Primary Percutaneous Coronary Angioplasty With and Without Eptifibatide in ST-Segment Elevation Myocardial Infarction: A Safety and Efficacy Study of Integrilin-Facilitated Versus Primary Percutaneous Coronary Intervention in ST-Segment Elevation Myocardial Infarction (ASSIST)
2009; Lippincott Williams & Wilkins; Volume: 2; Issue: 4 Linguagem: Inglês
10.1161/circinterventions.108.847582
ISSN1941-7632
AutoresM. R. Le May, G. A. Wells, Christopher Glover, Derek So, Michael Froeschl, J.-F. Marquis, Edward R. O’Brien, M. Turek, A. Thomas, M. Kass, S. Jadhav, Marino Labinaz,
Tópico(s)Acute Myocardial Infarction Research
ResumoHomeCirculation: Cardiovascular InterventionsVol. 2, No. 4Primary Percutaneous Coronary Angioplasty With and Without Eptifibatide in ST-Segment Elevation Myocardial Infarction Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessResearch ArticlePDF/EPUBPrimary Percutaneous Coronary Angioplasty With and Without Eptifibatide in ST-Segment Elevation Myocardial InfarctionA Safety and Efficacy Study of Integrilin-Facilitated Versus Primary Percutaneous Coronary Intervention in ST-Segment Elevation Myocardial Infarction (ASSIST) Michel R. Le May, MD, George A. Wells, PhD, Chris A. Glover, MD, Derek Y. So, MD, Michael Froeschl, MD, Jean-François Marquis, MD, Edward R. O'Brien, MD, Michele Turek, MD, Allyson Thomas, RN, Malek Kass, MD, Sachin Jadhav, MD and Marino Labinaz, MD Michel R. Le MayMichel R. Le May From the University of Ottawa Heart Institute, Division of Cardiology, Ottawa, Ontario, Canada. Search for more papers by this author , George A. WellsGeorge A. Wells From the University of Ottawa Heart Institute, Division of Cardiology, Ottawa, Ontario, Canada. Search for more papers by this author , Chris A. GloverChris A. Glover From the University of Ottawa Heart Institute, Division of Cardiology, Ottawa, Ontario, Canada. Search for more papers by this author , Derek Y. SoDerek Y. So From the University of Ottawa Heart Institute, Division of Cardiology, Ottawa, Ontario, Canada. Search for more papers by this author , Michael FroeschlMichael Froeschl From the University of Ottawa Heart Institute, Division of Cardiology, Ottawa, Ontario, Canada. Search for more papers by this author , Jean-François MarquisJean-François Marquis From the University of Ottawa Heart Institute, Division of Cardiology, Ottawa, Ontario, Canada. Search for more papers by this author , Edward R. O'BrienEdward R. O'Brien From the University of Ottawa Heart Institute, Division of Cardiology, Ottawa, Ontario, Canada. Search for more papers by this author , Michele TurekMichele Turek From the University of Ottawa Heart Institute, Division of Cardiology, Ottawa, Ontario, Canada. Search for more papers by this author , Allyson ThomasAllyson Thomas From the University of Ottawa Heart Institute, Division of Cardiology, Ottawa, Ontario, Canada. Search for more papers by this author , Malek KassMalek Kass From the University of Ottawa Heart Institute, Division of Cardiology, Ottawa, Ontario, Canada. Search for more papers by this author , Sachin JadhavSachin Jadhav From the University of Ottawa Heart Institute, Division of Cardiology, Ottawa, Ontario, Canada. Search for more papers by this author and Marino LabinazMarino Labinaz From the University of Ottawa Heart Institute, Division of Cardiology, Ottawa, Ontario, Canada. Search for more papers by this author Originally published22 Jul 2009https://doi.org/10.1161/CIRCINTERVENTIONS.108.847582.108.847582Circulation: Cardiovascular Interventions. 