Present and Potential Future Paradigms for the Treatment of ST-Segment Elevation Acute Myocardial Infarction (Part II)

Continued from previous page Review of Primary PCI Since the introduction of PTCA more than 20 years ago, technical advances and increased operator experience have contributed to a steady improvement in the success rate of this procedure. However, the benefits of PTCA have been limited by acute and long-term complications.⁴¹ A long-standing controversy in cardiology has focused on which management strategy, fibrinolysis or primary PCI, provides the best outcome for patients with AMI. Addition of potent platelet GP IIb/IIIa receptor inhibitors to reduced-dose fibrinolytic agents has improved early angiographic patency rates. However, the discrepancy between myocardial tissue perfusion and epicardial coronary flow limits the use of TIMI flow grade as a surrogate endpoint. Mechanical reperfusion has also been evolving with the addition of platelet GP IIb/IIIa receptor inhibitors and stents, both of which improve short- and long-term outcome of percutaneous intervention for AMI. The advantages of fibrinolysis are its widespread availability, its well-documented efficacy, and its ability to reduce mortality risk. However, its limitations include hemorrhage, reperfusion failure in up to 40% of patients and early reocclusion in up to 10% of patients.⁴² Primary, or direct, angioplasty offers the advantages of anatomic definition, the potential for higher rates of reperfusion, a lower mortality rate than fibrinolytic monotherapy and a lower rate of intracranial hemorrhage.^42,43 Thus, the balance would seem to tip in favor of primary PCI. However, despite the advantages of primary PTCA, certain drawbacks may affect its usefulness. In the United States, its availability is limited by the relatively small number of hospitals with catheterization laboratories where primary PTCA can be performed in a timely manner (44 Benefits of Facilitated PCI Facilitated early percutaneous coronary intervention, a term referring to planned PCI after pharmacologic reperfusion therapy, has the potential to fuse the best aspects of fibrinolysis and primary PTCA: rapid reperfusion, potential cost-effectiveness, improved patient stability, greater technical procedure success and higher TIMI 3 flow rates. Data from the Strategies for Patency Enhancement in the Emergency Department (SPEED) pilot trial of GUSTO-V suggest multiple benefits from the use of combination therapy with abciximab and reduced-dose reteplase for facilitation of early PCI.⁴⁵ The SPEED trial evaluated the combination of standard-dose abciximab combined with half-dose (5 U + another 5 U 30 minutes later) reteplase compared with standard-dose reteplase in 528 patients with ST-segment elevation AMI.⁴⁶ The utility of early percutaneous coronary intervention was studied in a subset of 323 patients in this trial who underwent PCI with a planned initial angiography at a median of 62 minutes after initiation of reperfusion therapy. Patients receiving the combination of abciximab and half-dose reteplase had the highest TIMI 3 flow rates (47%) at 60–65 minutes, and post-PCI their TIMI 3 rates increased to 86%. A trend toward improved 30-day outcomes was observed in patients who received combination therapy. The composite rate of death, MI or need for urgent revascularization in the combination group was 5.9% compared with 8.1% in patients who received abciximab alone and 7.1% in patients who received reteplase alone. Early PCI was performed less often in patients receiving combination therapy than in patients receiving abciximab alone (65% combination therapy versus 82% abciximab alone; p = 0.03), most likely due to the improved coronary flow achieved before PCI in these patients.⁴⁵ The possibility that an improved combination pharmacologic regimen could lessen the need for early PCI suggests that this strategy might be cost-effective. Patients receiving combination therapy were more likely to have a patent infarct-related artery (IRA) at initial angiography (47.1% combination therapy versus 24.3% abciximab alone; p = 0.05).45 In another study, a facilitated PCI approach stabilized patients before they arrived in the catheterization laboratory; patients arriving after earlier medical reperfusion were less likely to be in cardiogenic shock, to require an intra-aortic balloon pump or temporary pacemaker, or to suffer cardiac arrest.^47,48 Likewise, an improvement in early and late survival has been observed among patients who enter the catheterization laboratory with a patent rather than an occluded infarct coronary artery.⁴⁸ The pharmacologic approach of combined abciximab and reduced-dose reteplase appears to improve TIMI 3 flow by an absolute amount of 7–14% over reteplase alone at 60–90 minutes.