- Email: [email protected]
IIIa inhibitors
An overview of the results of clinical trials with glycoprotein IIb/IIIa inhibitors A.A. Jennifer Adgey, MD Belfast, Northern Ireland
The era of platelet glycoprotein (GP) IIb/IIIa receptor inhibition in cardiology was inaugurated in 1994 with the publication of the Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) trial results. EPIC demonstrated that the GP IIb/IIIa blocker abciximab, administered as a bolus and 12-hour infusion, afforded protection against ischemic complications in high-risk patients undergoing angioplasty and atherectomy, including those with unstable angina or evolving myocardial infarction (MI). A significant reduction in the incidence of death, acute MI, or revascularization was apparent at 30 days and also sustained at 6-month and 3-year follow-up. The subsequent Evaluation in PTCA to Improve Long-Term Outcome with Abciximab GP IIb/IIIa Blockade (EPILOG) study extended these findings to the full spectrum of coronary intervention patients, confirming that abciximab provided similar benefits in low-risk patients as well. The EPILOG trial also proved that any excess bleeding risk associated with potent antiplatelet therapy could be brought down to placebo levels through the use of a low-dose, weight-adjusted heparin regimen, early vascular sheath removal, and elimination of routine postprocedural heparinization. The potential for an advantage of GP IIb/IIIa blockade in patients with refractory unstable angina/non-Q-wave MI was demonstrated in the c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) trial, which showed that a 24-hour preprocedural abciximab infusion effectively stabilized these patients, thereby enhancing the safety of intervention and reducing the 30-day incidence of ischemic events. A similar pattern of benefit has emerged from clinical trials of such other GP IIb/IIIa inhibitors as eptifibatide, lamifiban, and tirofiban. Trials are currently underway to clarify the benefits of GP IIb/IIIa blockers in patients undergoing stenting and as an adjunct to thrombolytic therapy or primary angioplasty in patients with acute MI (ST-segment elevation). (Am Heart J 1998;135:S43-S55.)
Platelets are believed to play a preeminent role in the development of ischemic events complicating percutaneous coronary intervention and in the pathogenesis of unstable angina and acute myocardial infarction (MI). This hypothesis has provided the rationale for recent large-scale clinical trials exploring whether interruption of the final common pathway of platelet aggregation with agents that block the platelet surface glycoprotein (GP) IIb/IIIa receptor would improve the outcome in individuals undergoing coronary intervention procedures and in those with an acute coronary syndrome. To date, four parenteral GP IIb/IIIa receptor blockers have been evaluated in the clinic. The most extensively studied of these agents and the only one currently available commercially is abciximab (c7E3 Fab [ReoPro]). This chimeric monoclonal antibody Fab fragment binds to the GP IIb/IIIa receptor and the αvβ3 (vitronectin) receptor, which is involved in vascular smooth muscle cell migration and proliferation. In contrast, the investiFrom the Royal Victoria Hospital. Reprint requests: A.A. Jennifer Adgey, MD, Royal Victoria Hospital, Grosvenor Road, Belfast, Northern Ireland BT12 6BA. Copyright © 1998 jointly by Mosby, Inc. and The European Society of Cardiology. 0002-8703/98/$5.00 + 0 4/0/88307
gational agents eptifibatide (Integrilin), lamifiban, and tirofiban are all synthetic nonpeptide compounds of low molecular weight that are specific for the GP IIb/IIIa receptor. In comparison with abciximab, these agents exhibit shorter biologic half-lives. This article will survey the results of clinical trials of GP IIb/IIIa inhibitors in the interventional setting and in the management of acute coronary syndromes and discuss the implications of these findings.
Abciximab trials EPIC Goals and methods. The first large-scale test of the premise that antiplatelet treatment, as directed against the GP IIb/IIIa receptor, could protect against postprocedural abrupt vessel closure and acute MI was accomplished in the Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) study.1 The aim of this 56-center, randomized, double-blind trial was to determine whether a bolus dose of abciximab, coupled with either a 12-hour abciximab infusion or a placebo infusion, would be more effective than a placebo bolus and placebo infusion in reducing the incidence of ischemic complications in nearly 2100 high-risk patients undergo-
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Figure 1
A
B
C
Event-rate curves of patients reaching composite end point in three major abciximab trials for 30 days (A; composite end point of death, MI, or urgent intervention) and 6 months (B; composite end point of death, MI, or any intervention). According to EPIC 3-year follow-up results, clinical benefits of abciximab were maintained over long term (C). Three years after randomization, incidence of composite end point of death, acute MI, or revascularization remained lower among high-risk coronary intervention patients who received abciximab bolus plus infusion. A and B courtesy of Centocor, Inc. C Adapted with permission from Topol EJ, Ferguson JJ, Weisman HF, et al. JAMA 1997;278:479-84. Copyright © 1997, American Medical Association.
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Table I. GP IIb/IIIa inhibitor studies with composite death, MI, intervention end point Composite rate of death, MI, revascularization (%)* Study EPIC 30-Day1 6-Month2 3-Year3 EPILOG15
Placebo
12.8 35.1 47.2
30-Day 6-Month CAPTURE21 30-Day 6-Month IMPACT-II24
11.7 25.8
30-Day Canadian Lamifiban Study27 1-Month RESTORE34 30-Day
11.4
15.9 30.8
14.6 12.2
Drug Abciximab bolus + infusion 8.3 27.0 41.1 Abciximab bolus + infusion: low-dose heparin; standard-dose heparin 5.2; 5.4 22.8; 22.3 Abciximab infusion 11.3 31.0 Eptifibatide bolus + infusion: low-dose infusion; high-dose infusion 9.2; 9.9 Lamifiban infusion: all four dosage groups 10.3 Tirofiban bolus + infusion 10.3
p Value
0.008 0.001 0.009 <0.001; <0.001 0.07; 0.04 0.012 NS 0.063; 0.22 NS 0.160
*30-day rates include urgent revascularization. Longer term rates include any revascularization.
ing percutaneous transluminal coronary angioplasty (PTCA) or atherectomy. The EPIC investigators categorized study candidates as high risk if they had unstable angina, were undergoing direct or rescue intervention within 12 hours of acute MI, or had high-risk lesion morphologic characteristics. In addition to the study regimen, all participants received standard therapy with oral aspirin and intravenous, non-weight-adjusted heparin. 30-Day results. It could be said that the era of GP IIb/IIIa inhibition in interventional cardiology was effectively inaugurated by the EPIC 30-day results. Abciximab bolus plus an abciximab infusion yielded a 35% reduction compared with placebo (event rates of 8.3% vs 12.8%) in the 30-day primary end point of death, acute MI, or urgent reintervention (Fig. 1, A)1; Table I summarizes results of GP IIb/IIIa inhibitor trials using this composite end point. Treatment with an abciximab bolus alone (EPIC) resulted in a composite event rate that was intermediate between that seen with the bolus plus infusion and that documented with placebo. The major drawback of the active bolus and infusion regimen, however, was a 14% incidence of major bleeding events, which was double the risk associated with placebo bolus and placebo infusion. Bleeding complication rates in the trials shown in Table I are summarized in Table II. 6-Month results. Follow-up of the EPIC participants
revealed that the benefits of the abciximab bolus and infusion were maintained over a 6-month period (Fig. 1, B).2 Patients who received the active bolus and infusion showed a 23% lower composite event rate than did their placebo-treated counterparts (27% vs 35.1%). This reduction in the event rate mainly reflected a decreased need for coronary artery bypass grafting (CABG) or repeat percutaneous intervention. 3-Year results. The durable impact of treatment on long-term outcome with an abciximab bolus and infusion compared with placebo bolus and infusion was confirmed in a long-term follow-up study that demonstrated a 13% reduction in the 3-year composite event rate (41.1% vs 47.2%; Fig. 1, C).3 This benefit consisted of a 21% reduction in MI (10.7% vs 13.6%) and a 13% reduction in the need for repeat revascularization (34.8% vs 40.1%). The 3-year mortality rate reduction of 60% (5.1% vs 12.7%) was confined to the highest risk subgroup of EPIC patients, that is, those with evolving MI or unstable angina. At 3 years, the mortality rate end point for patients who were not classified as having evolving MI or unstable angina was 7.4% for the bolus plus infusion group and 7.2% for the placebo group. Interestingly, the investigators observed a correlation between long-term survival and the reduction in the incidence of periprocedural MI related to abciximab. They noted that the higher the magnitude of periproce-
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Table II. Major and minor bleeding complications in GP IIb/IIIa inhibitor trials Bleeding rates (%)* Study
Placebo
EPIC14 Major Minor EPILOG15 Major
6.6 9.8
Minor
3.7
CAPTURE21 Major Minor IMPACT-II24 Major Minor Canadian Lamifiban Study27 Major Minor RESTORE34 (major)
3.1
1.9 2.0† 4.8 Not reported 0.8 1.6 2.1
Drug Abciximab 14.0 16.9 Abciximab Low-dose heparin: 2.0 Standard-dose heparin: 3.5 Low-dose heparin: 4.0 Standard-dose heparin: 7.4 Abciximab 3.8 4.8† Eptifibatide Low-dose infusion: 5.1 High-dose infusion: 5.2 Not reported Lamifiban 2.9 11.1 Tirofiban 2.4
*All studies used TIMI criteria for major bleeding except the Canadian Lamifiban Study, which used criteria of intracranial hemorrhage, tamponade, ≥5 g/dl decrease in hemoglobin, or need for transfusion. †Excluding patients who underwent CABG.
