Long-term mortality benefit with abciximab in patients undergoing percutaneous coronary intervention.

OBJECTIVES: The goal of this study was to test: 1) if platelet glycoprotein IIb/IIIa (GP IIb/IIIa) blockade with abciximab bolus plus 12-h infusion reduces mortality after percutaneous coronary intervention (PCI); 2) if prevention of early myocardial infarction (MI) after PCI is a mechanism for reducing mortality; and 3) for risk factors for mortality after PCI. BACKGROUND: Studies of PCI suggest that MI after intervention is predictive of mortality. Abciximab, a platelet GP IIb/IIIa receptor inhibitor, has consistently reduced the incidence of MI among PCI patients in several trials. The presumed mechanism is prevention of platelet thrombus associated with vessel wall injury and downstream embolization into the microcirculation. METHODS: In eight trials, 5,154 patients were randomized to a regimen comprising conventional therapy plus a bolus of abciximab within 1 h before PCI followed by a 12-h infusion; 4,136 controls were randomized to conventional therapy alone. Patient follow-up from six months to three years was available. Survival differences are examined using proportional hazards regression and survival curves. RESULTS: A hazard ratio of 0.71 (95% confidence interval 0.57 to 0.89; p = 0.003) suggests a mortality benefit with abciximab. The absolute reduction in mortality was estimated to be 0.5% through 30 days, 0.7% through six months, 0.9% through one year and 1.8% through three years. Early MI explained 18% of the observed mortality benefit at one year. Multivariate regression suggests that patients with advanced cardiovascular disease may derive the greatest mortality benefit from abciximab. CONCLUSIONS: The evidence from 9,290 randomized PCI patients shows a mortality benefit provided by abciximab bolus plus 12-h infusion.

Therapeutic heparin concentrations augment platelet reactivity: implications for the pharmacologic assessment of the glycoprotein IIb/IIIa antagonist abciximab.

BACKGROUND: This study evaluated the effect of heparin on the platelet reactivity and the pharmacodynamic profile of abciximab. METHODS AND RESULTS: Ex vivo studies were performed on patients undergoing elective percutaneous coronary intervention (n = 26) who were at moderate to high risk of ischemic complications. Patients received a 12,000-U bolus of heparin followed by a 0.25-mg/kg bolus of abciximab. Before abciximab treatment, platelet aggregation responses to a variety of stimuli were assessed immediately before and 10 minutes after the heparin bolus. Heparin increased platelet aggregation to 2 and 5 micromol/L adenosine diphosphate (ADP) and 5 microg/mL collagen by 36%, 25%, and 46%, respectively (P < or =.001), but did not influence platelet reactivity to thrombin receptor-activating peptide or 20 micromol/L ADP and had no appreciable effect on platelet surface glycoprotein (GP) IIb/IIIa receptor numbers. To assess the impact of heparin on the pharmacodynamic profile of abciximab, GP IIb/IIIa receptor blockade and platelet aggregation inhibition estimates obtained after abciximab administration were calculated relative to the basal levels observed both before and after the heparin bolus. At 2 and 24 hours after the abciximab bolus, GP IIb/IIIa receptor blockade measurements normalized to either the preheparin or postheparin baseline determinations were equivalent. For all ADP concentrations tested, the 2-hour post-abciximab bolus platelet aggregation inhibition estimates based on the preheparin and postheparin baseline values were comparable. However, for 2 and 5 micromol/L ADP, the 24-hour post-abciximab platelet aggregation inhibition measurements based on preheparin baseline values were significantly lower than postheparin baseline determinations (both P < or =.003). In vitro studies revealed that therapeutic heparin doses induced a concentration-dependent reduction in the extent of platelet inhibition produced by amounts of abciximab that elicit partial inhibition of platelet aggregation. However, at abciximab concentrations that achieved platelet aggregation blockade of >80%, the levels of inhibition of platelet aggregation in the presence and absence of heparin were equivalent. CONCLUSIONS: The cumulative ex vivo and in vitro data indicate that for certain stimuli, heparin alters the platelet inhibitory profile of abciximab at concentrations of the agent that yield partial suppression of platelet function.

