Novel antithrombotic approaches to coronary artery disease

Novel Antithrombotic Approaches to Coronary Artery Disease Eric J. Topoi, MD

Current prevention or treatment of coronary

thrembos~ roues on anUpiate~ ngents (aspidn), antithrembin agents (hepadn), and plasmlungen activators (t-PA). The purpose of this review is to descrg)e navel antithrombatic agents In each of these classes and to discuss recent and future clinical trials with tbo new ageats. Whereas asp4rin is a cycio-oxygenase Inhibitor, the most promising new antipiatelats are directed at an integdn cell H n " I i ~ ~ (GP) UUb/ Ilia--which represents the final common pathway for platelat aggregation. The monocional F(ab) antibody c7E3, a chimeric murine-human immunoglobulln G (IgG) Wagmeat, is the most intensively studied to date. c7E3 was assessed by the Evaluation of Platelat Monoclonal Antibody to Prevent Ischemic Complications (EPIC) trial In which 2,099 high-risk angloplasty patients were randomized to bolus (placebo) plus Infusion (placebo), bolus (c7E3, 0.25 mg/kg) plus Infusion (placebo), and bolus (c7E3, 0.25 mg/kl0 plus iniSu. slion (c7E3, 10/Lg/mln; 12 hours). The overall event rate at 30 days was elgnlflcantly decreanad from 12.8°/0 (placebo) to 8.3% (c7E3), a 36% relative reduction (p = 0.009). Integrelin is a cycNc heptapeptide with marked specificity for GP lib/ Ilia Integrin. It was studied during the Integrelln to Manage Platelet Aggregation to Prevent Corenary Thrombosis (IMPACT) trial, which eeroNed 150 routine coronary Intervention patients. At endpelnt, overall event rate was reduced Worn 11.9°/0 (placebo) to 5.6°/0 (iategrellu). The much larger (4,010 patients) IMPACT-II trial has Just completed enrollment to confirm and extend these encouraging result~ Hlrudin Is the prototype of the direct antlthremMns; It binds to the active catalytic site and the substrate recogni. tion site (exoelte) of thrembin. Hlrulog is a dodecapeptide fashioned after hlruclin, and binds to From the Department of Cardiology and the Center for Thrombosis and Vascular Biology, Cleveland Clinic Foundation, Cleveland, Ohio. Address for reprints: Eric J. Topoi, MD, Desk F251'9500 Euclid Avenue, Cleveland Clinic Foundation, Cleveland, Ohio ~44195.

the active site via a Phe~Pro-Arg linker enolecule; argatroban and efegatran are active-site inhibitots of thrombln. All these direct thrombin inhlbi. tors have a potential mechanistic advantage over heparln in that they inactivate clot-bound thrombin and are not inactivated by platelat factor 4 or heparinase. Large trials of hlrudlu versus heparlu are under way. Two recently evaluated PAs are recombinant PA and prourokinase. Results of clinical trials are encouraging for equivalent or improved Infarct vessel patency compared with currently available thrombolytics. Another novel PA is Worn the vampire bat; it is resistant to PA inhibitor and is highly fibrin selective; clinical trials are Imminent. (Am J Cardlel 1995;75:27B-33B)

lthough there have been substantial refineents in our contemporary approaches to oronary artery thrombus, there are important indicators that meaningful progress is still requisite and vital in the future. Thrombosis plays a pivotal role in the acute coronary syndromes of myocardial infarction and unstable angina as well as the acute-phase response to percutaneous coronary interventions. Our current armamentarium to prevent or treat coronary thrombosis relies on aspirin, heparin, and plasminogen activators. In this review of novel antithrombotic approaches, the potential replacements or "upgrades" for these 3 conventional agents are discussed. In the next few years there will be intensive large-scale clinical investigations to determine whether the mechanistic advantages of the newer agents can be translated to clinically meaningful benefit. ASPIRIN VERSUS NEW ANTIPLATELETS Although there are compelling data on the benefit of aspirin for patients with acute coronary syndromes and percutaneous coronary interventional procedures, ~ the underlying efficacy of aspirin must be considered as only partial or modest. There are approximately 100 known agonists of platelet aggregation, including thromboxane, seroA SYMPOSIUM: ATHEROTHROMBOSIS 2711