dural creatine kinase (CK) elevation, the greater the risk for late cardiac death (Fig. 2). Unstable angina subgroup. In a subset of 489 EPIC patients with unstable angina,4 abciximab treatment with bolus plus infusion was associated with a 62% decrease in death, MI, or urgent revascularization compared with placebo at 30 days (4.8% vs 12.8%; p = 0.012), with marked reductions in death (1.2% vs 3.2%) and MI (1.8% vs 9.0%). At 6 months, cumulative death (1.8% vs 6.6%; p = 0.018) and MI (2.4% vs 11.1%; p = 0.002) were further reduced in abciximab patients. These benefits were even greater when analysis was restricted to the 470 patients who actually received study treatment. In these patients, composite end point rates were 3.8% in the abciximab bolus plus infusion group and 13.1% in the placebo group at 30 days (p = 0.004 for dose response), including a 94% reduction in death and MI (0.6% vs 11.1%; p < 0.001). At 6 months, composite end point rates (including any revascularization) were 24.3% and 35.0%, respectively (p = 0.024 for dose response), with an 88% reduction in risk for death or MI in the abciximab group (2.0% vs 16.6%; p < 0.001). As noted
above, 3-year analyses indicated that this mortality rate reduction was sustained in patients with unstable angina. Acute MI subgroup. The EPIC acute MI subpopulation, which included 42 patients who underwent primary PTCA for acute MI and 22 patients who had rescue PTCA after failed thrombolysis, likewise fared extremely well after treatment with the abciximab bolus and infusion. In this small series of patients, who were at especially high risk of recurrent ischemic events, the 6month composite end point was significantly reduced from 47.8% with placebo to 4.5% with abciximab bolus and infusion (91% reduction).5 There was also a trend toward a decrease in the 30-day event rate (26.1% vs 4.5%; 83% reduction; p = 0.06).5 Non-MI, nonunstable angina subgroup. In patients with high-risk coronary anatomy, 30-day primary end point rates were 12.7% in the placebo group and 9.3% in the abciximab bolus plus infusion group (hazard ratio 0.5 [range, 0.3 to 0.9]).1 Among patients with stable angina and high-risk coronary anatomy, 6-month composite event rates were 36.2% in the placebo group and 28.0% in the bolus plus infusion group (p = 0.013).2 Other subgroups
Atherectomy substudy. Among the 197 EPIC patients who underwent directional coronary atherectomy, those assigned to placebo treatment experienced a doubled incidence of non-Q-wave MI relative to the PTCA population.6 However, this excess risk was eliminated by treatment with the abciximab bolus plus infusion. Restenotic lesions and vein-graft lesions. In the 237 patients who had undergone prior PTCA of the target lesion within the preceding 12 months compared with placebo (n = 92), treatment with abciximab bolus plus infusion (n = 70) reduced the 30-day event rate from 14.1% to 2.9% and decreased the 6-month event rate from 39.4% to 26.0%.7 Urgent interventions fell from 14.1% to 0.0% and the clinical restenosis rate (defined as death, MI, or repeat revascularization) declined by 34% with abciximab. Similarly, among the 114 patients who underwent revascularization of saphenous vein grafts, bolus plus infusion treatment decreased the 30day rate of clinical events from 12.9% to 7.5%, although it did not significantly affect the 6-month composite end point.8 It should be noted that the small sample sizes of these subgroup analyses provide inadequate statistical power to detect differences reliably. Patients with diabetes. For the 506 high-risk patients with diabetes enrolled in EPIC, the benefits of treatment were tempered by an increase in bleeding complications.9 Regarding efficacy of abciximab, patients with diabetes
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Figure 2
Estimated mortality rates according to magnitude of periprocedural increase in CK level. Adapted with permission from Topol EJ, Ferguson JJ, Weisman HF, et al. JAMA 1997;278:479-84. Copyright © 1997, American Medical Association.
also had higher event rates (death, MI, or target vessel revascularization) at 6 months than patients without diabetes. Patients with diabetes who received abciximab bolus and infusion had a 36% rate of clinical restenosis. Patients without diabetes who received abciximab had a lower rate of restenosis (24%). Thus abciximab treatment did not appear to benefit patients with diabetes. Cost analysis. The current environment of health care cost containment mandates that new therapies be economically as well as medically justified. The EPIC economic substudy showed that the initial in-hospital cost savings afforded by the reduction in ischemic events with abciximab was offset by an increase in costs related to the treatment of bleeding complications.10 Long-term costs, however, were significantly lower in patients treated with abciximab, thanks to the decreased need for repeat hospitalization and revascularization. At 6-month follow-up, the average savings was $1270 per patient exclusive of drug cost; with the $1407 cost of bolus and infusion considered, the net cumulative 6month cost of treatment with abciximab averaged less than $300 per patient.10 Moreover, according to another analysis, the cost per patient treated was actually $3148 less with abciximab than with placebo to achieve a 6month event-free course.11 Another analysis of the pharmacoeconomics of EPIC, using 1-year results, appears in this issue (van Hout et al.).12
Favorable cost-effectiveness ratios for all high-risk patients undergoing PTCA, and particularly patients with unstable angina, are reported. The article by Murphy et al.13 explores the pharmacoeconomic issue of adopting abciximab therapy as the standard of care in percutaneous intervention. The standpoints of efficacy, safety, and economics are considered by using generalized models of the cost of coronary intervention, the EPIC economic substudy, the EPILOG economic data, and estimation of indirect costs. Bleeding risk. Bleeding complications unrelated to bypass surgery were two to three times more frequent in patients receiving abciximab than in those receiving placebo. Such complications occurred in 10.6% of those receiving abciximab bolus plus infusion and 3.3% of placebo recipients, with blood product transfusions being used in 16.8% and 7.5%, respectively.14 Further analysis suggested the possibility that use of low-dose, weight-adjusted heparin regimens might enhance safety of GP IIb/IIIa blockade. This assumption was subsequently confirmed in the Evaluation in PTCA to Improve Long-Term Outcome with Abciximab GP IIb/IIIa Blockade (EPILOG) trial. Clinical ramifications. EPIC was the first study to demonstrate conclusively that GP IIb/IIIa receptor blockade can prevent ischemic events in high-risk patients undergoing percutaneous intervention. The
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Figure 3
EPILOG study proved that benefits of abciximab extended beyond high-risk angioplasty population studied in EPIC to low-risk candidates for intervention as well. Abciximab plus low-dose heparin reduced incidence of 30day composite end point of death, acute MI, or revascularization by approximately 70% among low-risk patients and by approximately 50% among high-risk patients.
superior efficacy of the abciximab bolus teamed with a 12-hour infusion, relative to the bolus alone, highlighted the need for sustained postprocedural treatment. The advantages of abciximab were documented across the board, including the all-important subgroups of patients with the acute coronary syndromes of unstable angina or MI. Perhaps most strikingly, the short-term benefits of abciximab were maintained over 6 months of follow-up and also translated into a significantly improved 3-year outcome. Moreover, EPIC was the first trial to demonstrate that a treatment that reduces the incidence of periprocedural acute MI can also boost late survival.3
EPILOG Goals and methods. The dual objectives of the EPILOG trial were to determine (1) whether the benefits of abciximab demonstrated in the EPIC trial would extend to low-risk patients undergoing coronary intervention procedures and (2) whether the use of a low-dose heparin regimen in conjunction with abciximab would enhance the safety of GP IIb/IIIa blockade while preserving efficacy.15 To this end, patients at 69 North American centers were randomly assigned in doubleblind fashion to treatment with placebo plus standarddose heparin (100 U/kg plus bolus doses as needed to
achieve an activated coagulation time [ACT] of ≥300 sec) or abciximab (bolus plus 12-hour infusion) plus standard-dose heparin or abciximab (bolus plus 12-hour infusion) plus low-dose heparin (70 U/kg plus bolus doses as needed to achieve an ACT of ≥200 sec). In an effort to further improve safety, the protocol dictated that heparin be discontinued immediately after intervention and that vascular sheaths be removed once the ACT reached 175 seconds or less; the Precursor to EPILOG (PROLOG) study, performed to assess such a protocol, had shown that low-dose, weight-adjusted heparin and early sheath removal were associated with lower rates of bleeding and transfusion, with rates being lowest when both measures were used.16 Given the prior demonstration of substantial clinical benefit of abciximab in patients with acute ischemic syndromes, patients with unstable angina and associated changes on electrocardiographic analysis and patients who had had an acute MI within the past 24 hours were excluded, as were those scheduled to undergo stent implantation or atherectomy. 30-Day efficacy results. At interim analysis, evidence of unequivocal benefit with both regimens that contained abciximab necessitated premature termination of EPILOG after 2792 of the planned 4800 patients had been enrolled.15 The investigators reported an approximate
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56% reduction in the primary composite end point of death, acute MI, and urgent revascularization at 30 days in both the standard-dose heparin abciximab group and the low-dose heparin abciximab group compared with placebo (event rates of 5.4%, 5.2%, and 11.7%, respectively; Fig. 1, A). Similar reductions in risk were observed for each of the individual components of the composite end point as well. The benefits of abciximab were consistent across all patient groups, including high-risk patients who had had an infarct within the 7 days before randomization or had adverse lesion morphologic characteristics, and low-risk patients. Although patients with electrocardiographically documented unstable angina were excluded, abciximab with low-dose heparin was apparently effective in patients with clinical signs of unstable angina, who comprised nearly half of the study population. Safety results. In contrast to the EPIC results, no significant differences in major bleeding risk were documented among the three EPILOG treatment arms.15 Major bleeding events (defined by Thrombolysis In Myocardial Infarction [TIMI] criteria17) occurred in 3.5% and 2.0% of patients who received standard-dose heparin and abciximab and low-dose heparin and abciximab, respectively, compared with 3.1% of the placebo group. The incidence of minor bleeding events in the group that received abciximab plus low-dose heparin was comparable with the placebo plus standard dose heparin group (4%); in patients treated with abciximab plus standard-dose heparin, the rate of minor bleeding was higher (7.4%). 6-Month efficacy results. Death, MI, and urgent revascularization were significantly reduced in both abciximab groups by 43% (p < 0.001). Rates of death, MI, or urgent revascularization were 14.7% in the placebo group and 8.3% (p < 0.001) and 8.4% (p < 0.001) in the abciximab standard-dose and low-dose heparin groups, respectively. The 6-month composite event rate (death, MI, or any revascularization) was decreased by 12% to 14% in the standard- and low-dose heparin abciximab treatment arms compared with placebo: event rates of 22.3%, 22.8%, and 25.8%, respectively (p = 0.07 for placebo/low-dose heparin plus abciximab; p = 0.04 placebo/standard-dose heparin plus abciximab; Fig. 1, B).15 Death occurred in 1.7% of patients receiving placebo compared with 1.4% and 1.1% of the standard-dose and low-dose heparin abciximab groups (p = not significant for both); MI occurred in 9.9% of placebo recipients vs 5.3% (p < 0.001) and 5.0% (p < 0.001) of the respective abciximab groups. The reduction in the
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risk of nonurgent revascularization was apparently less durable over the long term than were the reductions in the risk of death and acute MI. It is possible that the early termination of this study reduced its statistical power to detect differences at 6 months. Patients with diabetes. In contrast to the results of EPIC, there was a substantial treatment benefit for patients with diabetes enrolled in the EPILOG study who received abciximab. Although patients with diabetes had higher overall rates of death, MI, and target vessel revascularization than those without, a subgroup analysis revealed that abciximab reduced the rate of death and MI at 30 days and 6 months at least as well for those with diabetes as for those without.18 The rate of target vessel revascularization, however, was not similarly reduced in this patient population. Economic analysis. Economic assessment of the EPILOG data pointed to a halving of in-hospital costs associated with abciximab use relative to EPIC.19 In particular, analysis of observed costs in EPIC showed an in-hospital difference between placebo and abciximab treatment of $1550, whereas analysis of estimated costs in EPILOG indicated an in-hospital difference of $880. This cost savings was attributable to the elimination of excess bleeding risk with the EPILOG heparin regimen. It is possible that this increased efficacy resulted from the ability to achieve complete infusions in more patients. The investigators suggested that the incremental cost of abciximab falls within the range of acceptable costeffectiveness ratios.19 Clinical ramifications. The EPILOG trial confirmed that the clinical benefits of abciximab can be extrapolated beyond high-risk patients to all patients undergoing percutaneous intervention (Fig. 3). The study also proved that the use of a low-dose heparin regimen, together with early sheath removal and elimination of postprocedural heparin infusions, makes it possible to dissociate the benefits of GP IIb/IIIa blockade in preventing ischemic complications from hemorrhagic risk (Fig. 4).
