot formation. Thrombin is characterizedy two binding sites (exosites 1 and 2), in additiono its active catalytic site, as shown in Fig 1. Theseites are essential for the binding of thrombin sub-trates such as fibrinogen.4 Thrombin cleaves fi-rinogen to form fibrin, activates other coagula-ion factors, and carries out other actionsediated by its binding sites to promote the for-ation, expansion, and organization of blood

lots.

r Diseases, Vol. 46, No. 6, (May/June) 2004: pp 506-523

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507ANTICOAGULATION FOR PCI

To inactivate thrombin, the heparin moleculeust bind to both antithrombin (AT) and throm-

in, forming a ternary complex. AT is an �-glob-lin occurring naturally in the body that, in the

Table 1. Limitations

imitation Conseq

onspecific binding to plasma proteins andendothelial cells34,69

Variabil

elease of platelet factor 4 and von Willibrandfactor from platelets during clotting

Results

nability of heparin to inactivate fibrin-boundthrombin6

Thrombactiva

eparin induces platelet activation60 Furtherprote

orms heparin antibodies Can ressyndr

ose-dependent half-life81 Nonlinell-defined dose to achieve target ACT level

in PCISupra-a

subopcomp

Abbreviations: ACT, activated clotting time; PCI, percu

ig 1. Thrombin binding sites and the inhibition of thr
ntithrombin; LMWH, low-molecular-weight heparins. (Sour
bsence of heparin, acts over the course of a fewours to inactivate thrombin. Once heparin bindso AT, a molecular change occurs in the hepari-:AT complex that accelerates the ability of AT to

ractionated Heparin

nticoagulant effect, especially in seriously ill patients88

arin resistance and a need for higher levels of heparin44

ains active when bound to fibrin and continues toelets89

es the clotting cascade and release of heparin-binding

eparin-induced thrombocytopenia and thrombosis

ease in half-life as dose increasesgulation resulting in increased bleeding risk oranticoagulation resulting in increase risk of ischemics90

s coronary intervention.

and factor Xa by UHF and LMWH. Abbreviations: AT,

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ind to thrombin. Binding of the heparin mole-ule to thrombin at exosite 2, with bridging be-ween AT and thrombin as shown in Fig 1, is alsoecessary for thrombin inhibition. Approximatelyne third of the heparin molecules in an UFHreparation contain the specific pentasaccharideequence necessary for binding to AT, and most ofhese have polysaccharide chains long enough (ateast 18 saccharide units) to bind to thrombin.1,5

Like thrombin, factor X is also inhibited indi-ectly by heparin through the binding of AT. How-ver, unlike thrombin, factor X does not requireirect heparin binding for inactivation (i.e., ter-ary complex formation). Thus, very short hepa-in molecules (�18 saccharide units in length)hat contain the pentasaccharide sequence allow-ng binding to AT can inhibit factor X, but nothrombin.

xcretion and Bioavailability

fter parenteral administration, heparin mole-ules are degraded into inactive compounds byhe reticuloendothelial system, and then excretedia the kidneys. Liver failure and renal insuffi-iency prolong the half-life of UFH. Heparin is aarge molecule that cannot cross the placental bar-ier, and is therefore considered an acceptable an-icoagulant for use during pregnancy.

ow-Molecular-Weight Heparins

MWHs are derived from UFH through a chemi-al and enzymatic depolymerization process re-ulting in preparations of shorter heparin mole-ules,6 which like UFH, consist of chains oflternating residues of D-glucosamine and uroniccid.7 LMWHs are characterized by a mean molec-lar weight of 4000 to 5000 daltons but range inize from 1,000 to 10,000 daltons. Similar to UFH,MWHs show heterogeneous anticoagulant ac-ivity.1

The LMWHs are also indirect thrombin inhibi-ors that bind to AT via the same pentasaccharideequence found in UFH.8 The anticoagulant ef-ects of LMWHs result from their inhibition ofactor Xa and thrombin as well as other factors,ncluding factors XIIa, XIa, and IXa, and tissueactor pathway inhibitor (TFPI). LMWHs demon-trate less inhibitory activity against thrombinhan against factor X, because only 25% to 50% of
he LMWH chains are long enough to bridge AT to v
hrombin.8-12 Because factor Xa inhibition doesot require bridging between factor Xa and AT,he smaller (�18 saccharide units) pentasaccha-ide-containing heparin chains in LMWH prepa-ations can inactivate factor Xa, but not thrombinsee Fig 1). LMWHs have anti-Xa to anti-IIathrombin) ratios that vary between 4:1 and 2:1,hereas UFH has nearly equal inhibitory effectsn factor Xa and thrombin8 for an anti-Xa:anti-IIaatio of 1:1.

One of the major disadvantages of indirecthrombin inhibition by UFH and LMWH is theirnability to inactivate thrombin bound to fibrin, oro the soluble fibrin degradation products thatncrease in concentration after t-PA–induced ly-is.13 At lower concentrations, heparin moleculesre unable to inhibit clot- or fibrin-bound throm-in molecules, because the heparin binding siteay be less accessible when these thrombin com-

lexes occur. This clot-bound thrombin is stillnzymatically active. The inability to fully inhibitlot-bound thrombin may be one of the potentialechanisms for the 3% to 6% reinfarction rate fol-

owing initially successful coronary thrombolysis.

onitoring of Anticoagulation Activity

ctivated clotting time (ACT) and activated par-ial thromboplastin time (aPTT) are not routinelysed to measure the anticoagulant effect ofMWHs. Because only 25% of LMWH moleculesre large enough to inactivate thrombin, LMWHso not prolong the ACT or the aPTT to the samextent as UFH. This is especially true for thegents with shorter chain lengths and higher anti-a:anti-IIa ratios.14 The uncertainty regardingeasurements of LMWH anticoagulant activityith bedside tests such as the ACT has become a

ritical issue in the settings of ACS and PCI . Anccepted method to gauge the anticoagulation sta-us of a patient treated with LMWHs is anti-factora testing. However, the test is time consuming,ostly, and not readily available as a point-of-careesting. Furthermore, clinical studies have dem-nstrated weak correlations between anti-Xa lev-ls and thrombin formation.15-17

Recently, a new test known as ENOX (enoxapa-in test card) has become available. This test spe-ifically measures the anticoagulant effects ofnoxaparin (�1.0 IU/mL) using a factor Xa–acti-
ated clotting method. However, this test has

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ever been formally validated in patients under-oing PCI. Furthermore, deficiencies in factors X,, or prothrombin can result in a prolongation of

he ENOX clotting test, even in the absence ofnoxaparin. UFH has also been found to interfereith the test results.18 In general, assays of antico-

gulation activity are dependent both on tech-ique and laboratory standardization, and are dif-cult to compare and evaluate owing to theirariability.

