(Circulation. 1995;92:727-733.)
© 1995 American Heart Association, Inc.
Articles |
Hirulog in the Treatment of Unstable Angina
Results of the Thrombin Inhibition in Myocardial Ischemia (TIMI) 7 Trial
From the Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Mass.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Direct thrombin inhibitors are a new class of drugs that may offer a more effective and potentially simpler alternative to heparin. Hirulog is a synthetic peptide based on the leech-derived compound hirudin and, like hirudin, is a highly specific, direct inhibitor of free and clot-bound thrombin.
Methods and Results TIMI 7 was a randomized, double-blind study of Hirulog, given with 325 mg/d aspirin to 410 patients with unstable angina. Patients received a constant infusion of Hirulog for 72 hours at one of four doses: 0.02 (n=160), 0.25 (n=81), 0.5 (n=88), and 1.0 (n=81) mg · kg-1 · h-1. The primary efficacy end point was "unsatisfactory outcome," defined as death, nonfatal myocardial infarction (MI), rapid clinical deterioration, or recurrent ischemic pain at rest with ECG changes by 72 hours. Unsatisfactory outcome was not different among the four dose groups: 8.1%, 6.2%, 11.4%, and 6.2% (P=NS). However, the secondary end point of death or nonfatal MI through hospital discharge occurred in 10.0% of patients treated with 0.02 mg · kg-1 · h-1 compared with 3.2% of patients treated with the three higher doses of Hirulog (0.25, 0.5, and 1.0 mg · kg-1 · h-1, P=.008). Only 2 of 410 patients (0.5%) experienced a major hemorrhage attributed to Hirulog.
Conclusions The direct thrombin inhibitor Hirulog is a promising new antithrombotic agent that deserves further study. The results of TIMI 7 lend support to the use of an antithrombin agent with aspirin in patients with unstable angina.
Key Words: Hirulog • angina • anticoagulants
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Plaque rupture, platelet activation, and coronary artery thrombus formation play important roles in the pathogenesis of unstable angina.1 2 3 4 5 6 7 8 Therefore, it follows that the antiplatelet agent aspirin9 10 11 12 and the anticoagulant heparin11 13 14 15 16 17 are effective in reducing the mortality and morbidity associated with this condition. Accordingly, these two agents are now considered standard therapy for the treatment of unstable angina. However, neither heparin nor aspirin is able to eliminate the significant risk of death, nonfatal myocardial infarction (MI), and recurrent ischemic pain in patients with unstable angina.8 Heparin is unable to inhibit clot-bound thrombin, and its clinical efficacy is mediated by its effect on circulating thrombin.18 In addition, heparin is susceptible to neutralization by activated platelets.19 20 The use of heparin requires frequent adjustments of dose and monitoring of its anticoagulant effects, and it is associated with a nontrivial bleeding risk.19 Although rare, heparin-induced thrombocytopenia can impose considerable risk.19
Direct antithrombins are a new class of drugs that have shown great promise in experimental and human studies. Hirulog (Biogen) is a novel 20-amino-acid synthetic peptide inhibitor of thrombin.21 In addition to its assessment in experimental models22 23 and healthy volunteers,24 previous clinical experience with Hirulog in patients with coronary artery disease has been encouraging.25 26 27 28 Sharma et al25 and Lidon et al26 treated a total of 75 patients with unstable angina, using doses of Hirulog ranging from 0.02 to 1.0 mg · kg-1 · h-1. Both studies found Hirulog to be active and well tolerated, with dose-dependent prolongation of the activated partial thromboplastin time (aPTT) and reduction in plasma fibrinopeptide A levels. No major hemorrhagic or allergic complications occurred in these 75 patients. Hirulog has also been used during cardiac catheterization27 and angioplasty.28 Both studies demonstrated that Hirulog provides a predictable level of anticoagulation with minimal bleeding and no allergic reactions. At doses >1.8 mg · kg-1 · h-1 during percutaneous transluminal coronary angioplasty (PTCA), the abrupt closure rate was decreased compared with the lower doses of Hirulog.28
TIMI 7 was designed as a randomized, double-blind pilot trial to evaluate whether a dose response existed in the efficacy of Hirulog used in conjunction with aspirin in patients with unstable angina.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Eligibility Criteria
Patients between the ages of 21 and 75 years with ischemic chest pain were screened for enrollment at 29 clinical centers (see "Appendix"). To be eligible for enrollment, patients had to experience ischemic pain at rest lasting at least 5 minutes and not longer than 60 minutes within 24 hours of randomization and at least 24 hours after a documented MI, if present. Associated evidence of coronary artery disease was also required. The latter included (1) a history of coronary artery disease, defined as one of the following: a documented prior MI, the presence of a 70% luminal diameter narrowing of a major coronary artery on a prior angiogram, or a positive thallium or sestamibi exercise test (ST-segment depression
0.1 mV and a definite reversible defect) or
(2) ECG evidence of myocardial ischemia obtained during an
episode of ischemic pain at rest within 7 days before
enrollment, defined as the presence of any of the following in two or
more contiguous leads: transient ST-segment elevation 0.1 mV,
transient or persistent ST-segment depression 0.1 mV, or transient or
persistent T-wave inversion.
