Comparison of Abciximab and Eptifibatide on Angiographic and Clinical Outcomes in (FULL TITLE BELOW)

TITLE: Comparison of Abciximab and Eptifibatide on Angiographic and Clinical Outcomes in Rescue Percutaneous Coronary Intervention for Failed Fibrinolytic Therapy

ABSTRACT: Background. Adjunctive administration of the glycoprotein IIb/IIIa platelet receptor antagonist (GPA), abciximab, improves outcomes in patients undergoing rescue percutaneous coronary intervention (PCI). However, it is unknown if other GPAs provide a similar benefit in this setting. Objective. We sought to compare angiographic and clinical outcomes of patients receiving abciximab or eptifibatide as an adjunct to rescue PCI. Methods. In this prospective, nonrandomized study, consecutive patients who underwent rescue PCI and received adjunctive preprocedural GPA comprised the study population. Thrombolysis in myocardial infarction (TIMI) flow, corrected TIMI frame count (CTFC) and myocardial blush grade (MBG) were determined before and immediately after rescue PCI. Residual ST-segment elevation at 90–120 minutes and peak creatine kinase (CK) values for 48 hours after PCI were recorded. Major adverse cardiac events (MACE) including death, reinfarction and target vessel revascularization (TVR) were determined at discharge, 1 and 6 months. Results. A total of 241 patients were included in the study. 162 patients received abciximab and 79 received eptifibatide. There were no differences in baseline clinical and angiographic characteristics between groups. Post-PCI TIMI flow was similar but post-PCI CTFC was significantly lower (17 ± 10 vs. 22 ± 18; p = 0.01) and post-PCI MBG significantly higher (2.8 ± 0.5 vs. 2.6 ± 0.6; p = 0.01) in the abciximab group. Patients in the abciximab group had less ST-segment elevation (1.0 ± 0.9 vs. 1.5 ± 1.0 mm; p = 0.003) and lower peak CK (2,484 ± 2176 vs. 2,650 ± 2,798 U/L; p = 0.001) after PCI. On multivariate analyses, abciximab administration (OR = 0.50, CI = 0.26, 0.96; p = 0.03), pre-PCI TIMI 3 flow (OR = 0.22, CI = 0.05, 0.99; p = 0.04) and female gender (OR = 0.24, CI = 0.08, 0.66; p = 0.006) were positive and cardiogenic shock (OR = 2.76, CI = 1.16, 6.58; p = 0.02) was a negative predictor of normal epicardial perfusion post PCI. Abciximab administration (OR = 0.46, CI = 0.24, 0.87; p = 0.02) and pre-PCI CTFC Conclusions. In the setting of rescue PCI, adjunctive administration of abciximab resulted in greater improvement in angiographic and electrical estimates of myocardial perfusion and smaller infarct size compared to eptifibatide. These findings suggest that all GPA may not provide equal benefit in rescue PCI.

J INVASIVE CARDIOL 2010;22:347–352

Key words: glycoprotein IIb/IIIa platelet receptor antagonist, rescue angioplasty, fibrinolytic therapy

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Mechanical reperfusion with percutaneous coronary intervention (PCI) is an established therapy for patients with ST-elevation myocardial infarction (STEMI) who fail to restore coronary perfusion after administration of fibrinolytic therapy.^1–3 The clinical setting of rescue PCI is characterized by marked platelet activation⁴ and stimulation of coagulation^5,6 and inflammatory⁷ pathways. Adjunctive administration of abciximab, a non-competitive monoclonal antibody-based glycoprotein IIb/IIIa platelet receptor antagonist (GPA), has been shown to improve clinical outcome in patients undergoing rescue PCI.^8–10 However, in the absence of comparative data for this clinical setting, many operators choose eptifibatide, a lower-cost small-molecule GPA. In the present study, we compared the angiographic and clinical outcomes of patients receiving abciximab or eptifibatide as an adjunct to rescue PCI after failed fibrinolytic therapy.