Sustained suppression of ischemic complications of coronary intervention by platelet GP IIb/IIIa blockade with abciximab: one-year outcome in the EPILOG trial. Evaluation in PTCA to Improve Long-term Outcome with abciximab GP IIb/IIIa blockade.

BACKGROUND: Blockade of the platelet glycoprotein IIb/IIIa receptor with the monoclonal antibody fragment abciximab was shown in a placebo-controlled randomized trial to reduce the incidence of acute ischemic complications within 30 days among a broad spectrum of patients undergoing percutaneous coronary revascularization. The durability of clinical benefit in this setting has not been established. METHODS AND RESULTS: A total of 2792 patients enrolled in the Evaluation in PTCA to Improve Long-term Outcome with abciximab GP IIb/IIIa blockade (EPILOG) trial were followed with maintenance of double-blinding for 1 year. Patients had been assigned at the time of their index coronary interventional procedure to receive placebo with standard-dose, weight-adjusted heparin (100 U/kg initial bolus), abciximab with standard-dose, weight-adjusted heparin, or abciximab with low-dose, weight-adjusted heparin (70 U/kg initial bolus). The primary outcome was the composite of death, myocardial infarction, or urgent repeat revascularization by 30 days; this composite end point and its individual components were also assessed at 6 months and 1 year. Rates of any repeat revascularization (urgent or elective), target vessel revascularization, and a composite of death, myocardial infarction, or any repeat revascularization were also reported. Follow-up at 1 year was 99% complete for survival status and 97% complete for other end points. By 1 year, the incidence of the primary composite end point was 16.1% in the placebo group, 9.6% in the abciximab with low-dose heparin group (P<0.001), and 9.5% in the abciximab with standard-dose heparin group (P<0.001). Each of the components of this composite end point was reduced to a similar extent. Nonurgent or target vessel repeat revascularization rates were not significantly decreased by abciximab therapy. Mortality rates over 1 year increased with increasing levels of periprocedural creatine kinase MB fraction elevation. CONCLUSIONS: Acute reductions in ischemic events after percutaneous coronary intervention by abciximab are sustained over follow-up to at least 1 year. Early periprocedural myocardial infarctions suppressed by this therapy are associated with long-term mortality rates.

Diabetes mellitus, glycoprotein IIb/IIIa blockade, and heparin: evidence for a complex interaction in a multicenter trial. EPILOG Investigators.

BACKGROUND: After angioplasty, major complications and ischemic events occur more frequently in diabetic than nondiabetic patients. To determine whether treatment with abciximab is effective in reducing these events in diabetics, we analyzed characteristics and outcomes of diabetic patients enrolled in a large multicenter study (EPILOG). METHODS AND RESULTS: Of 2792 patients enrolled, 638 (23%) were diabetic. Diabetic patients were older, shorter, and heavier; more likely to be female and have three-vessel disease, prior coronary artery bypass graft surgery, a history of hypertension, or a recent myocardial infarction; and less likely to be current smokers than their nondiabetic counterparts. During hospitalization, death, myocardial infarction, or urgent revascularization occurred in 7.1% of diabetics and 7.5% of nondiabetics. By 6 months, the composite of death and myocardial infarction had occurred in 8.8% of diabetic patients and 7.4% of nondiabetics, whereas death, myocardial infarction, or revascularization had occurred in 27.2% and 22.6%, respectively. Abciximab treatment reduced death or myocardial infarction among diabetic and nondiabetic patients (hazard ratios, 0.28 [95% confidence interval (CI), 0.13 to 0.57] and 0.47 [95% CI, 0.33 to 0.70] at 30 days for diabetics and nondiabetics, respectively, and 0.36 [95% CI, 0.21 to 0.61] and 0.60 [95% CI, 0.44 to 0.82] at 6 months for diabetics and nondiabetics, respectively). Abciximab reduced target vessel revascularization among nondiabetic patients (hazard ratio, 0.78 [95% CI, 0.63 to 0.96]) but not among diabetics (hazard ratio, 1.4 [95% CI, 0.94 to 2.08]). When standard- and low-dose heparin adjuncts were compared, diabetics receiving abciximab with standard-dose heparin had marginally greater reductions in the composite of death and myocardial infarction and in target vessel revascularization than diabetics assigned to abciximab with low-dose heparin. CONCLUSIONS: Abciximab treatment in diabetic patients led to a reduction in the composite of death and myocardial infarction, which was at least as great as that seen in nondiabetic patients. However, target vessel revascularization was reduced in nondiabetic but not diabetic patients. This effect may be associated in part with lower doses of heparin. These differences may be related to differences in the platelet and coagulation systems between diabetics and nondiabetics, the greater extent of coronary artery disease in diabetics, or patient selection and management factors.

