0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Clinical Cardiology |

Platelet Glycoprotein IIb/IIIa Receptor Antagonists in Cardiovascular Disease FREE

David A. Vorchheimer, MD; Juan Jose Badimon, PhD; Valentin Fuster, MD, PhD
[+] Author Affiliations

Author Affiliations: Department of Medicine, Mount Sinai School of Medicine and the Zena and Michael A. Weiner Cardiovascular Institute (Drs Vorchheimer, Badimon, and Fuster), Coronary Care Unit and Clinical Trials Unit (Dr Vorchheimer), and Cardiovascular Biology Research Laboratories (Dr Badimon), Mount Sinai Medical Center, New York, NY.


Clinical Cardiology Section Editors: Bruce Brundage, MD, University of California, Los Angeles School of Medicine; Margaret A. Winker, MD, Deputy Editor, JAMA.


JAMA. 1999;281(15):1407-1414. doi:10.1001/jama.281.15.1407.
Text Size: A A A
Published online

Context Thrombus formation on disrupted atherosclerotic plaque is the major cause of acute coronary events. Platelet inhibitors are the mainstay of drug therapy to reduce cardiac events in patients with acute coronary syndromes. The platelet glycoprotein (GP) IIb/IIIa receptor is the final common pathway of platelet aggregation.

Objectives To review mechanisms of platelet activation and aggregation and the role of the GP IIb/IIIa receptor in the acute coronary syndromes and to summarize completed clinical trials of GP IIb/IIIa receptor antagonists.

Data Sources English-language journal articles, reviews from a MEDLINE search from 1993 through 1998, as well as abstracts and presentations from major national or international cardiology meetings through November 1998.

Study Selection/Data Extraction Randomized, placebo-controlled clinical trials testing intravenous GP IIb/IIIa receptor antagonists and having more than 500 subjects were included. Data quality and validity included publication or presentation venue.

Data Synthesis/Conclusions The GP IIb/IIIa receptor is the final common pathway of platelet aggregation. Intravenous monoclonal antibody and peptide and nonpeptide antagonists of the GP IIb/IIIa receptor have been tested in randomized, placebo-controlled trials of the acute coronary syndromes and percutaneous coronary interventions. For patients undergoing percutaneous revascularization, these agents have demonstrated efficacy in reducing death, myocardial infarction, or urgent reintervention. Odds ratios of death or myocardial infarction at 30 days range from 0.42 to 0.84 for the drugs in these studies. More modest benefits have been seen in trials of IIb/IIIa receptor antagonists for patients with the acute coronary syndromes, with odds ratios for death or myocardial infarction at 30 days ranging from 0.70 to 0.89. The efficacy of oral agents for chronic GP IIb/IIIa receptor antagonism has not been sufficiently studied.

Figures in this Article

Atherosclerotic heart disease is the most common cause of death in developed countries.1 Thrombosis with platelet deposition and fibrin formation begins immediately (within 1-24 hours) after spontaneous or mechanical injury and is usually mural and subocclusive.2 Plaque disruption activates the coagulation cascade leading to thrombin generation. Exposure of deeper components of atherosclerotic plaques (collagen, tissue factor) and thrombin generated by arterial injury are powerful platelet activators (Figure 1). Angiographic,4,5 angioscopic,6 pathologic,7 and biochemical8 evidence support the role of thrombus in the pathogenesis of acute myocardial infarction (MI), unstable angina, and percutaneous coronary intervention.9

Platelets play a crucial role in thrombus formation. Platelet function depends on the interactions of membrane glycoproteins (GPs) that are receptors for adhesive proteins. The most abundant receptor is the integrin family, which includes GP IIb/IIIa and fibronectin and vitronectin receptors. The integrins consist of heterodimeric molecules composed of α and β subunits.10 The surface of the resting platelet contains 50,000 to 80,000 copies of the GP IIb/IIIa (αIIbβ3) receptor.11,12 Agonists of platelet activation (Figure 1) facilitate the conformational change necessary for the receptor to become receptive to fibrinogen, von Willebrand factor, and vitronectin.13 These ligands all contain the identical peptide sequence, arginine-glycine-aspartic acid (single-letter code, RGD). Fibrinogen is by far the most important ligand for IIb/IIIa, probably because of its high plasma concentration.12 Fibrinogen simultaneously binds to GP IIb/IIIa receptors on 2 separate platelets,14 resulting in platelet cross-linking critical to platelet aggregation (Figure 1).

Figure. Pathways of Platelet Activation
Graphic Jump Location
PAF indicates platelet activating factor; ADP, adenosine diphosphate; TXA, thromboxane A; GP IIb/IIIa, glycoprotein IIb/IIIa; and Epi, epinephrine. Thickness of line indicates strength of activator.3

The role of the GP IIb/IIIa receptor was elucidated from studies of patients with Glanzmann thrombasthenia.15 This inherited disease is characterized by recurrent mucocutaneous bleeding but rare significant visceral bleeding.16 Laboratory studies revealed bleeding time prolongation and absent platelet aggregation. The pathogenetic mechanism is the absence of or a significant decrease in functional GP IIb/IIIa receptors.

Platelet inhibitors are widely used in clinical practice. Aspirin is recommended for treatment of unstable angina, acute and following MI, and before and after percutaneous transluminal coronary angioplasty (PTCA).1720 Aspirin only partially inhibits platelet aggregation by inhibiting the thromboxane A2 pathway of platelet aggregation.21 Ticlopidine hydrochloride and clopidogrel selectively inhibit the binding of adenosine diphosphate to its platelet receptor and block adenosine diphosphate–dependent platelet activation.22 These platelet inhibitors inactivate only 1 pathway of platelet activation. Despite optimal inhibition of a specific pathway, platelet activation occurs through other pathways. Regardless of the stimulus for activation, platelet-platelet interaction and thrombus formation is ultimately regulated through the GP IIb/IIIa receptor complex. These observations provide the rationale for pharmacological intervention directed against the GP IIb/IIIa receptor. We review the studies of efficiency of GP IIa/IIIb antagonists to evaluate their efficacy and indications.

All original English-language journal articles, reviews from a MEDLINE literature search from 1993 through 1998 (using the Medical Subject Headings of platelet glycoprotein IIb/IIIa, unstable angina, myocardial infarction, and percutaneous transluminal coronary angioplasty), articles cited in reference lists of included articles, and abstracts and presentations from major national or international cardiology meetings through November 1998 were reviewed. All randomized controlled clinical trials of GP IIb/IIIa receptor antagonists with more than 500 subjects were included.