In addition, the premise of using anti-factor Xao gauge the activity of LMWH may in itself bencorrect because it focuses on an isolated step inhe coagulation cascade. Anti-factor Xa measure-ent would not effectively ascertain the extent of

nticoagulation exerted by LMWHs at multipleevels, through factors XIIa, XIa, and IXa, and TFPI.

In contrast, assays such as the ACT and the PTTive a more global assessment of the anticoagulantffects and more recent data suggest that thesessays may be useful when LMWH are adminis-ered IV as opposed to SQ.15 Data supporting theCT to monitor LMWH on PCI are presented in

he “Clinical Data in PCI” section.

harmacodynamics

MWHs are cleared predominantly by renalechanisms.8 The plasma half-life of LMWH

anges from 2 to 4 hours after IV injection and 3 tohours following a SQ injection.8 The half-life ofMWH increases in patients with renal failure.MWH dose should be reduced by approximately0% in patients with severe renal impairmentcreatinine clearance �30 mL/min), owing to theisk of accumulation that may lead to major bleed-ng, particularly at the sites of instrumentation.19-21

LMWHs have a longer half-life and, comparedo UFH, show less nonspecific binding to endo-helial cells, platelet factor 4 released from acti-ated platelets, and other plasma proteins. Fol-owing a dose of LMWH, the ability to inhibitactor Xa persists longer than the ability to sup-ress thrombin, owing to more rapid clearance ofhe longer LMWH chain units.

eparin-Induced Thrombocytopenia andeparin-Induced Thrombocytopenia andhrombosis Syndrome

eparin-induced thrombocytopenia (HIT) may
ccur following the formation of platelet antibod- t
es as a consequence of heparin therapy. The dis-rder is characterized by a reduction in the num-er of platelets approximately 6 to 10 days afterhe initiation of therapy, necessitating the imme-iate discontinuation of heparin. Heparin-in-uced thrombocytopenia and thrombosis syn-rome (HITTS) is characterized by decreasedumbers of circulating platelets and thrombosisithin the vasculature. The chronic use of UFHay lead to a decrease in the production and ac-

ivity of AT, which thus increases the risk ofhrombosis.

LMWH is presumed to have a lower incidencef HIT/HITTS. However, LMWHs do cross-reactith HIT antibodies and have been reported to

ause thrombocytopenia in a small percentage ofatients.22

eversibility

rotamine is the reversal agent for UFH. Theechanism through which protamine inhibitsFH is dependent on the degree of sulfation on

he molecule. The protamine-resistant fraction inMWH is due to the lower-molecular-weight frac-ion with a low sulphate charge density. Themount of anti-Xa neutralized is directly propor-ional to the number of sulphate groups attachedo the LMWH. LMWHs are at least partially re-ersible by protamine and therefore should beiven if a reversal state is needed rapidly in pa-ients who had LMWH administered23 (Table 2).

Direct Thrombin Inhibitors

n contrast to UFH and LMWH, DTIs (e.g., biva-irudin, argatroban, hirudin) are able to inhibit

Table 2. Protamine Neutralization of LMWH

eparin% Anti-XaNeutralized

%Sulphate

raxiparin 58 35inzaparin 86 39alteparin 74 37livarin 51 35noxaparin 54 32uper-sulphonated LMWH 100 42

Source: From Crowther et al.23

hrombin directly without the need for the cofac-

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or AT, and are able to inhibit both fibrin-boundnd soluble thrombin.

Because of their relatively small size, the inter-ction of the DTI’s with the active site of thrombins not compromised following binding of throm-in to fibrin at exosite 1.24 Thus, they are able tonactivate both free thrombin and thrombinound to fibrin or fibrin degradation products.his may be due to a greater affinity of thrombin

or exosite 1 (Table 3).Bivalirudin, lepirudin, and hirudin are bivalent

TIs that bind to thrombin at exosite 1 (the sub-trate recognition site) and at the active site25-27

Figs 2 and 3). The univalent DTI argatrobaninds thrombin only at its active site28 (Fig 4).In the direct thrombin inhibitor trialists’ collab-

rative group, hirudin and heparin were associ-ted with an increase in major bleeding complica-ions. However, the bivalent inhibitor, bivalirudinas associated with fewer major bleeding compli-

ations, probably because of its shorter half-life.ivalirudin was also associated with a lower deathate when compared to hirudin , or to univalentnhibitors29 (Fig 5).

