Low-Molecular-Weight Heparins 99 Trials in Cardiovascular Disease. Philadelphia: W.B. Saunders Company, 1999: 145–165. 70. Neuhaus KL, von Essen R, Tebbe U, et al. Safety observations from the pilot phase of the randomized r-Hirudin for Improvement of Thrombolysis (HIT-III) study. A study of the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausarzte (ALKK) [see comments]. Circulation 1994; 90:1638–1642. 71. Neuhaus KL, Molhoek GP, Zeymer U, et al. Recombinant hirudin (lepirudin) for the improvement of thrombolysis with streptokinase in patients with acute myocardial infarction: results of the HIT-4 trial. J Am Coll Cardiol 1999; 34:966–973. 6 Platelet Glycoprotein IIb/IIIa Inhibition in Acute Coronary Syndromes Christopher P. Cannon Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts Because approximately 4 million patients each year are admitted to hospitals worldwide with unstable angina or acute myocardial infarction (MI), and nearly 1 million patients annually worldwide undergo percutaneous coronary intervention (PCI), physicians have focused a great deal of attention on developing new treat- ments for these acute coronary syndromes (ACS). The initiating event of these acute coronary syndromes is rupture of an atherosclerotic plaque followed by local thrombosis. Similar pathophysiology is present during PCI, which is essen- tially a ‘‘planned’’ plaque disruption. Antiplatelet therapy is the cornerstone of treatment in ACS. Aspirin has been shown to have dramatic effects in reducing both mortality and nonfatal events in patients across the spectrum of acute coronary syndromes (1–8). In addition, the newer agents clopidogrel and ticlopidine have been shown to be beneficial in reducing clinical events compared with aspirin alone in coronary stenting (9–13) and in symptomatic patients with atherosclerosis (1,14,15). The newest class of drugs is the platelet glycoprotein (GP) IIb/IIIa receptor inhibitor group of agents, which directly inhibit platelet aggregation. I. MECHANISM OF ACTION GP IIb/IIIa inhibitors bind directly to the IIb/IIIa receptor, thereby preventing the binding of fibrinogen to the platelet and preventing formation (or progression) of a platelet aggregate. Thus, regardless of which stimuli lead to platelet activa- 101 102 Cannon tion, the IIb/IIIa inhibitor inhibits platelet aggregation. The doses of the IIb/IIIa inhibitors being tested clinically inhibit 20-µM adenosine diphosphate (ADP)– induced platelet aggregation by approximately 80 to 90%. II. TYPES OF GP IIb/IIIa INHIBITORS There are three broad categories of IIb/IIIa inhibitors: (1) monoclonal antibody fragment to the IIb/IIIa receptor, abciximab (ReoPro); (2) intravenous peptide and nonpeptide small molecule inhibitors, such as eptifibatide (Integrilin) and tirofiban (Aggrastat); and (3) oral IIb/IIIa inhibitors, such as xemilofiban, orbo- fiban, and sibrafiban. Abciximab is a monoclonal antibody fragment that binds very tightly to the IIb/IIIa receptor, with a long half-life of dissociation from the receptor (ap- proximately 40 min) (16). Thus, the antiplatelet effect lasts much longer than the infusion period—a potential benefit on improving efficacy. Thus, most drug circulates bound to platelets. To reverse the effect, transfusion of platelets will allow the drug to redistribute among all the platelets, thereby reducing the level of platelet inhibition. Abciximab also binds to other integrins on the platelet re- ceptor, such as the vitronectin (α v β 3 ) receptor (17). The peptide and peptidomimetic inhibitors (e.g., tirofiban and eptifibatide) are competitive inhibitors of the IIb/IIIa receptor, with very rapid half-lives of dissociation from the IIb/IIIa receptor (10–20 s) (18,19). Thus, the level of plate- let inhibition is directly related to the drug level in the blood. Since both inhibitors have short half-lives, when the drug infusion is stopped (18,19) the antiplatelet activity reverses after a few hours, which is a potential benefit for avoiding bleed- ing complications. The third group of GP IIb/IIIa inhibitors are the oral agents. Within this group, there are also the two broad types of agents, those that are competitive inhibitors, and those that bind tightly to the receptor. The oral drugs are usually prodrugs, which are absorbed and then converted to active compounds in the blood (20–22). The oral agents all have longer half-lives, such that they can be given once, twice, or three times daily in order