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


Derek P. Chew, MBBS, David J. Moliterno, MD, *Howard C. Herrmann, MD

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.52,68

ADMIRAL. 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 < 0.33). A significant increase in left ventricular ejection fraction (LVEF) was also observed at 24 hours in the stent-abciximab group compared with the stent-placebo group (57.0% versus 53.9%, respectively; p < 0.05). There was a significant 59% reduction at 30 days in the composite endpoint of death, recurrent MI or urgent TVR in the stent-abciximab group compared with the stent-placebo group (6.0% versus 14.6%, respectively; 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).69

ISAR-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.70

StopAMI. 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 < 0.001). The primary endpoint of the trial, the myocardial salvage index (the percentage of the left ventricle that was salvaged divided by the percentage that was compromised by the initial perfusion defect), was thus significantly greater with stenting plus abciximab than with alteplase alone (0.57 versus 0.26, respectively; p < 0.001). The composite endpoint of death, reinfarction and stroke at 6 months was significantly lower in the abciximab-stent patients than in those receiving alteplase alone (8.5% versus 23.2%, respectively; 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

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