2009;2:330–338Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2009: Previous Version 1 AbstractBackground— Primary percutaneous coronary intervention, if performed promptly, is the preferred strategy to restore flow to the infarct-related artery in patients with ST-segment elevation myocardial infarction. We sought to determine whether eptifibatide, a platelet glycoprotein IIb/IIIa inhibitor, given before catheterization would improve clinical outcomes in patients referred for primary percutaneous coronary intervention.Methods and Results— We randomly assigned a total of 400 patients with ST-segment elevation myocardial infarction referred for primary percutaneous coronary intervention to treatment initiated before cardiac catheterization, with either heparin plus eptifibatide (201 patients) or heparin alone (199 patients), in addition to oral aspirin (160 mg) and high-dose clopidogrel (600 mg). The primary end point was a composite of death from any cause, recurrent myocardial infarction, or recurrent severe ischemia during the first 30 days after randomization. At 30 days, the primary end point was reached by 13 patients (6.47%) assigned to heparin plus eptifibatide and by 11 patients (5.53%) assigned to heparin alone (relative risk, 1.18; 95% CI, 0.52 to 2.70; P=0.69). The rates of major or minor bleeding were higher in patients assigned to heparin plus eptifibatide than that in patients assigned to heparin alone (22.4% versus 14.6%; relative risk, 1.69; 95% CI, 1.01 to 2.83; P=0.04).Conclusions— In patients pretreated with high-dose clopidogrel who were referred for primary PCI, treatment with heparin plus eptifibatide, when compared with heparin alone, did not improve clinical outcomes and was associated with more bleeding complications.Activated platelets play a major role in the cascade of events leading to ST-segment elevation myocardial infarction (STEMI). Hence, antiplatelet therapy has become an important adjunct in the management of STEMI.1–4 This is particularly relevant for patients undergoing primary percutaneous coronary intervention (PCI), where antiplatelet therapy may prevent thrombotic reocclusion of the infarct-related artery.Clinical Perspective on p 330Trials have shown that abciximab, a monoclonal antibody that inhibits the platelet glycoprotein IIb/IIIa receptor, reduces major cardiac adverse events in patients treated with primary PCI.5–9 In 2 of these trials, benefits at long-term were sustained.10,11 Furthermore, a systematic overview of randomized trials reported that adjunctive treatment with abciximab improved survival at six months.12The evidence supporting the use of small-molecule glycoprotein IIb/IIIa inhibitors, such as eptifibatide, in patients with STEMI remains limited. Observational studies suggest that eptifibatide used during primary PCI yields clinical benefits similar to abciximab.13–15 Compared with abciximab, eptifibatide is significantly cheaper.13 One randomized trial concluded that in the setting of primary PCI, initiation of eptifibatide in the emergency department compared with that in the catheterization laboratory was safe and associated with superior angiographic results.16 Given the common mode of action of platelet glycoprotein IIb/IIIa inhibitors, and the clinical experience to date, the current guidelines support the use of small-molecule glycoprotein IIb/IIIa inhibitors, such as eptifibatide or tirofiban, during primary PCI, with a class IIb recommendation.17,18In patients with non-STEMI, the addition of the P2Y12 platelet receptor antagonist clopidogrel to aspirin before PCI improves early and late clinical outcomes.19 Although there are limited data on the benefits of pretreatment with clopidogrel in the setting of acute PCI for STEMI, it had become practice in many institutions, including our own, to prescribe 600 mg of clopidogrel before the intervention. We, therefore, designed this study to assess the safety and efficacy of eptifibatide in patients referred for primary PCI who received a high-loading dose (600 mg) of clopidogrel at the time of hospital presentation.MethodsTrialA Safety and Efficacy Study of Integrilin-Facilitated PCI