to achieve relatively steady levels of IIb/IIIa inhibition. III. IIb/IIIa INHIBITION DURING PCI ANGIOPLASTY A. Abciximab In the Evaluation of c7E3 for the Prevention of Ischemic Complication (EPIC) trial of patients undergoing high-risk PCI, abciximab bolus and infusion had a 35% lower rate of death, MI, or urgent revascularization at 30 days compared Platelet Glycoprotein IIb/IIIa Inhibition 103 to the placebo group, 8.3% vs. 12.8% (p ϭ 0.008) (23). In long-term follow-up, significant reduction in death or MI has been observed at 6 months and 3 years (24,25). Similar reductions in major cardiac events were observed in elective PCI in the Evaluation in PTCA to Improve Long-term Outcome with Abciximab Glycoprotein IIb/IIIa Blockade (EPILOG) trial. Death, MI, or urgent revasculari- zation at 30 days for the abciximab plus low-dose heparin group was 5.2% vs. 11.7% for heparin alone, a 58% risk reduction (p Ͻ 0.001) (26). Death or MI was similarly reduced by more than 50% when adding abciximab. When using a lower dose of heparin with abciximab, there was no difference in the incidence of major bleeding or the need for transfusion between abciximab-treated patients and placebo. Thus, the low-dose heparin regimen is the current recommendation with abciximab (and other agents): 70-U/kg initial bolus of heparin with addi- tional 20-U/kg boluses if the activated clotting time is Ͻ200 s. Abciximab was also found to be beneficial when started 24 h prior to a PCI in the c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) trial: death, MI, or urgent revascularization was reduced by abcix- imab from 15.9 to 11.3% (p ϭ 0.012) (27). In the Evaluation of IIb/IIIa inhib- itor for Stenting (EPISTENT) trial (28), compared with stenting with only aspirin and heparin, the rate of death, MI, or urgent revascularization at 30 days was significantly reduced in both abciximab groups—from 10.8 to 5.3% for stent plus abciximab (p Ͻ 0.001) and 6.9% for balloon angioplasty with abciximab (p ϭ 0.007) (28). Benefits were maintained at 6 months (29) and 1 year, with a significant reduction in 1 year mortality in patients treated with stent plus abcix- imab compared with stent alone (30). In addition, a metanalysis of abciximab trials has shown that there is a significant reduction in mortality when GP IIb/ IIIa inhibition is used (31,32) (Fig. 1). B. Eptifibatide Eptifibatide has been studied in three PCI trials and one large unstable angina trial. In the Integrilin to Minimise Platelet Aggregation and Coronary Thrombosis (IM- PACT) II trial, there was a trend toward a lower composite event rate in each of the doses of eptifibatide vs. placebo, 9.2% and 9.9% vs. 11.4%, respectively (p ϭ 0.063) for low-dose eptifibatide. However, the eptifibatide infusion rates of 0.5 µg/ kg/min and 0.75 µg/kg/h were later found to achieve only 50 to 60% platelet inhibi- tion. In the subsequent Platelet Glycoprotein IIb/IIIa in Unstable Angina Receptor Suppression Using Integrilin therapy (PURSUIT) trial of eptifibatide in ACS, which used a higher dose (180 µg/kg bolus followed by a 2.0-mg/kg/h infusion) among patients undergoing early angioplasty or stenting while on study drug, benefits were more dramatic: 16.7% for placebo vs. 11.6% for eptifibatide (p ϭ 0.01) (33,34). More recently, the Enhanced Suppression of the Platelet Receptor IIb/IIIa with Eptifibatide Therapy (ESPRIT) trial tested a higher dose, 180-µg/kg bolus 104 Cannon Figure 1 Metanalysis of mortality through follow-up in trials of percutaneous coronary intervention comparing abciximab and placebo. (Data from Ref. 31; reproduced from Ref. 32.) followed by a 2.0-µg/kg/min infusion, with a second bolus of 180 µg/kg given 10 min after the first bolus. This dose was targeted to achieve 85 to 95% platelet inhibition, with the second bolus to ensure no fall in the level of inhibition of platelet aggregation at the early periprocedural time point. In this trial, patients enrolled had either stable angina or unstable angina or a recent, but not acute, MI. The primary endpoint—death, MI, urgent revascularization, or thrombotic bailout at 48 h—was reduced by 37% (10.5 vs. 6.6%; p ϭ 0.0017) (35). Death or MI at 48 h was reduced from 9.2 to 5.5% (p ϭ 0.0013), a relative 40% reduc- tion. Death, MI, or target vessel revascularization was reduced from 9.3 to 6.0%; p ϭ 0.0045) (35). Thus, eptifibatide in the new double bolus and infusion regimen led to a substantial reduction in early complications