ADVERTISEMENT
Superior In-Hospital and 30-Day Outcomes with Abciximab Versus Eptifibatide: A Contemporary Analysis of 495 Consecutive Percutan
November 2004
Over the past decade clinical trials have demonstrated that platelet glycoprotein (GP) IIb/IIIa receptor inhibition dramatically reduces the ischemic complications of percutaneous coronary intervention (PCI).1–6 Currently, there are 3 approved GP IIb/IIIa inhibitors for use during PCI; the chimeric monoclonal antibody abciximab (Reopro® Eli Lilly and Co., Indianapolis, Ind.), the peptidomimetic tirofiban (Aggrastat® Merck & Co., Inc., ) and the heptapeptide eptifibatide (Integrilin™ Cor Therapeutics). Significant structural, pharmacokinetic, and cost differences exist between these agents, and according to at least one randomized trial, important efficacy differences may exist as well. Comparative data between abciximab and eptifibatide are very limited and the question remains whether efficacy differences between these 2 agents may exist as well.
Strategies for agent selection must therefore rely on critical review of the placebo-controlled PCI trials with agents, cost considerations and individual operator preference. Multiple trials with abciximab demonstrated robust (35–56%) reductions in 30-day ischemic events compared to placebo, with efficacy lasting out to at least 3 years.1-3,7 Particular benefit was noted for patients with acute coronary syndromes (ACS) and diabetes.8 The superiority of eptifibatide over placebo was demonstrated in the ESPRIT trial, which showed a 35% reduction in 30-day ischemic events.6 Based on interpretation of these trials, a strategy of abciximab for high-risk cases and eptifibatide for moderate- to low-risk cases has been proposed and reported.9 In this paper, we review short-term outcomes of 495 consecutive PCIs performed with the aforementioned strategy of abciximab use in higher risk and eptifibatide use in lower risk cases.
Methods
Study design. We retrospectively analyzed all PCIs (506) performed by a single operator (Efthymios N. Deliargyris) between July 2001 and November 2002 (506 consecutive procedures on 476 patients). Out of 506 PCIs, cardiogenic shock at the time of PCI requiring intra-aortic balloon counterpulsation (n = 6) was excluded. Since our aim is know the effect of GP IIb/IIIa inhibitors on 30-day clinical outcomes, some patients who underwent a second procedure within 30 days from their first procedure were also excluded (n = 5). All of these repeat procedures were staged PCIs. All PCIs were performed with GP IIb/IIIa inhibitor administration: 242 with abciximab and 253 with eptifibatide. The initial 444 cases were performed with unfractionated heparin and the last 51 with bivalirudin (16 with abciximab and 35 with eptifibatide). The selection of the GP IIb/IIIa inhibitor was at the operator’s discretion. All PCIs were performed using standard techniques through the femoral approach. Hemostasis was achieved with a closure device whenever possible, based on the access site angiogram (Angio-Seal,™ St. Jude Medical, Minnetonka, Minn., in the majority of the cases). Data for all PCI procedures were entered in a prospective database [Cardiovascular Automated Office Systems (CAOS), Intelligent Business Solutions (IBS) Winston-Salem, North Carolina] during the index admission that includes the baseline and procedural characteristics as well as in-hospital outcomes. Research fellows performed an independent review of all 470 patient charts. Thirty-day outcomes were collected from out-patient clinic visits or telephone follow-up and were available for 96% of patients.
Definitions. Peripheral vascular disease (PVD) included cerebrovascular disease and peripheral arterial disease based on objective evidence (stroke documented by computed tomography or magnetic resonance imaging or persistent focal neurologic deficit, carotid endarterectomy, peripheral vascular surgery or positive noninvasive lower arterial studies) obtained during chart review. Renal insufficiency was defined as a creatinine > 2 mg/dl, congestive heart failure as NYHA class >= class II symptoms, diabetes, hypertension and hyperlipidemia as a previous medical diagnosis, or the use of medications or blood sugar > 126 mg/dl, or admission blood pressure > 140/90 mmHg, or total cholesterol > 200 mg/dl; prior coronary artery disease (CAD) includes prior myocardial infarction (MI) or coronary artery bypass graft (CABG) or PCI. Indications for PCI included ST-elevation MI (primary or rescue), non-ST-elevation MI, unstable angina or stable CAD according to standard ACC definitions.