Versus Primary PCI in ST-Elevation Myocardial Infarction (ASSIST) was a prospective, randomized trial that compared treatment with heparin plus eptifibatide to heparin alone in patients referred for primary PCI. The study was conducted in 3 Ottawa hospitals, with the interventional facility located at the University of Ottawa Heart Institute.Patient SelectionPatients were eligible for enrollment if they presented within 12 hours of the onset of ischemic chest discomfort of at least 30 minutes duration and having ≥1 mm (0.1 mV) ST-elevation in 2 or more contiguous leads on a standard 12-lead ECG or left bundle branch block not known to be old. Exclusion criteria were active bleeding, stroke within 90 days, intracranial bleeding at any time, major surgery or trauma within 6 weeks, systolic blood pressure >200 mm Hg or diastolic blood pressure >110 mm Hg, prolonged cardiopulmonary resuscitation, PCI within 30 days, fibrinolytic agents within 7 days, any glycoprotein IIb/IIIa inhibitors within 7 days, low-molecular-weight heparin within 12 hours, coagulation disorder, current warfarin treatment, intolerance to aspirin or clopidogrel, other illness likely to result in death within 12 months, pregnancy, creatinine >200 μmol/L, cardiogenic shock, and severe contrast allergy. The protocol was approved by the institutional review board at each hospital, and all patients provided informed consent.Study DesignAll patients received 160 mg of chewable aspirin, 600 mg of oral clopidogrel, and 60 U/kg of intravenous unfractionated heparin to a maximum dose of 4000 U, before catheterization. Patients were randomly assigned in a 1:1 ratio to PCI with heparin plus eptifibatide or to PCI with heparin alone, in blocks of 10 at each site. Immediately after randomization, patients assigned to the eptifibatide group received open-label drug, 180 μg/kg of body weight bolus, followed by a continuous infusion of 2.0 μg/kg per minute with a second bolus of 180 μg/kg administered 10 minutes after the first bolus. The infusion was reduced to 1.0 μg/kg per minute in patients with a creatinine clearance of 250 s in patients assigned to heparin alone. The use of glycoprotein IIb/IIIa inhibitors in patients assigned to PCI with heparin alone was strongly discouraged but could be considered for “bailout” at the discretion of the operator, ie, large residual thrombus, Thrombolysis in Myocardial Infarction (TIMI)21 grade flow 0.05 mV measured 80 ms after the J-point in at least 2 contiguous leads), (2) an episode of acute pulmonary edema, sustained ventricular arrhythmia, or hemodynamic instability, (3) the need for urgent revascularization within 30 days, or (4) recurrent myocardial infarction.Secondary end points included stroke, congestive heart failure, and cardiogenic shock. Episodes of bleeding were classified by an independent adjudicator as major or minor according to the TIMI criteria.24 A blinded, off-site, independent Clinical Event Committee (Cathy McLellan, chair, Waitak Kong, and Paul Malik, Queen’s University, Kingston, Ontario, Canada) adjudicated all possible events related to the primary outcome. An independent Data Safety Monitoring Committee (Jean-Claude Tardif, chair, and Philippe L’Allier, Montreal Heart Institute, Montréal, Quebec, Canada) reviewed the data at regular intervals.Statistical AnalysisBased on previous studies,7,25 the incidence of the primary end point at 30 days in the group of patients assigned to heparin alone was estimated at 15% and in the group of patients assigned to heparin plus eptifibatide at 5%. In calculating sample size, we did not include studies where glycoprotein IIb/IIIa inhibitors were initiated in the catheterization laboratory, because less benefit was suggested from the available data. The sample size to detect a difference between 15% and 5.0%, with a level of