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Prevention of cardiovascular ischemic complications with new platelet glycoprotein IIbIIIa inhibitors
Prevention of cardiovascular ischemic complications with new platelet glycoprotein lib/Ilia inhibitors Eric J. Topol, MD Cleveland, Ohio Agents that block platelet glycoprotein lib/Ilia integrin, the receptor that mediates the final common pathway of platelet aggregation, represent a promising new approach to preventing cardiovascular ischemic complications and late restenosis after percutaneous coronary revascularization. In the large-scale Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC) trial that involved high-risk patients undergoing coronary intervention procedures, a monoclonal antibody Fab fragment (c7E3) directed against this receptor, administered as a bolus and through infusion, significantly reduced the 30-day incidence of major ischemic events relative to placebo. Treatment was associated with higher rates of bleeding complications and transfusion, the risk of which appeared to be inversely related to body weight. The c7E3 bolus and infusion also significantly decreased the need for repeat revascularization during the 6-month blinded follow-up period. Ongoing trials are now exploring strategies for refining the practical aspects of glycoprotein lib/Ilia therapy and minimizing the risk of bleeding. (AM HEARTJ 1995;130:666-72.)
Among the major stumbling blocks to successful percutaneous transluminal coronary angioplasty (PTCA) are abrupt closure of the coronary vessel, which occurs during or soon after the procedure in as m a n y as 9% of patients, and late restenosis, which develops in at least 30% of cases during the first 6 months after angioplasty.l-4 Platelets are believed to play a role in the ischemic complications of coronary angioplasty, and accordingly, aspirin has been used in an attempt to reduce the incidence of acute closure and acute myocardial infarction after angioplasty. However, its prophylactic efficacy in this setting has been only modest: 10% to 20% of patients treated with aspirin still experience ischemic complications. Similarly, although it is known that the vascular injury that causes restenosis is accompanied by platelet thrombus formation and smooth muscle cell
From the Department of Cardiology and the Joseph J. Jacobs Center for Thrombosis and Vascular Biology, The Cleveland Clinic Foundation. Reprint requests: Erie J. Topol, MD, Department of Cardiology, Cleveland Clinic Foundation, Desk F25, 9500 Euclid Ave., Cleveland, OH 44195. Copyright © 1995 by Mosby-Year Book, Inc. 0002-8703/95/$3.00 + 0 4/0165588
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changes, no agent directed against these mechanisms has yet been shown to reduce the incidence of restenosis. A recent breakthrough in molecular biology was the discovery that the platelet glycoprotein IIb/IIIa integrin is the receptor that mediates the final common pathway of platelet aggregation. Each platelet contains 50,000 to 100,000 glycoprotein IIb/IIIa receptors, which, in their normal conformation, are "tucked in" beneath the platelet membrane. When a platelet is acted on by an agonist, whether it be adenosine diphosphate, epinephrine, collagen, platelet activating factor, serotonin, thrombin, or shear stress, the receptors are exteriorized on the platelet surface and assume an active conformation. The activated receptor binds the fibrinogen ligand, which then cross-links receptors on adjacent platelets. It is this cross-linkage that causes platelet aggregation. Several agents that block the final common pathway ofplatelet aggregation have been developed, and a number of these agents are being tested clinically to determine whether such blockade would reduce the incidence of acute ischemic complications and restenosis after angioplasty. The largest experience to date has been with a chimeric monoclonal antibody Fab fragment (c7E3), which is directed against the glycoprotein IIb/IIIa receptor. This article discusses the results of recent clinical trials evaluating the efficacy and safety of glycoprotein IIb/IIIa blockade in patients undergoing angioplasty and explores the ramifications of these studies for interventional cardiology. PHARMACODYNAMICS OF GLYCOPROTEIN lib/Ilia INHIBITION WITH c7E3
The first study that used c7E3 in patients undergoing PTCA who were at high risk for ischemic complications confirmed that the antiplatelet antibody produces a dose-dependent blockade of platelet glycoprotein IIb/IIIa receptors and demonstrated that such receptor blockade correlated with inhibition of platelet aggregation. 1 Bolus doses of 0.15 and 0.25
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Table I. Thirty-day EPIC results: primary outcome events in the three treatment groups No. of patients (%)
Event* Primary endpoint Components of primary endpoint Death Nonfatal myocardial infarction Q wave Large non-Q-wave Small non-Q-wave Emergency PTCA Emergency CABG Stent placement Balloon-pump insertion
Placebo (n = 696)
c7E3 Fab bolus (n = 695)
c7E3 Fab bolus and infusion (n = 708)
89 (12.8)
79 (11.4)
59 (8.3)
12 (1.7) 60 (8.6) 16 (2.3) 28 (4.0) 16 (2.3) 31 (4.5) 35 (3.6) 4 (0.6) 1 (0.1)
9 (1.3) 43 (6.2) 7 (1.0) 19 (2.7) 17 (2.4) 25 (3.6) 16 (2.3) 12 (1.7) 1 (0.1)
12 (1.7) 37 (5.2) 6 (0.8) 21 (3.0) 10 (1.4) 6 (0.8) 17 (2.4) 4 (0.6) 1 (0.1)
p value for dose response 0.009t 0.96 0.013 0.020 0.265 0.239 <0.001 0.177 0.98 0.99
Reprinted with permission from The EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in highrisk coronary angioplasty. N Engl J Med 1994;330:956-61. Copyright 1994, Masschusetts Medical Society. CABG, Coronary artery bypass grafting. *PTCA denotes percutaneous coronary angioplasty or atherectomy, and CABG. tp = 0.009 for overall test for trend, p = 0.43 for comparison of the placebo group with the group given the bolus only, andp = 0.008 for comparison of the placebo group with the group given the bolus and infusion.
