COMMENTARY: Bolus-Only Glycoprotein IIb/IIIa Inhibitor Revisited

This paper has prospectively examined the efficacy of the use of bolus glycoprotein IIb/IIIa inhibitor (GPI) during percutaneous coronary intervention (PCI) in a single-arm registry. Both in-hospital outcomes and bleeding complications as defined in the REPLACE-2 trial¹ were examined. Oral antiplatelet therapy consisted of aspirin and preloading with clopidogrel 300 p.o. q.d. (immediately prior to PCI), followed up with 75 mg p.o. daily. The clopidogrel preloading issue is important since it has been shown that higher preloading with 600 mg of clopidogrel can achieve more rapid inhibition of platelet activation.² Using the 600 mg loading dose, the results of the ISAR-REACT trial³ indicated that use of the GPI abcixcimab during elective PCI will not further improve ischemic complications; this was further expanded to elective PCI in diabetics in the ISAR-SWEET trial.⁴ In both trials, bleeding indices were higher with GPI, therefore rendering their use rather inappropriate. Either a higher-risk indicator or a safer strategy/dose of GPI should be utilized to address these shortcomings. In the recent ISAR-REACT-2 trial,⁵ the higher-risk group of patients undergoing PCI for an acute coronary syndrome with positive cardiac biomarkers indeed derived a clinical benefit from treatment with abciximab, again at the expense of bleeding. Therefore, the present study is very timely, as it introduces a strategy that may spare bleeding complications, thereby potentially preserving the ischemic protection offered by abciximab in contemporary PCI. A bolus-only dosage has not been studied clinically with eptifibatide (due to the almost immediate elimination), but a bolus of abciximab has been previously studied in the EPIC trial⁶ and was found to yield intermediate results between the placebo and the efficacious bolus-plus-infusion dosage; since then it has been abandoned. However, there are several hints that the bolus-only dosage of abciximab may indeed be particularly attractive as an adjunctive pharmacological strategy: (i) the performance of balloon angioplasty studied in EPIC has been abandoned due to the dominant use of stents, and therefore any concerns about the prevention of delayed angioplasty closure are no longer applicable; (ii) ischemic protection intraprocedurally is considered more important than the extended postprocedure period, thereby rendering the utility of infusion questionable; (iii) bleeding risks could be trimmed by avoiding the abciximab infusion; (iv) abciximab is the only GPI with a bolus dose that enables somewhat durable antiplatelet effect, whereas the small-molecule inhibitors are dependent on a continuous infusion to maintain antiplatelet effect for more than a few minutes. The incorporation of both eptifibatide (double-bolus) and abciximab (single-bolus) in the present study is important, as it might potentially provide a hint about between-group differences. However, it is notable that 42–47% of patients in this study were referred for PCI due to a positive stress test. This suggests a low risk and may blunt such differences. It would have been beneficial to investigate such agent differences within acute coronary syndrome patients and according to the TIMI risk score of participants. The main limitations of this study have been acknowledged by the authors and include the absence of randomization or a control group, as well as the absence of long-term follow up; we would also add the absence of a pharmacodynamic component that could have been very useful either in the direct comparison of the two GPI agents, or the investigation of between-agent differences in the context of aspirin or clopidogrel resistance. It is therefore impossible to draw any reliable conclusions from this study in terms of (i) efficacy of bolus-only abciximab plus heparin compared to the direct thrombin inhibitor bivalirudin or other anticoagulants; (ii) efficacy of bolus abciximab versus double-bolus eptifibatide in terms of ischemic complications. Nonetheless, the investigators need to be commended for conducting a study with an innovative and simplified regimen without industry support. Certainly, these data can be utilized as preliminary information supporting the completion of a prospective trial. Very few developments in medicine in general involve using “less” or “established”, rather than “more” or “different/new” drugs to improve outcomes, both in healthcare and in health economics. Perhaps credible options have been around, but have not yet been seriously considered because they are/seem very simple!

References 1. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003;289:853–863. 2. Helft G, Osende JI, Worthlet SG, et al. Acute antithrombotic effect of a front-loaded regimen of clopidogrel in patients with atherosclerosis on aspirin. Arterioscler Thromb Vasc Biol 2000;20:2316–2321. 3. Kastrati A, Mehilli J, Schühlen H , et al. A Clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med 2004;350:232–238. 4. Mehilli J, Kastrati A, Schuhlen H, et al. Intracoronary stenting and antithrombotic regimen: Is abciximab a superior way to eliminate elevated thrombotic risk in diabetics (ISAR-SWEET) study investigators. Randomized clinical trial of abciximab in diabetic patients undergoing elective percutaneous coronary interventions after treatment with a high loading dose of clopidogrel. Circulation 2004;110:3627–3635. 5. Kastrati A, Mehilli J, Neumann FJ, et al. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: The ISAR-REACT 2 randomized trial. JAMA 2006;295:1531–1538. 6. The EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994;330:956–961.