Published online before print March 30, 2009, doi: 10.1161/CIRCULATIONAHA.108.818617
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(Circulation. 2009;119:1933-1940.)
© 2009 American Heart Association, Inc.
Interventional Cardiology |
Abciximab in Patients With Acute ST-Segment–Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention After Clopidogrel Loading
A Randomized Double-Blind Trial
From Deutsches Herzzentrum, Technische Universität, Munich, Germany (J.M., A.K., S.S., S.F., J.P., M.S., S.M., A.S.); 1. Medizinische Klinik rechts der Isar, Technische Universität, Munich, Germany (J.D., A.S.); Klinikum Traunstein, Traunstein, Germany (W.M.); Klinikum Garmisch-Partenkirchen, Garmisch-Partenkirchen, Germany (F.D.); Klinik und Poliklinik für Nuklearmedizin rechts der Isar, Technische Universität, Munich, Germany (S.G.N., M.S.); and 3. Medizinische Klinik, Wilhelminenspital Vienna, Austria (K.H.).
Correspondence to Dr Julinda Mehilli, Deutsches Herzzentrum, Lazarettstr 36; 80636 München, Germany. E-mail mehilli{at}dhm.mhn.de
Received September 2, 2008; accepted February 9, 2009.
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Abstract |
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Background— The glycoprotein IIb/IIIa receptor inhibitor abciximab has improved the efficacy of primary percutaneous coronary interventions in patients with acute myocardial infarction. However, it is not known whether abciximab remains beneficial after adequate clopidogrel loading in patients with acute ST-segment–elevation myocardial infarction.
Methods and Results— A total of 800 patients with acute ST-segment–elevation myocardial infarction within 24 hours from symptom onset, all treated with 600 mg clopidogrel, were randomly assigned in a double-blind fashion to receive either abciximab (n=401) or placebo (n=399) in the intensive care unit before being sent to the catheterization laboratory. The primary end point, infarct size measured by single-photon emission computed tomography with technetium-99m sestamibi before hospital discharge, was 15.7±17.2% (mean±SD) of the left ventricle in the abciximab group and 16.6±18.6% of the left ventricle in the placebo group (P=0.47). At 30 days, the composite of death, recurrent myocardial infarction, stroke, or urgent revascularization of the infarct-related artery was observed in 20 patients in the abciximab group (5.0%) and 15 patients in the placebo group (3.8%) (relative risk, 1.3; 95% CI, 0.7 to 2.6; P=0.40). Major bleeding complications were observed in 7 patients in each group (1.8%).
Conclusion— Upstream administration of abciximab is not associated with a reduction in infarct size in patients presenting with acute myocardial infarction within 24 hours of symptom onset and receiving 600 mg clopidogrel.
Key Words: abciximab • clopidogrel • infarction • randomized • scintigraphy • stents
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Introduction |
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Mechanical reperfusion strategies have been shown to be superior to pharmacological reperfusion strategies in acute ST-segment–elevation myocardial infarction (STEMI).1–3 The glycoprotein IIb/IIIa inhibitor abciximab has been shown to enhance microvascular flow4 in the jeopardized myocardial area, increasing the efficacy of reperfusion strategies in terms of reduced infarct size, improved ventricular pump function, and reduced thrombotic adverse events.4,5
Clinical Perspective p 1940
The introduction of thienopyridines made possible the safe use of percutaneous coronary intervention (PCI) with stent implantation.6 Although ticlopidine reduced the risk of thrombotic stent occlusion and MI within the first 30 days after PCI, its onset of action takes at least 48 hours.7,8 Clopidogrel, its successor, has been shown to act more rapidly, particularly after a loading dose.8–10 In patients with acute coronary syndromes, a loading dose of 300 mg clopidogrel followed by 75 mg daily resulted in a 20% reduction in thrombotic events at 1 year.11 Moreover, adding clopidogrel to pharmacological reperfusion therapy in patients with acute STEMI decreased the 30-day rate of thrombotic events by 10% to 20%.12,13
A loading dose of 600 mg clopidogrel has been shown to achieve a high degree of platelet aggregation inhibition within a shorter time than 300 mg clopidogrel.14,15 In a large population of low- to intermediate-risk patients, peri-interventional use of abciximab after pretreatment with 600 mg clopidogrel did not show any additional reduction in ischemic events.16 In contrast, pretreatment with 600 mg clopidogrel did not prevent abciximab from showing a positive effect in patients with acute coronary syndromes.17
Thus, the objective of this trial was to assess whether upstream administration of abciximab results in additional benefit in terms of infarct size reduction in patients with STEMI after loading with 600 mg clopidogrel before primary PCI (PPCI).