Table 3. Binding Characteris

rug Molecular Weight

ivalirudin �2.2 Kda (20 amino-Hirudin (lepirudin, desirudin) �7.0 Kda (65 aminorgatroban �527 Daltons

ig 2. Molecular interactions between the bivalent direinds to two sites on the thrombin molecule: its activehe active site. (c) The bond between thrombin and th
hrombin to resume its hemostatic function.
ivalirudin

ivalirudin is a synthetic 20 amino acid polypep-ide modeled after hirudin and comprised of anctive site-directed peptide linked via a tetragly-ine spacer to a dodecapeptide analog of the car-oxy-terminal of hirudin.27 Bivalirudin bindshrombin with high affinity at both the active sitend exosite 1. Once bound, thrombin slowlyleaves bivalirudin at the active site, resulting inecovery of the function of thrombin’s activeite.27 The carboxy-terminal dodecapeptide por-ion of the bivalirudin molecule remains bound toxosite 1 with low affinity. Therefore, bivalirudinnitially acts as a noncompetitive inhibitor ofhrombin, but then becomes a competitive inhib-tor, enabling thrombin to subsequently partici-ate in hemostatic reactions (Fig 2).

harmacodynamics

ivalirudin is cleared by a combination of proteo-ytic cleavage and renal mechanisms.30 Bivaliru-in has a half-life of about 25 minutes31 in patientsith normal renal function, with prolongation

een in patients with moderate (34 min) or severe

f Direct Thrombin Inhibitors

Mode of Binding Thrombin Binding Site

Reversible bivalent Active site, exosite 1Irreversible, bivalent Active site, exosite 1Reversible, univalent Adjacent to active site

mbin inhibitor bivalirudin and thrombin. (a) Bivalirudinnd exosite 1. (b) Bivalirudin is cleaved by thrombin ataining portion of bivalirudin is now weaker, allowing

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57 min) renal impairment (creatinine clearancef 30 to 59 mL/min and less than 30 mL/min,espectively). Dose adjustments of the bivalirudinnfusion may be required for patients with severeenal impairment and for dialysis-dependent pa-ients.30 Although there is no antidote to counter-ct the anticoagulant effects, this does not appearo be a major concern with bivalirudin because ofts short half-life. The short half-life of bivalirudinistinguishes it from lepirudin (recombinantirudin) and may contribute to a more favorableafety profile.

Bivalirudin exhibits linear dose-proportionallasma concentration responses with a positiveorrelation between dose and anticoagulant effect.he anticoagulant effect of bivalirudin is readilyeasured by both the ACT or the aPTT, making

his agent easy to use in the catheterization labo-atory.

Bivalirudin has not demonstrated any cross-re-ctivity with heparin-induced antibodies in theerum of patients with HIT.

epirudin

he recombinant agent lepirudin (hirudin), orig-nally isolated from the salivary glands of the me-icinal leech (Hirudo medicinalis) is a 65-aminocid polypeptide.32 Lepirudin specifically binds tohrombin with such high affinity that the lepiru-in/thrombin complex is considered irreversible,potential disadvantage for this agent because

here is no antidote to reverse its anticoagulant33

ig 3. The bivalent binding of hirudin, a direct throm-in inhibitor. Hirudin binding is highly specific andlmost irreversible. Like hirudin, lepirudin is also aivalent direct thrombin inhibitor, and also demon-trates nearly irreversible binding to thrombin.

ctivity. Lepirudin is cleared primarily via renal t

echanisms.34 After IV injection, the half-life ispproximately 50 to 60 minutes, increasing up tohours depending on comorbid diseases.35 Be-

ause the drug is cleared via the kidneys, drugccumulation occurs in patients with renal insuf-ciency. Consequently, both the bolus and infu-ion dose must be reduced in patients with renalmpairment (creatinine clearance �60 mL/min),nd the agent is not recommended for use in pa-ients with creatinine clearance �15 mL/min.35-37

The plasma concentrations of lepirudin in-rease proportionally to the dose administered.he standard ACT assay method, however, is un-uitable for routine monitoring of the anticoagu-ant effects of lepirudin. In general, an aPTT ratiothe patient’s aPTT value at any given time dividedy an aPTT reference value) is the method recom-ended for monitoring the anticoagulant with

epirudin. The ecarin clotting time assay has alsoeen reported as successful in predicting antico-gulant effect.38

harmacodynamics

epirudin antibodies have been detected in ap-roximately 40% of treated patients34,39 and ap-ear to have an effect on anticoagulant status.ome of these antibodies bind to lepirudin andotentially prolong its half-life leading to drugccumulation and subsequent hemorrhagic com-lications, and other antibodies reportedly neu-ralize lepirudin’s anticoagulant effect.40

rgatroban

rgatroban is a synthetic derivative of argininehat binds reversibly to the catalytic site of throm-

ig 4. The univalent binding of argatroban. Argatro-an reversibly binds only near the active site on
hrombin, and is characterized by a short half-life.

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in.28 Argatroban does not inhibit other serineroteases, but 54% of the argatroban dose binds touman serum proteins, albumin, and 1-acid gly-oprotein.41

harmacodynamics

he primary route of clearance for argatroban isy liver metabolism, with a half-life approxi-ately 54 minutes after IV administration. He-

atic impairment significantly decreases argatrobanlearance (approximately 4-fold) and increases itsalf-life to approximately 181 minutes.The anticoagulant effect of argatroban can beeasured using the ACT or the aPTT. Plasma con-

entrations, dose, and anticoagulant effects areell correlated. Argatroban has not demonstrated

ig 5. Direct thrombin inhibitor in ACS meta-analysollaborative Group.29

ny cross-reactivity to heparin-induced antibodies. r

nivalent Versus Bivalent Direct Thrombinnhibitors

ccording to a recent meta-analysis of 11 random-zed trials comparing DTIs to UFH in the manage-

ent of patients with ACS,42 the authors found a5% reduction in death/myocardial infarctionMI) in patients treated with a DTI, compared toreatment with UFH. An 0.8% absolute risk reduc-ion, maintained at 30 days, was also found. Sim-lar benefits were seen with the DTIs hirudin andivalirudin, but not with the univalent DTI ar-atroban.