CAPTURE Goals and methods. In the pilot study for the c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) trial performed in 60 patients—the first randomized, placebo-controlled trial of abciximab to be conducted in patients with refractory unstable angina— 12 major events occurred in seven placebo recipients during hospital stay, whereas one event occurred in abciximab recipients (p = 0.03).20
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Figure 4
EPILOG trial demonstrated that use of low-dose, weight-adjusted heparin regimen in combination with abciximab reduced incidence of major bleeding to levels observed with placebo.
The CAPTURE trial was the first major study specifically designed to determine whether abciximab would reduce the risk of angioplasty-associated thrombotic complications in patients with refractory unstable angina documented by electrocardiographic abnormalities.21 In this multicenter, international study (69 centers, mainly in Europe), an infusion of either abciximab or placebo was added to standard medical treatment consisting of aspirin, heparin adjusted to achieve an activated partial thromboplastin time between two and two-and-ahalf times normal continued for at least 1 hour after PTCA, and intravenous nitroglycerin administration plus optional use of other antianginal agents. In contrast to the EPIC and EPILOG studies, the infusion was administered for 18 to 24 hours preceding and 1 hour after PTCA. Efficacy results. The CAPTURE study was terminated after 1265 of the planned 1400 patients had been enrolled when interim analysis revealed the clear-cut superiority of active treatment.21 Abciximab yielded a 29% reduction in the primary end point of death, acute MI, or urgent intervention at 30 days (11.3% vs 15.9% for placebo; Fig. 1, A), a benefit that primarily reflected a 50% decrease in the incidence of both Q-wave (1.1% vs 2.7%) and non-Q-wave (3.0% vs 5.5%) acute MIs. The benefits of abciximab were consistent across all patient subgroups, irrespective of age, sex, entry elec-
trocardiogram characteristics, or the presence of diabetes, peripheral vascular disease, or renal dysfunction. Abciximab reduced the incidence of acute MI by 71% during the pre-PTCA treatment period (0.6% vs 2.1%) and by 53% during or within 24 hours after PTCA (2.6% vs 5.5%). The incidence of recurrent ischemia and the total ischemic burden were also reduced by abciximab during the 24 hours preceding and 6 hours after intervention.22 At 6 months, however, the difference between placebo and abciximab groups with regard to event rate was not significant (30.8% vs 31.0%, respectively; Fig. 1, B). Death or reinfarction occurred in 9.0% of abciximab patients and in 10.9% of placebo patients (p = 0.19).21 Safety results. Although the incidence of bleeding complications was somewhat higher with abciximab than with placebo, the frequency of both major (3.8% vs 1.9%) and minor (4.8% vs 2.0%) bleeding events was lower than in EPIC, a finding attributed by the investigators to the use of lower heparin doses and greater attention to the vascular access site. In addition, CAPTURE patients were in an intensive care environment and already receiving medical therapy; thus this more controlled situation may have positively influenced safety findings. Bleeding occurred most frequently in patients who received high intraprocedural heparin doses and in those of low body weight. Clinical ramifications. CAPTURE was the first trial to
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prove that treatment with abciximab during the 24 hours before PTCA reduces preprocedural and periprocedural events, apparently as a result of stabilization or passivation of unstable plaque. The study thus demonstrated that pretreatment with abciximab is warranted in patients with unstable angina scheduled to undergo percutaneous intervention. The investigators suggested that continuation of abciximab for at least 12 hours postprocedurally seems prudent given the long-term efficacy observed with such a regimen in EPIC. However, the total duration of infusion remains a subject of debate. Still to be resolved in future studies is the question of whether longer preprocedural treatment with abciximab might further reduce the event rate or even avert the need for PTCA entirely.
TAMI-8 Goals and methods. The first clinical assessment of
the activity and safety of GP IIb/IIIa inhibition in combination with thrombolytic therapy was performed by the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI)-8 investigators.23 Escalating bolus doses of murine-derived monoclonal antibody 7E3 Fab (m7E3 Fab) were administered to 60 patients with acute MI 3, 6, and 15 hours after initiation of a 100 mg recombinant tissue-type plasminogen activator (rtPA) infusion, whereas 10 control patients were treated with rtPA alone. Results. More than 90% of patients treated with the combination of m7E3 Fab and rtPA showed angiographic patency of the infarct-related artery (although angiography occurred late after treatment initiation), compared with five of nine patients not receiving abciximab; 87% were free of recurrent ischemia. Clinical ramifications. The observation that there was no excess of bleeding complications in patients treated with m7E3 Fab compared with the control group suggested that patients with acute MI might benefit from combination therapy with a thrombolytic agent and a GP IIb/IIIa receptor blocker. However, this series had only a small number of patients, and this observation requires testing in a much larger patient group.
Eptifibatide trials IMPACT-II Goals and methods. Integrilin to Minimise Platelet Aggregation and Coronary Thrombosis-II (IMPACT-II), a randomized, double-blind trial, enrolled 4010 patients undergoing elective, urgent, or emergency coronary
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intervention.24 Patients were assigned to treatment with placebo or eptifibatide bolus of 135 µg/kg followed by a 20- to 24-hour infusion of either 0.5 µg/kg/min or 0.75 µg/kg/min. The primary end point was the 30-day composite occurrence of death, MI, unplanned surgical or repeat percutaneous revascularization, or coronary stent implantation for abrupt closure. Results. Composite end point rates at 30 days were 11.4% in the placebo group, 9.2% in the 135/0.5 eptifibatide group, and 9.9% in the 135/0.75 eptifibatide group. Although the differences between eptifibatide and placebo were not significant, the trend was toward rate reduction. Analysis of outcome in patients who actually received study treatment revealed a significant difference between placebo and eptifibatide 135/0.5 (11.6% vs 9.1%). The investigators concluded that the doses studied appeared to be at the low end of the efficacy-response curve. Active treatment was not associated with increased rates of major bleeding or transfusion.
IMPACT-AMI Goals and methods. This randomized, placebo-controlled trial weighed the benefits of six different eptifibatide doses in enhancing reperfusion in 180 patients who were treated with accelerated rtPA within 6 hours of acute MI onset.25 Results. The primary study end point, TIMI grade 3 flow at 90 minutes, was achieved in 66% of patients treated with the highest eptifibatide dose compared with only 39% of placebo patients.25 The study was not statistically powered to detect significant differences between treatment arms with regard to the secondary composite end point of in-hospital death, reinfarction, stroke, revascularization, new heart failure, or pulmonary edema; no differences in rates of the secondary end point were observed between eptifibatide arms and the placebo group. No excess of bleeding complications was documented in any of the active treatment groups.
PURSUIT Goals and methods. The Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial evaluated the effects of eptifibatide bolus plus infusion in 10,948 patients with unstable angina/non-Q-wave MI.26 All patients received aspirin, with heparin being optional, and were randomly assigned to low- or high-dose eptifibatide or placebo bolus plus infusion lasting for up to 72 to 96 hours. As specified in the protocol, the low-dose eptifibatide arm
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Figure 5
→
p = 0.160 (Day 30)
p = 0.022 (Day 7)
→
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p = 0.005 (Day 2)
infusions of lamifiban (1, 2, 4, or 5 µg/min) vs placebo in preventing ischemic events in 365 patients with unstable angina. Results. Lamifiban treatment yielded a 60% reduction in risk of death, nonfatal MI, and urgent revascularization during the infusion period (3.3% vs 8.1%), although the benefit was not incremental with increasing doses of lamifiban.27 The incidence of death or nonfatal MI at 1 month was reduced by 70% with the two highest lamifiban doses (2.5% and 2.4% vs 8.1%). The increased incidence of bleeding observed with active treatment was related to lamifiban dose and to concomitant heparin therapy.
PARAGON Composite end point (death, MI, CABG, or repeat PTCA) analysis at 30 days for tirofiban and placebo groups. Adapted with permission from The RESTORE Investigators. Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Circulation 1997;96:1445-53. Copyright © 1997, American Medical Association.
was dropped. The primary end point was death or MI at 30 days. Results. Results of PURSUIT have recently been reported but are as yet unpublished.26 A significant decrease in the 30-day rate of death or MI was observed in eptifibatide recipients compared with placebo recipients, with rates of 14.2% vs 15.7% (p = 0.04) being reported for adjudicated events (8% vs 10% for investigator-judged events). The effects of active treatment were consistent in patients who underwent early percutaneous intervention within 72 hours of randomization (n = 2235) and in those who were not managed invasively; however, the benefits were amplified in the patients who were revascularized. There was no difference in treatment efficacy in patients whose enrollment diagnosis was MI (approximately 40% of patients) vs unstable angina. Eptifibatide was associated with some increase in major bleeding, but there was no increase in the rate of intracranial hemorrhage. A 6-month follow-up is currently underway.
Lamifiban trials Canadian Lamifiban Study Goals and methods. This double-blind, randomized, dose-finding study assessed the efficacy of 3- to 5-day
Goals and methods. The Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network (PARAGON) trial aimed to confirm the results of the Canadian Lamifiban Study on a larger scale.28-30 It likewise represented a novel attempt to assess the independent and additive effects of heparin and GP IIb/IIIa blockade in patients with acute coronary syndromes. The PARAGON-A study randomly assigned nearly 2300 patients to one of the following treatment arms: low-dose lamifiban plus heparin, low-dose lamifiban without heparin, high-dose lamifiban plus heparin, high-dose lamifiban without heparin, or heparin alone. Results. Minor and statistically insignificant differences between treatment groups were noted with regard to rates of death or reinfarction at 30 days: 10.8% for low-dose lamifiban without heparin, 10.3% for lowdose lamifiban with heparin, 11.6% for high-dose lamifiban without heparin, 12.3% for high-dose lamifiban with heparin, and 11.7% for placebo plus heparin.30 However, at 6 months, patients receiving low-dose lamifiban plus heparin had a significantly reduced rate of death or MI compared with placebo recipients (12.7% vs 18.1%; p < 0.02).31
PARADIGM Goals and methods. Platelet Aggregation Receptor Antagonist Dose Investigation for Reperfusion Gain in Myocardial Infarction (PARADIGM) is a multicenter, double-blind, randomized, placebo-controlled trial that tested the effect of adding various doses of lamifiban to either rtPA or streptokinase in patients seen within 12 hours of acute MI onset. Results. Results for the trial’s 353 patients have recently become available.32 More than 75% of patients
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treated with lamifiban achieved angiographic patency of the infarct-related artery at 90 minutes (as judged by continuous electrocardiographic monitoring) compared with the control group (62.5%). Lamifiban also reduced the time to steady-state reperfusion by about 28%, as measured by continuous ST-segment monitoring, and increased the number of patients who achieved steadystate reperfusion within 2 hours by about one third. In terms of clinical outcome, findings for lamifiban (all doses combined for the analysis) and placebo were similar: 30-day mortality rate was 2.1% in patients treated with lamifiban vs 2.6% in patients treated with placebo; reinfarction rates were 8.9% and 6.0%, respectively, and rates of urgent revascularization were 11.4% and 12.0%, respectively.32 The incidence of major bleeding was slightly higher in the lamifiban group (3.0% vs 1.7%).