Clinical Evidence

Glycoprotein IIb/IIIa receptor antagonists include the following: (1) the monoclonal antibody abciximab; (2) the peptide receptor antagonist eptifibatide; and (3) the nonpeptide receptor antagonists tirofiban and lamifiban (Table 1). Numerous oral nonpeptide mimetics of the IIb/IIIa receptor antagonist are in clinical development. More than 30,000 patients undergoing percutaneous intervention or who have unstable angina or non–Q-wave MI have been enrolled in randomized trials. Treatment with GP IIb/IIIa receptor antagonists consistently reduces the risk of ischemic end points (Table 2).

Table Graphic Jump LocationTable 1. Available Intravenous Platelet Glycoprotein IIb/IIIa Receptor Antagonists*
Table Graphic Jump LocationTable 2. Thirty-Day Death or Nonfatal Myocardial Infarction (MI) in All Randomized Controlled Trials of Glycoprotein IIb/IIIa Receptor Antagonists Involving at Least 1000 Patients*
Intravenous GP IIb/IIIa Receptor Antagonists in Percutaneous Coronary Intervention

In the Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC) study,23 2099 patients undergoing high-risk angioplasty or atherectomy were randomly assigned in a double-blind fashion to either bolus plus infusion of abciximab, bolus alone, or standard therapy for 12 hours. Patients receiving bolus plus infusion had a significant 35% reduction in the composite primary end point of death, nonfatal MI, refractory ischemia, or urgent revascularization within 30 days. Bleeding episodes and transfusions were doubled among patients receiving the bolus plus infusion regimen, although this was attributed to the high doses of heparin administered.24 The benefit of abciximab treatment persisted over 6 months of follow-up, with a significant 23% reduction in ischemic events or need for elective revascularization,25 and recent data showed improved outcome up to 3 years after the procedure.26

The Evaluation in PTCA to Improve Long-Term Outcome with Abciximab GP IIb/IIIa Blockade (EPILOG) trial27 was designed to determine whether the benefits of abciximab therapy could extend to all patients undergoing coronary intervention regardless of risk of ischemic complications and to evaluate whether hemorrhagic complications could be reduced by lowering the heparin dose. In the EPILOG trial, patients received abciximab with standard-dose weight-adjusted heparin, abciximab with low-dose weight-adjusted heparin, or standard-dose weight-adjusted heparin alone. This trial was terminated prematurely with only 2792 subjects enrolled (of a planned 4800) because patients treated with abciximab had a 57% reduction in the composite 30-day end point of death, MI, or urgent revascularization, compared with patients receiving standard heparin therapy (11.7% vs 5.2%). Bleeding rates were acceptably low in all 3 arms (major bleeding in 2.0%-3.5%), confirming that the higher bleeding rates noted in the EPIC study (major bleeding in 7%-14%) were related to adjuvant heparin therapy and demonstrating that the benefit of abciximab could be maintained with lower-dose heparin.

The EPIC and EPILOG trials examined the benefits of abciximab given at the time of intervention followed by a 12-hour infusion. The Chimeric 7E3 Antiplatelet Therapy in Unstable Angina Refractory to Standard Treatment (CAPTURE) trial28 studied prolonged preintervention treatment with abciximab in patients with refractory angina (recurrent ischemia despite heparin and nitrate therapy). Following angiography, patients were randomly assigned to receive abciximab or placebo for 18 to 24 hours before angioplasty, continuing until 1 hour after the intervention. The CAPTURE trial was terminated prematurely after enrollment of 1265 patients (of a planned 1400) when abciximab-treated patients had a significant reduction in the composite end point of death, MI, or revascularization at 30 days (11.3% vs 15.9%). In the CAPTURE trial, the progression to MI before PTCA was significantly lower in patients receiving abciximab (0.6% vs 2.1%; P=.03), suggesting that GP IIb/IIIa inhibition benefits unstable angina patients not undergoing angioplasty.

The Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT)29 trial assessed abciximab in 2399 patients undergoing elective stenting. The primary end point (composite 30-day death, MI, or urgent revascularization) occurred in 10.8% of patients in stent plus placebo, 5.3% in the stent plus abciximab group (P<.001), and 6.9% in the balloon angioplasty plus abciximab group (P=.007). The principal end points prevented with stent plus abciximab treatment were death and large MI.

In the ReoPro and Primary PTCA Organization and Randomized Trial (RAPPORT) study30 of 483 patients with acute MI less than 12 hours of undergoing primary PTCA, abciximab therapy reduced composite death, reinfarction, or urgent revascularization at 7 days (9.9% vs 3.3%, P=.003) and 30 days (11.2% vs 5.8%, P=.03). However, there was no difference in the primary 6-month end point of death, reinfarction, or target vessel revascularization.

In the Integrilin to Manage Platelet Activation to Prevent Coronary Thrombosis (IMPACT-II) study,31 4010 patients of all risk strata undergoing angioplasty were randomized to placebo or 1 of 2 doses of the synthetic cyclic heptapeptide eptifibatide (Integrilin). By 30 days, analysis of all randomized patients revealed a strong trend toward improved outcome in the low-dose arm. Analysis of treated patients only showed a 24% reduction in the composite end point of death, MI, or revascularization (11.6% vs 9.1%, P=.04).

In the Randomised Efficacy Study of Tirofiban for Outcomes and Restenosis (RESTORE) trial,32 2139 patients undergoing high-risk angioplasty or atherectomy were assigned to bolus plus infusion of placebo or the nonpeptide mimetic tirofiban. While there was a significant 38% reduction in the composite end point at 48 hours, by 30 days (the primary end point), only a nonsignificant 16% reduction was observed (12.2% vs 10.3%). When the 30-day end point was reanalyzed using the same composite end point as previous trials (counting repeat angioplasty or coronary artery bypass grafting only when performed urgently), a 24% relative reduction was seen (10.5%-8.0%, P=.052).

Indications for Therapy

Clinical Characteristics. These trials indicate benefit for patients undergoing coronary intervention with risk reductions of up to 50% in some studies. Treatment benefits were observed within hours following intervention, were sustained through 6 to 12 months, and occur regardless of revascularization technique (treatment is still beneficial in the setting of stent implantation). In the EPIC23 and EPILOG27 trials, abciximab resulted in similar reductions of ischemic end points in patients with stable angina, unstable angina, or after MI. In the EPIC study,23 the magnitude of risk reduction was greater among patients with unstable angina compared with patients without unstable angina.33 Patients at highest risk for ischemic complications identified on the basis of clinical presentation (during, or after MI, or unstable angina) or procedural considerations (lesion morphology, multivessel intervention, or bailout stent) may derive the greatest treatment effect.