In accord with various other trialists, the inves-igators found univalent DTIs (argatroban andwo other univalent agents, efegatran and inogat-

urce: From the Direct Thrombin Inhibitor Trialists’
is. So
an) to be less effective than the bivalent DTIs

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hirudin, bivalirudin) in preventing recurrentschemic events. However, the bivalent DTI hiru-in was associated with a higher cost and in-reased risk of bleeding compared with UFH.42

irudin was associated with an increased risk ofajor bleeding in patients presenting with ST-

egment elevation MI. In contrast to these find-ngs, bivalirudin was associated with a 50% reduc-ion in major bleeding in patients with ACS. In aubgroup analysis, there was a benefit of DTIs oneath or MI in trials of both ACS and PCI. Inontrast, the univalent DTIs showed a less robustecrease in major bleeding.42

Clinical Data

nfractionated Heparin and Low-Molecular-eight Heparin

arge clinical trials evaluating LMWH in the man-gement of patients with unstable angina andon–Q-wave MIs have been promising.43-48 Clin-

cal data from two of these trials comparing enox-parin to UFH demonstrated reductions in isch-mic events with LMWH versus UFH. However,here appeared to be moderate increases in majornd minor bleeding with LMWH compared toFH.43,48

Evidence for the clinical value of LMWH in PCIs much less clear than that supporting use in ACS.here are a number of publications reporting these of LMWH in PCI,49-54 but none are large-scale,andomized controlled trials that provide convinc-

Table 4. LMWH Com

rial/Study N Study Popul

EDUCE,54 1996(reviparin)

612 Elective PCI

RUISE,52 2003(enoxaparin)

261 Elective or u

egalery et al,57 2002(enoxaparin)

584 enox Unselected P581 UFH

(historicalcontrol)

Abbreviations: CRUISE, Coronary Revascularization Usow-molecular-weight heparin; MI, myocardial infarction; Pestenosis After PTCA, Early Administration of Revipaontrolled Evaluation; Revasc, revascularization; TIMI,eparin.

ng evidence of a meaningful benefit over UFH. v

The Coronary Revascularization Using Integre-in and Single Bolus Enoxaparin (CRUISE) studyvaluated a total of 261 patients comparing enox-parin plus eptifibatide with UFH plus eptifi-atide.52,53 The study was too small to reacheaningful conclusions, but there was no evident

enefit for enoxaparin in ischemic events (8.5 ver-us 7.6, p � .82) or major bleeding (2.5% versus.6%, p � .68) compared to UFH.52 This is inontrast to Thrombolysis in Myocardial InfarctionTIMI), where major bleeding occurred more fre-uently among patients receiving enoxaparin andIMI minor bleeding was more frequent withFH compared with enoxaparin (Table 4).Dalteparin, a LMWH, in doses of 40 IU/kg (n �

7) or 60 IU/kg (n � 76), was evaluated in a small,onrandomized pilot study of patients undergo-

ng PCI. Early assessment determined that the 40U/kg dose appeared inadequate to provide opti-al protection from ischemic events and conse-

uently the majority of patients in this pilot studyeceived the 60 IU/kg dose. In this study,55 theomposite endpoint of death/Q-wave MI/revascu-arization occurred at a rate of 3.7%, major bleed-ng at 2.8%, minor bleeding at 10.3%, and trans-usion at 2.8%.

Another study with dalteparin evaluated 110atients who were undergoing PCI received dosesf dalteparin 60 or 80 IU/kg alone or followed bybciximab infusion. This study evaluated whetherhe ACT could be used to monitor IV dalteparinuring PCI. In this trial, dalteparin induced a sig-ificant rise in the ACT with a smaller degree of

tive Studies in PCI

Outcomes (%) LMWH vs UFH

lesion Acute coronary eventsAt 24 h 3.9 vs 8.2Major bleeding 2.3 vs 2.6

CI D/MI/Revas at 30 days 8.5 vs 7.6TIMI major 2.5 vs 1.6TIMI minor 4.1 vs 10.5D/MI/Revas 1.3 vs 2.0Major bleeding 1.0 vs 0.0Hematoma 2.6 vs 1.7

tegrelin and Single Bolus Enoxaparin; D, death; LMWH,rcutaneous coronary intervention; REDUCE, Reduction ofa Double-Blind Unfractionated Heparin and Placebo-bolysis in Myocardial Infarction; UFH, unfractionated

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eath or urgent revascularization during the hos-ital course of the study population. Two of the 96CI patients had MI (2.1%), major bleeding withransfusion occurred at a rate of 1.0%, and minorleeding at a rate of 4.2%. This was the first studyo demonstrate that the ACT may be useful inonitoring the anticoagulant effect of IV admin-

stered dalteparin during PCI. Similar degrees oflevation of the ACT have been seen with enox-parin in 26 PCI patients with the ACT at 150econds at baseline to 208 seconds post-10 min-tes when enoxaparin was given at a dose of 0.5g/kg IV bolus.56

One randomized study compared reviparin, an-ther LMWH, to UFH in 612 patients.54 Reviparinn � 306) was administered as a 7000-U bolusollowed by a 10,500-U infusion for 24 hours andtwice-daily 3500-U SQ injection. UFH (n � 306)as given as a 10,000-U bolus followed by a4,000-U infusion for 24 hours. No GP IIb/IIIanhibitors were used, and stent implantation waserformed only for bailout purposes. The rate ofescue stent implantation on the day of PCI waseduced with UFH compared to reviparin, from.9% to 2.0%. However, reviparin did not reducehe composite of ischemic events at 6 monthshen compared to heparin (1.3% versus 2.0%).herefore, the agent was not promoted further for

his indication.Another comparative study employed a histor-

cal control as a basis for assessing the relativeafety and efficacy of enoxaparin in PCI.57 Thistudy compared 584 unselected ACS patient un-ergoing PCI with enoxaparin versus a historicalFH control group of 581 patients. There were no

ignificant differences between the two groups

Table 5. LMWH R

EPISTENTa Control(UFH)(N � 809)

NICE-1b

(Enox 1 m(N � 828

/MI/Revasc at 30 days 10.8 7.7IMI major, all 2.2 1.1IMI major non-CABG 1.0 0.5IMI minor all 1.7 6.2ransfusion all 2.2 2.7

aThe EPISTENT Investigators, 1998.59bKereiakes, 2001.51

Abbreviations: CABG, coronary artery bypass graft; D, dhrombolysis in Myocardial Infarction; MI, myocardial inf