mg/kg blocked 54% and 87% of glycoprotein IIb/IIIa receptors, respectively, and decreased platelet aggregation in response to adenosine diphosphate to 46% and 18% of baseline values, respectively. Prolongation of the bleeding time beyond 30 minutes was observed shortly after administration of a bolus dose of 0.25 mg/kg. The effects of the 0.25 mg/kg bolus on receptor blockade, platelet aggregation, and bleeding time peaked in the first hour after administration and gradually returned to near normal by 24 to 36 hours after administration. When the 0.25 mg/kg bolus was followed by a 12-hour infusion of 10 ]Jg/kg, these antiplatelet effects were sustained for the entire duration of the infusion, with recovery beginning after discontinuation of the infusion. It has subsequently been shown that the increase in bleeding time produced by c7E3 does not correlate with bleeding events. 2 THE EPIC TRIAL
The Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC) trial was the first large-scale randomized study to address the question of whether platelet inhibition achieved through blockade of the platelet glycoprotein IIb/IIIa receptor would reduce the incidence of acute ischemic events and late restenosis after PTCA or directional coronary atherectomy. 3, 4 Patients and methods. The EPIC project enrolled 2099 high-risk patients undergoing angioplasty or atherectomy at 56 U.S. sites during a 10-month period. Candidates defined as being at high risk for
vessel closure included patients who had either an evolving or recent acute myocardial infarction, early postinfarction angina, unstable angina, or particular angiographic and clinical risk factors such as a lesion that contained thrombus, female gender, or diabetes. Criteria for exclusion from the study were an age of 80 years or older, a known hemorrhagic diathesis, a history of stroke within 2 years before the study, recent major surgery, or gastrointestinal bleeding. EPIC participants were randomized in doubleblind fashion to receive either c7E3 in a bolus dose of 0.25 mg/kg followed by an infusion of 10 l~g/min (708 patients), a c7E3 bolus followed by a placebo infusion (695 patients), or a placebo bolus and a placebo infusion (696 patients). All patients received aspirin, 325 mg by mouth, at least 2 hours before coronary intervention and daily thereafter, as well as intravenous bolus doses ofheparin, titrated to maintain the activated clotting time at 300 to 350 seconds during the procedure and to keep the activated partial thromboplastin time at 1.5 to 2.5 times the control value for at least 12 hours after the procedure. Thirty-day results. The incidence of death, myocardial infarction, emergency bypass surgery, emergency angioplasty, stent placement, or intraaortic balloon pump insertion was 12.8% in the double-placebo group, 11.4% in the c7E3 bolus placebo infusion group, and only 8.3% in patients treated with both active bolus and active infusion (Table I). 3 Thus treatment with a bolus and infusion of c7E3 reduced the rate of this primary composite endpoint by 35% relative to double placebo (p = 0.008). The reduction
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Topo! 1.0
c7E3 boluS+ c7E3 infusion ,=.=,,,.= c7E3 bolus + placebo infusion - Placebo bolus + placebo infusion
E 0.9O Z •~-
0.8-
.~_ 0.7-
o.6 1 0
i 1
, 2
, 3
, 4
, 5
i 6
Months from Randomization
Fig. 1. Six-month EPIC results. Kaplan-Meier curve of all events (death, myocardial infarction, coronary revascularization) for all patients enrolled. A significant reduction of events occurred in the c7E3 bolus + infusion group, compared with bolus alone or placebo groups (p = 0.001). A substantial number of events occurred within the first month. (From Topol EJ, CaliffRM, Weisman HF, et al. Randomised trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: results at six months. Lancet 1994;343:881-6. ©by The Lancet Ltd, 1994.)
in the event rate achieved with the c7E3 bolus alone did not reach statistical significance. The improvement in the composite endpoint observed with the c7E3 bolus and infusion was attributable mainly to a 40% reduction in the incidence of nonfatal myocardial infarction (p = 0.013) and a 65% reduction in Qwave infarction in particular (p= 0.02) and to a halving of the need for emergency angioplasty or bypass surgery. However, the 30-day mortality rate, which ranged from 1.3% to 1.7%, did not differ between the three treatment groups. The principal disadvantage of treatment with the c7E3 bolus and infusion was a doubling in the incidence of major bleeding (14%, compared with 7% in the placebo group; p = 0.001) and the need for transfusion (15%, compared with 7% for placebo; p < 0.001). Fortunately, however, there was no excess of intracranial hemorrhages associated with c7E3 treatment. Body weight was the principal determin a n t of bleeding risk. Among patients who weighed 90 kg or more, the incidence of major bleeding was the same in all three treatment groups. In contrast, in the lightest tertile of patients, the incidence of major bleeding was 21% with the c7E3 bolus and infusion, 15% with the c7E3 bolus and placebo infusion, and only 7% with the double placebo. Interestingly, there was no excess of bleeding complications among actively treated patients who required emergency bypass surgery. It should be noted t h a t the EPIC protocol's omission of a standardized threshold for transfusion facilitated a high rate. At least half of
the transfusions could have been avoided if prospectively defined criteria such as hemoglobin less t h a n 9 gm/dl had been used. Six-month results. During a 6-month blinded follow-up period, the incidence of the combined endpoint of death, myocardial infarction, or elective revascularization was 23% lower among patients who had received the c7E3 bolus and infusion (27%) t h a n in the double-placebo group (35.1%). 4 The striking separation between the event-free curves over time is illustrated in Fig. 1. The difference in outcome was accounted for mainly by a 26% reduction in the need for repeat angioplasty or bypass, from 22.3% among patients who received placebo bolus and placebo infusion to 16.5% among patients given the c7E3 bolus and infusion (Fig. 2). As was true for the shortterm results, patients who received the c7E3 bolus alone had an intermediate outcome t h a t was not significantly better t h a n t h a t in the double-placebo group. These findings are the first to suggest t h a t clinical restenosis can be prevented pharmacologically. Overall, the EPIC data indicate t h a t the administration ofc7E3 as a bolus and infusion to 100 patients would avoid abrupt closure events in five patients and would spare an additional eight patients the need for repeat revascularization. R i s k f a c t o r s f o r r e s t e n o s i s . As in past restenosis trials, 5 multivariate analysis of the EPIC results revealed t h a t diabetes was an important factor in increasing the risk of clinical restenosis.
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c7E3 bolus + c7E3 infusion ..==.~ c7E3 bolus + placebo infusion
2
~.
0.9
o
0.
0.8
0
I
I
I
I
I
I
1
2
3
4
5
6
Months from Randomization
Fig. 2. Six-month EPIC results. Need for subsequent target vessel revascularization, either by coronary angioplasty or coronary bypass surgery. Repeat revascularization was significantly reduced in the c7E3 bolus + infusion group, compared with placebo (p = 0.007). (From Topol EJ, CaliffRM, Weisman HF, et al. Randomised trial of coronary intervention with antibody against plateiet IIb/IIIa integrin for reduction of clinical restenosis: results at six months. Lancet 1994;343:881-6. © by The Lancet Ltd, 1994.)