Pharmacodynamic profile of short-term abciximab treatment demonstrates prolonged platelet inhibition with gradual recovery from GP IIb/IIIa receptor blockade.

BACKGROUND: The glycoprotein (GP) IIb/IIIa receptor antagonist abciximab is approved for use in high-risk percutaneous coronary interventions. The purpose of the present study was to establish the pharmacodynamic profile and platelet-bound life span of abciximab. METHODS AND RESULTS: The pharmacodynamics of abciximab (inhibition of ex vivo platelet aggregation and GP IIb/IIIa receptor blockade) were measured in 41 individuals who were randomized to receive a 0.25-mg/kg bolus and a 12-hour infusion of either 10 microg/min (EPIC regimen) or 0.125 microg x kg(-1) x min(-1) (EPILOG regimen) of the antiplatelet agent. At extended times, the amount and distribution of platelet-bound abciximab were monitored by flow cytometry. The EPIC and EPILOG infusion regimens exhibited equivalent blockade of both GP IIb/IIIa receptors and platelet aggregation throughout the duration of abciximab treatment. Flow cytometry revealed a single, highly fluorescent platelet population during treatment, consistent with complete saturation and homogeneous distribution of abciximab on circulating platelets. For 15 days after treatment, the fluorescence histograms remained unimodal with gradually diminishing fluorescence intensity, indicating decreasing levels of platelet-bound abciximab. At 8 and 15 days, which exceeds the normal circulating life span of platelets, median relative fluorescence intensity corresponded to 29100 (29% GP IIb/IIIa receptor blockade) and 13300 (13% GP IIb/IIIa receptor blockade) abciximab molecules bound per platelet, respectively. CONCLUSIONS: These results are consistent with continuous reequilibration of abciximab among circulating platelets and may explain the gradual recovery of platelet function and long-term prevention of ischemic complications by abciximab after coronary intervention.

Abciximab therapy and unplanned coronary stent deployment: favorable effects on stent use, clinical outcomes, and bleeding complications. EPILOG Trial Investigators.

BACKGROUND: The clinical and angiographic demographics of patients requiring unplanned coronary stent deployment and the optimal adjunct pharmacotherapy in this population are not well described. This report details the EPILOG trial experience with unplanned coronary stent deployment and the effect of abciximab platelet glycoprotein IIb/IIIa blockade to improve clinical outcomes during 6 months of follow-up. METHODS AND RESULTS: After randomization in the EPILOG double-blind, placebo-controlled trial of abciximab therapy during percutaneous coronary intervention, 326 (12%) of 2792 patients required unplanned coronary stent deployment. Although stented patients were not distinguished by clinical variables, they had greater coronary lesion complexity by American Heart Association/American College of Cardiology criteria (P=.003) and greater incidence of lesion length >10 mm (P=.002), lesion eccentricity (P=.027), irregular lesion contour (P=.001), and bifurcation involvement (P=.019) than nonstented patients. Unplanned stents were required less often in patients treated with abciximab and low-dose, weight-adjusted heparin than in patients receiving placebo and standard-dose heparin (9.0% versus 13.7%; P=.001). Although adverse clinical outcomes including target-vessel revascularization and bleeding events were more frequent in patients requiring unplanned coronary stent deployment, abciximab therapy reduced adverse outcomes in these patients at 30 days and 6 months to a greater extent than was observed in patients not requiring stent placement. Among stented patients, abciximab therapy did not increase bleeding events. CONCLUSIONS: Patients requiring unplanned coronary stent deployment have more complex coronary lesion morphology and a more complicated clinical course after coronary intervention. Abciximab therapy both reduces the need for unplanned stent deployment and confers clinical benefit to patients requiring an unplanned stent, without increasing bleeding complications.