Clinical trials have shown greater magnitude of benefit with abciximab. The optimal regimen includes a bolus followed by a 12-hour infusion. Compared with the abciximab studies, more modest benefits were observed in the IMPACT-II31 and RESTORE32 studies. Perhaps this is due to differences between the agents (abciximab has a longer biological half-life, with a lower dissociation constant than eptifibatide and also binds to the vitronectin receptor). It could also be due to trial design features such as shorter duration of preintervention treatment in the IMPACT-II study31 (10-60 minutes) vs the EPIC study23 (18-24 hours), underdosing of eptifibatide (preclinical studies of eptifibatide measured platelet aggregation in blood anticoagulated with citrate, which chelates calium, and overestimated the in vivo platelet inhibitory effect of eptifibatide),34 or failure to deliver GP IIb/IIIa antagonists until after the guidewire had crossed the lesion (RESTORE study).32 In both the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT)35 and Platelet Receptor Inhibition for Ischemic Syndrome Management in Patients Limited to Very Unstable Signs and Symptoms (PRISM-Plus)36 studies, the patient subgroup ultimately referred for coronary angiography and percutaneous intervention experienced a larger treatment benefit compared with the study populations as a whole. These data support the use of eptifibatide and tirofiban in patients initially presenting with unstable angina or non–ST-segment elevation MI who then require coronary revascularization. In the PURSUIT35 and PRISM-Plus36 studies, treatment reduced 30-day death and MI by 31% to 44%. It is, therefore, unclear whether patients initially treated with eptifibatide or tirofiban would benefit if their GP IIb/IIIa antagonist were switched to abciximab for subsequent intervention, and it is unclear whether such a practice would be safe, since the conventional abciximab bolus and infusion regimen has not been studied when administered following pretreatment with a different GP IIb/IIIa antagonist.

Adjunctive Heparin. Heparin is administered routinely during coronary intervention. The low-dose, weight-adjusted regimen used in the EPILOG study27 (70 U/kg bolus, target activated clotting time of ≥200 seconds) is associated with the most favorable risk-benefit profile. In the absence of specific data regarding heparinization from the RESTORE32 or IMPACT II31 trials, this heparin regimen should also be used for patients undergoing interventional procedures treated with tirofiban or eptifibatide.

Intravenous GP IIb/IIIa Receptor Antagonists in Acute Coronary Syndromes

Unstable Angina/Non–ST-Segment Elevation MI. In the Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndromes Events in a Global Organization Network (PARAGON) study,37 2282 patients were randomized to 72 hours of high- or low-dose lamifiban, with or without heparin, or heparin alone in a 2 × 2 factorial design. No difference in the primary end point of 30-day death myocardial infarction or reinfarction was seen among any of the groups (10.3%-12.3%). However, reexamination at the 6-month follow-up revealed a significant reduction in the low-dose lamifiban arm and especially in the group receiving low-dose lamifiban plus heparin (17.9% in the placebo/heparin arm vs 12.6% in the lamifiban arm, a 30% reduction).37

The Platelet Receptor Inhibition for Ischemic Syndrome Management (PRISM) study38 randomized 3232 patients to either tirofiban or heparin. At 48 hours (the primary end point), the incidence of the composite end point of death, MI, or refractory ischemia was reduced by 33% from 5.9% in the heparin group to 3.8% in the tirofiban group (P=.01). However, at 30 days, there was no significant difference in the composite end point (including readmission for unstable angina) between the 2 groups (17.1% vs 15.9%).

The PRISM-Plus study36 enrolled 1915 patients with prolonged or repetitive chest pain (<24 hours) with either significant electrocardiographic changes or enzymatic confirmation of myocardial necrosis. Thus, patients in the PRISM-Plus study36 were at higher risk than those enrolled in the PRISM study.38 The PRISM-Plus study36 was initially designed to compare 3 study arms testing heparin, tirofiban, and tirofiban plus heparin for an average of 72 hours. However, after interim analysis by the data and safety monitoring committee revealed an apparent high mortality rate in the tirofiban monotherapy arm (4.6% vs 1.5% in tirofiban plus heparin arm and 1.1% in the heparin monotherapy arm, P=.01), the tirofiban monotherapy arm was terminated. Compared with heparin monotherapy, treatment with tirofiban and heparin was associated with a 32% reduction in the primary end point (composite of death, MI or refractory ischemia) at 7 days (17.9% vs 12.9%, P=.004). The benefit for death, or MI was maintained to 30 days (11.9% vs 8.7%, P=.03), although this finding did not achieve statistical significance at the prespecified level (P=.025) for this trial, which initially commenced with a comparison of 3 treatment arms.

The PURSUIT trial35 enrolled 10,948 patients within 24 hours of the last episode of chest pain and electrocardiographic changes to placebo and 2 eptifibatide arms. The study was designed to have an interim safety analysis after enrollment of 2100 patients, with the elimination of the low-dose eptifibatide arm, and continuation of the study with patients enrolled in a 1-to-1 manner in the placebo or high-dose eptifibatide arms (all patients received aspirin at the discretion of the treating physician and heparin was recommended). The eptifibatide group had a 1.5% absolute reduction in the incidence of the primary end point of death or MI at 30 days (15.7% placebo vs 14.2% eptifibatide, P=.04). This benefit was apparent by 96 hours and persisted through 30 days, up to 6 months.35,39 Treatment effect varied among the 4 geographic enrollment regions. The greatest benefit was observed among North American patients (16.2% in the placebo group vs 12.4% in the eptifibatide group, P=.006). Differences in baseline patient characteristics or management strategies may explain the observed geographic variability.

Acute MI. Glycoprotein IIb/IIIa antagonists could be effective in acute MI given the role of platelets in thrombus development and data that thrombolysis stimulates platelet aggregation.40 Early observations from small trials showed that coronary flow increased by at least 1 TIMI (Thrombolysis in Myocardial Infarction) flow grade in 11 of 13 patients with acute MI who were treated with aspirin, heparin, and abciximab without adjunctive thrombolytic therapy.41 However, data from the TIMI 14 trial42 showed reperfusion rates of only 20% to 40% with abciximab monotherapy.