from PCI. The 30-day data showed durability of the results (Fig. 2). The rate of death, MI, or urgent target vessel revascularization was reduced by 35% with eptifiba- tide (p ϭ 0.003), and there was a 38% relative reduction in the rate of death or MI (6.3% with eptifibatide vs. 10.2% with placebo; p ϭ 0.002, representing an absolute 3.9% reduction). Again, the individual endpoints each showed similar relative reductions, including a nonsignificant trend for reduced mortality, 0.4% eptifibatide vs. 0.6% for placebo. Overall, the rates of bleeding were relatively low. Severe bleeding occurred in 0.7% of eptifibatide patients vs. 0.5% of placebo (p ϭ NS). Moderate bleeding, as coded by the investigator, occurred in 1.3 and 1.1%, respectively. Major bleed- ing using Thrombolysis in Myocardial Infarction (TIMI) criteria (greater than 15% absolute drop in hematocrit or 5 g/dL drop in hemoglobin) (36) did show a small increase in bleeding (1.4 vs. 0.4%, eptifibatide vs. placebo). Most of these events involved the vascular access site for the cardiac catheterization. These Platelet Glycoprotein IIb/IIIa Inhibition 105 Figure 2 Thirty-day results from the ESPRIT trial. (Data from Ref. 35.) rates compare favorably with prior IIb/IIIa inhibitor trials and may be due in part to the low-dose, weight-adjusted heparin that was used in both the placebo and eptifibatide groups. C. Tirofiban Tirofiban is a nonpeptide GPIIb/IIIa receptor antagonist with a short half-life (approximately 2 h). The RESTORE trial enrolled 2139 patients undergoing high- risk PCI, and randomized patients to tirofiban (10-mg/kg bolus followed by 0.15- mg/kg/h infusion for 36 h). Tirofiban led to a lower but not statistically significant reduction in the primary composite endpoint of death, MI, revascularization for target vessel ischemia, or stent placement for abrupt vessel closure at 30 days (10.3 vs. 12.2%, a 16% risk reduction; p ϭ 0.16) (37). Death, MI, or urgent revascularization to 30 days was reduced by tirofiban by 24% (8.0 vs. 10.5%; p ϭ 0.052). In this trial, however, systematic collection of cardiac enzymes peri- procedurally was not carried out, and thus uniform ascertainment of a major endpoint was not carried out as in the other trials. The TARGET trial directly compared abciximab and tirofiban in PCI and found a lower death rate, MI, or urgent revascularization at 30 days (6.0 vs. 7.5%) favoring abciximab (37a). However, at 6 months there was no significant difference in death, MI, or target vessel revascularization, or in mortality. D. Primary PCI In the setting of ‘‘primary’’ PCI for acute ST-elevation MI, favorable results were first observed in a subgroup of the EPIC trial, with more than 50% reductions in 106 Cannon Figure 3 Facilitation of early reperfusion with IIb/IIIa inhibition prior to primary PCI. Mins ϭ time in minutes from start of IIb/IIIa inhibitor to angiogram. (Data from Refs. 41–44.) cardiac events (38). Subsequently, the ReoPro and Primary Angioplasty Organi- zation and Randomized Trial (RAPPORT) trial found that abciximab reduced death, MI, or urgent revascularization at 30 days by 48%, from 11.2 to 5.8% (p ϭ 0.03). This beneficial effect was sustained at 6 months (17.8% vs. 11.6%; p ϭ 0.05) (39). Two other randomized trials have also shown benefit of abciximab in primary PCI, each with a similar 50% reduction in death, MI, or urgent revas- cularization at 30 days (40,41). Another important finding has been observed from treatment of patients with ST-elevation MI with GP IIb/IIIa inhibitors in the Emergency Department 30 to 90 min prior to carrying out the PCI. Early TIMI grade 3 flow is achieved in 20 to 30% of patients, with TIMI grade 2 or 3 flow of approximately 50% (Fig. 3) (41–44). Thus, use of GP IIb/IIIa inhibitors can ‘‘facilitate’’ the PCI by providing better preprocedural flow and consequently better procedural out- comes. Thus, given this broad experience with GP IIb/IIIa inhibitors in PCI, and with reductions in death or MI of approximately 50%, their use has become a new therapeutic standard for ‘‘primary’’ PCI. IV. IIb/IIIa INHIBITION IN UNSTABLE ANGINA AND NON-ST-ELEVATION MI The three IIb/IIIa inhibitors discussed above have also been shown to be benefi- cial in treating patients with unstable angina and non-ST-elevation MI. Platelet Glycoprotein IIb/IIIa Inhibition 107 A. Tirofiban The PRISM-PLUS trial enrolled 1915 patients with unstable angina/non-ST- elevation MI with either