Tirofiban trials RESTORE Goals and methods. The Randomized Efficacy Study
of Tirofiban for Outcomes and Restenosis (RESTORE) trial was conducted to determine whether a bolus dose of tirofiban followed by a 36-hour infusion would reduce the risk of ischemic complications in patients undergoing PTCA within 72 hours of onset of unstable angina or acute MI. This double-blind, placebo-controlled trial involved approximately 2100 patients.33 Results. The composite event rate of death, acute MI, and revascularization was reduced by 38% in patients treated with tirofiban at 48 hours.33 Tirofiban reduced the 48-hour incidence of nonfatal MI by 39% (4.4% vs 2.7%) and the frequency of repeat PTCA by 66% (3.2% vs 1.1%). Composite end point analysis at 30 days showed an insignificant 16% reduction for the treatment group (12.2% placebo vs 10.3% tirofiban) (Fig. 5).34 When a post hoc analysis was conducted in which urgent and not routine revascularization was included in the 30-day composite end point, there was a strong trend in favor of tirofiban: 10.5% for placebo vs 8.0% for tirofiban (24% reduction; p = 0.052).34
PRISM and PRISM-PLUS Goals and methods. The aims of the Platelet Receptor Inhibition for Ischemic Syndrome Management (PRISM)35 and PRISM-PLUS (Patients Limited by Unstable Signs and Symptoms)36 trials were to determine whether tirofiban was superior to standard medical therapy with heparin and aspirin in patients with unstable angina/non-Q-wave MI. In PRISM, more than 3200 patients with unstable angina/non-Q-wave MI
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were assigned to receive a 48-hour infusion of either tirofiban alone or heparin.37 PRISM-PLUS compared a combination of tirofiban with or without heparin and heparin alone, but in a high-risk patient population. The tirofiban-alone arm was prematurely discontinued because of excess events. This is in contrast to PRISM’s 48-hour composite end point (death, new MI, or refractory ischemia) of 3.8% in the tirofiban-alone group compared with 5.9% in the heparin group (p = 0.007).37 Results. As stated above, the major findings of the PRISM trial were a 36% reduction (5.9% heparin group vs 3.8% tirofiban group) in the primary composite end point of death, acute MI, and refractory ischemia at 48 hours.37 The survival benefit afforded by tirofiban was maintained at 30 days (a reduction in death from 3.6% to 2.3%; p = 0.02), although the reductions in acute MI and in the combined end point of death and acute MI were no longer significant. PRISM-PLUS demonstrated that the combination of GP IIb/IIIa blockade with heparin significantly reduced the combined end point of death, acute MI, and refractory ischemia by 28% (17.9% to 12.9%) at 7 days and by 23% at 30 days.37 In comparing the PRISM and PRISM-PLUS data with findings from other GP IIb/IIIa inhibitor trials, some caveats should be mentioned. First, a twofold or greater rise in CK levels was used to define acute MI in PRISM-PLUS, whereas most other trials have used a definition of a threefold rise in CK-MB levels.1,15,21,24 Second, PRISM-PLUS did not require urgent intervention as a criterion for the refractory ischemia end point, whereas need for urgent revascularization was a required outcome for the composite primary end point in trials of other agents.1,15,21,24,27 In addition, the discontinuation of the tirofiban-alone arm in PRISM-PLUS leaves open questions concerning the role of adjunctive heparin therapy, particularly as tirofiban alone provided benefit in PRISM but tirofiban plus heparin was effective in PRISM-PLUS. These trials support further exploration and use of GP IIb/IIIa-inhibition therapy. Clinical ramifications. The findings of PRISM, PRISM-PLUS, PARAGON, and PURSUIT are consistent with those of other trials in favoring the use of GP IIb/IIIa receptor blockers in patients with unstable angina/non-Q-wave MI. In particular, these trials demonstrate the value of GP IIb/IIIa inhibition outside of the interventional setting, providing a large database of treated patients with acute coronary syndromes.
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Conclusions Clinical studies involving more than 15,000 patients have now clearly established that the use of GP IIb/IIIa receptor blockers can reduce the risk of death, acute MI, and reintervention across the board in both highrisk and low-risk patients undergoing percutaneous intervention procedures. Much of the data comes from trials of abciximab, which remains the best studied agent in the interventional setting. Perhaps most importantly, the benefits of abciximab are not confined to the periprocedural period but are sustained over the long term, for up to 3 years. Early safety concerns have been effectively laid to rest by the demonstration that the use of low-dose heparin, early vascular sheath removal, and elimination of routine postprocedural heparin administration reduces any excess bleeding risk. Analysis of combined data from EPIC, EPILOG, and CAPTURE has also demonstrated that the use of abciximab poses no clinically meaningful danger of stroke.38 Abciximab pretreatment has likewise been proven to be advantageous in patients with unstable angina scheduled to undergo percutaneous intervention. Issues to be resolved include whether the benefits can be enhanced by prolonging the duration of postprocedural abciximab therapy, the optimal total duration of abciximab treatment, and whether the use of abciximab might stabilize the patient sufficiently so as to eliminate the need for intervention altogether. Emerging, although limited, clinical experience has suggested that abciximab confers equal benefits in patients undergoing stenting.39,40 However, prospective evidence should be forthcoming from the EPILOG Stent Study and the Evaluation of ReoPro and Stenting to Eliminate Restenosis (ERASER) trial, which are now underway. In the ERASER trial, patients are treated with intracoronary stents and one of three drug regimens: placebo bolus plus 24-hour infusion, abciximab bolus (0.25 mg/kg) plus 12-hour abciximab infusion (0.125 µg/kg/hr) plus 12-hour placebo infusion, or abciximab bolus (0.25 mg/kg) plus 24-hour abciximab infusion (0.125 µg/kg/hr). At 6 months, patients undergo intravascular ultrasound to determine the rate of restenosis. The accumulating data on investigational GP IIb/IIIa inhibitors continue to support the utility of this class, particularly in noninterventional settings. Indeed, more than 18,000 patients with acute coronary syndromes have been randomly assigned to treatment with either peptide or nonpeptide GP IIb/IIIa antagonists
(PARAGON, PRISM, PRISM-PLUS, and PURSUIT), and trial results overall demonstrate a consistent reduction in ischemic complications. Whether the benefits of these other GP IIb/IIIa blockers match those of abciximab in the setting of coronary intervention or acute coronary syndromes remains to be definitively proven in clinical trials. Clarification of the role of GP IIb/IIIa blockade as an adjunct to thrombolytic therapy or as a prelude to primary PTCA in patients with acute MI also must await the completion of ongoing trials.
References 1. The EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994;330:956-61. 2. Topol EJ, Califf RM, 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. 3. Topol EJ, Ferguson JJ, Weisman HF, et al. Long-term protection from myocardial ischemic events in a randomized trial of brief integrin β3 blockade with percutaneous coronary intervention. JAMA 1997;278:479-84. 4. Lincoff AM, Califf RM, Anderson KM, et al. Evidence for prevention of death and myocardial infarction with platelet membrane glycoprotein IIb/IIIa receptor blockade by abciximab (c7E3 Fab) among patients with unstable angina undergoing percutaneous coronary revascularization. J Am Coll Cardiol 1997;30:149-56. 5. Lefkovits J, Ivanhoe RJ, Califf RM, et al. Effects of platelet glycoprotein IIb/IIIa receptor blockade by a chimeric monoclonal antibody (abciximab) on acute and six-month outcomes after percutaneous transluminal coronary angioplasty for acute myocardial infarction. Am J Cardiol 1996;77:1045-51. 6. Lefkovits J, Blankenship JC, Anderson KM, et al. Increased risk of nonQ wave myocardial infarction after directional atherectomy is platelet dependent: evidence from the EPIC Trial. J Am Coll Cardiol 1996;28:849-55. 7. Lefkovits J, Stoner GL, Anderson KM, Weisman HF, Topol EJ. Can conjunctive platelet glycoprotein IIb/IIIa receptor blockade improve outcomes of coronary interventions for restenotic lesions [abstract]? Circulation 1995;92(suppl I):I-607. 8. Challapalli RM, Eisenberg MJ, Sigmon K, Lemberger J. Platelet glycoprotein IIb/IIIa monoclonal antibody (c7E3) reduces distal embolization during percutaneous intervention of saphenous vein grafts [abstract]. Circulation 1995;92(suppl I):I-607. 9. Moliterno DJ, Califf RM, Anderson K, Weisman HF, Topol EJ, EPIC Study Investigators. Special considerations for diabetics receiving platelet IIb/IIIa antagonists during coronary interventions: results from the EPIC Trial [abstract]. J Am Coll Cardiol 1995;25:155A-156A. 10. Mark DB, Talley JD, Topol EJ, et al. Economic assessment of platelet glycoprotein IIb/IIIa inhibition for prevention of ischemic complications of high-risk coronary angioplasty. Circulation 1996;94:629-35. 11. Hillegass WB. The economics of IIb/IIIa therapy. J Invas Cardiol 1996;8(suppl B):30B-3B. 12. Van Hout BA, Bowman L, Zelinger DJ, Simoons ML. Costs and effects in acute coronary syndrome: the case of ReoPro in high risk PTCA patients. Am Heart J 1998;135:S98-S106. 13. Goklaney AK, Murphy JD, Hillegass WB Jr. Abciximab therapy in per-
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cutaneous intervention: economic issues in the United States. Am Heart J 1998;135:S90-S97. Aguirre FV, Topol EJ, Ferguson JJ, et al. Bleeding complications with the chimeric antibody to platelet glycoprotein IIb/IIIa integrin in patients undergoing percutaneous coronary intervention. Circulation 1995; 91:2882-90. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997;336:1689-96. Lincoff AM, Tcheng JE, Califf RM, et al. Standard versus low-dose weight-adjusted heparin in patients treated with the platelet glycoprotein IIb/IIIa receptor antibody fragment abciximab (c7E3 Fab) during percutaneous coronary revascularization. Am J Cardiol 1997;79:286-91. Rao AK, Pratt C, Berke A, et al. Thrombolysis in Myocardial Infarction (TIMI) trial—phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol 1988;11:1-11. Kleiman NS, Lincoff AM, Miller DP, et al. Abciximab (c7E3) reduces death and myocardial infarction but not target vessel revascularization in diabetics undergoing percutaneous transluminal coronary angioplasty: the EPILOG experience [abstract]. Eur Heart J 1997;18(suppl):13. Lincoff AM, Mark DB, Califf RM, et al. Economic assessment of platelet glycoprotein IIb/IIIa receptor blockade during coronary intervention in the EPILOG Trial [abstract]. J Am Coll Cardiol 1997;29:240A. Simoons ML, de Boer MJ, van den Brand MJBM, et al. Randomized trial of a GPIIb/IIIa platelet receptor blocker in refractory unstable angina. Circulation 1994;89:596-603. The CAPTURE Investigators. Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE Study. Lancet 1997;349:1429-35. Klootwijk P, Meij S, Melkert R, Simoons ML. Reduction of recurrent ischemia with abciximab during continuous ECG-ischemia monitoring in patients with unstable angina refractory to standard treatment (CAPTURE) [abstract]. J Am Coll Cardiol 1997;29:367A. Kleiman NS, Ohman EM, Califf RM, et al. 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 Coll Cardiol 1993;22:381-9. The IMPACT-II Investigators. Randomised placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II. Lancet 1997;349:1422-8. Ohman EM, Kleiman NS, Gacioch G, et al. Combined accelerated tissue-plasminogen activator and platelet glycoprotein IIb/IIIa integrin receptor blockade with Integrilin in acute myocardial infarction: results
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26. 27.