The IMPACT-AMI43 and Platelet Aggregation Receptor Antagonist Dose Investigation and Reperfusion (PARADIGM)44 trials studied GP IIb/IIIa receptor antagonists in conjunction with thrombolysis. These small pilot trials showed acceptable safety profiles and modest benefits in angiographic or electrocardiographic markers of reperfusion but no differences in major clinical end points. Recent trials studied the role of abciximab combined with lower-dose thrombolytic agents. The results of TIMI 1442 (higher levels of TIMI 3 flow with abciximab plus half-dose [50-mg] accelerated tissue-type plasminogen activator) and the Strategies for Patency Enhancement in the Emergency Department (SPEED) pilot trial,45 using a half-dose of retaplase, form the basis for Global Strategies to Open Occluded Coronary Arteries (GUSTO-IV), a large-scale phase 3 trial evaluating treatment with a full dose of abciximab plus a half dose of retaplase vs treatment with a full dose of retaplase alone.

Indications for Therapy

Clinical Characteristics. Differences in the contribution of thrombus to the pathophysiology of various subgroups of patients with acute syndromes, particularly the broad populations studied in the larger clinical trials, result in more variable effect with GP IIb/IIIa receptor antagonists for the acute coronary syndromes compared with the percutaneous intervention population. Compared with aspirin and intravenous heparin, the addition of a 48- to 96-hour infusion of a GP IIb/IIIa antagonist reduces the 30-day incidence of death and myocardial reinfarction by 10% to 30% (Table 1). This benefit is sustained at 6 months. In the PURSUIT35 and PRISM-Plus36 trials, a significant proportion of patients ultimately underwent percutaneous revascularization, and these patients may derive the greatest treatment benefit. Importantly, in the PURSUIT,35 PRISM-Plus,36 and CAPTURE37 trials, treatment benefit was most pronounced prior to the performance of the coronary intervention. For patients treated with a conservative, medical approach, the addition of a GP IIb/IIIa receptor antagonist also adds an incremental benefit beyond aspirin and heparin, although the treatment benefit is more modest than for those patients treated with an interventional approach.

Clinical markers of patients with the acute coronary syndromes at high risk for ischemic complications may guide patient selection. In post hoc analyses, patients with ST-segment depression36 vs other electocardiographic abnormalities or with elevations in serum troponin levels46 vs normal troponin levels appeared to derive greatest benefit from GP IIb/IIIa receptor antagonist treatment.

In the PURSUIT study, eptifibatide treatment was effectively combined with either an aggressive (percutaneous revascularization within 72 hours) or conservative (no revascularization) practice approach. Tirofiban was effective within the confines of more narrowly defined aggressive strategy encouraged in the PRISM-Plus study (coronary angiography with angioplasty if indicated). Thus far, abciximab has been evaluated only in patients with unstable angina in whom coronary anatomy is already known and intervention is planned within the next 24 hours. No direct comparisons of these 3 agents have been made, and indirect comparisons of end-point efficacy from the currently available trials may be hampered by significant differences in trial design and end-point evaluation.

Adjunctive Heparin. The role of adjunctive heparin for patients with acute coronary syndromes treated with GP IIb/IIIa antagonists has not been thoroughly studied: minimal prospective data exists directly comparing GP IIb/IIIa receptor antagonist use with and without unfractionated heparin. The only study to examine prospectively this question was PRISM-Plus,36 in which an excess hazard for early mortality in the tirofiban monotherapy arm was observed. Some uncertainty exists about the significance of these findings, since the excess mortality observed was based on an interim analysis of only 345 patients in the tirofiban monotherapy arm, and the total number of events was small (n = 16). Thus, the findings from PRISM-Plus36 might be due to chance. Although a recent retrospective analysis from the PURSUIT study suggested a similar hazard of GP IIb/IIIa monotherapy, this analysis is more controversial due to the exclusion of all patients undergoing revascularization (to whom heparin was routinely administered) from the analysis.47 Conversely, in the PARAGON study,37 no benefit was seen at 30 days for lamifiban plus heparin vs lamifiban alone. Currently, intravenous heparin is indicated for all approved GP IIb/IIIa receptor antagonists, although the optimal level of anticoagulation remains unknown.

Hemorrhagic Complications

No increase in intracerebral hemorrhage has been observed with the GP IIb/IIIa antagonists. Most bleeding occurred in patients who underwent percutaneous intervention; the majority of the reported bleeding events involved vascular access puncture sites. For example, in the CAPTURE study,28 19 (79%) of 24 cases of major bleeding in the abciximab arm and 9 (75%) of 12 cases in the placebo arm occurred at the puncture site. Reduction in adjunctive heparin dosing to a target activated partial thromboplastin between 2.0 and 2.5 times control prior to percutaneous intervention and target activated partial thromboplastin time of 70 seconds or activated clotting time of 300 seconds during percutaneous coronary intervention reduced the incidence of vascular access site complications to levels comparable to control in the EPILOG and CAPTURE studies.27,28 Accordingly, the need for platelet transfusion to treat life-threatening bleeding is extremely rare, particularly for the short-acting agents tirofiban and eptifibatide. For patients undergoing percutaneous intervention with abciximab plus low-dose heparin, platelet transfusions were required in 2.1% of patients in the CAPTURE study.28 Platelet transfusions are more frequently required for patients treated with abciximab undergoing urgent coronary artery bypass graft surgery.48

Thrombocytopenia

Thrombocytopenia (platelet count <100 × 109) occurs infrequently with abciximab and tirofiban; no increase in the incidence of thrombocytopenia was observed in eptifibatide-treated patients compared with those who had received placebo in the PURSUIT and IMPACT-II studies.31,35 Treatment with eptifibatide or tirofiban is associated with an absolute increase of approximately 0.2% in the risk of severe (platelet count <50×109/L) thrombocytopenia. The absolute excess in incidence of severe thrombocytopenia with abciximab appears to be higher (0.4%-1.4%): in a composite analysis of all abciximab trials,26,49 the incidence increased from 0.35% to 1.0%. However, excluding the EPIC study23 (for which the reported increase in severe thrombocytopenia from 0.72%-1.55% was likely attributable to high-dose heparin), analysis of the 3 other abciximab trials shows increases in the incidence of severe thrombocytopenia from 0.31% to 1.75% (CAPTURE study),28 0.43% to 0.65% (EPILOG study),27 and 0.0% to 1.0% (EPISTENT study).29 Acute profound thrombocytopenia (platelet count <20 × 109) has been reported in approximately 0.69% of patients receiving abciximab,49 and platelet transfusions maybe required.50 Since onset of such profound thrombocytopenia is generally acute, platelet counts should be measured within the first 2 to 4 hours after the GP IIb/IIIa receptor antagonist has been administered, repeated, and followed through the course of therapy.50

