Platelet Glycoprotein IIb/IIIa Inhibitor Use During Percutaneous Coronary Intervention: “IIb or Not IIb, What is the Question?”

The primary pathophysiologic mechanism for myocardial ischemia secondary to ACS or as an acute complication of PCI is thrombotic occlusion of a coronary artery in response to vascular injury.1 Endothelial denudation caused by disruption or erosion of atherosclerotic plaque or mechanical injury during PCI promotes deposition of platelets and the formation of a hemostatic plug. Platelet adhesion, mediated primarily through binding of platelet GP Ib and IIb receptors to subendothelial von Willebrand factor, is rapidly followed by platelet activation.2 Local biochemical and mechanical stimuli activate signal transduction pathways within platelets that induce a conformational change in the platelet GP IIb/IIIa receptor, making it capable of binding adhesive plasma proteins, primarily fibrinogen or von Willebrand factor. These proteins cross-link activated GP IIb/IIIa receptors on adjacent platelets, leading to platelet aggregation and coronary thrombus formation.3 Platelet aggregates form the partly occlusive “white” thrombus, which has been shown to be the cause of ischemia in patients with non-ST segment elevation ACS.4 Conversely, in patients with ST-segment elevation myocardial infarction, the culprit thrombi are more often completely occlusive and contain a network of cross-linked fibrin and entrapped red blood cells (“red thrombus”) superimposed on the underlying platelet-rich thrombus.4 Based on the above aforementioned pathophysiologic mechanisms, aspirin and heparin have traditionally formed the cornerstones of antithrombotic therapy for patients with non-ST segment elevation ACS. Clinical trials of aspirin and heparin therapy for ACS have demonstrated improved clinical outcomes in patients who receive these agents in combination.5 Despite such combination therapy, significant morbidity and mortality persists among patients with non-ST segment elevation ACS due to the limitations of aspirin and heparin based on their mechanisms of action. For example, aspirin is a relatively weak antiplatelet agent that blocks only one of several pathways for platelet activation. In addition, heparin is limited by its requirement for antithrombin III, its ineffectiveness against clot-bound thrombin, and the fact that it binds to cellular and plasma proteins, which leads to an unpredictable anticoagulant effect. Recognition of these limitations, along with an improved understanding of the vascular biology underlying coronary thrombosis, has provided the impetus for the development of better anti-thrombotic agents. GP IIb/IIIa receptor inhibitors. The advent of competitive inhibitors for fibrinogen binding to the platelet GP IIb/IIIa receptor has further expanded the therapeutic options available for treating thrombotic disorders. To date, only 3 intravenous GP IIb/IIIa inhibitors have been approved for clinical use: abciximab (ReoPro, Centocor/Eli Lilly), tirofiban (Aggrastat, Merck) and eptifibatide (Integrilin, COR Therapeutics). Although this class of therapeutic agents has been defined by a common affinity for the platelet GP IIb/IIIa receptor, the 3 currently available agents differ in pharmacodynamic and pharmacokinetic profile.6,7 Differences in the duration of action at the platelet target receptor, specific receptor affinity, as well as differential binding sites on the GP IIb/IIIa receptor have been demonstrated for the monoclonal antibody, abciximab, compared with both the cyclic heptapeptide eptifibatide and the nonpeptide tyrosine derivative tirofiban.7,8 Distinct and specific binding sites on the GP IIb/IIIa receptor have been delineated through the use of site-specific monoclonal antibodies and their differential displacement by the various GP IIb/IIIa receptor inhibitors.8 Differential binding sites likely explain the observation that tirofiban does not influence the t1/2 on-rate or Kd of abciximab binding to platelets.8,9 These agents also manifest different affinities for the GP IIb/IIIa receptor. Abciximab is a low Kd (high affinity) agent with a very short plasma t1/2 and a prolonged duration of action at the platelet target receptor while eptifibatide and tirofiban are high Kd (low affinity) agents with a relatively long plasma t1/2 