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(Circulation. 2003;107:238.)
© 2003 American Heart Association, Inc.

Clinical Investigation and Reports

Randomized Evaluation of the Safety and Efficacy of Enoxaparin Versus Unfractionated Heparin in High-Risk Patients With Non-ST-Segment Elevation Acute Coronary Syndromes Receiving the Glycoprotein IIb/IIIa Inhibitor Eptifibatide

Shaun G. Goodman, MD, MSc; David Fitchett, MD; Paul W. Armstrong, MD; Mary Tan, BSc; Anatoly Langer, MD, MSc, for the Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment (INTERACT) Trial Investigators^*

From the Canadian Heart Research Centre and Terrence Donnelly Heart Centre, Division of Cardiology, St Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada (S.G.G., D.F., M.T., A.L.); and the Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada (P.W.A.).

Correspondence to Dr Shaun G. Goodman, St Michael’s Hospital, Division of Cardiology, 30 Bond St, Room 4-072 Queen, Toronto, Ontario, Canada M5B 1W8. E-mail goodmans{at}smh.toronto.on.ca

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix References

 
Background— Current pharmacotherapeutic options for high-risk non-ST-segment elevation acute coronary syndrome patients include aspirin, clopidogrel, heparin, and platelet glycoprotein IIb/IIIa inhibition. A key issue of uncertainty is the safety and efficacy of combination glycoprotein IIb/IIIa inhibitor and low-molecular-weight heparin therapy.

Methods and Results— We randomized 746 patients with rest ischemic discomfort within 24 hours after the onset of symptoms and ST-segment deviation and/or elevation of serum cardiac markers to receive open-label enoxaparin (1 mg/kg subcutaneously twice daily) or unfractionated heparin (70-U/kg bolus; 15 U · kg^-1 · h^-1 infusion, titrated to an activated partial thromboplastin time of 1.5 to 2 times control) for 48 hours. All patients received aspirin and eptifibatide (180-µg/kg bolus; 2 µg · kg^-1 · min^-1 infusion). Major non-coronary artery bypass surgery-related bleeding at 96 hours (primary safety outcome) was significantly lower among enoxaparin-treated patients than among heparin-treated patients (1.8% versus 4.6%, P=0.03). Minor bleeding was more frequent in the enoxaparin group (30.3% versus 20.8%, P=0.003). Patients in the enoxaparin group were less likely to experience ischemia as detected by continuous ECG evaluation (primary efficacy outcome) during the initial (14.3% versus 25.4%, P=0.0002) and subsequent (12.7% versus 25.9%, P<0.0001) 48-hour monitoring periods. Death or myocardial infarction at 30 days was significantly lower in the enoxaparin group (5% versus 9%, P=0.031).

Conclusions— When aspirin and eptifibatide are used in high-risk non-ST-segment elevation acute coronary syndrome patients, enoxaparin improves outcomes (determined on the basis of better safety and efficacy) compared with currently recommended unfractionated heparin therapy and provides a useful novel alternative therapeutic strategy.

Key Words: myocardial infarction • angina, unstable • heparin • anticoagulants

	Introduction

Top Abstract Introduction Methods Results Discussion Appendix References

 
Current pharmacotherapeutic options for patients with high-risk non-ST-segment elevation acute coronary syndromes (ACS) include aspirin, clopidogrel, heparin, and platelet glycoprotein IIb/IIIa inhibition.¹ Although the low-molecular-weight heparin (LMWH) enoxaparin has been demonstrated to be superior to unfractionated heparin (UFH) in two trials,^2,3 these did not include concomitant therapy with glycoprotein IIb/IIIa antagonists. Hence, a key remaining issue is the safety and efficacy of combination glycoprotein IIb/IIIa inhibitor and LMWH therapy. We hypothesized that the rates of major hemorrhage would be equivalent and rates of ischemia lower in glycoprotein IIb/IIIa inhibitor-treated patients receiving enoxaparin versus UFH.

