High-Dose, Single-Bolus Eptifibatide: A Safe and Cost-Effective Alternative to Conventional Glycoprotein IIb/IIIa Inhibitor Use

Rupture of an atherosclerotic coronary arterial plaque, as occurs spontaneously in patients with acute coronary syndromes, or as the result of a percutaneous coronary intervention (PCI), may serve as a stimulus for platelet adhesion, aggregation and thrombus formation. Resultant platelet-mediated thromboembolic events are believed to cause a large percentage of the non-Q-wave myocardial infarctions (MIs) observed after PCI. Activation of the platelet-surface glycoprotein (GP) IIb/IIIa receptor is the final common pathway in the process leading to platelet aggregation and, eventually, thrombus formation.¹ Eptifibatide (Integrelin®, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts) is a cyclic heptapeptide competitive inhibitor of the GP IIb/IIIa receptor, and is a potent agent for preventing platelet aggregation. Eptifibatide has a rapid onset of action and a relatively short plasma half-life.² A number of clinical trials have shown a beneficial effect of eptifibatide in reducing the incidence of non-Q-wave MI in both urgent and elective PCI.^3–8 The REPLACE-2 Trial recently compared the outcomes using eptifibatide versus bivalirudin, a direct thrombin inhibitor, in elective PCI.^9,10 Although both agents appeared similarly effective in reducing the incidence of non-Q-wave MI, the incidence of major bleeding was lower in the bivalirudin arm compared to the heparin plus eptifibatide arm (2.4% vs. 4.1%; p 9 Importantly, the eptifibatide arm in this trial received prolonged (12–24 hours) eptifibatide infusion after the PCI. This significantly increases the cost of this regimen and may also have contributed to the higher observed incidence of major bleeding. In order to address the limitations of current GP IIb/IIIa inhibitor regimens, we evaluated a novel approach using a high-dose, single-vial bolus of eptifibatide in patients undergoing elective PCI. This study was conducted in order to determine whether this regimen might provide a safe, effective and cost-effective alternative to conventional bolus-plus-infusion regimens that are currently used with GP IIb/IIIa inhibitors. Methods Study population. The outcomes of 401 consecutive patients who underwent elective coronary stenting following single-vial bolus of eptifibatide (from May 2002 to December 2004) were assessed prospectively. Institutional Review Board approval was obtained for this registry and informed consent was received from all patients. Two experienced operators performed all of these interventions. The clinical indications for the PCI were stable, as well as unstable angina, with one or more coronary lesions of >/= 70% diameter stenosis by visual estimate, and suitability for stenting. Patients were excluded from the study if they had suffered a recent Q-wave or non-Q-wave MI (within 24 hours of the procedure). Patients requiring stenting of saphenous vein bypass grafts or those requiring rotational atherectomy or brachytherapy were also excluded. Study Protocol. All patients were treated with aspirin before and after the procedure. All patients received clopidogrel bisulfate (300 mg; n = 397) or ticlopidine (250 mg; n = 4) loading before (n = 31) or after (n = 359) the intervention, unless they were already on standing dose of one of these agents prior to the stent procedure (n = 12). Ninety-seven percent of the patients received weight-adjusted unfractionated heparin prior to the intervention (average dose of 71 ± 14 units/kg). Activated clotting time (ACT) was measured at the discretion of the operator after administration of weight-adjusted heparin. Just prior to the intervention, eptifibatide was administered as a single, intravenous, 20 mg bolus (single vial: 10 ml; 2mg/ml). Platelet inhibition scores were measured for the first 32 patients in this study using the Accumetrix™ Ultegra Rapid Platelet Function Assay (San Diego, California) from blood samples drawn 10 minutes after administration of the eptifibatide 20 mg bolus.^11,12 Details of this point-of-care platelet function test have been described previously.^11,12 Following these pilot data, the operators adopted this single-vial bolus dosage as their routine anticoagulation regimen for elective stenting, under protocol. All patients were treated via the femoral approach with the modified Seldinger entry technique. Seven-French (Fr) sheaths were used in 384/401 (96%) of cases, with 6 Fr sheaths in 8 cases (2.0%), and 8 Fr sheaths in 9 cases (2.2%). Following anticoagulation administration stenting was performed using standard techniques. High-pressure stent deployment was used to ensure good stent apposition and minimize the risks of subacute stent thrombosis. Bare-metal stents were placed in 123/401 (31%) patients, and drug-eluting stents were used in 278/401 (69%). Sheaths were removed by trained nursing staff using manual compression in 398/401 cases, and with the Angio-Seal™ hemostatic puncture closure device (St. Jude Medical, St. Paul, Minnesota) in 3 cases (0.9%). Sheaths were pulled after measured ACT levels were (Radi Medical Systems, Inc., Wilmington, Massachusetts) was used to assist manual compression in 388/398 patients. Efficacy-related adverse events. Procedural success was defined as successful revascularization of target lesion(s) with 5,9 The primary composite endpoint for the study was the 30-day incidence of death, myocardial infarction, urgent repeat revascularization or in-hospital major bleeding.