One-year clinical outcomes with abciximab in acute myocardial infarction: results of the BRAVE-3 randomized trial
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In the Bavarian Reperfusion Alternatives Evaluation (BRAVE)-3 study upstream administration of abciximab additional to 600 mg clopidogrel loading did not reduce the infarct size in patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary interventions. The aim of this study was to investigate 1-year clinical outcomes in the BRAVE-3 study patients.
A total of 800 patients with acute STEMI within 24 h from symptom onset, all treated with 600 mg of clopidogrel were randomized 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 main outcome of interest of the present study, the composite of death, recurrent myocardial infarction, stroke or revascularization of the infarct-related artery (IRA) at 1 year, was 23.0% (92 patients) in the abciximab versus 25.7% (102 patients) in the placebo group [relative risk (RR) = 0.90, 95% confidence interval (CI) 0.67–1.20; P = 0.46]. The combined incidence of death, recurrent myocardial infarction or stroke was 9.3% in the abciximab group versus 6.0% in the placebo group (RR = 1.55, 95% CI 0.93–2.58; P = 0.09). There was a significant reduction of the IRA revascularization with abciximab compared to placebo (16.3 vs. 22.3%, RR = 0.71, 95% CI 0.52–0.98; P = 0.04).
In patients with STEMI, all receiving 600 mg clopidogrel, abciximab did not improve overall clinical outcomes at 1 year after primary coronary stenting.
KeywordsAbciximab Clopidogrel Acute myocardial infarction Randomized
Bavarian Reperfusion Alternatives Evaluation
Primary percutaneous coronary intervention
Intracoronary stenting and antithrombosis research
Major adverse cardiovascular events
Major adverse cardiovascular and cerebrovascular events
ST-segment elevation myocardial infarction
Thrombolysis in myocardial infarction
Glycoprotein IIb/IIIa inhibitor, abciximab, given peri-procedurally during primary percutaneous coronary intervention (PPCI) for acute ST-segment elevation myocardial infarction (STEMI) has been reported to substantially reduce long-term mortality [2, 4, 17]. New antiplatelet and anticoagulation therapy including high-dose clopidogrel, new thienopyridine, prasugrel, and direct thrombin inhibitor bivalirudin [11, 18, 27, 30] dictate the immediate need to revise the place and importance of glycoprotein IIb/IIIa inhibitors as adjunctive therapy to PPCI in STEMI patients.
In the Bavarian Reperfusion Alternatives Evaluation-3 (BRAVE-3) study, which investigated upstream administration of abciximab following treatment with 600 mg of clopidogrel in patients with acute STEMI undergoing PPCI, abciximab did not reduce scintigraphic infarct size as compared with placebo . Furthermore, the 30-day combined incidence of death, recurrent myocardial infarction, stroke or urgent revascularization of infarct-related artery (IRA) did not differ significantly among patients who received abciximab (5.0%) versus those who received placebo (3.8%). Late benefit of abciximab additional to 600 mg clopidogrel loading has been demonstrated in patients undergoing PCI for stable or unstable angina pectoris, derived mostly from a reduction of restenosis-related target vessel revascularization [6, 20], particularly in diabetic patients . No information exists regarding late outcomes of abciximab additional to 600 mg loading dose of clopidogrel in patients with STEMI after PPCI. In this study, we report the 1-year clinical outcome in 800 patients enrolled in the BRAVE-3 trial.
Patient population, randomization and treatment protocol
Detailed information of BRAVE-3 trial has been described previously . Briefly, 800 patients with acute STEMI presenting <24 h after the symptom onset without cardiogenic shock or prolonged cardio-pulmonary resuscitation, thrombolytic therapy for the index infarction, active bleeding, history of stroke within the last 3 months or trauma or major surgery during the last month, suspected aortic dissection, oral anticoagulation therapy with coumarin derivatives within the last 7 days or use of glycoprotein IIb/IIIa inhibitors within the last 14 days, relevant hematologic deviations or malignancies, who gave informed consent for participation in the study were randomized at the emergency room or intensive care units of the five participating interventional centers in a double-blind fashion to receive abciximab or placebo. Before study drug administration, all patients received a loading dose of 600 mg of clopidogrel orally, a bolus of 500 mg aspirin and 60 U/kg body weight heparin (up to a maximal dose of 5,000 U) intravenously at the emergency room or intensive care unit of the admitting hospital. Abciximab (ReoPro®, Lilly Pharma Produktion GmbH & Co., Hamburg, Germany) was given as a bolus of 0.25 mg/kg of body weight followed by a continuous infusion of 0.125 μg/kg per min (up to a maximal dose of 10 μg/min) for 12 h. Patient assigned to placebo received an intravenous bolus of 70 U/kg of body weight heparin followed by infusion of placebo for 12 h. Double blinding was achieved by using identically appearing vials in both study arms. Thereafter, all patients were sent to the catheterization laboratory for coronary angiography and PPCI. Coronary stents were used in 93% of the patients. After reperfusion, all patients were treated with clopidogrel 75 mg twice a day for 3 days and 75 mg/day thereafter for at least 30 days and with aspirin 100 mg twice a day, indefinitely. Other cardiac medications were left to the judgment of the patient’s physician. The study protocol was approved by the institutional ethics committees of all participating centers.