TAliLE I Clinical Trials of Platelet Glycoprotein lib/Ilia Integrin Blockers

Agent c7E3

Type Antibody

Company

Indications

Centocor/Lilly Percutaneous transluminal coronary angioplasty Integrelin Peptide COR Percutaneous transluminal coronary angioplasty, myocardial infarction, unstable angina pectoris MK-383 Small molecule Merck Unstable angina pectoris, percutaneous transluminal coronary angioplasty Ro-44 Small molecule HoffmannUnstable angina LaRoche pectoris

Patients Studied (n) 3,000

2,000

300

500

tonin, platelet-activating factor, collagen, thrombin, epinephrine, adenosine diphosphate (ADP), and shear stress. Aspirin acts solely by inhibition of the cyclooxygenase pathway and thus is only capable of inhibiting thromboxane A2. Molecular biology has elucidated the final common pathway for platelet aggregation: the platelet glycoprotein (GP) IIb/IIIa integrin. This adhesive molecule is a heterodimer that is expressed on the cell surface in response to platelet activation; it binds fibrinogen, which in turn binds other platelets, initiating activation. The most promising new antiplatelets are directed at the platelet GP IIb/IIIa integrin, also known as the platelet fibrinogen receptor. Several types of agents fit into the class of platelet GP IIb/IIIa integrin antagonists, as summarized in Table 1.2 The monoclonal F(ab) antibody known as c7E3 (CentoRx; Centocor, Malvern, PA) is a murine-human chimeric immunoglobulin G fragment with heavy (human) and light (murine) chain components. The hybrid or chimeric makeup has markedly decreased the antigenicity so that only 5-8% of patients exhibit a serologic response, and no allergic reactions of rash, fever, anaphylaxis, or serum sickness have been documented in approximately 3,000 patients studied to date. It has marked potency and has been the GP IIb/IIIa inhibitor most extensively tested to date. c7E3 has a long biologic half-life. Reestablishment of platelet function after c7E3 administration is chiefly due to new platelets released into the circulation. Its binding demonstrates some nonspecificity for integrins with homologous structure, particularly the vitronectin receptor. 288

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 75

Integrelin (COR Therapeutics, South San Francisco, CA) is the only true peptide being actively pursued in clinical trials. This agent is a cyclic heptapeptide that confers marked specificity on the GP IIb/IIIa integrin. Unlike the antibody, the biologic half-life is short, approximately 10 minutes, so that the effect of marked antiplatelet aggregation diminishes relatively quickly after infusion stops. Two peptidomimetics have been studied in Phase II clinical trials. One of these is MK-383 (Merck Research Laboratories, West Point, PA); the other is Ro 4483 (Hoffman-LaRoche, Basel, Switzerland). 3 As small molecules, both agents have a pharmacokinetic profile (short half-life, high potency) similar to Integrelin. Unlike Integrelin, however, they have relative lack of specificity for GP IIb/IIIa, with some affinity for other closely related integrins. Several trials have been completed with these agents. The first large-scale trial, Evaluation of Platelet Monoclonal Antibody to Prevent Ischemic Complications (EPIC), was of 2,099 patients undergoing high-risk coronary intervention.4 The category of high risk included patients with recent or evolving myocardial infarction, unstable angina, or angiographic features associated with increased propensity for abrupt vessel closure. All of the patients received aspirin and intravenous heparin. Patients were randomized to 1 of 3 groups: placebo bolus plus placebo infusion, c7E3 bolus (0.25 mg/kg) plus placebo infusion, or c7E3 bolus (0.25 mg/kg) plus 12-hour continuous infusion of c7E3 at 10 ~g/min. The primary endpoint was the composite of events at 30 days: death, myocardial infarction, and need for emergency revascularization with either coronary artery bypass surgery or repeat angioplasty. These data are summarized in Figure 1. Although there was no reduction in death rate, there was a significant reduction in nonfatal myocardial infarction and emergency revascularization. The overall event rate decreased from 12.8% to 8.3%, a relative reduction of 36%, for placebo compared with c7E3 bolus plus infusion, respectively. In addition to the acute phase findings that indicate a suppression of the platelet-thrombus response to coronary intervention, there was evidence of a reduction in the need for repeat revascularization during the 6-month follow-up phase. 5 The 25% reduction of restenosis as determined by clinical events during follow-up (Figure 2) is the first evidence that a pharmacologic intervention can reduce the need for subsequent revasFEBRUARY 23, 1995