^46,49 Primary PCI can achieve higher patency rates, although at later time points.50,51 The addition of early facilitated PCI in the SPEED trial resulted in an extremely high TIMI 3 flow rate of 86% and a normal mean corrected TIMI frame count without sacrificing the early benefit of a pharmacologic approach. Pharmacology of Available GP IIb/IIIa Inhibitors The two therapeutic approaches to the initial treatment of AMI — direct angioplasty and fibrinolytic therapy — share the same objective: rapid and sustained coronary reperfusion to obtain optimal long-term clinical outcomes. Although both approaches have been shown to reduce mortality, each has limitations.⁵² With the growing appreciation for the role of the platelet in the pathophysiology of coronary thrombosis, inhibition of platelet aggregation offers a promising therapeutic approach. Evidence from clinical trials indicates that GP IIb/IIIa inhibitors improve outcomes in primary PCI: TIMI 3 flow rates prior to and post-PCI are improved; cardiac function and procedural success are enhanced; and short- and long-term ischemic events are reduced. Evidence is also accumulating that platelet GP IIb/IIIa inhibition, specifically with abciximab, is effective in reducing adverse ischemic events in patients with AMI whether it is used in combination pharmacotherapy with fibrinolysis, peri-procedurally before PCI or with stenting. Receptor specificity, affinity and reversibility are among the properties that define the efficacy and safety of platelet GP IIb/IIIa inhibitors. Although the three currently available agents in this class (abciximab, eptifibatide and tirofiban) all share a common affinity to the GP IIb/IIIa receptor, they differ in terms of the physical binding site on that receptor, relative receptor affinity, platelet-bound half-life and additional receptor affinities. The small molecule inhibitors (eptifibatide and tirofiban) “fit” into the binding pocket of the GP IIb/IIIa receptor, and are highly specific for the ß3 subunit. In contrast, the much larger abciximab antibody Fab fragment does not fit into the ligand-binding pocket, but instead “covers” the receptor and interferes with a secondary fibrinogen-binding site (complex-specific) (Table 3).^53–55 Abciximab, a chimeric monoclonal antibody Fab fragment with affinity for the GP IIb/IIIa receptor, was the first platelet GP IIb/IIIa inhibitor to be tested in a large-scale trial and the first to be approved by the Food and Drug Administration (FDA) for clinical use. Subsequently, eptifibatide (a peptide) and tirofiban (a nonpeptide tyrosine derivative), which compete with fibrinogen for binding to the GP IIb/IIIa receptor, have been developed. All three agents are currently approved by the United States FDA for the treatment of non-ST segment elevation acute coronary syndromes (ACS), but only abciximab and eptifibatide are currently approved for use during PCI.^3,53 These GP IIb/IIIa blocking agents have markedly different pharmacokinetic properties. Abciximab has a short plasma half-life of approximately 10 minutes, whereas eptifibatide and tirofiban have a plasma half-life of approximately 2 hours. Abciximab is associated with a gradual tapering of receptor blockade over time after termination of infusion and appears to provide some degree of platelet inhibition for up to 2–3 days following initial therapy. Because eptifibatide and tirofiban are competitive antagonists that exhibit a concentration-dependent antiplatelet effect, physiologic platelet aggregation and normal hemostasis generally return within 4–6 hours after termination of infusion.^53,54,56 In addition, abciximab exhibits an affinity to the CD 11b/18 or macrophage-1 (MAC-1) receptor that is found on neutrophils and monocytes. The MAC-1 receptor modulates white cell adhesion, white cell-platelet interactions, and the inflammatory response to both vessel injury and distal vessel embolization. This receptor is inhibited by abciximab and has been found to be activated following PCI (especially stenting).⁵⁷ Because the pathophysiologic response to stent deployment comprises thrombosis, inflammation and neointimal proliferation over time, the “multiple-receptor” affinity of abciximab may have clinical relevance, although this remains speculative. To date, only one study has directly compared the safety and efficacy of two GP IIb/IIIa inhibitors. In the Do Tirofiban and ReoPro Give Similar Efficacy Trial (TARGET) protocol, a total of 4,809 patients with stable coronary artery disease or ACS who were scheduled for urgent or elective PCI with intent for coronary stent deployment were randomized to receive either tirofiban or abciximab in addition to aspirin and clopidogrel prior to PCI. Abciximab therapy demonstrated superior 30-day outcomes in the composite endpoint of death, nonfatal MI or urgent revascularization (6.0% abciximab versus 7.6% tirofiban; p = 0.038). Abciximab’s relative therapeutic benefit was consistent across each component of the composite endpoint and was evident soon after the procedure.