^9,10 This included all patients who died from any cause, Q-wave or non-Q-wave myocardial infarction (MI), urgent target vessel revascularization (TVR) by PCI or coronary artery bypass graft surgery (CABG), and/or any major in-hospital bleeding complications. The secondary endpoint was defined as the composite of death, MI or urgent TVR at 30-day follow up. Samples for evaluation of the CPK and CK-MB were drawn 14–20 hours after PCI in 399/401 (99.5%) patients. CPK-MB was measured in all patients who had total CPK above the upper limit of normal in our laboratory (normal range: 5–190 mg/dl), or any post-procedure electrocardiographic (ECG) changes, or any post-procedure chest pain. Myocardial infarction was defined as the occurrence of an elevated CPK-MB fraction > 3 times the upper limit of normal for our laboratory.^9,15–17 All patients with evidence of enzymatic MI underwent serial ECGs to assess whether the MI was a Q-wave or non-Q-wave MI. A Q-wave MI was defined as development of new Q-waves (at least 0.04 seconds), in 2 or more contiguous leads, or new left-bundle branch block on ECG, along with elevation of total serum creatinine kinase (CK) and its MB iso-enzyme (CK-MB) fraction at 3 times the upper limit of normal range. A non-Q-wave MI was defined as elevation of CK and/or CK-MB fraction to 3 or more times the upper limit of normal range, without new Q-waves on the ECG. Urgent TVR was defined as a second PCI on the original target vessel or CABG performed on an emergent basis for recurrent myocardial ischemia or MI. The Thrombolysis in Myocardial Infarction (TIMI)^16,17 and REPLACE-29 study criteria were used to define major bleeding complications. Thirty-day follow-up data for adverse events (as defined above) were obtained in 398/401 patients (99% follow up) by phone interview, clinic visit(s) and/or chart review. Cost-related endpoints. The drug costs for anticoagulation/antiplatelet treatment from this registry were compared to the drug costs as published from conventional use of eptifibatide and bivalirudin from the REPLACE-2 trial.¹⁰Statistical analysis. Data are presented as mean ± standard deviation. Cost analysis was performed comparing the actual cost per case in the current series versus the reported cost from the REPACE-2 trial.¹⁰ Since this represents a nonrandomized, historical comparison, no statistics were used to evaluate the relative outcomes from this study as compared to outcomes from preceding GP IIb/IIIa inhibitor trials. There was no assigned control group in this registry. Results Patients. Between May 2002 and December 2004, 401 consecutive patients underwent elective coronary stenting using single-vial bolus eptifibatide treatment. The efficacy, safety and costs of this regimen were analyzed in this cohort. Baseline demographic and procedural data for the patients are listed in Table 1. Forty-five percent of the patients (182/401) were admitted with a diagnosis of unstable angina, and 55% underwent intervention for stable angina. Procedural success was achieved in 399/401 patients (99.5%). There were no procedure-related deaths or any deaths out to the 30-day follow-up point. Many of these interventions were relatively complex (Figure 1), requiring multiple stents, and/or multivessel intervention. Thirty-nine percent of the patients underwent multivessel intervention, and 9% had >/= 3-vessel intervention. There were an average of 1.46 ± 0.42 vessels treated per patient and 1.82 ± 0.65 stents placed per patient. The average total implanted stent length was 38 ± 26 mm stents per patient. Despite the disease complexity of the patients treated, the average total procedural time for the PCI was 48 ± 21 minutes per patient. Platelet inhibition with a single-vial bolus. Point-of-care platelet inhibition scores were measured for the first 32 patients in this study using the Accumetrix Ultegra Rapid Platelet Function Assay.^11,12 These data demonstrated excellent platelet inhibition using this dose (mean platelet inhibition = 92 ± 6%; range = 82–99% inhibition). This level of intraprocedural platelet inhibition has been shown to correlate with reduced MACE after PCI.