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Methods |
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Study Population
Eligible patients were those with acute MI presenting <24 hours after the onset of symptoms, defined as chest pain lasting
20 minutes and 0.1 mV ST-segment elevation in 2 limb leads, 0.2 mV in 2 contiguous precordial leads, or presumed new left bundle-branch block on surface ECG, who gave informed consent for participation in the study. Patients who had received thrombolytic therapy for the index infarction; those with previous stroke (within the last 3 months), active bleeding or bleeding diatheses, recent trauma or major surgery (during the last month), suspected aortic dissection, oral anticoagulation therapy with coumarin derivatives (within the last 7 days), recent use of glycoprotein IIb/IIIa inhibitors (within the last 14 days), severe uncontrolled hypertension (>180 mm Hg, unresponsive to therapy), relevant hematologic deviations (hemoglobin <100 g/L or hematocrit <34%, platelet count <100x109/L or >600x109/L), malignancies, prolonged cardiopulmonary resuscitation, or cardiogenic shock; those >80 or <18 years of age; those with known or suspected pregnancy; and those who were allergic to study drugs were considered ineligible for this study. The study protocol was approved by the institutional ethics committees of all participating centers.
Randomization
Randomization was performed according to a computer-generated random sequence enclosed in sealed envelopes in the emergency room or intensive care unit of the 5 participating PCI centers. The size of the block was preselected by the statistician and was unknown to the investigators and medical staff caring for the patients. Patients were randomly assigned to one of the treatment groups, abciximab or placebo. Patients, medical staff, and investigators were blinded to assigned treatment. Blinding was maintained by the use of vials of identical appearance containing abciximab, heparin, or placebo.
Procedures
All patients received 600 mg clopidogrel orally and a bolus of 500 mg aspirin and 60 U heparin/kg body weight (up to a maximal dose of 5000 U) intravenously at the emergency room or intensive care unit of the admitting hospital. Thereafter, they received the randomly assigned study drug, which also was started in the emergency room or intensive care unit of the admitting hospital. Patients assigned to abciximab therapy received intravenous abciximab (ReoPro, Lilly Pharma Production GmbH & Co, Hamburg, Germany) given as a bolus of 0.25 mg/kg body weight followed by a continuous infusion of 0.125 µg · kg–1 · min–1 (up to a maximal dose of 10 µg/min) for 12 hours. Patients assigned to placebo received an intravenous bolus of 70 U heparin/kg body weight followed by infusion of placebo for 12 hours.
All patients were sent to the catheterization laboratory for coronary angiography and PCI. The decision to perform a coronary intervention was at the discretion of the operator. The recommended intervention was coronary stenting. No additional study drugs were administered, and no activated clotting time monitoring was performed during the coronary intervention. Although this is a common practice in Germany, avoidance of activated clotting time monitoring also was intended to eliminate the risk of involuntary unblinding. After reperfusion, all patients were treated with clopidogrel 75 mg twice daily for 3 days and 75 mg/d thereafter for at least 30 days and with aspirin 100 mg twice daily indefinitely. Other cardiac medications were given as directed by the patient’s physician.
Infarct Size Measurement
A single-photon emission computed tomography (SPECT) study was performed at a median of 4.6 days (25th to 75th percentile, 4.2 to 5.5 days) in the abciximab group and 4.5 days (25th to 75th percentile, 4.1 to 5.4 days) in the placebo group (P=0.21) after randomization using technetium-99m sestamibi. SPECT imaging was done in all centers that participated in the trial. The methods used for the SPECT studies have been described in detail previously.2 All measurements were performed in the Scintigraphic Core Laboratory, affiliated with the Klinik und Poliklinik für Nuklearmedizin rechts der Isar, Technische Universität, Munich, Germany, by operators blinded to drug assignment. The Scintigraphic Core Laboratory is independent of patient enrolling centers and the Data Coordinating Center. Final infarct size was measured as the perfusion defect at the SPECT study and expressed as percent of the left ventricle.
Angiographic Evaluation
Qualitative and quantitative analyses of all angiographic parameters were performed at the Angiographic Core Laboratory by operators blinded to the randomly assigned treatment. Left ventricular angiograms in the right anterior oblique projection were used to measure the left ventricular ejection fraction. Initial and final flow in the infarct-related artery (IRA) was graded according to the Thrombolysis in Myocardial Infarction (TIMI) flow classification.18 Collaterals were graduated according to the Rentrop classification.19 Digital angiograms were analyzed offline with the automated CMS version 7.1 (Medis Medical Imaging Systems, Leiden, the Netherlands) edge detection system.