Medications. All patients were on 325 mg of daily aspirin prior to the procedure and were advised to continue its use indefinitely. Most patients were also treated with adenosine diphosphate inhibitors (97%, almost exclusively clopidogrel), including all patients who received stents (78%). The timing of clopidogrel treatment varied with some patients on chronic treatment, with some receiving the 300 mg load before PCI, while others received it immediately post-PCI. During PCI, abciximab was administered as 0.25 mg/kg IV bolus, followed by an infusion of 0.125 mcg/kg/min and continued for 12 hours. Eptifibatide was given as a double bolus of 180 mcg/kg IV 10 minutes apart, followed by an infusion of 2.0 mcg/kg/min for 18 hours; 8% of the patients also received the drug before the procedure. The UFH was administered following a standard bolus-dose, weight-adjusted heparin regimen, with additional boluses as needed to achieve and maintain an ACT of 225–275 seconds, while bivalirudin was given as a 0.75 mg/kg bolus followed by a 1.75 mg/kg per hour infusion for the duration of the PCI without ACT monitoring.
Outcomes. Creatine kinase (CK) and CK-MB measurements were performed every 8 hours post-PCI for a total of 3 assays, or until the patient was discharged. In-hospital outcomes included death, MI (new Q-waves in at least 2 contiguous leads [Q-MI], or CK-MB > 3 times the upper limit of normal [non-Q-MI]), stroke, urgent revascularization (URV), bleeding and thrombocytopenia (platelets 10 Adjudication was performed by an independent physician reviewer. Stroke was defined as a new, focal, neurologic deficit that was confirmed by either a consulting neurologist and/or CT or MRI findings. Angiographic success was based on all lesions successfully dilated. Target vessel revascularization (TVR) was substituted for URV for 30-day outcomes. In-hospital and 30-day outcomes were analyzed as 3 composite endpoints: a triple “ischemic” endpoint (death, MI, and URV for in-hospital or TVR for 30-day outcomes), a quadruple endpoint (triple composite + major bleeding), and as major adverse cardiac events (MACE) was defined as sum of triple composite, all bleeding and stroke.
Statistical analysis. Continuous variables are expressed as mean ± SD and comparisons are made with unpaired t-test. Categorical variables are expressed as percentages and comparisons made with the chi-square test or the Fisher’s exact test, where appropriate. The Cox proportional hazard model was used to calculate hazard ratios (HR) and 95% confidence intervals (CI).