and short duration of action at the platelet receptor. Thus, high affinity — prolonged duration of action at the platelet receptor — contributes to the gradual tapering of platelet inhibition that follows discontinuation of abciximab therapy in comparison to the abrupt recovery in platelet aggregability that follows cessation of eptifibatide or tirofiban.9,10 GP IIb/IIIa receptor occupancy by abciximab exceeds 30% at 8 days and 10% at 15 days after discontinuation of therapy. Furthermore, abciximab demonstrates affinity for receptors other than GP IIb/IIIa including aVB3 (vitronectin) and CD 11b/18 (MAC 1). This poly-receptor affinity likely contributes to the phenomenon of “gradual redistribution” as the monoclonal antibody “wanders” across different receptors over time. Prolonged platelet receptor occupancy by abciximab “transforms” the platelet into a drug delivery system and provides for a gradual taper of antiplatelet effect. Uncertainty exists as to whether these pharmacodynamic differences will translate into measurable differences in clinical outcomes for patients treated with different agents. Subtle differences in clinical events observed in nonrandomized comparisons of clinical trials may reflect the relative rate of platelet recovery or differences in receptor affinity between different GP IIb/IIIa inhibitors. Current assays that evaluate both platelet receptor inhibition as well as platelet receptor occupancy may help elucidate the more appropriate measure of platelet function to assess clinical efficacy of these agents.10 In addition to different pharmacokinetics at the platelet GP IIb/IIIa receptor, as noted above, abciximab also demonstrates affinity for the activated conformation of the CD 11b/18 (MAC 1) receptor, which is present on granulocytes, monocytes, and natural killer cells.11,12 The MAC-1 receptor undergoes a conformational change when the white cell is stimulated by a variety of agonists and contributes to the processes of neutrophil adhesion, transmigration across endothelium, neutrophil aggregation, chemotaxis, and phagocytosis of opsonized particles.12 This receptor also modulates white cell-platelet interactions and the inflammatory response to vessel injury. White cell surface expression of MAC-1 may be increased in patients with coronary heart disease or after PCI, and white cell adhesion to the site of stent deployment is significantly reduced by abciximab.13,14 Since leukocyte-platelet interactions mediate, in part, atherogenesis, restenosis, and reperfusion injury, abciximab may provide a potentially beneficial cellular response to inflammatory injury. In this respect, it is noteworthy that monoreceptor blockade of the GP IIb/IIIa receptor by a small molecule inhibitor (lamifiban) did not enhance microvascular reperfusion or reduce leukocyte accumulation in a porcine model of myocardial infarction.15 Abciximab demonstrates a similar affinity for the vitronectin (aVb3) receptor which shares the same b3 subunit as the GP IIb/IIIa receptor.16 The vitronectin receptor is increased on smooth muscle cells after vascular injury and has been implicated in the intimal hyperplasia response that follows vascular injury and thus, to restenosis after PCI. Blockade of the vitronectin receptor by abciximab may prevent intimal hyperplasia after PCI.17 The survival advantage of abciximab demonstrated in clinical trials may, in part, be due to these “anti-inflammatory” effects distinct from the degree of platelet GP IIb/IIIa receptor inhibition.10 GP IIb/IIIa Receptor Inhibitors During PCI Abciximab. The Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) trial was the first study to test the efficacy of adjunctive GP IIb/IIIa receptor blockade for PCI.18 Treatment with abciximab was associated with a 35% reduction in the primary endpoint of death, nonfatal myocardial infarction (MI), or requirement for urgent revascularization through 30 days.18 Three-year follow-up demonstrated sustained clinical benefit.19 A more recent analysis of all patients by intention to treat at 7-year follow-up demonstrated a significant and similar reduction in mortality for all abciximab-treated patients (17.3% bolus plus infusion; 16.1% bolus only) versus placebo (mortality 20.1%)20 (Figure 1). This observation suggests an effect of abciximab on mortality in