electrocardiographic changes or positive enzymes. The combination of tirofiban, heparin, and aspirin led to a 32% reduction in the rate of death, MI, or recurrent refractory ischemia at 7 days (the primary endpoint) compared with aspirin plus heparin, 12.9 vs. 17.9%, respectively (p ϭ 0.004) (45). This benefit was due to a 47% reduction in MI (p ϭ 0.006) and a 30% reduction in refractory ischemia (p ϭ 0.02). Early benefits were observed: there was a significant 66% reduction in death or MI by 48 h (0.9% vs. 2.6%; p ϭ 0.01). These benefits were preserved during follow-up, with a 30% reduction in the rate of death or MI (11.9 to 8.7%; p ϭ 0.03) and a significant reduction in the composite event rate at 6 months (45). All subgroups had similar relative benefits of the combination therapy, but the absolute benefit, in terms of the number of events prevented, was greater in higher risk patient subgroups, such as the elderly, diabetics, those who were already taking aspirin, and with ST segment changes or positive cardiac markers (Fig. 4). The benefit of the combination of tirofiban plus heparin and aspirin was observed across all management strategies: death or MI at 30 days was reduced by 25% in patients managed medically, by 34% in those who had angioplasty, and by 30% in those who subsequently went on to bypass surgery. Figure 4 Absolute reduction in the primary endpoint (death, MI, or refractory angina at 7 days) in various subgroups in the PRISM-PLUS trial when treated with tirofiban, aspirin, and heparin as compared with aspirin and heparin alone. As shown, there is, with the addition of tirofiban, an absolute benefit of 6 to 8 fewer patients per 100 treated who suffer a primary event in the various high-risk subgroups. (Data from Ref. 45.) 108 Cannon The PRISM trial, involving 3232 patients with unstable angina/non-ST- elevation MI, randomized patients to receive either heparin or tirofiban (not the combination of both as in PRISM PLUS), with all patients receiving aspirin (46). The goal of the trial was to determine whether the IIb/IIIa inhibitor could reduce events during medical therapy only. Accordingly, the primary endpoint was a composite of death, MI, and refractory ischemic conditions at 48 h, and coronary procedures were not permitted during the first 48 h unless required by refractory ischemia. Tirofiban-treated patients had a significant 32% lower composite event rate than the placebo group, 3.8 vs. 5.6% (p ϭ 0.01) (46). At 30 days, the im- provement on the composite endpoint or death or MI was a trend toward reduction only (death or MI, risk ratio 0.80; p ϭ 0.11). Thus, the effects of GP IIb/IIIa inhibition appeared to have greater long-term effects when used in conjunction with heparin (as was the case in PRISM-PLUS). B. Eptifibatide Eptifibatide was studied in the PURSUIT trial, which involved 10,948 patients with unstable angina and non-ST-elevation MI. Patients received aspirin and were recommended to receive heparin, and were randomized to receive eptifibatide or placebo. Of two initial doses, eptifibatide 180-µg/kg bolus and 2.0-µg/kg/h infu- sion significantly reduced the rate of death or MI at 30 days from 15.7 to 14.2% (p ϭ 0.042) (33). This reduction of 15 events per 1000 patients treated was achieved after only 72 h (i.e., while the patients were receiving study drug), 7.6% for placebo vs. 5.9% for eptifibatide (p ϭ 0.001). The benefits were more dra- matic among patients undergoing PCI within 72 h (i.e., while on study drug), 16.7% for placebo vs. 11.6% for eptifibatide (p ϭ 0.01) (33). In this group, there were reductions in death or MI observed prior to PCI and during the first 24 to 48 h post-PCI (47). Moderate or severe hemorrhage was more common in the eptifibatide group (12.8 vs. 9.9%; p Ͻ 0.001). C. Abciximab Abciximab was tested in the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IV–ACS trial for the medical management of patients with unstable angina and non-ST-elevation MI. The results were surprisingly negative. A total of 7800 patients were enrolled at 458 hospitals in 24 countries around the world, with 48% coming from western Europe, 31% from eastern Europe, and only 14% from North America. Patients received aspirin and heparin, and were randomized to receive in a double-blind fashion, a 24-h infusion of abciximab, a 48-h infusion of abciximab, or placebo. The dose was similar to the dose used in the more recent PCI trials, with a 0.25-mg/kg bolus and a 0.125- µg/kg/min (weight-adjusted) infusion for 24 or 48 h. [...]