Methods

All patients undergoing rescue PCI after failed fibrinolytic therapy for STEMI from April 2003 to March 2009 at St. Michael’s Hospital, a tertiary-care hospital with an annual PCI volume of > 1,500 cases, were identified from a prospectively collected database. Patients were admitted to the local hospital or referred from other institutions for rescue PCI after failure of fibrinolytic therapy for STEMI. Consecutive patients undergoing rescue PCI within 12 hours of symptom onset with adjunctive GPA initiated before the PCI procedure comprised the study population. The use and choice of GPA was at the discretion of the operating physician. Patients were excluded if they received additional reduced or full-dose fibrinolytic therapy, received GPA after beginning the PCI procedure or had coronary angiograms that could not be assessed for accurate determination of epicardial and myocardial perfusion scores as specified. Baseline clinical variables, procedural characteristics and clinical outcomes including post-PCI bleeding, reinfarction, target vessel revascularization (TVR) and death were prospectively collected. Residual ST-segment elevation was calculated from the lead with maximum ST-segment elevation on a 12-lead electrocardiogram recorded 90–120 minutes post PCI to assess the adequacy of myocardial perfusion.¹² Peak CK levels were used to estimate infarct size.¹³ Coronary angiograms were reviewed for determination of thrombolysis in myocardial infarction (TIMI) flow, CTFC and MBG before and after the rescue PCI procedure and changes in TIMI flow (∆TIMI), CTFC (∆CTFC) and MBG (∆MBG) were calculated. All angiographic analyses were completed by two investigators blinded to GPA allocation, and any difference in opinion was resolved by consensus. Definitions. Failed thrombolytic therapy was defined as lack of ≥ 50% resolution of ST-segment elevation determined at 90 minutes post fibrinolytic therapy in the worst lead compared to the pretreatment electrocardiogram. TIMI flow, CTFC and pre- and post-PCI MBG were classified into normal and abnormal blood flow. TIMI flow and MBG values of 3 and CTFC 11 Post-PCI thrombocytopenia was defined as a platelet count Statistical analyses. Continuous data are reported as mean ± standard deviation and discrete variables as absolute values and percentages. The Student’s t-test or Wilcoxon’s rank sum test was used for comparison of continuous and Chi-square test or Fisher’s exact test was used for comparison of categorical data. Step-wise logistic regression models were used to identify the predictors of normal epicardial and myocardial blood flow as defined earlier. These models had dichotomized post-PCI TIMI flow, CTFC and MBG as dependent variables and age, gender, history of diabetes, hypertension, dyslipidemia, smoking, MI location (anterior vs. inferior), multivessel disease by angiography, cardiogenic shock, GPA type (abciximab vs. eptifibatide) and dichotomized pre-PCI epicardial and myocardial blood flow as independent variables. All analyses were performed using SAS version 9.1 (SAS Institute, Cary, North Carolina). A p-value Results A total of 453 patients underwent rescue PCI during the study period and 241 patients were included in the present study after meeting inclusion criteria (Figure 1). A total of 162 (67%) patients received abciximab and 79 (33%) patients received eptifibatide. The mean age of the study population was 57 ± 12 years and 80% were male. Baseline clinical characteristics (Table 1) were similar except for male gender (84% vs. 72%; p = 0.04) and history of smoking (20% vs. 5%; p = 0.002), which were more common in the abciximab group. Prior MI was more common in the eptifibatide group (12% vs. 21%; p = 0.05). A total of 122 (51%) patients presented with anterior MI and 31 (13%) were in cardiogenic shock. Angiographic and procedural characteristics are presented in Table 2. Changes in epicardial and myocardial perfusion. Pre-PCI epicardial (TIMI flow) and myocardial (CTFC and MBG) perfusion were similar in both groups and improved significantly post PCI (Table 2, Figures 2A and 2B). Post-PCI TIMI flow was similar in the two treatment groups (2.7 ± 0.5 vs. 2.6 ± 0.5 in the abciximab and eptifibatide group, respectively; p = ns). However, post-PCI CTFC was significantly lower (17 ± 10 vs. 22 ± 18; p = 0.01) and post-PCI MBG was significantly higher (2.8 ± 0.5 vs. 2.6 ± 0.6; p = 0.01) in the abciximab group. Patients receiving abciximab had greater improvement in both epicardial flow (∆TIMI flow 1.3 ± 1.0 vs. 1.0 ± 0.9; p = 0.06) and myocardial perfusion (∆CFTC 33 ± 33 vs. 21 ± 34; p = 0.006; ∆MBG 1.2 ± 1.2 vs. 0.8 ± 1.1; p = 0.01). Predictors of normal epicardial and myocardial perfusion. On multivariate analyses, abciximab administration (OR = 0.50, CI = 0.26, 0.96; p = 0.03), pre-PCI TIMI 3 flow (OR = 0.22, CI = 0.05, 0.99; p = 0.04) and female gender (OR = 0.24, CI = 0.08, 0.66; p=0.006) were positive and cardiogenic shock (OR = 2.76, CI = 1.16, 6.58; p = 0.02) was a negative predictor of normal epicardial perfusion post PCI (Figure 3A). Abciximab administration (OR = 0.46, CI = 0.24, 0.87; p = 0.02) and pre-PCI CTFC Resolution of ST-segment elevation and MI size. Residual ST-segment elevation post PCI was significantly lower in the abciximab group (1.0 ± 0.9 vs. 1.5 ± 1.0 mm; p = 0.003) compared to the eptifibatide group. In addition, peak CK was significantly lower in patients treated with abciximab (2,484 ± 2,176 vs. 2,650 ± 2798 U/L; p = 0.001) compared to the eptifibatide group. Clinical outcomes and MACE. Post-procedural bleeding occurred in 13 (8%) patients in the abciximab group and 5 (6%) patients in the eptifibatide group. Thrombocytopenia was observed in 4 (2%) patients in the abciximab group and 2 (3%) patients in the eptifibatide group. At hospital discharge, the cardiac medication use was 94% for aspirin, 91% for thienopyridine, 86% for statin, 65% for beta blocker and 58% for angiotension converting enzyme inhibitor (ACEI) in the abciximab group compared to 95% for aspirin, 90% for thienopyridine, 80% for statin, 65% for beta blocker and 62% for ACEI in the eptifibatide group, with no significant difference between the two treatment groups. Predischarge left ventricular function grade determined by echocardiography was 2.3 ± 1 vs. 2 ± 1; p = ns, for the abciximab and eptifibatide groups, respectively. In-hospital, 1- and 6-month clinical events and MACE rates were similar for the two treatment groups as detailed in Table 3 and did not change after exclusion of patients presenting with cardiogenic shock (data not shown).