Prolonged angioplasty procedures were also associated with a higher risk of restenosis in the EPIC study, with the rate of restenosis increasing significantly for every 30-minute increase in procedure length. 6 In fact, for procedures longer than 70 minutes in duration, the protective effect ofplatelet IIb/ IIIa inhibition was no longer significant (Table II). However, for procedures lasting less than 40 minutes or between 40 and 70 minutes, the effectiveness of c7E3 in reducing the event rate was sustained. Outcome in patients with unstable angina.A dramatic improvement in outcome with the c7E3 bolus and infusion was observed in the 470 EPIC subjects who fulfilled the criteria for unstable angina. 7 With the active bolus and infusion, the 30-day incidence of death or myocardial infarction dropped from 9.2% to 0.6% and the incidence of urgent revascularization fell from 5.9% to 3.2%, with the composite 30-day endpoint rate decreasing by 70.6%, from 13% to 3.8% (Fig. 3). Interestingly, although the reduction in restenosis was not as substantial during the 6-month follow-up period, the rate of myocardial infarction was reduced from 11.3% to 1.3% and the death rate was reduced from 6.7% to 0.7% among patients who were given the c7E3 bolus and infusion. It is likely that the more marked clinical benefits ofplatelet inhibition in patients with unstable angina may be explained by heightened platelet activity in the unstable coronary plaque. Outcome in patients undergoing atherectomy. The EPIC results provided independent confirmation of the Coronary Angioplasty Versus Excisional Ather-
Table IL Relationship between duration of coronary inter-
vention procedure and efficacy of c7E3 bolus and infusion in the EPIC trial
Duration (rain) <40
Bolus + p-value (bolus Placebo Bolus infusion + infusion (%) (%) (%) vs placebo)
56/206 54/207 (27.7) (26.3) 40-70 59/190 48/200 (31.6) (24.5) >70 77/214 79/214 (36.4) (37.2) Univariate duration <0.001 0.033 p value
40/212 (19.2) 48/227 (21.5) 53/172 (31.3) <0.001
0.042 0.012 NS <0.001
NS, Not significant. Reproduced with permission from Omoigui N, Lefkovits J, Elliot J, Weisman H, for the EPIC Investigators• Does length of the coronary intervention procedtLre affect efficacy of platelet glycoprotein IIb/IIIa blockade? Results from the EPIC trial [Abstract]. Circulation 1994;90(suppl I):I-568. Copyright 1994, American Heart Association.
ectomy Trial (CAVEAT) finding that atherectomy results in a higher incidence of non-Q-wave infarction than does angioplasty, s The rate of non-Q-wave infarction was 15.2% among the 199 EPIC patients who underwent directional coronary atherectomy, compared with only 8.1% among those treated with PTCA. 9 However, this excess risk w a s virtually eliminated by treatment with the c7E3 bolus and infusion (Fig. 4), which suggests that the mechanism underlying the occurrence of non-Q-wave infarction after atherectomy may be platelet dependent.
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15 D
PL
[]BO
10
B
13
BO+IN
p = 0.004
9.2
p = 0.011
p = 0.001
p = NS
8.1
-(2_
=o
-
5.9
5
~3.8
0 Death
MI CABG/PTCA 30-Day Endpoints
Composite
Fig. 3. Effect of c7E3 bolus (BO) and infusion (IN) on 30-day endpoints in patients with unstable angina in the EPIC trial. (Reproduced with permission from LincoffAM, Califf RM, Anderson K, Weisman HF, Topol EJ, for the EPIC Investigators. Striking clinical benefit with platelet GP IIb/IIIa inhibition by c7E3 among patients with unstable angina [Abstract]. Circulation 1994;90(suppl I):I-21. Copyright 1994, American Heart Association.)
I
I 15.2
16
12.1 o
& a
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8.1 5.7
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~
0
PTCA
5.0
4.5
II
DCA
B
30-Day Endpoints
Fig. 4. Impact ofc7E3 bolus (BO) and infusion (IN) on the incidence of non-Q-wave infarction after PTCA and directional coronary atherectomy in the EPIC trial. (Reproduced with permission from Lefkovits J, Anderson K, Weisman H, Topol EJ, for the EPIC Investigators. Increased risk ofnon-Q MI following DCA: evidence for a platelet dependent mechanism from the EPIC trial [Abstract]. Circulation 1994;90(suppl I):I-214. Copyright 1994 American Heart Association.)
Outcome in patients undergoing primary and rescue PTCA. The impact of c7E3 treatment on the event
rate was particularly noteworthy in the 66 EPIC patients who underwent primary or rescue PTCA for acute myocardial infarction. 1° Only 4.5% of the patients in this small subgroup who received the c7E3 bolus and infusion experienced an adverse event throughout the 6-month follow-up period, compared with nearly half of their placebo-treated
counterparts (Table III). At 30 days the reinfarction rate was zero with the active bolus and infusion versus 8.7% with double placebo, the incidence of urgent intervention was zero versus 17% with placebo, and the rate of the composite endpoint was 4.5% versus 26% with placebo. These findings suggest the need for further study of the role of potent platelet antagonism in the setting of primary angioplasty for acute myocardial infarction.
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Table III. Effect of c7E3 bolus and infusion on 30-day and 6-month composite endpoints in patients undergoing
primary and rescue PTCA in the EPIC trial
Results
Placebo (n = 23) (%)
Bolus (n = 19) (%)
Bolus + infusion (n = 22) (%)
p value (bolus + infusion vs placebo)
30-day composite endpoint Major bleeding 6-month composite endpoint
26.1 13 47.8
21.1 31.6 32.3
4.5 18.2 4.5
0.058 NS 0.002
NS, Not significant. Reproduced with permission from Lefkovits J, Ivanhoe R, Anderson K, Weisman H, Topol EJ, for the EPIC Investigators. Platelet IIb/iIIa receptor inhibition during PTCA for acute myocardial infarction: insights from the EPIC trial [Abstract]. Circulation 1994;90(suppl I):I-564. Copyright 1994, American Heart Association.
ONGOING CLINICAL TRIALS OF GLYCOPROTEIN lib/Ilia INHIBITION PROLOG and EPILOG trials, In the nine-center PRO-
LOG pilot study to the forthcoming Evaluation in PTCA to Improve Long-Term Outcome with Reo-Pro Glycoprotein IIb/IIIa Blockade (EPILOG) trial, 103 patients undergoing coronary intervention procedures were randomized to receive c7E3 plus either the standard dose of heparin (to achieve activated clotting time >300 seconds) or a low heparin dose, both of which were adjusted according to body weight, n The results suggested that the low weightadjusted heparin dose, which averaged approximately two thirds of the normal dose, decreased the activated clotting time from a median of 330 to 250 seconds, substantially reducing both the need for transfusion and the incidence of hematoma. In addition, patients in the PROLOG trial were randomly assigned either to undergo removal of the vascular sheath soon after the procedure or to have their sheaths left in place until the day after the procedure. Interestingly, early sheath removal appeared to be associated with lower rates of transfusion and hematomas at the access site. This finding suggests that platelet aggregation need not be intact to achieve hemostasis after sheath removal. Thus the PROLOG data may help us to modulate bleeding complications and further refme the practical aspects of therapy with IIb/IIIa blockade in patients undergoing coronary intervention. The ongoing EPILOG trial will attempt to confirm the PROLOG results in a large population undergoing routine coronary intervention. An anticipated 5000 patients undergoing angioplasty will be randomly assigned to receive a c7E3 bolus and infusion along with either low or high doses ofheparin. In addition to clinical follow-up, 300 patients in each treatment group will be evaluated by quantitative angiography. IMPACT and IMPACT-2 studies. The phase II Integrelin to Manage Platelet Aggregation to Prevent
Coronary Thrombosis (IMPACT) study assessed the efficacy and safety of another glycoprotein IIb/IIIa inhibitor, Integrelin, which is a cyclic heptapeptide with a short half-life.12 In this study, 150 patients undergoing routine elective PTCA at 14 centers were randomly assigned to receive either Integrelin or placebo 30 minutes before and for either 4 or 12 hours after the procedure. All participants were also treated with aspirin and heparin. The primary composite endpoint of death, myocardial infarction, repeat angioplasty, bypass surgery, or stent implantation, was reached at the time of release from the hospital by 7.9% of patients treated with Integrelin and by 10.2% of patients in the placebo group, and at 30 days by 8.1% of patients treated with Integrelin versus 11.1% of those who received placebo. The favorable effects of Integrelin were accomplished without an accompanying increase in the incidence of moderate or severe bleeding. In the randomized, placebo-controlled IMPACT-2 trial that was recently completed, 4010 patients undergoing coronary intervention procedures were assigned to receive Integrelin in a bolus dose of 135 mg/kg followed by an infusion of either 0.5 or 0.75 mg/kg for 20 to 24 hours. Along with clinical followup, 900 IMPACT-2 patients also underwent systematic coronary angiography to probe the antirestenotic effects of Integrelin. It is expected that the results of the IMPACT-2 trial will be made known by mid-1995. Oral lib/Ilia blocker. A phase I trial has demonstrated that the orally administered agent Xemlofiban can likewise achieve striking blockade of the glycoprotein IIb/IIIa receptor and commensurate inhibition of platelet aggregation. 18 A trial known as ORBIT (Oral Glycoprotein IIb/IIIa Receptor Blockade to Inhibit Thrombosis) to evaluate the agent's efficacy and safety in 480 patients undergoing coronary intervention procedures is planned for launch in mid-1995.