FIGURE 1. Evaluation of Platelet

~mck,~Otnmody to Prevem Complications (EPIC) data for 2,099 patients . ~ hl~l~rtsk a ~ . For the bolus and Inthumkam(inf.) there was a MIpMflcant deorease In myocardial infarction (MI) and need for emergency m v a s ~ l a r Izatton. Ovorall, t h e m was a 36% decrease M composRe eve0ets = 0.009). CABG = coronary PlrCA = ~ trac~luml. nal coronary angloplas~. (Data

from N Engl J IVled,4 rewlMed wRh ~ . )

2.0]

I

I

[ ] Placebo (n=696)

[ ] Bolus (n=695)

1~

1.7

[ ] Bolus & Inf. (n=708)

i

10"

1.7 8"

1.5

6"

.~ 10 ~.

4'

0.5

2.

!

o.o Death

cularization in a large-scale trial of coronary intervention. The sustained effect of acute pharmacologic intervention in a subset of patients in current trials, while awaiting confirmation by systematic angiography, supports the concept of "passivation"--i.e., change of an arterial surface from one that supports platelet deposition to one that does not. This may be an important effect of platelet GP lib/Ilia inhibition, and it remains unclear whether the c7E3 antibody preparation will be more or less effective than other GP IIb/IIIa antagonists in achieving this effect. The peptide Integrelin has been studied in routine angioplasty, in unstable angina, and as an adjunct to thrombolysis in acute myocardial infarction. The Integrelin to Manage Platelet Aggregation to Prevent Coronary Thrombosis (IMPACT) trial enrolled 150 patients undergoing intervention, randomized to placebo, a 4-hour infusion (1.0 lxg/kg/min) of Integrelin and a 12-hour infusion of integrelin. 6 Unlike the c7E3 angioplasty protocol, in IMPACT the patients enrolled were undergoing routine rather than high-risk coronary intervention. In this cohort, there was a reduction in composite clinical events (death, myocardial infarction, need for emergency bypass surgery or coronary interve0tion) from 11.9% to 5.6%. These findings are encouraging but require extension and confirmation; to this end, a much larger trial (IMPACT-II) of 4,010 patients has just completed enrollment, and results, including 6-month angioplasty in a subset of 900 patients, are expected in 1995. Other platelet GP IIb/IIIa inhibitors and other clinical indications are also being explored. Four agents---c7E3, MK-383, Integrelin, and Ro 4483-have been studied in unstable angina. A small European pilot, placebo-controlled, randomized trial of 60 patients with refractory myocardial ischemia, despite intensive medical therapy for

O'

Nonfatal MI

Any Event

Emerg. PTCA/ CABG

unstable angina, showed a marked reduction in clinical events from 20% to 3% for c7E3. 7 The results for the other 3 agents from Phase II unstable angina trials are currently pending. Both c7E3 and integrelin have been tested as adjuncts to thrombolytic therapy. The c7E3 pilot trial only tested delayed administration after tissue-type plasminogen activator (t-PA), but the results suggested improvement in sustained coronary artery patency and reduction in recurrent ischemic events. 8 Simultaneous administration of accelerated t-PA and integrelin is presently being assessed in a Phase Ii effort studying 200 patients. In summary, a variety of platelet glycoprotein IIb/IIIa inhibitors are being evaluated in 3 different coronary disease settings--angioplasty and related catheter interventions, unstable angina, and acute myocardial infarction. Currently, angioplasty is the potential indication most intensively studied, and c7E3 emerged as the first agent in the antiplate1.0

...........