Table 4). c

A series of registry studies, National Investiga-ors Collaboration on Enoxaparin (NICE),50,51,58

rovide the majority of patient exposure to enox-parin in ACS patients undergoing PCI. The NICEegistries are open label and noncomparative inature and continue to suggest relative equiva-

ence to UFH in ACS patients undergoing electiver urgent PCI.The primary endpoint of both NICE-1 (1.0g/kg IV bolus of enoxaparin) and NICE-4 (0.75g/kg enoxaparin plus abciximab) was major

leeding (in-hospital and at 30 days) defined as arop in hemoglobin �5 g/dL, a drop in hematocritf �15%, or intracranial bleeding.51,58 Secondaryndpoints included death/MI/revascularization,eed for transfusion, and minor bleeding, whichas defined as spontaneous and observed hema-

uria or hematemesis, �3 g/dL in hemoglobin orematocrit drop of �10%. The investigators

ound an absolute reduction in the compositendpoint of death/MI/revascularization and inajor bleeding compared to the historical UFH

ontrol arm of the EPISTENT trial (a trial of sim-lar design). In addition, a corresponding in-reased absolute risk in minor bleeding and inransfusion rates was also reported for NICE-1Table 5). Similar observations were made whenesults of NICE-4 were compared to the abcix-mab-treated group of EPISTENT (Table 5).

The NICE-3 registry assessed the safety ofnoxaparin in conjunction with one of the threevailable GP IIb/IIIa antagonists in ACS pa-ients.50 This study also addressed the feasibilityf bringing ACS patients treated with enoxaparino the catheterization laboratory without furthernticoagulation using UFH. The NICE-3 study in-

ry Studies in PCI

EPISTENT Treated(UFH � abciximab)(N � 794)

NICE-4b

(Enox 0.75 mg/kg � abciximab)(N � 813)

5.3 6.81.5 0.40.8 0.22.9 7.02.8 1.8

I, myocardial infarction; Revasc, revascularization; TIMI,.

egist

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ary artery disease who received open-label enox-parin (1mg/kg SQ twice daily) in addition to a GPIb/IIIa inhibitor. The choice of GP IIb/IIIa inhib-tor was left to the discretion of the participatingnstitution. For patients requiring subsequentatheterization and intervention, no additionalnticoagulation was given if enoxaparin had beeniven within the previous 8 hours. If the last dosef enoxaparin had been administered more than 8ours prior to PCI, an additional IV bolus dose ofnoxaparin (0.3 mg/kg) was given. For the entireCS population (n � 616) the primary endpoint,on–coronary artery bypass graft (CABG) majorleeding, occurred in 1.9% of patients and in 1.0%f patients undergoing PCI (n � 292). The inci-ence of all major bleeding was 4.5% for all ACSatients and 1.7% for those undergoing PCI.ransfusions and minor bleeding occurred at aate of 10.5% and 25.0%, respectively, in the en-ire cohort with a 5.7% incidence of death/MI/

Table 6. Combined Ev

ESPRITa � EPISTECombined event ra

Control(N � 1833)

/MI/Revasc at 30 days 10.6IMI major, all 1.3IMI major non-CABG NRIMI minor all 1.7ransfusion all 1.6

aThe EPISTENT Investigators, 1998.60bESPRIT Investigators, 2000.59cESPRIT Investigators, 2000.50

Abbreviations: ACS, acute coronary syndrome; CABG, cR, not reported; PCI, percutaneous coronary interventio

Table 7. LMW

rial/Study

ereiakes et al.56 2001 (dalteparin) 40 IU/kg and 60 IU/kg

houssat,61 2002 (enoxaparin) 0.5 mg/kg IV

ollet et al49 2001 (enoxaparin) 1 mg/kg q 12 h

Abbreviations: ACS, acute coronary syndrome; D, d
ntervention; Revasc, revascularization.
evascularization. Event rates for transfusion, mi-or bleeding and death/MI/revascularization haveot been reported for the PCI patients.By combining the event rates from EPISTENT59

UFH � abciximab) and ESPRIT60 (UFH � epti-batide) an approximate historical control arman be used as a basis of comparison for the resultsf NICE-3. This comparison again suggests com-arability between LMWH and UFH in terms ofschemic and major hemorrhagic complicationsith potential increases in the risk of minor bleed-

ng and transfusions (Table 6).Other registries of enoxaparin in PCI, employ-

ng a variety of dosing regimens, have reportedimilar outcomes49,56,61 (Table 7).

A retrospective chart review of 103 patientsho received 2 or more doses of enoxaparin for aariety of indications suggests a significantlyigher incidence of bleeding in patients with renal

nsufficiency (serum creatinine �2.0 mg/dL) (n �

ates (UFH � LMWH)

NICE-3c

Enox 1 mg/kg � GPI

Treated(N � 1834)

All ACS(616)

PCI only(292)

6.2 5.7 NR1.25 4.5 1.7NR 1.9 1.02.8 25.0 NR1.9 10.5 NR

ry artery bypass graft; D, death; MI, myocardial infarction;asc, revascularization.

udies in PCI

Study Population Outcomes (%)

3 Elective PCI D/MI/Revasc 3.7Major bleed 2.8Minor bleed 10.3Transfusion 2.8

0 Elective PCI D/MI/Revasc 3.9Major bleed 0.6Minor bleed 2.2

2/451 Unselected populationof ACS patientsundergoing PCI

D/MI 3.0Major bleed 0.8Minor bleed 2.4

I, myocardial infarction; PCI, percutaneous coronary

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516 KOKOLIS ET AL.

3) versus patients with normal renal function (n50) (51% versus 22%, P � .01).62 Collet et al63

eport that patients with severe renal impairmentndergoing angioplasty should have 64% of thetandard dose of enoxaparin administered.