The “modified” TIMI risk score (that could be applied retrospectively) was calculated using the following established clinical variables; age > 65 years, 3 or more coronary risk factors (diabetes, hypertension, hyperlipidemia, smoking, positive family history), known coronary stenosis > 50%, ST-segment elevation at presentation, use of aspirin within the previous 7 days and elevated levels of cardiac markers.11 Patients received 1 point for each risk factor, with a maximum score of 6, and a minimum score of 0. Low risk was defined as 0–2 risk factors, intermediate risk was defined as 3–4 risk factors, and high risk was defined as 5–6 risk factors. Patients with the low, intermediate and high risk scores, then evaluated for clinical outcomes by the treatment received (abciximab versus eptifibatide). A p-value In-hospital and 30-day outcomes. Rates for all ischemic complications and bleeding were lower in the abciximab group (Table 3 and Figure 1). The triple “ischemic” composite endpoint (death/MI/urgent revascularization) was also lower in the abciximab group compared with the eptifibatide group; however, the difference was not significant (3.3% versus 6.7%; OR: 0.46; 95% CI: 0.20–1.12; p = 0.1). The reduction in overall bleeding rates with abciximab (1.2% versus 5.1%; OR: 0.23; 95% CI: 0.07–0.82; p = 0.03) was contributed to by reductions in both minor and major bleeding. In fact, no major bleeds were noted in the abciximab group. There were also no PCI-related strokes in the abciximab group while there were 3 in the eptifibatide group (all are non-hemorrhagic stroke). The quadruple (OR: 0.38; 95% CI: 0.16–0.87; p = 0.029) and MACE (OR: 0.34; 95% CI: 0.17–0.7; p = 0.004) composite endpoints were lower with abciximab and reached statistical significance (Table 3). Thrombocytopenia was only observed among abciximab-treated patients (4 of 242, 1.7%). Out of 495 PCIs, the last 51 were performed using bivalirudin (16 with abciximab and 35 with eptifibatide). No major bleeds were noted with bivalirudin. All minor bleeding was associated with the eptifibatide-treated group. Seven patients in the abciximab group and 12 patients in the eptifibatide group were lost to follow-up (96% capture rate). There were 3 additional events in the eptifibatide group (1 death, 1 non-Q-wave MI and 1 TVR) and 2 additional events in the abciximab group (1 non-Q-wave MI and 1e TVR) (Table 3 and Figure 2).
Subgroup analysis. Subgroup analysis demonstrated that the 61% reduction in the overall 30-day MACE rates in the abciximab group compared with the eptifibatide group (5.5 versus 14%, p = 0.003, OR: 0.36; 95% CI: 0.19-0.71]) was consistent among high-risk subsets such as older (> 65 years), female and diabetic patients, as well as patients with pre-existing CAD and those presenting with ACS (Figure 3). The most robust benefit was noted among diabetic and female patients. Specifically, diabetic patients treated with abciximab demonstrated practically identical 30-day MACE compared with the overall abciximab population (4.2% versus 5.5%, p = ns), and 87% reduction in MACE compared with eptifibatide-treated diabetic patients (4.2% versus 25.6%; OR: 0.13; 95% CI: 0.04–0.41; p 12-15 Careful review of the data of Suleiman et al. shows lower rates of all ischemic outcomes with abciximab as well as lower rates of both major and minor bleeding. In fact, if a comparison for total bleeding rates is made between the 2 agents, then a significant reduction with abciximab is noted (22/342, 6.4% with eptifibatide versus 7/300, 2.3% with abciximab; p = 0.02).15 Abciximab, a monoclonal antibody, has a long biological half-life with a lower dissociation constant for the glycoprotein IIb/IIIa receptor and also blocks the vitronectin (avb3) and Mac-1 receptors.16 In contrast, eptifibatide is a short-acting, highly reversible competitive peptide, with specific binding to the glycoprotein IIb/IIIa receptor.17 Although potent platelet inhibition may be achieved with both agents, there are subtle differences in the time course of inhibition that may have important clinical implications. For example, although abciximab binds more tightly to the GP IIb/IIIa receptor than eptifibatide, there is evidence for greater antiplatelet effect with eptifibatide, especially at the end of the infusion period and at pre-hospital discharge.18 This is an important mechanistic difference that may explain the difference in bleeding rates. Although it was initially believed that prolonged, potent antiplatelet action may be beneficial, more contemporary studies suggest that the ultimate benefit is derived from powerful platelet inhibition (> 95%) at the time of PCI rather than during the prolonged infusion.19 Therefore, the theoretical advantage of eptifibatide in maintaining higher levels of antiplatelet activity during the infusion period may actually be detrimental by contributing to higher bleeding rates.