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CONCLUSIONS
REFERENCES
The EPIC study results have shown that c7E3 administered as a bolus followed by an infusion not only reduces the incidence of abrupt closure and acutephase adverse outcomes after coronary intervention procedures but also diminishes the need for subsequent revascularization. However, because this therapy carries a risk of bleeding complications and has been studied only in high-risk patients, further evaluation is needed before it can be applied to other patient groups. It will be necessary to develop strategies for minimizing bleeding complications, such as reducing the heparin dose, adjusting the dose of glycoprotein IIb/IIIa blocker according to body weight, and paying meticulous attention to the femoral vascular access site. Whether the glycoprotein IIb/ IIIa blockers will also prove effective in preventing ischemic complications in other acute coronary syndromes, such as with thrombolysis for acute myocardial infarction, is an important area for future study. Another intriguing question Concerns the different receptor specificities of the various glycoprotein IIb! IIIa blockers under development. For example, c7E3 binds not only to the glycoprotein IIb/IIIa receptor but also to other integrins, including vitronectin, which is found on the luminal surface of the endothelial cells. In contrast, Integrelin and other experimental agents such as MK-383 and Ro-44 are more specific for the glycoprotein IIb/IIIa receptor. Whether greater or lesser specificity is more desirable and whether these differences will actually translate into different clinical effects are issues that remain to be resolved. The EPIC findings demonstrated that the shortterm administration ofc7E3 results in a benefit that is sustained over time, which raises the possibility that blockade of integrin receptors may be involved in the process of passivation, in which an arterial surface that supports platelet deposition is transformed into a surface that will no longer support platelet deposition. This concept and the possible roles of integrin receptors other than glycoprotein IIb/IIIa in the biology of passivation will require further exploration.
1. Tcheng JE, Ellis SG, George BS, Kereiakes DJ, Kieiman NS, Talley JD, Wang AL, Weisman HF, Califf RM, Topol EJ. Pharmacodynamics of chimeric glycoprotein IIb/IIIa integrin antiplatelet antibody Fab 7E3 in high-risk coronary angioplasty. Circulation 1994;90:1757-64. 2. Bernardi MM, CaliffRM, Kieiman N, Ellis SG, Topol EJ. Lack of usefulness of prolonged bleeding times in predicting hemorrhagic events in patients receiving the 7E3 glycoprotein IIb/IIIa platelet antibody. Am J Cardiol 1993;72:1121-5. 3. The EPIC Investigators. Use ofa monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994;330:956-61. 4. Topol E J, Califf RM, Weisman HF, Ellis SG, Tcheng JE, Worly S, Ivanhoe R, George BS, Fintel D, Weston M, Sigmon K, Anderson KM, Lee KL, Willerson JT on behalf of the EPIC Investigators. Randomised trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: results at six months. Lancet 1994;343:881-6. 5. Stein B, Weintraub WS, Gebhart SSP, Cohen-Bernstein CL, Grosswald R, Liberman HA, Douglas JS, Morris DC, King SB. Influence of diabetes mellibus on early and late outcome after PTCA. Circulation 1995;91:979-89. 6. Omoigui N, Lefkovits J, Elliot J, Weisman H, for the EPIC Investigators. Does length of the coronary intervention procedure affect efficacy of platelet glycoprotein IIb/IIIa blockade? Results from the EPIC trial ]Abstract]. Circulation 1994;90(suppl I):I-568. 7. Lincoff AM, Califf RM, Anderson K, Weisman HF, Topol EJ, for the EPIC Investigators. Striking clinical benefit with platelet GP IIb/IIIa inhibition by c7E3 among patients with unstable angina [Abstract]. Circulation 1994;90(suppl I):I-21. 8. Topol EJ, Leya F, Pinkerton CA, Whitlow PL, Hofling B, Simonton CA, Masden RR, Serruys PW, Leon MB, Williams DO, King SB, Mark DB, Isner JM, Holmes DR, Ellis SG, Lee KL, Keeler Glycoprotein, Berdan LG, Hinohara T, CaliffRM, for the CAVEAT Study Group. A comparison of directional atherectomy with coronary angioplasty in patients with coronary artery disease. N Engl J Med 1993;329:221-7. 9. Lefkovits J, Anderson K, Weisman H, Topol E J, for the EPIC Investigators. Increased risk of non Q MI following DCA: evidence for a platelet dependent mechanism from the EPIC trial ]Abstract]. Circulation 1994;90(suppl I):I-214. 10. Lefkovits J, Ivanhoe R, Anderson K, Weisman H, Topol EJ, for the EPIC Investigators. Plateiet IIb/IIIa receptor inhibition during PTCA for acute myocardial infarction: insights from the EPIC trial [Abstract[. Circulation 1994;90(suppl I):I-564. 11. LincoffAM, Tcheng JE, Bass TA, Popma JJ, Teirstein PS, Kleiman NS, Weisman HF, Musco MH, Cabot CF, Berdan LG, CaliffRM, Topol EJ on behalf of the PROLOG Investigators. A multicenter, randomized, double-blind pilot trial of standard versus low dose weight-adjusted • heparin in patients treated with the platelet GP IIb/IIIa receptor antibody c7E3 during percutaneous coronary revascularization [Abstract]. J Am Coll Cardiol 1995;25:81. 12. Tcheng JE, Ellis SG, Kleiman NS, Harrington RA, Mick MJ, Navetta FI, Worley S, Smith JE, Kereiakes DJ, Kitt MM, Miller JA, Sigmon KN, Califf RM, Topol EJ. Outcome of patients treated with the GP IIb/IIIa inhibitor integrelin during coronary angloplasty: results of the IMPACT study [Abstract]. Circulation 1993;88(suppl I):I-595. 13. Anders RJ, Alexander JC, Hantsbarger GL, Burns DM, Oliver SD, Cole G, Fitzgerald DJ. Demonstration of potent inhibition ofplatelet aggregation with an orally active GP IIb/IIIa receptor antagonist [Abstract]. J Am Cell Cardiol 1995;25:117.