Thus, to date, the results of available LMWHtudies have yet to provide convincing clinicalvidence of the therapeutic benefit of LMWH overnd above the use of UHF as a base anticoagulant.

irect Thrombin Inhibitors

ivalirudin, lepirudin, and argatroban are the onlyTIs approved in the United States. Lepirudin and

rgatroban are approved for treatment and man-gement of patients with HIT. Argatroban is alsopproved for use in patients with HIT or at risk forIT undergoing PCI. Bivalirudin is indicated forse in a broader population of patients with un-table angina undergoing PCI.

ivalirudin

f all the available DTIs, bivalirudin appears toffer an alternative to UFH in PCI. In the Bivaliru-in Angioplasty Trial (BAT), 4312 patients withnstable angina or post-MI, requiring PCI wereandomized in a double-blind fashion to receiveivalirudin or heparin during the procedure.64

his trial demonstrated a 22% relative risk reduc-ion with bivalirudin in the rate of the compositendpoint of death/MI/repeat revascularization at 7ays (6.2% versus 7.9%, P � .039) when com-ared to heparin. In addition, there was signifi-antly less major bleeding (3.5% versus 9.3%, P �001), with a 62% relative risk reduction in thisndpoint (Table 8). Major bleeding was defined as

Table 8. Bivalirudin

rial N Population

AT,64 2001 4312 PCI

ACHET,70 2002 288 PCI

EPLACE-1,69 2002 1056 PCI

EPLACE-2,71 2003 6029 PCI

Abbreviations: D, death; MI, myocardial infarction; PCI,

vert bleeding resulting in a hemoglobin drop of t

3 g/dL, the need for transfusion of �2 U, andither retroperitoneal or intracranial bleeding.

In addition, reduction of both ischemic andemorrhagic events was observed in a random-

zed subgroup of post-MI patients (n � 741).hose treated with bivalirudin had a 51% relativeisk reduction in death, MI, or revascularizationersus heparin (4.9% versus 9.9%, P � .009) and a3% relative risk reduction for major bleeding64

2.4% versus 11.8%, P � .001).The BAT trial was conducted before the wide-

pread use of stents and GP IIb/IIIa inhibitors. Theesults provided information and suggestions ofmproved outcomes with the use of bivalirudinver heparin. To assess bivalirudin in the modernnterventional setting, several pilot trials haveeen conducted. Three randomized studies eval-ating the safety of bivalirudin and GP IIb/IIIa

nhibitors versus UFH and GP IIb/IIIa inhibitorsave been completed. Although the number ofatients in these studies is small, bivalirudin plusbciximab (n � 60), eptifibatide (n � 42), andirofiban (n � 33) all provide positive safety dataonsistent with the results seen in BAT for com-ining bivalirudin with GP IIb/IIIa inhibitors.65-67

The CACHET B/C and REPLACE-1 trials68,69

rovide additional preliminary results with biva-irudin in the setting of stents and GPIIb/IIIa inhi-ition. CACHET B/C (n � 208) was an open-labelrial of patients undergoing elective PCI, random-zed to receive either heparin plus abciximab orivalirudin with provisional abciximab.68,70 Theivalirudin arm (n � 144) had only 24% abcix-mab use. The CACHET B/C demonstrated a 64%elative risk reduction of death/MI/revasculariza-

parative PCI Trials

omes (%) Biv vs UFH

/R at 7 days 6.2 vs 7.9r bleeding 3.5 vs 9.3/R at 7 days 2.8 vs 7.8r bleeding 1.4 vs 6.3/R at 48 h 5.6 vs 6.9r bleeding 2.2 vs 2.7/R/in-hospital major bleed at 30 days 9.2 vs 10.0/R at 30 days 7.6 vs 7.1r bleeding 2.4 vs 4.1

taneous coronary intervention; R, revascularization.

Com

Outc

D/MIMajoD/MIMajoD/MIMajoD/MID/MIMajo

ion for bivalirudin compared with UFH plus ab-

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iximab (n � 64; 2.8% versus 7.8%). Similarly,ivalirudin treatment resulted in a 74% relativeisk reduction of major bleeding (1.4% versus.3%). This small trial provided preliminary evi-ence of a unique reduction in both ischemic andemorrhagic events associated with the use ofivalirudin.REPLACE-1, a slightly larger trial69 of 1056 pa-

ients, provided continued evidence of reducedschemic and hemorrhagic complications in pa-ients undergoing elective or urgent PCI. Stentsere used in 85% of patients, and GPIIb/IIIa inhi-ition was administered to 72% of patients at theiscretion of the operator. As found in prior inves-igations, this large pilot study demonstrated aimultaneous reduction in both ischemic andleeding complications. There was a relative riskeduction of 19% for the composite 48-hour end-oint death/MI/revascularization and a 22% re-uction in major bleeding events observed69 (Ta-le 8).The REPLACE-2 trial71 was a randomized, dou-

le-blind trial of bivalirudin conducted in 6010atients. The use of bivalirudin plus provisionaldministration of GP IIb/IIIa inhibitors was com-ared to UFH with planned GP IIb/IIIa inhibition

n patients undergoing PCI. Bivalirudin with pro-isional GP IIb/IIIa inhibitor use demonstrated aumerically reduced incidence of the compositendpoint (death, MI, revascularization, majorleeding) compared with heparin and GP IIb/IIIanhibitors. With respect to more traditional end-oints, the incidences of death and revasculariza-ion were lower for bivalirudin-treated patients.owever, the incidence of non–Q-wave MIs in

his group was higher. No statistically significantifferences were found. The incidences of bleed-

ng, transfusions, and thrombocytopenia, how-ver, were significantly lower in patients receivingivalirudin compared with heparin and provi-ional GP IIb/IIIa arm (Table 8). The 6-monthollow-up data from the REPLACE-2 trial demon-trated that patients randomized to heparin withPIIb/IIIa inhibitor and bivalirudin experiencedery similar rates of MI (1.5%) and revasculariza-ion (9.0%). Although it did not reach statisticalignificance, the death rate at 6 months and 1 yearas numerically lower in the bivalirudin arm

ompared to UFH and glycoprotein IIb/IIIa in-ibitors. This suggests that bivalirudin plus a
lycoprotein IIb/IIIa inhibitor administered on a t
rovisional basis only may be an appropriate an-icoagulation strategy in a large portion of PCIatients.Bivalirudin has also been evaluated in 50 pa-

ients with HIT undergoing PCI, in the (Anticoag-lant Therapy with Bivalirudin to Assist in percu-aneous coronary intervention in patients witheparin-induced Thrombocytopenia [ATBAT])rial. Bivalirudin was well tolerated in these pa-ients. A report on the interim data from the first1 patients in this study, in addition to data from9 additional patients in previous studies, suggesthat bivalirudin may provide a superior alterna-ive to currently available agents.72,73