Unresolved Issues

A combined analysis of all randomized clinical trials of at least 1000 patients receiving GP IIb/IIIa receptor antagonists in all areas of ischemic heart disease demonstrates the significant benefit of these agents (Table 2).51 However, unresolved clinical questions persist. No direct head-to-head comparisons have been performed, so the relative efficacy of the GP IIb/IIIa receptor antagonists remains to be determined. Abciximab also binds to the vitronectin (αvβ3) receptor; the peptide and nonpeptide antagonists do not. Since the vitronectin receptor is present mostly on endothelial and smooth muscle cells,52 clinical implications of this cross-reactivity regarding prevention of restenosis,26 inhibition of thrombin generation,53 or other effects are unknown.54 Whether the antibody abciximab can be readministered without significant rise of immunological reactions is unclear.55,56 Preliminary results of a prospective 4500 patient registry undergoing percutaneous coronary intervention, including approximately 500 patients receiving abciximab readministration, showed similar efficacy and incidence of hypersensitivity or anaphylaxis as first-time abciximab recipients and no significant increase in the incidence of severe thrombocytopenia.57 The optimal intensity and duration of unfractionated heparin with GP IIb/IIIa receptor antagonists has not been determined. It is unknown whether low-molecular-weight heparins or other direct thrombin inhibitors would prove safer and more effective than unfractionated heparin in conjunction with GP IIb/IIIa receptor antagonists.

Oral Administration

In patients who have survived an episode of unstable angina or MI, increased levels of activation of the clotting system persist for months after the acute event, suggesting that oral administration of GP IIb/IIIa antagonists might be beneficial.8 Numerous oral GP IIb/IIIa antagonists are in clinical trials58 and early reports from several phase 2 studies are appearing,5961 but important questions regarding the safety of the oral agents remain.62 Such safety concerns were magnified when the Orbofiban in Patients with Unstable Coronary Syndrome (OPUS) trial63 showed minimum benefit of the oral IIb/IIIa antagonists orbofiban (11%, statistically nonsignificant reduction in the 30-day composite end point) but a hazard for a small increase from 1.5% to 2.3% in early mortality in 1 of the orbofiban arms, which resulted in the premature termination of the OPUS trial. The optimal duration of oral GP IIb/IIIa receptor blockade62 and the need for adjunctive aspirin or dose monitoring64 remain unknown.

