Comparison of Abciximab Versus Eptifibatide During Percutaneous Coronary Intervention in ST-Segment Elevation Myocardial Infarction (from the HORIZONS-AMI Trial)

Comparison of Abciximab Versus Eptifibatide During Percutaneous Coronary Intervention in ST-Segment Elevation Myocardial Infarction (from the HORIZONS-AMI Trial) Harsimran S. Singh, MD, MSca, George D. Dangas, MD, PhDb,c,*, Giulio Guagliumi, MDd, Jennifer Yu, MBBSc, Bernhard Witzenbichler, MDe, Ran Kornowski, MDf, Cindy Grines, MDg, Bernard Gersh, MB, ChB, DPhilh, Darius Dudek, MDi, Roxana Mehran, MDi, and Gregg W. Stone, MDa,b There are limited safety and effectiveness data comparing glycoprotein IIb/IIIa inhibitors in the setting of primary percutaneous coronary intervention. In this substudy of the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, the clinical and bleeding outcomes of eptifibatide versus abciximab were evaluated in patients with ST-segment elevation myocardial infarction who underwent percutaneous coronary intervention. Three-year clinical outcomes of patients in the heparin plus glycoprotein IIb/IIIa inhibitor arm were compared according to treatment with abciximab (n ⴝ 907) versus eptifibatide (n ⴝ 803). Adjudicated end points included major adverse cardiovascular events (MACEs; mortality, reinfarction, ischemia-driven target vessel revascularization, or stroke), major bleeding, and net adverse clinical events (MACEs or major bleeding). Propensity score matching was used to identify 1,342 matched cases (671 each in the abciximab and eptifibatide groups). Multivariate analysis was performed in the entire cohort and the propensity-matched groups. At 3-year follow-up, eptifibatide and abciximab resulted in nonsignificantly different rates of MACEs (18.3% vs 19.6%, hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.74 to 1.16, p ⴝ 0.51), major bleeding (10.7% vs 11.9%, HR 0.90, 95% CI 0.67 to 1.19, p ⴝ 0.44), and net adverse clinical events (24.5% vs 25.5%, HR 0.96, 95% CI 0.79 to 1.17, p ⴝ 0.69). Similarly, at 3 years by multivariate analysis, there was no statistically significant difference between abciximab and eptifibatide for net adverse clinical events (HR 0.89, 95% CI 0.73 to 1.09, p ⴝ 0.27), MACEs (HR 0.96, 95% CI 0.77 to 1.20, p ⴝ 0.73), and major bleeding (HR 1.05, 95% CI 0.78 to 1.41, p ⴝ 0.75). The propensity-matched groups also had similar outcomes. In conclusion, abciximab and eptifibatide have comparable bleeding risks and clinical efficacy in primary percutaneous coronary intervention. © 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;110:940 –947) In the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONSAMI) trial, 3,602 patients with ST-segment elevation myocardial infarctions were preloaded with a thienopyridine and Columbia University Medical Center; bCardiovascular Research Foundation; cMount Sinai Medical Center, New York, New York; dCardiovascular Ospedali Riuniti di Bergamo, Bergamo, Italy; eCharite Universitätsmedizin Campus Benjamin Franklin, Berlin, Germany; fRabin Medical Center, Petach Tikva, Israel; gDepartment of Cardiology, William Beaumont Hospital, Royal Oak, Michigan; hDivision of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota; iJagiellonian University, Krakow, Poland. Manuscript received March 17, 2012; revised manuscript received and accepted May 23, 2012. The Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial was sponsored by the Cardiovascular Research Foundation, New York, New York, with grant support from Boston Scientific Corporation, Natick, Massachusetts, and The Medicines Company, Parsippany, New Jersey. Dr. Dangas has received honoraria from Sanofi-Aventis, Paris, France; Bristol-Myers Squibb, New York, New York; The Medicines Company; and Boston Scientific Corporation. Dr. Guagliumi is a consultant for Boston Scientific Corporation and Volcano Corporation, San Diego, California. Dr. Guagliumi has received research grants from Abbott Vascular;

randomized to receive heparin plus glycoprotein IIb/IIIa inhibitors (GPIs) or bivalirudin during primary percutaneous coronary intervention (PCI).1 In the present analysis, we examined the early and late outcomes of those patients

a

0002-9149/12/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2012.05.026

Medtronic, Inc., Minneapolis, Minnesota; Boston Scientific Corporation; and LightLab Imaging, Westford, Massachusetts. Dr. Gersh has received consulting fees and honoraria from Merck, Inc.; Abbott Vascular; Ortho-McNeil Janssen Scientific Affairs, Titusville, New Jersey; GE Healthcare, Milwaukee, Wisconsin; St. Jude Medical, St. Paul, Minnesota; Medispec, Germantown, Maryland; Novartis, Basel, Switzerland; Cedars-Sinai Medical Center, Los Angeles, California; and Boston Scientific Corporation. Dr. Mehran has received grants for clinical research from Bristol-Myers Squibb and SanofiAventis and has served as an adviser or consultant for Abbott Vascular; AstraZeneca; Bristol-Myers Squibb; Cordis Corporation, Miami Lakes, Florida; Regado Biosciences, Basking Ridge, New Jersey; and Sanofi-Aventis. Dr. Stone has served as a consultant for Boston Scientific Corporation; Abbott Vascular, Santa Clara, California; AstraZeneca, Wilmington, Delaware; Bristol-Myers Squibb/Sanofi-Aventis, New York, New York; Eli Lilly/Daiichi Sankyo, Indianapolis, Indiana; Merck, Inc., Whitehouse Station, New Jersey; and The Medicines Company. *Corresponding author: Tel: 212-241-7019; fax: 212-241-0273. E-mail address: [email protected] (G.D. Dangas). www.ajconline.org

