High-Dose, Bolus-Only, Glycop rotein IIb/IIIa Inhibitors for
Elective Coronary Intervention: Logical, Safe, Cost-Effective,
an

Platelet-mediated thromboembolic events are believed to cause the majority of non-Q-wave myocardial infarctions (MI) observed after an otherwise uncomplicated percutaneous coronary intervention (PCI).¹
Activation of the platelet-surface glycoprotein IIb/IIIa (GP IIb/IIIa) receptor is the final common pathway in the process leading to platelet aggregation, and thrombus formation after PCI.^1,2 The use of weight-adjusted bolus, plus prolonged infusion of IIb/IIIa inhibitors has been shown to reduce the risk of non-Q-wave MI (CPK-MB leaks) after PCI.^3–9 A number of recent studies, however, have suggested that the administration of a high-dose bolus of a IIb/IIIa inhibitor may be equally efficacious, as safe or safer, and more cost-effective than the (historical) use of a bolus-plusinfusion regimen.^10–15
In this issue of the Journal of Invasive Cardiology, Marmur and his colleagues have further strengthened the case for the routine use of high-dose, bolus administration of competitive glycoprotein IIb/IIIa inhibitors in elective PCI.¹⁵
Rationale for high-dose bolus IIb/IIIa inhibitors. The benefits of IIb/IIIa inhibition during PCI are presumably related to an interruption of platelet aggregation that can trigger thromboembolic events, leading to non-Q-wave MI. There is a rationale, supported by a significant body of clinical trial data, demonstrating the benefits of GP IIb/IIIa inhibitor use during coronary stenting.^3–15
Unfortunately, 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 major adverse cardiac events (MACE), when compared to unfractionated heparin alone.^5–9,13 It is estimated that less than 50% of elective coronary stent interventions are currently performed using GP IIb/IIIa inhibitors.
The concept of using a high-dose single bolus of a GP IIb/IIIa inhibitor is logical and is based upon a number of observations and assumptions. The rationale for this approach includes the following: 1) high-dose IIb/IIIa inhibition given as a single bolus has been demonstrated to be very potent in inhibiting platelet aggregation,^3,15–18 without evidence of incremental bleeding risk; 2) based upon the pharmacokinetics of tirofiban and eptifibatide (competitive IIb/IIIa inhibitors), one could expect the potent antiplatelet effect to last for approximately 2–3 hours after a high-dose bolus;^{12,13,15–18} 3) the average procedure time for elective stenting in most centers is less than 1 hour (i.e., the current study had a mean procedural time of only 27 ± 15 minutes);^13–15 4) with high-pressure stent deployment, followed by high-dose thienopyridine loading immediately before or after PCI (300–600 mg), there are extremely few abrupt closure or inhospital acute thrombotic complications (0/857 in the currently reported series¹⁵; 0/401 in our series¹³); 5) the elimination of the prolonged IIb/IIIa inhibitor infusion may reduce postprocedural bleeding complications (e.g., hematoma); and 6) if a high-dose bolus IIb/IIIa receptor regimen could be shown to be equivalent to conventional IIb/IIIa inhibitor regimens (i.e., bolus plus drip) in reducing non-Q-wave MI, at a small fraction of the cost and with the same or lower bleeding risks, this should encourage the routine adoption of these agents. High-dose bolus, without infusion, becomes even more appealing as we rapidly move towards a healthcare climate pushing for cost-effective approaches for outpatient PCI in lower-risk patients.¹⁹
Clinical outcomes using high-dose bolus IIb/IIIa inhibitors. The level of platelet inhibition after a highdose bolus of tirofiban (current study) or after a high-dose bolus of eptifibatide is equivalent to the inhibition reported by the TEAM investigators after 2 weight-adjusted boluses of eptifibatide.^{10,13,15,17,18}
The clinical outcomes in the current study using a highdose, single bolus of tirofiban are excellent (5.5% risk of bleeding and/or non-Q-wave MI), and appear to be at least equivalent to the outcomes observed from the ESPRIT trial using a 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 abciximab⁹ in both the eptifibatide arm and the bivalirudin arm from the REPLACE-2 trial.⁷
The low incidence of major bleeding complications (~1%) is similar to the bleeding rates observed in the ESPRIT study with eptifibatide, and from the bivalirudin arm of the REPLACE-2 study (1.3% and 2.4%, respectively).^5,7 Thus, compared to major trials evaluating abciximab, eptifibatide and bivalirudin in coronary stenting, the MACE ratesobserved are favorable with high-dose tirofiban. The low bleeding and MACE rates observed in the current study are also similar to the very low MACE rates reported by our group using a strategy of a high-dose, single-vial (20 mg) bolus of eptifibatide for elective PCI.¹³
An important recent randomized clinical study has demonstrated the safety and efficacy of bolus-only abciximab with outpatient PCI compared to overnight stay after PCI with conventional bolus plus infusion of abciximab.¹⁴ This randomized clinical trial adds further support for the use of a bolus-only IIb/IIIa inhibitor for elective PCI.
Cost savings using high-dose bolus IIb/IIIa inhibitors. The hospital-discounted price of an eptifibatide regimen in the PURSUIT study was $1,014.²⁰ The median cost of an eptifibatide regimen in the ESPRIT study was $502.²¹ The costs of anticoagulant in the bivalirudin and eptifibatide arms of the REPLACE-2 study were $530 and $930, respectively.⁷ In contrast, a single vial of eptifibatide used in our study¹³ was only $59. The cost of a dose of 25 μg/kg of tirofiban (1.75 mg bolus dose for a 70 kg male), as was used in the current study by Marmur et al,¹⁵ would cost $52.80 at our medical center. When combined with the small cost for weight-adjusted heparin, the total cost for procedural anticoagulation using a high-dose single bolus eptifibatide or tirofiban would be ~$70 per patient. This represents a substantial cost savings for centers currently using either conventional IIb/IIIa inhibitors (bolus + drip) or bivalirudin. Additional cost savings may also be realized with the elimination of prolonged intravenous dosing after the procedure, as well as the costs associated with incremental bleeding, which may be associated with conventional (prolonged) dosing of IIb/IIIa inhibitors.
Limitations of current data on high-dose bolus IIb/IIIa inhibitors. There are some limitations in the interpretation of the high-dose, bolus-only IIb/IIIa inhibitor studies. The majority of the data, including the current study, are prospective, observational studies, without a defined (conventional IIb/IIIa inhibitor) control group. Despite this limitation, comparison to previously published studies such as ESPRIT and REPLACE-2 provide contemporary historical control data from a similar cohort of patients undergoing elective intervention. There is only one randomized clinical trial using bolus IIb/IIIa inhibition versus conventional dosing, which demonstrated equivalency of a high-dose bolus compared to bolus plus infusion.¹⁴ However, this study utilized only a transradial approach and may not be directly translatable to transfemoral PCI.
Conclusions. Despite the limitations of the studies of high-dose bolus IIb/IIIa inhibitor use, the current study by Marmur et al adds to the growing body of evidence suggesting that a high-dose bolus administration of potent IIb/IIIa inhibitors may provide a safe, clinically effective and highly cost-effective strategy for elective PCI.^11–15
Ultimately, it will be important to perform a large-scale randomized clinical trial examining the relative safety, efficacy and cost-effectiveness of high-dose bolus IIb/IIIa inhibition compared to conventional IIb/IIIa inhibitor dosing (bolus plus drip) and to conventional dosing with the direct thrombin inhibitor, bivalirudin. Since it is unlikely that the pharmaceutical industry would sponsor such a trial, it is incumbent upon the interventional cardiology community to organize and find alternative funding for this important study.