IIIa antagonists in percutaneous coronary revascularization

Platelet glycoprotein IIb/IIIa antagonists in percutaneous coronary revascularization George Dangas, MD, and Antonio Colombo, MD Washington, DC, and Milan, Italy

Coronary dissections and intracoronary thrombosis are the most important determinants of acute and subacute complications occurring during coronary interventions. Stents have proved efficacious to repair coronary dissections. The formation of intracoronary thrombi during percutaneous coronary intervention (PCI), the other main pathogenic mechanism for acute complications of PCI, has also been implicated in the pathogenesis of long-term ischemic outcomes. To reduce intracoronary thrombosis, all PCIs have been historically performed during intense short-term anticoagulation with the combination of unfractionated heparin plus aspirin. Compelling data on the central role of platelets in arterial thrombosis have made apparent the need for more potent antiplatelet agents for the treatment of patients undergoing PCI. (Am Heart J 1999;138:S16-S23)

Vessel wall injury during percutaneous coronary intervention (PCI) and exposure of the deep components to the circulation activates blood coagulation and leads to the formation of platelet thrombi and generation of thrombin. Several pathways lead to platelet aggregation, including release of chemical mediators (adenosine diphosphate, serotonin, thromboxane A2) with platelet degranulation, translocation of the adhesion mediator Pselectin to the platelet membrane, and structural changes of the platelet surface to a spiny sphere shape, which is more efficient for increased interplatelet adhesion and platelet-factor X contact.1,2 These interactions lead to the generation of thrombin, which provides a potent positive feedback to the entire process. In addition, rheologic parameters (that is, high shear stress) further promote platelet formation of thrombi.3 Despite the existence of multiple mediators of platelet activation, the final common pathway for platelet aggregation depends on activation of the GP IIb/IIIa receptor.4 The glycoprotein IIb/IIIa receptor is a heterodimer consisting of 2 transmembrane proteins that are noncovalently bound to each other: a 136-kd α subunit, consisting of a heavy and a light chain, and a 92-kd β subunit. Calcium is required for the structural integrity of the complex. The surface of 1 resting platelet contains approximately 50,000 to 80,000 randomly distributed glycoprotein IIb/IIIa receptors.4,5 Platelet activation renders this receptor receptive to ligands such as fibrinogen, vitronectin, and fibronectin, or von Willebrand factor, all of which contain the peptide sequence arginine-glycine-aspartic acid (RGD).6-8 The RGD sequence is abundant in many proteins involved in cell adhesion interactions, including the platelet glycopro-

From the Cardiology Research Foundation and the Centro Cuore Columbus. Reprint requests: Antonio Colombo, MD, Centro Cuore Columbus, Via Michelangelo Buonarroti 48, Milano 20145, Italy. Copyright © 1999 by Mosby, Inc. 0002-8703/99/$8.00 + 0 4/0/99077

tein IIb/IIIa receptor activation. Fibrinogen is the most important ligand for platelet aggregation because it exists in high concentration in the blood and, because it is a divalent molecule, it can simultaneously bind to glycoprotein IIb/IIIa receptors on different platelets.9 Conventional antiplatelet therapy has been aimed at specific pathways of platelet activation; aspirin is an inhibitor of the thromboxane A2–mediated platelet aggregation,10,11 and ticlopidine and clopidogrel inhibit the adenosine diphosphate–mediated platelet aggregation.12 However, despite inhibition of a specific pathway, platelet aggregation may still occur through alternative pathways. Because glycoprotein IIb/IIIa activation is the final common pathway for platelet aggregation, its inhibitors potentially abolish platelet aggregation completely regardless of the initial thrombogenic stimuli.4,13 The chimeric (human/mouse) monoclonal antibody, abciximab (c7E3 Fab), was the first glycoprotein IIb/IIIa antagonist to be developed. Since then, a series of peptide (eptifibatide) and nonpeptide (tirofiban) inhibitors of the RGD sequence of the glycoprotein IIb/IIIa receptors have also been developed and studied during PCIs. Abciximab has a high affinity for the receptor, whereas the newer agents competitively antagonize the RGD-containing ligands, binding with relatively low affinity. In addition, abciximab has a longer biologic half-life and also binds to the vitronectin receptor.14 These pharmacologic differences among the various agents may explain certain differences observed in the clinical trials that used them in the context of PCI.