Although the reductions in ischemic complications were not statistically significant, they all favored abciximab. A possible explanation for the relative benefit of abciximab may lie in its unique effect on the vitronectin (avb3) and Mac-1 (aMb2) receptors. Abciximab is known to bind with equal affinity to avb3 and aIIbb3 (GP IIb/IIIa), resulting in functional blockade of both receptors.17 Blocking avb3 could have beneficial effects such as reducing matrix metalloproteinase-2 activation,20 smooth muscle cell migration,21 and tumor growth factor-b1 (TGF-b1) production.22 Furthermore, platelet-supported thrombin production is blocked more completely by abciximab than by antibodies to GP IIb/IIIa alone, implicating a role for platelet avb3 in thrombin production.23 Finally, inhibiting the Mac-1 receptor could block the interaction of macrophages with fibrinogen and intracellular adhesion molecule-1, thereby providing an anti-inflammatory effect.24
Abciximab is shown to favorably alter the PCI-related inflammatory activation with the ability to reduce the rise in CRP (-32%), interleukin-6 (-76%) and tumor necrosis factor-a (-100%), as well as block neutrophil and monocyte activation compared with placebo.25,26 Although both abciximab and eptifibatide suppress the rise in markers of inflammation than that which occurs following PCI, differences in the patterns and mechanisms of anti-inflammatory effects may exist between these agents. There is no significant difference in CRP and IL-6 elevations after coronary stenting between abciximab and eptifibatide.27 Eptifibatide may suppress the rise in IL-1 receptor antagonist27 and RANTES28 more potently than abciximab, but may have partial agonist activity that enhances total GP IIb/IIIa and P-selectin expression29 Furthermore, the relatively short half-life of eptifibatide may lead to an early recurrent inflammatory effect.30
Finally, a recent study reported yet another potentially beneficial mechanism of action of abciximab, namely its ability to disperse newly formed platelet aggregates.31 The combination of platelet disaggregation and reduction of peri-procedural inflammation may be especially beneficial in diabetic and ACS patients in whom platelet activation and ongoing inflammation are most pronounced.32–34 Accordingly, our data showed a relatively greater reduction of the triple ischemic composite endpoint with abciximab in the diabetic cohort versus the study group as a whole.
Study Limitations. The obvious limitation to our study is the retrospective, non-randomized design. In our study, however, there is no attempt to propose an unbiased sample. In fact, based on the rationale for agent selection, we intended to bias our use of GP IIb/IIIa inhibitors so that diabetic and high-risk patients would undergo PCI with abciximab, whereas lower risk cases would be selected for PCI with eptifibatide. Accordingly, our patient groups were clearly unequal with all the high-risk clinical and procedural features more prevalent among the abciximab–treated patients. It is therefore highly unlikely that biased patient selection can explain the results. There is always a possibility that an unknown and unaccounted for variable may have influenced the results. A second limitation is the lack of data regarding the percentage of patients who received clopidogrel pre- versus post-PCI. In the CREDO trial, pre-treatment with clopidogrel at least 6 hours prior to PCI was associated with lower ischemic event rates, but with a 36% increase in minor bleeding rates.35 In our study, clopidogrel pre-treatment was not factored in the GP IIb/IIIa selection process. It is conceivable that the number of patients pre-treated varied greatly between the 2 groups and favored abciximab, thereby influencing the results. However, the 64% reduction in minor bleeding with abciximab suggests a low likelihood that the abciximab-treated patients were more frequently pre-treated.
There are 2 relative strengths to our non-randomized, retrospective analysis that also deserve mention. First, this is truly a contemporary experience with the cases included in this analysis performed within a recent 15-month window (7/01–11/02). Finally, this is an analysis of a truly all inclusive, consecutive “real-world” PCI cohort since in our institution, GP IIb/IIIa inhibitors are used in > 99% of all PCIs. Other studies have reported on “consecutive” patients when in reality they were selected cohorts of patients whom the operators had deemed candidates for GP IIb/IIIa therapy.
Conclusion. Our data suggest that substantial differences exist in clinical efficacy between the 2 dominant GP IIb/IIIa inhibitors for PCI. Abciximab appears to result in superior clinical outcomes, especially through reduction in bleeding rates compared with eptifibatide. Studies documenting important mechanistic differences between abciximab and eptifibatide exist; a randomized clinical trial to assess possible efficacy differences is long overdue.