WHO-MONICA Project.  Myocardial infarction and coronary deaths in the World Health Organization MONICA project: registration procedures, event rates, and case fatality rates in 38 populations from 21 countries in four continents.  Circulation.1994;90:583-612.
Falk E. Coronary thrombosis: pathogenesis and clinical manifestations.  Am J Cardiol.1991;68:28B-35B.
Fuster V, Badimon L, Badimon JJ.  et al.  The pathogenesis of coronary artery disease and the acute coronary syndromes.  N Engl J Med.1992;326:310-318.
Dewood MA, Spores J, Notske R.  et al.  Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction.  N Engl J Med.1980;303:897-902.
Bresnahan DR, Davis DR, Holmes Jr DR.  et al.  Angiographic occurrence and clinical correlates of intraluminal coronary artery thrombus: role of unstable angina.  J Am Coll Cardiol.1985;6:285-289.
Mizuno K, Satomura K, Miyamoto A.  et al.  Angioscopic evaluation of coronary artery thrombi in acute coronary syndromes.  N Engl J Med.1992;326:287-291.
Falk E. Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis: characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi.  Br Heart J.1983;50:127-134.
Merlini PA, Bauer KA, Oltrona L.  et al.  Persistent activation of the coagulation system in unstable angina and myocardial infarction.  Circulation.1994;90:61-68.
Fernandez-Ortiz A, Badimon JJ, Falk E, Fuster V, Chesebro JH, Badimon L. Thrombogenicity of human arterial wall: implications for vascular interventions.  J Am Coll Cardiol.1994;23:1562-1569.
Hynes RO. Integrins: versatility, modulation and signaling in cell adhesion.  Cell.1992;69:11-25.
Lefkovits J, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine.  N Engl J Med.1995;332:1553-1559.
Marcus AJ. Platelet activation. In: Fuster V, Ross R, Topol EJ, eds. Atherosclerosis and Coronary Artery Disease. Philadelphia, Pa: Lippincott-Raven; 1996:607-637.
Plow EF, McEver RP, Coller BS, Woods Jr VL, Marguerie GA, Ginsberg MH. Related binding mechanisms for fibrinogen, fibronectin, von Willebrand factor, and thrombospondin on thrombin-stimulated human platelets.  Blood.1985;66:724-727.
Plow EF, Marguerie G, Ginsberg M. Fibrinogen, fibrinogen receptors, and the peptides that inhibit these interactions.  Biochem Pharmacol.1987;36:4035-4040.
Coller BS, Seligsohn U, Peretz H, Newman PJ. Glanzmann thrombasthenia: new insights from an historical perspective.  Semin Hematol.1994;31:301-311.
Geirge JN, Caen JP, Nurden JT. Glanzmann thrombasthenia: the spectrum of clinical disease.  Blood.1990;75:1383-1395.
Antiplatelet Trialists' Collaboration.  Collaborative overview of randomised trials of antiplatelet therapy, I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients.  BMJ.1994;308:81-106.
Antiplatelet Trialists' Collaboration.  Collaborative overview of randomised trials of antiplatelet therapy, II: maintenance of vascular graft or arterial patency by antiplatelet therapy.  BMJ.1994;308:159-168.
Cairns JA, Lewis Jr D, Meade TW, Sutton GC, Theroux P. Antithrombotic agents in coronary artery disease.  Chest.1998;114(suppl 5):611S-633S.
Barnathan ES, Schwartz JS, Taylor L.  et al.  Aspirin and dipyridamole in the prevention of acute coronary thrombosis complicating coronary angioplasty.  Circulation.1987;76:125-134.
Coller BS. The role of platelets in arterial thrombosis and the rationale for blockade of platelet GP IIb/IIIa receptors as antithrombotic therapy.  Eur Heart J.1995;16(suppl L):11-15.
Fitzgerald GA, Patrono C. Antiplatelet drugs. In: Verstraete M, Fuster V, Topol EJ, eds. Cardiovascular Thrombosis. 2nd ed. Philadelphia, Pa: Lippincott Raven; 1998:121-140.
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;330:956-961.
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;91:2882-2890.
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;323:881-886.
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;278:479-484.
The EPILOG Investigators.  Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization.  N Engl J Med.1997;336:1689-1696.
The CAPTURE Investigators.  Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory angina: the CAPTURE study.  Lancet.1997;349:1429-1435.
The EPISTENT Investigators.  Randomized placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade.  Lancet.1998;352:87-92.
Brener SJ, Barr LA, Burchenal JEB.  et al.  Randomized, placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction.  Circulation.1998;98:734-741.
The IMPACT-II Investigators.  Randomised placebo-controlled trial of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II.  Lancet.1997;349:1422-1428.
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;96:1445-1453.
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;30:149-156.
Phillips DR, Teng W, Arfsten A.  et al.  Effect of Ca2+ on GPIIb/IIIa interactions with integrilin: enhanced GPIIb/IIIa binding and inhibition of platelet aggregation by reductions in the concentration of ionized calcium in plasma anticoagulated with citrate.  Circulation.1997;96:1488-1494.
The PURSUIT Trial Investigators.  Inhibition of the platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes.  N Engl J Med.1998;339:436-443.
The PRISM-Plus Study Investigators.  Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction.  N Engl J Med.1998;338:1488-1497.
The PARAGON Investigators.  International, randomized, controlled trial of lamifiban (a platelet glycoprotein IIb/IIIa inhibitor), heparin, or both in unstable angina.  Circulation.1998;97:2386-2395.
The PRISM Study Investigators.  A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina.  N Engl J Med.1998;338:1498-1505.
Harrington RA, Lincoff AM, Berdan LG.  et al.  Maintenance of clinical benefit at 6 months in patients treated with the platelet glycoprotein IIb/IIIa inhibitor eptifibatide versus placebo during an acute ischemic coronary event [abstract].  Circulation.1998;98(suppl I):359.
Vaughn DE, Van Houtte E, Declerck PJ, Collen D. Streptokinase-induced platelet aggregation: prevalence and mechanism.  Circulation.1991;84:84-91.
Gold HK, Garabedian HD, Dinsmore RE.  et al.  Restoration of coronary flow in myocardial infarction by intravenous chimeric 7E3 antibody without exogenous plasminogen activators: observations in animals and humans.  Circulation.1997;95:1755-1759.
Antman EM, Guigliano RP, McCabe CH.  et al.  Abciximab (ReoPro) potentiates thrombolysis in ST segment elevation myocardial infarction: results of TIMI 14 trial [abstr].  J Am Coll Cardiol.1998;31:191.
Ohman EM, Kleiman NA, Gacioch G.  et al. for the IMPACT-AMI Investigators.  Combined accelerated tissue-plasminogen activator and platelet glycoprotein IIb/IIIa integrin receptor blockade with Integrilin in acute myocardial infarction: results of a randomized, placebo-controlled, dose-ranging trial.  Circulation.1997;95:846-854.
The PARADIGM Investigators.  Combining thrombolysis with the platelet glycoprotein IIb/IIIa inhibitor lamifiban: results of the Platelet Aggregation Receptor Antagonist Dose Investigation and Reperfusion Gain in Myocardial Infarction (PARADIGM) trial.  J Am Coll Cardiol.1998;32:2003-2010.
Ohman EM. Preliminary results of the SPEED pilot trial. In: Program and abstracts of the 20th Congress of the European Society of Cardiology; August 22-26, 1998; Vienna, Austria.
Hamm CW, Heeschen C, Goldmann B.  et al.  Troponin T predicts the benefit of abciximab in patients with unstable angina in the CAPTURE study [abstract].  Eur Heart J.1998;19(suppl):117.
Peterson JG, Lauer MA, Sapp SK.  et al.  Heparin is required for clinical benefit of GP IIb/IIIa inhibitor eptifibatide in acute coronary syndromes: insights from the PURSUIT trial. [abstract].  Circulation.1998;98(suppl I):360.
Boehner JD, Kereiakes DJ, Navetter FI, Califf RM, Topol EJ.for the EPIC Investigators.  Effects of profound platelet inhibition with c7E3 before coronary angioplasty on complications of coronary bypass surgery.  AM J Cardiol.1994;74:1166-1170.
Berkowitz SD, Harrington RA, Rund MM.  et al.  Acute profound thrombocytopenia after c7E3 Fab (abciximab) therapy.  Circulation.1997;96:3810.
Berkowitz SD, Harrington RA, Rund MM.  et al.  Acute profound thrombocytopenia after c7E3 Fab (abciximab) therapy.  Circulation.1997;95:809-813.
Topol EJ, Byzova TV, Plow EF. Platelet GPIIb-IIIa blockers.  Lancet.1999;353:227-231.
Felding-Habermann B, Cheresh DA. Vitronectin and its receptors.  Curr Opin Cell Biol.1993;5:864-868.
Reverter JC, Beguin S, Kessels H, Kumar R, Hemker HC, Coller BS. Inhibition of platelet-mediated, tissue factor-induced thrombin generation by the mouse/human chimeric 7E3 antibody: potential implications for the effect of c7E3 Fab treatment on acute thrombosis and "clinical restenosis."  J Clin Invest.1996;98:863-874.
Ellis SG, Serruys PW, Popma JJ.  et al.  Can abciximab prevent neointimal proliferation in Palmaz-Schatz stents? the final ERASER results [abstract].  Circulation.1997;96(suppl I):87.
Coller BS. GPIIb/IIIa antagonists: pathophysiologic and therapeutic insights from studies of c7E3 Fab.  Thromb Haemost.1997;78:730-735.
Madan M, Kereiakes DJ, Rund M.  et al.  Abciximab readministration for coronary interventions: is it safe? [abstract].  Circulation.1997;96(suppl I):162.
Tcheng JE, Kereiakes DJ, George BS.  et al.  Safety of readministration of abciximab: interim results of the ReoPro Readministration Registry [abstract].  J Am Coll Cardiol.1998;31:55A.
Badimon JJ, Meyer B, Feigen LP.  et al.  Thrombosis triggered by severe arterial lesions is inhibited by oral administration of a glycoprotein IIb/IIIa antagonist.  Eur J Clin Invest.1997;27:568-574.
Kereiakes DJ, Kleiman N, Ferguson JJ.  et al.  Sustained platelet glycoprotein IIb/IIIa blockade with oral Xemilofiban in 170 patients after coronary stent deployment.  Circulation.1997;96:1117-1121.
Muller TH, Weisenberger H, Brickl R, Narjes H, Himmelsbach F, Krause J. Profound and sustained inhibition of platelet aggregation by fradafiban, a nonpeptide platelet glycoprotein IIb/IIIa antagonist, and its orally active prodrug, lefradafiban, in men.  Circulation.1997;96:1130-1138.
Cannon CP, McCabe CH, Borzak S.  et al. and the TIMI 12 Investigators.  A randomized trial of an oral platelet glycoprotein IIb/IIIa antagonist, sibrafiban, in patients after an acute coronary syndrome.  Circulation.1998;97:340-349.
Vorchheimer DA, Fuster V. Oral platelet glycoprotein IIb/IIIa antagonists: the present challenge is safety.  Circulation.1998;97:312-314.
Cannon C. Preliminary results of the OPUS-TIMI 16 trial. In: Program and abstracts of the 48th Annual Scientific Sessions of the American College of Cardiology; March 10, 1999; New Orleans, La.
Coller BS. Monitoring platelet GP IIb/IIIa antagonist therapy.  Circulation.1997;96:3828-3832.