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33. 34.
35. 36.
37. 38.
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of a randomized, placebo-controlled, dose-ranging trial. Circulation 1997;95:846-54. Califf RM. PURSUIT. Presented at the 70th Scientific Sessions of the American Heart Association; November 9-12, 1997, Orlando, Fla. Théroux P, Kouz S, Roy L, et al. Platelet membrane receptor glycoprotein IIb/IIIa antagonism in unstable angina: the Canadian Lamifiban Study. Circulation 1996;94:899-905. Alexander JH, Newby LK, Moliterno DJ, et al. Relationship of outcomes to treatment with lamifiban in patients undergoing PTCA: analysis of PARAGON A [abstract]. J Am Coll Cardiol 1997;29:409A. Harrington RA, Moliterno DJ, Van de Werf F, et al. Delaying and preventing ischemic events in patients with acute coronary syndromes using the platelet glycoprotein IIb/IIIa inhibitor lamifiban [abstract]. J Am Coll Cardiol 1997;29:409A. Van de Werf F. Clinical trials with glycoprotein IIb/IIIa receptor antagonists in acute coronary syndromes. Thromb Haemost 1997;78:210-3. Van de Werf F. PARAGON. Presented at the 19th Congress of the European Society of Cardiology; August 24-28, 1997, Stockholm, Sweden. Harrington RA. PARADIGM. Presented at the 69th Scientific Sessions of the American heart Association, November 10-13, 1996, New Orleans, La. RESTORE Economic Study Group. Analysis of hospital costs and outcomes in RESTORE [abstract]. J Am Coll Cardiol 1997;29:395A. The RESTORE Investigators. Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Circulation 1997;96:1445-53. White HD. PRISM. Presented at the 46th Annual Scientific Session of the American College of Cardiology; March 16-19, 1997, Anaheim, Calif. Théroux P. PRISM-PLUS. Presented at the 46th Annual Scientific Session of the American College of Cardiology; March 16-19, 1997, Anaheim, Calif. Cody RJ. Results from late breaking clinical trials sessions at ACC ‘97. J Am Coll Cardiol 1997;30:1-7. Deckers J, Califf RM, Topol EJ, Lincoff AM, Tcheng JE, Simoons ML. Use of abciximab (ReoPro) is not associated with an increase in the risk of stroke: overview of three randomized trials [abstract]. J Am Coll Cardiol 1997;29:241A. Guzman LA, Whitlow PL, Topol EJ, Ellis SG. A platelet glycoprotein IIb/IIIa inhibitor (ReoPro) as an adjunctive therapy in elective stenting: initial experience with safety and efficacy [abstract]. J Invas Cardiol 1996;8:46. Yaryura RA, Simek S, Benrey J, et al. ReoPro plus stenting: pushing the envelope of clinical applications for stents [abstract]. J Inv Cardiol 1996;8:67.
The era of platelet glycoprotein (GP) IIb/IIIa receptor inhibition in cardiology was inaugurated in 1994 with the publication of the Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) trial results. EPIC demonstrated that the GP IIb/IIIa blocker abciximab, administered as a bolus and 12-hour infusion, afforded protection against ischemic complications in high-risk patients undergoing angioplasty and atherectomy, including those with unstable angina or evolving myocardial infarction (MI). A significant reduction in the incidence of death, acute MI, or revascularization was apparent at 30 days and also sustained at 6-month and 3-year follow-up. The subsequent Evaluation in PTCA to Improve Long-Term Outcome with Abciximab GP IIb/IIIa Blockade (EPILOG) study extended these findings to the full spectrum of coronary intervention patients, confirming that abciximab provided similar benefits in low-risk patients as well. The EPILOG trial also proved that any excess bleeding risk associated with potent antiplatelet therapy could be brought down to placebo levels through the use of a low-dose, weight-adjusted heparin regimen, early vascular sheath removal, and elimination of routine postprocedural heparinization. The potential for an advantage of GP IIb/IIIa blockade in patients with refractory unstable angina/non-Q-wave MI was demonstrated in the c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) trial, which showed that a 24-hour preprocedural abciximab infusion effectively stabilized these patients, thereby enhancing the safety of intervention and reducing the 30-day incidence of ischemic events. A similar pattern of benefit has emerged from clinical trials of such other GP IIb/IIIa inhibitors as eptifibatide, lamifiban, and tirofiban. Trials are currently underway to clarify the benefits of GP IIb/IIIa blockers in patients undergoing stenting and as an adjunct to thrombolytic therapy or primary angioplasty in patients with acute MI (ST-segment elevation). (Am Heart J 1998;135:S43-S55.)
Platelets are believed to play a preeminent role in the development of ischemic events complicating percutaneous coronary intervention and in the pathogenesis of unstable angina and acute myocardial infarction (MI). This hypothesis has provided the rationale for recent large-scale clinical trials exploring whether interruption of the final common pathway of platelet aggregation with agents that block the platelet surface glycoprotein (GP) IIb/IIIa receptor would improve the outcome in individuals undergoing coronary intervention procedures and in those with an acute coronary syndrome. To date, four parenteral GP IIb/IIIa receptor blockers have been evaluated in the clinic. The most extensively studied of these agents and the only one currently available commercially is abciximab (c7E3 Fab [ReoPro]). This chimeric monoclonal antibody Fab fragment binds to the GP IIb/IIIa receptor and the αvβ3 (vitronectin) receptor, which is involved in vascular smooth muscle cell migration and proliferation. In contrast, the investiFrom the Royal Victoria Hospital. Reprint requests: A.A. Jennifer Adgey, MD, Royal Victoria Hospital, Grosvenor Road, Belfast, Northern Ireland BT12 6BA. Copyright © 1998 jointly by Mosby, Inc. and The European Society of Cardiology. 0002-8703/98/$5.00 + 0 4/0/88307
gational agents eptifibatide (Integrilin), lamifiban, and tirofiban are all synthetic nonpeptide compounds of low molecular weight that are specific for the GP IIb/IIIa receptor. In comparison with abciximab, these agents exhibit shorter biologic half-lives. This article will survey the results of clinical trials of GP IIb/IIIa inhibitors in the interventional setting and in the management of acute coronary syndromes and discuss the implications of these findings.
Abciximab trials EPIC Goals and methods. The first large-scale test of the premise that antiplatelet treatment, as directed against the GP IIb/IIIa receptor, could protect against postprocedural abrupt vessel closure and acute MI was accomplished in the Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) study.1 The aim of this 56-center, randomized, double-blind trial was to determine whether a bolus dose of abciximab, coupled with either a 12-hour abciximab infusion or a placebo infusion, would be more effective than a placebo bolus and placebo infusion in reducing the incidence of ischemic complications in nearly 2100 high-risk patients undergo-
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Figure 1
A
B
C
Event-rate curves of patients reaching composite end point in three major abciximab trials for 30 days (A; composite end point of death, MI, or urgent intervention) and 6 months (B; composite end point of death, MI, or any intervention). According to EPIC 3-year follow-up results, clinical benefits of abciximab were maintained over long term (C). Three years after randomization, incidence of composite end point of death, acute MI, or revascularization remained lower among high-risk coronary intervention patients who received abciximab bolus plus infusion. A and B courtesy of Centocor, Inc. C Adapted with permission from Topol EJ, Ferguson JJ, Weisman HF, et al. JAMA 1997;278:479-84. Copyright © 1997, American Medical Association.
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Table I. GP IIb/IIIa inhibitor studies with composite death, MI, intervention end point Composite rate of death, MI, revascularization (%)* Study EPIC 30-Day1 6-Month2 3-Year3 EPILOG15
Placebo
12.8 35.1 47.2
30-Day 6-Month CAPTURE21 30-Day 6-Month IMPACT-II24
11.7 25.8
30-Day Canadian Lamifiban Study27 1-Month RESTORE34 30-Day
11.4
15.9 30.8
14.6 12.2
Drug Abciximab bolus + infusion 8.3 27.0 41.1 Abciximab bolus + infusion: low-dose heparin; standard-dose heparin 5.2; 5.4 22.8; 22.3 Abciximab infusion 11.3 31.0 Eptifibatide bolus + infusion: low-dose infusion; high-dose infusion 9.2; 9.9 Lamifiban infusion: all four dosage groups 10.3 Tirofiban bolus + infusion 10.3
p Value
0.008 0.001 0.009 <0.001; <0.001 0.07; 0.04 0.012 NS 0.063; 0.22 NS 0.160
*30-day rates include urgent revascularization. Longer term rates include any revascularization.