Study follow-up, outcomes and definitions
The hypothesis, endpoints and 30-day results of the BRAVE-3 trial has been previously published . The primary outcome of this analysis was the incidence of major adverse cardiovascular and cerebrovascular events, defined as all-cause death, recurrent myocardial infarction, IRA revascularizations or stroke at 1 year after randomization. Secondary outcomes were 1-year survival, the combined incidence of all-cause death or recurrent myocardial infarction and the incidence of IRA revascularizations.
The information on death and its cause was obtained from hospital records, death certificate, or phone contact with relatives of the patient or attending physician. Diagnosis of recurrent infarction was based on the following criteria: if the biomarkers of the index MI were still increasing or peak was not reached patients had to have both new ECG changes consistent with MI (new or re-elevation of ST-segment ≥0.2 mV in ≥2 contiguous precordial leads or ≥0.1 mV in ≥2 adjacent limb ECG leads or development of new, abnormal Q-waves considered to be distinct from the evolution of the index MI) and recurrent ischemic discomfort lasting more than 20 min at rest or ischemia-triggered hemodynamic instability; if biomarkers of the index MI were falling but still above the upper limit of normal (ULN), patients had to have either an increase of creatine kinase (CK) or creatine kinase myocardial band (CK-MB) ≥50% over the nadir level or new ECG changes consistent with MI (see above); if the biomarkers of the index MI were normalized, patients had to have a new increase of CK-MB (CK) ≥3 times the ULN . The diagnosis of stroke required confirmation by computed tomography or magnetic resonance imaging of the head. The IRA revascularization was defined as coronary bypass graft surgery or repeat PCI involving the IRA in presence of restenosis-induced symptoms or signs of myocardial ischemia. Time intervals were defined as follows: pain to admission time was the interval between the onset of pain and the admission to hospital; study drug to PPCI time was the interval between injection of the first bolus of the study drug and first balloon inflation; clopidogrel to PPCI time was the interval between clopidogrel loading and first balloon inflation.
The assessment of clinical status was made by phone interviews or outpatient visits at 30 days, 6 and 12 months. Patients with cardiac complaints underwent a complete clinical, electrocardiographic, and laboratory evaluation. If patients suffered a qualifying event at another hospital the appropriate source documents were solicited (including discharge summaries, laboratory values, ECGs and angiograms). Family doctors, referring cardiologists, patients or their relatives were contacted for additional information if necessary.
All data were collected by research coordinators and forwarded to ISAResearch Center affiliated to the Deutsches Herzzentrum, Munich, Germany. All events were adjudicated and classified by an event adjudication committee blinded to the treatment groups throughout the follow-up interval.
All analyses were done on the basis of the intention-to-treat principle using data from all patients as randomized. Continuous data were presented as mean ± standard deviation and compared with the use of two-tailed t test. Categorical data were presented as count or percentages (Kaplan–Meier estimates). Time-to-event data were analyzed using survival techniques (Kaplan–Meier method). Differences in survival parameters were assessed for significance and relative risks associated with abciximab were calculated using the log-rank test. Heterogeneity of treatment differences across various subsets was checked by assessing the interaction between assigned treatment and variable defining the subset with respect to the end point of interest. Analyses were performed using the S-plus statistical package (S-PLUS, Insightful Corp, Seattle, Wash). A two-sided P value <0.05 was considered statistical significance.
Key baseline and procedure characteristics
Abciximab (n = 401)
Placebo (n = 399)
62.4 ± 11.7
61.8 ± 12.2
Body mass index
27.1 ± 3.8
27.0 ± 4.1
History of myocardial infarction
History of CABG surgery
Symptom onset to hospital admission
Bare metal stent
Final TIMI flow grade post-PPCI
Clinical outcome at 1 year
In 1.6% of the population (13 patients, 6 in abciximab and 7 in placebo group) follow-up interval was less than 12 months. In these patients the median follow-up interval was 7.0 months (range 6.6–9.0 months).
The BRAVE-3 trial, investigated the impact of upstream abciximab in acute STEMI patients undergoing PPCI after pre-treatment with 600 mg clopidogrel on the scintigraphic infarct size. The study found no additional benefit with abciximab neither in terms of reduction of infarct size nor in terms of improvement of clinical outcomes at 30 days after PPCI .