~

~

B o l u s + Infusion

--."

BOlus

~

Placebo

0.9

0.8 I

i

Months from Randomization FIGURE 2. Kaplan-Malor event curve of aH events (death, myocardial Infae~dlon, coronary revascularlzatlon) for all patients enm41ed In the tdal. Thore was a algnmcant r ~ duction of ewmts for the c7E3 bolus and Infusion grmip compamd wnh the baAusoaly or placebo treatmen~ (p = 0.001). Note that a substmdJal proportion ofevents occurmd aftor 1 month. (Repdntnd wUh ~ from Lancet. s) A SYMPOSIUM: ATHEROTHROMBOSIS

TABLE II Clinical Trials of Direct Thrombin Inhibitors

Agent

Company

Indications

Appropriate No. Patients Studied

Recombinant Ciba-Geigy hirudin

Acute myocardial infarction, unstable angina pectoris, percutaneous transluminal coronary angioplasty

6,000

Recombinant hirudin

Hoe~chstRoussel

500

Hirulog

Biogen

Acute myocardial infarction, unstable angina pectoris Acute myocardial infarction, percutaneous transluminat coronary angioplasty, unstable angina pectoris

Argatroban

Texas Biotech- Unstable angina nology pectoris LY-294468 Eli Lilly Unstable angina (Efegatran) pectoris, acute myocardial infarction

2,000

200 100

let class to receive approval by the Food and Drug Administration in December 1994. HEPARIN VERSUS DIRECT ANTITHROMBINS Four direct thrombin inhibitors have been tested in patients with coronary artery disease 9-18 (Table II). Of these, hirudin is considered the prototype of the class; it binds to both the active catalytic site and the substrate recognition site (anion exosite) of thrombin, in addition to many other attachment sites on the thrombin molecule. Hirulog is a dodecapeptide fashioned after hirudin; it binds to the substrate recognition site and has a Phe-Pro-Arg linker that attaches to the active site. Argatroban, an arginine derivative, and efegatran are both active site inhibitors of thrombin. The key mechanistic advantages for these thrombin inhibitors over heparin include the ability to inactivate clotbound thrombin, lack of inactivation by heparinase o r platelet factor IV, and lack of dependence on a cofactor, antithrombin III, to mediate the effect. Hirudin has been the most extensively tested antithrombin. It is,produced via recombinant techniques, and several different recombinant hirudins are being manufactured. The desulfatohirudin (Ciba-Geigy, Basel, Switzerland) has been evaluated as a replacement for heparin as an adjunct in the setting of thrombolysis in myocardial infarction, 9-H unstable angina, 12 and in coronary angioplasty. 13 In the Thrombolysis in Myocardial Infarction (TIMI)-5 trial, accelerated t-PA plus intravenous heparin and aspirin was compared with acceler30B