Exclusion Criteria
Exclusion criteria were persistent
ST-segment elevation 0.1 mV
in two or more contiguous leads, left bundle-branch block, a treatable
cause of angina pectoris, acute pulmonary edema, other major
illness including renal failure with serum creatinine >3.0
mg/dL, confirmed systolic blood pressure <90 mm Hg, inability to be
compliant with the protocol, positive pregnancy test, PTCA within the
previous 6 months, coronary artery bypass surgery within the
previous 2 months, current enrollment in another clinical trial or
treatment with an investigational drug or therapy, current
anticoagulation therapy with aPTT >41 seconds and/or prothrombin time
>14 seconds, history of active peptic ulcer, gastrointestinal
bleeding, thrombocytopenia or coagulopathy within the previous month,
stroke within the previous month, sensitivity or allergy to aspirin,
and previous participation in TIMI 7.
The protocol was approved by each hospital's Institutional Review Board, and informed consent was obtained from each patient.
Study Design and Protocol
Eligible patients were randomized
to receive one of four doses
of Hirulog in conjunction with aspirin, designed to span a range of
levels of anticoagulation. The doses of Hirulog were 0.02, 0.25, 0.50,
and 1.0 mg · kg-1 · h-1, with
a randomization ratio of 2 (0.02
mg · kg-1 · h-1) to 1 (0.25
mg · kg-1 · h-1) to 1 (0.50
mg · kg-1 · h-1) to 1 (1.0
mg · kg-1 · h-1). Patients
were
randomized by use of consecutive sealed envelopes, and 420 patients
were enrolled.
Dose-blinded study drug was administered as a continuous infusion for 72 hours unless the patient experienced a major safety or efficacy end point. After the Hirulog infusion, the use of heparin was at the discretion of the treating physician and was carried out in 46% of patients. On-site measurement of coagulation parameters such as aPTT, prothrombin time, or activated clotting time was not permitted except for emergency management. Blood samples for aPTT determination in a central laboratory were obtained at baseline, 12 to 24 and 36 to 48 hours after the start of infusion, and 12 to 24 hours after the discontinuation of study drug.
All patients received 325 mg of aspirin daily. Additional conventional medical therapy for unstable angina, including bed rest, ß-blockers, calcium antagonists, nitrates, and oxygen, was administered at the discretion of the treating physician. Coronary angiography was deferred during the study drug infusion. During hospitalization, patients were monitored for recurrent ischemic pain and MI. ECGs were obtained for ischemic pain at rest lasting at least 5 minutes. Serial creatine kinase isoenzymes and ECGs were obtained after enrollment and for recurrent ischemic pain at rest lasting more than 30 minutes. ECGs and enzyme measurements were interpreted by the ECG Core Laboratory, which was blinded to treatment assignment.
Patients were also monitored during and through 24 hours after the study drug infusion for clinical evidence of bleeding and other adverse study events. Patients were contacted by telephone to determine the incidence of clinical events between hospital discharge and 6 weeks.