1. 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;30:956–961.
2. The EPILOG Investigators. Platelet glycoprotein IIb-IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997;336:1689–1696.
3. The EPISTENT Investigators. Randomized placebo–controlled and balloon angioplasty-controlled trial to assess safety of coronary stenting with the use of platelet glycoprotein –IIb/IIIa blockade. Lancet 1998;352:87–92.
4. The IMPACT-II Investigators. Randomized placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT II. Lancet 1997; 349:1422–1428.
5. The RESTORE Investigators. Effect of platelet glycoprotein-IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Circulation 1997;96:1445–1453.
6. The ESPRIT Investigators. Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): A randomized, placebo-controlled trial. Lancet 2000;356:2037–2044.
7. Topol EJ, Lincoff AM, Kereiakes DJ, et al. Multi-year follow-up of abciximab therapy in three randomized, placebo-controlled trials of percutaneous coronary revascularization. Am J Med 2002;113:1–6.
8. Marso SP, Lincoff AM, Ellis SG, et al. Optimizing the percutaneous interventional outcomes for patients with diabetes mellitus: Results of the EPISTENT (Evaluation of platelet IIb/IIIa inhibitor for stenting trial) diabetic substudy. Circulation 1999;100:2477–2484.
9. Kini AS, Reich D, Mitre CA, et al. A risk stratification scheme for selection of a glycoprotein IIb/IIIa inhibitor during percutaneous coronary intervention based on clinical and angiographic criteria. Am J Cardiol 2001;88:1287–1290.
10. Rao AK, Pratt C, Berke A, et al. Thrombolysis in Myocardial Infarction (TIMI) Trial -phase I: Hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol 1988;11:1–11.
11. Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina/non-ST elevation MI: A method for prognostication and therapeutic decision making. J Am Med Assoc 2000; 284:835–842.
12. Kimmelstiel C, Phang R, Rehman A, et al. Short-term comparative outcomes associated with the use of GP IIb/IIIa antagonists in patients undergoing coronary intervention. J Thromb Thrombolysis 2001;11:203–209.
13. The PRICE Investigators. Comparative 30-day economic and clinical outcomes of platelet glycoprotein IIb/IIIa inhibitor use during elective percutaneous coronary intervention. The Prairie Reopro versus Integrilin Cost Evaluation (PRICE) Trial. Am Heart J 2001;141:402–409.
14. Schweiger MJ, Changezi HU, Naglieri-Prescod D, et al. Open-label, sequential comparison of eptifibatide with abciximab for patients undergoing percutaneous coronary intervention. Clin Ther 2003;25:225–34.
15. Suleiman M, Gruberg L, Hammerman H, et al. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, eptifibatide and abciximab: Outcomes, complications and thrombocytopenia during percutaneous coronary intervention. J Invas Cardiol 2003;15:319–323.
16. Tam SH, Sassoli PM, Jordan RE, et al. Abciximab (ReoPro, Chimeric 7E3 Fab) demonstrates equivalent affinity and functional blockade of glycoprotein IIb/IIIa and alpha(v)beta3 integrins. Circulation 1998;98:1085–1091.
17. Gilchrist IC, O'Shea JC, Kosoglou T, et al. Pharmacodynamics and pharmacokinetics of higher-dose, double-bolus eptifibatide in percutaneous coronary intervention. Circulation 2001;104:406–411.
18. Kereiakes DJ, Broderick TM, Roth EM, et al. Time course, magnitude, and consistency of platelet inhibition by abciximab, tirofiban, or eptifibatide in patients with unstable angina pectoris undergoing percutaneous coronary intervention. Am J Cardiol 1999;84:391–395.
19. Steinhubl SR, Talley JD, Braden GA, et al. Point-of-care measured platelet inhibition correlates with a reduced risk of an adverse cardiac event after percutaneous intervention; Results of the GOLD (AU- Assessing Ultegra) multicenter study. Circulation 2001;103:2572–2578.