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 75

ated t-PA plus hirudin and aspirin. 9 A total of 246 patients were randomly assigned, with escalating dosages of hirudin. Angiography was performed at 90 minutes and at 18--36 hours after thrombolytic therapy. Hirudin (combining the data for all dosages tested) was demonstrated to be superior to heparin with respect to infarct vessel patency at 18-36 hours (98% vs 89%; p = 0.002) but only slightly better than heparin at 90 minutes (65% vs 57%; difference not significant) or in a lesser number of patients studied at 60 rhinutes (62% vs 50%; difference not significant). Of note, the clinical events for death and reinfarction appeared to be favorably influenced by hirudin, but a larger trial is necessary (and is under way) to verify and extend these initial findings. Similar encouraging data were obtained in the TIMI-6 trial of streptokinase with heparin or hirudin, but no angiography was performed by protocol to assess early or sustained infarct vessel patency, and the number of patients assessed was less. 1° Neuhaus and colleagues 11 have evaluated accelerated t-PA plus hirudin or heparin in the Hirudin in Thrombolysis (HIT) trial and have found, using systematic angiography, similar advantages of hirudin over heparin with respect to reduced reocclusion. In the setting of unstable angina, hirudin has been compared with heparin in a randomized trial of 160 patients using sequential, paired angiography for the endpoint of culprit vessel luminal caliber improvement, an indirect marker for prevention (or dissolution) of coronary artery thrombus accumulation. 12 As shown in Figure 3, there was evidence of better angiographic results for hirudin, even when controlling for the activated partial thromboplastin time (APTT) by including an arm of high-dosage heparin to raise the APTT to 90-110 seconds, which is similar to the effect of hirudin at dosages >0.1 mg/kg/hour. Of note, in this trial, the relative improvement in stability and consistency of APTT with hirudin was documented (Figure 4). This finding suggests a practical advantage of hirudin with respect to a more stable anticoagulant effect: Only 30% of patients required adjustment of hirudin compared with 70% of patients treated with heparin to maintain the APTT in the target range. The potential benefit of recombinant hirudin versus heparin for patients with acute coronary syndromes is currently being assessed in 3 largescale trials: Global Utilization of Streptokinase and t-PA for Occluded Arteries (GUSTO-II), TIMI-9, and HIT-II. GUSTO-II is a 12,000 patient FEBRUARY 23, 1995

100

All Heparin 0.4

i

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80"

74

73

68 0~ ea

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0.3

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40-1

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65

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Average Cross Section (mm 2)

Minimum Cross Section (ram2)

Minimum Lumen Diameter (mm)

mmJm s. h r graph showing poo~d amColpapidc average cross-sectional area Improvummt, area minimal crosssectional data, and minimal luminal diameter, for all hepatin,.and hlrudin-treated paUents. (Repdnted wiDthpennis,. sion from C'/rcu/affon. ~ )

trial of acute coronary syndromes, including unstable angina, non-Q wave myocardial infarction, and ST-segment elevation infarction (Figure 5). TIMI-9 is a 3,000 patient trial of thrombolysis with accelerated t-PA or streptokinase plus heparin or hirudin; HIT-II is a similar trial assessing hirudin as an adjunct to thrombolysis with a different form of recombinant hirudin. All 3 trials had temporary cessation due to an increased rate of intracerebral hemorrhage at higher doses of hirudin. The projects of GUSTO-II and TIMI-9 have restarted~3; in the next 2 years there should be available considerable data from large-scale, randomized trials for the potential use of recombinant hirudin in patients with myocardial infarction and unstable angina. Hirudin has also been studied for use during coronary angioplasty. In a pilot randomized trial of 150 patients receiving either hirudin or heparin, there were fewer significant complications of myocardial infarction, emergency bypass surgery, and abrupt vessel closure with hirudin. 14 This led to a 1,200 patient trial with repeat angiographic assessment at 6 months to detect any effect on restenosis; the preliminary results of this angioplasty trial (known as H E L V E T I C A ) indicate superior shortterm suppression of ischemic events with hirudin compared with heparin. The other direct thrombin inhibitor that has been rather extensively evaluated is hirulog. In the first phase II trial of 261 patients undergoing elective coronary angioplasty, there appeared to be a dose-response curve for hirulog's effect on inhibiting abrupt vessel closure. 15 There was no control arm with heparin in this study, but a large-scale effort with 4,000 patients undergoing routine angioplasty with heparin or hirulog is in progress. A pilot study of 45 patients receiving streptokinase with conjunctive hirulog suggests facilitation of infarct

90 - 110

0.15/0.05

Heparln (see)

0.30/0.10

0.60/0.20

0.60/0.30

Hlrudln (mg/kg/hr)

FIGURE 4. Bar graph showing the ~ of paUea~ In whom tho a e t ~ partial ~ n thno (APTT) was within a ,lO-second target range when serially assessed every 12 hours. The h l n d n group had a more conshC~nt proka~mon of APTT. (nepdntod wnh ~ from C J ~ u ~ n . = )

vessel thrombolysis, 16 but this limited observation in a small number of patients requires confirmation in future controlled trials. Argatroban was initially studied in a cohort of 43 patients with unstable angina 17 and a fairly large proportion (27%) with rebound ischemia, occurring after the drug infu-

Acute Coronary Syndromes (MI or Unstable Angina) Chest Pain < 1 2 h o u r s

1. ]J

Stratify

'

'-. No ST ?