excess of that explained solely by suppression of early periprocedural ischemic events. The Evaluation in PTCA (percutaneous transluminal coronary angioplasty) to Improve Long-term Outcome with Abciximab Glycoprotein IIb/IIIa Blockade (EPILOG) study investigated whether the benefits of abciximab could be extended to a more broad spectrum of patients undergoing angioplasty, and whether low-dose, weight-adjusted regimen for concomitant heparin administration would reduce the excessive bleeding rates observed in the EPIC trial without a loss of clinical efficacy.21 Treatment with abciximab was associated with a 55% reduction in death, nonfatal MI, or urgent revascularization through 30 days.21 The primary endpoint rates observed with abciximab and standard-dose heparin were nearly identical to those observed in the group receiving abciximab and low-dose heparin. As with EPIC, long-term follow-up data confirmed a sustained beneficial effect on primary endpoint events at 1-year follow-up.22 Furthermore, the rate of major bleeding was similar in all 3 treatment groups.22 A recent analysis of all patients by intention to treat with follow-up through 4.5 years demonstrated a trend toward reduction in late mortality associated with abciximab bolus plus infusion (8%) versus placebo (9.6%)20 (Figure 2). In the Evaluation of Platelet GP IIb/IIIa Inhibitor for Stenting (EPISTENT) trial, patients with ischemic heart disease and suitable coronary lesions were randomly assigned to stenting plus placebo, stenting plus abciximab, or balloon angioplasty plus abciximab.23 The primary clinical endpoint was the composite occurrence of death, MI, or need for urgent revascularization through 30 days. The primary endpoint was observed in 10.8% of patients in the stent-plus-placebo group, 5.3% in the stent-plus-abciximab group, and 6.9% in the balloon-plus-abciximab group.23 The outcomes most dramatically reduced by abciximab were death and large MI — a composite occurrence of 7.8% in the stent-placebo group, 3.0% in the stent-abciximab group, and 4.7% in the balloon-abciximab group. At 1-year follow-up, one percent of patients in the stent-abciximab group had died, compared with 2.4% of patients in the stent-placebo group. The combined endpoint of death or MI was observed in 5.3% and 11%, respectively. By multivariate modeling, factors independently associated with improved survival were assigned to stenting with abciximab and more severe preprocedural angiographic coronary stenosis. A prospectively defined substudy was performed in diabetics with the main endpoint being a composite of death, MI, or target-vessel revascularization (TVR) through 6 months.24 Abciximab therapy, irrespective of revascularization strategy (PTCA or stent), significantly reduced the rate of death or MI to 6 months in the diabetic cohort. The 1-year mortality rate for diabetic patients was 4.1% in stent-placebo and 1.2% in stent-abciximab treatment groups.25 A recent analysis of all patients by intention to treat with follow-up through 3 years demonstrated a trend toward reduction in mortality associated with abciximab especially in combination with stenting (stent + placebo, 4.8%; balloon + abciximab: 4.6%; stent + abciximab: 3.3%)20 (Figure 3). Clinical studies of the benefits of abciximab as an adjunct to primary angioplasty in patients with ST-segment elevation MI (STEMI) include: ReoPro in Acute Myocardial Infarction and Primary PTCA Organization and Randomization Trial (RAPPORT),26 Intracoronary Stenting and Antithrombotic Regimen 2 (ISAR-2),27 Abciximab Before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-term Follow-up (ADMIRAL),28 and Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC).29 In all 4 trials, abciximab significantly decreased the incidence of death, reinfarction, and the need for urgent TVR; at the cost of increased bleeding mainly at the sites of vascular access. In the CADILLAC trial, the combination of stent plus abciximab had the best results, with 96.7% achieving thrombolysis in MI (TIMI) grade 3 flow following PCI with very low mortality rates.29 Abciximab in combination with reduced-dose fibrinolysis for acute MI was initially studied in the TIMI-14 trial.30 Patients with acute MI were randomly assigned to either full dose alteplase (100 mg) alone, reduced-dose alteplase (20–65 