Does intracoronary thrombus influence the outcome of high risk percutaneous transluminal coronary angioplasty? Clinical and angiographic outcomes in a large multicenter trial. EPIC Investigators. Evaluation of IIb/IIIa Platelet Receptor Antagonist 7E3 in Preventing Ischemic Complications.

OBJECTIVES: We sought to evaluate the impact of angiographically visible thrombus on short- and long-term clinical outcomes after percutaneous transluminal coronary angioplasty (PTCA). BACKGROUND: Intracoronary thrombus is frequently seen on angiography in patients with acute ischemic coronary syndromes or complex lesion morphology, or both, and is often considered to predict a higher rate of complications in patients undergoing PTCA. METHODS: Prospectively collected data from 2,099 patients undergoing high risk PTCA in the Evaluation of IIb/IIIa Platelet Receptor Antagonist 7E3 in Preventing Ischemic Complications (EPIC) trial were analyzed. In addition to aspirin and heparin, patients were randomized to receive either abciximab bolus and infusion, abciximab bolus alone or placebo. Based on an angiographic core laboratory interpretation, patients were classified into three groups: thrombus absent, thrombus possible or thrombus present. The primary end point at 30 days was the composite of death, myocardial infarction or urgent revascularization. The 6-month end point was the composite of death, myocardial infarction or any revascularization. RESULTS: Although abrupt closure was most common in patients with thrombus present compared with thrombus absent or possible (13%, 10.0% and 7.4%, respectively), neither the 30-day nor the 6-month clinical end points were different among the three groups (9%, 11% and 11.7%, respectively, and 30%, 34% and 31%, respectively). Most notably, the benefit of treatment with abciximab was present in all three thrombus groups, and the magnitude of benefit was not different among the thrombus groups. CONCLUSIONS: In high risk patients undergoing percutaneous coronary revascularization, features of thrombus on the preprocedure angiogram do not indicate an augmented risk of adverse clinical outcomes. Abciximab therapy reduces the rate of adverse outcomes regardless of the presence of thrombus and should therefore not necessarily be reserved for patients whose angiograms have features of intraluminal thrombus.

Rapid assessment of platelet function with a modified whole-blood aggregometer in percutaneous transluminal coronary angioplasty patients receiving anti-GP IIb/IIIa therapy.

BACKGROUND: The glycoprotein (GP) IIb/IIIa receptor antagonist abciximab (c7E3 Fab, ReoPro) is approved for use in high-risk percutaneous transluminal coronary angioplasty (PTCA). At present, no "point of care" exists for measuring pharmacological GP IIb/IIIa blockade. To address this need, the Chrono-log Whole Blood Aggregometer, which measures platelet aggregation by electrical impedance, was adapted to test platelet function at the bedside. METHODS AND RESULTS: GP IIb/IIIa receptor blockade, impedance (5 microg/mL collagen), and turbidimetric aggregation (5 and 20 micromol/L ADP) measurements were obtained on 14 PTCA patients who received the standard bolus plus a 12-hour infusion of abciximab. During abciximab administration, mean GP IIb/IIIa receptor blockade was > 91%, and both impedance and turbidimetric aggregation were inhibited by > or = 90%. At 12 hours after abciximab treatment, the mean inhibition of turbidimetric platelet aggregation to 5 and 20 micromol/L ADP was 65+/-20% and 49+/-14%, respectively, and inhibition of impedance aggregation was 69+/-12%. GP IIb/IIIa receptor blockade was 67+/-8%. At 36 hours after abciximab treatment (n=8), the mean inhibition of turbidimetric platelet aggregation to 5 and 20 micromol/L ADP was 44+/-21% and 30+/-14%, respectively, whereas impedance aggregation was inhibited by 60+/-14%. GP IIb/IIIa receptor blockade was 57+/-7%. CONCLUSIONS: During and at 12 hours after abciximab therapy, impedance and turbidimetric platelet aggregation to 5 micromol/L ADP were comparable and closely correlated with GP IIb/IIIa receptor blockade. However, at 36 hours after abciximab treatment, impedance platelet aggregation more closely paralleled GP IIb/IIIa receptor blockade and indicated a slower recovery of platelet function than turbidimetric aggregometry.

