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(Circulation. 2000;102:149.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Oral Glycoprotein IIb/IIIa Inhibition With Orbofiban in Patients With Unstable Coronary Syndromes (OPUS-TIMI 16) Trial
From Brigham and Women’s Hospital, Boston, Mass (C.P.C., C.H.M., E.B.); Queen’s Medical Centre, UK (R.G.W.); St Michael’s Hospital, Toronto, Canada (A.L.); Kaplan Medical Center, Israel (A.C.); Martini Ziekenhuis, The Netherlands (P.B.); Hospital Gregorio Maranon, Spain (J.L.-S.); University Hospital of St Anna, Czech Republic (J.T.); Nottingham Clinical Research Group, Nottingham, UK (A.C., A.S.); and Searle, Skokie, Ill (R.J.A., J.C.A.).
 |
Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionAppendix 1References |
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Background—Although intravenous glycoprotein IIb/IIIa inhibitors are beneficial in patients with acute coronary syndromes, prolonged oral IIb/IIIa inhibition might provide an additional reduction in recurrent events.
Methods and Results—Investigators at 888 hospitals in 29 countries enrolled 10 288 patients with acute coronary syndromes, which was defined as ischemic pain at rest within 72 hours of randomization, associated with positive cardiac markers, electrocardiographic changes, or prior cardiovascular disease. Patients received aspirin and were randomized to receive, for the duration of the trial, (1) 50 mg of orbofiban twice daily (50/50 group), (2) 50 mg of orbofiban twice daily for 30 days followed by 30 mg of orbofiban twice daily (50/30 group), or (3) a placebo. The primary composite end point was death, myocardial infarction, recurrent ischemia requiring rehospitalization, urgent revascularization, or stroke. The trial was terminated prematurely because of an unexpected increase in 30-day mortality in the 50/30 orbofiban group. Mortality through 10 months was 3.7% for the placebo group versus 5.1% in the 50/30 group (P=0.008) and 4.5% in the 50/50 group (P=0.11). There were no differences in the primary end point (22.9%, 23.1%, and 22.8%, for the placebo, 50/30, and 50/50 groups, respectively). Major or severe bleeding (but not intracranial hemorrhage) was higher with orbofiban; it occurred in 2.0%, 3.7% (P=0.0004), and 4.5% (P<0.0001) of patients, respectively. Exploratory subgroup analyses found that patients who underwent percutaneous coronary intervention had a lower mortality and a significant reduction in the composite end point (P=0.001) with orbofiban.
Conclusions—Fixed-dose orbofiban failed to reduce major cardiovascular events and was associated with increased mortality in this broad population of patients with acute coronary syndromes; however, a benefit was observed among patients who underwent percutaneous coronary intervention.
Key Words: coronary disease • myocardial infarction • heart diseases • stroke • platelet aggregation inhibitors
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Intravenous platelet glycoprotein (GP) IIb/IIIa receptor antagonists reduce ischemic complications after percutaneous coronary intervention (PCI) and in patients with acute coronary syndromes.1 2 3 Great interest has emerged in the potential for oral GP IIb/IIIa inhibitors to provide benefits in the long-term treatment of patients with acute coronary syndromes, because platelets remain activated long after a patient has become stabilized clinically.4 Orbofiban is an oral ethyl-ester pro-drug that specifically blocks the binding of fibrinogen to the platelet GP IIb/IIIa receptor (with a higher affinity for the activated versus unactivated receptor), thereby interfering with the platelet aggregation induced by various agonists. The active molecule is excreted renally and has a terminal elimination half-life of 16 to 18 hours. The 2 doses selected for the Orbofiban in Patients with Unstable Coronary Syndromes (OPUS-TIMI 16) trial targeted mean trough and peak levels of platelet inhibition of 45% to 65% and 55% to 80%, respectively.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Study Population
Between October 16, 1997 and November 5, 1998, 10 302 patients were enrolled at 888 hospitals in 29 countries (Appendix). Informed consent documents could not be retrieved from 14 patients, which left a total of 10 288 patients in the study. Inclusion criteria were ischemic discomfort at rest lasting
5 minutes with onset
within 72 hours of randomization and associated with 1 of the
following features: new or presumably new ST segment deviation
0.5 mm, T-wave inversion 3 mm in 3 leads or left bundle
branch block, positive cardiac markers, or (for the first 3000 patients
only) history of myocardial infarction (MI), PCI, coronary
artery bypass grafting, coronary stenosis 50%, age
65 years and a history of angina or positive stress test, prior
peripheral arterial or cerebrovascular disease,
or diabetes mellitus.