End Points
Efficacy
The primary efficacy end
point was "unsatisfactory
outcome," a composite end point defined as the occurrence of any of
the following at 72 hours: death, MI not present at enrollment,
recurrent ischemia at rest with ECG changes, and rapid clinical
deterioration (other than ischemic pain) necessitating
emergency angiography/revascularization. MI was
defined as in TIMI 3,8 and ischemia was defined as
ischemic pain at rest lasting >5 minutes with documented ECG
changes sufficient to satisfy inclusion criteria. Secondary efficacy
end points were the individual components of the primary end point and
the incidence of death and nonfatal MI at 6 weeks.
Safety
The incidence of hemorrhagic events (classified as major or
minor) was determined for each dose group. Major hemorrhage was
defined as intracranial, retroperitoneal, or clinically overt
hemorrhage with a fall in hemoglobin of at least 3 g/dL or
leading to a transfusion of two or more units of blood. Minor
hemorrhage was defined as clinically overt bleeding that did
not fulfill the criteria for major hemorrhage.
Components of the primary end point were confirmed by the ECG Core Laboratory (MI, recurrent ischemia, rapid clinical deterioration) and by the Morbidity and Mortality Classification Committee (death, MI, rapid clinical deterioration, major hemorrhage), both of which were blinded to treatment assignment.
Statistical Considerations
The sample size and allocation
ratio were chosen so that tests
conducted using a combined response of two of the three higher-dose
groups versus the 0.02
mg · kg-1 · h-1 dose group
response
would have at least 90% power to detect a reduction in the incidence
of unsatisfactory outcome by 60%, assuming an incidence of 25% in
patients treated with 0.02
mg · kg-1 · h-1. Significance
testing
was performed with the Fisher exact test. For the primary
analysis, a value of P<.05 was considered
significant; for secondary analyses, to account for multiple
comparisons, a value of P<.01 was considered significant.
Two cohorts of patients were prospectively identified for efficacy
analysis. The primary analysis was of all patients who
received any amount of study drug. A second cohort of "evaluable"
patients consisted of patients who met all eligibility criteria and
received at least 4 hours of study drug.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Patient Population
A total of 420 patients were randomized in the trial. Ten patients did not receive study drug, of whom 7 had an exclusion criterion identified after randomization, 2 became clinically unstable, and 1 subsequently refused to participate, leaving 410 patients in the prespecified study group. Three patients did not fulfill the inclusion criteria, and 6 received <4 hours of study drug, resulting in 401 evaluable patients. The results of the analyses of the evaluable cohort were similar to those of the primary analyses, and only the latter results are presented.
Baseline Characteristics
The mean age of the patients was 60
years, and one third were
women (Table 1
). Nearly half of the patients had a prior
MI, and 30% of patients presented with new-onset angina.
Protocol-defined ECG changes were present at enrollment in 220
patients (54%), divided equally between ST-segment deviation and
isolated T-wave inversion. Thirty-three patients (8%) were
subsequently determined to have had a non–Q-wave MI at the time of
enrollment. The baseline characteristics were similar in each of the
four dose groups. After the 72-hour study drug infusion, heparin was
used in 46% of patients overall, with a smaller proportion of patients
in the highest-dose group receiving heparin, 32% (four-way
P=.03).
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Unsatisfactory Outcome
There was no difference in the primary
end point
"unsatisfactory outcome" (ie, death, nonfatal MI, rapid clinical
deterioration, or recurrent ischemic pain at rest with ECG
changes) at 72 hours, which occurred in 8.1%, 6.2%, 11.4%, and 6.2%
of patients, respectively, across the four ascending dose groups
(four-way P=.56) (Fig 1). Similarly, although
the event rates were higher, no difference was seen for this end point
at hospital discharge (P=.38) (Table 2).
Across the four dose groups, there was no difference in the incidence
of recurrent rest pain with ECG changes, occurring in 6% to 8% of
patients by hospital discharge.