*ST f

/ Hirudin

Heparin

Hirudin

~

Heparin

f

30 Day Follow-up Death & Non-fatal MI

* ST ?: ~ 0.1 mV ST 1' in ~ 2 leads & thrombolytic eligible or not eligible

Secondary Endpoints: Refractory angina Revascularization procedures Stroke Bleeding complications Cost

FIGURE5. Global UtiRmUon of Streptokkmse and t-PA for HI = myocardial Im~mcllma. A SYMPOSIUM: ATHEROTHROMBOSIS

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~: t-PA + SK ~t-PA

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40-

v

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2'0 2?

2'4 2'8 2'8 3'0

Days from Randomization

SK+SQ Hep

SK+IV Hep

Accel. t-PA+SK t-PA

FIGURE 6. ~ 11drty-day mortality In the 4 t r e u ~ , ~ n t groups. The group receiving accelerated treatment with tissue plasmlnogen activator (t.PA) had lower mortality than the 2 streptoklnase (SILOgroups (p = 0.001) and than each individual treatment group: streptoMnase plus subcutaneous (SQ) heparin (Hep; p = 0.009), s t r q 4 o k M a s e plus intravenous (IV) hepadn (p = 0.003), and t-PA plus ~ combined with Intravenous heparln (p = 0.04). (Reprinted with perm~ss~n fr~m N Eng~J Med~) R ~ . The T~M~grade 3 perfusi~n status 9~ m~nutes after therapy f~r pat~ents ~n~ a ~ graphic tdal ~

supedodty for accelerated t-PA compared with the other 3 thrombolyUc strategies. (Data

from N en~ J Med,2x reprhCcedw#h ~ . )

sion was terminated, was demonstrated. However, the phenomenon of rebound ischemia after cessation of hirudin or hirulog has not yet been documented, despite a relatively extensive clinical experience accumulated to date. It is possible that appropriate conjunctive use of aspirin will help to reduce the likelihood of such events after treatment with direct thrombin inhibitors. Currently, argatroban is being tested for coronary angioplasty and efegatran TM for unstable angina and as an adjunct to thrombolytic therapy. In summary, Phase II data on direct thrombin inhibitors are encouraging to date. Major bleeding complications have thus far not been found in excess compared with heparin. A much more accurate assessment of the issue of bleeding complications should be possible after completion of current major trials. Of note, thrombin inhibitors are being pursued for the same indications as the GP IIb/IIIa antiplatelets; thus the 2 classes of ~gents can be considered competitive, but in many respects, owing to their different mechanisms, they are complementary. In the canine model of electrolytic wire-induced coronary injury, Nicolini et a119 have recently shown that low dosages of integrelin combined with low dosages of recombinant hirudin produce an additive effect on coronary thrombolysis, and such a combined approach may ultimately prove to be clinically advantageous. OLD AND NEW PLASMINOGEN ACTIVATORS Until the recent completion of the GUSTO-I trial, it remained unclear whether very early restoration of coronary artery patency via enhanced 32B

thrombolysis was necessary or desirable. GUSTO showed that the chief determinant of improved survival was restoration of TIMI grade 3 (brisk) flow by angiography. The strategy was associated with 14% reduction of mortality compared with standard streptokinase treatment strategies. At 90 minutes of therapy, accelerated t-PA/achieved TIMI grade 3 5 4 % o f the time, compared with 29-38% for the other 3 plasminogen activator strategies 2°,21 (Figure 6). The finding that early complete restoration of coronary blood flow is the paramount objective of therapy is important because only about half the patients had successful thrombolysis. This sets up the potential for improved adjuncts, such as platelet GP IIb/IIIa inhibitors, direct thrombin inhibitors, or improved plasminogen activators. Two plasminogen activators recently evaluated in clinical trials are recombinant plasminogen activator (r-PA) and prourokinase. The data for r-PA, which is a deletion mutant of t-PA, are encouraging because this agent has a long elimination half-life, is given as a double bolus several minutes apart, and has an efficacy track record for infarct vessel patency similar to accelerated t-PA. 22 r-PA is the subject of ongoing investigation in the INJECT trial (r-PA vs streptokinase; 5,000 patients), and a large-scale effort with accelerated t-PA versus r-PA (GUSTO-III) is being planned. Prourokinase has been evaluated in angiographic studies, and, like r-PA, the results have been encouraging. 23Vampire bat plasminogen activator (bat-PA) is homologous to human (wildtype) t-PA but without kringle 2 or a plasminsensitive processing site; it is resistant to