Long-term protection from myocardial ischemic events in a randomized trial of brief integrin beta3 blockade with percutaneous coronary intervention. EPIC Investigator Group. Evaluation of Platelet IIb/IIIa Inhibition for Prevention of Ischemic Complication.

CONTEXT: Abciximab, a monoclonal antibody fragment against the platelet receptor alphaIIb beta3 integrin, prevents platelet aggregation. A randomized, placebo-controlled study showed that abciximab improves outcomes for patients undergoing percutaneous coronary angioplasty at 30 days and at 6 months. OBJECTIVE: To determine whether abciximab improves outcomes 3 years after coronary angioplasty. DESIGN: Double-blind, placebo-controlled, randomized trial. SETTING: A total of 56 academic and community hospitals in the United States. PATIENTS: A total of 2099 high-risk patients undergoing coronary angioplasty were randomized. Sufficient time elapsed for 2.5 years of follow-up among 2001 patients and for 3 years of follow-up among 1599 patients. INTERVENTIONS: Abciximab bolus of 0.25 mg/kg followed by infusion at 10 microg/min for 12 hours; abciximab bolus of 0.25 mg/kg followed by placebo infusion; or placebo bolus followed by placebo infusion. MAIN OUTCOMES MEASURES: The primary outcome was the composite of death, myocardial infarction, or coronary revascularization. Secondary outcomes were death, myocardial infarction, or coronary revascularization individually. Subgroups having refractory unstable angina or evolving myocardial infarction and having different elevations of creatine kinase during initial angioplasty were analyzed. RESULTS: At 3 years, composite end points occurred in 41.1% of those receiving abciximab bolus plus infusion; 47.4% of those receiving abciximab bolus only; and 47.2% of those receiving placebo only (for abciximab bolus plus infusion vs placebo, P=.009). Death occurred in 6.8%, 8.0%, and 8.6%, respectively (for abciximab bolus plus infusion vs placebo, P=.20); myocardial infarction in 10.7%, 12.2%, and 13.6%, respectively (for abciximab bolus plus infusion vs placebo, P=.08); and revascularization in 34.8%, 38.6%, and 40.1%, respectively (for abciximab bolus plus infusion vs placebo, P=.02). Among those with refractory unstable angina or evolving myocardial infarction, death occurred in 5.1%, 9.2%, and 12.7%, respectively (for abciximab bolus plus infusion vs placebo, P=.01). Death rates increased as periprocedural creatine kinase levels increased. CONCLUSIONS: Abciximab bolus with infusion given at the time of coronary angioplasty improves outcomes as long as 3 years after the procedure.

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. EPIC Investigators. Evaluation of 7E3 in Preventing Ischemic Complications.

OBJECTIVES: We sought to evaluate whether patients with unstable angina undergoing coronary intervention derive particular clinical benefit from potent platelet inhibition. BACKGROUND: Plaque rupture and platelet aggregation are pathogenetic processes common to unstable angina and ischemic complications of percutaneous coronary intervention. METHODS: Of the 2,099 patients undergoing a coronary intervention in the Evaluation of 7E3 in Preventing Ischemic Complications (EPIC) trial, 489 were enrolled with the diagnosis of unstable angina and randomized to receive placebo, an abciximab (c7E3) bolus immediately before the intervention or an abciximab bolus followed by a 12-h infusion. The primary end point was a composite of death, myocardial infarction (MI) or urgent repeat revascularization within 30 days of randomization. The occurrence of death, MI or any revascularization within 6 months was also assessed. RESULTS: Compared with placebo, the bolus and infusion of abciximab resulted in a 62% reduction in the rate of the primary end point (12.8% vs. 4.8%, p = 0.012) among patients with unstable angina, due primarily to a reduction in the incidences of death (3.2% vs. 1.2%, p = 0.164) and MI (9% vs. 1.8%, p = 0.004). By 6 months, cumulative death and MI were further reduced by abciximab (6.6% vs. 1.8%, p = 0.018 and 11.1% vs. 2.4%, p = 0.002, respectively). The magnitude of the risk reduction with abciximab was greater among the patients with unstable angina than among other patients in the EPIC trial without unstable angina for the end points of death (interaction: p = 0.008 at 30 days, p = 0.002 at 6 months) and MI (interaction: p = 0.004 at 30 days, p = 0.003 at 6 months). CONCLUSIONS: The syndrome of unstable angina identifies patients who will experience particularly marked reductions in the risk of death and MI with abciximab during coronary intervention.