20. Silletti S, Kessler T, Goldberg J, et al. Disruption of matrix metalloproteinase-2 binding to integrin alpha vbeta 3 by an organic molecule inhibits angiogenesis and tumor growth in vivo. Proc Natl Acad Sci USA 2001;98:119–124.
21. Coleman KR, Braden GA, Willingham MC, et al. Vitaxin, a humanized monoclonal antibody to the vitronectin receptor (alphavbeta3), reduces neointimal hyperplasia and total vessel area after balloon injury in hypercholesterolemic rabbits. Circ Res 1999;84:1268–1276.
22. Ribeiro SM, Schultz-Cherry S, Murphy-Ullrich JE. Heparin-binding vitronectin up-regulates latent TGF-beta production by bovine aortic endothelial cells. J Cell Sci 1995;108:1553–1561.
23. Reverter JC, Beguin S, Kessels H, et al. Inhibition of platelet-mediated, tissue factor-induced thrombin generation by the mouse/human chimeric 7E3 antibody. J Clin Invest 1996;98:863–874.
24. Simon DI, Xu H, Ortlepp S, et al. 7E3 monoclonal antibody directed against the platelet glycoprotein IIb/IIIa cross-reacts with the leukocyte integrin Mac-1 and blocks adhesion to fibrinogen and ICAM-1. Arterioscler Thromb Vasc Biol 1997;17:528–535.
25. Lincoff AM, Kereiakes DJ, Mascelli MA, et al. Abciximab suppresses the rise in levels of circulating inflammatory markers after percutaneous coronary revascularization. Circulation 2001;104:163–167.
26. Mickelson JK, Ali MN, Kleiman NS, et al. Chimeric 7E3 Fab (Reopro) decreases detectable CD11b on neutrophils from patients undergoing coronary angioplasty. J Am Coll Cardiol 1999:33:97–106.
27. Aggarwal A, Schneider DJ, Terrien EF, et al. Comparison of effects of abciximab versus eptifibatide on C-reactive protein, interleukin-6, and interleukin-1 receptor antagonist after coronary arterial stenting. Am J Cardiol 2003;91:1346–1349.
28. Welt FGP, Rogers SD, Zhang X, et al. GP IIb/IIIa inhibition with eptifibatide lowers levels of soluble CD40L and RANTES after percutaneous coronary intervention. Cathet Cardiovasc Interv 2004;61:185–189.
29. Dalby M, Montalescot G, dit Sollier CB, et al. Eptifibatide provides additional platelet inhibition in non-ST-elevation myocardial infarction patients already treated with aspirin and clopidogrel. J Am Coll Cardiol 2004;43:162–168.
30) Merino A, Segura I, Vidal B, et al. Eptifibatide blocks C-reactive protein increases after coronary angioplasty. J Am Coll Cardiol 2003;41:233A.
31. Marciniak SJ Jr, Mascelli MA, Furman MI, et al. An additional mechanism of action of abciximab: Dispersal of newly formed platelet aggregates. Thromb Haemost 2002;87:1020–1025.
32. Biondi-Zoccai GGL, Abbate A, Liuzzo G, et al. Atherothrombosis, inflammation, and diabetes. J Am Coll Cardiol 2003;41:1071–1077.
33. Buffon A, Biasucci LM, Liuzzo G, et al. Wide spread coronary inflammation in unstable angina. N Engl J Med 2002;347:5–12.
34. Deliargyris EN, Raymond RJ, Theoharides TC, et al. Sites of interleukin-6 release in patients with acute coronary syndromes and in patients with congestive heart failure. Am J Cardiol 2000;86:913–918.
35. Steinhubl SR, Berger PB, Mann JT III, et al. CREDO Investigators. Clopidogrel for the Reduction of Events during Observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: A randomized controlled trial. J Am Med Assoc 2002;288:2411–2420.