Clinical trials Several large trials15-22 have evaluated the efficacy of glycoprotein IIb/IIIa antagonists in reducing ischemic complications during PCI (Tables I and II). All trials have evaluated glycoprotein IIb/IIIa inhibitor therapy versus placebo in addition to heparin plus aspirin. A treatment arm of glycoprotein IIb/IIIa inhibitor without

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heparin was evaluated only in the Platelet Receptor Inhibition for Ischemic Syndrome Management in Patients Limited to Very Unstable Signs and Symptoms (PRISM-PLUS; n=345) trial; the glycoprotein IIb/IIIaalone arm was interrupted after an interim analysis that showed an excessive 7-day mortality rate compared with the heparin arm (4.6% versus 1.1%, respectively).20 In the Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) trial, patients (n = 2099) who were undergoing high-risk angioplasty and who were treated with heparin and aspirin were randomized to abciximab bolus plus 12-hour infusion, abciximab bolus only, or placebo.15,16 Patients receiving abciximab bolus plus infusion experienced a 35% reduction in the 30-day primary end point compared with placebo, but this benefit was accompanied by a 14% incidence of major bleeding and a 16.9% incidence of minor bleeding complications. Subgroup analyses showed that the treatment benefit was greater in patients with angina at rest23 and evolving myocardial infarction (MI)24 and in patients undergoing directional atherectomy.25 The high bleeding rate with abciximab was attributed to the lack of weight adjustment in heparin dose and the target activated clotting time (ACT) of more than 300 seconds, and for this reason, subsequent trials used reduced doses of heparin and weight adjustment in the glycoprotein IIb/IIIa arms (Table I). The abciximab bolus-only arm in the EPIC trial had outcomes similar to those observed with placebo at all study points, suggesting the requirement for more sustained platelet receptor blockade after PCI to achieve clinically significant benefit. The Evaluation in PTCA to Improve Long-term Outcome with Abciximab GPIIb/IIIa blockade (EPILOG) trial enrolled patients (n = 2792) undergoing elective PCI and randomly assigned them to 1 of 3 treatment regimens: abciximab (bolus and 12-hour infusions) in combination with low-dose (70 U/kg) weight-adjusted heparin; abciximab in combination with standard-dose (100 U/kg) heparin; or placebo in combination with standard-dose heparin.17 This study was terminated prematurely because patients treated with abciximab had a 57% reduction in the 30-day composite end point of death, MI, or urgent revascularization compared with placebo (combination of heparin plus aspirin; Table I). The lower adjustment of the heparin dose in the EPILOG trial in comparison to the EPIC trial was accompanied by lower bleeding rates both in the abciximab and the placebo arms. Thus the EPILOG trial demonstrated that abciximab could be administered with low-dose weight-adjusted heparin and target ACT 200 or more seconds during PCI and have low bleeding complications while still maintaining strong efficacy against ischemic complications. In both the EPIC and EPILOG trials, abciximab was administered at the time of the PCI, in the cardiac catheterization laboratory, with the initial bolus given