^13,14Major adverse events. Major adverse cardiac events occurred in 7/401 (1.75%) patients in-hospital, and in 11/401 (2.75%) patients out to 30-day follow up. One patient had a guidewire-related distal perforation in the distal left circumflex territory. This resulted in pericardial tamponade and an elevation of the CK-MB fraction. A second patient had a recurrence of chest pain and had to be taken to the catheterization laboratory for repeat stent placement related to an edge dissection and subacute stent thrombosis 1 day after the initial intervention. A third patient had 3 stents placed to treat a chronic total occlusion of the LAD, and suffered an asymptomatic CPK and CPK-MB elevation (455 mg/dl and 16 mg/dl, respectively). Four additional patients had asymptomatic CPK and CPK-MB elevation (mean: 255 ± 108 mg/dl and 12 ± 9 mg/dl) after stenting. At least 1 of these 4 events could be attributed to loss of a side branch after main-vessel stenting with jailing and loss of blood flow (TIMI 1) to the side branch. No patient had a CPK-MB > 8 times the upper limit of normal. CPK values were measured in all of the patients. CPK-MB fraction was measured in 399/401 patients with post-procedural ischemic symptoms, ECG changes or elevated total CPKs (above 190 mg/dl). Among the patients with normal CPK values after the procedure, the mean CPK total was 71 ± 26 mg/dl. Bleeding-related adverse events. Major in-hospital bleeding complications per the REPLACE-2 guidelines occurred in 2/401 (0.49%) patients. This included the patient with the guidewire perforation, and a second patient with a large hematoma requiring a blood transfusion. 30-Day follow up. There were no deaths in-hospital or at 30-day follow up. There were 2 non-target vessel interventions performed between hospital discharge and 30-day follow up. One of these was planned/staged, and one was urgent, related to unstable symptoms from a non-target lesion, with a non-Q-wave MI. There was 1 additional TVR at 18 days in a patient with evidence of plaque rupture at a lesion site in the LAD proximal to the target lesion. No other MACE events occurred between hospital discharge and 30-day clinical follow up. Thus, all MACE plus major bleeding was seen in 13/401 cases (3.25%) at 30-day follow up (Table 2, Figure 2). Cost-related endpoints. The cost for the single vial was $59/patient. The cost for unfractionated heparin was $7 ± 4/patient. Thus, the average cost of procedural anticoagulation was $66 ± 4 per patient. For comparative purposes, the drug costs for anticoagulation/antiplatelet treatment from this registry were compared to the drug costs, as published from conventional use of eptifibitide and bivalirudin from the REPLACE-2 trial^9,10 (Figure 2). Discussion This study suggests that a simplified and highly cost-effective glycoprotein (GP) IIb/IIIa inhibitor regimen utilizing a large (20 mg) single-vial bolus of eptifibitide can produce clinical outcomes that appear at least equivalent to those obtained using conventional weight-adjusted boluses and prolonged GP IIb/IIIa inhibitor infusion in elective coronary stenting.^7–10,18Rationale for high-dose single bolus. A number of trials have demonstrated the potential importance of GP IIb/IIIa inhibition as a means to reduce the incidence of periprocedural MACE during coronary stenting.^6–10,18 The benefits of GP IIb/IIIa inhibition during these interventions are presumably related to an interruption of platelet aggregation that can trigger thromboembolic events, leading to non-Q-wave MI. These platelet-mediated events are most likely initiated by plaque disruption during the stent implantation(s).^7–10 Thus there is rationale, supported by a significant body of clinical trial data, demonstrating the benefits of GP IIb/IIIa inhibitor use during coronary stenting. Despite these potential benefits, many interventional cardiologists and hospitals have resisted the routine use of these agents due to the relatively high drug-related costs, concerns about a possible increase in bleeding complications and skepticism related to a relatively modest absolute reduction of MACE, when compared to unfractionated heparin alone.