⁵⁸ However, by 6 months, patients treated with abciximab had no significant benefit in terms of mortality or need for target vessel revascularization compared to those treated with tirofiban.⁵⁹ Eptifibatide has also shown promise in the treatment of low-risk patients undergoing elective coronary stenting. The Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin in Therapy (ESPRIT) trial was designed to evaluate whether a double-bolus dose (180 µg/kg 10 minutes apart) plus continuous infusion (2.0 µg/kg/minute for 18–24 hours) of eptifibatide could improve patient outcomes compared with placebo. The trial, which enrolled a total of 2,064 patients, was terminated early for efficacy after an interim analysis revealed a 43% risk reduction in the composite endpoint of death or MI at 48 hours in favor of eptifibatide versus placebo (p = 0.0017). Compared with placebo, the combined incidence of death, MI, need for urgent repeat intervention, or need for thrombotic bail-out therapy at 48 hours was reduced by eptifibatide from 10.5% to 6.6% (p = 0.0015). At 30 days, the combined incidence of death, MI, or need for urgent revascularization was reduced from 10.5% to 6.8% with eptifibatide (p = 0.0034). These results suggest that GP IIb/IIIa inhibitor pretreatment with eptifibatide substantially reduces ischemic complications of elective coronary stent deployment in low-risk patients and produces better patient outcomes than a strategy of reserving GP IIb/IIIa inhibitor treatment for “bail-out” therapy.⁶⁰ Follow-up data at 6 months demonstrated continued benefit from eptifibatide therapy. The composite endpoint of death or MI was reduced from 11.5% in placebo-treated patients compared to 7.5% in those treated with eptifibatide (p = 0.002). The composite of death, MI or target vessel revascularization was also reduced from 18.3% in the placebo arm compared with 14.2% in the eptifibatide group (p = 0.008).⁶¹ Applying GP IIb/IIIa receptor inhibition to reperfusion therapy is not a novel idea. The clinical efficacy of GP IIb/IIIa inhibitors as adjunctive therapy for primary PCI is well documented. In the clinical trials of abciximab, it was shown to provide over 50% reduction in death, recurrent MI or urgent revascularization within the context of elective or urgent angioplasty and coronary stenting. Moreover, impact on microvascular recovery and LV preservation has also been observed.^62,63 Early trials investigated the role of GP IIb/IIIa receptor inhibitors added to full-dose fibrinolysis, and demonstrated improved rates of TIMI 3 flow at the cost of increased bleeding. Bleeding events were especially problematic following the combination of GP IIb/IIIa receptor inhibitors with streptokinase, a non-f ibrin specific plasminogen activator associated with substantial fibrinogen depletion.^64–66 Thus, by reducing the dose of the fibrinolytic agent, it was hoped that bleeding events would be attenuated without compromising recanalization efficacy. Several trials have examined the angiographic efficacy of varying doses of fibrinolytic therapy combined with GP IIb/IIIa receptor inhibition in patients with ST-segment elevation MI. The phase-II TIMI-14 trial evaluated alteplase alone, abciximab alone or increasing doses of alteplase plus standard-dose abciximab.⁴⁹ The phase-II SPEED trial, which was the pilot study to GUSTO-V, assessed reteplase alone, abciximab alone or abciximab in combination with escalating doses of reteplase.^45,46 The phase-III ASSENT-3 trial compared full-dose tenecteplase plus enoxaparin sodium (a low-molecular-weight heparin); half-dose tenecteplase plus standard-dose abciximab and weight-adjusted, reduced-dose unfractionated heparin (UFH); and full-dose tenecteplase plus weight-adjusted UFH.²⁴ The largest phase-III trial of combination therapy to date has been GUSTO-V, which examined half-dose reteplase plus standard-dose abciximab with standard-dose reteplase.¹⁹ These trials have provided critical information that has helped define the relationship between increasing doses of fibrinolytic agents, TIMI 3 flow at 60 and 90 minutes and bleeding events when administered alone or in combination with GP IIb/IIIa receptor inhibition and UFH therapy. Combining PCI and GP IIb/IIIa Inhibitors Our recognition of the pivotal role of platelets in the pathophysiology of ST-segment elevation AMI has improved our understanding of the problem of so-called lytic “resistance.”