Dangas and Colombo S17

20 minutes before the procedure. In the c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) trial (n = 1265) the efficacy of prolonged pre-PCI treatment with abciximab was evaluated.18 Patients with unstable angina refractory to treatment with heparin, aspirin, and intravenous nitrates were randomized to treatment with abciximab or placebo initiated 18 to 24 hours before PCI and continued until 1 hour after the completion of PCI. Patients treated with abciximab had fewer ischemic complications at 30-day follow-up and also experienced significantly less frequent progression to MI before PCI (0.6% abciximab vs 2.1% placebo; P < .03). The significantly higher bleeding rate observed with abciximab compared with placebo in this trial could have been due to prolonged vascular access sheath times between coronary angiography performed before randomized pharmacotherapy and the subsequent performance of PCI 18 to 24 hours later (Table I). Although the EPIC, EPILOG, and CAPTURE trials have provided strong evidence for the efficacy of the addition of abciximab to heparin and aspirin during PCI to prevent ischemic complications, the degree of longterm benefit observed in the EPIC trial population has not been achieved in the other 2 studies. For example, at the 6-month follow-up in the EPIC trial,26 the rate or death/MI/revascularization was 27% with abciximab (bolus plus infusion) versus 35% with placebo (P = .001) and death/MI rate 8.9% versus 12.8% (P = .02). Furthermore, long-term follow-up of the same population showed that the benefit from abciximab therapy was maintained even at 3 years27 (death/MI/revascularization rates were 41.1% for abciximab bolus plus infusion arm vs 47.4% for abciximab bolus only arm vs 47.2% for placebo; P = .009). However, the CAPTURE trial showed no difference in the 6-month death/MI/revascularization rate with abciximab versus placebo (31% vs 30.8%); 6-month follow-up in the EPILOG trial revealed the composite occurrences of death/MI/any revascularization or death/MI to be 22.8% and 5.8%, respectively, after abciximab therapy, and 25.8% and 11.1%, respectively, after placebo (P = .07 and P < .0001, respectively, for abciximab vs placebo). Explanations for these apparently differential long-term effects of abciximab include the lower relative risk reduction rendered by abciximab when tested in the more stable population of the EPILOG trial compared with the EPIC trial; the relatively brief (1-hour) administration of abciximab after PCI in the CAPTURE trial compared with the 12-hour infusion used in the EPIC and EPILOG trials; and the relatively low efficacy of abciximab in reducing the long-term target lesion revascularization rate. The nonpeptide RGD inhibitor tirofiban was tested in the Randomized Efficacy Study of Tirafiban for Outcome and Restenosis (RESTORE) trial (n = 2139) during

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Table I. Concomitant anticoagulation, dosage and approved indications for intravenous glycoprotein IIb/IIIa inhibitors in the United States FDA approval

Glycoprotein llb/llla Abciximab

Eptifibatide

Tirofiban

Indications

Recommended dose

PCI

As in EPIC

Refractory UA and planned PCI within 24 h

As in CAPTURE

PCI UA/ non–Q-wave MI UA/non–Q-MI

Glycoprotein IIb/IIIa dosage

As in IMPACT II (the low dose) As in PURSUIT (the high dose) As in PRISM-PLUS

Clinical trials

Bolus

Timing of bolus

Infusion

EPIC

0.25 mg/kg 5 min

10-60 min before PCI

10 µg/min

EPILOG

0.25 mg/kg 5 min

10-60 min pre-PCI

0.125 µg/kg/min

CAPTURE

0.25 mg/kg 5 min

UA, planned PCI

10 µg/min

EPISTENT IMPACT II

20 min before PCI 20 min before PCI

PURSUIT*

0.25 mg/kg 5 min 135 µg/kg 135 µg/kg 180 µg/kg

RESTORE PRISM-PLUS†

10 µg/kg 3 min 0.4 µg/kg/min ×30 min

Immediately before PCI UA/non–Q-MI

0.125 µg/kg/min 0.50 µg/kg/min 0.75 µg/kg/min 1.3 µg/kg/min 2.0 µg/kg/min 0.15 µg/kg/min 0.10 µg/kg/min

UA/non–Q-MI

FDA, Food and Drug Administration; PTT, activated partial thromboplastin time; UA, unstable angina. *After interim analysis showing the safety of the high dose, the low-dose arm was discontinued. †The tirofiban-alone arm (dose, 0.6 µg/kg/min × 30 min + 0.15 µg/kg/min) was discontinued because of excess 7-day deaths versus the heparin-alone arm.

Table II. Safety and efficacy of intravenous glycoprotein IIb/IIIa platelet receptor antagonists during percutaneous coronary interventions Major bleeding (%) Trial

Agent

EPIC EPILOG§

Abciximab Abciximab

CAPTURE EPISTENT§

Abciximab Abciximab

IMPACTII§

Eptifibatide

Eptifibatide PURSUIT‡¶ RESTORE Tirofiban PRISM-PLUS‡ Tirofiban

Glycoprotein IIb/IIIa 14‡ 2 3.5 3.8‡ 1.5; 1.4 5.1 5.2 10.6‡ 5.3 4

Placebo 7 3.1 1.9 2.2 4.8 9.1 3.7 3

30-day Events * (%)