Coronary Artery Disease/Abciximab Versus Eptifibatide in Primary PCI

941

assigned to heparin plus GPIs according to treatment with abciximab or eptifibatide. Methods The HORIZONS-AMI trial design has been described previously.1 In brief, this study was a large-scale, prospective, 2 ⫻ 2 factorial randomized trial of 3,602 patients enrolled at 123 centers worldwide. The study protocol was approved by the institutional review board or ethics committee at each center, and written informed consent was obtained from all patients. Patients were randomized 1:1 in the emergency room to anticoagulation with unfractionated heparin plus routine use of a GPI (control arm) or bivalirudin plus provisional GPI use reserved for refractory thrombotic complications. After angiography, patients with lesions eligible for stenting underwent a second randomization (3:1) to either Taxus Express-2 paclitaxel-eluting stents or otherwise identical uncoated Express-2 bare-metal stents (Boston Scientific Corporation, Natick, Massachusetts). The choice of GPI was made on an institutional level, and each center declared before study initiation if its study patients would be treated with abciximab or eptifibatide. Randomization was then stratified by the choice of GPI. Abciximab dose was a 0.25 mg/kg bolus followed by a 12-hour infusion at 0.125 ␮g/kg/min (maximum 10 ␮g/ min). Eptifibatide dosing included 2 boluses at 180 ␮g/kg administered 10 minutes apart and followed by an infusion at 2.0 ␮g/kg/min for 12 to 18 hours. Doses were adjusted for renal impairment per the United States Food and Drug Administration label. Unfractionated heparin was administered intravenously as a 60 IU/kg bolus with subsequent boluses to achieve an activated clotting time of 200 to 250 seconds. Aspirin (100 to 324 mg orally or 500 mg intravenously) was administered daily during the index hospitalization, and a minimum of 75 mg/day was prescribed indefinitely after discharge. The initial loading dose of thienopyridine was left to the investigator’s discretion, although a ⱖ300-mg clopidogrel loading dose was required to be administered in the emergency room. Randomization was also stratified by thienopyridine loading dose (300 vs 600 mg). Clopidogrel (75 mg/day) was mandated for ⱖ6 months (ⱖ1 year recommended) after discharge. Ticlopidine was permitted in the case of clopidogrel allergy or unavailability. The designated primary end points of HORIZONS-AMI have previously been described.1 The composite end points used in this study included (1) major adverse cardiovascular events (MACEs), a composite of all-cause death, reinfarction, ischemia-driven target vessel revascularization, or stroke, and (2) net adverse clinical events (NACEs), composed of MACEs or major bleeding not related to coronary artery bypass grafting. Major bleeding was defined as intracranial or intraocular bleeding, bleeding at the access site with a hematoma of ⬎5 cm or requiring intervention, decrease in hemoglobin by 3 g/dl with a recognized bleeding source or 4 g/dl without an overt source, reoperation for bleeding, or requiring a blood transfusion. MACE and major bleeding end points were adjudicated by an independent clinical events committee (Cardiovascular Research Founda-

Figure 1. Flow chart of present study. ED ⫽ emergency department; GP ⫽ glycoprotein; UFH ⫽ unfractionated heparin.

tion, New York, New York) blinded to treatment assignment after review of source documents. Bleeding was also adjudicated according to the Thrombolysis In Myocardial Infarction (TIMI) and Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) bleeding scales.2,3 Angiographic measures of baseline and postprocedural TIMI flow were determined at an independent core angiographic laboratory (Cardiovascular Research Foundation) as previously described.4 Baseline and 60minute post-PCI electrocardiograms were interpreted at an independent electrocardiographic core laboratory (Cardiovascular Research Foundation). ST-segment deviation was evaluated using standardized techniques.5 ST-segment resolution from baseline to the 60-minute post-PCI electrocardiogram was categorized as complete (⬎70%), partial (30% to 70%), or absent (⬍30%). Categorical variables were compared using the chisquare test. Continuous variables were displayed as median values with interquartile ranges and analyzed using Wilcoxon’s rank-sum test. Time-to-event outcomes using the Kaplan-Meier method were assessed with the log-rank test. The independent predictors of MACEs and NACEs at 30 days and 3 years and major bleeding at 30 days were identified using Cox proportional-hazards regression using a stepwise multivariate algorithm with entry and exit criteria set at p ⫽ 0.10. Variables included were limited to a maximum of 1 covariate per every 10 measured clinical events to avoid model overfitting. Candidate variables for multivariate analysis included age, gender, diabetes, hypertension, hyperlipidemia, history of heart failure, current cigarette smoking, history of myocardial infarction, history of PCI, history of coronary artery bypass grafting, creatinine clearance, anemia, platelet count, the left ventricular ejection fraction, Killip class, clopidogrel loading dose (600 mg vs other), symptom-to-balloon time, access site (radial vs femoral), baseline TIMI flow, the use of prerandomization heparin, and index PCI vessel. GPI use was forced into the multivariate model as an entry criteria. To further account for confounding variables and bias, propensity matching was performed on the study cohort.