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Death and Nonfatal MI
The secondary end point of death or
nonfatal MI at hospital
discharge occurred in 16 of 160 patients (10.0%) in the low-dose group
compared with 8 of 250 patients (3.2%) who received one of the three
higher doses of Hirulog (0.25, 0.5, or 1.0
mg · kg-1 · h-1,
P=.008) (Fig 2). A similar finding was
observed at 6 weeks (12.5% versus 5.2%, P=.009). When
patients with ST-segment deviation at enrollment, those with ST-segment
deviation and/or T-wave inversion, and those without ECG changes were
examined, trends were similar to those seen in the entire population:
the rate of death or MI in the low- versus higher-dose groups was
13.0% versus 3.0% in patients with ST deviation (P=.06)
and 9.3% versus 2.6% in those without ECG changes
(P=.05).
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Angiography and Revascularization
Procedures
Coronary angiography was performed before hospital
discharge in 259 patients (63%). Angioplasty was performed in 72
patients (18% of the total population), and 84 (20%) underwent
coronary artery bypass surgery, with no significant differences
between the dose groups. Of the 250 patients with satisfactory
angiograms, 88 (35%) had three-vessel disease, 130 (52%) had one- or
two-vessel disease, and 32 (13%) had no stenoses 70%. In
patients undergoing angioplasty, there were no in-hospital deaths or
MIs in patients treated with the higher doses of Hirulog, compared with
3 of 33 (9.1%) in the low-dose group (P=.09).
Hematologic Findings
At 12 to 24 hours after the start of
infusion, the mean aPTT in
the 0.02 mg · kg-1 · h-1 dose
group
was 38.1 seconds (139% of baseline), indicating that even this low
dose of Hirulog was biologically active (Table 3). The
mean aPTTs in the three high-dose groups at 12 to 24 hours were 65.2,
79.1, and 87.9 seconds, respectively. The mean aPTTs in all dose groups
remained constant at the 24- to 36-hour time point. After the study
drug was discontinued, aPTT values returned to baseline.
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Of the patients who received one of the three higher doses, 57.1% maintained an aPTT within a 10-second range throughout the study drug infusion without dose adjustment, 78.6% maintained a 20-second range, 92.9% a 30-second range, and 99.1% a 40-second range.
Safety End Points
Major spontaneous hemorrhage attributed to
study drug
occurred in two patients (0.5%); one patient in the 0.50
mg · kg-1 · h-1 dose group
experienced a gastrointestinal bleed, and one patient who had received
1.0 mg · kg-1 · h-1 ruptured
an
abdominal aortic aneurysm 12 hours after the termination of the
Hirulog infusion. Two additional patients in the 1.0
mg · kg-1 · h-1 dose group had
minor
bleeding that required termination of the study drug. There were no
intracranial or retroperitoneal hemorrhages related to the
study drug. Anaphylaxis was not observed.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The treatment of unstable angina requires rapid inhibition of intracoronary thrombus formation or extension, a reduction of myocardial oxygen demand, and coronary vasodilation.29 While an aggressive regimen of ß-blockers, nitrates, calcium antagonists, and bed rest can reduce myocardial oxygen requirements and coronary vasospasm, results of clinical trials indicate that intracoronary plaque rupture and superimposed thrombus are best treated with anticoagulants and/or antiplatelet agents. Aspirin has been shown to reduce death and MI in patients with unstable angina and is now part of standard therapy.9 10 11 12 Heparin has also been shown to be effective in improving the clinical outcome of patients with unstable angina.11 13 14 15 16 17 In a study by Theroux et al,17 heparin was superior to aspirin in the management of these patients, supporting the concept that thrombin plays a central role in the pathogenesis of unstable angina. Recombinant hirudin, one of the new direct thrombin inhibitors, has also been studied in patients with unstable angina and, compared with heparin, demonstrated a trend toward more improvement in the average cross-sectional area of culprit lesion stenosis.30 These results suggest that direct thrombin inhibition may be even more effective in unstable angina than heparin.