Among the major stumbling blocks to successful percutaneous transluminal coronary angioplasty (PTCA) are abrupt closure of the coronary vessel, which occurs during or soon after the procedure in as m a n y as 9% of patients, and late restenosis, which develops in at least 30% of cases during the first 6 months after angioplasty.l-4 Platelets are believed to play a role in the ischemic complications of coronary angioplasty, and accordingly, aspirin has been used in an attempt to reduce the incidence of acute closure and acute myocardial infarction after angioplasty. However, its prophylactic efficacy in this setting has been only modest: 10% to 20% of patients treated with aspirin still experience ischemic complications. Similarly, although it is known that the vascular injury that causes restenosis is accompanied by platelet thrombus formation and smooth muscle cell
From the Department of Cardiology and the Joseph J. Jacobs Center for Thrombosis and Vascular Biology, The Cleveland Clinic Foundation. Reprint requests: Erie J. Topol, MD, Department of Cardiology, Cleveland Clinic Foundation, Desk F25, 9500 Euclid Ave., Cleveland, OH 44195. Copyright © 1995 by Mosby-Year Book, Inc. 0002-8703/95/$3.00 + 0 4/0165588
666
changes, no agent directed against these mechanisms has yet been shown to reduce the incidence of restenosis. A recent breakthrough in molecular biology was the discovery that the platelet glycoprotein IIb/IIIa integrin is the receptor that mediates the final common pathway of platelet aggregation. Each platelet contains 50,000 to 100,000 glycoprotein IIb/IIIa receptors, which, in their normal conformation, are "tucked in" beneath the platelet membrane. When a platelet is acted on by an agonist, whether it be adenosine diphosphate, epinephrine, collagen, platelet activating factor, serotonin, thrombin, or shear stress, the receptors are exteriorized on the platelet surface and assume an active conformation. The activated receptor binds the fibrinogen ligand, which then cross-links receptors on adjacent platelets. It is this cross-linkage that causes platelet aggregation. Several agents that block the final common pathway ofplatelet aggregation have been developed, and a number of these agents are being tested clinically to determine whether such blockade would reduce the incidence of acute ischemic complications and restenosis after angioplasty. The largest experience to date has been with a chimeric monoclonal antibody Fab fragment (c7E3), which is directed against the glycoprotein IIb/IIIa receptor. This article discusses the results of recent clinical trials evaluating the efficacy and safety of glycoprotein IIb/IIIa blockade in patients undergoing angioplasty and explores the ramifications of these studies for interventional cardiology. PHARMACODYNAMICS OF GLYCOPROTEIN lib/Ilia INHIBITION WITH c7E3
The first study that used c7E3 in patients undergoing PTCA who were at high risk for ischemic complications confirmed that the antiplatelet antibody produces a dose-dependent blockade of platelet glycoprotein IIb/IIIa receptors and demonstrated that such receptor blockade correlated with inhibition of platelet aggregation. 1 Bolus doses of 0.15 and 0.25
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Table I. Thirty-day EPIC results: primary outcome events in the three treatment groups No. of patients (%)
Event* Primary endpoint Components of primary endpoint Death Nonfatal myocardial infarction Q wave Large non-Q-wave Small non-Q-wave Emergency PTCA Emergency CABG Stent placement Balloon-pump insertion
Placebo (n = 696)
c7E3 Fab bolus (n = 695)
c7E3 Fab bolus and infusion (n = 708)
89 (12.8)
79 (11.4)
59 (8.3)
12 (1.7) 60 (8.6) 16 (2.3) 28 (4.0) 16 (2.3) 31 (4.5) 35 (3.6) 4 (0.6) 1 (0.1)
9 (1.3) 43 (6.2) 7 (1.0) 19 (2.7) 17 (2.4) 25 (3.6) 16 (2.3) 12 (1.7) 1 (0.1)
12 (1.7) 37 (5.2) 6 (0.8) 21 (3.0) 10 (1.4) 6 (0.8) 17 (2.4) 4 (0.6) 1 (0.1)
p value for dose response 0.009t 0.96 0.013 0.020 0.265 0.239 <0.001 0.177 0.98 0.99
Reprinted with permission from The EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in highrisk coronary angioplasty. N Engl J Med 1994;330:956-61. Copyright 1994, Masschusetts Medical Society. CABG, Coronary artery bypass grafting. *PTCA denotes percutaneous coronary angioplasty or atherectomy, and CABG. tp = 0.009 for overall test for trend, p = 0.43 for comparison of the placebo group with the group given the bolus only, andp = 0.008 for comparison of the placebo group with the group given the bolus and infusion.