942

The American Journal of Cardiology (www.ajconline.org)

Table 1 Baseline patient, angiographic, and procedural characteristics Variable Age (years) Men Diabetes mellitus Hypertension* Hyperlipidemia† Current smoker Body mass index (kg/m2) Previous myocardial infarction Previous PCI Previous coronary artery bypass grafting Previous congestive heart failure Left ventricular ejection fraction (%) Chronic kidney disease Creatinine clearance (ml/min)‡ Baseline anemia§ Platelet count (⫻103) Platelet count ⬍150 (⫻103) Killip class II–IV Catheterization access Femoral Radial Brachial Primary management strategy Primary PCI Deferred PCI Coronary artery bypass grafting without PCI Medical management Symptom-to-balloon time (minutes) Index vessel for PCI Left anterior descending Left circumflex Right coronary Left main Saphenous venous graft Baseline TIMI flow grade 0/1 2 3 Number of stents implanted Total length of stents (mm) Stent implantation Paclitaxel-eluting stent Bare-metal stent Closure device used

Abciximab (n ⫽ 907)

Eptifibatide (n ⫽ 803)

61.3 (53.4–70.2) 664 (73.2%) 148 (16.3%) 482 (53.1%) 379 (41.8%) 551 (61.2%) 27.1 (24.7–30.1) 110 (12.1%) 85 (9.4%) 15 (1.7%) 30 (3.3%) 50 (41–55) 26 (2.9%) 86.8 (67.8–112.3) 95 (11.6%) 237 (201–286) 54 (5.9%) 92 (10.1%)

59.7 (52.5–69.9) 647 (80.6%) 149 (18.6%) 453 (56.4%) 351 (43.7%) 503 (62.6%) 27.0 (24.6–30.1) 83 (10.3%) 102 (12.7%) 26 (3.2%) 23 (2.9%) 50 (42–60) 22 (2.7%) 90.5 (69.1–111.5) 77 (9.7%) 251 (211–294) 23 (2.9%) 52 (6.5%)

813 (89.6%) 92 (10.1%) 2 (0.2%)

788 (98.1%) 13 (1.6%) 2 (0.2%)

872 (96.1%) 0 (0.0%) 8 (0.9%) 27 (3.0%) 233 (166–345)

763 (95.0%) 0 (0.0%) 12 (1.5%) 28 (3.5%) 210 (154–322)

p Value 0.14 0.0003 0.22 0.18 0.42 0.28 0.95 0.24 0.02 0.03 0.60 0.0002 0.87 0.29 0.22 0.0003 0.0018 0.007 ⬍0.001 ⬍0.001 1.0 0.26 0 0.24 0.55 0.006

378/940 (40.2%) 146/940 (15.5%) 405/940 (43.1%) 5/940 (0.5%) 6/940 (0.6%)

358/819 (43.7%) 124/819 (15.1%) 324/819 (39.6%) 2/819 (0.2%) 11/819 (1.3%)

0.14 0.82 0.13 0.46 0.13

626/939 (66.7%) 54/939 (5.8%) 864/939 (92.0%) 1.5 ⫾ 0.8 24.0 (20.0–32.0)

502/815 (61.6%) 51/819 (6.2%) 748/819 (91.3%) 1.6 ⫾ 0.9 24.0 (18.0–36.0)

0.03 0.67 0.61 0.01 0.22

591/817 (72.3%) 236/817 (28.9%) 189/782 (24.2%)

521/718 (72.6%) 207/718 (28.8%) 259/751 (34.5%)

0.92 0.98 ⬍0.0001

Data are expressed as median (interquartile range), number (percentage), or mean ⫾ SD. * Defined as per patient report or medical chart review documentation of history of systemic arterial hypertension or current diagnosis. † Defined as per patient report or medical chart review documentation of history of hyperlipidemia or current diagnosis. ‡ Creatinine clearance was calculated using the Cockcroft-Gault formula. § Baseline anemia was defined as hematocrit ⬍39% for men and ⬍36% for women.

A logistic regression model was fit for GPI use (abciximab vs eptifibatide) to pretreatment patient characteristics. Propensity score matching was performed using the Caliper matching algorithm and the SAS “GREEDY” macro (SAS Institute Inc., Cary, North Carolina). With GPI use included as an entry criteria, multivariate analysis was then performed on the propensity-matched population. Statistical analysis was performed using SAS versions 9.1.3 and 9.2.

Results A total of 1,802 patients were assigned to receive unfractionated heparin plus a GPI. As shown in Figure 1, 92 patients were excluded because GPIs were not given (n ⫽ 84), tirofiban was used (n ⫽ 4), or it was unclear which GPI was administered (n ⫽ 4). The present analysis cohort thus includes 1,710 patients, 907 (53.0%) treated with abciximab and 803 (47.0%) treated with eptifibatide. The baseline

Coronary Artery Disease/Abciximab Versus Eptifibatide in Primary PCI

943

Table 2 Electrocardiographic ST-segment deviation analysis Variable Baseline Sum ST-segment deviation (mm) ST-segment elevation Location of ST-segment elevation* Anterior Septal Anteroseptal Lateral Inferior Posterior Inferoposterior Inferolateral Anterolateral Inferoposterolateral 60 minutes after PCI Sum ST-segment deviation (mm) ST-segment resolution Complete (⬎70%) Partial (30%–70%) None (⬍30%) Left bundle branch block Q waves after PCI