mg) in combination with abciximab, reduced-dose streptokinase (500,000 U–1.5 MU) in combination with abciximab, or abciximab alone. Coronary angiography performed at 90 minutes following study drug administration demonstrated normal TIMI grade 3 flow in 32% of patients receiving abciximab alone, in 62% of patients treated with full-dose alteplase alone, and in 77% of patients receiving the combination of reduced-dose alteplase plus full-dose abciximab.30 Moreover, at 60 minutes following initiation of study drug, TIMI grade 3 flow rates were 43% with alteplase alone and 72% with reduced-dose alteplase plus abciximab. Based on previous data derived from the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)-1 trial, a 23% improvement in TIMI grade 3 flow at 90 minutes should translate into a 1% decrease in mortality.31 The recently completed GUSTO-V trial examined the clinical efficacy and safety of half-dose reteplase (Retavase, Centocor) and full-dose abciximab compared to full-dose reteplase in an open-label design.32 At 30 days, the all cause mortality was similar between the two groups (reteplase + abciximab, 5.6%, and reteplase alone, 5.9%) (Figure 4). However, at 7 days, recurrent ischemia, reinfarction, and the need for urgent coronary intervention were all significantly less frequent in the reduced dose reteplase + abciximab group (Figure 4). The frequencies of major cardiac complications following an MI were significantly reduced and there was no significant difference for hemorrhagic stroke in the overall population, although a trend towards more intracranial hemorrhage was present in elderly patients (age > 75 years, 2.1% for combination vs. 1.1% for monotherapy). The incidence of non-intracranial bleeding and thrombocytopenia was higher with combination therapy. GUSTO V demonstrated an alternative reperfusion strategy with “noninferiority” to fibrinolytic monotherapy and reassures the concept of combined fibrinolysis and GP IIb/IIIa inhibition in acute MI. These results encourage the ongoing efforts for testing other combinations of these agents (Table 1). The attractiveness of the combination approach is that for patients who fail to achieve prompt pharmacologic reperfusion, this strategy facilitates a smooth transition from medical to catheter-based revascularization. The Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events (FINESSE) trial, which compares reduced dose reteplase + abciximab with abciximab alone before primary stenting, will be another step in evaluating a “facilitated PCI” strategy for acute MI. Eptifibatide. The clinical benefit of eptifibatide in PCI was demonstrated by the IMPACT-II (Integrilin to Minimize Platelet Aggregation and Prevent Coronary Thrombosis II)33 and ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy)34 trials. In the IMPACT-II trial the primary endpoint was the 30-day clinical composite occurrence of death, MI, unplanned coronary revascularization, or coronary stent implantation for abrupt or threatened coronary closure. By 24 hours, treatment with eptifibatide was associated with a statistically significant 25% reduction in the primary endpoint, but by 30 days, no difference between treatment groups was observed.33 Eptifibatide treatment did not increase rates of major bleeding or transfusion. The ESPRIT trial was a randomized, placebo-controlled trial to assess whether a novel, double-bolus dose of eptifibatide could improve outcomes of patients undergoing coronary stenting. The primary endpoint was the composite occurrence of death, MI, urgent TVR, or the requirement for bailout GP IIb/IIIa inhibitor therapy for thrombotic complications through 48 hours after randomization. The secondary endpoint was the composite of death, MI, or urgent TVR at 30 days. The primary endpoint was reduced from 10.5% in patients receiving placebo to 6.6% in patients treated with eptifibatide, a 37% reduction.34 The secondary endpoint was also reduced from 10.5% in patients receiving placebo to 6.8% in patients receiving eptifibatide, a 35% reduction. At 6-month follow-up, the beneficial effect of eptifibatide persisted mainly due to early ( 80% inhibition by Accumetrics Rapid Platelet Function Analyzer) was confirmed at 5 minutes and 4–12 hours following initiation of tirofiban in a small substudy cohort of patients. This