Bivalirudin appears to be well-tolerated in high-isk patient populations. Women, patients over5, and patients with serum creatinine �1.2g/dL have been observed to experience fewer

dverse clinical events, in comparison with UFHreatment.74,75 Although a reduced dose of biva-irudin may be considered for patients with severeenal insufficiency or for patients on renal dialy-is, it is noteworthy that with dose adjustment inatients with renal impairment in the BAT trialatients with any degree of renal impairment hadewer bleeding complications than similar pa-ients treated with UFH.

epirudin (Hirudin)

lthough thrombotic complications are lowerith lepirudin compared to heparin when used to

reat ACS patients, the risk of major bleeding ap-ears greater.76 To date, lepirudin is not indicatedor use in PCI patients. A recent analysis suggestsreason for the increased risk of bleeding may be

elated to the development of thrombocytopeniaith lepirudin (0.9%), which was similar to the

ncidence reported for heparin (1.1%).77

A single large randomized trial of 1141 unstablengina patients treated with desirudin or UFH wasonducted. Like lepirudin, desirudin is a recom-inant DTI based on hirudin. After undergoingngioplasty, patients in the study demonstratedignificant reduction in death/MI/revascularizationt 96 hours. However, there were no significantifferences at 7 months for event-free survival.78

rgatroban

rgatroban has been evaluated in small clinical
rials for a number of uses. Two studies have eval-

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518 KOKOLIS ET AL.

ated the use of argatroban for PCI in HIT pa-ients. Fifty patients with a current or historicalIT diagnosis were evaluated by Matthai et al.79

atients who required CABG, who were receivingP IIb/IIIa inhibitors, or had hepatic dysfunctionere excluded. Argatroban was administered as aolus of 350 �g/kg and followed by an IV infusionf 25 to 30 �g/kg/min to maintain an ACT of 300o 450 seconds. The result was a 98% success rate,efined as less than 50% stenosis of the vesselostprocedure and the absence of bypass surgery,cute MI, or death. Significant complications inatients given argatroban included 1 retroperito-eal hematoma and 1 abrupt vessel closure thatequired bypass surgery. Because this was a HITopulation, inclusion of a control group was con-idered unethical.

Lewis et al80 evaluated 91 HIT patients under-oing PCI in 3 similarly designed studies. Theydministered a bolus of 350 �g/kg was followedy an IV infusion of 25 �g/kg/min, with a targetCT of 300 to 450 seconds. Among patients un-ergoing initial PCI (n � 91), 94.5% had a suc-essful procedure defined as lack of death, emer-ency coronary bypass or Q-wave MI. Adequatenticoagulation was demonstrated in 97.8% of thetudy population. Death/MI/revascularization oc-urred within 24 hours in 7.7% of patients. Theate of major bleeding, which was defined as overtleeding resulting in a �5 g/dL drop in hemoglo-in, a transfusion of �2 U, intracranial or retro-eritoneal bleeding, or bleeding into a major pros-hetic joint, was 1.1%. Minor bleeding was defineds overt bleeding that failed the criteria for majorleeding, and occurred in 32% of initial patientshat were treated. It is difficult to assess the overallffectiveness of this agent given the short 24-hourime point for the primary endpoint, and thereas no direct comparison group.Because patients with HIT cannot receive hep-

rin, argatroban offers an alternative antico-gulant in this special population.81 There are noublished clinical trial data establishing the com-arative efficacy of argatroban in PCI for patientsith a history of HIT.In a meta-analysis of 35,970 patients in compar-

tive trials of DTIs versus heparin in patients withCS or undergoing PCI, reductions in death or MIith hirudin or bivalirudin were observed. How-

ver, similar findings were not observed with uni-42
alent agents such as argatroban. These differ- c
nces may be because of statistical power, but noomparative studies between DTIs exist to estab-ish clear superiority for 1 agent over the other.

There are no data suggesting limitations of ar-atroban use in patients with renal impairment.owever, the use of argatroban use in patientsith hepatic dysfunction may increase the risk ofleeding complications. Even moderate liver dys-unction can prolong the half-life of argatroban by

ore than double compared to its half-life in pa-ients with normal hepatic function.82

Strategies for Treatment

eparin has been used as the standard anticoagu-ant in PCI since the 1970s. Its limitations includenpredictable anticoagulant effects, inability to

nhibit fibrin-bound thrombin, activation of plate-ets, and the lack of a defined optimal dose. Thisas led to the addition of aspirin, thienopyridines,PIIb/IIIa inhibitors, and closure devices withCI procedures, to reduce ischemic events whilettempting to maintain acceptable rate of hemor-hagic complications.

In evaluating optimal strategies for coagulationn PCI, it is important to assess ischemic outcomesnd bleeding complications. Assessing bleedingomplications between trials is difficult owing toarious definitions for major and minor bleeding,uch as the definitions used by the GUSTO andhe TIMI trials.83,84 Many PCI investigations, in-luding the majority of the LMWH studies, utilizehe TIMI definitions for the bleeding endpoint.84

TIMI criteria were initially established for thevaluation of bleeding complications in thrombo-ytic trials where relatively high rates of such com-lications were expected. However, the use of theIMI criteria for bleeding in the setting of PCI mayot be most appropriate measure for a procedurehere the extent of bleeding complications is not

s high. Furthermore, it has been well establishedhat bleeding resulting in �3 g/dL drop in hemo-lobin, as well as the need for transfusions, haveignificant adverse implications for the patientorbidity and mortality, as well as for hospital

osts. Studies have shown an increased length oftay with TIMI minor bleeding and increased riskf morbidity and mortality with transfusions.85

here are also some data to suggest that bleedingomplications can actually result in ischemic

86
omplications. Consequently, minor bleeding

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vents should not be dismissed as an insignificantonsequence when evaluating outcomes in clini-al trials.