Figures

Figure. Pathways of Platelet Activation
Graphic Jump Location
PAF indicates platelet activating factor; ADP, adenosine diphosphate; TXA, thromboxane A; GP IIb/IIIa, glycoprotein IIb/IIIa; and Epi, epinephrine. Thickness of line indicates strength of activator.3

Tables

Table Graphic Jump LocationTable 1. Available Intravenous Platelet Glycoprotein IIb/IIIa Receptor Antagonists*
Table Graphic Jump LocationTable 2. Thirty-Day Death or Nonfatal Myocardial Infarction (MI) in All Randomized Controlled Trials of Glycoprotein IIb/IIIa Receptor Antagonists Involving at Least 1000 Patients*

References

WHO-MONICA Project.  Myocardial infarction and coronary deaths in the World Health Organization MONICA project: registration procedures, event rates, and case fatality rates in 38 populations from 21 countries in four continents.  Circulation.1994;90:583-612.
Falk E. Coronary thrombosis: pathogenesis and clinical manifestations.  Am J Cardiol.1991;68:28B-35B.
Fuster V, Badimon L, Badimon JJ.  et al.  The pathogenesis of coronary artery disease and the acute coronary syndromes.  N Engl J Med.1992;326:310-318.
Dewood MA, Spores J, Notske R.  et al.  Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction.  N Engl J Med.1980;303:897-902.
Bresnahan DR, Davis DR, Holmes Jr DR.  et al.  Angiographic occurrence and clinical correlates of intraluminal coronary artery thrombus: role of unstable angina.  J Am Coll Cardiol.1985;6:285-289.
Mizuno K, Satomura K, Miyamoto A.  et al.  Angioscopic evaluation of coronary artery thrombi in acute coronary syndromes.  N Engl J Med.1992;326:287-291.
Falk E. Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis: characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi.  Br Heart J.1983;50:127-134.
Merlini PA, Bauer KA, Oltrona L.  et al.  Persistent activation of the coagulation system in unstable angina and myocardial infarction.  Circulation.1994;90:61-68.
Fernandez-Ortiz A, Badimon JJ, Falk E, Fuster V, Chesebro JH, Badimon L. Thrombogenicity of human arterial wall: implications for vascular interventions.  J Am Coll Cardiol.1994;23:1562-1569.
Hynes RO. Integrins: versatility, modulation and signaling in cell adhesion.  Cell.1992;69:11-25.
Lefkovits J, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine.  N Engl J Med.1995;332:1553-1559.
Marcus AJ. Platelet activation. In: Fuster V, Ross R, Topol EJ, eds. Atherosclerosis and Coronary Artery Disease. Philadelphia, Pa: Lippincott-Raven; 1996:607-637.
Plow EF, McEver RP, Coller BS, Woods Jr VL, Marguerie GA, Ginsberg MH. Related binding mechanisms for fibrinogen, fibronectin, von Willebrand factor, and thrombospondin on thrombin-stimulated human platelets.  Blood.1985;66:724-727.
Plow EF, Marguerie G, Ginsberg M. Fibrinogen, fibrinogen receptors, and the peptides that inhibit these interactions.  Biochem Pharmacol.1987;36:4035-4040.
Coller BS, Seligsohn U, Peretz H, Newman PJ. Glanzmann thrombasthenia: new insights from an historical perspective.  Semin Hematol.1994;31:301-311.
Geirge JN, Caen JP, Nurden JT. Glanzmann thrombasthenia: the spectrum of clinical disease.  Blood.1990;75:1383-1395.
Antiplatelet Trialists' Collaboration.  Collaborative overview of randomised trials of antiplatelet therapy, I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients.  BMJ.1994;308:81-106.
Antiplatelet Trialists' Collaboration.  Collaborative overview of randomised trials of antiplatelet therapy, II: maintenance of vascular graft or arterial patency by antiplatelet therapy.  BMJ.1994;308:159-168.
Cairns JA, Lewis Jr D, Meade TW, Sutton GC, Theroux P. Antithrombotic agents in coronary artery disease.  Chest.1998;114(suppl 5):611S-633S.
Barnathan ES, Schwartz JS, Taylor L.  et al.  Aspirin and dipyridamole in the prevention of acute coronary thrombosis complicating coronary angioplasty.  Circulation.1987;76:125-134.
Coller BS. The role of platelets in arterial thrombosis and the rationale for blockade of platelet GP IIb/IIIa receptors as antithrombotic therapy.  Eur Heart J.1995;16(suppl L):11-15.
Fitzgerald GA, Patrono C. Antiplatelet drugs. In: Verstraete M, Fuster V, Topol EJ, eds. Cardiovascular Thrombosis. 2nd ed. Philadelphia, Pa: Lippincott Raven; 1998:121-140.
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;330:956-961.
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;91:2882-2890.
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;323:881-886.
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;278:479-484.
The EPILOG Investigators.  Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization.  N Engl J Med.1997;336:1689-1696.
The CAPTURE Investigators.  Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory angina: the CAPTURE study.  Lancet.1997;349:1429-1435.
The EPISTENT Investigators.  Randomized placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade.  Lancet.1998;352:87-92.
Brener SJ, Barr LA, Burchenal JEB.  et al.  Randomized, placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction.  Circulation.1998;98:734-741.
The IMPACT-II Investigators.  Randomised placebo-controlled trial of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II.  Lancet.1997;349:1422-1428.
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;96:1445-1453.
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;30:149-156.
Phillips DR, Teng W, Arfsten A.  et al.  Effect of Ca2+ on GPIIb/IIIa interactions with integrilin: enhanced GPIIb/IIIa binding and inhibition of platelet aggregation by reductions in the concentration of ionized calcium in plasma anticoagulated with citrate.  Circulation.1997;96:1488-1494.
The PURSUIT Trial Investigators.  Inhibition of the platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes.  N Engl J Med.1998;339:436-443.