Follow-Up and End Points
During the hospital stay, ECG recordings and determination of creatine kinase, creatine kinase-MB, hemoglobin content, and platelet count were performed before and 8, 16, and 24 hours after the randomization, as well as daily thereafter. After discharge, the assessment of clinical status was made by means of a phone interview at 30 days or an outpatient visit in case of complaints. All data were collected by research coordinators and forwarded to the ISAResearch Center affiliated with Deutsches Herzzentrum, Munich, Germany.
The primary end point of the study was infarct size in the SPECT study. Secondary end points were death resulting from any cause, recurrent MI, stroke, urgent IRA revascularization at 30 days, and in-hospital incidence of major and minor bleeding complications. Diagnosis of recurrent infarction was based on the following criteria: If the biomarkers of the index MI were still increasing or the peak had not been reached, the patients had to have both new ECG changes consistent with MI (new or re-elevation of ST segments 0.2 mV in 2 contiguous precordial leads, 0.1 mV in 2 adjacent limb ECG leads, or development of new, abnormal Q waves considered distinct from the evolution of the index MI) and recurrent ischemic discomfort lasting >20 minutes at rest or ischemia-triggered hemodynamic instability; if the biomarkers of the index MI were falling but still above the upper limit of normal, the patients had to have either an increase in creatine kinase-MB (creatine kinase) 50% over the nadir level or new ECG changes consistent with MI (see above); if the biomarkers of the index MI were normalized, the patients had to have a new increase in creatine kinase-MB (creatine kinase) 3 times the upper limit of normal.18 The diagnosis of stroke required confirmation by computed tomography or magnetic resonance imaging of the head. A bleeding complication was defined as major if it was intracranial or if clinically significant overt signs of hemorrhage were associated with a drop in hemoglobin of >5 g/dL (or, when hemoglobin was not available, an absolute drop in hematocrit of at least 15%).18 All events were adjudicated and classified by an Event Adjudication Committee blinded to treatment group.
Time intervals were defined as follows: Time onset of symptom to admission was the interval between the onset of symptoms and admission to hospital; time admission to study drug was the time interval between admission to hospital and injection of the first bolus of the study drug; time admission to PPCI was the time interval between hospital admission and first balloon inflation; time clopidogrel to PPCI was the interval between clopidogrel loading and first balloon inflation; time clopidogrel to study drug was the interval between clopidogrel loading and injection of the first bolus of the study drug; and time study drug to PPCI was the interval between injection of the first bolus of the study drug and first balloon inflation.
Statistical Analysis
Sample size calculation was performed on the basis of the primary end point of the trial. The assumptions used for this purpose included an infarct size of 16.9% (SD, 13.9%) of the left ventricle in the placebo group (based on the value reported for patients who were not pretreated with a loading dose of clopidogrel2,3) and a 20% reduction with abciximab. Choosing a 2-sided 
level of 0.05 and power of 90%, we needed 353 patients with scintigraphic follow-up study in each group. We allowed for the possibility that not all patients would have a follow-up SPECT and included a total of 800 patients.
All analyses were done on the basis of the intention-to-treat principle using data from all patients as randomized. There were no treatment crossovers in the 30-day study period. Depending on the distribution, the continuous data are presented as median (25th to 75th percentiles) or as mean±SD. Categorical data are presented as counts or proportions. The differences between groups were assessed with the 
2 test or Fisher’s exact test for categorical data and the nonparametric Wilcoxon rank-sum test or Student t test for continuous data. Heterogeneity of treatment differences across various subsets was checked by assessing the interaction between assigned treatment and variables defining the subset with respect to the end point of interest. Survival analysis was made by applying the Kaplan-Meier method. Differences in survival parameters were assessed for significance, and relative risks were calculated by means of the log-rank test. A 2-tailed value of P<0.05 was considered to indicate statistical significance.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Patient Characteristics
From June 2003 through January 2008, 800 STEMI patients pretreated with 600 mg clopidogrel were enrolled and randomly assigned to either abciximab or placebo. Figure 1 displays the trial profile. Table 1 shows the baseline characteristics of the patients, which were comparable between the 2 treatment groups. More than 40% of patients presented with anterior wall STEMI; >75% were in Killip class 1 at hospital admission. Table 2 displays initial and final angiographic results and the performed procedures. Initial TIMI grade 3 flow in the IRA was seen in 20% of patients in both groups. Half of the patients received a bare metal stent, and 44% received a drug-eluting stent. The distribution of final TIMI flow was comparable between the 2 groups, with 92% of patients having a TIMI grade 3 flow. Relevant time intervals are displayed in Table 3. Median symptom onset to hospital admission interval was 210 minutes in the abciximab group and 216 minutes in the placebo group (P=0.68), and median time from hospital admission to PPCI interval was 78 minutes in the abciximab group and 80 minutes in the placebo group (P=0.77).