⁶⁷ Proposed mechanisms for this include: incomplete clot dissolution due to the action of fibrinolytic agents on only one component of the clot; release of PAI-1 and alpha-2 plasma inhibitor, vasoconstriction due to platelet-derived thromboxane A₂; enhanced fibrin activation by exposure of clot-bound thrombin; and the direct platelet-activating effect of fibrinolytics.⁶⁷ This new understanding of the role of platelets in AMI has led to several clinical trials that have evaluated the benefits of adding GP IIb/IIIa receptor inhibition to PCI. RAPPORT. The ReoPro and Primary PCI Organization and Randomized Trial (RAPPORT) was a multicenter, prospectively defined, randomized, double-blind, placebo-controlled phase-IV trial designed to evaluate the safety and efficacy of abciximab as adjunctive therapy to primary PTCA in 483 patients. Patients presenting within 12 hours of AMI symptom onset were randomized to receive either abciximab bolus plus infusion or placebo bolus plus infusion, and both groups received weight-adjusted heparin. Study drug was initiated in the emergency department or catheterization laboratory prior to PTCA, and stent use was discouraged. The primary endpoint was the composite occurrence of death (any cause), recurrent MI, or any target vessel revascularization (TVR) within 6 months of randomization. Secondary endpoints were the composites of death, MI, or urgent TVR at 7 days and 30 days. Safety was assessed by the occurrence of major bleeding events to 30 days.⁶⁸ Analysis by intent-to-treat demonstrated a statistically significant 48% reduction in the 30-day composite endpoint for abciximab-treated patients compared with placebo (11.2% placebo versus 5.8% abciximab; p = 0.03). Among those patients who underwent PCI and received study drug (treated patients), the 30-day composite major secondary endpoint showed much greater treatment benefit for abciximab compared with placebo (12.0% placebo versus 4.6% abciximab; p = 0.005). At 6-month follow-up, the primary endpoint of death, MI or any TVR by intent-to-treat was comparable for placebo and abciximab groups, and when analyzed by actual treatment received, there was a trend favoring abciximab treatment that did not reach statistical significance. The secondary composite endpoint of death, MI or urgent TVR to 6 months by intent-to-treat showed a significant difference in favor of abciximab treatment (17.8% placebo versus 11.6% abciximab; p = 0.048), and when analyzed by actual treatment, a statistically significant benefit in favor of abciximab was observed (19.9% placebo versus 10.6% abciximab; p = 0.004). As has been seen in other abciximab trials (EPILOG, CAPTURE), the need for unplanned stenting is reduced with abciximab therapy. In the treated-only analysis, the need for “bail-out” stenting was reduced by 40%, an absolute reduction of 8 stents per 100 patients treated.^52,68ADMIRAL. The Abciximab Before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-term Follow-up (ADMIRAL) trial was a multicenter, randomized, double-blind, placebo-controlled study designed to examine the effects of abciximab in primary stenting in 300 patients with AMI. Initial TIMI 3 flow rates were 5.4% in the stent-placebo group compared with 16.8% in the stent-abciximab group (p = 0.01). Following stent implantation, TIMI 3 flow at 24 hours rose to 92.6% and 95.9%, respectively, for the placebo and abciximab groups (p p p = 0.01). This early benefit was maintained at 6 months, with a similar reduction in the composite endpoint of death, recurrent MI or urgent TVR (7.4% versus 15.9%, respectively; p = 0.02).⁶⁹ISAR-II. The Intracoronary Stenting and Antithrombotic Regimen (ISAR)-II trial was a randomized, open-label study to evaluate the effect of abciximab on restenosis and clinical outcome in 401 patients following primary stenting. Patients undergoing stenting within 48 hours after AMI onset were assigned to receive either standard-dose heparin or abciximab plus reduced-dose heparin. By 30 days, the composite rates of death, reinfarction or target lesion revascularization were 5.0% for the stent-plus-abciximab group compared with 10.5% for the heparin-only group (p = 0.038). The addition of abciximab to stenting was thus associated with a substantial reduction in major adverse cardiac events at 30 days. However, at 1-year follow-up, abciximab treatment did not provide any additional benefit in reducing the need for target lesion revascularization or the rate of angiographic restenosis.⁷⁰StopAMI. The Stent Versus Thrombolysis for Occluded Coronary Arteries in Patients with AMI (StopAMI) was a single-center, prospective, randomized study of 140 patients with AMI designed to evaluate the degree of myocardial salvage that could be attained by coronary stenting combined with abciximab compared with fibrinolysis alone using an accelerated-dose regimen of alteplase. Patients in the stent-abciximab group were administered standard-dose abciximab during stent placement and patients in the fibrinolysis group received a standard accelerated dose of alteplase. The primary endpoint of this trial was the degree of myocardial salvage achieved, as determined by serial nuclear scintigraphic studies. A secondary endpoint was the composite of death, reinfarction or stroke within 6 months after randomization.