significance of 0.05 and 90% power using a χ2 test, was determined to be 187 patients per group. With an anticipated loss to follow-up rate of 5%, the minimum number of patients required was 200 per group.All analyses on the primary end point and its components were performed on an intention-to-treat basis. Categorical variables were compared by Fisher exact test. Normally distributed continuous variables were compared by Student t test. Time intervals were analyzed with the Mann–Whitney U test. Analyses were conducted using SAS version 9.13 (SAS Institute Inc, Cary, NC). Time to the occurrence of primary outcome in each treatment group was described using Kaplan–Meier curves, and the groups were compared using the log-rank test. A P value ≤0.05 was considered statistically significant.ResultsPatientsBetween August 2005 and March 2008, a total of 400 patients referred for primary PCI were randomly assigned to heparin plus eptifibatide (n=201) or to heparin alone (n=199; Figure 1). The baseline characteristics of the patients were similar between the 2 groups (Table 1). The proportion of high-risk patients defined by the TIMI investigators26 (age >70 years, anterior myocardial infarction, or history of previous myocardial infarction) was 56.7% in patients assigned to heparin plus eptifibatide and 64.8% in patients assigned to heparin alone (P=0.10). Data on end points at 30-day follow-up were available for all patients and data for the 6-month follow-up were available for all patients assigned to heparin plus eptifibatide and for 99.0% of patients assigned to heparin alone. Download figureDownload PowerPointFigure 1. Trial profile.Table 1. Baseline Characteristics of the PatientsCharacteristicHeparin Plus Eptifibatide (n=201)Heparin Alone (n=199)Data are presented as mean�SD, n (%), or median (interquartile range). CK indicates creatine kinase.Age, y60.4�12.160.6�11.8Male sex162 (80.6)143 (71.9)Hypertension92 (45.8)99 (49.8)Diabetes mellitus29 (14.4)36 (18.1)Current smoker90 (44.8)76 (38.2)Hyperlipidimia67 (33.3)77 (38.7)Prior MI21 (10.5)27 (13.6)Prior angioplasty16 (8.0)16 (8.0)Prior bypass surgery10 (5.0)8 (4.0)Anterior MI73 (36.3)75 (37.7)Heart rate, bpm74�1676�18Systolic blood pressure, mm Hg130�23134�24Diastolic blood pressure, mm Hg77�1480�15Killip class I182 (90.6)172 (86.4) II19 (9.5)27 (13.6) III or IV0 (0.0)0 (0.0)Body mass index, kg/m228.4�4.927.5�4.6Eptifibatide started before initial catheterization189 (94.0)0Baseline creatinine clearance, mL/min93.3�35.287.3�31.1Peak CK, U/L2009�18792047�1628No. diseased vessels Left main1 (0.5)1 (0.5) 1 vessel98 (48.8)92 (46.2) 2 vessel62 (30.9)57 (28.6) 3 vessel39 (19.4)49 (24.6) None significant1 (0.5)0 (0.0)Infarct-related artery Left main coronary1 (0.5)1 (0.5) Left anterior descending72 (35.8)74 (37.2) Left circumflex29 (14.4)23 (11.6) Right coronary92 (45.8)95 (47.7) Bypass graft7 (3.5)2 (1.0) Unknown0 (0.0)4 (2.0)Time intervals, min Symptom onset to hospital arrival90 (46 to 148)88 (55 to 76) Hospital arrival to randomization46 (13 to 80)31 (13 to 74) Randomization to first balloon inflation48 (37 to 67)50 (35 to 64) Clopidogrel to first balloon inflation75 (55 to 93)75 (55 to 99) Eptifibatide first bolus to first balloon inflation43 (26 to 56)… Hospital arrival to first balloon inflation96 (72 to 130)95 (67 to 122) Symptom onset to first balloon inflation196 (148 to 269)194 (142 to 284) Symptom onset to eptifibatide first bolus144 (105 to 230)…Initial Treatment ReceivedAll patients received aspirin, clopidogrel, and heparin before catheterization. Eptifibatide was administered to all patients assigned to heparin plus eptifibatide; the first bolus was given before catheterization in 94.0%, and the duration of infusion averaged 16.2�5.0 hours after the procedure. In patients assigned to heparin alone, 9 patients (4.5%) were given abciximab and 