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Scintigraphic Results
SPECT imaging was performed in 756 patients (94.5% of the entire study population). Reasons for missing SPECT imaging were death, urgent IRA revascularization, technical problems related to the availability of imaging equipment, image quality, and patient refusal (Figure 1). Infarct size, the primary end point of the trial, was 15.7±17.2% of the left ventricle in the abciximab group and 16.6±18.6% of the left ventricle in the placebo group (P=0.47; Figure 2).
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The primary end point also was analyzed in different subgroups of patients according to age, gender, infarct localization, history of MI, time interval from symptom onset to hospital admission, time interval from study drug administration to PPCI, and time interval from clopidogrel loading to PPCI. No significant differences in infarct size were observed in any of these subgroups (Figure 3).
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Clinical Outcome
Within the first 30 days after randomization, 13 patients (3.2%) in the abciximab and 10 patients (2.5%) in the placebo group died (P=0.53). Only 1 patient (0.3%) in the abciximab and 3 patients (0.8%) in the placebo group experienced definite stent thrombosis (acute coronary syndrome with angiographic or autopsy evidence of thrombus or occlusion20; P=0.31). The cumulative incidence of death, recurrent MI, urgent IRA revascularization, and stroke was similar in both groups: 5.0% in the abciximab and 3.8% in the placebo group (P=0.40; Figure 4). In each group, 7 patients (1.8%) experienced major bleeding complications. Transfusion of blood products occurred in 12 patients (3.0%) in the abciximab and 13 patients (3.3%) in the placebo group. A trend toward a higher risk of minor bleeding complications was observed in the abciximab group (3.7%) versus the placebo group (1.8%; P=0.09). Six patients (1.5%) in the abciximab group and none in the placebo group experienced profound thrombocytopenia (P=0.03; Table 4).
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Discussion |
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The main finding of this trial is that abciximab is not associated with a reduction in infarct size when used in patients with acute STEMI undergoing mechanical reperfusion after loading with 600 mg clopidogrel.
Using technetium-99m sestamibi SPECT to determine infarct size is a very sensitive and reliable method, the accuracy of which has been validated in several studies.21 The infarct size quantified by SPECT imaging strongly correlates to left ventricular function and mortality, making it an accurate end point in studies comparing different treatment strategies in acute MI.21–23 The magnitude of the infarct size depends not only on the amount of initially jeopardized myocardium but also on the degree of myocardial salvage resulting from reperfusion.24 With PPCI achieving higher and sustained IRA patency rates, a greater proportion of ischemic myocardium can be salvaged compared with pharmacological reperfusion modalities.2,3,25,26
Adding glycoprotein IIb/IIIa receptor inhibitors to PPCI has been shown to improve outcomes in patients with acute STEMI. In virtually all studies investigating the role of abciximab in patients with acute STEMI and an antiplatelet therapy regimen based on ticlopidine, abciximab more frequently restored blood flow in the occluded artery, improved left ventricular function, and reduced short- and long-term thrombotic complications.4,5,27 There are data suggesting that earlier administration of glycoprotein IIb/IIIa inhibitors before PPCI increases the chances of benefit from these drugs.28–30 The delayed onset of action of ticlopidine has been well studied; a high loading dose of clopidogrel presents advantages in this regard.7,31,32 In several clinical trials, administration of abciximab during a PCI procedure after pretreatment with 600 mg clopidogrel was not associated with a measurable clinical benefit.16,33,34 At odds with this, in patients with acute coronary syndrome in the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment-2 (ISAR-REACT-2) trial, abciximab was able to reduce the incidence of ischemic complications by 25%, from 11.9% to 8.9%.17 This reduction was generated by the prevention of postprocedural infarctions, which constituted almost 90% of all ischemic events in that trial. In the present trial, the incidence of postprocedural recurrent MI was only 1.5%, too low, it may be argued, for abciximab to demonstrate its favorable preventive effects. In fact, the incidence of recurrent MI has also been low (range, 0.8% to 1.8%) in other recent trials including patients with STEMI.35,36
Several previous trials on reperfusion strategies in acute STEMI have included mostly patients presenting within 12 hours from symptom onset. In the BRAVE-3 trial, we enrolled patients presenting within 24 hours from symptom onset. There were 2 main reasons for doing this. First, strong time dependence in efficacy has been shown for thrombolysis but not for PPCI. A 44% reduction in infarct size has been reported with PPCI even when performed 12 to 48 hours after symptom onset.37 Second, although patients presenting between 12 and 24 hours from symptom onset are often excluded from reperfusion trials, treating them with PPCI is a common practice. Exclusion of these patients from randomized trials would leave unanswered the question of optimal adjunct drug therapy during PPCI. However, although there was no significant interaction between the interval from symptom onset to treatment effect, the interval-based analysis showed some sign that abciximab might be superior in patients presenting within 6 hours from symptom onset. This sign deserves additional, specifically designed studies.