ing percutaneous transluminal coronary angioplasty (PTCA) or atherectomy. The EPIC investigators categorized study candidates as high risk if they had unstable angina, were undergoing direct or rescue intervention within 12 hours of acute MI, or had high-risk lesion morphologic characteristics. In addition to the study regimen, all participants received standard therapy with oral aspirin and intravenous, non-weight-adjusted heparin. 30-Day results. It could be said that the era of GP IIb/IIIa inhibition in interventional cardiology was effectively inaugurated by the EPIC 30-day results. Abciximab bolus plus an abciximab infusion yielded a 35% reduction compared with placebo (event rates of 8.3% vs 12.8%) in the 30-day primary end point of death, acute MI, or urgent reintervention (Fig. 1, A)1; Table I summarizes results of GP IIb/IIIa inhibitor trials using this composite end point. Treatment with an abciximab bolus alone (EPIC) resulted in a composite event rate that was intermediate between that seen with the bolus plus infusion and that documented with placebo. The major drawback of the active bolus and infusion regimen, however, was a 14% incidence of major bleeding events, which was double the risk associated with placebo bolus and placebo infusion. Bleeding complication rates in the trials shown in Table I are summarized in Table II. 6-Month results. Follow-up of the EPIC participants
revealed that the benefits of the abciximab bolus and infusion were maintained over a 6-month period (Fig. 1, B).2 Patients who received the active bolus and infusion showed a 23% lower composite event rate than did their placebo-treated counterparts (27% vs 35.1%). This reduction in the event rate mainly reflected a decreased need for coronary artery bypass grafting (CABG) or repeat percutaneous intervention. 3-Year results. The durable impact of treatment on long-term outcome with an abciximab bolus and infusion compared with placebo bolus and infusion was confirmed in a long-term follow-up study that demonstrated a 13% reduction in the 3-year composite event rate (41.1% vs 47.2%; Fig. 1, C).3 This benefit consisted of a 21% reduction in MI (10.7% vs 13.6%) and a 13% reduction in the need for repeat revascularization (34.8% vs 40.1%). The 3-year mortality rate reduction of 60% (5.1% vs 12.7%) was confined to the highest risk subgroup of EPIC patients, that is, those with evolving MI or unstable angina. At 3 years, the mortality rate end point for patients who were not classified as having evolving MI or unstable angina was 7.4% for the bolus plus infusion group and 7.2% for the placebo group. Interestingly, the investigators observed a correlation between long-term survival and the reduction in the incidence of periprocedural MI related to abciximab. They noted that the higher the magnitude of periproce-
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Table II. Major and minor bleeding complications in GP IIb/IIIa inhibitor trials Bleeding rates (%)* Study
Placebo
EPIC14 Major Minor EPILOG15 Major
6.6 9.8
Minor
3.7
CAPTURE21 Major Minor IMPACT-II24 Major Minor Canadian Lamifiban Study27 Major Minor RESTORE34 (major)
3.1
1.9 2.0† 4.8 Not reported 0.8 1.6 2.1
Drug Abciximab 14.0 16.9 Abciximab Low-dose heparin: 2.0 Standard-dose heparin: 3.5 Low-dose heparin: 4.0 Standard-dose heparin: 7.4 Abciximab 3.8 4.8† Eptifibatide Low-dose infusion: 5.1 High-dose infusion: 5.2 Not reported Lamifiban 2.9 11.1 Tirofiban 2.4
*All studies used TIMI criteria for major bleeding except the Canadian Lamifiban Study, which used criteria of intracranial hemorrhage, tamponade, ≥5 g/dl decrease in hemoglobin, or need for transfusion. †Excluding patients who underwent CABG.
dural creatine kinase (CK) elevation, the greater the risk for late cardiac death (Fig. 2). Unstable angina subgroup. In a subset of 489 EPIC patients with unstable angina,4 abciximab treatment with bolus plus infusion was associated with a 62% decrease in death, MI, or urgent revascularization compared with placebo at 30 days (4.8% vs 12.8%; p = 0.012), with marked reductions in death (1.2% vs 3.2%) and MI (1.8% vs 9.0%). At 6 months, cumulative death (1.8% vs 6.6%; p = 0.018) and MI (2.4% vs 11.1%; p = 0.002) were further reduced in abciximab patients. These benefits were even greater when analysis was restricted to the 470 patients who actually received study treatment. In these patients, composite end point rates were 3.8% in the abciximab bolus plus infusion group and 13.1% in the placebo group at 30 days (p = 0.004 for dose response), including a 94% reduction in death and MI (0.6% vs 11.1%; p < 0.001). At 6 months, composite end point rates (including any revascularization) were 24.3% and 35.0%, respectively (p = 0.024 for dose response), with an 88% reduction in risk for death or MI in the abciximab group (2.0% vs 16.6%; p < 0.001). As noted
above, 3-year analyses indicated that this mortality rate reduction was sustained in patients with unstable angina. Acute MI subgroup. The EPIC acute MI subpopulation, which included 42 patients who underwent primary PTCA for acute MI and 22 patients who had rescue PTCA after failed thrombolysis, likewise fared extremely well after treatment with the abciximab bolus and infusion. In this small series of patients, who were at especially high risk of recurrent ischemic events, the 6month composite end point was significantly reduced from 47.8% with placebo to 4.5% with abciximab bolus and infusion (91% reduction).5 There was also a trend toward a decrease in the 30-day event rate (26.1% vs 4.5%; 83% reduction; p = 0.06).5 Non-MI, nonunstable angina subgroup. In patients with high-risk coronary anatomy, 30-day primary end point rates were 12.7% in the placebo group and 9.3% in the abciximab bolus plus infusion group (hazard ratio 0.5 [range, 0.3 to 0.9]).1 Among patients with stable angina and high-risk coronary anatomy, 6-month composite event rates were 36.2% in the placebo group and 28.0% in the bolus plus infusion group (p = 0.013).2 Other subgroups
Atherectomy substudy. Among the 197 EPIC patients who underwent directional coronary atherectomy, those assigned to placebo treatment experienced a doubled incidence of non-Q-wave MI relative to the PTCA population.6 However, this excess risk was eliminated by treatment with the abciximab bolus plus infusion. Restenotic lesions and vein-graft lesions. In the 237 patients who had undergone prior PTCA of the target lesion within the preceding 12 months compared with placebo (n = 92), treatment with abciximab bolus plus infusion (n = 70) reduced the 30-day event rate from 14.1% to 2.9% and decreased the 6-month event rate from 39.4% to 26.0%.7 Urgent interventions fell from 14.1% to 0.0% and the clinical restenosis rate (defined as death, MI, or repeat revascularization) declined by 34% with abciximab. Similarly, among the 114 patients who underwent revascularization of saphenous vein grafts, bolus plus infusion treatment decreased the 30day rate of clinical events from 12.9% to 7.5%, although it did not significantly affect the 6-month composite end point.8 It should be noted that the small sample sizes of these subgroup analyses provide inadequate statistical power to detect differences reliably. Patients with diabetes. For the 506 high-risk patients with diabetes enrolled in EPIC, the benefits of treatment were tempered by an increase in bleeding complications.9 Regarding efficacy of abciximab, patients with diabetes
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Figure 2
Estimated mortality rates according to magnitude of periprocedural increase in CK level. Adapted with permission from Topol EJ, Ferguson JJ, Weisman HF, et al. JAMA 1997;278:479-84. Copyright © 1997, American Medical Association.
also had higher event rates (death, MI, or target vessel revascularization) at 6 months than patients without diabetes. Patients with diabetes who received abciximab bolus and infusion had a 36% rate of clinical restenosis. Patients without diabetes who received abciximab had a lower rate of restenosis (24%). Thus abciximab treatment did not appear to benefit patients with diabetes. Cost analysis. The current environment of health care cost containment mandates that new therapies be economically as well as medically justified. The EPIC economic substudy showed that the initial in-hospital cost savings afforded by the reduction in ischemic events with abciximab was offset by an increase in costs related to the treatment of bleeding complications.10 Long-term costs, however, were significantly lower in patients treated with abciximab, thanks to the decreased need for repeat hospitalization and revascularization. At 6-month follow-up, the average savings was $1270 per patient exclusive of drug cost; with the $1407 cost of bolus and infusion considered, the net cumulative 6month cost of treatment with abciximab averaged less than $300 per patient.10 Moreover, according to another analysis, the cost per patient treated was actually $3148 less with abciximab than with placebo to achieve a 6month event-free course.11 Another analysis of the pharmacoeconomics of EPIC, using 1-year results, appears in this issue (van Hout et al.).12
Favorable cost-effectiveness ratios for all high-risk patients undergoing PTCA, and particularly patients with unstable angina, are reported. The article by Murphy et al.13 explores the pharmacoeconomic issue of adopting abciximab therapy as the standard of care in percutaneous intervention. The standpoints of efficacy, safety, and economics are considered by using generalized models of the cost of coronary intervention, the EPIC economic substudy, the EPILOG economic data, and estimation of indirect costs. Bleeding risk. Bleeding complications unrelated to bypass surgery were two to three times more frequent in patients receiving abciximab than in those receiving placebo. Such complications occurred in 10.6% of those receiving abciximab bolus plus infusion and 3.3% of placebo recipients, with blood product transfusions being used in 16.8% and 7.5%, respectively.14 Further analysis suggested the possibility that use of low-dose, weight-adjusted heparin regimens might enhance safety of GP IIb/IIIa blockade. This assumption was subsequently confirmed in the Evaluation in PTCA to Improve Long-Term Outcome with Abciximab GP IIb/IIIa Blockade (EPILOG) trial. Clinical ramifications. EPIC was the first study to demonstrate conclusively that GP IIb/IIIa receptor blockade can prevent ischemic events in high-risk patients undergoing percutaneous intervention. The
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Figure 3
EPILOG study proved that benefits of abciximab extended beyond high-risk angioplasty population studied in EPIC to low-risk candidates for intervention as well. Abciximab plus low-dose heparin reduced incidence of 30day composite end point of death, acute MI, or revascularization by approximately 70% among low-risk patients and by approximately 50% among high-risk patients.