6-month Events † (%)

Glycoprotein IIb/IIIa

Placebo

Glycoprotein IIb/IIIa

Placebo

8.3‡ 5.2 5.4‡ 11.3‡ 5.3‡ 6.9‡ 9.2 9.9 11.5‡ 8 8.8‡

12.8

27.0‡ 22.8 22.3‡ 31 5.6‡ 7.8‡ 10.5 10.1 NA NA 12.3‡

35.1

11.7 15.9 10.8 11.4 16.4‡ 10.5 13.1‡

25.8 30.8 11.4 11.6 NA NA 15.3‡

*Death, MI, or urgent revascularization, except PRISM-PLUS, PURSUIT (only death or MI). †Death, MI, or any revascularization, except IMPACT II, EPISTENT, PRISM-PLUS (only death or MI). ‡P < .05 glycoprotein IIb/IIIa inhibitor versus placebo. §Glycoprotein IIb/IIIa results in EPILOG are for low (top) and high-heparin-dose arms; in EPISTENT for stent (top) and angioplasty arms; and in IMPACT-II for low (top) and higheptifibatide-dose arms. IIPURSUIT and PRISM-PLUS 30-day and 6-month results are only in patients who underwent interventions. ¶In PURSUIT, glycoprotein IIb/IIIa results are for the 180 mg/kg + 2.0 mg/kg/min eptifibatide dose.

high-risk PCI.19 The RESTORE trial population (unstable angina or MI) and the use of adjunctive heparin dosing were similar to those in the EPIC trial. Tirofiban therapy was associated with a reduction in death/MI/revascularization of 38% at 48 hours and 27% at 7 days. This benefit had eroded to only 16% (statistically insignificant) at the prespecified time point of 30 days (Table I).

Tirofiban has also been evaluated in the treatment of unstable angina and non–Q-wave MI as medical management and before subsequent percutaneous surgical revascularization.20 In the PRISM-PLUS trial, tirofiban was administered in a dose of 0.4 µg/kg intravenous bolus over 30 minutes, followed by 0.1 µg/kg/min infusion. This dose has been reported to achieve an 80% or more

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Dangas and Colombo S19

Initial heparin dose

Target-anti coagulation

12 h

10,000-12,000 U bolus

ACT>300s PTT 2×control

12 h

70 U/kg bolus 100 U/kg bolus ≤100 U/kg bolus

ACT>200s ACT>300s PT 60-85s ACT 300s ACT>200s ACT 300-350s

Duration

18-24 h pre PCI until 1 h after PCI 12 h 20-24 h 72 hr +24 h after PCI (total≤96 h) 36 h Total 48-108 h, 12-24 h after PCI

70 U/kg bolus 100 U/kg bolus 5000 U bolus + 1000 U/h 150 U/kg 5000 U bolus + 1000 U/h

PTT 50-70s ACT 300-400s PTT 2×control

inhibition of platelet aggregation at 30 minutes of infusion.19,20 In the PRISM-PLUS trial, there was a significant reduction in the prespecified composite end point of death/MI/refractory ischemia at 30 days with tirofiban versus placebo (18.5% vs 22.3%; P = .03). With respect to the subgroup of patients who underwent PCI (n = 475), the percentage reduction in death/MI at 30 days was 42% and at 6 months was 34% (Table I). The cyclic heptapeptide RGD-mimetic eptifibatide was evaluated in a placebo-controlled comparison of 2 dosing regimens (high-dose 135 µg/kg bolus and 0.75 µg/kg/min infusion or low-dose 135 µg/kg bolus and 0.5 µg/kg/min infusion), which were administered during PCI in 4010 patients enrolled into the IMPACT-II trial.21 Although the primary end point (death/MI/urgent revascularization) was not significantly reduced by high-dose eptifibatide when compared with placebo, a trend toward improved outcomes was observed in patients who received low-dose eptifibatide (Table I). The apparent superior efficacy of the low-dose versus high-dose regimen of eptifibatide is difficult to explain and may reflect the lack of a differential bolus. In addition, the degree of platelet inhibition by eptifibatide that was achieved in this trial (approximately 60%) was well below the targeted level of inhibition (≥80%) desired because of a systematic error introduced by the type of anticoagulant used during platelet function testing. As described by Phillips et al,28 citrate binds ionized calcium in blood samples of patients treated with eptifibatide. Because ionized calcium inversely influ-