In the present trial, abciximab did not show a significant reduction in infarct size even in subgroups thought to derive benefit from new developments in the treatment of acute STEMI such as those patients with anterior infarction, young patients, women, and patients with first infarction.24,38
The BRAVE-3 trial was specifically designed to investigate the value of abciximab started after hospital admission in patients with acute STEMI undergoing PPCI after high-dose clopidogrel loading. Recent randomized trials have shown divergent results on the value of prehospital treatment with glycoprotein IIb/IIIa inhibitors in patients undergoing PPCI. In the Facilitated Intervention With Enhanced Reperfusion Speed to Stop Events (FINESSE) trial, 40% of patients received abciximab in the referral hospital, yet abciximab did not improve outcomes even in this subgroup.39 In the Ongoing Tirofiban in Myocardial Infarction Evaluation (On-TIME) 2 trial, prehospital initiation of high-bolus dose tirofiban on top of 600 mg clopidogrel loading improved ST-segment resolution 1 hour after PPCI.40 It is not known whether high-dose tirofiban is superior to abciximab as a prehospital treatment in patients with acute STEMI undergoing PPCI. In an additional study, a high-bolus dose of tirofiban was beneficial even if started primarily in the interventional center.41
The recruitment period in BRAVE-3 was relatively long (4.5 years), during which time changes in clinical practice could have happened. Another recent study has shown that bivalirudin, a direct thrombin inhibitor not evaluated in the present trial, also is a useful antithrombotic therapy for PPCI after clopidogrel loading.35 The lack of a study group consisting of bivalirudin therapy during PPCI should be acknowledged as a limitation of the present trial and accounted for during the interpretation of its results and evaluation of its potential implications. Other limitations also need to be mentioned. We used infarct size measured by SPECT as the primary end point of the study. Despite its sensitivity, it cannot replace clinical end points in value. Our trial was not sufficiently powered for the evaluation of clinical outcomes associated with study treatments. Accordingly, it is difficult to interpret the numerically lower stent thrombosis rate in the abciximab group. Moreover, because of the exclusion of patients with cardiogenic shock, we cannot draw any conclusions about this very high-risk subset of patients. Finally, randomization was performed in each participating center separately for practical reasons at the cost of loss of benefit of a central patient randomization procedure.
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Conclusions |
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In patients with acute MI within 24 hours of symptom onset undergoing PPCI, upstream administration of abciximab after treatment with 600 mg clopidogrel is not associated with a reduction in infarct size. Whether this finding reflects a lack of clinical outcome benefit with abciximab remains to be investigated by larger trials powered for clinical events.
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Acknowledgments |
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We highly appreciate the invaluable contribution of the medical and technical staffs operating in the coronary care units and nuclear medicine and catheterization laboratories of the participating institutions.
Source of Funding
BRAVE-3 was supported by grants from Deutsches Herzzentrum, Munich, Germany.
Disclosures
Dr Mehilli has received lecture fees from Lilly and Daiichi Sankyo. Dr Kastrati has received lecture fees from Bristol-Meyers Squibb, Lilly, and Sanofi-Aventis. Dr Seyfarth has received lecture fees from Lilly and Sanofi-Aventis. Dr Huber has received honoraria and lecture fees from Lilly and Sanofi-Aventis. The other authors report no conflicts.
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Clinical trial registration information—URL: www.clinicaltrials.gov. Unique identifier: NCT00133250.
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