EDITORIAL COMMENT
The Safety and Efficacy of Glycoprotein IIb/IIIa Inhibitors for Primary AngioplastyMore Options to Choose and More Time to Decide*
David J. Moliterno, MD, FACC1,* and
Khaled M. Ziada, MD, FACC
Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky.
* Reprint requests and correspondence: Dr. David J. Moliterno, Division of Cardiovascular Medicine, University of Kentucky, 900 South Limestone, 317 Wethington Building, Lexington, Kentucky 40536-0200. (Email: moliterno{at}uky.edu).
In this issue of the Journal, Gurm et al. (1) present observational data showing no apparent difference in early outcome among primary percutaneous coronary intervention (PCI) patients receiving the small-molecule platelet glycoprotein (GP) IIb/IIIa inhibitor eptifibatide versus those receiving the monoclonal antibody abciximab. Their findings are from the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2) database, a large regional PCI registry that includes demographic, procedural, and hospital outcome information from several interventional cardiology centers. Importantly, all patients undergoing PCI at these centers are included; the data are prospectively collected; the definitions are standardized, and samples of data are audited for accuracy. Thus, the registry should accurately represent contemporary PCI practice in this region of the U.S.
There is good evidence that abciximab as adjunctive pharmacologic therapy for primary PCI improves outcomes. Several randomized, placebo-controlled trials have consistently demonstrated a 40% to 60% reduction in a 30-day composite ischemic end point (death, myocardial reinfarction, and urgent target vessel revascularization [TVR]) with abciximab in this setting (2–6). This benefit has been primarily driven by a marked reduction in the rates of reinfarction and urgent TVR. No individual trial has observed a statistically significant reduction in 30-day mortality. However, a meta-analysis of placebo-controlled abciximab trials for ST-segment elevation myocardial infarction (STEMI) did demonstrate a moderate reduction in mortality at 30 days (2.4% vs. 3.4%, p = 0.047) and at 6 to 12 months (4.4% vs. 6.2%, p = 0.01) among those receiving abciximab during primary angioplasty (7). In a subsequent analysis of this combined dataset, the mortality benefit was shown to be proportional to the baseline risk; the benefit was more robust among higher-risk patients (8) and progressively less evident in lower risk patients (5). Likely for several reasons, including the lack of consistent benefit across patient risk groups and the small sample size of individual trials, the American College of Cardiology/American Heart Association guideline writing committees for the management of STEMI and for PCI issued a Class IIa recommendation (Level of Evidence B) for the use of abciximab in primary PCI (9,10).
Improved outcome with particularly early administration of abciximab (i.e., before-hospital or prior to arrival in the catheterization laboratory) was first suggested by Montalescot et al. (4), was reinforced in subsequent reports (11,12), and seemed intuitive. On the basis of these findings, early administration was emphasized in the guideline recommendations (9,10). Since then, however, the more adequately powered FINESSE (Facilitated Intervention With Enhanced Reperfusion Speed to Stop Events) trial (13) (n = 2,452) has shown that early abciximab administration does not reduce ischemic end points when compared with abciximab given immediately before angioplasty. The benefit of abciximab use in primary PCI may also be affected by increased bleeding risk. In the STEMI–abciximab meta-analysis, bleeding complications were higher with abciximab than placebo (5.2% vs. 3.2%; odds ratio [OR] 1.66; 95% confidence interval [CI] 1.47 to 1.88; p < 0.001) for all comers. That difference was attenuated when facilitated PCI trials were excluded and only primary PCI (without fibrinolytic administration) studies were considered (4.7% vs. 4.1%; OR 1.16; 95% CI 0.85 to 1.59; p = 0.36) (7). The FINESSE data show a similar pattern with an increase in major bleeding complications in the abciximab-lytic facilitated-PCI group. The lowest rate of major and minor bleeding in the FINESSE study was in the group receiving abciximab in the catheterization laboratory, thereby putting another dent in the hopes of improved outcomes with early GP IIb/IIIa administration.
Despite limited efficacy data, and mainly because of cost concerns, the small-molecule agents eptifibatide and tirofiban are used more commonly than abciximab in the U.S. and Europe, respectively. Two single-center retrospective comparisons of primary PCI patients receiving abciximab or eptifibatide (14,15) have suggested similar outcomes for these agents. Likewise, small randomized studies of abciximab versus a higher-dose tirofiban regimen have suggested similar angiographic and clinical outcomes (16,17). These limited datasets and the similarity of the mechanism of action with abciximab were credited for giving the small-molecule IIb/IIIa inhibitors a Class IIb recommendation (Level of Evidence C) for use in primary PCI in the recently updated guidelines (10).
So how do the findings of Gurm et al. (1) add to our knowledge of GP IIb/IIIa inhibitors during primary PCI? First, this is the largest prospective registry report of primary PCI patients (>2,800) treated with eptifibatide. Second, their patient population should accurately represent contemporary practice and evidences high-risk features ( 25% above the age of 70 years, >50% with an abnormal baseline ejection fraction, and >12% presenting with cardiogenic shock) not seen in many randomized studies. Third, this study confirms the bleeding risk associated with polypharmacy anticoagulation in STEMI. Although bleeding definitions have not been standardized across all trials, blood product transfusion is probably the simplest intertrial metric. In the present report, the transfusion rate of 12% is relatively high (2–6). Likewise, the 8% to 10% occurrence of major adverse cardiovascular events in both groups of the registry is somewhat higher than those reported in the placebo-controlled abciximab trials (2–6). These ischemic and hemorrhagic event rates are a reflection of real-world outcome. Finally, although not adjudicated and examined only to the time of discharge, the specific rates of death, reinfarction, stroke, and TVR were similar in the eptifibatide and abciximab groups.