ences the degree of platelet inhibition by eptifibatide, lower levels of ionized calcium resulted in falsely elevated (overestimated) levels of platelet inhibition. This calcium-chelating effect of citrate is not present with DPhenylalanyl-L-Prolyl-L-Arginyl Chloromethyl Ketone (PPACK) as the anticoagulant. Subsequent studies using PPACK as the anticoagulant have established more appropriate dose strategies for eptifibatide to achieve the desired 80% or more platelet inhibition. Such a regimen, 180 µg/kg bolus followed by 2.0 µg/kg/min intravenous infusion, was administered to 10,948 patients with ACS in the PURSUIT trial.22 The primary end point of the PURSUIT trial was the composite occurrence of death or MI rate at 30 days. This end point was observed in 14.2% of the patients who received eptifibatide versus 15.7% of those receiving placebo (relative reduction, 9.6%; P = .04). In PURSUIT trial, the subgroup of patients who underwent PCI within 72 hours after randomization also had a significant reduction in the incidence of death/MI before PCI (1.7% eptifibatide vs 5.5% placebo; P < .001). Further analyses of patients who underwent PCI demonstrated a 17.7% relative reduction in death/MI rate at 30-days with eptifibatide versus those patients receiving placebo, which did not reach statistical significance (10.2% vs 12.4%, respectively; P = NS). One element common to all of the previous studies is that elective coronary stenting was not allowed by protocol, with provisions made for unplanned or “bail-out” stent deployment. For example, stents were placed in only 1.7% of the patients who were receiving bolus abciximab only, in 0.6% of those patients who were receiving placebo, and in only 0.6% of patients who were receiving abciximab bolus plus infusion, in the EPIC study. In the EPILOG trial, stents were deployed in 12% of the patients. This practice is obviously not consistent with current trends in PCI; therefore the results must be viewed in this perspective. Table III is a side-byside comparison of results from the EPILOG study with the PTCA arm of the Benestent II trial.29 The discrepancies between the results of these trials may have several explanations. First, the Benestent II trial population was more clinically stable and therefore less likely to experience the development of complications, provided dissections were promptly treated by provisional stenting. Second, stenting was performed at an earlier time during the course of intervention when many of the consequences of threatened vessel occlusion were not yet operative. Third, the incidence of non–Q-wave MI was not systematically assessed by protocol in the Benestent II trial.

Glycoprotein IIb/IIIa inhibitors in stenting The impact of abciximab on the requirement for unplanned stenting during PCI was evaluated in a secondary analysis of the EPILOG trial. The requirement for

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Table III. Comparisons of the incidence of major cardiac events in the Benestent II and EPILOG trials

Patients (n) 1-mo Events (%) Death Q-wave MI Non–Q-wave M Repeat revascularization Any event Stenting (%) 6-mo Events (%) Death Q-wave MI Non–Q-wave MI Repeat revascularization Any event

Benestent II (PTCA)

EPILOG (abciximab + low heparin)

EPILOG (placebo)