	Methods

Top Abstract Introduction Methods Results Discussion Appendix References

 
Study Patients
Patients were eligible if they were 18 years of age and hospitalized with ischemic chest discomfort of 10 minutes’ duration occurring at rest and 24 hours before enrollment. In addition, patients were required to have: (1) ST-segment depression 0.1 mV or transient ST-segment elevation 0.1 mV in 2 contiguous ECG leads; and/or (2) elevation (determined by the local laboratory) of troponin I or T 3 times the upper reference limit, or creatine kinase (CK)-MB higher than normal.

Patients were excluded if they had any of the following findings:

(1) Cardiovascular: uninterpretable ST segment based on baseline 12-lead ECG (eg, left bundle-branch block); ischemia due to an established precipitating cause (eg, heart failure); cardiogenic shock; or scheduled or recent revascularization (coronary artery bypass surgery in previous 2 months or percutaneous coronary intervention [PCI] in previous 6 months).

(2) Bleeding risk: blood pressure >200 mm Hg systolic or >110 mm Hg diastolic; hemoglobin <11 g/dL for men or 9 g/dL for women; thrombocytopenia; ulcerative gastrointestinal disease in previous 6 months; history of cerebral hemorrhage or known intracerebral vascular disease; nonhemorrhagic stroke in previous month; eye, spinal, or central nervous system surgery in previous 2 months; major surgery, organ biopsy, puncture of noncompressible vessel in previous 2 weeks; or known or suspected pregnancy.

(3) Prior or concomitant therapy: treatment with abciximab in previous 14 days or with tirofiban or eptifibatide in previous 7 days; allergy or contraindication to aspirin or study drugs; oral anticoagulation treatment in previous 5 days or INR >1.2; fibrinolysis in previous 24 hours; or treatment with investigational agents in previous 30 days.

(4) General: renal failure (estimated creatinine clearance <30 mL/min or creatinine >2 mg/dL) or other serious disease, including liver failure; or inability to commence ST-segment monitoring 8 hours after randomization.

Initially, patients were also excluded if they had received UFH or LMWH 24 hours before enrollment. However, after 265 patients had been enrolled, the independent data and safety monitoring board and the Therapeutics Protection Directorate of Canada approved an amended protocol that included patients who had received UFH or enoxaparin 12 hours before enrollment.

Study Medications
After they had given written informed consent, patients were treated with eptifibatide (Schering Canada Inc): 180-µg/kg bolus followed by a 2.0-µg · kg^-1 · min^-1 infusion for 48 hours.⁴ All patients received oral aspirin in a dose of 160 mg initially, followed by 80 to 325 mg daily. On the basis of a computer-generated randomization code, with stratification according to center, a sequential, sealed envelope was opened at the enrolling site and patients were randomized to receive either enoxaparin (Aventis Canada; 1 mg/kg of body weight [100 anti-factor Xa units/kg] subcutaneously every 12 hours for 48 hours²) or UFH (70-U/kg intravenous bolus followed by a 15-U · kg^-1 · h^-1 continuous infusion, titrated to an activated partial-thromboplastin time [aPTT] of 1.5 to 2 times control for 48 hours¹).

Use of any other medications, the decision to proceed with angiography, and the use of revascularization were left to the discretion of the investigator.

Study Organization
Patients were recruited between September 1, 2000, and December 21, 2001, at 50 centers in Canada. The ethics review board at each institution approved the study. The study was conceived, designed, coordinated, and all the data managed and analyzed, by the Canadian Heart Research Center. The steering committee oversaw the study and the data were periodically reviewed by an independent data and safety monitoring board.

Outcome Measures
The primary safety outcome was the incidence of 96-hour, non-coronary artery bypass surgery (CABG)-related major bleeding.³ Major bleeding included bleeding resulting in death, or retroperitoneal hemorrhage, or bleeding at a specific site accompanied by a drop in hemoglobin 3 g/dL. Minor bleeding was defined as overt bleeding that did not meet the criteria for major bleeding.