Exclusion criteria were as follows: age 
18 or legal age, pregnancy,
comorbidity with life expectancy <2 years, prior PCI within the
previous 6 months (other than for the index event) or coronary
artery bypass grafting within 2 months, prior hemostatic disorder,
thrombocytopenia, significant systemic bleeding, documented peptic
ulcer within 6 months, prior intracranial hemorrhage or
vascular abnormality, current or future need for warfarin, need for
chronic daily nonsteroidal anti-inflammatory drugs, receipt of >2
doses of ticlopidine/clopidogrel within 48 hours or abciximab within 24
hours, creatinine >1.6 mg/dL (142 µmol/L) or a
calculated creatinine clearance of <40 mL/min,
hypersensitivity to aspirin or a IIb/IIIa inhibitor,
uncontrolled hypertension, participation in another investigational
drug or device trial within 30 days, or prior treatment with
orbofiban.
Trial Design
Eligible patients were treated with 150 to 162 mg of aspirin
daily and were randomized in a 1:1:1 fashion to receive, for the
duration of the trial, (1) 50 mg of orbofiban twice daily (50/50
group), (2) 50 mg of orbofiban twice daily for 30 days followed by 30
mg of orbofiban twice daily (50/30 group), or (3) placebo. In patients
who experienced 2 episodes of unprovoked minor bleeding, a dose
adjustment was made from 50 mg to 30 mg or from 30 mg to 20 mg.
Patients who had stent placement were given double-blinded stent
medication for 2 to 4 weeks, with those in the placebo group receiving
250 mg of ticlopidine twice daily and those in the orbofiban groups
receiving a matching placebo for ticlopidine (plus orbofiban for the
duration of the trial). Other therapies were given at the discretion of
the treating physician. Patients were seen in follow-up at 14 and 30
days and every 3 months thereafter, with complete blood counts
performed at each visit. Treatment and follow-up were planned to
continue for an average of 1 year (minimum of 6 months).
Statistical Analyses
The primary end point was a composite of death, MI, recurrent
ischemia at rest leading to rehospitalization or urgent
revascularization, or stroke, using standard TIMI
definitions (definitions can be found at
www.circulationaha.org).5 6 Severe or life-threatening
bleeding was defined as an intracranial hemorrhage or bleeding
associated with severe hemodynamic compromise; major
bleeding was that associated with >15% absolute reduction in
hematocrit or requiring a blood transfusion; minor bleeding was
(nonmajor) bleeding that required medical treatment or laboratory
evaluation. The Clinical Events Committee adjudicated all end points in
a blinded fashion.
Outcome results are presented with Kaplan-Meier event rates,
and probability values were determined from log-rank tests. The
interaction probability values are from Cox regression
analysis. Prespecified primary analyses were through
follow-up (with 
=0.02 for each dose versus placebo) or to 30 days
(both orbofiban groups were combined because all patients received 50
mg twice daily; =0.01). The planned sample size of 12 000 patients
would have provided, assuming a 22% control group event rate, 97%
power to detect a 20% difference in each orbofiban group versus
placebo through follow-up and 88% power to detect a 20% difference of
orbofiban versus placebo at 30 days.
Subgroup and exploratory analyses were also performed with univariate and multivariate analysis looking for interactions with treatment assignment for both mortality and the composite end point. Cause of death was reviewed in a blinded fashion by members of the Operations Committee and categorized by underlying cause as follows: new thrombotic event (subcategorized into recurrent MI, stroke, peripheral vascular event, and venous thromboembolism); sudden, progressive early deterioration from the index event (defined as patients with evidence of instability or hemodynamic compromise at randomization resulting from the index acute coronary syndrome, who clinically worsened over the subsequent 24 to 72 hours to death, which could not be explained by a new clinical event); nonischemic event; and uncertain.
Interim Analyses
The independent Data and Safety Monitoring Board monitored the
trial with monthly safety reports (reviewed by the Chairman), a safety
analysis after 3000 patients were followed for 30 days, and
interim efficacy analyses after 
33% and 66% of end
points had occurred. Interim analyses to support an early
stopping decision were based on mortality using the Lan-DeMets
implementation of the O’Brien-Fleming boundary.7
At the recommendation of the Data and Safety Monitoring Board, enrollment in the trial was terminated prematurely on November 5, 1998 due to increased 30-day mortality in the 50/30 orbofiban group compared with placebo. All patients enrolled within the prior 30 days were taken off the study drug. Because no excess mortality was observed between 30 days through follow-up at that point, the remaining patients continued on the study drug. A weekly review of the data showed no improvement in the composite end point or mortality, and the trial was terminated on January 18, 1999.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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The baseline characteristics of the 3 groups were similar (Table 1
). Patients were, on
average, 60 years old; 28% were women, and 21% had diabetes mellitus.