410

935

939

0.2 1.0 2.2

0.3 0.4 3.2

0.8 0.8 7.9

1.7 5.1 13.4

1.6 5.2 11.0

5.2 11.7 13.0

0.5 1.2 2.4

1.1 1.3 3.9

1.7 1.6 8.4

13.2 19.3

19.0 22.8

19.4 25.8

unplanned stent deployment was significantly less in patients who previously underwent abciximab therapy in combination with low-dose heparin (9.1%) versus patients who were randomly administered placebo (14.7%; P < .01). The relative benefit of prophylactic abciximab was more pronounced for eccentric or AHA/ACC type B2/C lesions (compared with concentric or A/B1 lesions); abciximab therapy was not associated with an increase in bleeding complications.30 The major study to evaluate the efficacy of abciximab in elective coronary stenting was the recent Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) trial in 2399 patients.31 One half of the patients had angina pain at rest, within 48 hours, or MI within 1 week before the PCI. Only patients with a single treated lesion were accepted for inclusion in the EPISTENT trial, and patients had to be adequate for revascularization with balloon angioplasty alone. Thus patients with multivessel disease or those patients requiring complex, multidevice PCI were excluded. Only the Palmaz-Schatz stent was used in the trial, and more than 1 stent was required in 30% of cases. The protocol provided 3 treatment arms: stent plus placebo, stent plus abciximab, or angioplasty plus abciximab. Patients undergoing angioplasty had a 19% rate of crossover to stenting. The primary end point of this trial, a composite occurrence of death/MI/urgent revascularization at 30 days, was reduced from 10.8% (stent plus placebo) to 5.3% (stent plus abciximab) and 6.9% (PTCA plus abciximab). The rate of major bleeding was lower in both abciximab arms (1.5%), compared with heparin alone (2.2%). At 6-month follow-up, the incidence of death/MI was reduced from 11.4% (stent plus placebo) to 5.6% (stent plus abciximab) and 7.8% (PTCA plus abciximab). Among patients who received a stent, abciximab reduced the composite occurrence

of death/MI/revascularization from 18.3% (placebo) to 13% (P = .003; Topol EJ, oral presentation at the XXth European Congress of Cardiology, Vienna, Austria, August 1998). These results strongly support the concept that efficacy of abciximab in PCI is independent of and additive to the benefit rendered by stenting alone. Furthermore, a lower rate of death/MI was observed with balloon angioplasty plus abciximab, compared with stent alone. However, the composite end point results of the EPISTENT trial have been mainly driven by the particularly marked reduction of in-hospital non–Q-wave MI. Stenting (by aggressive vessel stretch, plaque extrusion, or side-branch compromise) appears to be associated with a higher non–Q-wave MI rate than balloon angioplasty alone. Although debate exists about the long-term clinical significance of these periprocedural events, myocardial necrosis after otherwise successful stenting may have clinical ramifications, particularly in such subgroups as elderly patients or patients with decreased baseline ventricular function or diabetes.

Glycoprotein IIb/IIIa inhibitors in acute MI interventions Because the prothrombotic effects of thrombolysis in acute MI have been mainly attributed to platelet activation, potent antiplatelet strategies may offer a valuable adjunctive approach for both primary or rescue angioplasty. The combination of glycoprotein IIb/IIIa inhibitors with thrombolytic agents (tPA, rPA) for primary pharmacologic reperfusion is also being evaluated in ongoing trials (Thrombolysis In Myocardial Infarction [TIMI-14B] study, Strategies for Patency Enhancement in the Emergency Department [SPEED], Global Use of Strategies to Open Occluded coronary arteries [GUSTO IV]).

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In the EPIC trial, a total of 64 patients underwent primary or rescue angioplasty.15 In this subgroup, abciximab bolus plus infusion therapy significantly decreased recurrent ischemic events, both at 30 days and at 6 months. Based on these preliminary data, the RAPPORT trial evaluated the role of abciximab as an adjunct to primary angioplasty in patients with evolving MI.32 Abciximab was administered in the standard, weight-adjusted bolus and 12-hour infusion, and heparin was administered in a dose of 100 U/kg (bolus), with subsequent heparin administered to maintain the ACT at 300 or more seconds. This heparin dosage (100 U/kg) was higher than that used in the low-dose arm (70 U/kg) of the EPILOG trial and was associated with higher rates of major bleeding in patients treated with abciximab (16.6% abciximab vs 9.5% placebo; P = .02). However, abciximab therapy provided benefit with a significant reduction in composite occurrence of death/MI/urgent revascularization assessed at 7 days, 30 days, and 6 months after randomization. The relative risk reduction at these time intervals was 67%, 48%, and 35%, respectively. Despite this apparent benefit, no statistically significant difference in the occurrence rates of the primary end point (death/MI/urgent revascularization) was observed at the 6-month follow-up (28.2% abciximab vs 28.1% placebo). The combination of abciximab with lower heparin dose and stenting during acute MI is currently under evaluation in both the Controlled Abciximab and Devices Investigation to Lower Late Angioplasty Complications (CADILLAC), and Abciximab Before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long Term Follow-up (ADMIRAL) trials. Preliminary results from a smaller study33 have indicated that adjunctive glycoprotein IIb/IIIa inhibition with abciximab provides added benefit to patients undergoing stent deployment for treatment of acute MI. In patients receiving adjunctive therapy with abciximab, further improvement in regional wall motion was observed at 14 days, and the composite occurrence of death/MI/urgent revascularization at 30 days was reduced (2% with abciximab vs 9% with placebo; P = .03).