Abciximab (n ⫽ 907)

Eptifibatide (n ⫽ 803)

p value

7.7 (4.5–13.2) 787/810 (97.2%) n ⫽ 787 127 (16.1%) 0 (0.0%) 84 (10.7%) 23 (2.9%) 343 (43.6%) 2 (0.3%) 4 (0.5%) 80 (10.2%) 108 (13.7%) 16 (2.0%

7.5 (4.4–12.2) 719/748 (96.1%) n ⫽ 719 125 (17.4%) 1 (0.1%) 110 (15.3%) 18 (2.5%) 279 (38.8%) 1 (0.1%) 11 (1.5%) 74 (10.3%) 90 (12.5%) 10 (1.4%)

0.46 0.26

2.0 (0.0–5.3) n ⫽ 696 357 (51.3%) 191 (27.4%) 148 (21.3%) 10/778 (1.3%) 489/778 (62.9%)

2.1 (0.5–5.2) n ⫽ 651 317 (48.7%) 194 (29.8%) 140 (21.5%) 9/731 (1.2%) 445/732 (60.8%)

0.52 0.48 0.007 0.62 0.06 1.00 0.05 0.94 0.49 0.34 0.52 0.34 0.34 0.91 0.93 0.41

Data are expressed as median (interquartile range) or as number (percentage). * In evaluable electrocardiograms.

Table 3 Unadjusted 30-day and 3-year outcomes Variable

NACEs* MACEs† Death, all-cause Cardiac Noncardiac Reinfarction Q-wave Non-Q-wave Target vessel revascularization Stent thrombosis ARC definite ARC probable Stroke Protocol major bleeding, non–coronary artery bypass grafting Protocol major bleeding, all Blood transfusion TIMI major bleeding TIMI minor bleeding TIMI major or minor bleeding GUSTO life-threatening or severe bleeding GUSTO moderate bleeding

30-Day Outcomes

3-Year Outcomes

Abciximab (n ⫽ 907)

Eptifibatide (n ⫽ 803)

HR (95% CI)

p Value

Abciximab (n ⫽ 907)

Eptifibatide (n ⫽ 803)

HR (95% CI)

p Value

12.7% (115) 5.3% (48) 3.2% (29) 3.0% (27) 0.2% (2) 1.3% (12) 1.0% (9) 0.3% (3) 1.7% (15) 0.2% (2) 0.1% (1) 0.1% (1) 0.7% (6) 9.3% (84)

12.8% (103) 5.6% (45) 3.0% (24) 2.9% (23) 0.1% (1) 2.3% (18) 1.5% (12) 1.0% (8) 2.1% (17) 0.3% (2) 0.3% (2) 0.0% (0) 0.5% (4) 8.9% (71)

0.99 (0.76–1.30) 0.95 (0.63–1.42) 1.07 (0.63–1.85) 1.04 (0.60–1.82) 1.78 (0.16–19.59) 0.59 (0.28–1.23) 0.67 (0.28–1.58) 0.33 (0.09–1.26) 0.78 (0.39–1.57) 0.88 (0.12–6.21) 0.44 (0.04–4.83) NA 1.33 (0.38–4.72) 1.05 (0.77–1.44)

0.97 0.79 0.79 0.88 0.63 0.15 0.35 0.09 0.49 0.89 0.49 0.35 0.65 0.74

27.3% (242) 21.3% (187) 8.4% (74) 5.6% (49) 3.0% (25) 7.2% (60) 3.2% (27) 4.1% (34) 11.6% (97) 6.5% (50) 4.1% (32) 1.0% (8) 2.3% (19) 10.9% (97)

28.4% (222) 22.8% (176) 7.0% (54) 4.5% (35) 2.6% (19) 9.3% (69) 4.7% (35) 5.6% (41) 15.0% (111) 6.4% (45) 4.8% (33) 1.0% (7) 1.6% (12) 10.2% (81)

0.96 (0.80–1.15) 0.93 (0.75–1.14) 1.21 (0.85–1.72) 1.24 (0.80–1.91) 1.16 (0.64–2.10) 0.76 (0.54–1.08) 0.68 (0.41–1.12) 0.73 (0.46–1.15) 0.76 (0.58–1.00) 0.98 (0.65–1.46) 0.85 (0.53–1.39) 1.01 (0.36–2.77) 1.41 (0.68–2.90) 1.06 (0.79–1.43)

0.64 0.47 0.28 0.33 0.63 0.12 0.13 0.17 0.048 0.92 0.53 0.99 0.35 0.68

9.9% (89) 4.4% (40) 3.7% (33) 4.7% (42) 8.3% (75) 0.7% (6)

11.4% (91) 3.3% (26) 5.4% (43) 4.8% (38) 10.0% (80) 0.5% (4)

0.87 (0.65–1.16) 1.37 (0.84–2.25) 0.68 (0.43–1.07) 0.98 (0.63–1.53) 0.83 (0.61–1.14) 1.33 (0.38–4.71)

0.34 0.21 0.09 0.94 0.24 0.66

11.7% (104) 5.7% (50) 4.5% (40) 4.9% (44) 9.3% (83) 0.9% (8)