Electrocardiographic changes were present in 84% of patients. The
index event was MI in 60% of patients. In the total cohort, 18.5% had
received thrombolytic therapy and 7% had undergone
primary PCI. PCI was performed before enrollment in 10% of patients
and after randomization in 18% (n=1852); of these 1852 patients, 1423
(77%) had stent placement and 324 (17%) received abciximab. Heparin
was administered before enrollment in 87% of patients, of whom 17%
received low-molecular-weight heparin (LMWH). Baseline
creatinine clearance (calculated)8 was >100
mL/min in 50% of patients, 60 to 100 mL/min in 40%, and <60 mL/min
in 10%. The median time from onset of the index event to randomization
was 41 hours (interquartile range, 25 to 56 hours).
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30-Day Outcomes
Because the 2 orbofiban groups received the same dose (50 mg twice
daily) for the first 30 days, the results from the groups were
combined. Although the composite end point was not different between
the orbofiban and placebo groups (9.9% for orbofiban versus 10.8% for
placebo; P=0.12), death occurred more frequently (2.0%
versus 1.4%; P=0.02) in the orbofiban group. The increase
in death only occurred in the orbofiban 50/30 group (2.3% versus 1.6%
in the 50/50 group; P=0.04) (Table 2). Recurrent MI, stroke, and recurrent
ischemia requiring rehospitalization were not significantly
reduced by orbofiban, but ischemia leading to urgent
revascularization was significantly reduced by the
drug (2.7% versus 4.4%; P<0.0001).
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Events to Long-Term Follow-Up
The rates of the composite end point and mortality through
10-month follow-up are shown in Figures 1 and 2. The primary composite end point
was not reduced by either of the orbofiban dosing
strategies (Table 3). However, mortality remained higher
with orbofiban, although no significant increase in mortality occurred
after 30 days (2.4% for placebo versus 2.9% in each orbofiban group;
P=0.24). Recurrent MI was numerically, but not
statistically, higher in orbofiban-treated patients. Urgent
revascularization remained significantly lower with
orbofiban. The rate of any revascularization
procedure was 40% for placebo, 40% for orbofiban 50/30, and 39% for
orbofiban 50/50.
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More deaths due to new thrombotic events occurred in the
orbofiban-treated groups (Table 4): overall rates were
0.7% for placebo and 1.2% in each orbofiban group (each dose versus
placebo, P=0.03). Bleeding explained only 5% of the deaths
in the orbofiban groups. More deaths were due to progressive
deterioration from the index event in the 50/30 orbofiban group, which
might explain some of the increased 30-day mortality in that group.
|
Bleeding Events and Thrombocytopenia
Intracranial hemorrhage (0.2%) and severe bleeding
(0.5%) were similar between the placebo and orbofiban groups (Tables 3
and 5). Major and minor bleeding were significantly
more common with orbofiban; however, the absolute increase in major
bleeding was only 1.5% to 2% greater than that in the placebo group
during 10 months of active treatment (Table
5). Thrombocytopenia was
rare, but more common with orbofiban. Interestingly, platelet
counts were higher during follow-up in patients receiving orbofiban;
they rose from a baseline mean of 218x109
cells/L (in all groups) to 243, 249, and 251x109
cells/L in the placebo, orbofiban 50/30, and orbofiban 50/50 groups,
respectively, by days 5 to 7 (P=0.0001).
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Subgroup Analyses
Patient subgroups who were generally at a higher risk of death
(eg, age >65 years, women, Killip class II to IV, and
creatinine clearance <100 mL/min) tended to have higher
mortality rates at 30 days with orbofiban (Figure 3). A significant interaction with
increased 30-day mortality was observed in patients with prior
congestive heart failure, whereas a significantly lower mortality was
seen in those who underwent PCI for the index event (P=0.005
for interaction). No significant interaction was seen in diabetics by
MI type or treatment (thrombolysis, primary PCI, or
medical treatment).