mg/kg blocked 54% and 87% of glycoprotein IIb/IIIa receptors, respectively, and decreased platelet aggregation in response to adenosine diphosphate to 46% and 18% of baseline values, respectively. Prolongation of the bleeding time beyond 30 minutes was observed shortly after administration of a bolus dose of 0.25 mg/kg. The effects of the 0.25 mg/kg bolus on receptor blockade, platelet aggregation, and bleeding time peaked in the first hour after administration and gradually returned to near normal by 24 to 36 hours after administration. When the 0.25 mg/kg bolus was followed by a 12-hour infusion of 10 ]Jg/kg, these antiplatelet effects were sustained for the entire duration of the infusion, with recovery beginning after discontinuation of the infusion. It has subsequently been shown that the increase in bleeding time produced by c7E3 does not correlate with bleeding events. 2 THE EPIC TRIAL
The Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC) trial was the first large-scale randomized study to address the question of whether platelet inhibition achieved through blockade of the platelet glycoprotein IIb/IIIa receptor would reduce the incidence of acute ischemic events and late restenosis after PTCA or directional coronary atherectomy. 3, 4 Patients and methods. The EPIC project enrolled 2099 high-risk patients undergoing angioplasty or atherectomy at 56 U.S. sites during a 10-month period. Candidates defined as being at high risk for
vessel closure included patients who had either an evolving or recent acute myocardial infarction, early postinfarction angina, unstable angina, or particular angiographic and clinical risk factors such as a lesion that contained thrombus, female gender, or diabetes. Criteria for exclusion from the study were an age of 80 years or older, a known hemorrhagic diathesis, a history of stroke within 2 years before the study, recent major surgery, or gastrointestinal bleeding. EPIC participants were randomized in doubleblind fashion to receive either c7E3 in a bolus dose of 0.25 mg/kg followed by an infusion of 10 l~g/min (708 patients), a c7E3 bolus followed by a placebo infusion (695 patients), or a placebo bolus and a placebo infusion (696 patients). All patients received aspirin, 325 mg by mouth, at least 2 hours before coronary intervention and daily thereafter, as well as intravenous bolus doses ofheparin, titrated to maintain the activated clotting time at 300 to 350 seconds during the procedure and to keep the activated partial thromboplastin time at 1.5 to 2.5 times the control value for at least 12 hours after the procedure. Thirty-day results. The incidence of death, myocardial infarction, emergency bypass surgery, emergency angioplasty, stent placement, or intraaortic balloon pump insertion was 12.8% in the double-placebo group, 11.4% in the c7E3 bolus placebo infusion group, and only 8.3% in patients treated with both active bolus and active infusion (Table I). 3 Thus treatment with a bolus and infusion of c7E3 reduced the rate of this primary composite endpoint by 35% relative to double placebo (p = 0.008). The reduction
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c7E3 boluS+ c7E3 infusion ,=.=,,,.= c7E3 bolus + placebo infusion - Placebo bolus + placebo infusion
E 0.9O Z •~-
0.8-
.~_ 0.7-
o.6 1 0
i 1
, 2
, 3
, 4
, 5
i 6
Months from Randomization
Fig. 1. Six-month EPIC results. Kaplan-Meier curve of all events (death, myocardial infarction, coronary revascularization) for all patients enrolled. A significant reduction of events occurred in the c7E3 bolus + infusion group, compared with bolus alone or placebo groups (p = 0.001). A substantial number of events occurred within the first month. (From Topol EJ, CaliffRM, Weisman HF, et al. Randomised trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: results at six months. Lancet 1994;343:881-6. ©by The Lancet Ltd, 1994.)
in the event rate achieved with the c7E3 bolus alone did not reach statistical significance. The improvement in the composite endpoint observed with the c7E3 bolus and infusion was attributable mainly to a 40% reduction in the incidence of nonfatal myocardial infarction (p = 0.013) and a 65% reduction in Qwave infarction in particular (p= 0.02) and to a halving of the need for emergency angioplasty or bypass surgery. However, the 30-day mortality rate, which ranged from 1.3% to 1.7%, did not differ between the three treatment groups. The principal disadvantage of treatment with the c7E3 bolus and infusion was a doubling in the incidence of major bleeding (14%, compared with 7% in the placebo group; p = 0.001) and the need for transfusion (15%, compared with 7% for placebo; p < 0.001). Fortunately, however, there was no excess of intracranial hemorrhages associated with c7E3 treatment. Body weight was the principal determin a n t of bleeding risk. Among patients who weighed 90 kg or more, the incidence of major bleeding was the same in all three treatment groups. In contrast, in the lightest tertile of patients, the incidence of major bleeding was 21% with the c7E3 bolus and infusion, 15% with the c7E3 bolus and placebo infusion, and only 7% with the double placebo. Interestingly, there was no excess of bleeding complications among actively treated patients who required emergency bypass surgery. It should be noted t h a t the EPIC protocol's omission of a standardized threshold for transfusion facilitated a high rate. At least half of
the transfusions could have been avoided if prospectively defined criteria such as hemoglobin less t h a n 9 gm/dl had been used. Six-month results. During a 6-month blinded follow-up period, the incidence of the combined endpoint of death, myocardial infarction, or elective revascularization was 23% lower among patients who had received the c7E3 bolus and infusion (27%) t h a n in the double-placebo group (35.1%). 4 The striking separation between the event-free curves over time is illustrated in Fig. 1. The difference in outcome was accounted for mainly by a 26% reduction in the need for repeat angioplasty or bypass, from 22.3% among patients who received placebo bolus and placebo infusion to 16.5% among patients given the c7E3 bolus and infusion (Fig. 2). As was true for the shortterm results, patients who received the c7E3 bolus alone had an intermediate outcome t h a t was not significantly better t h a n t h a t in the double-placebo group. These findings are the first to suggest t h a t clinical restenosis can be prevented pharmacologically. Overall, the EPIC data indicate t h a t the administration ofc7E3 as a bolus and infusion to 100 patients would avoid abrupt closure events in five patients and would spare an additional eight patients the need for repeat revascularization. R i s k f a c t o r s f o r r e s t e n o s i s . As in past restenosis trials, 5 multivariate analysis of the EPIC results revealed t h a t diabetes was an important factor in increasing the risk of clinical restenosis.
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c7E3 bolus + c7E3 infusion ..==.~ c7E3 bolus + placebo infusion
2
~.
0.9
o
0.
0.8
0
I
I
I
I
I
I
1
2
3
4
5
6
Months from Randomization
Fig. 2. Six-month EPIC results. Need for subsequent target vessel revascularization, either by coronary angioplasty or coronary bypass surgery. Repeat revascularization was significantly reduced in the c7E3 bolus + infusion group, compared with placebo (p = 0.007). (From Topol EJ, CaliffRM, Weisman HF, et al. Randomised trial of coronary intervention with antibody against plateiet IIb/IIIa integrin for reduction of clinical restenosis: results at six months. Lancet 1994;343:881-6. © by The Lancet Ltd, 1994.)
Prolonged angioplasty procedures were also associated with a higher risk of restenosis in the EPIC study, with the rate of restenosis increasing significantly for every 30-minute increase in procedure length. 6 In fact, for procedures longer than 70 minutes in duration, the protective effect ofplatelet IIb/ IIIa inhibition was no longer significant (Table II). However, for procedures lasting less than 40 minutes or between 40 and 70 minutes, the effectiveness of c7E3 in reducing the event rate was sustained. Outcome in patients with unstable angina.A dramatic improvement in outcome with the c7E3 bolus and infusion was observed in the 470 EPIC subjects who fulfilled the criteria for unstable angina. 7 With the active bolus and infusion, the 30-day incidence of death or myocardial infarction dropped from 9.2% to 0.6% and the incidence of urgent revascularization fell from 5.9% to 3.2%, with the composite 30-day endpoint rate decreasing by 70.6%, from 13% to 3.8% (Fig. 3). Interestingly, although the reduction in restenosis was not as substantial during the 6-month follow-up period, the rate of myocardial infarction was reduced from 11.3% to 1.3% and the death rate was reduced from 6.7% to 0.7% among patients who were given the c7E3 bolus and infusion. It is likely that the more marked clinical benefits ofplatelet inhibition in patients with unstable angina may be explained by heightened platelet activity in the unstable coronary plaque. Outcome in patients undergoing atherectomy. The EPIC results provided independent confirmation of the Coronary Angioplasty Versus Excisional Ather-
Table IL Relationship between duration of coronary inter-
vention procedure and efficacy of c7E3 bolus and infusion in the EPIC trial
Duration (rain) <40
Bolus + p-value (bolus Placebo Bolus infusion + infusion (%) (%) (%) vs placebo)
56/206 54/207 (27.7) (26.3) 40-70 59/190 48/200 (31.6) (24.5) >70 77/214 79/214 (36.4) (37.2) Univariate duration <0.001 0.033 p value
40/212 (19.2) 48/227 (21.5) 53/172 (31.3) <0.001
0.042 0.012 NS <0.001
NS, Not significant. Reproduced with permission from Omoigui N, Lefkovits J, Elliot J, Weisman H, for the EPIC Investigators• Does length of the coronary intervention procedtLre affect efficacy of platelet glycoprotein IIb/IIIa blockade? Results from the EPIC trial [Abstract]. Circulation 1994;90(suppl I):I-568. Copyright 1994, American Heart Association.