superior efficacy of the abciximab bolus teamed with a 12-hour infusion, relative to the bolus alone, highlighted the need for sustained postprocedural treatment. The advantages of abciximab were documented across the board, including the all-important subgroups of patients with the acute coronary syndromes of unstable angina or MI. Perhaps most strikingly, the short-term benefits of abciximab were maintained over 6 months of follow-up and also translated into a significantly improved 3-year outcome. Moreover, EPIC was the first trial to demonstrate that a treatment that reduces the incidence of periprocedural acute MI can also boost late survival.3
EPILOG Goals and methods. The dual objectives of the EPILOG trial were to determine (1) whether the benefits of abciximab demonstrated in the EPIC trial would extend to low-risk patients undergoing coronary intervention procedures and (2) whether the use of a low-dose heparin regimen in conjunction with abciximab would enhance the safety of GP IIb/IIIa blockade while preserving efficacy.15 To this end, patients at 69 North American centers were randomly assigned in doubleblind fashion to treatment with placebo plus standarddose heparin (100 U/kg plus bolus doses as needed to
achieve an activated coagulation time [ACT] of ≥300 sec) or abciximab (bolus plus 12-hour infusion) plus standard-dose heparin or abciximab (bolus plus 12-hour infusion) plus low-dose heparin (70 U/kg plus bolus doses as needed to achieve an ACT of ≥200 sec). In an effort to further improve safety, the protocol dictated that heparin be discontinued immediately after intervention and that vascular sheaths be removed once the ACT reached 175 seconds or less; the Precursor to EPILOG (PROLOG) study, performed to assess such a protocol, had shown that low-dose, weight-adjusted heparin and early sheath removal were associated with lower rates of bleeding and transfusion, with rates being lowest when both measures were used.16 Given the prior demonstration of substantial clinical benefit of abciximab in patients with acute ischemic syndromes, patients with unstable angina and associated changes on electrocardiographic analysis and patients who had had an acute MI within the past 24 hours were excluded, as were those scheduled to undergo stent implantation or atherectomy. 30-Day efficacy results. At interim analysis, evidence of unequivocal benefit with both regimens that contained abciximab necessitated premature termination of EPILOG after 2792 of the planned 4800 patients had been enrolled.15 The investigators reported an approximate
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56% reduction in the primary composite end point of death, acute MI, and urgent revascularization at 30 days in both the standard-dose heparin abciximab group and the low-dose heparin abciximab group compared with placebo (event rates of 5.4%, 5.2%, and 11.7%, respectively; Fig. 1, A). Similar reductions in risk were observed for each of the individual components of the composite end point as well. The benefits of abciximab were consistent across all patient groups, including high-risk patients who had had an infarct within the 7 days before randomization or had adverse lesion morphologic characteristics, and low-risk patients. Although patients with electrocardiographically documented unstable angina were excluded, abciximab with low-dose heparin was apparently effective in patients with clinical signs of unstable angina, who comprised nearly half of the study population. Safety results. In contrast to the EPIC results, no significant differences in major bleeding risk were documented among the three EPILOG treatment arms.15 Major bleeding events (defined by Thrombolysis In Myocardial Infarction [TIMI] criteria17) occurred in 3.5% and 2.0% of patients who received standard-dose heparin and abciximab and low-dose heparin and abciximab, respectively, compared with 3.1% of the placebo group. The incidence of minor bleeding events in the group that received abciximab plus low-dose heparin was comparable with the placebo plus standard dose heparin group (4%); in patients treated with abciximab plus standard-dose heparin, the rate of minor bleeding was higher (7.4%). 6-Month efficacy results. Death, MI, and urgent revascularization were significantly reduced in both abciximab groups by 43% (p < 0.001). Rates of death, MI, or urgent revascularization were 14.7% in the placebo group and 8.3% (p < 0.001) and 8.4% (p < 0.001) in the abciximab standard-dose and low-dose heparin groups, respectively. The 6-month composite event rate (death, MI, or any revascularization) was decreased by 12% to 14% in the standard- and low-dose heparin abciximab treatment arms compared with placebo: event rates of 22.3%, 22.8%, and 25.8%, respectively (p = 0.07 for placebo/low-dose heparin plus abciximab; p = 0.04 placebo/standard-dose heparin plus abciximab; Fig. 1, B).15 Death occurred in 1.7% of patients receiving placebo compared with 1.4% and 1.1% of the standard-dose and low-dose heparin abciximab groups (p = not significant for both); MI occurred in 9.9% of placebo recipients vs 5.3% (p < 0.001) and 5.0% (p < 0.001) of the respective abciximab groups. The reduction in the
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risk of nonurgent revascularization was apparently less durable over the long term than were the reductions in the risk of death and acute MI. It is possible that the early termination of this study reduced its statistical power to detect differences at 6 months. Patients with diabetes. In contrast to the results of EPIC, there was a substantial treatment benefit for patients with diabetes enrolled in the EPILOG study who received abciximab. Although patients with diabetes had higher overall rates of death, MI, and target vessel revascularization than those without, a subgroup analysis revealed that abciximab reduced the rate of death and MI at 30 days and 6 months at least as well for those with diabetes as for those without.18 The rate of target vessel revascularization, however, was not similarly reduced in this patient population. Economic analysis. Economic assessment of the EPILOG data pointed to a halving of in-hospital costs associated with abciximab use relative to EPIC.19 In particular, analysis of observed costs in EPIC showed an in-hospital difference between placebo and abciximab treatment of $1550, whereas analysis of estimated costs in EPILOG indicated an in-hospital difference of $880. This cost savings was attributable to the elimination of excess bleeding risk with the EPILOG heparin regimen. It is possible that this increased efficacy resulted from the ability to achieve complete infusions in more patients. The investigators suggested that the incremental cost of abciximab falls within the range of acceptable costeffectiveness ratios.19 Clinical ramifications. The EPILOG trial confirmed that the clinical benefits of abciximab can be extrapolated beyond high-risk patients to all patients undergoing percutaneous intervention (Fig. 3). The study also proved that the use of a low-dose heparin regimen, together with early sheath removal and elimination of postprocedural heparin infusions, makes it possible to dissociate the benefits of GP IIb/IIIa blockade in preventing ischemic complications from hemorrhagic risk (Fig. 4).
CAPTURE Goals and methods. In the pilot study for the c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) trial performed in 60 patients—the first randomized, placebo-controlled trial of abciximab to be conducted in patients with refractory unstable angina— 12 major events occurred in seven placebo recipients during hospital stay, whereas one event occurred in abciximab recipients (p = 0.03).20
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Figure 4
EPILOG trial demonstrated that use of low-dose, weight-adjusted heparin regimen in combination with abciximab reduced incidence of major bleeding to levels observed with placebo.
The CAPTURE trial was the first major study specifically designed to determine whether abciximab would reduce the risk of angioplasty-associated thrombotic complications in patients with refractory unstable angina documented by electrocardiographic abnormalities.21 In this multicenter, international study (69 centers, mainly in Europe), an infusion of either abciximab or placebo was added to standard medical treatment consisting of aspirin, heparin adjusted to achieve an activated partial thromboplastin time between two and two-and-ahalf times normal continued for at least 1 hour after PTCA, and intravenous nitroglycerin administration plus optional use of other antianginal agents. In contrast to the EPIC and EPILOG studies, the infusion was administered for 18 to 24 hours preceding and 1 hour after PTCA. Efficacy results. The CAPTURE study was terminated after 1265 of the planned 1400 patients had been enrolled when interim analysis revealed the clear-cut superiority of active treatment.21 Abciximab yielded a 29% reduction in the primary end point of death, acute MI, or urgent intervention at 30 days (11.3% vs 15.9% for placebo; Fig. 1, A), a benefit that primarily reflected a 50% decrease in the incidence of both Q-wave (1.1% vs 2.7%) and non-Q-wave (3.0% vs 5.5%) acute MIs. The benefits of abciximab were consistent across all patient subgroups, irrespective of age, sex, entry elec-
trocardiogram characteristics, or the presence of diabetes, peripheral vascular disease, or renal dysfunction. Abciximab reduced the incidence of acute MI by 71% during the pre-PTCA treatment period (0.6% vs 2.1%) and by 53% during or within 24 hours after PTCA (2.6% vs 5.5%). The incidence of recurrent ischemia and the total ischemic burden were also reduced by abciximab during the 24 hours preceding and 6 hours after intervention.22 At 6 months, however, the difference between placebo and abciximab groups with regard to event rate was not significant (30.8% vs 31.0%, respectively; Fig. 1, B). Death or reinfarction occurred in 9.0% of abciximab patients and in 10.9% of placebo patients (p = 0.19).21 Safety results. Although the incidence of bleeding complications was somewhat higher with abciximab than with placebo, the frequency of both major (3.8% vs 1.9%) and minor (4.8% vs 2.0%) bleeding events was lower than in EPIC, a finding attributed by the investigators to the use of lower heparin doses and greater attention to the vascular access site. In addition, CAPTURE patients were in an intensive care environment and already receiving medical therapy; thus this more controlled situation may have positively influenced safety findings. Bleeding occurred most frequently in patients who received high intraprocedural heparin doses and in those of low body weight. Clinical ramifications. CAPTURE was the first trial to
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prove that treatment with abciximab during the 24 hours before PTCA reduces preprocedural and periprocedural events, apparently as a result of stabilization or passivation of unstable plaque. The study thus demonstrated that pretreatment with abciximab is warranted in patients with unstable angina scheduled to undergo percutaneous intervention. The investigators suggested that continuation of abciximab for at least 12 hours postprocedurally seems prudent given the long-term efficacy observed with such a regimen in EPIC. However, the total duration of infusion remains a subject of debate. Still to be resolved in future studies is the question of whether longer preprocedural treatment with abciximab might further reduce the event rate or even avert the need for PTCA entirely.
TAMI-8 Goals and methods. The first clinical assessment of
the activity and safety of GP IIb/IIIa inhibition in combination with thrombolytic therapy was performed by the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI)-8 investigators.23 Escalating bolus doses of murine-derived monoclonal antibody 7E3 Fab (m7E3 Fab) were administered to 60 patients with acute MI 3, 6, and 15 hours after initiation of a 100 mg recombinant tissue-type plasminogen activator (rtPA) infusion, whereas 10 control patients were treated with rtPA alone. Results. More than 90% of patients treated with the combination of m7E3 Fab and rtPA showed angiographic patency of the infarct-related artery (although angiography occurred late after treatment initiation), compared with five of nine patients not receiving abciximab; 87% were free of recurrent ischemia. Clinical ramifications. The observation that there was no excess of bleeding complications in patients treated with m7E3 Fab compared with the control group suggested that patients with acute MI might benefit from combination therapy with a thrombolytic agent and a GP IIb/IIIa receptor blocker. However, this series had only a small number of patients, and this observation requires testing in a much larger patient group.
Eptifibatide trials IMPACT-II Goals and methods. Integrilin to Minimise Platelet Aggregation and Coronary Thrombosis-II (IMPACT-II), a randomized, double-blind trial, enrolled 4010 patients undergoing elective, urgent, or emergency coronary
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intervention.24 Patients were assigned to treatment with placebo or eptifibatide bolus of 135 µg/kg followed by a 20- to 24-hour infusion of either 0.5 µg/kg/min or 0.75 µg/kg/min. The primary end point was the 30-day composite occurrence of death, MI, unplanned surgical or repeat percutaneous revascularization, or coronary stent implantation for abrupt closure. Results. Composite end point rates at 30 days were 11.4% in the placebo group, 9.2% in the 135/0.5 eptifibatide group, and 9.9% in the 135/0.75 eptifibatide group. Although the differences between eptifibatide and placebo were not significant, the trend was toward rate reduction. Analysis of outcome in patients who actually received study treatment revealed a significant difference between placebo and eptifibatide 135/0.5 (11.6% vs 9.1%). The investigators concluded that the doses studied appeared to be at the low end of the efficacy-response curve. Active treatment was not associated with increased rates of major bleeding or transfusion.
IMPACT-AMI Goals and methods. This randomized, placebo-controlled trial weighed the benefits of six different eptifibatide doses in enhancing reperfusion in 180 patients who were treated with accelerated rtPA within 6 hours of acute MI onset.25 Results. The primary study end point, TIMI grade 3 flow at 90 minutes, was achieved in 66% of patients treated with the highest eptifibatide dose compared with only 39% of placebo patients.25 The study was not statistically powered to detect significant differences between treatment arms with regard to the secondary composite end point of in-hospital death, reinfarction, stroke, revascularization, new heart failure, or pulmonary edema; no differences in rates of the secondary end point were observed between eptifibatide arms and the placebo group. No excess of bleeding complications was documented in any of the active treatment groups.