The authors correctly point out that their findings are not adequate to prove noninferiority of eptifibatide compared with abciximab in primary PCI. That would require a very large and expensive trial, which is unlikely to ever be conducted. But the aggregate evidence for the use of small-molecule GP IIb/IIIa inhibitors in primary PCI is favorable, with no clear disadvantage compared with abciximab. The data of Gurm et al. (1) are probably not enough to upgrade the guideline recommendations for small-molecule IIb/IIIa inhibitors from Class IIb to IIa, but they greatly add to the accumulating support and may raise the Level of Evidence classification from C to B. With the recent report of the FINESSE trial casting doubt on the value of early administration of abciximab, these combined findings suggest that there are more options for GP IIb/IIIa inhibitors during primary PCI and more time to decide.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
1 Dr. Moliterno has received past consultancy honoraria from Eli Lilly, Schering-Plough, Merck, and Medicure, the respective manufacturers or distributors for abciximab, eptifibatide, and tirofiban.
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References
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1. Gurm HS, Smith DE, Collins JS, et al. Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2) The relative safety and efficacy of abciximab and eptifibatide in patients undergoing primary percutaneous coronary intervention: insights from a large regional registry of contemporary percutaneous coronary intervention J Am Coll Cardiol 2008;51:529-535.[Abstract/Free Full Text]2. Brener SJ, Barr LA, Burchenal JE, et al. ReoPro and Primary PTCA Organization and Randomized Trial (RAPPORT) Investigators Randomized, placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction Circulation 1998;98:734-741.[Abstract/Free Full Text] 3. Neumann FJ, Kastrati A, Schmitt C, et al. Effect of glycoprotein IIb/IIIa receptor blockade with abciximab on clinical and angiographic restenosis rate after the placement of coronary stents following acute myocardial infarction J Am Coll Cardiol 2000;35:915-921.[Abstract/Free Full Text] 4. Montalescot G, Barragan P, Wittenberg O, et al. Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction N Engl J Med 2001;344:1895-1903.[Abstract/Free Full Text] 5. Stone GW, Grines CL, Cox DA, et al. Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction N Engl J Med 2002;346:957-966.[Abstract/Free Full Text] 6. Antoniucci D, Rodriguez A, Hempel A, et al. A randomized trial comparing primary infarct artery stenting with or without abciximab in acute myocardial infarction J Am Coll Cardiol 2003;42:1879-1885.[Abstract/Free Full Text] 7. De Luca G, Suryapranata H, Stone GW, et al. Abciximab as adjunctive therapy to reperfusion in acute ST-segment elevation myocardial infarction: a meta-analysis of randomized trials JAMA 2005;293:1759-1765.[Abstract/Free Full Text] 8. De Luca G, Suryapranata H, Stone GW, et al. Relationship between patient’s risk profile and benefits in mortality from adjunctive abciximab to mechanical revascularization for ST-segment elevation myocardial infarction: a meta-regression analysis of randomized trials J Am Coll Cardiol 2006;47:685-686.[Free Full Text] 9. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction) J Am Coll Cardiol 2004;44:e1-e211.[CrossRef][Medline] 10. Smith Jr. SC, Feldman TE, Hirshfeld Jr. JW, et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention—summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention) J Am Coll Cardiol 2006;47:216-235.[Free Full Text] 11. Montalescot G, Borentain M, Payot L, Collet JP, Thomas D. Early vs late administration of glycoprotein IIb/IIIa inhibitors in primary percutaneous coronary intervention of acute ST-segment elevation myocardial infarction: a meta-analysis JAMA 2004;292:362-366.[Abstract/Free Full Text] 12. Maioli M, Bellandi F, Leoncini M, Toso A, Dabizzi RP. Randomized early versus late abciximab in acute myocardial infarction treated with primary coronary intervention (RELAx-AMI Trial) J Am Coll Cardiol 2007;49:1517-1524.[Abstract/Free Full Text] 13. Ellis SG. Report of the FINESSE trial findings. Paper presented at: European Society of Cardiology Congress; September 1–5, 2007; Vienna, Austria. 14. Raveendran G, Ting HH, Best PJ, et al. Eptifibatide vs abciximab as adjunctive therapy during primary percutaneous coronary intervention for acute myocardial infarction Mayo Clin Proc 2007;82:196-202.[Abstract/Free Full Text] 15. Midei MG, Coombs VJ, Lowry DR, et al. Clinical outcomes comparing eptifibatide and abciximab in ST elevation acute myocardial infarction patients undergoing percutaneous coronary interventions Cardiology 2007;107:172-177.[CrossRef][Web of Science][Medline] 16. Danzi GB, Sesana M, Capuano C, Mauri L, Berra Centurini P, Baglini R. Comparison in patients having primary coronary angioplasty of abciximab versus tirofiban on recovery of left ventricular function Am J Cardiol 2004;94:35-39.[Web of Science][Medline] 17. Valgimigli M, Campo G, Arcozzi C, et al. Two-year clinical follow-up after sirolimus-eluting versus bare-metal stent implantation assisted by systematic glycoprotein IIb/IIIa Inhibitor Infusion in patients with myocardial infarction: results from the STRATEGY study J Am Coll Cardiol 2007;50:138-145.[Abstract/Free Full Text]
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The Relative Safety and Efficacy of Abciximab and Eptifibatide in Patients Undergoing Primary Percutaneous Coronary Intervention: Insights From a Large Regional Registry of Contemporary Percutaneous Coronary Intervention
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