|
For the 10-month composite end point, interactions and increased event
rates existed in patients in Killip class II to IV at the time of
randomization (P=0.03), patients >65 years
(P=0.07), and those with prior congestive heart failure
(P=0.09) (Figure 4). In
contrast, a significant interaction (P=0.0006) with a lower
composite event rate was seen for those treated with orbofiban who had
undergone PCI for the index event (either before or after
randomization) (Figure 4). In these 2851 patients, orbofiban
treatment was associated with a significantly lower 30-day composite
event rate (10.5% versus 14.6%; P=0.0007), with a
nonsignificantly lower mortality (0.9% versus 1.5% for placebo;
P=0.14) (Figure 3). At 10 months, among those
undergoing PCI, the composite end point was 27.5% in the placebo
group, 23.9% for orbofiban 50/30 (P=0.01), and 21.8% for
orbofiban 50/50 (P=0.002). This benefit was present
among patients undergoing either stenting or balloon angioplasty and
among patients receiving peri-PCI abciximab versus those not receiving
abciximab (P=NS for interaction).
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Early Events and Effect of Heparin
An additional exploratory analysis of events occurring
during the first 2 days of treatment is shown in Table 6; this analysis
was then stratified by the use of concomitant unfractionated heparin or
LMWH during the initial days after randomization. A 30% to 40%
reduction occurred in the composite event rate in the orbofiban-treated
patients; this was due to significant reductions in MI and in recurrent
ischemia leading to urgent
revascularization. A higher rate of death existed
in the orbofiban 50/30 dose group but not the 50/50 group; the majority
of these deaths were classified as due to progressive deterioration
from the index event (Table 4). The benefit of orbofiban on the
composite end point was restricted to the patients who received
concomitant heparin or LMWH (Table 6), whereas the increased
mortality in the orbofiban 50/30 group seemed to occur in patients
regardless of concomitant heparin use. Analysis of events
relative to cessation of study drug showed no evidence of a
"rebound" increase in clinical events over the first or second day
after stopping orbofiban.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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OPUS-TIMI 16 was the first large trial to study an oral GP IIb/IIIa inhibitor in the long-term treatment of acute coronary syndromes; in contrast to the trials with intravenous IIb/IIIa inhibitors,1 2 3 no significant benefit of orbofiban was observed. A low overall rate of mortality existed in this patient population, but unexpected excess mortality occurred in patients treated with orbofiban. Orbofiban treatment caused a modest excess of major bleeding (1% to 2%) over the 10 months of active treatment. Exploratory analyses revealed that the cause of death seemed to relate to new thrombotic events. Excess mortality and higher composite event rates were observed in patients who were more unstable at entry (eg, Killip class II to IV). In contrast, those who underwent PCI for the index event seemed to have significant benefit (absolute reduction of
5% in the composite event rate), with a
trend toward lower mortality.
Potential Explanations for Lack of Benefit
Numerous hypotheses can be considered for the lack of benefit of
this first generation of oral GP IIb/IIIa
inhibitors9 10 in the light of the striking
benefit of intravenous GP IIb/IIIa inhibitors.
First, there are pharmacokinetic and pharmacodynamic differences
between these 2 routes of administration. Intravenous
compounds are dosed to achieve high levels of platelet inhibition,
whereas lower levels are achieved with the oral agents (from 45% to
65% to 55% to 80% for orbofiban doses used in OPUS-TIMI 16). This
level of inhibition might not provide optimal protection against
events; this hypothesis is supported by the highly significant
reduction in death or MI in the Enhanced Suppression of the Platelet
Receptor GP IIb/IIIa Using Integrilin Therapy (ESPRIT) trial, which
used eptifibatide targeted to an inhibition of 85% to 95%, compared
with the Integrilin to Minimize Platelet Aggregation and Coronary
Thrombosis (IMPACT) II trial, which used doses of eptifibatide
that achieved only 50% to 60% inhibition.11
With oral administration, peaks and troughs (corresponding to the drug’s half-life) exist in the level of platelet inhibition; these are not present with intravenously administered IIb/IIIa inhibitors. In addition, substantial variability between patients in the level of inhibition has been observed with all oral agents12 13 ; this is related in part to differences in bioavailability. As such, with a fixed dose, some orbofiban-treated patients have as high as 100% inhibition at peak and others as low as 0% to 20% inhibition at trough. These pharmacodynamic differences may explain some of the differences observed in clinical efficacy.