Hirulog: Structure and Function
Hirulog was designed with the
natural leech-derived thrombin
inhibitor hirudin as a model.21
Structure-function studies of Hirulog show that it is composed of three
domains: (1) a COOH-terminal domain whose sequence was derived from the
hirudin COOH-terminus, which binds to a substrate recognition site
unique to thrombin; (2) an NH2-terminal domain capable of
blocking the catalytic-site activity of thrombin; and (3) a linker
domain of four glycine residues.21 31 Hirulog
reversibly
inhibits all of the major actions of thrombin, including the cleavage
of fibrinogen to fibrin, activation of platelets, and activation of
factors V and VIII, a positive amplification reaction that generates
more thrombin.32 33 It inhibits both free and
clot-bound
thrombin, which may prevent thrombus extension as well as
formation.31 34 35
Clinical Effects
TIMI 7 was a randomized trial that examined
the effects of four
ascending doses of Hirulog used together with aspirin in patients with
unstable angina. Although the lowest dose, 0.02
mg · kg-1 · h-1, was used as a
control, even this dose had a modest effect, causing an 11-second
(39%) prolongation of the aPTT. Even though the prespecified composite
primary end point did not differ between dose groups, patients who
received one of the three higher doses of Hirulog had a lower incidence
of the secondary end point of death and nonfatal MI at hospital
discharge (3.2%) than patients who received the low dose (10.0%).
This difference in outcome persisted at 6 weeks. All four doses of
Hirulog had stable effects on the aPTT and a very low incidence of
major hemorrhage (0.5%).
Effective Anticoagulation
One of the potential advantages of
Hirulog over heparin is its
ability to establish a predictable and stable level of anticoagulation
without dose titration. The aPTT response was stable over time in all
dose groups; 92.9% and 99.1% of patients maintained aPTTs within 30-
and 40-second ranges, respectively. Topol et al30 compared
heparin and hirudin in unstable angina and reported that only 16% of
patients who received heparin and 71% of those who received hirudin
maintained aPTTs within a 40-second range. Similar results were
observed in patients with acute MI who were also treated with TPA in
TIMI 5; 19% of heparin-treated patients and 55% of hirudin-treated
patients maintained a 40-second range.36 The stable level
of anticoagulation provided by a constant infusion of Hirulog may
contribute to both its safety and efficacy and certainly adds to the
convenience of using this drug by reducing the need to obtain frequent
aPTTs for dose titration.
All four doses were well tolerated, with a very low incidence of spontaneous major hemorrhage; these results support the findings of previous pilot trials that did not demonstrate excessive bleeding with Hirulog.25 26 27 28 31 The encouraging safety profile of this direct thrombin inhibitor may be due to its primary clearance by metabolic pathways; <20% of the administered dose is cleared by renal excretion.24 31 With a short half-life of 36 minutes,24 27 31 Hirulog is likely to be a relatively safe anticoagulant.
Combination Antithrombotic Therapy
Controversy persists
concerning the relative benefits of aspirin,
heparin, and their combination when used for acute ischemic
syndromes. Several randomized trials have confirmed the efficacy of
antiplatelet agents in unstable
angina,9 10 11 12 37
while
other trials have shown the clinical benefit of
heparin.11 13 14 15 16 17
Although there appears to be benefit in
the combination of an antiplatelet and an
antithrombin,38 an additive effect on clinical outcome at
hospital discharge or during follow-up by using heparin has not been
definitively demonstrated to
date.11 12 38 39 In this
trial, all patients received 325 mg of aspirin daily, and those who
received the higher doses of Hirulog, which achieved aPTT values in the
range of 65 to 90 seconds, appeared to have an improved outcome (based
on the secondary end point of death or MI) compared with patients who
received aspirin and the low dose of Hirulog, which achieved aPTT
values of approximately 40 seconds. These observations suggest that
using aspirin plus a direct thrombin inhibitor, at a level
of anticoagulation similar to what is considered the therapeutic range
for heparin,19 may be more effective than aspirin and a
low level of anticoagulation (or aspirin alone).