ectomy Trial (CAVEAT) finding that atherectomy results in a higher incidence of non-Q-wave infarction than does angioplasty, s The rate of non-Q-wave infarction was 15.2% among the 199 EPIC patients who underwent directional coronary atherectomy, compared with only 8.1% among those treated with PTCA. 9 However, this excess risk w a s virtually eliminated by treatment with the c7E3 bolus and infusion (Fig. 4), which suggests that the mechanism underlying the occurrence of non-Q-wave infarction after atherectomy may be platelet dependent.
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15 D
PL
[]BO
10
B
13
BO+IN
p = 0.004
9.2
p = 0.011
p = 0.001
p = NS
8.1
-(2_
=o
-
5.9
5
~3.8
0 Death
MI CABG/PTCA 30-Day Endpoints
Composite
Fig. 3. Effect of c7E3 bolus (BO) and infusion (IN) on 30-day endpoints in patients with unstable angina in the EPIC trial. (Reproduced with permission from LincoffAM, Califf RM, Anderson K, Weisman HF, Topol EJ, for the EPIC Investigators. Striking clinical benefit with platelet GP IIb/IIIa inhibition by c7E3 among patients with unstable angina [Abstract]. Circulation 1994;90(suppl I):I-21. Copyright 1994, American Heart Association.)
I
I 15.2
16
12.1 o
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~
0
PTCA
5.0
4.5
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B
30-Day Endpoints
Fig. 4. Impact ofc7E3 bolus (BO) and infusion (IN) on the incidence of non-Q-wave infarction after PTCA and directional coronary atherectomy in the EPIC trial. (Reproduced with permission from Lefkovits J, Anderson K, Weisman H, Topol EJ, for the EPIC Investigators. Increased risk ofnon-Q MI following DCA: evidence for a platelet dependent mechanism from the EPIC trial [Abstract]. Circulation 1994;90(suppl I):I-214. Copyright 1994 American Heart Association.)
Outcome in patients undergoing primary and rescue PTCA. The impact of c7E3 treatment on the event
rate was particularly noteworthy in the 66 EPIC patients who underwent primary or rescue PTCA for acute myocardial infarction. 1° Only 4.5% of the patients in this small subgroup who received the c7E3 bolus and infusion experienced an adverse event throughout the 6-month follow-up period, compared with nearly half of their placebo-treated
counterparts (Table III). At 30 days the reinfarction rate was zero with the active bolus and infusion versus 8.7% with double placebo, the incidence of urgent intervention was zero versus 17% with placebo, and the rate of the composite endpoint was 4.5% versus 26% with placebo. These findings suggest the need for further study of the role of potent platelet antagonism in the setting of primary angioplasty for acute myocardial infarction.
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Table III. Effect of c7E3 bolus and infusion on 30-day and 6-month composite endpoints in patients undergoing
primary and rescue PTCA in the EPIC trial
Results
Placebo (n = 23) (%)
Bolus (n = 19) (%)
Bolus + infusion (n = 22) (%)
p value (bolus + infusion vs placebo)
30-day composite endpoint Major bleeding 6-month composite endpoint
26.1 13 47.8
21.1 31.6 32.3
4.5 18.2 4.5
0.058 NS 0.002
NS, Not significant. Reproduced with permission from Lefkovits J, Ivanhoe R, Anderson K, Weisman H, Topol EJ, for the EPIC Investigators. Platelet IIb/iIIa receptor inhibition during PTCA for acute myocardial infarction: insights from the EPIC trial [Abstract]. Circulation 1994;90(suppl I):I-564. Copyright 1994, American Heart Association.
ONGOING CLINICAL TRIALS OF GLYCOPROTEIN lib/Ilia INHIBITION PROLOG and EPILOG trials, In the nine-center PRO-
LOG pilot study to the forthcoming Evaluation in PTCA to Improve Long-Term Outcome with Reo-Pro Glycoprotein IIb/IIIa Blockade (EPILOG) trial, 103 patients undergoing coronary intervention procedures were randomized to receive c7E3 plus either the standard dose of heparin (to achieve activated clotting time >300 seconds) or a low heparin dose, both of which were adjusted according to body weight, n The results suggested that the low weightadjusted heparin dose, which averaged approximately two thirds of the normal dose, decreased the activated clotting time from a median of 330 to 250 seconds, substantially reducing both the need for transfusion and the incidence of hematoma. In addition, patients in the PROLOG trial were randomly assigned either to undergo removal of the vascular sheath soon after the procedure or to have their sheaths left in place until the day after the procedure. Interestingly, early sheath removal appeared to be associated with lower rates of transfusion and hematomas at the access site. This finding suggests that platelet aggregation need not be intact to achieve hemostasis after sheath removal. Thus the PROLOG data may help us to modulate bleeding complications and further refme the practical aspects of therapy with IIb/IIIa blockade in patients undergoing coronary intervention. The ongoing EPILOG trial will attempt to confirm the PROLOG results in a large population undergoing routine coronary intervention. An anticipated 5000 patients undergoing angioplasty will be randomly assigned to receive a c7E3 bolus and infusion along with either low or high doses ofheparin. In addition to clinical follow-up, 300 patients in each treatment group will be evaluated by quantitative angiography. IMPACT and IMPACT-2 studies. The phase II Integrelin to Manage Platelet Aggregation to Prevent
Coronary Thrombosis (IMPACT) study assessed the efficacy and safety of another glycoprotein IIb/IIIa inhibitor, Integrelin, which is a cyclic heptapeptide with a short half-life.12 In this study, 150 patients undergoing routine elective PTCA at 14 centers were randomly assigned to receive either Integrelin or placebo 30 minutes before and for either 4 or 12 hours after the procedure. All participants were also treated with aspirin and heparin. The primary composite endpoint of death, myocardial infarction, repeat angioplasty, bypass surgery, or stent implantation, was reached at the time of release from the hospital by 7.9% of patients treated with Integrelin and by 10.2% of patients in the placebo group, and at 30 days by 8.1% of patients treated with Integrelin versus 11.1% of those who received placebo. The favorable effects of Integrelin were accomplished without an accompanying increase in the incidence of moderate or severe bleeding. In the randomized, placebo-controlled IMPACT-2 trial that was recently completed, 4010 patients undergoing coronary intervention procedures were assigned to receive Integrelin in a bolus dose of 135 mg/kg followed by an infusion of either 0.5 or 0.75 mg/kg for 20 to 24 hours. Along with clinical followup, 900 IMPACT-2 patients also underwent systematic coronary angiography to probe the antirestenotic effects of Integrelin. It is expected that the results of the IMPACT-2 trial will be made known by mid-1995. Oral lib/Ilia blocker. A phase I trial has demonstrated that the orally administered agent Xemlofiban can likewise achieve striking blockade of the glycoprotein IIb/IIIa receptor and commensurate inhibition of platelet aggregation. 18 A trial known as ORBIT (Oral Glycoprotein IIb/IIIa Receptor Blockade to Inhibit Thrombosis) to evaluate the agent's efficacy and safety in 480 patients undergoing coronary intervention procedures is planned for launch in mid-1995.