The main finding of the present study is that upstream abciximab administration additional to 600 mg clopidogrel loading did not improve overall outcomes up to 12 months after PPCI. Furthermore, although there was no significant difference between both strategies regarding thrombotic complications (death, recurrent MI, stroke), a tendency toward lower rates of IRA revascularization with abciximab therapy was observed.
Periinterventional administration of glycoprotein IIb/IIIa receptor inhibitors, particularly abciximab, was reported to positively impact the outcomes of patients with STEMI undergoing PPCI [4, 8, 17, 22]. In a meta-analysis including all randomized trials investigating the effect of abciximab during PPCI in STEMI, all performed in the ticlopidine era, 30-day and 6- to 12-month mortality risk was reduced by 30% (significantly) with the administration of abciximab . This abciximab-related mortality reduction was driven by a reduction of recurrent myocardial infarction rates at 30 days mainly observed in studies enrolling high-risk patients [3, 23]. However, this benefit seems not to be consistent in all trials [16, 29, 30]. In the largest randomized trial of abciximab in STEMI, the CADILLAC (controlled abciximab and device investigation to lower late angioplasty complications) trial, the incidence of both recurrent myocardial infarction and mortality were not different between treatment groups at 1 year after PPCI . Moreover, in the HORIZONS-AMI (the harmonizing outcomes with revascularization and stents in acute myocardial infarction) trial, the administration of glycoprotein IIb/IIIa inhibitors in STEMI patients after pre-treatment with 300 or 600 mg clopidogrel not only did not reduce the recurrent infarction rates but were also associated with a significantly higher mortality at 1 year compared to a strategy of clopidogrel loading and bivalirudin . The lower bleeding rates observed with bivalirudin have been suggested as a possible explanation to these findings .
There is increasing evidence about the importance of bleeding in attrition of the clinical benefit of glycoprotein IIb/IIIa inhibitors after PCI . Recent data suggest that the relative weight of bleeding complications in determining mortality after PCI, even at long term, may exceed that of myocardial infarction . Even though in our study the use of abciximab additional to clopidogrel loading did not increase the incidence of major bleeding [assessed by thrombolysis in myocardial infarction (TIMI) grading system], the incidence of minor bleeding—part of them considered as major bleeds by new definitions used in modern studies —was considerably increased. Moreover, severe thrombocytopenia was observed only in abciximab-treated patients. In the CADILLAC trial, periinterventionally observed thrombocytopenia was associated with 2.5-times higher 1-year all-cause mortality risk .
Although it has not been constantly reported [2, 6, 21, 29], a meta-analysis by Kandzari et al.  showed that abciximab given as adjunct therapy during PPCI reduced the need for short-term and long-term repeat revascularization which was associated with a reduction in the 1-year mortality. The reduction of the IRA revascularization by 40% found in the BRAVE-3 may have balanced the slightly higher thrombotic event rate observed at 1 year with abciximab. The antirestenotic effect of abciximab has been reported in several studies, particularly in those including patients at high risk of restenosis such as diabetic patients [12, 13, 14]. The most striking evidence of differential short- and long-term action of abciximab after PCI has been observed in the ISAR-REACT 2 (the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2) trial [7, 10, 20]. While the 30-day MACE rate was significantly reduced with abciximab on top of 600 mg of clopidogrel in the subset of biomarker positive patients; mostly due to reduction of periinterventional myocardial infarctions, the observed benefit at 1 year in the whole ISAR-REACT-2 sample mostly derived from the lower need of revascularizations with abciximab . These data may reflect the pleotropic action of abciximab at the cellular level including its interaction not only with glycoprotein IIb/IIIa receptors, but also with vitronectin receptor (αvβ3) on platelet surface and smooth muscle cells which blockage leads to less neointimal hyperplasia [25, 28].
This study presents some limitations. The current study was not sufficiently powered to investigate clinical endpoints. This limitation may become more obvious during interpretation of 1-year MACCE in various subgroups of patients. Additionally high-risk patients such as the one presenting with high Killip class or severe comorbidities were not included in BRAVE-3 trial. Thus, we cannot draw any definitive conclusion about the additional effects of abciximab in this category of patients. Finally, the lack of a study group consisting of bivalirudin or double-bolus tirofiban, recently shown to reduce mortality on top of 300 or 600 mg clopidogrel loading regimen [5, 16], should be taken into consideration during interpretation of the BRAVE-3 results and evaluation of their potential implications.
In conclusion, in patients with acute STEMI within 24 h of symptom onset, upstream administration of abciximab after treatment with loading dose of 600 mg clopidogrel was not associated with reduction of overall outcomes 1 year after primary percutaneous coronary intervention.
We highly appreciate the invaluable contribution of the medical and technical staffs operating in the coronary care units, nuclear medicine and catheterization laboratories of the participating institutions. BRAVE-3 was supported by grants from Deutsches Herzzentrum, Munich, Germany.
Conflict of interest statement
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 coauthors have no conflicts of interest.
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