Bailout Use of Platelet Glycoprotein IIb/IIIa Inhibition During Coronary Stent Implantation: Observations from the ESPRIT Trial

Potent inhibition of platelet aggregation during percutaneous coronary intervention (PCI) using intravenous antagonists of the platelet glycoprotein (GP) IIb/IIIa receptor results in a significant and sustained reduction in the occurrence of ischemic complications.^1–4 In all of these clinical trials, the GP IIb/IIIa inhibitors were strated prior to the first balloon inflation or device activation. However, in clinical practice, these intravenous agents are often used in a rescue, or “bailout” mode after procedural complications arise.⁵ This bailout strategy has not been formally or prospectively studied. The Enhanced Suppression of the Platelet GP IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial studied the use of eptifibatide during PCI and allowed investigators to administer a bailout kit containing eptifibatide or placebo boluses, followed by open-label eptifibatide infusion.⁶ In this prospective substudy of the ESPRIT trial, we evaluated the characteristics and outcomes of patients requiring bailout treatment. The primary objective of this analysis was to determine whether patient characteristics could reliably predict which patients initially treated with placebo would be likely to require bailout treatment and to describe outcomes following bailout therapy. Methods Study population. The design and results of the ESPRIT trial have been previously published.^4,6 Briefly, 2,064 patients undergoing non-urgent coronary stenting in the United States or Canada were randomized to receive eptifibatide, administered as two 180 mcg/kg boluses given 10 minutes apart, or placebo. The first bolus of eptifibatide was immediately followed by a continuous infusion of 2.0 mcg/kg/minute until hospital discharge or up to 18–24 hours, whichever occurred first. Randomization assignment was performed immediately before the initiation of PCI. A weight-adjusted heparin regimen was recommended using an initial bolus of 60 units/kg to target an activated clotting time between 200 and 300 seconds. Heparin after PCI was discouraged. Blood samples were collected at baseline and every 6 hours (up to 24 hours or hospital discharge), and sent to a biochemical core laboratory for creatine kinase (CK) and CK-myocardial band (MB) assays. Endpoints. The major endpoints for this analysis were death, myocardial infarction (MI), and urgent target vessel revascularization (TVR) at 48 hours and 30 days. MI was defined as either the presence of CK-MB ? 3 times the upper limit of normal in ? 2 samples in the first 24 hours after PCI, or as the appropriate clinical syndrome with clinical corroboration in the form of supportive electrocardiographic or cardiac marker data. Urgent TVR included coronary artery bypass surgery or a second PCI procedure performed within 24 hours after documented ischemia (any of the following: chest pain at rest lasting at least 5 minutes, new ischemic electrocardiographic changes, acute pulmonary edema, or presumed ischemic ventricular arrhythmias). Bailout protocol. The study protocol included a provision allowing investigators to administer the contents of a blinded bailout kit if complications occurred during the study drug infusion. Bailout kits contained two eptifibatide boluses for patients randomized to placebo and two placebo boluses for patients randomized to eptifibatide. When bailout treatment was required, the bailout kit boluses were adminstered and the study drug infusion was replaced with open-label eptifibatide, continued until hospital discharge or up to 18–24 hours, whichever occurred first. Sites were provided with guidelines recommending the use of bailout therapy primarily for thrombotic complications such as abrupt closure, no-reflow, distal embolization, and thrombus formation, although the decision to administer bailout therapy was ultimately left to the discretion of the operator. Detailed information regarding the timing and rationale for bailout was collected on the case report forms. An independent Clinical Events Committee blinded to treatment assignment classified all bailout events as being thrombotic or non-thrombotic. Bailout for non-thrombotic indications was discouraged per protocol. Thrombotic bailout was performed for the following indications: abrupt or threatened closure, no-reflow, visible intracoronary thrombus, side branch closure, and distal embolization. Thrombus was defined as presence of an intraluminal filling defect, staining of contrast in the absence of dissection, or angiographic haziness. Bailout was classified as non-thrombotic when done for coronary dissection, difficulty in reaching or crossing the lesion, multiple stent use, suboptimal