12.6% (100) 4.5% (35) 6.2% (49) 5.2% (51) 11.1% (88) 0.8% (6)

0.92 (0.70–1.21) 1.27 (0.82–1.96) 0.72 (0.47–1.09) 0.95 (0.62–1.46) 0.83 (0.62–1.12) 1.18 (0.41–5.40)

0.54 0.28 0.12 0.83 0.23 0.76

4.3% (39)

5.0% (40)

0.87 (0.56–1.35)

0.53

5.5% (48)

6.0% (47)

0.90 (0.60–1.35)

0.62

Data are Kaplan-Meier estimates, displayed as percentage (number). * Any MACEs or major bleeding events, excluding those related to coronary artery bypass grafting. † Death, reinfarction, ischemic target vessel revascularization, or stroke. ARC ⫽ Academic Research Consortium; CI ⫽ confidence interval; HR ⫽ hazard ratio; NA ⫽ not available.

944

The American Journal of Cardiology (www.ajconline.org)

Figure 2. Three-year unadjusted time-to-event curves in patients treated with abciximab versus eptifibatide. (A) NACEs; (B) MACE; (C) protocol major bleeding (excluding events related to coronary artery bypass graft surgery).

patient and angiographic characteristics of the groups are listed in Table 1. Compared to patients treated with eptifibatide, those treated with abciximab were more likely female, with Killip class III or IV heart failure on presentation, with higher baseline rates of TIMI grade 0 or 1 flow, with lower baseline platelet counts, and with longer symptom-to-balloon times. Conversely, patients treated with eptifibatide had higher rates of previous PCI and coronary artery bypass grafting and use of femoral vascular access and closure device use. Immediate procedural revascularization success was high in the 2 groups, with TIMI grade 3 flow in the culprit vessel achieved in 92% of the abciximab group and 91% of the eptifibatide group (p ⫽ 0.60). The abciximab and eptifibatide treatment arms achieved similar rates of complete ST-segment resolution at 60 minutes (Table 2). Rates of postprocedural thrombocytopenia (platelet count ⬍100,000 cells/mm3), were 5.3% with abciximab versus 2.1% with eptifibatide (p ⫽ 0.0008). Unadjusted safety and efficacy outcomes according to GPI treatment were not significantly different at 30 days and 3 years (Table 3, Figure 2). There

were no significant differences in patient outcomes between the GPI groups when stratified by clopidogrel loading dose (Table 4). By multivariate analysis, there was no statistically significant difference between abciximab and eptifibatide treatment strategies for NACEs, MACEs, or major bleeding at 30 days and at 3 years (Table 5). A total of 1,342 matched cases (671 each in the abciximab and eptifibatide groups) were found. Similar to the univariate and multivariate results of the total study population, there was no statistically significant difference between the matched groups of abciximab and eptifibatide treatment with regard to MACEs, NACEs, or major bleeding (Table 6). Discussion This present study represents the largest comparison between abciximab and eptifibatide in the setting of primary PCI for ST-segment elevation myocardial infarction. The 2 agents resulted in comparable rates of angiographic and electrocardiographic reperfusion success. By univariate analysis, no sig-

Coronary Artery Disease/Abciximab Versus Eptifibatide in Primary PCI

945

Table 4 Three-year clinical outcomes stratified by clopidogrel loading dose Variable

NACEs* MACEs† Death Cardiac Noncardiac Reinfarction Q-wave Non-Q wave Death or reinfarction Stroke Target vessel revascularization Stent thrombosis (ARC definite or probable) Major bleeding (non– coronary artery bypass related)

Abciximab ⫹ Clopidogrel 300 mg (n ⫽ 346)

Eptifibatide ⫹ Clopidogrel 300 mg (n ⫽ 276)

HR (95% CI)

p Value for Interaction

Abciximab ⫹ Clopidogrel 600 mg (n ⫽ 612)

Eptifibatide ⫹ Clopidogrel 600 mg (n ⫽ 565)

HR (95% CI)

p Value for Interaction

28.3% (96) 22.2% (75) 8.0% (27) 5.9% (20) 2.2% (7) 6.6% (21) 2.8% (9) 3.8% (12) 13.7% (46) 2.8% (9) 11.6% (37)

33.4% (89) 25.4% (67) 7.6% (20) 4.5% (12) 3.2% (8) 11.6% (30) 5.8% (15) 6.3% (16) 16.7% (44) 1.1% (3) 16.8% (43)

0.83 (0.63–1.11) 0.88 (0.63–1.23) 1.08 (0.61–1.93) 1.34 (0.65–2.73) 0.70 (0.25–1.93) 0.55 (0.32–0.96) 0.48 (0.21–1.09) 0.59 (0.28–1.25) 0.82 (0.54–1.25) 2.42 (0.65–8.93) 0.68 (0.44–1.05)

0.22 0.45 0.79 0.43 0.49 0.03 0.07 0.16 0.36 0.17 0.09

26.1% (155) 20.1% (118) 8.7% (51) 5.5% (32) 3.4% (19) 7.3% (41) 3.2% (18) 4.3% (24) 14.3% (84) 2.1% (12) 10.8% (61)

26.1% (142) 21.6% (116) 6.5% (35) 4.2% (23) 2.4% (12) 8.3% (43) 4.0% (21) 5.5% (28) 14.1% (76) 1.9% (10) 13.8% (71)