A third possibility is that the benefit of GP IIb/IIIa inhibition is modest overall in patients with acute coronary syndromes managed medically and greatest in those who undergo PCI.1 We observed just such a difference in OPUS-TIMI 16, with those patients who underwent PCI for the index event as the only group of patients to have significant benefit from orbofiban. Further trials could be considered using oral IIb/IIIa inhibitor agents administered on hospital admission and through PCI, as was done in this study but not in the Evaluation of Oral Xemilofiban in Controlling Thrombotic Events (EXCITE) trial, which administered xemilofiban 30 to 90 minutes before PCI.9
A fourth possibility is that the means of inhibiting platelets might impact the ability to reduce events during long-term treatment. Aspirin and clopidogrel act to decrease platelet activation, whereas the GP IIb/IIIa inhibitors decrease only platelet aggregation. For acute treatment, the direct inhibition of the platelet aggregate may be most important, whereas for long-term treatment, decreasing the propensity of platelets to become activated may be a more effective strategy. Ultimately, one could consider the combination of aspirin, a thienopyridine such as clopidogrel, and an oral GP IIb/IIIa inhibitor.
A fifth possibility is that the GP IIb/IIIa inhibitors may require concomitant antithrombin therapy for their benefits to be realized, as seen with the intravenous agents.2 14 Our data show significant reductions in recurrent ischemic events over the first 2 days in patients receiving concomitant heparin or LMWH, which is consistent with this hypothesis.
Finally, the agents tested to date are the first generation of oral IIb/IIIa inhibitors (orbofiban, xemilofiban, and sibrafiban), and they may not have optimal pharmacodynamic characteristics. We have documented, in 2 separate laboratories, an increase in platelet surface P-selectin, a marker of increased platelet activation, in patients receiving orbofiban in OPUS-TIMI 16.15 We also observed higher platelet counts in patients receiving orbofiban. In addition, Cox et al16 documented that orbofiban is both an antagonist and a partial agonist of the GP IIb/IIIa receptor. Increased platelet-monocyte interactions have also been noted with GP IIb/IIIa antagonists.17 These data suggest that some agents in this class may be prothrombotic.
Increased fibrinogen binding and platelet aggregation can occur when only low doses of various GP IIb/IIIa inhibitors are added to platelets in vitro.18 19 Thus, it is possible that at trough periods, low blood concentrations of the oral IIb/IIIa inhibitor induced a prothrombotic state, thereby increasing the propensity to new thrombotic events. Our findings of increased rates of new thrombotic events leading to death, with a similar trend toward increased rates of MI, are potential clinical manifestations of this hypothesized "prothrombotic" mechanism of the adverse effects of the first generation of oral IIb/IIIa inhibitors.
Future Directions
The results of OPUS-TIMI 16 provide a wealth of data to plan
future trials and direct research efforts in this field. First, more
careful titration of dosing appears to be important; this might be
aided by bedside testing of platelet aggregation.20
Thus, as is done routinely for warfarin, a titrated dose for each
patient may provide optimal platelet inhibition and improve
clinical outcomes. In addition, newer drugs with longer
half-lives21 will be associated with fewer peaks and
troughs in the level of platelet inhibition, thereby providing a
more stable antiplatelet action. The development of "second
generation" drugs, such as those with a very tight binding affinity
for the receptor, might also avoid low levels of platelet
inhibition and the potential prothrombotic effect seen with the
first-generation inhibitors that rapidly move on and off
the receptor (eg, orbofiban, sibrafiban, or xemilofiban). Initial
comparative studies in experimental models suggest that agents with
tight binding to the GP IIb/IIIa receptor have improved efficacy
compared with agents with rapid dissociation from the
receptor,22 and a large clinical trial is underway.
Although exploratory analyses have limitations, we observed excess mortality largely in higher-risk patients, suggesting that future studies should target stabilized patients and avoid using the oral agents early in the course of very sick patients (eg, those with congestive heart failure). Further exploration of the need for concomitant antithrombin (or anticoagulant) therapy is warranted, and one might consider coadministration of warfarin, oral factor Xa inhibitors, or subcutaneous LMWH for several weeks during the initial treatment phase, when passivation of the artery is needed. Finally, promise exists in the testing of different drugs, notably those with tight GP IIb/IIIa receptor binding.21 22
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Footnotes |
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Reprint requests to Christopher P. Cannon, MD, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115.
A list of the OPUS-TIMI 16 investigators and coordinators can be found in the Appendix; a complete list of all centers and participants can be found in the Online Appendix (www.circulationaha.org).
Dr Anders is an employee of Searle, Skokie, Ill, which sponsored the study; Dr Alexander is a former employee of Searle.
This article originally appeared Online Only on June 12, 2000.