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. PROLOG Investigators.

Blockade of the platelet glycoprotein IIb/IIIa receptor by abciximab (c7E3 Fab) during coronary intervention reduces the incidence of ischemic complications, but has been associated with a doubling of the risk for bleeding complications. The present pilot study investigated whether modification of heparin dosing and/or early sheath removal would reduce the hemorrhagic complications associated with abciximab. One hundred three patients undergoing coronary intervention received abciximab (0.25 mg/kg bolus, 10 microg/min infusion for 12 hours) and aspirin and were randomized by a 2 x 2 factorial design to 1 of 2 weight-adjusted heparin doses and to 1 of 2 strategies for heparin discontinuation and vascular sheath removal. In the "standard-dose heparin" group, an initial bolus of 100 U/kg was administered to achieve a procedural activated clotting time (ACT) > or = 300 seconds; in the "low-dose heparin" group, an initial bolus of 70 U/kg was administered without adjustment for ACT. In the "late sheath removal" arm, heparin infusion was continued for the 12-hour duration of abciximab infusion, followed by sheath removal; in the "early sheath removal" group, heparin was stopped after the interventional procedure and sheaths were removed during the abciximab infusion. There were no apparent differences between patients randomized to the different treatment groups with regard to the occurrence of ischemic end points. Rates of bleeding and blood transfusion were reduced by low-dose heparin and early sheath removal and were lowest when both strategies were combined. Reduction and weight adjustment of heparin dose and early sheath removal in the setting of platelet inhibition with abciximab during coronary intervention may be useful in diminishing the incidence of hemorrhagic complications without loss of clinical efficacy.

Increased risk of non-Q wave myocardial infarction after directional atherectomy is platelet dependent: evidence from the EPIC trial. Evaluation of c7E3 for the Prevention of Ischemic Complications.

OBJECTIVES: We sought to determine the effects of platelet glycoprotein IIb/IIIa receptor blockade on adverse outcomes, especially non-Q wave myocardial infarction, in patients undergoing directional atherectomy in the Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC) trial. BACKGROUND: Randomized trials comparing directional atherectomy with percutaneous transluminal coronary angioplasty (PTCA) have demonstrated modest benefits favoring atherectomy but at a cost of increased acute ischemic complications, notably non-Q wave myocardial infarction. The mechanism for this excess risk is unknown. METHODS: Of 2,038 high risk patients undergoing coronary intervention in the EPIC trial, directional atherectomy was performed in 197 (10%). Patients randomly received the chimeric glycoprotein IIb/IIIa antibody 7E3 (c7E3), as a bolus or a bolus and 12-h infusion or placebo. Study end points included death, myocardial infarction, repeat intervention or bypass surgery. RESULTS: Patients undergoing directional atherectomy had a lower baseline risk for acute complications but had a higher incidence of any myocardial infarction (10.7% vs. 6.3%, p = 0.021) and non-Q wave myocardial infarction (9.6% vs. 4.9%, p = 0.006). Bolus and infusion of c7E3 reduced non-Q wave myocardial infarctions by 71% after atherectomy (15.4% for placebo vs. 4.5% for bolus and infusion, p = 0.046). Non-Q wave myocardial infarction rates after PTCA were not affected by c7E3, although Q wave myocardial infarctions were reduced from 2.6% to 0.8% (p = 0.017). CONCLUSIONS: The EPIC trial confirmed the increased risk of non-Q wave myocardial infarction with directional atherectomy use compared with PTCA. A bolus and 12-h infusion of the glycoprotein IIb/IIIa receptor inhibitor c7E3 abolished this excess risk. Directional atherectomy-related non-Q wave myocardial infarction appears to be platelet aggregation dependent.