1.01 (0.81–1.27) 0.92 (0.61–1.19) 1.34 (0.87–2.07) 1.29 (0.75–2.20) 1.45 (0.70–2.99) 0.87 (0.57–1.33) 0.78 (0.42–1.47) 0.78 (0.45–1.35) 1.01 (0.74–1.38) 1.11 (0.48–2.56) 0.78 (0.55–1.09)

0.92 0.52 0.18 0.35 0.31 0.52 0.45 0.38 0.95 0.81 0.15

4.2% (12)

7.4% (17)

0.56 (0.27–1.17)

0.12

5.5% (28)

5.0% (24)

1.07 (0.62–1.85)

0.80

10.9% (37)

13.3% (36)

0.81 (0.51–1.28)

0.37

10.7% (64)

8.7% (48)

1.25 (0.86–1.82)

0.24

Data are Kaplan-Meier estimates, displayed as percentage (number). * Any MACEs or major bleeding events, excluding those related to coronary artery bypass grafting. † Death, reinfarction, ischemic target vessel revascularization, or stroke. Abbreviations as in Table 3.

nificant differences were present between the 2 groups for NACEs, MACEs, and major bleeding. Given baseline differences between groups, multivariate analysis was performed on the entire study population as well as on a propensity-matched cohort. Despite multivariate adjustments, abciximab and eptifibatide yielded similar composite end points of NACEs, MACEs, and major bleeding at 30day and 3-year follow-up. Whether the inherent pharmacologic differences between abciximab and eptifibatide result in differences in clinical outcomes has been a subject of considerable interest. Abciximab is a monoclonal antibody Fab fragment that irreversibly binds to glycoprotein IIb/IIIa receptors with almost 1:1 stoichiometry, a short plasma half-life of ⬍30 minutes, and a disassociation halftime of 18 to 24 hours. These properties allow abciximab to inhibit platelet aggregation for several days after medication discontinuation, which may also lead to an increased risk for bleeding.6 Abciximab also demonstrates an affinity for other integrin receptors on endothelial cells and leukocytes and may thus possess antiinflammatory properties beyond platelet inhibition.7–9 Eptifibatide is a small-molecule peptide with highly specific inhibition of glycoprotein IIb/IIIa receptors in a reversible, dose-dependent fashion. Unlike abciximab, eptifibatide is a competitive inhibitor of the fibrinogen receptor and has a short half-life of about 2.5 hours, with normalization of platelet aggregation realized approximately 4 hours after drug cessation.10,11 The currently recommended dosing regimen of double bolus plus infusion has been reported to achieve ⬎90% inhibition of ex vivo platelet aggregation in ⬎90% of patients and prevents the decrease in platelet inhibition that may be seen 30 to 60 minutes after only a single bolus.12

There have been several clinical trials demonstrating reduced rates of death, myocardial infarction, and repeat revascularization in patients who undergo primary PCI with abciximab compared to placebo.13–15 Eptifibatide also has proved clinical benefit, although this agent has been mostly studied in patients with stable coronary artery disease who undergo PCI.16 Until recently, there were few direct comparisons between abciximab and eptifibatide in the setting of primary PCI. In the Eptifibatide Versus Abciximab in Primary PCI for Acute Myocardial Infarction (EVA-AMI) trial, 427 patients who underwent primary PCI were randomized to receive eptifibatide or abciximab with the primary outcome of ST-segment resolution.17 There was no statistically significant difference between the 2 agents in ST-segment resolution, and the study was not powered to compare clinical end points. Similar equipoise was found in 2 registries and in a meta-analysis comparing eptifibatide and abciximab.18 –20 In our study of 1,710 patients who underwent primary PCI with either abciximab or eptifibatide, the 2 agents resulted in similar rates of TIMI grade 3 flow. As in the EVA-AMI trial, we also observed comparable rates of ST-segment resolution between the 2 agents. GPI type was not predictive of different rates of stent thrombosis at any time point after PCI,21 although there was a statistically significant difference in 3-year target vessel revascularization rates between abciximab and eptifibatide. Late clinical benefits secondary to GPI agents in the setting of acute coronary syndromes have been linked to the passivation of clinical plaque, especially with abciximab.22 However, the reason for this difference between the 2 GPIs is not clear from the present study and should be interpreted with caution. After multivariate analysis, patients treated with abciximab or eptifibatide had statis-

946

The American Journal of Cardiology (www.ajconline.org)

Table 5 Independent predictors of clinical events in the full patient cohort Variable 30-day events Major bleeding Abciximab (vs eptifibatide) Male gender Age (10-year increase) Killip class II–IV Femoral (vs radial) access MACEs* Abciximab (vs eptifibatide) Diabetes mellitus Age (10-year increase) NACEs† Abciximab (vs eptifibatide) Male gender Baseline creatinine clearance‡ Baseline anemia§ Killip class II–IV Symptom-to-balloon time 3-year events Major bleeding Abciximab (vs eptifibatide) Male gender Age (10-year increase) Killip class II–IV Femoral (vs radial) access MACEs Abciximab (vs eptifibatide) Age (10-year increase) Diabetes mellitus Prior congestive heart failure Prior PCI Current smoker Baseline anemia§ Killip class II–IV Left anterior descending coronary artery Femoral (vs radial) access NACEs Abciximab (vs eptifibatide) Prior congestive heart failure Baseline creatinine clearance‡ Baseline anemia§ Clopidogrel 600 vs 300 mg Killip class II–IV Left anterior descending artery Femoral (vs radial) access Symptom-to-balloon time

HR

95% CI

p Value

Table 6 Independent predictors of clinical events in the propensity-matched groups Variable

1.03 0.61 1.24 1.65 2.57

0.75–1.42 0.43–0.85 1.08–1.43 1.04–2.60 0.95–6.99

0.84 0.004 0.003 0.03 0.06

0.94 1.98 1.40

0.63–1.42 1.27–3.08 1.17–1.68

0.78 0.003 ⬍0.0001

0.87 0.59 0.99 1.49 2.04 1.03

0.65–1.18 0.43–0.81 0.99–1.00 1.00–2.23 1.36–3.04 1.02–1.05

0.37 0.001 0.001 0.05 0.001 ⬍0.0001

1.05 0.64 1.31 1.54 2.96

0.78–1.41 0.47–0.89 1.15–1.50 1.00–2.38 1.09–8.02

0.75 0.007 ⬍0.0001 0.05 0.03

0.96 1.30 1.31 1.56 1.52 1.48 1.41 1.84 1.44

0.77–1.20 1.17–1.45 1.01–1.70 0.99–2.44 1.13–2.04 1.16–1.89 1.04–1.90 1.36–2.51 1.11–1.87

0.73 ⬍0.0001 0.04 0.05 0.006 0.002 0.03 ⬍0.0001 0.007

2.07

1.13–3.79

0.02

0.89 2.12 0.99 1.55 0.82 1.64 1.24 2.27 1.03

0.73–1.09 1.39–3.24 0.99–1.00 1.18–2.05 0.67–1.02 1.21–2.22 0.98–1.83 1.23–4.18 1.02–1.04

0.27 0.001 ⬍0.0001 0.002 0.07 0.16 0.12 0.009 ⬍0.0001

Data are Kaplan-Meier estimates, displayed as percentage (number). * Death, reinfarction, ischemic target vessel revascularization, or stroke. Abbreviations as in Table 3. † Any MACEs or major bleeding events, excluding those related to coronary artery bypass grafting. ‡ Creatinine clearance was calculated using the Cockcroft-Gault formula. § Baseline anemia was defined as hematocrit ⬍39% for men and ⬍36% for women. Abbreviations as in Table 3.

tically similar ischemic and bleeding end points at 30 days and 3 years. As the largest comparison of GPIs in ST-segment elevation myocardial infarction, drawn from a prospective ran-

3-year events Major bleeding Abciximab (vs eptifibatide) Male gender Age (10-year increase) MACEs* Abciximab (vs eptifibatide) Age (10-year increase) Diabetes mellitus Hypertension† Previous congestive heart failure Previous PCI Current smoker Killip class II–IV Left anterior descending coronary artery Symptom-to-balloon time NACEs‡ Abciximab (vs eptifibatide) Age (10-year increase) Diabetes mellitus Previous congestive heart failure Current smoker Baseline creatinine clearance§ Baseline anemia储 Clopidogrel 600 vs 300 mg Killip class II–IV Femoral (vs radial) access Symptom-to-balloon time

HR

95% CI

p Value

1.06 0.54 1.22

0.77–1.47 0.38–0.78 1.05–1.41

0.72 0.001 0.008

0.91 1.29 1.40 1.24 1.56 1.49 1.48 1.65 1.45

0.72–1.15 1.15–1.45 1.06–1.86 0.96–1.59 0.93–2.62 1.07–2.07 1.14–1.92 1.17–2.32 1.10–1.91

0.44 ⬍0.0001 0.02 0.09 0.09 0.02 0.003 0.004 0.009

1.00

1.00–1.00

0.07

0.88 1.14 1.33 2.19 1.31 0.99 1.46 0.82 1.42 5.56 1.03

0.71–1.09 0.99–1.30 1.01–1.73 1.37–3.52 1.03–1.67 0.99–1.00 1.09–1.97 0.66–1.03 1.02–1.97 0.78–39.62 1.02–1.05

0.25 0.06 0.04 0.001 0.03 ⬍0.0001 0.01 0.09 0.04 0.09 ⬍0.0001

Data are Kaplan-Meier estimates, displayed as percentage (number). * Death, reinfarction, ischemic target vessel revascularization, or stroke. Abbreviations as in Table 3. † Defined as per patient report or medical chart review documentation of history of systemic arterial hypertension or current diagnosis. ‡ Any MACEs or major bleeding events, excluding those related to coronary artery bypass grafting. § Creatinine clearance was calculated using the Cockcroft-Gault formula. 储 Baseline anemia was defined as hematocrit ⬍39% for mend and 36% for women. Abbreviations as in Table 3.

domized trial with careful data monitoring and independent core laboratories, and with the longest follow-up yet reported, the present study has several strengths. The major study limitation is that the choice of GPI was allocated by institutional choice rather than through randomization. We performed multivariate analysis using Cox proportional hazards on the entire study population as well as a propensity score–matched cohort to better confirm the validity of our findings. Although institution-based GPI selection likely led to less bias than had GPI selection been made by individual operators in individual patients after viewing their coronary anatomy, some baseline differences were present between the 2 groups, and unmeasured confounders may persist despite multivariate correction for these differences. 1. Stone GW, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D, Kornowski R, Hartmann F, Gersh BJ, Pocock SJ, Dangas G,

Coronary Artery Disease/Abciximab Versus Eptifibatide in Primary PCI

2. 3.

4.

5.

6. 7.

8.

9.

10.

11. 12. 13.

Wong SC, Kirtane AJ, Parise H, Mehran R. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358:2218 – 2230. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329:673– 682. Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, Dodge HT, Francis CK, Hillis D, Ludbrook P. Thrombolysis in Myocardial Infarction (TIMI) trial, phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge. Circulation 1987;76:142– 154. Popma J, Almonacid A, Lansky A. Qualitative and quantitative coronary angiography. In: Topol EJ, ed. Textbook of Interventional Cardiology. Philadelphia, Pennsylvania: W. B. Saunders, 2008:1071– 1093. Forest RS, Shofer FS, Sease KL, Hollander JE. Assessment of the standardized reporting guidelines ECG classification system: the presenting ECG predicts 30-day outcomes. Ann Emerg Med 2004;44: 206 –212. Ibbotson T, McGavin JK, Goa KL. Abciximab: an updated review of its therapeutic use in patients with ischaemic heart disease undergoing percutaneous coronary revascularisation. Drugs 2003;63:1121–1163. Tam SH, Sassoli PM, Jordan RE, Nakada MT. 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. Neumann FJ, Zohlnhofer D, Fakhoury L, Ott I, Gawaz M, Schomig A. Effect of glycoprotein IIb/IIIa receptor blockade on platelet-leukocyte interaction and surface expression of the leukocyte integrin Mac-1 in acute myocardial infarction. J Am Coll Cardiol 1999;34:1420 –1426. Lincoff AM, Kereiakes DJ, Mascelli MA, Deckelbaum LI, Barnathan ES, Patel KK, Frederick B, Nakada MT, Topol EJ. Abciximab suppresses the rise in levels of circulating inflammatory markers after percutaneous coronary revascularization. Circulation 2001;104:163– 167. Tardiff BE, Jennings LK, Harrington RA, Gretler D, Potthoff RF, Vorchheimer DA, Eisenberg PR, Lincoff AM, Labinaz M, Joseph DM, McDougal MF, Kleiman NS. Pharmacodynamics and pharmacokinetics of eptifibatide in patients with acute coronary syndromes: prospective analysis from PURSUIT. Circulation 2001;104:399 – 405. Schror K, Weber AA. Comparative pharmacology of GP IIb/IIIa antagonists. J Thromb Thrombolysis 2003;15:71– 80. Flaherty ML, Kissela B, Broderick JP. ESPRIT trial. Lancet 2006;368: 448. Stone GW, Grines CL, Cox DA, Garcia E, Tcheng JE, Griffin JJ, Guagliumi G, Stuckey T, Turco M, Carroll JD, Rutherford BD, Lansky

14.

15.

16.

17.

18.

19.

20.

21.

22.

947

AJ. Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction. N Engl J Med 2002;346: 957–966. Montalescot G, Barragan P, Wittenberg O, Ecollan P, Elhadad S, Villain P, Boulenc JM, Morice MC, Maillard L, Pansieri M, Choussat R, Pinton P. Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. N Engl J Med 2001;344: 1895–1903. Brener SJ, Barr LA, Burchenal JE, Katz S, George BS, Jones AA, Cohen ED, Gainey PC, White HJ, Cheek HB, Moses JW, Moliterno DJ, Effron MB, Topol EJ; 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. The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 1998;339:436 – 443. Zeymer U, Margenet A, Haude M, Bode C, Lablanche JM, Heuer H, Schroder R, Kropff S, Bourkaib R, Banik N, Zahn R, Teiger E. Randomized comparison of eptifibatide versus abciximab in primary percutaneous coronary intervention in patients with acute ST-segment elevation myocardial infarction: results of the EVA-AMI trial. J Am Coll Cardiol 2010;56:463– 469. Akerblom A, James SK, Koutouzis M, Lagerqvist B, Stenestrand U, Svennblad B, Oldgren J. Eptifibatide is noninferior to abciximab in primary percutaneous coronary intervention: results from the SCAAR (Swedish Coronary Angiography and Angioplasty Registry). J Am Coll Cardiol 2010;56:470 – 475. Ottani F, La Vecchia L, De Vita M, Catapano O, Tarantino F, Galvani M. Comparison by meta-analysis of eptifibatide and tirofiban to abciximab in patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention. Am J Cardiol 2010; 106:167–174. Raveendran G, Ting HH, Best PJ, Holmes DR Jr, Lennon RJ, Singh M, Bell MR, Long KH, Rihal CS. Eptifibatide vs abciximab as adjunctive therapy during primary percutaneous coronary intervention for acute myocardial infarction. Mayo Clin Proc 2007;82:196 –202. Dangas GD, Caixeta A, Mehran R, Parise H, Lansky AJ, Cristea E, Brodie BR, Witzenbichler B, Guagliumi G, Peruga JZ, Dudek D, Moeckel M, Stone GW. Frequency and predictors of stent thrombosis after percutaneous coronary intervention in acute myocardial infarction. Circulation 2011;123:1745–1756. Monroe VS, Kerensky RA, Rivera E, Smith KM, Pepine CJ. Pharmacologic plaque passivation for the reduction of recurrent cardiac events in acute coronary syndromes. J Am Coll Cardiol 2003;41:23S–30S.