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Participants in the OPUS-TIMI 16 Study
Operations Committee
J Alexander, R Anders, E Braunwald, P Corr, CP Cannon, A Foxley, CH McCabe, AM Skene, H Watson, and RG Wilcox
Steering Committee
P Bernink (Netherlands), J Bett (Australia), A Caspi (Israel), J
Col (Belgium), J Ferguson (United States), D Gulba (Germany), E
Gurfinkel (Argentina and Chile), D Kereiakes (United States), A Langer
(Canada), J Lopez-Sendon (Spain), M Martinez-Rios (Mexico), D Marx
(South Africa), G Maurer (Austria), P Merlini (Italy), T Mocetti
(Switzerland), JC Nicolau (Brazil), E Östör (Hungary), T
Pederson (Norway), JL Providencia (Portugal), M Ruda (Russia), Z
Sadowski (Poland), M Schweiger (United States), PK Shah (United
States), J Toman (Czech Republic), and RG Wilcox (European Lead
Investigator; United Kingdom)
TIMI Study Chairman’s Office
Located at Brigham and Women’s Hospital, Boston, Mass: E
Braunwald (Study Chairman), CP Cannon (Principal Investigator), CH
McCabe (Director), S Coulter, A Lewis, and S McHale
Sponsor: GD Searle, Skokie, Ill
J Alexander, R Anders, D Burns, R Clemmer, P Corr, D Hinds, D
Korts, and H Watson
Nottingham Clinical Research Group, Nottingham, United
Kingdom
E Adams, R Ardill, L Bennett, J Bentley, A Charlesworth, A
Foxley, A Hankin, Y Ince, A Kempton, E Lindley, I Little, J Parsons, A
Peters, M Ramet, J Simmons, AM Skene, S Stead, J Taylor, E Townsend, K
Ward, S Watson, and L Wolf
Almedica: J Hadley; Covance: B Archer (Indianapolis, Ind) and L Mullins (Nashville, Tenn); Clinphone (Nottingham, United Kingdom): K Bishop; Quintiles (Marlow, United Kingdom): P Galtry; Statistics Collaborative, Inc: J Wittes
Data and Safety Monitoring Board
G Beller, B Chaitman, G Jensen, D Julian, J Loscalzo (Chair),
and D DeMets
Clincal Events Committee
Western Hemisphere
Chairman (non-voting): S Coulter
Cardiology: C Albert, R Aurora, C Chae, M
Cohen, T Desalvo, D Esakov, J Fang, M Furman, L Ganz, K Ho, J Hung, E
Isselbacher, J Keaney, D Losordo, M Mathier, C O’Donnell, R Piana, L
Rabbani, S Reimold, C Rogers, D Schneider, D Simon, S Solomon, and F
Spencer, M Tishler, J Vita; Neurology: S Feske and L
Schwamm
Eastern Hemisphere
Chairman (non-voting): RG
Wilcox Cardiology: A Ahsan, D Gray, JR
Hapton, RAA Henderson, AJ McCance, MW Miller-Craig, GK Morris, SO
Nunain, and J Rowley; Neurology: G Lennox and G Sawle
Top 25 Enrolling Clinical Centers
Assafe Harofhe Hospital: A Golik; Broward
General Medical Center: A Niederman, T Kellerman; Western
Galilee Medical Centre: S Shasha; Sacred Heart
Hospital: WD Doty, EA Steck; Kaplan Medical Centre: A
Caspi; University of Alabama Hospital: W Rogers, K
Mulrooney; Institute de Coracao do Hospital das Clinicas: JC
Nicolau; Humber River Regional Hospital: MT Cheung;
Barzily Medical Center: L Reisin; Centre Hospitalier
Regional de Lanaudirie: S Kouz; The Mississauga
Hospital: T Rebane; Hospital Gregorio Maranon: R
Rubio-Sanz; Wake Heart Center: T Mann, M Arrowood;
Centre Hospitalier Universitaire de Quebec: G Houde; Laval
Hospital: P Bogaty; Elkerliek Ziekenhuis / Lok Helmond:
RR Lalisang; Faculty Hospital: RA Spacek;
Evangelisches Krankenhaus: T Horacek; Streekziekenhuis
Zevenaar: JMC van Hal; Tweesteden Ziekenhuis: HF Baars;
Wolfson Hospital: R Zimlichman; Hospital Jihlava:
P Svitil; Hospital Ste Croix: R Roux; Centenary Health
Center: N Singh; Hospital Torrecardenas: R
Martos-Ferres
Received May 16, 2000; revision received May 26, 2000; accepted May 26, 2000.
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