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CONCLUSIONS
REFERENCES
The EPIC study results have shown that c7E3 administered as a bolus followed by an infusion not only reduces the incidence of abrupt closure and acutephase adverse outcomes after coronary intervention procedures but also diminishes the need for subsequent revascularization. However, because this therapy carries a risk of bleeding complications and has been studied only in high-risk patients, further evaluation is needed before it can be applied to other patient groups. It will be necessary to develop strategies for minimizing bleeding complications, such as reducing the heparin dose, adjusting the dose of glycoprotein IIb/IIIa blocker according to body weight, and paying meticulous attention to the femoral vascular access site. Whether the glycoprotein IIb/ IIIa blockers will also prove effective in preventing ischemic complications in other acute coronary syndromes, such as with thrombolysis for acute myocardial infarction, is an important area for future study. Another intriguing question Concerns the different receptor specificities of the various glycoprotein IIb! IIIa blockers under development. For example, c7E3 binds not only to the glycoprotein IIb/IIIa receptor but also to other integrins, including vitronectin, which is found on the luminal surface of the endothelial cells. In contrast, Integrelin and other experimental agents such as MK-383 and Ro-44 are more specific for the glycoprotein IIb/IIIa receptor. Whether greater or lesser specificity is more desirable and whether these differences will actually translate into different clinical effects are issues that remain to be resolved. The EPIC findings demonstrated that the shortterm administration ofc7E3 results in a benefit that is sustained over time, which raises the possibility that blockade of integrin receptors may be involved in the process of passivation, in which an arterial surface that supports platelet deposition is transformed into a surface that will no longer support platelet deposition. This concept and the possible roles of integrin receptors other than glycoprotein IIb/IIIa in the biology of passivation will require further exploration.
1. Tcheng JE, Ellis SG, George BS, Kereiakes DJ, Kieiman NS, Talley JD, Wang AL, Weisman HF, Califf RM, Topol EJ. Pharmacodynamics of chimeric glycoprotein IIb/IIIa integrin antiplatelet antibody Fab 7E3 in high-risk coronary angioplasty. Circulation 1994;90:1757-64. 2. Bernardi MM, CaliffRM, Kieiman N, Ellis SG, Topol EJ. Lack of usefulness of prolonged bleeding times in predicting hemorrhagic events in patients receiving the 7E3 glycoprotein IIb/IIIa platelet antibody. Am J Cardiol 1993;72:1121-5. 3. The EPIC Investigators. Use ofa monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994;330:956-61. 4. Topol E J, Califf RM, Weisman HF, Ellis SG, Tcheng JE, Worly S, Ivanhoe R, George BS, Fintel D, Weston M, Sigmon K, Anderson KM, Lee KL, Willerson JT on behalf of the EPIC Investigators. Randomised trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: results at six months. Lancet 1994;343:881-6. 5. Stein B, Weintraub WS, Gebhart SSP, Cohen-Bernstein CL, Grosswald R, Liberman HA, Douglas JS, Morris DC, King SB. Influence of diabetes mellibus on early and late outcome after PTCA. Circulation 1995;91:979-89. 6. Omoigui N, Lefkovits J, Elliot J, Weisman H, for the EPIC Investigators. Does length of the coronary intervention procedure affect efficacy of platelet glycoprotein IIb/IIIa blockade? Results from the EPIC trial ]Abstract]. Circulation 1994;90(suppl I):I-568. 7. Lincoff AM, Califf RM, Anderson K, Weisman HF, Topol EJ, for the EPIC Investigators. Striking clinical benefit with platelet GP IIb/IIIa inhibition by c7E3 among patients with unstable angina [Abstract]. Circulation 1994;90(suppl I):I-21. 8. Topol EJ, Leya F, Pinkerton CA, Whitlow PL, Hofling B, Simonton CA, Masden RR, Serruys PW, Leon MB, Williams DO, King SB, Mark DB, Isner JM, Holmes DR, Ellis SG, Lee KL, Keeler Glycoprotein, Berdan LG, Hinohara T, CaliffRM, for the CAVEAT Study Group. A comparison of directional atherectomy with coronary angioplasty in patients with coronary artery disease. N Engl J Med 1993;329:221-7. 9. Lefkovits J, Anderson K, Weisman H, Topol E J, for the EPIC Investigators. Increased risk of non Q MI following DCA: evidence for a platelet dependent mechanism from the EPIC trial ]Abstract]. Circulation 1994;90(suppl I):I-214. 10. Lefkovits J, Ivanhoe R, Anderson K, Weisman H, Topol EJ, for the EPIC Investigators. Plateiet IIb/IIIa receptor inhibition during PTCA for acute myocardial infarction: insights from the EPIC trial [Abstract[. Circulation 1994;90(suppl I):I-564. 11. LincoffAM, Tcheng JE, Bass TA, Popma JJ, Teirstein PS, Kleiman NS, Weisman HF, Musco MH, Cabot CF, Berdan LG, CaliffRM, Topol EJ on behalf of the PROLOG Investigators. A multicenter, randomized, double-blind pilot trial of standard versus low dose weight-adjusted • heparin in patients treated with the platelet GP IIb/IIIa receptor antibody c7E3 during percutaneous coronary revascularization [Abstract]. J Am Coll Cardiol 1995;25:81. 12. Tcheng JE, Ellis SG, Kleiman NS, Harrington RA, Mick MJ, Navetta FI, Worley S, Smith JE, Kereiakes DJ, Kitt MM, Miller JA, Sigmon KN, Califf RM, Topol EJ. Outcome of patients treated with the GP IIb/IIIa inhibitor integrelin during coronary angloplasty: results of the IMPACT study [Abstract]. Circulation 1993;88(suppl I):I-595. 13. Anders RJ, Alexander JC, Hantsbarger GL, Burns DM, Oliver SD, Cole G, Fitzgerald DJ. Demonstration of potent inhibition ofplatelet aggregation with an orally active GP IIb/IIIa receptor antagonist [Abstract]. J Am Cell Cardiol 1995;25:117.