6 patients (3.0%) were given eptifibatide during PCI.Angiographic and Procedural ResultsThe results of the angiographic procedure are given in Table 2. After coronary angiography, PCI was performed in 190 patients (94.5%) assigned to heparin plus eptifibatide and in 184 patients (92.4%) assigned to heparin alone. There was no difference in the initial TIMI flow grade between the 2 groups. After PCI, TIMI flow grade 3 was achieved in 93.5% of patients assigned to heparin plus eptifibatide and in 91.5% of patients assigned to heparin alone (P=0.33). Seven patients (3.6%) in the eptifibatide group and 3 patients (1.5%) in the heparin-alone group were treated with bypass surgery within 24 hours of admission, and 1 patient in the eptifibatide group required emergency bypass surgery because primary PCI failed. Table 2. Procedural Results of Initial CatheterizationVariableHeparin Plus Eptifibatide (n=201)PCI Alone (n=199)PData are presented as mean�SD or n (%).Coronary angiography performed201 (100)199 (100)1.0Access site: femoral175 (87.1)174 (87.4)0.91Initial diameter stenosis, %97.6�5.797.0�5.70.31Initial TIMI flow0.16 Grade 0 or 1111 (55.2)126 (63.3) Grade 239 (19.4)26 (13.1) Grade 351 (25.4)47 (23.6)Preprocedure-corrected TIMI frame count, s76.3�32.679.7�31.20.30Preprocedure myocardial blush0.27 Grade 0 or 1140 (73.3)143 (76.5) Grade 218 (9.4)22 (11.8) Grade 333 (17.3)22 (11.8)PCI performed190 (94.5)184 (92.5)0.40Stent insertion187 (93.0)183 (92.0)0.68Stents per patient1.4�0.91.5�0.90.35Drug-eluting stent38 (18.9)31 (15.6)0.38Use of aspiration catheter21 (10.5)14 (7.0)0.22Intra-aortic balloon pump4 (2.0)4 (2.0)1.00PCI final balloon size, mm3.2�0.5 (n=190)3.2�0.5 (n=184)0.93PCI maximal balloon pressure, atm17.1�2.8 (n=187)17.1�2.8 (n=182)0.93Final diameter stenosis, %9.4�28.311.5�31.00.49Postprocedure TIMI flow0.43 Grade 0 or 15 (2.5)10 (5.0) Grade 28 (4.0)7 (3.5) Grade 3188 (93.5)182 (91.5)Postprocedure corrected TIMI frame count, s24.3�15.726.0�21.90.37Postprocedure myocardial blush0.56 Grade 0 or 132 (17.1)33 (17.8) Grade 229 (15.5)36 (19.5) Grade 3126 (67.4)116 (62.7)Clinical ResultsAt 30 days, the primary end point—the composite of death from any cause, recurrent myocardial infarction, or recurrent severe ischemia—was reached by 13 patients (6.47%) in the heparin plus eptifibatide group and 11 patients (5.53%) in the heparin-alone group (relative risk, 1.18; 95% CI, 0.52 to 2.70; P=0.69; Table 3). Similarly, at 6 months, there was no difference in the incidence of the primary end point between the 2 groups: 7.96% versus 7.11%, respectively, (relative risk, 1.13; 95% CI, 0.54 to 2.38; P=0.75). The Kaplan–Meier curves of the cumulative incidence of the primary end point at 30 days and at 6 months are shown in Figure 2. Post hoc analysis according to clinical, angiographic, and time-to-treatment variables did not show any differences in the risk ratios for the incidence of the primary end point at 30 days among subgroups (Figure 3). Table 3. Clinical EventsOutcomesHeparin Plus Eptifibatide (n=201)Heparin Alone (n=199)PRelative Risk (95% CI)Data are presented as n (%). CABG indicates coronary artery bypass grafting.*All events presented as chest discomfort with dynamic ECG changes and none as acute pulmonary edema, sustained ventricular arrhythmia, or hemodynamic instability.†Repeat PCI of infarct-related artery or CABG after PCI.Randomization to 30 d Death7 (3.5)4 (2.0)0.541.76 (0.51 to 6.11) Reinfarction3 (1.5)1 (0.5)0.623.00 (0.31 to 29.09) Death or reinfarction10 (5.0)5 (2.5)0.192.03 (0.68 to 6.05) Severe recurrent ischemia*6 (3.0)7 (3.5)0.760.84 (0.28 to 2.56) Death, reinfarction, or severe recurrent ischemia13 (6.5)11 (5.5)0.691.18 (0.52 to 2.70) Congestive heart failure15 (7.5)22 (11.1)0.220.65 (0.33 to 1.29) Cardiogenic shock8 (4.0)6 (3.0)0.601.33 (0.45 to 3.92) Stroke0 (0.0)1 (0.5)0.50(n=196)(n=195)Randomization to 6 months Death9 (4.6)6 (3.1)0.441.52 (0.53 to 4.34) Reinfarction4 (2.0)2 (1.0)0.692.01 (0.36 to 11.11) Death or reinfarction13 (6.6)7 (3.6)0.171.91 (0.74 to 4.89) Severe recurrent ischemia*9 (4.5)9 (4.6)0.970.98 (0.38 to 2.52) Death, reinfarction, or severe recurrent ischemia16 (8.0)14 (7.1)0.751.13 (0.54 to 2.38) Congestive heart failure15 (7.7)24 (12.3)0.120.59 (0.30 to 1.16) Cardiogenic shock8 (4.1)9 (4.6)0.800.88 (0.33 to 2.33) Stroke0 (0.0)4 (2.0)0.06Revascularizations at 30 d CABG10 (5.0)6 (3.0)0.321.68 (0.60 to 4.73) Repeat PCI of infarct-related artery5 (2.5)2 (1.0)0.452.51 (0.48 to 13.11) Repeat target vessel revascularization†8 (4.0)4 (2.0)0.381.76 (0.51 to 6.11)At 6 months CABG10 (5.0)8 (4.0)0.651.25 (0.48 to 3.24) Repeat PCI infarct-related artery6 (3.0)3 (1.5)0.502.01 (0.50 to 8.15) Repeat target vessel revascularization†8 (4.0)6 (3.0)0.601.33 (0.45 to 3.92)TIMI bleeding in hospital (initial) Major bleeding19 (9.5)11 (5.5)0.141.78 (0.83 to 3.85) Major bleeding, non-CABG related11 (5.5)5 (2.5)0.202.25 (0.77 to 6.59) Minor bleeding26 (12.9)18 (9.1)0.211.49 (0.79 to 2.82) Minor bleeding, non-CABG related25 (12.4)18 (9.1)0.271.43 (0.75 to 2.71) Major or minor bleeding45 (22.4)29 (14.6)0.041.69 (1.01 to 2.83) Major or minor bleeding, non-CABG related36 (17.9)23 (11.6)0.071.67 (0.95 to 2.94) Blood transfusion15 (7.5)9 (4.5)0.221.70 (0.73 to 3.99) Thrombocytopenia ( 0.05 for all subgroups.The rates of stroke, congestive heart failure, and cardiogenic shock did not differ between the 2 groups at 30 days and at 6 months (Table 3). Subsequent need for revascularization did not differ between the 2 groups. There was no difference between the 2 groups in the cardiac medications prescribed at hospital discharge and at 6 months (Table 4). Table 4. Cardiac MedicationsHeparin Plus Eptifibatide (n=201)PCI Alone (n=199)PData are presented as n (%).Medications at dischargen=198n=196 Aspirin192 (97.0)193 (98.5)0.50 Clopidogrel186 (93.9)189 (96.4)0.25 β-blockers184 (92.9)184 (93.9)0.70 Angiotensin converting enzyme inhibitors173 (87.4)173 (88.3)0.79 Angiotensinogen receptor blockers2 (1.0)2 (1.0)1.00 Statins188 (95.0)191 (97.5)0.19Medications at 6 monthsn=187n=189 Aspirin183 (97.9)185 (97.9)1.00 Clopidogrel173 (92.5)177 (94.2)0.53 β-blockers160 (85.6)171 (90.5)0.14 Angiotensin-converting enzyme inhibitors160 (85.6)159 (84.1)0.70 Angiotensinogen receptor blockers2 (1.1)4 (2.1)0.69 Statins181 (96.8)183 (96.8)1.00BleedingDuring the initial hospitalization, when compared with patients assigned to heparin alone, the rates of TIMI bleeding (major or minor) were significantly higher in the patients assigned to heparin plus eptifibatide, 22.4% versus 14.6% (relative risk, 1.69; 95% CI, 1.01 to 2.83; P=0.04). Two patients treated with dual antiplatelet therapy plus warfarin in the heparin-alone group experienced nonfatal intracranial hemorrhage after hospital discharge.DiscussionThe principal finding of our trial is that in patients pretreated with high-dose clopidogrel and referred for primary PCI, treatment with heparin plus eptifibatide, when compared with heparin alone, did not improve clinical outcomes. Furthermore, the incidence of bleeding was higher in patients assigned to heparin plus eptifibatide.The ASSIST trial is the first to report on the use of eptifibatide in patients with STEMI pretreated with a 600-mg loading dose of clopidogrel before cardiac catheterization. Two other randomized trials that assessed the benefits of a glycoprotein IIb/IIIa inhibitors in this setting.27,28 The Bavarian Reperfusion AlternatiVes Evaluation 3 study examined the effect of abciximab versus placebo and found no difference in infarct size between groups as measured by MRI and no difference in death, reinfarction, target vessel revascularization, or stroke at 30 days.27 The Ongoing Tirofiban In Myocardial infarction Evaluation 2 study reported that early administration of tirofiban was associated with improved ST-segment resolution but did not reduce the composite of death, reinfarction, or target vessel revascularization at 30 days nor have an impact on final TIMI perfusion grade or myocardial blush scores.28Five randomized trials have shown that abciximab improves clinical outcomes in patients treated with primary PCI.5–9 However, patients enrolled in these trials were not pretreated with high-dose thienopyridines before catheterization, and many did not receive a thienopyridine until after the procedure. Current data on the pharmacokinetics of clopidogrel in the context of STEMI remain limited. The bioavailability of clopidogrel may be restricted in these patients.29 Studies that excluded patients with STEMI have shown that pretreatment with 300 mg of clopidogrel before PCI improves clinical outcomes.19,30 However, in the Clopidogrel for the Reduction of Events During Observation trial, the difference in clinical outcomes between placebo and clopidogrel was not significant until at least 15 hours of pretreatment.30 In the Antiplatelet therapy for Reduction of Myocardial Damage during Angioplasty 2 study, when compared with the conventional 300-mg loading dose of clopidogrel, a 600-mg loading dose given 4 to 8 hours before PCI reduced periprocedural myocardial infarction.31Analysis from the Primary Angioplasty In Myocardial Infarction trials found that a thienopyridine given in the emergency department was associated with increased rates of TIMI grade 3 flow before PCI.32 In a recent study, initial patency and clinical outcome were improved in patients undergoing primary PCI that received pretreatment with clopidogrel.33 The clinical benefits of pretreatment with clopidogrel have also been reported in patients treated initially with fibrinolytic therapy, who subsequently required urgent PCI.4 The high-loading dose of clopidogrel given to our patients before the procedure may account for the lack of clinical benefit with eptifibatide. Although many patients in the heparin-alone group may not have achieved maximal inhibition of platelet activity at the time of balloon inflation, the vulnerable period for abrupt vessel closure may have been abbreviated by administering high-dose clopidogrel before the intervention. Further studies to assess the effect of high-dose clopidogrel are needed.Other factors could have contributed to the observed lack of effect of eptifibatide on the primary end point. Our study was performed after the establishment of an integrated city-wide rapid response STEMI system, which resulted in relatively short ischemic time intervals.34 A very high adherence to guidelines of medication during the entire study period may have also prompted a low event rate at follow-up.35Time to presentation <2 to 3 hours is critical to improve myocardial salvage and survival with reperfusion therapy.36 The lack of benefit of abciximab before cardiac catheterization in the Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events study was attributed to the long delay between symptom onset and initiation of therapy.37 In our study, subgroup analysis demonstrated that even patients randomized within 180 minutes of symptom onset did not benefit from the addition of eptifibatide.Bleeding is now reported as an independent predictor of 30-day mortality in patients with acute coronary syndromes.38,39 In the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction trial, anticoagulation with bivalirudin alone, when compared with heparin plus glycoprotein IIb/IIIa inhibitors, yielded significantly lower 30-day rates of major bleeding and net adverse clinical events.40 In our study, bleeding rates were lower in the
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