The primary efficacy outcome was assessed by the rate of recurrent ischemia detected during continuous ECG monitoring. Seven-lead, three-channel ST-segment monitoring (Applied Cardiac Systems) was performed for 96 hours after randomization. Evaluation within the first 48 hours and in the >48- to 96-hour window was prespecified and based on the hypothesis that treatment differences would be evident both during study drug administration and after study drug discontinuation.⁵ Analysis was performed initially by use of an automated algorithm and subsequently reviewed twice by a cardiologist blinded to the clinical data and treatment assignment. Significant ST-segment shift was defined as horizontal or downsloping ST depression 0.1 mV below the baseline or upward ST elevation 0.1 mV above the baseline, lasting 1 minute in duration, and separated from other episodes of ST-segment shift by 1 minute.⁵

Secondary clinical outcomes were prespecified and included the composite of 30-day (1) death or nonfatal myocardial (re)infarction (MI), or (2) death, MI, or recurrent angina (with ECG changes and/or urgent revascularization). MI was considered postenrollment if CK-MB was above the upper limit of normal (ULN), increased by 50% over the previous value, and not elevated 16 hours before enrollment; if the troponin T or I was >3 times the upper reference limit and not elevated 12 hours before enrollment; or if 24 hours after coronary revascularization, the CK-MB was >3 times (PCI) or 5 times (CABG) the ULN and increased by 50% of the previous value. Recurrent angina with ECG changes was defined as symptoms of ischemia with new ECG changes detected on 12-lead ECG despite the use of nitrates and either ß-blockers or calcium-channel blockers. Recurrent angina requiring urgent revascularization was defined as symptoms of ischemia, either during the index hospitalization or resulting in rehospitalization, that prompted coronary revascularization.

Safety and efficacy outcomes were adjudicated independently on two separate occasions by a cardiologist who was blinded to treatment assignment, and included review of all laboratory tests (regardless of whether an end point was identified by the site investigator), ECGs, and reports of bleeding and ischemia.

Statistical Analysis
Safety
This was a noninferior safety comparison between the two treatment groups, designed to show that the 96-hour incidence of major hemorrhage after eptifibatide and enoxaparin did not exceed by >2% that after eptifibatide and UFH therapy. The estimated sample size of 720 patients was determined with a one-sided 95% confidence interval for the difference between the two treatments, assuming an equal major bleeding rate of 2% and an upper limit of 4% for the confidence interval.

Efficacy
This was a superiority efficacy comparison between the two treatment groups consistent with our previous finding⁵ and was designed to show that treatment with enoxaparin would reduce the incidence of ischemia monitored during the initial 48- and >48- to 96-hour periods of continuous electrocardiographic monitoring from 30% to 21% with a power ranging from 69% to 74% (with an estimated nonevaluable/dropout rate ranging from 10% to 20%; 2-sided ² test, =0.05).

All safety and efficacy analyses were based on the intention-to-treat principle and used either the log-rank or ² statistic. Follow-up to 30 days was complete in all patients.

	Results

Top Abstract Introduction Methods Results Discussion Appendix References

 
The baseline characteristics, medical history, ECG changes, and drug therapies of the patients were similarly distributed in the two treatment groups and are shown in Table 1. Treatments and procedures are listed in Table 2.

View this table: [in this window] [in a new window]   TABLE 1. Baseline Characteristics, Medical History, Electrocardiographic Changes, and Cardiac Marker Status

View this table: [in this window] [in a new window]   TABLE 2. Treatments and Procedures

Safety
The primary safety outcome of 96-hour non-CABG-related major hemorrhage was significantly lower in eptifibatide and enoxaparin as compared with eptifibatide and UFH-treated patients (1.8% versus 4.6%; P=0.03) (Table 3). This difference was already evident during the initial 48-hour treatment period (1.1% versus 3.8%; P=0.014). All major hemorrhage, including CABG-related bleeding, was lower in the enoxaparin as compared with UFH group at 96 hours (2.1% versus 5.5%; P=0.016) and at 30 days (5.3% versus 8.7%; P=0.062). There were no intracranial hemorrhages. Rates of major bleeding among patients undergoing PCI (1 of 20 versus 5 of 57 patients, P=1.0) and CABG (1 of 1 versus 6 of 7 patients, P=1.0) within 12 hours of receiving enoxaparin or UFH were similar. Transfusion rates were similar in the two treatment groups, including those who underwent CABG (Table 3). There were no major CABG-related bleeds that required surgical reexploration.