Limitations of the Study
The overall event rates were lower
than expected, making the study
underpowered to demonstrate a dose response. Because the protocol
required that cardiac catheterization and
revascularization be deferred during the initial
72-hour infusion, there may have been a reluctance to enroll the most
acutely ill patients, and this may have contributed to the low overall
event rate. Patients with chest pain lasting >1 hour were not eligible
for the trial, which may also have contributed to the
lower-than-expected event rate. For a definitive comparison with
current therapy (ie, heparin), a single dose of Hirulog needs to be
used in a much larger trial. Based on the findings of this trial, an
appropriate dose would be one of the three higher doses. In addition,
future trials in unstable angina should focus on death and nonfatal MI,
which are more likely to be mediated by intracoronary thrombus
and progression to occlusion.
Conclusions
In this pilot trial of 410 patients with unstable
angina, the new
direct thrombin inhibitor Hirulog, when added to aspirin,
appears to be well tolerated and provides a stable aPTT without dose
adjustment. While the incidence of unsatisfactory outcome at 72 hours
did not differ among the various doses used, patients treated with the
three higher doses of Hirulog had a lower incidence of the secondary
end point of death and nonfatal MI, both at hospital discharge and 6
weeks, than those who received the low dose in addition to aspirin.
Thus, Hirulog appears to be a promising new agent for use in the
treatment of unstable angina. A larger, definitive study to compare its
efficacy and safety with those of heparin appears warranted.
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Acknowledgments |
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This study was supported by a grant from Biogen, Cambridge, Mass. Additional support was supplied by Genentech, South San Francisco, Calif.
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Footnotes |
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Reprint requests to Eugene Braunwald, MD, Department of Medicine, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail timi@bwh.harvard.edu.
1 A complete list of the TIMI 7 Investigators is in the
"Appendix." 
Guest editor for this article was J. David Bristow, MD, Oregon Health Sciences University, Portland.
Study Chairman's Office: Brigham and Women's Hospital, Harvard Medical School, Boston, Mass. Study Chairman, Eugene Braunwald, MD. Coinvestigators, Joanna Fuchs, MD, Christopher P. Cannon, MD, Elliott M. Antman, MD. Project Director, Carolyn H. McCabe, BS. Study Coordinator, Tia DeFeo-Fraulini, MS.
Data Coordinating Center: Quintiles, Research Triangle Park, NC. Director, Bill Sollecito, DrPH. Project Manager, Laurence Wallman. Statistician, Gail Tudor, PhD.
Angiographic Core Laboratory: Rhode Island Hospital, Providence, RI. Principal Investigator, David O. Williams, MD. Director, Barry Sharaf, MD. Research Coordinators, Paula Ferreira, RN, Nicholas Miele, BA.
ECG Core Laboratory: St Louis University, St Louis, Mo. Principal Investigator, Bernard Chaitman, MD. Research Coordinator, Karen Stocke, BS.
Steering Committee: The members of the Steering Committee are the Study Chairman and the principal investigators of the core laboratories and of the clinical centers listed below.
Data and Safety Monitoring Board: Charles Hennekens, MD, DrPH (chair); John Kelton, MD, Gottlieb C. Friesinger II, MD, Bernard Gersh, MB, ChB, DPhil, Richard Gorlin, MD.
Morbidity and Mortality Classification Committee: Christopher P. Cannon, MD (chair); Steven Borzak, MD, Nieca Goldberg, MD, Timothy D. Henry, MD, Christopher Thompson, MD.
Clinical centers (in the order of the number of patients enrolled):
Henry Ford Hospital, Detroit, Mich. Principal Investigator, Steven Borzak, MD. Co–Principal Investigator, Philip L. Kraft, MD. Research Coordinator, Lori Douthat, RN.
Hopital du Sacre-Coeur de Montreal, Quebec, Canada. Principal Investigator, Donald Palisaitis, MD. Research Coordinator, Ginette Gaudette, RN.
Emerson Hospital, Concord, Mass. Principal Investigator, Steven Herson, MD. Co–Principal Investigator, Richard Daum, MD. Research Coordinator, Gail Carey, RN.
Robert Wood Johnson Medical School, New Brunswick, NJ. Principal Investigator, Sebastian Palmeri, MD. Research Coordinator, Laurie Casazza, RN.
University of Miami, Miami, Fla. Principal Investigator, Rafael Sequeira, MD. Coinvestigator, Eduardo de Marcena, MD. Research Coordinator, Carmen Prieto, RN.
West Roxbury VA Hospital, West Roxbury, Mass. Principal Investigator, G.V.R.K. Sharma, MD. Research Coordinator, Diane Lapsley, RN.
University of Calgary, Foothills Hospital, Calgary, Alberta, Canada. Principal Investigator, J. Wayne Warnica, MD. Research Coordinators, Terry Churchill-Smith, RN, Lorraine Granberg, RN.
Beth Israel Hospital, Boston, Mass. Principal Investigator, Daniel J. Diver, MD. Research Coordinator, Susan Marble, RN, MS.
Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY. Principal Investigator, Hiltrud Mueller, MD. Research Coordinator, Joseph Cosico, RN.
Ohio State University, Columbus, Ohio. Principal Investigator, Raymond Magorien, MD. Research Coordinator, Jennifer Wilmer, RN.
Downstate Medical Center, Brooklyn, NY. Principal Investigator, Nieca Goldberg, MD. Research Coordinator, Rosa Julien, RN.
Loyola University Medical Center, Maywood, Ill. Principal Investigator, Ferdinand Leya, MD. Research Coordinator, Ellen Galbraith, RN.
Rhode Island Hospital, Providence, RI. Principal Investigator, David O. Williams, MD. Co–Principal Investigator, George R. McKendall, MD. Research Coordinator, Louise Erickson, RN.
St Paul's Hospital, Vancouver, BC. Principal Investigator, Christopher Thompson, MD. Research Coordinator, Etta Lau, RN.
Miami VA Hospital, Miami, Fla. Principal Investigator, Simon Chakko, MD. Research Coordinator, Carmen Prieto, RN.
Yale University, New Haven, Conn. Principal Investigator, Michael Remetz, MD. Research Coordinator, Gayle Mirto, RN.
Brigham and Women's Hospital, Boston, Mass. Principal Investigator, Elliott M. Antman, MD. Research Coordinator, Paul Sedgwick, RN.
St Luke's Hospital, New York, NY. Principal Investigator, Judith S. Hochman, MD. Research Coordinator, Mary McAnulty, RN.
Roosevelt Hospital, New York, NY. Principal Investigator, Anthony J. Pepe, MD. Research Coordinator, Mary McAnulty, RN.
Hennepin County Medical Center, Minneapolis, Minn. Principal Investigator, Timothy D. Henry, MD. Research Coordinator, Lorri Knox, RN.
Baystate Medical Center, Springfield, Mass. Principal Investigator, Marc Schweiger, MD. Research Coordinator, Deborah Warwick, RN.
Lenox Hill Hospital, New York, NY. Principal Investigator, James Wilentz, MD. Research Coordinator, Denise McDermott, RN.
University of Sherbrooke, Sherbrooke, Quebec, Canada. Principal Investigator, Vincent Dangoisse, MD. Research Coordinator, Jacqueline Dangoisse.
Kaiser Permanente Medical Center, Los Angeles, Calif. Principal Investigator, Peter Mahrer, MD. Research Coordinators, Judy Fletcher, RN, Joni Noceda, RN.
Victoria General Hospital, Halifax, NS. Principal Investigator, Catherine Kells, MD. Research Coordinator, Vivian Nedelcu, RN.
Lahey Medical Center, Burlington, Mass. Principal Investigator, Sherif Labib, MD. Research Coordinator, Gail Woodhead, RN.
Hospital of the Good Samaritan, Los Angeles, Calif. Principal Investigator, Thomas Shook, MD. Research Coordinator, Lucille Junio, RN.
LDS Hospital, Salt Lake City, Utah. Principal Investigator, Jeffrey L. Anderson, MD. Research Coordinator, Ann Allen, RN.
Received January 9, 1995; accepted February 19, 1995.
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