LMWHs represent a theoretical advance in an-ithrombotic therapy because of their greaterharmacokinetic predictability and reduced pro-ensity to stimulate platelet aggregation. This al-

ows for a simplified administration scheme (SQnjections twice daily rather than continuous IVnfusions) for management of ACS patients.

hether these theoretical advantages translatento clinical benefits in PCI remains to be demon-trated. Although there are convincing data thatupport the use of LMWH in ACS, such data aretill lacking in PCI. To date, the most appropriateoses of LMWHs and how to combine them opti-ally with GPIIB/IIIa inhibitors in the cardiac

atheterization laboratory have not been ade-uately established in a large-scale, randomizedlinical trial.

LMWH use in open-label pilot and registry PCItudies, and in ACS patients, have been inter-reted as indicating that they provide a benefitver UFH. However, critical review of this datauggests that the benefit is limited to being noorse than UFH for ischemic and major bleeding

omplications. In some investigations, LMWHse has been demonstrated to markedly increasehe risk of minor bleeding and transfusion.52,53

Among the available DTIs, bivalirudin repre-ents the agent with the most robust data in sup-ort of superior benefits over UFH in PCI. Whenhe BAT data or more contemporary trials andegistry data are evaluated, bivalirudin remainsonsistent in providing reductions in ischemicnd hemorrhagic events across all patient popula-ions studied.

Although the management of anticoagulationn patients treated with SQ LMWH remains un-lear, data with bivalirudin suggests that patientseceiving either UFH or LMWH prior to PCI maye safely switched to bivalirudin for the PCI pro-edure. In 1006 patients pretreated with heparinnd switched to bivalirudin, Bittl87 found that pa-ients treated with bivalirudin (n � 512) com-ared to heparin (n � 494) had fewer ischemicvents (6.3% versus 9.5%; P � .043) and fewerleeding complications (4.1% versus 11.9%, p �

001). The significant difference in adverse clini-
al outcomes may be because of heparin’s inability l
o effectively inhibit fibrin-bound thrombin in theigh-risk ACS population.Another small pilot study investigated the pos-

ibility that bivalirudin may provide an alternativeo UFH in PCI for ACS patients initially treatedith SQ LMWH. In this open-label trial of 40atients treated with LMWH for management ofCS, patients were randomized to either UFH orivalirudin prior to angioplasty. The last dose ofMWH was administered at least 8 hours prior toandomization. Coagulation parameters and ad-erse events were assessed. Adverse events wereound to be comparable between the two groups.ne patient in the UFH group had a postproce-ure MI; no deaths or major hemorrhages oc-urred in either group. Coagulation parametersere more predictable in bivalirudin-treated pa-

ients compared with the heparin-treated patients,ith 2 to 3 times less variability, and returned to aormal level rapidly in patients receiving bivaliru-in (L. Wallentin, MD, unpublished data, data onle with The Medicines Co., June 2003). Theseata suggest that switching from LMWH to biva-irudin for PCI procedures is feasible and may bedvantageous. However, additional investigationsre needed to confirm these preliminary results.

Summary

he evidence supporting the superiority ofMWH over UFH in the non-PCI setting is over-helming. However, the data favoring the use ofMWH over UFH during PCI are more limited.dequate, well-controlled, randomized trials in-olving numbers of patients large enough to es-ablish the comparative benefit and optimal use ofMWHs in PCI are lacking. In theory, benefits anddvantages of LMWH in PCI should be similar tohat observed in non-PCI. The use of LMWHs viaV administration allows for the achievement of aapid and controlled anticoagulation during PCI.ontrary to traditional belief, recent studies sug-est that the level of anticoagulation induced byMWHs can in fact be measured using the stan-ard ACT test.15 In addition, LMWH does notppear to activate platelets, thereby potentially re-ucing the need for administration of concomi-ant glycoprotein IIb/IIIa inhibitors. Such a reduc-ion could lead to reduced bleeding and costsssociated with PCI. LMWHs, unlike DTIs, are at
east partially reversible with protamine. As a re-

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ult, LMWH agents appear to represent an antico-gulation option during PCI. This needs furthernvestigation to ascertain their relative benefit inomparison to UFH, as well as to novel DTIs, suchs bivalirudin.

In contrast to LMWH, the advantages of theTI, bivalirudin, have been well established. Inarticular, the REPLACE-2 trial demonstrated thenequivocal superiority of the DTI, bivalirudin,ompared to UFH in PCI. Thus, at present, atronger case can be made in favor of bivalirudinhan LMWH to replace UFH. Whether or not DTIs superior to LMWH in patients undergoing PCIas not been established. A head-to-head random-

zed double blind clinical trial of bivalirudin ver-us a high-dose IV bolus of LMWH in PCI (ideallyith ACT guidance) would be of interest to the

ardiovascular and interventional communities.able 9

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Table 9. Bivalirudi

rial N Population

damian,91 2002 28 Renal impairBaseline Cr 1

undergoingdamian,92 2002 146 Diabetes und

ho,93 2003 162 biv Elective or u172 historical heparin

Abbreviations: biv, bivalirudin; Cr, creatinine; D, death;ion; R, revascularization.

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Registry Studies

Outcomes (%) Biv vs UFH

CIN 0.7 mg/dL Major vascular complications 0

Bleeding comps 0g PCI Major vascular comps 0 vs 1.4

Transfusion 1.4 vs 0Hematoma 0 vs 1.4

CI D/MI/R at 120 days 4.2 vs 12.7Bleeding 4.3 vs 6.4

ocardial infarction; PCI, percutaneous coronary interven-

n PCI

ed.9 � 0PCI

ergoin

rgent P

MI, my

Xa, anti-IIa activities, and D-dimer plasma levels in

1

1

2

2

2

2

2

2

2

2

2

2

3

3

3

3

3

3

3

3

3

3

4

4

4

4

4

4

4

4


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