View this table: [in this window] [in a new window]   TABLE 3. Bleeding

Minor bleeding was more frequent in the enoxaparin than in the UFH group at 96 hours (30.3% versus 20.8%; P=0.003) (Table 3). The higher rate of 96-hour minor bleeding mainly was due to more local skin injection site ecchymoses (8.9% versus 4.1%; P=0.01) and oropharyngeal bleeding (predominantly epistaxis; 15.8% versus 11.2%; P=0.07).

Within the first 12 hours, only 16.7% of patients receiving UFH had an aPTT within the therapeutic range (1.5 to 2 times control); 69% were above the therapeutic range (>2 times control) and the median aPTT was 97 (25th, 75th percentiles: 61, 48) seconds. By 24 hours, 46.7% of UFH patients were in the therapeutic range; the median aPTT was 67 (54, 90) seconds.

Continuous ECG Monitoring
Patients receiving eptifibatide and enoxaparin compared with eptifibatide and UFH had lower rates of ischemia during the first 48 hours (14.3% versus 25.4%; P=0.0002) and subsequent 48 hours (12.7% versus 25.9%; P<0.0001) (Figure 1). Regardless of treatment, patients experiencing ST-segment shift compared with those without ST shift during continuous monitoring had a significantly higher 30-day rate of death or MI (15% versus 3.6%; P<0.0001), or death, MI, or recurrent angina with ECG changes (22.3% versus 6%; P<0.0001).

View larger version (29K): [in this window] [in a new window]   Figure 1. Rate of ischemia detected by 7-lead, 3-channel continuous ECG monitoring through the initial 48 hours and subsequent 48 to 96 hours after randomization.

Clinical Outcomes
Death, MI, and recurrent angina events are listed in Table 4. The 30-day composite end point of death or MI was significantly lower in the eptifibatide- and enoxaparin-treated group as compared with eptifibatide- and UFH-treated group (5% versus 9%; P=0.031) (Figure 2). The composite end point of death, MI, or recurrent angina with adjudicated 12-lead ECG changes tended to be lower in the enoxaparin group (9% versus 12.6%; P=0.11) (Figure 3). The composite end point of death, MI, or recurrent angina requiring urgent revascularization was similar in the two treatment groups (12.4% versus 12.6%; P=0.93).

View this table: [in this window] [in a new window]   TABLE 4. Clinical Outcomes

View larger version (11K): [in this window] [in a new window]   Figure 2. Kaplan-Meier curves for prespecified secondary outcome of death or nonfatal myocardial (re)infarction during the first 30 days after randomization.

View larger version (11K): [in this window] [in a new window]   Figure 3. Kaplan-Meier curves for prespecified secondary outcome of death, nonfatal myocardial (re)infarction, or recurrent angina with ECG changes during the first 30 days after randomization.

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix References

 
In this high-risk group of non-ST-segment elevation ACS patients receiving aspirin and the glycoprotein IIb/IIIa inhibitor eptifibatide, the addition of the LMWH enoxaparin as compared with UFH resulted in lower rates of major bleeding and recurrent ischemia during and immediately after treatment, and lower 30-day rates of the composite of death or MI.

This is the largest randomized trial of combination glycoprotein IIb/IIIa inhibitor and LMWH therapy as part of initial medical management in a high-risk non-ST-elevation population to date and demonstrates that this combination is superior, not only as it relates to safety, but also in reducing objective ECG and clinical measures of ischemia. Previous studies demonstrating the value of IIb/IIIa inhibition have utilized UFH as the main antithrombotic therapy.^4,6 The Antithrombotic Combination Using Tirofiban and Enoxaparin (ACUTE) II study,⁷ was a double-blind, randomized comparison of enoxaparin versus UFH in 525 patients with non-ST-segment ACS who were receiving aspirin and tirofiban. It demonstrated a similar safety profile (major hemorrhage 0.3% versus 1.0%) and 30-day rates of death (2.5% versus 1.9%) and MI (6.7% versus 7.1%). Cohen et al⁷ did observe a significant reduction in the incidence of refractory ischemia requiring urgent intervention (0.6% versus 4.3%, P=0.01) and rehospitalization for unstable angina (1.6% versus 7.1%, P=0.002) in the enoxaparin group.

The INTERACT study results may differ from the ACUTE II study findings in part because of differences in patient population, sample size, antithrombin treatment duration, and definitions of end points. For example, the high-risk nature of the larger INTERACT trial cohort is highlighted by the finding that 22.5% of patients with core laboratory-evaluated baseline ECGs had significant ST-segment deviation and 83.5% sustained an index MI. Other experiences with combination LMWH and IIb/IIIa inhibition as initial medical management in non-ST-elevation ACS patients are limited to either registry or other nonrandomized comparisons within clinical trials.

Patients in the eptifibatide plus UFH group had their intravenous study drug stopped after a median of 52 hours, whereas those in the eptifibatide plus enoxaparin group received their last subcutaneous administration at a median of 44 hours. However, it is unlikely that this difference accounts for the observation of a higher 96-hour rate of major bleeding in the UFH group. First, the actual therapeutic duration of enoxaparin, based on a much longer half-life of antithrombotic action, was quite similar to that experienced by the UFH group. Second, the difference in major hemorrhage between the two treatment groups was already evident within the first 48 hours of treatment.

Importantly, the majority of patients receiving UFH were supratherapeutic within the first 24 hours according to the aPTT measurements. Despite strict adherence to the currently recommended dosing and administration of UFH in non-ST-elevation ACS patients,¹ and consistent with previous large-scale trials utilizing UFH, the minority of patients are in the therapeutic range during the critically important first day of therapy. Thus, the strategy of combining potent antiplatelet therapies with UFH as compared with enoxaparin may lead to a higher risk of both major bleeding and thrombosis when a substantial number of patients are outside of the narrow therapeutic range.⁸

Although our study was not powered to definitively address clinical outcomes, the lower rate of death or MI and trend toward a lower incidence of death, MI, or recurrent angina with 12-lead ECG changes is consistent with the blinded continuous ECG monitoring findings in this and previous studies.^5,9–12 In addition to being an important predictor of outcome, continuous ST-segment monitoring has identified superior antiplatelet/thrombotic therapies in the management of non-ST-elevation ACS.^5,13,14 Furthermore, the recurrence of ischemic events ("rebound") after UFH withdrawal portends a worse prognosis.^15–17 Because combination aspirin, eptifibatide, and enoxaparin therapy resulted in significantly lower rates of recurrent ischemia (during initial management and after treatment withdrawal), it is not surprising that the incidence of manifest myocardial necrosis and death was also reduced.

Study Limitations
Our study was open label; however, the continuous ECG monitoring results were blinded, and all bleeding and clinical end points were adjudicated independently. The sample size was modest for evaluation of clinical outcomes, but the results are consistent with all previous comparisons of enoxaparin and UFH in the spectrum of ACS syndromes.^2,3,18–20 Optimal management of high-risk non-ST-elevation ACS patients includes an early invasive strategy,^1,21,22 and the median duration of combination therapy (48 hours) was shorter than the time to angiography (100 hours) and subsequent revascularization. Thus, the minority of patients in INTERACT received uninterrupted randomized treatment until the time of coronary angiography or revascularization. Therefore, the results of the Aggrastat to Zocor (A-to-Z)²³ and Superior Yield of the New strategy of Enoxaparin, Revascularization, and GlYcoprotein IIb/IIIa inhibitors (SYNERGY)²⁴ trials will better define the efficacy and safety of combination therapy in non-ST-elevation ACS patients managed with an early invasive approach.

In addition to aspirin, all patients in Fast Revascularization during InStability in Coronary artery disease (FRISC) II²¹ received LMWH therapy for 96 hours, and all patients in Treat angina with Aggrastat and determine Costs of Therapy with Invasive or Conservative Strategies (TACTICS)²² received UFH and glycoprotein IIb/IIIa inhibition 22 hours before angiography; thus, even an invasive strategy requires initial medical management with potent antiplatelet/thrombotic therapy. The role of clopidogrel has also been clearly established in non-ST-elevation ACS patients since our study was designed²⁵; hence, only 15% of patients received this therapy simultaneously. Although the benefit of initial treatment with eptifibatide and enoxaparin could presumably still be realized as part of a treatment strategy that included clopidogrel and an early invasive approach, the risk-benefit ratio of this approach remains unknown and warrants further study.

Conclusions
When aspirin and eptifibatide are used in high-risk non-ST-segment elevation ACS patients, enoxaparin improves outcomes (determined on the basis of better safety and efficacy) compared with currently recommended UFH therapy and provides a useful novel alternative therapeutic strategy.

	Acknowledgments

 
This research was sponsored by the Canadian Heart Research Centre, Key Pharmaceuticals, Division of Schering Canada Inc, and Millennium Pharmaceuticals Inc. Enoxaparin was provided by Aventis Canada.

	Footnotes

 
This article originally appeared Online on January 13, 2003 (Circulation. 2003;107:r8–r14).

*The INTERACT Trial investigators are listed in the Appendix.

Drs Goodman, Fitchett, Armstrong, and Langer have received research grant support and/or honorarium for educational activities and/or have served as consultants to Key Pharmaceuticals, Millennium Pharmaceuticals, and Aventis.

	Appendix

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The following persons participated in the INTERACT trial.

Steering Committee
Shaun Goodman (Principal Investigator), David Fitchett, Paul Armstrong, Anatoly Langer (Chair).

Data and Safety Monitoring Committee Co-Chairs
Graham Turpie, Peter Liu.

Canadian Heart Research Center
Mary Tan, Mona Oh, Caroline Spindler, Glennis Taylor, Janet Wawrzyniak, Aiala Barr, Damir Boras, David Burry, Diane Camara, Sue Francis, Etienne Grima, Quamrul Hassan, Tricia Hugh, Gail Karaim, Amy Lavorato, Pathmini Moharajan, Mary Triantafillou, Nalin Walgama.

Investigators (in Italics) and Coordinators Who Participated (in Order of Enrollment)
Centenary Health Center, Toronto, Ontario: Narendra Singh, Bev Bozek, Pauline Parsons, Kim Brown; Hopital Charles LeMoyne, Greenfield Park, Quebec: Jean Robert Timothee, Denise Racicot; Gray Nun’s Hospital, Edmonton, Alberta: Manohara Senaratne, Kim Heck, Marion Andreas; St Michael’s Hospital, Toronto, Ontario: David Fitchett, Mona Oh; Thunder Bay Regional Hospital-McKellar Site, Thunder Bay, Ontario: Andrew Weeks, Sandra Stoger, Gloria Russak; Medicine Hat Regional Hospital, Medicine Hat, Alberta: Michael Weigel, Paula Chisholm; Hotel-Dieu Hospital, Cornwall, Ontario: J. Paul DeYoung, Mona Burrows; Center Hospitalier de la Region de l’Amiante, Thetford Mines, Quebec: Claude Lauzon, Francine Ouimet; Royal Alexandra Hospital, Edmonton, Alberta: William Hui, Linda Kvill, Rosa Nichol; Saskatoon City Hospital, Saskatoon, Saskatchewan: Nawal Sharma, Dolores Bayne; Nanaimo Research Institute, Nanaimo, British Columbia: Kevin Lai, Francise Kernachan, Jana Stensland; Western Memorial Regional Hospital, Corner Brook, Newfoundland: Jamie Graham, Joanne Bennett; Rockyview General Hospital, Calgary, Alberta: Patrick T.S. Ma, Theresa Calmusky; Hopital General de Montreal, Montreal, Quebec: Thao Huynh, Joanne Kimball, Caroline Boudreault; Cornwall General Hospital, Cornwall, Ontario: J. Paul DeYoung, Marian Watt; The Scarborough Hospital-General Division, Scarborough, Ontario: Ted Davies, Jennifer Smith; Greater Niagara General Hospital, Niagara Falls, Ontario: Y.K. Chan, Dianna Zaniol, Donna Mallette; Toronto East General Hospital, Toronto, Ontario: Charles Lefkowitz, Michelle Thornely; Gray Bruce Health Services, Owen Sound, Ontario: George Kuruvilla, Jean Hawken; Clinique de Cardiologie de Levis, Levis, Quebec: Francois Grondin, Noella Bilodeau, Francine Dumont; Ridge Meadows Hospital, Maple Ridge, British Columbia: Francis Ervin, Ruth Ackerman; Lakeshore General Hospital, Pointe Claire, Quebec: Mladan Palaic, Sue Mitges; Campbell River and District General Hospital, Campbell River, British Columbia: John William Heath, Jill Bernard, Lisa Saffarek; Sarnia General Hospital, Sarnia, Ontario: Bal Sahay, Cheryl DeGroot; Center Hospitalier Regional du Grand Portage, Riviere-du-Loup, Quebec: Susanne Carignan, Linda Arsenault; Ottawa Heart Institute, Ottawa, Ontario: Marino Labinaz, Jo Williams, Joanna Steele, Tanya Abarbanel; CHUQ-Center Hospitalier Universitaire de Quebec, Sainte-Foy, Quebec: Louis Desjardins, Louise St-Pierre, Jocelyne Cote; Brandon General Hospital, Brandon, Manitoba: Michael Turabian, Lana Hunter; Red Deer Regional Hospital, Red Deer, Alberta: Kym Lee Jim, Carmen Petersen, Sandy Dickau; St Paul’s Hospital, Saskatoon, Saskatchewan: Sanjay Dhingra, Lynne Kuspira; Orillia Soldier’s Memorial Hospital, Orillia, Ontario: John MacFadyen, Lori Fotherby; Niagara Health System-The St Catharines General Site, St Catharines, Ontario: Govanrajan Venkatesh, Carla Feltrin, Maryann Magnotta; Center Hospitalier le Gardeur, Repentigny, Quebec: Gilbert Gosselin, Margaux David, Yvan Carrier; South East Health Care Corporation-The Moncton Hospital, Moncton, New Brunswick: Carolyn Baer, Candice MacLoughlin; Queen Elizabeth Hospital, Charlottetown, Prince Edward Island: Donald Steeves, Marcella Knox, Elenor McMillan; Health Sciences Center, Winnipeg, Manitoba: John Ducas, Angie Munoz, Sioban Loeza Aceves, Georgette Price, Cindy Kozman; Lakeridge Health Corporation-Bowmanville, Bowmanville, Ontario: David Shrives, Joy Foster; Cite de la Sante de Laval, Laval, Quebec: Gebran Boutros, Renee Major; Mineral Springs Hospital, Banff, Alberta: Michael Shuster, Pam Little; Southlake Regional Health Center, Newmarket, Ontario: Remo Zadra, Christine Benke; Humber River Regional Hospital-Finch Site, Toronto, Ontario: Teosar Bhesania, Kim Caufield; Polyclinique Maisonneuve-Rosemont, Montreal, Quebec: Christian M. Constance, Manon Maltais, Marie France Gauthier; Norfolk General Hospital, Simcoe, Ontario: Sylvester S. Chiu, Jayn Szpakowski, Patricia Loshaw, Marlene Robinson; Royal Inland Hospital, Kamloops, British Columbia: Russell Reid, Lauren Kembel; Calgary Regional Health Authority, Calgary, Alberta: Peter Giannoccaro, Peggy Beresford; The Scarborough Hospital-Grace Division, Scarborough, Ontario: John Charles, Mary Bevins, Darlene Hutton; Vancouver Hospital & Health Science Center, Vancouver, British Columbia: John Jue, Denise Delane, Cheryl Davies, Heather Abbey, L. Tarry; Dr Georges-L Dumont Regional Hospital, Moncton, New Brunswick: Michel D’Astous, Marie-Claude Theriault; Misericordia Community Hospital & Health Center, Edmonton, Alberta: Paul V. Greenwood, Anne Prosser; Atlantic Health Sciences Corporation-Saint John Regional Hospital, Saint John, New Brunswick: James Ducharme, Kim Matheson.

Received October 7, 2002; revision received November 15, 2002; accepted November 15, 2002.

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