Quests for the future: appropriate dosing, relative efficacy, and cost All of the previously noted trials provide evidence for the adjunctive use of glycoprotein IIb/IIIa inhibitors during PCI. However, multiple logistic questions remain. For example, the differential efficacy of the various available agents needs to be established. Abciximab differs from other glycoprotein IIb/IIIa inhibitors in pharmacokinetic and pharmacodynamic properties, and it is unclear which of these special attributes may be responsible for the apparent greater efficacy of this therapy. If the main objective of ther-

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apy is prolonged receptor inhibition, the combination of a short-acting intravenous agent, in sequence with an oral glycoprotein IIb/IIIa inhibitor, may be capable of producing equivalent results at lower cost. However, if the objective is concomitant blockade of the vitronectin (αvβ3) receptor or receptors related to white-cell function (MAC1, CD 11/18), then “pure”glycoprotein IIb/IIIa receptor inhibition by small-molecule antagonists would not be expected to produce results equivalent to abciximab, which has multireceptor affinity. The problem of optimal antithrombotic therapy in conjunction with glycoprotein IIb/IIIa inhibitors is a major issue that has not been completely resolved for any of the glycoprotein IIb/IIIa inhibitors. The availability of methods to monitor the platelet inhibition 34 may favorably affect this problem and may provide a means for adjusting the dose of the glycoprotein IIb/IIIa inhibitor to optimize the therapeutic result. Indeed, whether a target of 80% or more platelet inhibition is required to achieve maximal clinical benefit and over what duration potent platelet inhibition should be maintained are the subjects of ongoing investigation. The optimal dosing of concomitant antithrombotic therapy in combination with a glycoprotein IIb/IIIa inhibition is in evolution as well. Higher doses of heparin have been associated with both increased bleeding rates and reduced glycoprotein IIb/IIIa inhibitor efficacy (Table II). Prophylactic administration of glycoprotein IIb/IIIa inhibition during PCI allowed the safe, effective use of remarkably low heparin doses even in patients with ACS. Although it is likely that some degree of concomitant antithrombotic therapy will be required for optimal glycoprotein IIb/IIIa benefit, definitive dose recommendations for adjunctive administration of heparin will require further study. The observed efficacy of abciximab to reduce fibrin thrombus in addition to platelet aggregates implies an intrinsic anticoagulant effect of this potent antiplatelet agent.35 Furthermore, the observed marginal increase in both thrombus components after PCI despite an ACT of 300 to 350 seconds underlines the potential for stimulation of platelets by heparin.31 Preliminary experiences have shown that, after successful stenting, heparin reversal can be performed safely.36,37 The significant cost of glycoprotein IIb/IIIa inhibitor therapy adds to the already high economic burden of PCI, especially with stents. Therefore there is wide skepticism with respect to their universal use. Although an economic analysis of the EPIC trial38 indicated that the long-term benefit from abciximab compensates for a large part of its initial cost, similar analyses with multiple devices and stents during PCI in a broader-based patient population have not been performed. Accordingly, provisional use of “rescue” glycoprotein IIb/IIIa

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inhibition for PCI has been developed without clinical data in support of this strategy. It is unknown whether the benefits demonstrated in clinical trials, after prophylactic administration of glycoprotein IIb/IIIa blockade, remain valid with rescue use.

Conclusions The prophylactic use of glycoprotein IIb/IIIa inhibitors during PCI markedly reduces ischemic complications of coronary intervention. Several issues remain to be resolved with respect to optimal dose strategies, differences in relative efficacy, and side effects. The benefit of glycoprotein IIb/IIIa inhibition extends across interventional devices, from balloon angioplasty to atherectomy and stenting.39,40

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