⁶³ In the abciximab-stent group, the size of the final infarct was 14.3% of the left ventricle compared with 19.4% in the group that received alteplase alone (p = 0.02). This difference resulted from a greater degree of myocardial salvage in the abciximab-stent group compared to the alteplase group (16.1% versus 7.4% of the left ventricle, respectively; p p p = 0.02). Patients who received stent plus abciximab also had a lower incidence of death at 6 months than those who were treated with alteplase (4.2% versus 13.0%, respectively; p = not significant). These findings suggest that the combination of coronary stenting plus abciximab in patients with AMI produces a greater degree of myocardial salvage and better clinical outcomes than fibrinolysis with alteplase alone.⁶³ Summary There are four principal reasons for using GP IIb/IIIa inhibition in the treatment of AMI: to improve early reperfusion; to stabilize patients before, during, and after PCI; to improve cardiac function; and to confer an overall survival advantage. The advent of platelet GP IIb/IIIa inhibition in the management of AMI has created the opportunity to bridge the treatment gap between fibrinolytic monotherapy and PCI, both of which are effective but have practical and clinical limitations. Fibrinolysis is more widely available and does not require in-hospital catheterization laboratory access, whereas primary PCI offers the potential for increased rates of reperfusion and reduced rates of mortality and ICH. Platelet GP IIb/IIIa inhibition offers the clinician a variety of therapeutic choices for the treatment of AMI; it can be used in combination pharmacotherapy with reduced-dose fibrinolysis and offers several advantages prior to PCI (some dethrombosis effects and reduced peri-procedural incidence of death or MI) with and without stents.^45,71 Of the three available GP IIb/IIIa inhibitors, abciximab is the most studied agent in PCI, in direct and rescue PTCA, with stenting, and in combination with reduced-dose fibrinolytics. Compared with placebo or conventional therapy, abciximab has been shown to produce significant reductions in death, reinfarction and urgent TVR, as well as higher TIMI 3 flow rates, more rapid resolution of ST-segment elevation, improved 30-day and 6-month mortality, reduced infarct size and improved LV function.^71,72 Nevertheless, several issues remain to be clarified. First, while heparin (or alternative forms of antithrombin therapy) is an essential component of strategies to establish microvascular perfusion and achieve mortality reduction, it is also clearly linked to bleeding risk. Attempts to determine the optimal dosing of UFH within the context of combined fibrinolysis and GP IIb/IIIa inhibition have yielded conflicting results, perhaps reflecting the use of different fibrinolytic agents and the ability of the GP IIb/IIIa inhibitor to suppress thrombin generation.^46,62 Second, the clinical importance of the following is uncertain: the differences among GP IIb/IIIa antagonists with respect to potency; effects on the other adhesion molecules such as MAC-1 and the vitronectin receptor; and efficacy in protecting the microvasculature.⁷³ Third, the timing of microembolization (either before or after complete occlusion of the epicardial vessel) is uncertain. Potentially, pharmacologic reperfusion with combined attenuated fibrinolysis and GP IIb/IIIa inhibition may actually increase the degree of distal embolization observed. Furthermore, the benefits of this combined approach may be dependent on the extent and duration of microvascular injury (beyond a point of no return). Whether a novel pharmacologic approach to reperfusion may narrow or broaden the window of opportunity in which maximal mortality benefit is achieved remains to be demonstrated.⁴⁷ Despite these issues, the GUSTO-V trial is a key outcomes study defining the benefits of combined fibrinolytic and GP IIb/IIIa inhibition for coronary reperfusion. Moreover, while further refinement of this strategy may be required, such a combination may form a logical basis for merging pharmacological and catheter-based (facilitated PCI) reperfusion. However such a strategy will require prospective evaluation. Table 4 represents the many studies supporting the use of GP IIb/IIIa inhibitors in ST-segment elevation AMI.^{19,24,40,46,48,52,62,63,70,74–78}Acknowledgments. The authors wish to thank Eileen L. Sullivan, PharmD and Gordon Beck, RPh, for their assistance in preparing this manuscript.