results, or side branch compromise. Statistical analysis and population characteristics. Baseline clinical, procedural and angiographic characteristics are summarized as medians with 25th and 75th percentiles for continuous measures and as percentages for discrete measures. For comparison between groups, the likelihood-ratio chi-square test was used for categorical variables, and the Wilcoxan rank-sum test was used for continuous variables. Event rates are summarized as percentages, and differences between event rates are presented with likelihood ratio 95% confidence intervals. Backward stepwise logistic multivariable modeling was used to identify predictors of the need for bailout in patients treated initially with placebo. Results Bailout to eptifibatide or placebo for any reason (thrombotic or non-thrombotic) was used in 43 (4.2%) of the placebo patients and 34 (3.3%) of the eptifibatide patients (p = 0.3). The median time from randomization to bailout was 1.1 horus (25th, 75th percentiles: 0.8, 1.6 hours) with no significant difference between treatment groups. The indications for bailout are listed in Table 1. Patients randomized to placebo had significantly higher rates of thrombotic bailout (2.1% versus 1.0%, absolute difference 1.2% [0.1%, 2.3%]; p = 0.03), which appeared attributable to a higher rate of abrupt closure (0.9% versus 0.1%, absolute difference = 0.8% [0.2%, 1.5%]; p = 0.02). There was no difference in the use of non-thrombotic bailout (2.1% versus 2.3%; p = 0.7), which was used for a combination of coronary dissection, difficulty in reaching or crossing the lesion with the stent or balloon, multiple stent use, suboptimal results, and compromise of side branches after stent insertion. The baseline clinical characteristics for patients requiring and not requiring bailout (for thrombotic or non-thrombotic indications) are shown in Table 2. There were no significant differences in baseline demographics, cardiac risk factors, or reason for intervention. Patients who received thrombotic bailout were less likely to have received aspirin on or prior to the day of the PCI procedure and more likely to have received heparin prior to PCI. The absolute number of patients who did not receive pre-procedural aspirin was quite small (3 of the 77 bailout patients). The procedural characteristics for the three groups are shown in Table 3. Patients requiring thrombotic bailout had higher peak activated clotting times and patients requiring non-thrombotic bailout received higher total procedural doses of heparin. Bailout patients (for thrombotic or non-thrombotic indications) were also more likely to receive multiple stents. Patients requiring thrombotic bailout were more likely to have right coronary artery target lesions, lesions with diamter stenosis ? 90%, and visible intracoronary thrombus prior to intervention. Pre-procedural thrombus was present in 8 of the 22 (38%) placebo group patients who received eptifibatide bailout for thrombotic indications, and 5 of the 10 (50%) of the eptifibatide group patients who received placebo bailout for thrombotic indications (p = 0.7). A multivariable logistic regression model was created to determine independent predictors of the need for bailout in the placebo-treated group. The three predictors identified were: no treatment with aspirin prior to PCI (odds ratio [OR] 6.98 [95% CI: 1.92–25.40]; p = 0.003), diameter stenosis ? 90% (OR 2.13 [95% CI: 1.16, 3.93]; p = 0.02) and thrombus prior to intervention (OR 5.40 [95% CI: 2.92, 9.99]; p Discussion Glycoprotein IIb/IIIa inhibitors are often used as a bailout therapy after peri-procedural complications occur, although this strategy has not been systematically evaluated. In this large trial of PCI, provisions for bailout therapy were incorporated into the design of the study to specifically evaluate the bailout approach. A total of 4% of patients developed peri-procedural complications requiring bailout therapy. Of these patients, those who did not receive prophylactic eptifibatide and developed complications had poor clinical outcomes despite the use of bailout GP IIb/IIIa inhibition. In addition, pre-treatment with eptifibatide reduced the incidence of thrombotic complications requiring bailout, particularly abrupt closure. Although these complications occurred more often in severely stenotic and thrombotic lesions and less often with aspirin pre-treatment, the ability to predict such complications in individual patients using baseline characteristics was poor. Several large randomized trials have clearly demonstrated that pre-treatment with GP IIb/IIIa inhibitors before and during PCI significantly lowers the risk of ischemic complications, and this benefit is maintained long term.