The PRISM-Plus Study Investigators.  Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction.  N Engl J Med.1998;338:1488-1497.
The PARAGON Investigators.  International, randomized, controlled trial of lamifiban (a platelet glycoprotein IIb/IIIa inhibitor), heparin, or both in unstable angina.  Circulation.1998;97:2386-2395.
The PRISM Study Investigators.  A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina.  N Engl J Med.1998;338:1498-1505.
Harrington RA, Lincoff AM, Berdan LG.  et al.  Maintenance of clinical benefit at 6 months in patients treated with the platelet glycoprotein IIb/IIIa inhibitor eptifibatide versus placebo during an acute ischemic coronary event [abstract].  Circulation.1998;98(suppl I):359.
Vaughn DE, Van Houtte E, Declerck PJ, Collen D. Streptokinase-induced platelet aggregation: prevalence and mechanism.  Circulation.1991;84:84-91.
Gold HK, Garabedian HD, Dinsmore RE.  et al.  Restoration of coronary flow in myocardial infarction by intravenous chimeric 7E3 antibody without exogenous plasminogen activators: observations in animals and humans.  Circulation.1997;95:1755-1759.
Antman EM, Guigliano RP, McCabe CH.  et al.  Abciximab (ReoPro) potentiates thrombolysis in ST segment elevation myocardial infarction: results of TIMI 14 trial [abstr].  J Am Coll Cardiol.1998;31:191.
Ohman EM, Kleiman NA, Gacioch G.  et al. for the IMPACT-AMI Investigators.  Combined accelerated tissue-plasminogen activator and platelet glycoprotein IIb/IIIa integrin receptor blockade with Integrilin in acute myocardial infarction: results of a randomized, placebo-controlled, dose-ranging trial.  Circulation.1997;95:846-854.
The PARADIGM Investigators.  Combining thrombolysis with the platelet glycoprotein IIb/IIIa inhibitor lamifiban: results of the Platelet Aggregation Receptor Antagonist Dose Investigation and Reperfusion Gain in Myocardial Infarction (PARADIGM) trial.  J Am Coll Cardiol.1998;32:2003-2010.
Ohman EM. Preliminary results of the SPEED pilot trial. In: Program and abstracts of the 20th Congress of the European Society of Cardiology; August 22-26, 1998; Vienna, Austria.
Hamm CW, Heeschen C, Goldmann B.  et al.  Troponin T predicts the benefit of abciximab in patients with unstable angina in the CAPTURE study [abstract].  Eur Heart J.1998;19(suppl):117.
Peterson JG, Lauer MA, Sapp SK.  et al.  Heparin is required for clinical benefit of GP IIb/IIIa inhibitor eptifibatide in acute coronary syndromes: insights from the PURSUIT trial. [abstract].  Circulation.1998;98(suppl I):360.
Boehner JD, Kereiakes DJ, Navetter FI, Califf RM, Topol EJ.for the EPIC Investigators.  Effects of profound platelet inhibition with c7E3 before coronary angioplasty on complications of coronary bypass surgery.  AM J Cardiol.1994;74:1166-1170.
Berkowitz SD, Harrington RA, Rund MM.  et al.  Acute profound thrombocytopenia after c7E3 Fab (abciximab) therapy.  Circulation.1997;96:3810.
Berkowitz SD, Harrington RA, Rund MM.  et al.  Acute profound thrombocytopenia after c7E3 Fab (abciximab) therapy.  Circulation.1997;95:809-813.
Topol EJ, Byzova TV, Plow EF. Platelet GPIIb-IIIa blockers.  Lancet.1999;353:227-231.
Felding-Habermann B, Cheresh DA. Vitronectin and its receptors.  Curr Opin Cell Biol.1993;5:864-868.
Reverter JC, Beguin S, Kessels H, Kumar R, Hemker HC, Coller BS. Inhibition of platelet-mediated, tissue factor-induced thrombin generation by the mouse/human chimeric 7E3 antibody: potential implications for the effect of c7E3 Fab treatment on acute thrombosis and "clinical restenosis."  J Clin Invest.1996;98:863-874.
Ellis SG, Serruys PW, Popma JJ.  et al.  Can abciximab prevent neointimal proliferation in Palmaz-Schatz stents? the final ERASER results [abstract].  Circulation.1997;96(suppl I):87.
Coller BS. GPIIb/IIIa antagonists: pathophysiologic and therapeutic insights from studies of c7E3 Fab.  Thromb Haemost.1997;78:730-735.
Madan M, Kereiakes DJ, Rund M.  et al.  Abciximab readministration for coronary interventions: is it safe? [abstract].  Circulation.1997;96(suppl I):162.
Tcheng JE, Kereiakes DJ, George BS.  et al.  Safety of readministration of abciximab: interim results of the ReoPro Readministration Registry [abstract].  J Am Coll Cardiol.1998;31:55A.
Badimon JJ, Meyer B, Feigen LP.  et al.  Thrombosis triggered by severe arterial lesions is inhibited by oral administration of a glycoprotein IIb/IIIa antagonist.  Eur J Clin Invest.1997;27:568-574.
Kereiakes DJ, Kleiman N, Ferguson JJ.  et al.  Sustained platelet glycoprotein IIb/IIIa blockade with oral Xemilofiban in 170 patients after coronary stent deployment.  Circulation.1997;96:1117-1121.
Muller TH, Weisenberger H, Brickl R, Narjes H, Himmelsbach F, Krause J. Profound and sustained inhibition of platelet aggregation by fradafiban, a nonpeptide platelet glycoprotein IIb/IIIa antagonist, and its orally active prodrug, lefradafiban, in men.  Circulation.1997;96:1130-1138.
Cannon CP, McCabe CH, Borzak S.  et al. and the TIMI 12 Investigators.  A randomized trial of an oral platelet glycoprotein IIb/IIIa antagonist, sibrafiban, in patients after an acute coronary syndrome.  Circulation.1998;97:340-349.
Vorchheimer DA, Fuster V. Oral platelet glycoprotein IIb/IIIa antagonists: the present challenge is safety.  Circulation.1998;97:312-314.
Cannon C. Preliminary results of the OPUS-TIMI 16 trial. In: Program and abstracts of the 48th Annual Scientific Sessions of the American College of Cardiology; March 10, 1999; New Orleans, La.
Coller BS. Monitoring platelet GP IIb/IIIa antagonist therapy.  Circulation.1997;96:3828-3832.

Letters

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 80

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles