Efthymios N. Deliargyris, MD; Bharathi Upadhya, MD; Robert J. Applegate, MD; Michael A. Kutcher, MD; Sanjay K Gandhi, MD; David C. Sane, MD

J Invasive Cardiol 16(11):611-616, 2004. © 2004 Health Management Publications, Inc.

Posted 12/23/2004

Abstract

Background: Both abciximab (AB) and eptifibatide (EP) are approved for use during percutaneous coronary intervention (PCI) but comparative data between the 2 agents are limited.
Methods: We compared in-hospital and 30-day outcomes of contemporary 495 consecutive PCIs performed by a single operator between July 2001 and November 02 with AB and EP (242 with AB and 253 with EP). Cardiogenic shock patients who underwent a second procedure within 30 days from their first procedure were excluded. Selection of glycoprotein IIb/IIIa was at the operator's discretion. The initial 444 cases were performed with unfractionated heparin and the last 51 with bivalirudin.
Results: AB cases comprised a higher risk group with more patients with diabetes, peripheral vascular disease, ST-elevation myocardial infarction and renal failure (p < 0.05 for each) and more rotablator use and longer lesions (p < 0.01 for each). AB was associated with less in-hospital (4.6 versus 12.3%; OR: 0.34; 95% CI: 0.17–0.7; p = 0.004) as well as 30-day (5.5 versus 14%; OR: 0.37; 95% CI: 0.19–0.71; p = 0.003]) major adverse cardiac events (sum of death, MI, urgent revascularization, all bleeding and stroke).
Conclusion: Despite its use in higher risk PCI patients, AB resulted in superior short-term outcomes compared with EP. Our data suggest that significant efficacy differences may exist between these 2 agents and that a randomized comparison is warranted.

Introduction

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.

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 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 < 50 K, prospectively measured and compared with baseline value). Bleeding was adjudicated as major or minor according to the TIMI classification.^[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 < 0.05 was considered significant. Statistical analysis was performed with the SIGMASTAT (version 2) statistical software (SPSS Science Marketing Development, SPSS Inc., Chicago, Illinois).

Baseline characteristics between the 2 groups are shown in Table 1. The most striking difference was the very high number of diabetic patients in the abciximab group (49% versus 15%; OR: 5.4; 95% CI: 3.5–8.49; p < 0.001). Within the ACS population, there were more ST-elevation MI patients treated with primary or rescue PCI in the abciximab group. As shown in Table 2, there were also significant differences in procedural and lesion characteristics between the 2 groups with abciximab more frequently used in the treatment of long lesions, restenotic lesions, lesions requiring rotational atherectomy and vein graft interventions. There were no differences in use the of closure devices between the 2 groups.

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).

Figure 1. The graph depicts risk ratios and 95% confidence intervals of in-hospital outcomes for abciximab-treated and eptifibatide-treated groups.

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 < 0.001). Female patients treated with abciximab experienced a 75% reduction in 30-day MACE compared to those treated with eptifibatide (5.3% versus 20.5%; OR: 0.22; 95% CI: 0.07–0.68; p = 0.009).

Figure 3. Subgroup analysis for all composite endpoints. The number of events, the total number of patients and the event rate (%) for each subgroup according to treatment are shown on the left. The graph depicts risk ratios and 95% confidence intervals for each subgroup according to treatment for all 3 composite endpoints.

As shown in Table 4, fewer patients treated with abciximab were in the low-risk category (TIMI Score 0, 1) and greater percentages were high-risk (TIMI score 5–6). There was a graded increase in both 30-day MACE and 30-day composite endpoint, with higher TIMI risk scores (Figure 4 and 5). Both 30-day MACE and 30-day triple composite were higher in the eptifibatide-treated patients in all 3 risk categories. For 30-day MACE, there was a statistically significant increase in events in patients treated with eptifibatide compared with abciximab. The differences did not reach statistical significance for the composite endpoint, although there was a strong trend (p = 0.056) in the high-risk patients.

Figure 4. In-hospital and 30-day triple composite (%) among the patients with different risk scores according to treatment received.

Our data demonstrate significant differences in post-PCI outcomes between the 2 most widely used GP IIb/IIIa inhibitors. Specifically, abciximab-treated patients had fewer ischemic incidents, and bleeding complications in particular, despite having a clearly higher pre-procedural risk profile compared with eptifibatide-treated patients. The benefit associated with the use of abciximab was consistent for all high-risk subgroups analyzed and especially pronounced among diabetic and female patients.

Our analysis is the first to report significant differences in short-term outcomes post-PCI between abciximab and eptifibatide. Previous comparative studies have been limited and in aggregate support the notion of equivalent efficacy between the 2 agents, as well as cost savings with eptifibatide.^[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 (α_vβ₃) 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 (α_vβ₃) and Mac-1 (aMβ₂) receptors. Abciximab is known to bind with equal affinity to α_vβ₃ and α_IIbβ₃ (GP IIb/IIIa), resulting in functional blockade of both receptors.^[17] Blocking α_vβ₃ 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 α_vβ₃ 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 antagonist^[27] and RANTES^[28] more potently than abciximab, but may have partial agonist activity that enhances total GP IIb/IIIa and P-selectin expression^[29] 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.

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Reprint Address

Address correpondence to: David C. Sane, MD, Cardiology Section, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1045. E-mail: dsane@wfubmc.edu