trial concluded that tirofiban was inferior to abciximab which remains the reference standard for PCI (Figure 5). The efficacy of tirofiban in the setting of STEMI in combination with fibrinolysis is currently under investigation (Table 1). Single-center PCI experience. The overall death rate in all PCI trials is low. A meta-analysis of multiple trials found that the mortality rate following PCI at 30 days was lower among patients who received adjunctive pharmacotherapy with a platelet GP IIb/IIIa inhibitor, although this trend was not statistically significant.41 Analysis of pooled data from the EPIC, EPISTENT, and EPILOG trials demonstrates a statistically significant 2.0% (absolute) reduction in 1-year mortality following PCI in patients who received adjunctive abciximab (versus placebo).25 Furthermore, a recent meta-analysis of patients enrolled into these trials at maximum follow-up available in EPIC (7 years), EPILOG (4.5 years), and EPISTENT (3 years) substantiates a persistent survival advantage in favor of abciximab with a widening of the mortality benefit over time20 (Figure 6). Thus, data from clinical trials support a consistent, significant survival advantage in favor of abciximab versus placebo following PCI. A study at our institution analyzed 1,472 consecutive PCI procedures performed in 1997 through 6-month follow-up.10,42 In this high-volume clinical practice (average: 280 PCI/operator in 1997), abciximab was administered prophylactically to 70% of patients and associated with a significant 6-month survival advantage for all PCI and stent procedures (Figure 7). A sophisticated technique of propensity scoring was used to adjust for nonrandomization in this observational study. Adjustment for nonrandomized administration of abciximab enhanced the associated reduction in mortality from 3.4% (unadjusted) to 4.9% (adjusted) at 6-month follow-up.10,42 These data demonstrate a consistent reduction in mortality by abciximab following PCI in pooled and meta-analyses of multiple trials, the randomized EPISTENT trial, and in high-volume clinical practice. Summary. Platelet GP IIb/IIIa inhibitors are powerful antiplatelet agents that have proven to be beneficial in the management of patients with coronary artery disease. In patients undergoing PCI, GP IIb/IIIa receptor blockers reduce the rate of periprocedural myocardial ischemic events. Based on the evidence accumulated over the last decade, abciximab occupies a prominent role in ACS patients undergoing PCI. Eptifibatide and tirofiban have been shown to be beneficial in patients with non-ST segment elevation ACS and should be administered soon after hospitalization in moderate to high-risk ACS patients if immediate PCI is not planned. However, to date, abciximab alone has been associated with a survival advantage in patients undergoing primary PCI and remains the reference standard of GP IIb/IIIa inhibitors used in the cardiac catheterization laboratory. This survival advantage associated with abciximab is not explained by the degree of measured platelet receptor inhibition alone, and may partly relate to abciximab’s affinity for other integrin receptors (CD 11b/18; aVb3). For ST-segment elevation MI, catheter-based coronary intervention with stent deployment and adjunctive abciximab administration is the reperfusion modality of choice in the context of available catheterization laboratory facilities and personnel. Combination therapy with reduced-dose reteplase and abciximab appears safe and effective, and results of trials using various other combination strategies of fibrinolytic and GP IIb/IIIa inhibitor therapy will soon be available. Combination therapy is associated with a trend towards higher risk of intracranial hemorrhage in the elderly (age > 75 years) population and catheter based reperfusion or fibrinolytic monotherapy may be more suitable for acute MI in this subgroup. For patients undergoing early PCI (within 12 hours of therapy), the combination pharmacotherapy strategy appears attractive due to the beneficial effects of GP IIb/IIIa blockade during PCI. Further evaluation of combination therapy with respect to cost-effectiveness ratios (cost per life year gained) will influence the choice of optimal pharmacologic regimen for acute MI.

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