The anti-GPIIb-IIIa agents: fundamental and clinical aspects.

The platelet GPIIb/IIIa receptor mediates platelet aggregation induced by all physiologic agonists. Blockade of the receptor, either by monoclonal antibodies or small molecules patterned after the arginine glycine-aspartic acid (RGD) cell recognition domain, prevents arterial thrombosis in animal models much better than does aspirin. c7E3 Fab, the Fab fragment of the mouse/human chimeric antibody 7E3 (abciximab: ReoPro), was shown to reduce ischemic events after angioplasty when given in conjunction with heparin and aspirin to patients at high risk in the EPIC study, but its was associated with an increase in bleeding. Preliminary data from the subsequent EPILOG study, in which a lower dose of heparin was used, demonstrated efficacy in low risk as well as high risk patients and no significant increase in major bleeding. Preliminary data from the CAPTURE study support the use of c7E3 Fab in patients with unstable angina who are candidates for PTCA within 24 hours. Positive trends toward decreased thrombotic events have also been observed in patients treated with small molecule inhibitors of GPIIb/IIIa receptors. This new class of agents thus holds promise for improving the therapy of angioplasty as well as perhaps other thrombotic phenomena.

Analysis of GPIIb/IIIa receptor number by quantification of 7E3 binding to human platelets.

A large number of glycoprotein (GP) IIb/IIIa receptors are present on the surface of platelets. Studies to define precisely the number of GPIIb/IIIa receptors using specific monoclonal antibodies (MoAbs) or fibrinogen binding have, however, yielded varying estimates of receptor number. To refine the quantitative estimation of GPIIb/IIIa receptors on resting platelets, we have used the MoAb 7E3, which has high affinity for GPIIb/IIIa. Quantitative binding studies were performed using radiolabeled conjugates of 7E3 IgG, as well as fragments and derivatives of 7E3. For platelets obtained from any single individual, the numbers of 7E3 F(ab')2 and IgG molecules bound per platelet were equivalent (approximately 40,000), whereas the number of Fab molecules bound per platelet was consistently approximately twofold higher (approximately 80,000). To investigate the basis of the quantitative disparity in binding of intact 7E3 and 7E3 F(ab')2 versus 7E3 Fab, we studied the binding of a newly constructed, bispecific (Fab')2 molecule containing only a single 7E3 combining site. Because this construct bound to the same extent as the Fab species, the larger size of the intact 7E3 and 7E3 F(ab')2 molecules could not explain the reduced number of molecules that bound per platelet compared to the Fab fragment. Rather, it appears that the valency of the antibody is the critical factor determining the number of antibody molecules bound per platelet. Thus, we conclude that the binding of 7E3 Fab corresponds most closely with surface GPIIb/IIIa number and that the number of GPIIb/IIIa receptors is approximately 80,000 per platelet.

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. EPIC investigators.

Percutaneous transluminal coronary angioplasty (PTCA) for acute myocardial infarction is an attractive alternative to thrombolysis, but is still limited by recurrent ischemia and restenosis. We determined whether adjunctive platelet glycoprotein IIb/IIIa receptor blockade improved outcomes in patients undergoing direct and rescue PTCA in the Evaluation of c7E3 for Prevention of Ischemic Complications (EPIC) trial. Of the 2,099 patients undergoing percutaneous intervention who randomly received chimeric 7E3 Fab (c7E3) as a bolus, a bolus and 12-hour infusion, or placebo, 42 underwent direct PTCA for acute myocardial infarction and 22 patients had rescue PTCA after failed thrombolysis. The primary composite end point comprised death, reinfarction, repeat intervention, or bypass surgery. Outcomes were assessed at 30 days and 6 months. Baseline characteristics were similar in direct and rescue PTCA patients. Pooling the 2 groups, c7E3 bolus and infusion reduced the primary composite end point by 83% (26.1% placebo vs 4.5% c7E3 bolus and infusion, p = 0.06). No reinfarctions or repeat urgent interventions occurred in c7E3 bolus and infusion patients at 30 days, although there was a trend toward more deaths in c7E3-treated patients. Major bleeding was increased with c7E3 (24% vs 13%, p = 0.28). At 6 months, ischemic events were reduced from 47.8% with placebo to 4.5% with c7E3 bolus and infusion (p = 0.002), particularly reinfarction (p = 0.05) and repeat revascularization (p = 0.002). We conclude that adjunctive c7E3 therapy during direct and rescue PTCA decreased acute ischemic events and clinical restenosis in the EPIC trial. These data provide initial evidence of benefit for glycoprotein IIb/IIIa receptor blockade during PTCA for acute myocardial infarction.