^6,8 It is estimated that less than 50% of elective coronary stent interventions are currently performed using GP IIb/IIIa inhibitors. Thus, the routine use of GP IIb/IIIa inhibitors probably cannot be viewed as the “standard of care”, regardless of current guidelines. The concept of using a high-dose, single-vial bolus of eptifibitide is based upon a number of observations and assumptions. The rationale for this approach includes the following: (1) high-dose GP IIb/IIIa inhibition given as a single bolus has been demonstrated to be very potent in inhibiting platelet aggregation,¹⁹ without evidence of incremental bleeding risk; (2) based upon the pharmacokinetics of eptifibitide, one could expect this potent antiplatelet effect to last for at least 2–3 hours after a high-dose bolus of eptifibatide;^10,19 (3) the average procedure time for elective stenting in most centers is i.e., the actual time that operators are manipulating the coronary artery and/or rupturing plaque(s) with balloon inflation(s) is relatively short in most cases]; (4) with high-pressure stent deployment, followed by high-dose thienopyridine loading, there are very few abrupt closure or acute thrombotic complications that occur after the stent procedure is completed and prior to hospital discharge; (5) the elimination of the prolonged GP IIb/IIIa inhibitor infusion may reduce post-procedural bleeding complications (e.g., hematoma); and (6) if a high-dose bolus of GP IIb/IIIa receptor regimen could be shown to be equivalent to conventional GP IIb/IIIa inhibitor regimens (i.e., bolus plus drip) in reducing non-Q-wave MI, at a fraction of the cost, and with the same or lower bleeding risks, this should encourage the more routine adoption of these agents. Clinical outcomes using high-dose bolus of eptifibatide. The level of platelet inhibition after a single 20 mg intravenous (full vial) bolus of eptifibatide was found to be equivalent to the inhibition reported by the TEAM investigators after two weight-adjusted boluses.¹³ In the GOLD study this level of platelet inhibition was correlated with reduced MACE in elective stenting.¹⁴ The clinical outcomes in the current study using a high-dose, single-vial bolus of eptifibitide are excellent and appear to be at least equivalent to the outcomes observed from the ESPRIT trial, using weight-adjusted bolus plus infusion of eptifibatide in elective stenting.⁵ Similarly, the current study’s clinical results compare favorably with the EPISTENT data, using abxiximab¹⁸ and both the eptifibitide arm and the bivalrudin arm from the REPLACE-2 trial⁹ (Figure 2). The low incidence of major bleeding complications (0.5%) is similar to the bleeding rates observed in the ESPRIT study with eptifibitide, and from the bivalirudin arm of the REPLACE-2 study (1.3% and 2.4%, respectively).^5,9 Thus, compared to major trials evaluating abximimab, eptifibatide and bivalirudin in coronary stenting, the MACE rates observed are favorable. Cost savings using a high-dose bolus of eptifibatide. The hospital’s discounted price of eptifibatide regimen in the PURSUIT study was $1,014.¹⁰ The median cost of eptifibatide regimen in the ESPRIT study was $502.¹¹ The costs of anticoagulants in the bivalirudin arm and the eptifibatide arms of the REPLACE-2 study were $530 and $930, respectively.¹⁰ In contrast, the average cost of a single vial of eptifibatide used in our study was only $59. When combined with the small cost for weight-adjusted heparin, the total cost for procedural anticoagulation was $66 ± 4 per patient. Additional cost savings were also realized, but not calculated, related to the elimination of prolonged intravenous dosing after the procedure. Study limitations. There are several limitations of the current study. First, this was a prospective, observational study without a defined control group. Despite this limitation, comparison to previously published studies such as ESPRIT and REPLACE-2 do provide contemporary historical control data from a similar cohort of patients undergoing elective intervention. If anything, our consecutive registry may constitute a somewhat higher-risk population than the patients from the ESPRIT and REPLACE-2 trials. We excluded patients with Q-wave or non-Q-wave MI, and those requiring stenting of CABG vessels, rotational atherectomy and brachytherapy. As such, our observations of a low MACE rate with a single-vial bolus of eptifibatide may not necessarily be applicable to higher-risk cohorts, such as those patients presenting with myocardial infarction. This may warrant additional study. We used predominantly manual compression techniques for sheath removal. This may have favorably influenced our low rate of major bleeding complications. Finally, two experienced operators performed all of the interventions in this study. It is possible that lower-volume operators might not achieve the same results. However, the cited comparative studies, such as REPLACE-2, also utilized high-volume, experienced operators, and therefore should provide a reasonable historical control for the current study. Conclusions Intravenous eptifibatide, administered as a high-dose (20 mg), single-vial bolus is a safe, effective and highly cost-effective alternative to the conventional regimens of bolus plus prolonged intravenous GP IIb/IIIa inhibitor infusion for patients undergoing elective PCI. These findings suggest a need for a randomized clinical trial of this dosing regimen compared to conventional dosing regimen(s) to confirm the results of this real-world registry.

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