THE AMERICANJOURNALOF CARDIOLOGY VOLUME75 FEBRUARY23, 1995

plasminogen activator inhibitor and is highly fibrinselective. 24 Clinical trials with bat-PA are expected to begin late in 1995. This represents one of many novel plasminogen activators, either naturally occurring or man made, that show promise for improved coronary thrombolysis and related clinical outcomes. CONCLUSION Although it remains unclear whether facilitation of thrombolysis is best achieved with a more potent plasminogen activator, better antiplatelet or antithrombin agents, or combinations of the 3 agents, the quest for new and improved approaches to avoid or dissolve coronary artery thrombus is critical for progress in cardiovascular therapeutics. REFERENCES 1. Antiplatelet Trialists' Collaboration. Collaborative overview of randomized trials of antiplatelet therapy. I. Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Br Med J 1994;308:81-106. 2. Lincoff AM, Topoi El. Abrupt vessel closure. In: Topoi El, ed. Textbook of lnterventional Cardiology, 2nd ed. Philadelphia: WB Saunders, 1994:207-230. 3. Topoi EJ, Plow EF. Clinical trials of platelet receptor inhibitors. Thromb Haemost 1993;70:94-98. 4. The EPIC Investigators. Use of a monoclonal antibody directed aganist the platelet glycoprotein lib/Ilia receptor in high-risk coronary angioplasty. N Engl J Med 1994;330:965-961. 5. Topoi EJ, Califf RM, Weisman HF, Ellis SG, Tcheng JE, Worley S, Ivanhoe R, George BS, Fintel D, Weston M, Sigmon K, Anderson K, Lee KL Wilierson JT, for the EPIC Investigators. Randomised trial of coronary intervention with antibody against platelet lib/Ilia integrin for reduction of restenosis results at six months. Lancet 1994;343:881--886. 9o Tcheug JE, Ellis SG, Kleiman NS, Harrington RA, Mick MJ, Navetta FI, Wofley S, Smith JE, Kereiakes DJ, Kitt MM, Miller JA, Sigmon KN, Califf RM, Topoi EJ. Outcome of patients treated with the GPllb/Illa inhibitor integrelin during coronary angioplasty: results of the IMPACT study. Circulation 1993;88(suppl II):I-595. 7. Simoons ML, Jan de Boer M, Brand M, van Miltenburg A, Hoorntje J, Heyndrickx GR, Wieken L, De Bono D, Rutsch W, Scha~le TF, Weisman HF, Nijssen KM, Stibbe J, de Feyter P. Randomized trial of a GPIIb/IIIa platelet receptor blocker in refractory unstable angina. Cbrulation 1994;89: 596-603, 8. Kleiman NS, Ohman ME, Califf RM, George B, Kereiakes D, Aquirre F, Weisman H, Schaible T, Topoi El. Profound inhibition of platelet aggregation with monoclonal antibody 7E3 Fab after thrombolytic therapy:, results of the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) 8 pilot study. J Am Coil Cardiol 1993;22:381-389. 9. Cannon CP, McCabe CH, Henry TD, Schweiger MJ, Gibson RS, Mueller HS, Becker RC, Kleiman NS, Haugland JM, Anderson JL, Sharaf BL, Edwards SJ, Rogers W J, Williams DO, Braunwald E. A pilot trial of recombinant

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