Differential inhibition of platelet aggregation induced by adenosine diphosphate or a thrombin receptor-activating peptide in patients treated with bolus chimeric 7E3 Fab: implications for inhibition of the internal pool of GPIIb/IIIa receptors.

OBJECTIVES: This study sought to describe in detail the pharmacokinetics and pharmacodynamics of chimeric monoclonal 7E3 Fab (c7E3 Fab) and to compare platelet responses to adenosine diphosphate (ADP) and the 11-amino acid thrombin receptor-activating peptide (TRAP [SFLLRNPNDKY-NH2]) in patients undergoing elective coronary angioplasty. BACKGROUND: Inhibition of platelet aggregation with monoclonal antibody c7E3 Fab directed against glycoprotein (GP) IIb/IIIa has been shown to reduce ischemic complications after angioplasty and is being considered for treatment of other acute ischemic syndromes. METHODS: Patients undergoing elective coronary angioplasty received aspirin (325 mg orally), heparin (12,000 U intravenously) and a bolus of c7E3 Fab (0.25 mg/kg body weight). Surface GPIIb/IIIa receptor blockade and aggregation in response to 20 mumol/liter ADP, 5 micrograms/ml collagen and 7.5 and 15 mumol/liter TRAP were assessed. RESULTS: Surface GPIIb/IIIa receptor blockade by c7E3 Fab was 80% 2 h after injection and decreased to 50% at 24 h. Platelet aggregation in response to 20 mumol/liter ADP was inhibited by 73% at 2 h, and this inhibition decreased to 27% at 24 h. Platelet aggregation in response to 7.5 mumol/liter TRAP was inhibited by 53% at 2 h and 30% at 24 h. In contrast, aggregation in response to 15 mumol/liter TRAP was inhibited only 37% at 2 h and 10% at 24 h (p < 0.001 and p = 0.006, respectively vs. 20 mumol/liter ADP). Addition of exogenous c7E3 Fab to platelet-rich plasma led to more complete inhibition of 7.5 mumol/liter TRAP-induced aggregation. CONCLUSIONS: After c7E3 Fab treatment, inhibition of platelet aggregation depends on the agonist and can be overcome by increased thrombin activity but is restored if additional c7E3 Fab is added to block additional GPIIb/IIIa receptors. This phenomenon may be related to an internal pool of GPIIb/IIIa receptors joining the surface membrane and has implications concerning the duration of therapy with c7E3 Fab for patients with unstable angina or acute myocardial infarction.

The immunogenicity of the 7E3 murine monoclonal Fab antibody fragment variable region is dramatically reduced in humans by substitution of human for murine constant regions.

A murine monoclonal antibody (7E3) directed against the platelet glycoprotein IIb/IIIa was engineered to reduce immunogenicity by substituting human for murine constant regions. The chimeric antibody is functionally identical to the murine antibody in vitro. Results from clinical trials with 7E3 Fab antibody fragments, however, show that the 7E3 variable region, which elicits the vast majority of the immune response to murine 7E3 Fab, is rendered dramatically less immunogenic (incidence reduced from 17% to 1%) when the identical variable region is linked to human rather than murine constant regions. Neither murine nor human constant regions were highly immunogenic themselves. We conclude that the constant regions of the Fab fragments are critical in modulating the immune response elicited by the linked 7E3 variable region. Because naturally occurring anti-human Fab fragment antibodies are prevalent both in the normal human population and in the patient population studied here, murine 7E3 Fab and chimeric 7E3 Fab may be fundamentally different in their interactions with the human immune system. This difference may be related to the dramatic difference in immunogenicity observed between murine 7E3 Fab and chimeric 7E3 Fab.