^1–4 However, in many institutions, these agents are used in fewer than 50% of patients undergoing PCI.⁵ The strategy of reserving GP IIb/IIIa inhibitors as bailout has evolved, in part, in an attempt to minimize the costs and risk of hemorrhage associated with these agents. However, the utility of this approach has not been established. The ESPRIT study is the first randomized trial of GP IIb/IIIa inhibitors for PCI to include a bailout option that allowed cross-over to open-label treatment with a platelet GP IIb/IIIa inhibitor to manage thrombotic complications. This study design provided a unique opportunity to evaluate the characteristics and outcomes of patients requiring bailout, both with and without eptifibatide pre-treatment. Bailout for non-thrombotic indications was discouraged, and as expected, was not reduced by pre-treatment with eptifibatide. Bailout for thrombotic indications, however, occurred less often in the eptifibatide group. Bailout use was associated with a high rate of MI, irrespective of treatment group assignment. In addition, bailout from placebo to eptifibatide was associated with a significantly higher rate of urgent re-intervention compared with patients who received prophylactic eptifibatide and bailout with placebo. In this analysis, we were not able to directly evaluate whether bailout use of a GP IIb/IIIa inhibitor improved outcomes in patients with thrombotic complications. Two previous reports of angiographic outcomes suggested a beneficial effect of “rescue” abciximab for procedural complications.^7,8 Muhlestein and colleagues showed that rescue administration of abciximab for new or worsening coronary thrombosis was associated with resolution of thrombus and an improvement in coronary flow.⁷ In a multicenter series of 138 patients treated with bailout abciximab, the proportion of patients with TIMI grade 3 flow improved from 32% to 88% with abciximab (p = 0.03).⁸ Bailout use of eptifibatide has not been previously studied. Several studies have evaluated clinical outcomes following rescue or prophylactic use of GP IIb/IIIa inhibitors during PCI. In a non-randomized study comparing rescue versus planned abciximab use, patients treated with rescue abciximab had a significantly higher rate of non-Q-wave MI (20% versus 5%; p = 0.001) and trends for higher rates of bleeding (18% versus 13%) and death (4.5% versus 2.2%) than those receiving planned abciximab.⁹ Fuchs and colleagues have also observed a high incidence of non-Q-wave MI with rescue abciximab (31%).¹⁰ Velianou and colleagues compared rescue versus planned abciximab use and found similar in-hospital outcomes, but higher rates of ischemic complications at 6 months with rescue use (31% versus 15%; p = 0.01).¹¹ In this analysis, use of bailout eptifibatide was associated with high rates of myocardial infarction and urgent PCI. Perhaps the most compelling evidence for the superiority of prophylactic rather than rescue use of eptifibatide comes from the main ESPRIT trial results. Despite the provision of bailout eptifibatide in the placebo group, the incidence of death, MI, and urgent revascularization at 48 hours was significantly reduced by prophylactic treatment with eptifibatide, with a sustained benefit up to one year after intervention.¹² There are several limitations to this analysis that need to be acknowledged. The decision to use bailout in this study was left to the discretion of the treating physicians. In more than 50% of cases, bailout was used for non-thrombotic complications, despite guidelines which discouraged bailout in these circumstances. Inclusion of bailout for non-thrombotic indications may have influenced the results of this analysis. We were not able to directly compare clinical outcomes after bailout versus prophylactic GP IIb/IIIa inhibitor use due to baseline differences and the relatively small number of patients requiring bailout therapy. The limited number of patients adjudicated as requiring bailout for thrombosis precluded the development of a formal multivariable regression model evaluating predictors of thrombotic bailout. Nonetheless, the main ESPRIT trial results indicate that a strategy of prophylactic eptifibatide use is superior to a strategy of reserving eptifibatide for procedural complications. Conclusions Pre-treatment with eptifibatide reduces the incidence of thrombotic complications during PCI requiring bailout. Although patients with stenotic or thrombotic lesions and patients not pre-treated with aspirin are more likely to require bailout, the need for bailout cannot be reliably predicted for individual patients based on baseline characteristics. Patients who require bailout have poor clinical outcomes despite the use of rescue eptifibatide. cantorw@smh.toronto.on.ca

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