Discussion

To our knowledge, this is the first report on the angiographic and clinical outcome of two widely used classes of GPA in the setting of rescue PCI. Our study demonstrates that adjunctive administration of abciximab during rescue PCI results in significantly greater improvements in epicardial flow and myocardial perfusion and smaller infarct size compared to eptifibatide. Recent studies have demonstrated the efficacy of mechanical reperfusion by PCI in reducing adverse cardiac events following failure of fibrinolytic therapy for STEMI.^1–3 These patients are characterized by marked activation of platelets,⁴ coagulation pathways^5,6 and the inflammatory system.⁷ Adjunctive administration of GPA has been shown to reduce adverse events in these patients.^8,9 Although, the published data are limited to the use of one specific GPA, abciximab,^8,9 many physicians use small-molecule GPAs such as eptifibatide in view of its lower cost and shorter half-life. There is growing evidence that despite similar effects on platelet function, different GPAs may not provide equivalent benefit for patients undergoing PCI in diverse clinical settings.^14–17 Abciximab is a monoclonal antibody that inhibits the platelet glycoprotein IIb/IIIa receptor in a non-competitive manner¹⁸ and possesses additional inhibitory activity for avb3 integrin receptors on endothelial and smooth muscle cells¹⁹ and amb2 integrin receptors on leukocytes,^20,21 properties not observed with other GPAs.^22,23 In addition, abciximab promotes thrombus breakdown and dissolution^24–26 and has been shown to improve recovery of coronary flow and left ventricular function after stenting in acute MI,^27,28 an effect not observed with eptifibatide.^29,30 At present, there have not been any adequately powered randomized trials comparing the safety and efficacy of approved GPAs in patients undergoing PCI. In addition, the registry data and small randomized studies have produced conflicting results. Some studies have shown no significant difference in clinical outcomes among GPAs,^31–35 while others have demonstrated superiority of abciximab.^14,15,36 It is important to note, however, that none of these studies included patients undergoing rescue PCI. Speich et al³⁷ recently reported on the effects of abciximab and eptifibatide on ADP, thrombin receptor agonist peptide (TRAP) and collagen-induced platelet aggregates. They found greater platelet disaggregation with eptifibatide on ADP and collagen-induced platelet aggregates with effects most pronounced at 5 and 10 minutes after GPA introduction. However, no significant difference in platelet disaggregation between eptifibatide and abciximab was observed at 15 minutes. In addition, both eptifibatide and abciximab had little effect on TRAP-induced platelet aggregation. These findings suggest that eptifibatide may result in early and greater dispersion of platelet aggregates in fresh platelet thrombi characterized by decreased fibrin content in a low thrombin state. Such a milieu is more commonly observed in patients presenting with unstable angina or NSTEMI. However, it remains unclear if eptifibatide demonstrates better platelet disaggregation compared to abciximab in well-organized occlusive thrombi with high fibrin content in patients with ongoing thrombin generation as seen in patients undergoing rescue PCI after failure of systemic fibrinolysis. The present findings of improved angiographic and clinical outcomes with abciximab compared to eptifibatide in rescue PCI are consistent with previous studies comparing adjunctive use of GPA in patients undergoing PCI in other clinical settings.^14,15,38 Abciximab and tirofiban were compared in patients undergoing PCI for acute coronary syndromes in the TARGET trial.¹⁵ This study demonstrated that abciximab was superior to tirofiban with regard to the primary endpoint of death, MI and TVR at 30 days, a benefit that was sustained at 6 months, but not at 1 year. Adjunctive use of abciximab was compared with eptifibatide in patients undergoing primary PCI for acute MI in the FATA trial.14 Complete resolution of ST-segment elevation was observed in 70% of patients receiving abciximab compared to 67% of patients receiving tirofiban, which did not meet the equivalency criteria for the two GPA agents.¹⁴ Similarly, a prespecified analysis of the ACUITY study demonstrated that adjunctive administration of abciximab for PCI in patients with moderate- to high-risk acute coronary syndrome was associated with a reduction in adverse clinical events compared to eptifibatide.³⁶ Our findings are also consistent with previous studies which demonstrated greater ST-segment resolution with abciximab either in combination with fibrinolytic therapy³⁹ or compared to eptifibatide in patients with STEMI¹⁴ undergoing primary PCI. The risk of bleeding and vascular complications in patients undergoing PCI with adjunctive GPA after fibrinolytic therapy has been a major concern in previous studies.^40,41 The study by Jong et al⁴⁰ reported a bleeding incidence of 12% for major and 54% for major/minor bleeding in the abciximab compared to 3% for major and 38% for major/minor bleeding in the control group. Similarly, Sandlof et al⁴¹ reported 23% risk of major bleeding with abciximab in patients undergoing rescue PCI. However, both of these studies were quite small and reported on PCI practices from a decade ago. Recent studies have reported a much lower incidence of bleeding complications for both rescue and primary PCI,^33,42,43 with similar event rates as observed in the current study. This lower risk of bleeding complications in recent studies is likely related to the use of weight-adjusted heparin, smaller sheath sizes and change in the sheath management practices including use of vascular closure devices during PCI procedures. In addition, 75 years of age, suggesting a lower-risk population for bleeding complications. Study limitations. There are important limitations for interpretation of findings in the present study. This was a nonrandomized study with potential for selection bias in the choice of GPA. However, preprocedural epicardial and myocardial perfusion scores were similar in the two treatment groups, suggesting that the results are unlikely to be affected by selection bias. In addition, the present study represents a single-center experience and sample size was inadequate to detect clinically important differences in hard endpoints such as mortality. An appropriately designed large multicenter, double-blind, randomized study is needed to confirm the findings of the present study.

References

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__________________________________________________ From the Terrence Donnelly Heart Center and the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada. The authors report no conflicts of interest regarding the content herein. Manuscript submitted January 15, 2010, provisional acceptance given March 1, 2010, final version accepted May 20, 2010. Address for correspondence: Asim N. Cheema, MD, PhD, Division of Cardiology, St. Michael’s Hospital, 30 Bond Street, Toronto, Ontario, Canada M5B 1W8. E-mail: cheemaa@smh.toronto.on.ca\