CLINICAL RESEARCH: INTERVENTIONAL CARDIOLOGY
Abbreviated Infusion of Eptifibatide After Successful Coronary InterventionThe BRIEF-PCI (Brief Infusion of Eptifibatide Following Percutaneous Coronary Intervention) Randomized Trial
Anthony Y. Fung, MB, BS, FACC*,*,
Jacqueline Saw, MD*,
Andrew Starovoytov, MD*,
Cameron Densem, MD*,
Percy Jokhi, MB, BChir, PhD*,
Simon J. Walsh, MD*,
Rebecca S. Fox, PA, MSc*,
Karin H. Humphries, MSc, MBA, DSc ,
Eve Aymong, MD, MSc,
Donald R. Ricci, MD, FACC*,
John G. Webb, MD, FACC,
Jaap N. Hamburger, MD, PhD*,
Ronald G. Carere, MD, FACC and
Christopher E. Buller, MD, FACC*
* Vancouver General Hospital, Vancouver, British Columbia, Canada
St. Paul's Hospital, Vancouver, British Columbia, Canada
Manuscript received April 15, 2008;
revised manuscript received September 4, 2008,
accepted September 8, 2008.
* Reprint requests and correspondence: Dr. Anthony Y. Fung, Cardiac Catheterization Laboratories, Vancouver General Hospital, University of British Columbia, 2775 Laurel Street, 9th Floor, Vancouver, British Columbia V5Z 1M9, Canada (Email: funga{at}interchange.ubc.ca).
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Abstract
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Objectives: The purpose of this study was to assess whether the early discontinuation of eptifibatide infusion in nonemergent percutaneous coronary intervention (PCI) is associated with a higher frequency of periprocedural ischemic myonecrosis.
Background: The recommended regimen for eptifibatide is a double bolus followed by an infusion for 18 h. It is not known whether the infusion can be shortened if the PCI is uncomplicated.
Methods: We enrolled 624 patients with stable angina, acute coronary syndrome, or recent ST-segment elevation myocardial infarction (>48 h) who underwent successful coronary stenting and received eptifibatide. Patients were randomly assigned to receive either an 18-h infusion or an abbreviated infusion of <2 h. The primary end point was the incidence of periprocedural myonecrosis defined as troponin-I elevation >0.26 µg/l. Secondary end points included death, myocardial infarction, urgent target vessel revascularization at 30 days, and in-hospital major bleeding using the REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events) trial criteria.
Results: The incidence of periprocedural myonecrosis was 30.1% in the <2-h group versus 28.3% in the 18-h group (mean difference: 1.8%; upper bound of 95% confidence interval: 7.8%; p < 0.012 for noninferiority). The 30-day incidence of myocardial infarction, death, and target vessel revascularization was similar in both groups (p = NS). Major bleeding was less frequent in the <2-h group (1.0% vs. 4.2%, p = 0.02).
Conclusions: After uncomplicated PCI, eptifibatide infusion can be abbreviated safely to <2 h. It is not inferior to the standard 18-h infusion in preventing ischemic outcome, and it may be associated with less major bleeding. (Brief Infusion of Eptifibatide Following Percutaneous Coronary Intervention [BRIEF PCI]; NCT00111566
[ClinicalTrials.gov]
)
Key Words: eptifibatide • glycoprotein IIb/IIIa inhibitors • platelet • stenting
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Abbreviations and Acronyms
| | ACS = acute coronary syndrome | | CK-MB = creatine kinase-myocardial band | | GP = glycoprotein | | MI = myocardial infarction | | NHLBI = National Heart, Lung, and Blood Institute | | PCI = percutaneous coronary intervention |
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Glycoprotein (GP) IIb/IIIa inhibitors are potent antagonists of platelet aggregation proven to be beneficial in preventing periprocedural ischemic complications after PCI with or without routine stenting (1–3). The efficacy of eptifibatide, a widely used cyclic heptapeptide belonging to this class, was established in the placebo-controlled, randomized ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor With Integrilin Therapy) trial (4,5). In the ESPRIT study, high-dose eptifibatide administered in 2 boluses before PCI (180 µg/kg each 10 min apart) followed by an extended infusion of 2.0 µg/kg/min for 18 to 24 h after PCI resulted in a 35% reduction in death or myocardial infarction (MI) at 30 days, leading to early termination of the trial. Although this regimen is now recommended standard care, the trial did not distinguish the contribution made by the boluses versus the extended 18- to 24-h infusion.
The use of extended infusions of eptifibatide after routine and angiographically successful PCI procedures has several potential disadvantages. Prolonged and uninterrupted exposure may increase bleeding, particularly early after arterial sheath removal. Indeed, eptifibatide administered in this manner increases bleeding compared with heparin or bivalirudin alone (4–6). Infusions of 18-h duration also obligate overnight hospitalization after PCI, and may raise practical issues related to post-PCI interhospital transport.
Clinical experience suggests that interventionalists can accurately identify patients at low risk for early ischemic complications upon conclusion of PCI procedures (7–10). We hypothesized that an extended infusion of eptifibatide in such patients is unnecessary for prevention of ischemic complications, and may lead to excess bleeding and cost. We, therefore, performed a randomized trial comparing abbreviated and extended infusions of eptifibatide after angiographically successful nonemergent stent-based PCI procedures.
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Methods
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The BRIEF-PCI (Brief Infusion of Intravenous Eptifibatide Following Successful Percutaneous Coronary Intervention) trial was a randomized and double-blinded controlled study comparing abbreviated infusion of eptifibatide (<2-h group) to a standard 18-h infusion (18-h group). All patients provided written informed consent before participation in the study. The study protocol was approved by the University of British Columbia Research Ethics Board.
Study population.
Patients scheduled for nonemergent PCI, or referred for diagnostic catheterization and possible PCI, were potentially eligible if older than 18 years. Patients became eligible for enrollment upon successful completion of a PCI with stenting and primary use of eptifibatide. Patients were excluded for any of the following reasons: recent (<48 h) ST-segment elevation MI; visible thrombus; bivalirudin treatment; unprotected left main intervention; use of ablative or thrombectomy devices; allergy or intolerance to aspirin, thienopyridines, or eptifibatide; or unsatisfactory PCI results. Unsatisfactory PCI was defined by any of the following: final Thrombolysis In Myocardial Infarction (TIMI) flow grade <3; type B or worse dissection according to the National Heart, Lung, and Blood Institute classification (11); definite thrombus or distal embolization; in-stent residual stenosis >20% by visual estimate; loss of a major side branch (estimated >1.5-mm diameter); transient vessel closure or prolonged ischemia (>15 min); hemodynamic collapse; unsatisfactory deployment of a femoral artery closure device; or significant access site bleeding during PCI.
Study protocol.
Pre-treatment with aspirin was required. For patients not receiving adequate clopidogrel pre-treatment (defined as 75 mg/day >4 days, 300 mg loading >6 h, or 600 mg loading >2 h), clopidogrel 600 mg was given orally before or immediately after PCI in the laboratory (12–14). Either unfractionated heparin or enoxaparin were acceptable antithrombin agents. Heparin was administered as an intravenous bolus 50 to 70 IU/kg to achieve a target activated clotting time of 200 to 300 s. Its use after PCI was strongly discouraged. Intravenous eptifibatide (Integrilin, Schering, Kenilworth, New Jersey) was administered before first balloon inflation as a bolus of 180 µg/kg twice, 10 min apart, followed by an intravenous infusion of 2 µg/kg/min (dose reduction for patients with renal impairment as per product monograph).
For patients who received adequate clopidogrel pre-treatment, open-label eptifibatide infusions would be discontinued in the cardiac catheterization laboratory immediately after PCI. After randomization using sealed envelopes in blocked sequences, such patients received blinded treatment with eptifibatide or placebo for 18 h. In contrast, patients who did not receive adequate clopidogrel pre-treatment were given oral clopidogrel loading 600 mg, and open-label eptifibatide infusion for 2 h. After randomization, these patients received blinded treatment with eptifibatide or placebo for 16 h. Figure 1
shows the flow of study participants.
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Figure 1 Flow of Study Participants
See Methods section for explanation. CABG = coronary artery bypass graft surgery; PCI = percutaneous coronary intervention; PTCA = percutaneous transluminal coronary angioplasty.
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Troponin-I, total creatine kinase, and creatine kinase-myocardial band (CK-MB) were evaluated on samples collected immediately before the procedure, after PCI (6 to 8 h), and the next day (18 to 24 h). All blood samples were forwarded to our center core laboratory for analysis. All patients had electrocardiograms performed before the procedure and before discharge. Patients were seen by research coordinators during hospitalization, and telephone interviews were conducted at 30 days.
Study end points and definitions.
The primary end point was the incidence of ischemic myonecrosis within 24 h of PCI and before hospital discharge. Ischemic myonecrosis was defined as the following: 1) elevated post-procedure troponin-I level >0.26 µg/l if the baseline level was normal; 2) if the baseline troponin-I level was elevated, then injury was diagnosed when CK-MB was >3 times the upper limit of normal; and 3) if both troponin-I and CK-MB were elevated at baseline, then injury was diagnosed if CK-MB was >3 times the upper limit of normal and >50% higher than baseline. Biomarkers were measured at the Core Chemistry Laboratory at the Vancouver General Hospital under the direction of Dr. M. Pudek. Troponin-I was measured using the assay (Dimension RxL) manufactured by Dade-Behring, Inc. (Mississauga, Ontario, Canada). The cutoff value of 0.26 µg/l was chosen as this value exceeded 3 times the 99th percentile for a reference control group with a total test imprecision of <10% as recommended by the Joint Committee of the European Society of Cardiology and American College of Cardiology in 2000 (15). There were 2 secondary composite end points: 1) death, MI, or urgent target vessel revascularization (TVR) at 30 days; and 2) death, MI, urgent TVR at 30 days, or in-hospital major bleeding. The diagnosis of MI was made according to the TIMI study criteria and on the basis of the development of new abnormal Q waves in 2 or more contiguous pre-cordial or adjacent limb leads, elevation of CK-MB levels >3 times the upper limit of normal, and if the pre-PCI CK-MB level was higher than the upper limit of normal, then an increase by at least 50% over the previous value (16).
Bleeding end points were defined according to the REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events) criteria (6). Major bleeding included intracranial, intraocular, or retroperitoneal hemorrhage, clinically overt blood loss resulting in a decrease in hemoglobin >3 g/dl, any decrease in hemoglobin >4 g/dl, or transfusion of at least 2 U of packed red blood cells or whole blood. Minor bleeding included clinically overt bleeding that did not meet criteria for major bleeding.
All major events were adjudicated and classified by an event adjudication committee blinded to the assigned treatments. An independent data and safety monitoring committee received periodic reports blinded to assigned treatments.
Sample size and data analysis.
The study was designed as a noninferiority trial of a brief infusion of eptifibatide. We assumed the incidence of ischemic myocardial injury within the first 24 h to be 50% in the 18-h group. The upper margin for the difference between the 18-h group and the <2-h group was set at 10%. Setting power at 80% and a 1-sided alpha at 0.05, a sample size of 620 was obtained using nQUERY, version 5.0 (Statistical Solutions, Saugus, Massachusetts). To account for the randomization with sequence blocks of 6, we further expanded randomization to include 624 patients.
Descriptive data are presented as mean (SD) or as proportions (%). Categorical data were compared with the chi-square tests. The primary and secondary end points were analyzed using the test statistic described for a 1-sided null hypothesis that 18-h infusion of eptifibatide is superior to <2-h infusion of eptifibatide (17). Mean differences and the respective 1-sided, upper bound of the 95% confidence interval were computed for 3 key subgroups including diabetic patients treated with insulin or oral agents; adequate clopidogrel pre-treatment; and presentation with ACS or recent MI. The presence of effect modification was assessed using logistic regression modeling of the interaction between the subgroup of interest and the treatment modality on outcome.
All analyses were conducted according to the intention-to-treat principle, and p < 0.05 was designated as statistically significant. Statistical tests were performed using SPSS software, version 13 (SPSS Inc., Chicago, Illinois) and R versions 2.4.0 (The R Foundation for Statistical Computing, Vienna, Austria).
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Results
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The study was conducted at 2 University of British Columbia teaching hospitals (Vancouver General Hospital and St. Paul's Hospital) in Vancouver, British Columbia, Canada, with recruitment from December 2004 through July 2007. Figure 1 shows the flow of study participants. There were no significant differences between treatment groups in baseline characteristics (Table 1). Approximately one-half of the population presented with acute coronary syndrome (ACS) or had a recent (>48 h) ST-segment elevation infarction. Most patients with ACS presentation had elevated biomarkers during the hospitalization (80%). No significant differences in procedural characteristics existed between the 2 treatment groups (Table 2).
The primary end point of ischemic myocardial injury within 24 h after PCI was similar in both groups (30.1% in the <2-h group vs. 28.3% in the 18-h group; mean difference: 1.8%; upper bound of 95% confidence interval: 7.8%; p < 0.012 for noninferiority). Among key patient subgroups, neither diabetes mellitus (treated with insulin or oral agents), clopidogrel pre-treatment, nor presentation with ACS or recent MI showed a significant interaction with assigned treatments (Fig. 2). The primary end point analysis was repeated using the "per-protocol" principle, after excluding all the patients who had the eptifibatide/placebo infusion terminated prematurely (19 patients in the 18-h group and 20 patients in the <2-h group). Again, there was no significant difference between the 2 groups (31.4% in the <2-h group vs. 29.4% in the 18-h group, p < 0.001 for noninferiority).
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Figure 2 <2-h Versus 18-h Eptifibatide Infusion in Selected Subgroups
Frequency and effects of <2-h (2H) versus 18-h (18H) eptifibatide infusion on periprocedural myonecrosis in selected subgroups. ACS = acute coronary syndrome; PreRx = pre-treatment; UCL = upper confidence limit.
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Clinical follow-up at 30 days was 100%. No death, stent thrombosis, or Q-wave MI occurred in either group (Table 3). Non–Q-wave MI occurred with similar frequency in both groups (4.8% in the <2-h group vs. 4.5% in the 18-h group, p = 1.0). Two patients in the <2-h group and 3 patients in the 18-h group had post-procedure non–Q-wave MI and underwent urgent TVR with repeat PCI (1 patient on the same admission and 4 patients after readmission within 30 days).
In-hospital bleeding was adjudicated to be major on the basis of the REPLACE-2 study criteria in a total of 16 patients, 3 in the <2-h group and 13 in the 18-h group (1.0% vs. 4.2%, p = 0.02) (Table 4). One patient had upper gastrointestinal bleeding, and 15 patients had bleeding at vascular access sites (4 patients with false aneurysms that required surgical repair or ultrasound-guided thrombin injections, 1 patient with retroperitoneal bleeding treated conservatively, and 10 patients with hematomas associated with a hemoglobin drop >3 g/dl). Among the 624 patients randomized, 29 patients had early termination of the eptifibatide/placebo infusions due to clinically overt bleeding complications (20 in the <2-h group and 19 in the 18-h group); and transfusion of blood products was given to 2 patients because of access site bleeding (both in the <2-h group). Unblinding of the study drug assignment was never required.
Pre-defined secondary end points included the 30-day composite triple end points of death, MI, and urgent TVR. The event rates were similar in the 2 groups (<2-h group 4.8% vs. 18-h group 4.5%, p = NS). Pre-defined secondary quadruple end points included the triple end points plus REPLACE-2 study criterion of major bleeding, and again, the 2 groups were not statistically different (<2-h group 5.4% vs. 18-h group 8.7%, p = NS).
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Discussion
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Our data show that post-procedure eptifibatide infusion can be safely abbreviated to <2 h after successful and uncomplicated PCI performed with heparin and double-bolus eptifibatide. In comparison with the standard 18-h infusion, the abbreviated regimen was not inferior in preventing ischemic events, and resulted in less post-procedural major bleeding.
We believe our results are applicable to most candidates for contemporary PCI with stenting. Patients with stable angina and those hospitalized with ACS or recovering from ST-segment elevation MI were enrolled, and these 2 groups were equally represented ( 50% each). However, patients with high thrombus burden (e.g., acute myocardial infarction of <48 h, or obvious filling defects seen on angiography) were excluded because such patients seemed likely to benefit from a more prolonged infusion. Among 711 consenting patients who were candidates for inclusion before PCI and received primary eptifibatide in the cardiac catheterization laboratory, only 80 (11%) were excluded before enrollment.
We specified troponin-I release as the marker of ischemic myonecrosis (primary end point). This very sensitive biomarker was selected to minimize the chance of failing to detect a low intensity signal of harm attributable to abbreviating eptifibatide infusions. Although troponin release after PCI does not always predict adverse long-term outcome (18,19), studies with magnetic resonance imaging have confirmed that minor elevation of troponin after PCI is due to MI. Moreover, a positive quantitative relationship between the magnitude of troponin release and the extent of infarction has been demonstrated (20,21).
The ISAR-REACT (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment) trial showed that GP IIb/IIIa inhibition is not beneficial in patients identified as low risk before PCI, provided patients are pre-treated with high-dose clopidogrel (600 mg orally given >2 h) and aspirin (22). This approach may not be applicable to many patients in our study because 50% had recent ST-segment elevation MI or ACS (80% with elevated biomarkers). Indeed, in the ISAR-REACT-2 trial, GP IIb/IIIa inhibition was superior to placebo in the subgroup of patients with ACS and troponin elevation (23). Analysis of the subgroup of patients with recent ST-segment elevation MI or ACS in our study showed that the abbreviated eptifibatide regimen provided results similar to those of the standard 18-h infusion arm, and there was no interaction between the mode of presentation and treatment assignments (Fig. 2). Thus, while the use of GP IIb/IIIa inhibitors may be beneficial in ACS, we believe the infusion can be abbreviated for appropriate patients after uncomplicated stenting. The ISAR-REACT-2 trial also emphasized the importance of clopidogrel pre-treatment (600 mg >2 h before PCI). However, clopidogrel is frequently withheld in ad hoc PCI because of the potential for bleeding should the patient require early CABG (24). In our study, 31% of our patients did not receive adequate pre-treatment with clopidogrel. Current guidelines support the use of GP IIb/IIIa inhibitors for such patients (25). Our study results were consistent with noninferiority for the abbreviated eptifibatide infusion in this common and important subgroup. Among the 624 patients enrolled in our study, only 165 patients (26.4%) were "ISAR-REACT eligible" (Fig. 3).
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Figure 3 Proportion of Patients Potentially Eligible for Entry Into ISAR-REACT Study (n = 624)
ACS = acute coronary syndrome; ISAR-REACT = Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment trial; STEMI = ST-segment elevation myocardial infarction.
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Less major bleeding.
In the ESPRIT trial, patients treated with eptifibatide were more likely to have major bleeding than the placebo group (4). Data from the NHLBI dynamic registry showed GP IIb/IIIa inhibition in PCI was associated with a higher likelihood of developing access site hematomas that required blood transfusion (26). The REPLACE-2 study showed that there was more major bleeding with heparin plus GP IIb/IIIa blockade than with the bivalirudin plus provisional GP IIb/IIIa blockade (9.8% vs. 3.8%, p < 0.001) (6). Our study showed that shortening the infusion of eptifibatide provides an alternative means of reduced bleeding without eliminating the role of GP IIb/IIIa inhibition altogether.
Bertrand et al. (27) have previously tested the safety of truncating the administration of a GP IIb/IIIa inhibitor during PCI. They randomly allocated 1,005 patients after a bolus of abciximab and uncomplicated transradial PCI to either same-day discharge and no abciximab infusion, or to overnight hospitalization and a standard 12-h abciximab infusion. They found that same-day discharge and abciximab bolus only was not inferior to the standard overnight hospitalization and bolus plus 12-h infusion, with respect to the 30-day incidence of death, MI, urgent revascularization, major bleeding, repeat hospitalization, access site complications, and severe thrombocytopenia. Unlike our study, they used abciximab instead of eptifibatide; they measured troponin-T instead of troponin-I; and they used the transradial approach (100%) whereas we used the transfemoral approach (96%). Abciximab has prolonged antiplatelet effects even after a single bolus, whereas eptifibatide has a shorter duration of action (28,29). Abciximab bolus accounts for 75% of total dose, and our abbreviated regimen was 37% of the dose of the standard regimen. Both studies showed low clinical ischemic events and similar effectiveness in preventing troponin release. The major bleeding rate was very low in the study by Bertrand et al. (27), at 0.5%, attributed to the use of transradial approach. On the contrary, the EPIC (Evaluation of c7E3 for the prevention of Ischemic Complications) trial showed that abciximab bolus followed by a 12-h infusion was superior to the bolus-only regimen, with a 35% reduction in the rate of death, MI, unplanned revascularization, unplanned implantation of a coronary stent, or insertion of an intra-aortic balloon pump for refractory ischemia at 30 days (p = 0.008), compared with only a 10% nonsignificant reduction in patients who received the abciximab bolus only. However, the higher event rate was mostly driven by urgent repeat revascularization (3.8% bolus only, 0.8% bolus plus infusion, p < 0.001), which could be accounted for by the lack of stent utilization (<1% of patients). Furthermore, the EPIC study enrolled high-risk patients with evolving MI, refractory unstable angina, or unfavorable clinical or angiographic features. These 2 key features may explain the necessity of prolonged platelet inhibition in the EPIC study, unlike the study by Bertrand et al. (27) and our study. In the stent era, the ESPRIT trial studied lower-risk patients and showed that eptifibatide boluses followed by an infusion for 18 to 24 h was superior to placebo, resulting in a 35% reduction in death or MI at 30 days. However, the ESPRIT trial did not study the bolus-only or the short infusion approaches.
Suggested use of eptifibatide in contemporary nonemergent PCI.
One feasible approach is to risk-stratify patients on the basis of clinical presentation (stable angina vs. ACS), and to reserve eptifibatide for patients with ACS. Some operators may also choose to use eptifibatide if the coronary intervention is complex (e.g., bifurcation lesions, long lesions, small vessels, large plaque burden, diabetic, and so forth). However, risk stratification is a dynamic process, and it may be easier to predict short-term outcome after completion of the PCI procedures. Previous studies have shown that while the prophylactic use of GP IIb/IIIa inhibitors is effective, its use as a rescue agent is much less so (4,30). Thus, our study supports discontinuation of the eptifibatide infusion early if the PCI proves successful and uncomplicated. The pharmaceutical cost for a full course of eptifibatide is $450 U.S. for an average-weight patient in our hospital. With the abbreviated regimen, most patients can be treated with approximately one-third of the total dose, and there will be cost saving. Bleeding risk can also be minimized with the abbreviated regimen. Another reasonable approach is to use bivalirudin for most cases.
Study limitations.
A key entry criterion of our study is the "successful" completion of an "uncomplicated" PCI. The operator should be certain that the angiographic result is satisfactory without complications that necessitate prolonged GP IIb/IIIa inhibition such as the presence of intracoronary thrombus or "unsealed" dissection. We did not study acutely ill patients, such as those with acute MI, refractory ischemia, or hemodynamic compromise. All of our patients with ACS were stabilized before inclusion. Thus, our results may not be applicable to ACS patients who underwent very early intervention (within hours) or those with ongoing chest pain. The incidence of ischemic myonecrosis after PCI (18-h group, 28.3%) was lower than anticipated when we wrote the protocol (50%) (31,32) and was likely related to the fact that patients with suboptimal PCI results were not enrolled. As a result, our study lacked power to detect small differences between the 2 treatment groups. Although the pre-specified 10% upper margin to denote noninferiority was not exceeded, results should be interpreted with some reservation in view of the lower event rate. Post hoc analysis showed the upper bound of the 95% confidence interval for the primary end point to be 7.8%, which we believe is an acceptable clinical boundary. The absolute difference between the 2 treatment groups using the troponin I criteria was modest at 1.8%, and it was also small using the more stringent CK-MB criteria (>3 times the upper limit of normal) at 0.3%.
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Conclusions
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After successful and uncomplicated nonemergent PCI with stenting, the post-procedural infusion of eptifibatide can be safely abbreviated to <2 h, and it is not inferior to the standard 18-h infusion in preventing periprocedural ischemic events. The abbreviated regimen will reduce pharmaceutical cost and also reduce the likelihood of post-procedural major bleeding.
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Appendix
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The BRIEF-PCI study was organized as follows: Steering Committee: A. Fung, Principal Investigator, E. Aymong, C. Buller, R. Fox, K. Humphries, J. Saw, and J. Webb (Vancouver, British Columbia). Dr. Fung has full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Data and Safety Monitoring Board: W. D. Weaver, Chair (Detroit, Michigan), S. Dixon (Royal Oak, Michigan), and K. Ramanathan (Vancouver, British Columbia). Clinical Event Adjudication Committee: G. Wong (Vancouver, British Columbia). Cardiac Biomarkers Core Laboratory: M. Pudek (Vancouver, British Columbia).
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Acknowledgments
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The authors gratefully acknowledge the research and cardiology nursing staffs for their invaluable contribution to the study.
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Footnotes
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The study was funded in part by Vancouver General Hospital and University of British Columbia Hospital Foundation, Cardiology Research Fund #11011500, 2006. The Division of Cardiology, Vancouver General Hospital, has received unrestricted educational grants from Schering and Sanofi-Aventis (>$10,000) for the UBC Interventional Cardiology Conference in Vancouver, 2006.
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