... aspirin and heparin, with the initial heparin dosage being 70-U/kg bolus and a 15-U/kg/h infusion in the tPA control arm, and 60-U/kg bolus and a 7-U/kg/h infusion in the abciximab groups Abciximab alone was associated with a rate of TIMI grade 3 flow at 90 min of 32% and patency rate of 48 % (43 ) The combination of streptokinase and abciximab produced only slight improvement in 90-min TIMI grade 3 flow: 42 %... recovery of coronary flow and left ventricular function after placement of coronary-artery stents in acute myocardial infarction Circulation 1998; 98:2695– 2701 122 41 42 43 44 45 46 47 48 49 50 51 52 53 Cannon Montalescot G, Barragan P, Wittenberg O, et al Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction N Engl J Med 2001; 344 :1895–1903 van den Merkhof... The CAPTURE Investigators Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE study Lancet 1997; 349 : 142 9– 143 5 [published erratum appears in Lancet 1997; 350: 744 ] Platelet Glycoprotein IIb/IIIa Inhibition 28 121 The EPISTENT Investigators Randomised placebo-controlled and balloon-angioplasty-controlled trail to assess... reteplase; and in INTRO-AMI and several ongoing trials In the TIMI- 14 trial dose-ranging phase, 681 patients with ST-segmentelevation MI meeting with standard eligibility criteria were randomized within 12 h of onset of chest pain to receive one of four reperfusion regimens (each with several dose levels): accelerated (full-dose) tPA alone (the control arm); reduced-dose tPA plus abciximab; reduced-dose... Neumann F-J, Kastrati A, et al A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents N Engl J Med 1996; 3 34: 10 84 1089 Bertrand ME, Legrand V, Boland J, et al Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting The full anticoagulation versus aspirin and ticlopidine... 1995; 92:1 743 –1 748 60 Bhatt DL, Marso SP, Houghtaling P, Labinaz M, Lauer MA Does earlier administration of eptifibatide reduce death and MI in patients with acute coronary syndromes? Circulation 1998; 98(suppl I):I-561 61 The IMPACT-II investigators Randomised placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II Lancet 1997; 349 : 142 2– 142 8 62... TIMI grade 3 flow: 42 % in the 0.5-MU group; 39% in the 0.75-MU group; and 47 % in the 1.25-MU group The 1.5-MU regimen plus abciximab was discontinued after four of six patients developed a major hemorrhage, one of whom had an ICH Of the various dosing regimens of tPA tested, the best angiographic results were obtained using a 50-mg dose given as a 15-mg bolus and a 35-mg infusion over 60 min The rate... half-dose rPA (5U ϩ 5U) and abciximab achieved 60-min TIMI grade 3 flow in 62% of patients (44 ) The GUSTO V and ASSENT III trials each found that the combination Platelet Glycoprotein IIb/IIIa Inhibition 115 Figure 7 Results from the Thrombolysis in Myocardial Infarction (TIMI )-1 4 Trial Comparison of 90-min accelerated tissue plasminogen activator (tPA) with combination therapy using abciximab (abcix) and. .. bleeding and was discontinued Further testing of eptifibatide is planned with reduced-dose thrombolytic agents 1 14 D Cannon Reduced-Dose Fibrinolysis Plus GP IIb/IIIa Inhibition The combination of a reduced-dose fibrinolytic agent and a GP IIb/IIIa inhibitor was tested in the TIMI- 14 trial, using tPA, streptokinase, and reteplase; in SPEED (Strategies for Patency Enhancement in the Emergency Department)... Inhibition 54 123 Cannon CP Overcoming thrombolytic resistance: Rationale and initial clinical experience combining thrombolytic therapy and glycoprotein IIb/IIIa receptor inhibition for acute myocardial infarction J Am Coll Cardiol 1999; 34: 1395– 140 2 55 Alexander JH, Sparapani RA, Mahaffey KW, et al Eptifibatide reduces the size and incidence of myocardial infarction in patients with non-ST-elevation . rete- plase; and in INTRO-AMI and several ongoing trials. In the TIMI- 14 trial dose-ranging phase, 681 patients with ST-segment- elevation MI meeting with standard eligibility criteria were randomized. eastern Europe, and only 14% from North America. Patients received aspirin and heparin, and were randomized to receive in a double-blind fashion, a 2 4- h infusion of abciximab, a 48 -h infusion of. 32% and patency rate of 48 % (43 ). The combination of streptokinase and abciximab produced only slight improvement in 90-min TIMI grade 3 flow: 42 % in the 0.5-MU group; 39% in the 0.75-MU group; and