PURSUIT Goals and methods. The Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial evaluated the effects of eptifibatide bolus plus infusion in 10,948 patients with unstable angina/non-Q-wave MI.26 All patients received aspirin, with heparin being optional, and were randomly assigned to low- or high-dose eptifibatide or placebo bolus plus infusion lasting for up to 72 to 96 hours. As specified in the protocol, the low-dose eptifibatide arm
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Figure 5
→
p = 0.160 (Day 30)
p = 0.022 (Day 7)
→
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p = 0.005 (Day 2)
infusions of lamifiban (1, 2, 4, or 5 µg/min) vs placebo in preventing ischemic events in 365 patients with unstable angina. Results. Lamifiban treatment yielded a 60% reduction in risk of death, nonfatal MI, and urgent revascularization during the infusion period (3.3% vs 8.1%), although the benefit was not incremental with increasing doses of lamifiban.27 The incidence of death or nonfatal MI at 1 month was reduced by 70% with the two highest lamifiban doses (2.5% and 2.4% vs 8.1%). The increased incidence of bleeding observed with active treatment was related to lamifiban dose and to concomitant heparin therapy.
PARAGON Composite end point (death, MI, CABG, or repeat PTCA) analysis at 30 days for tirofiban and placebo groups. Adapted with permission from The RESTORE Investigators. Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Circulation 1997;96:1445-53. Copyright © 1997, American Medical Association.
was dropped. The primary end point was death or MI at 30 days. Results. Results of PURSUIT have recently been reported but are as yet unpublished.26 A significant decrease in the 30-day rate of death or MI was observed in eptifibatide recipients compared with placebo recipients, with rates of 14.2% vs 15.7% (p = 0.04) being reported for adjudicated events (8% vs 10% for investigator-judged events). The effects of active treatment were consistent in patients who underwent early percutaneous intervention within 72 hours of randomization (n = 2235) and in those who were not managed invasively; however, the benefits were amplified in the patients who were revascularized. There was no difference in treatment efficacy in patients whose enrollment diagnosis was MI (approximately 40% of patients) vs unstable angina. Eptifibatide was associated with some increase in major bleeding, but there was no increase in the rate of intracranial hemorrhage. A 6-month follow-up is currently underway.
Lamifiban trials Canadian Lamifiban Study Goals and methods. This double-blind, randomized, dose-finding study assessed the efficacy of 3- to 5-day
Goals and methods. The Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network (PARAGON) trial aimed to confirm the results of the Canadian Lamifiban Study on a larger scale.28-30 It likewise represented a novel attempt to assess the independent and additive effects of heparin and GP IIb/IIIa blockade in patients with acute coronary syndromes. The PARAGON-A study randomly assigned nearly 2300 patients to one of the following treatment arms: low-dose lamifiban plus heparin, low-dose lamifiban without heparin, high-dose lamifiban plus heparin, high-dose lamifiban without heparin, or heparin alone. Results. Minor and statistically insignificant differences between treatment groups were noted with regard to rates of death or reinfarction at 30 days: 10.8% for low-dose lamifiban without heparin, 10.3% for lowdose lamifiban with heparin, 11.6% for high-dose lamifiban without heparin, 12.3% for high-dose lamifiban with heparin, and 11.7% for placebo plus heparin.30 However, at 6 months, patients receiving low-dose lamifiban plus heparin had a significantly reduced rate of death or MI compared with placebo recipients (12.7% vs 18.1%; p < 0.02).31
PARADIGM Goals and methods. Platelet Aggregation Receptor Antagonist Dose Investigation for Reperfusion Gain in Myocardial Infarction (PARADIGM) is a multicenter, double-blind, randomized, placebo-controlled trial that tested the effect of adding various doses of lamifiban to either rtPA or streptokinase in patients seen within 12 hours of acute MI onset. Results. Results for the trial’s 353 patients have recently become available.32 More than 75% of patients
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treated with lamifiban achieved angiographic patency of the infarct-related artery at 90 minutes (as judged by continuous electrocardiographic monitoring) compared with the control group (62.5%). Lamifiban also reduced the time to steady-state reperfusion by about 28%, as measured by continuous ST-segment monitoring, and increased the number of patients who achieved steadystate reperfusion within 2 hours by about one third. In terms of clinical outcome, findings for lamifiban (all doses combined for the analysis) and placebo were similar: 30-day mortality rate was 2.1% in patients treated with lamifiban vs 2.6% in patients treated with placebo; reinfarction rates were 8.9% and 6.0%, respectively, and rates of urgent revascularization were 11.4% and 12.0%, respectively.32 The incidence of major bleeding was slightly higher in the lamifiban group (3.0% vs 1.7%).
Tirofiban trials RESTORE Goals and methods. The Randomized Efficacy Study
of Tirofiban for Outcomes and Restenosis (RESTORE) trial was conducted to determine whether a bolus dose of tirofiban followed by a 36-hour infusion would reduce the risk of ischemic complications in patients undergoing PTCA within 72 hours of onset of unstable angina or acute MI. This double-blind, placebo-controlled trial involved approximately 2100 patients.33 Results. The composite event rate of death, acute MI, and revascularization was reduced by 38% in patients treated with tirofiban at 48 hours.33 Tirofiban reduced the 48-hour incidence of nonfatal MI by 39% (4.4% vs 2.7%) and the frequency of repeat PTCA by 66% (3.2% vs 1.1%). Composite end point analysis at 30 days showed an insignificant 16% reduction for the treatment group (12.2% placebo vs 10.3% tirofiban) (Fig. 5).34 When a post hoc analysis was conducted in which urgent and not routine revascularization was included in the 30-day composite end point, there was a strong trend in favor of tirofiban: 10.5% for placebo vs 8.0% for tirofiban (24% reduction; p = 0.052).34
PRISM and PRISM-PLUS Goals and methods. The aims of the Platelet Receptor Inhibition for Ischemic Syndrome Management (PRISM)35 and PRISM-PLUS (Patients Limited by Unstable Signs and Symptoms)36 trials were to determine whether tirofiban was superior to standard medical therapy with heparin and aspirin in patients with unstable angina/non-Q-wave MI. In PRISM, more than 3200 patients with unstable angina/non-Q-wave MI
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were assigned to receive a 48-hour infusion of either tirofiban alone or heparin.37 PRISM-PLUS compared a combination of tirofiban with or without heparin and heparin alone, but in a high-risk patient population. The tirofiban-alone arm was prematurely discontinued because of excess events. This is in contrast to PRISM’s 48-hour composite end point (death, new MI, or refractory ischemia) of 3.8% in the tirofiban-alone group compared with 5.9% in the heparin group (p = 0.007).37 Results. As stated above, the major findings of the PRISM trial were a 36% reduction (5.9% heparin group vs 3.8% tirofiban group) in the primary composite end point of death, acute MI, and refractory ischemia at 48 hours.37 The survival benefit afforded by tirofiban was maintained at 30 days (a reduction in death from 3.6% to 2.3%; p = 0.02), although the reductions in acute MI and in the combined end point of death and acute MI were no longer significant. PRISM-PLUS demonstrated that the combination of GP IIb/IIIa blockade with heparin significantly reduced the combined end point of death, acute MI, and refractory ischemia by 28% (17.9% to 12.9%) at 7 days and by 23% at 30 days.37 In comparing the PRISM and PRISM-PLUS data with findings from other GP IIb/IIIa inhibitor trials, some caveats should be mentioned. First, a twofold or greater rise in CK levels was used to define acute MI in PRISM-PLUS, whereas most other trials have used a definition of a threefold rise in CK-MB levels.1,15,21,24 Second, PRISM-PLUS did not require urgent intervention as a criterion for the refractory ischemia end point, whereas need for urgent revascularization was a required outcome for the composite primary end point in trials of other agents.1,15,21,24,27 In addition, the discontinuation of the tirofiban-alone arm in PRISM-PLUS leaves open questions concerning the role of adjunctive heparin therapy, particularly as tirofiban alone provided benefit in PRISM but tirofiban plus heparin was effective in PRISM-PLUS. These trials support further exploration and use of GP IIb/IIIa-inhibition therapy. Clinical ramifications. The findings of PRISM, PRISM-PLUS, PARAGON, and PURSUIT are consistent with those of other trials in favoring the use of GP IIb/IIIa receptor blockers in patients with unstable angina/non-Q-wave MI. In particular, these trials demonstrate the value of GP IIb/IIIa inhibition outside of the interventional setting, providing a large database of treated patients with acute coronary syndromes.
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Conclusions Clinical studies involving more than 15,000 patients have now clearly established that the use of GP IIb/IIIa receptor blockers can reduce the risk of death, acute MI, and reintervention across the board in both highrisk and low-risk patients undergoing percutaneous intervention procedures. Much of the data comes from trials of abciximab, which remains the best studied agent in the interventional setting. Perhaps most importantly, the benefits of abciximab are not confined to the periprocedural period but are sustained over the long term, for up to 3 years. Early safety concerns have been effectively laid to rest by the demonstration that the use of low-dose heparin, early vascular sheath removal, and elimination of routine postprocedural heparin administration reduces any excess bleeding risk. Analysis of combined data from EPIC, EPILOG, and CAPTURE has also demonstrated that the use of abciximab poses no clinically meaningful danger of stroke.38 Abciximab pretreatment has likewise been proven to be advantageous in patients with unstable angina scheduled to undergo percutaneous intervention. Issues to be resolved include whether the benefits can be enhanced by prolonging the duration of postprocedural abciximab therapy, the optimal total duration of abciximab treatment, and whether the use of abciximab might stabilize the patient sufficiently so as to eliminate the need for intervention altogether. Emerging, although limited, clinical experience has suggested that abciximab confers equal benefits in patients undergoing stenting.39,40 However, prospective evidence should be forthcoming from the EPILOG Stent Study and the Evaluation of ReoPro and Stenting to Eliminate Restenosis (ERASER) trial, which are now underway. In the ERASER trial, patients are treated with intracoronary stents and one of three drug regimens: placebo bolus plus 24-hour infusion, abciximab bolus (0.25 mg/kg) plus 12-hour abciximab infusion (0.125 µg/kg/hr) plus 12-hour placebo infusion, or abciximab bolus (0.25 mg/kg) plus 24-hour abciximab infusion (0.125 µg/kg/hr). At 6 months, patients undergo intravascular ultrasound to determine the rate of restenosis. The accumulating data on investigational GP IIb/IIIa inhibitors continue to support the utility of this class, particularly in noninterventional settings. Indeed, more than 18,000 patients with acute coronary syndromes have been randomly assigned to treatment with either peptide or nonpeptide GP IIb/IIIa antagonists
(PARAGON, PRISM, PRISM-PLUS, and PURSUIT), and trial results overall demonstrate a consistent reduction in ischemic complications. Whether the benefits of these other GP IIb/IIIa blockers match those of abciximab in the setting of coronary intervention or acute coronary syndromes remains to be definitively proven in clinical trials. Clarification of the role of GP IIb/IIIa blockade as an adjunct to thrombolytic therapy or as a prelude to primary PTCA in patients with acute MI also must await the completion of ongoing trials.
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