(Circulation. 1995;91:2725-2732.)
© 1995 American Heart Association, Inc.
Articles |
More Rapid, Complete, and Stable Coronary Thrombolysis With Bolus Administration of Reteplase Compared With Alteplase Infusion in Acute Myocardial Infarction
Presented in part at the 66th Scientific Sessions of the American Heart Association, Atlanta, Ga, November 8-11, 1993.
From the University of Texas Medical School at Houston (R.W.S.); the Klinikum der Universität Heidelberg, Germany (C.B.); Cardiology of Tulsa (Okla), Inc (J.K.); the Medizinische Universitätsklinik Homburg/Saar, Germany (S.S.); the Stadtkrankenhaus Worms, Germany (P.L.); the Krankenhaus Neukoelln, Germany (F.F.); Baylor College of Medicine and VA Medical Center, Houston, Tex (G.H.); Munroe Regional Medical Center, Ocala, Fla (R.F.); the Klinikum der Universität Freiburg, Germany (S.H.); and Memorial Medical Center, Jacksonville, Fla (A.S.).
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Early restoration and maintenance of normal (TIMI 3) blood flow during acute myocardial infarction is critical for optimal preservation of left ventricular function and survival. Recombinant plasminogen activator (r-PA, reteplase) is a nonglycosylated deletion mutant of wild-type tissue-type plasminogen activator (TPA) that has been shown to achieve more rapid and complete thrombolysis compared with other plasminogen activators in animal models.
Methods and Results The RAPID Trial was designed to test the hypothesis that bolus administration of one or more dosage regimens of r-PA was superior to standard-dose alteplase (TPA) in achieving infarct-related artery patency 90 minutes after initiation of treatment. Six hundred six patients with acute myocardial infarction were randomized to one of four treatment arms: (1) TPA 100 mg IV over 3 hours, (2) r-PA as a 15-MU single bolus, (3) r-PA as a 10-MU bolus followed by 5 MU 30 minutes later, or (4) r-PA as a 10-MU bolus followed by 10 MU 30 minutes later. Coronary arteriography was performed at 30, 60, and 90 minutes after initiation of treatment and at hospital discharge. The 10+10-MU r-PA group achieved better 90-minute and 5- to 14-day TIMI 3 flow (63% [CI, 55% to 71%] versus 49% [41% to 57%], P=.019, and 88% [82% to 94%] versus 71% [63% to 79%], P<.001, respectively) than the TPA group. The TIMI 3 flow in the 10+10-MU r-PA group at 60 minutes was equivalent to that in the TPA group at 90 minutes (51 versus 49%). Global ejection fraction and regional wall motion in the 10+10-MU r-PA group were superior to those of the TPA group at hospital discharge (53±1.3% versus 49±1.3%, P=.034; -2.19±0.12 versus -2.61±0.13 SD per chord, P=.02, respectively). The 15-MU and 10+5-MU r-PA patency and left ventricular function results were similar to those of the TPA and inferior to those of the 10+10-MU r-PA group. Bleeding complications were similar between the groups.
Conclusions r-PA given as a double bolus of 10+10 MU achieves more rapid, complete, and sustained thrombolysis of the infarct-related artery than standard-dose TPA, without an apparent increased risk of complications. This was associated with improved global and regional left ventricular function at hospital discharge.
Key Words: myocardial infarction • thrombolysis • plasminogen activators
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Thrombolytic therapy has become an accepted form of treatment for acute myocardial infarction. The GUSTO trial suggested that accelerated intravenous infusion of alteplase (tissue-type plasminogen activator, TPA) was associated with an improved mortality compared with intravenous streptokinase or the combination of streptokinase and TPA.1 Weaver and colleagues2 demonstrated that treatment with TPA resulted in a reduced mortality of 1.2% when given within 70 minutes of onset of chest pain compared with 8.7% when given between 70 minutes and 3 hours after onset of pain. Others have shown that restoration of TIMI 3 flow in the infarct-related artery was associated with an in-hospital mortality rate of 2.7% to 4.4% compared with a mortality rate of 6.6% to 7.4% in patients with TIMI 2 flow and 7.1% to 8.9% in patients with TIMI 0 to 1 flow.3 4 5 Similarly, better global and regional (infarct-zone) myocardial function has been reported in patients with TIMI 3 flow compared with those with TIMI 0, 1, or 2 infarct-related artery flow.4 5 It also has been shown that reocclusion after successful infarct-related artery thrombolysis results in a doubling of in hospital mortality as well as a significant deterioration in left ventricular function.5 6 7 Unfortunately, the current optimal thrombolytic therapy, accelerated TPA plus intravenous heparin, is associated with a TIMI 3 flow rate at 90 minutes of only 54% and a late (5 to 7 days) TIMI 3 flow rate of only 58%.5 The GUSTO angiographic substudy demonstrated that delayed (>90 minutes) restoration of TIMI 3 flow was not associated with an improved outcome compared with restoration of TIMI 3 flow at 90 minutes.5 It is therefore clear that for optimal treatment of acute myocardial infarction, normal blood flow (TIMI 3) in the infarct-related artery should be reestablished as rapidly as possible and maintained.
Recombinant plasminogen activator (r-PA, reteplase) is a nonglycosylated deletion mutant of wild-type TPA. It consists of the kringle-2 and the protease domains but lacks the kringle-1, finger, and growth-factor domains of TPA. The modification results in less high-affinity fibrin binding, a longer half-life, and greater thrombolytic potency than TPA. In an animal model, r-PA has been shown to be superior to other plasminogen activators, including TPA, anistreplase, streptokinase, and urokinase, achieving more rapid, complete, and sustained thrombolysis.8 Initial nonrandomized, clinical trials with r-PA have also been encouraging.9 10 The RAPID trial was designed to test the hypothesis that bolus administration of one or more regimens of r-PA would result in more rapid, complete, and sustained coronary perfusion compared with the standard FDA-approved dose of TPA.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Patient Population
Patients 18 to 75 years old with at least 30 minutes of typical chest pain not relieved by nitroglycerin and ST-segment elevation of 0.1 mV in the inferior or lateral leads or 0.2 mV in the precordial leads and presenting <6 hours after onset of chest pain were considered candidates for the trial. Patients were excluded from the study if their ECG demonstrated left bundle branch block or if they had had prior coronary bypass surgery, a previous Q-wave myocardial infarction in the same anatomic region, previous percutaneous transluminal coronary angioplasty (PTCA) within 2 weeks, previous cerebral vascular accident, or severe hypertension with a systolic blood pressure >180 or diastolic blood pressure >110 mm Hg at presentation to hospital. Patients gave informed consent for participation, and the protocol was approved by the institutional review board or ethics committee at each hospital or region.
Study Organization
The RAPID trial consisted of 38 centers in
the United States,
Germany, England, and Austria and was overseen by an international
safety committee. Cine films from the investigators were evaluated in
angiographic core laboratories in the United States and Europe for
blinded and objective interpretation of TIMI flow in the
infarct-related artery. A random sample of films was interpreted by
both core laboratories to ensure uniformity of interpretation. Of 18
films analyzed with TIMI 2 or 3 flow, 17 had identical evaluations. In
the remaining film, agreement diverged at one time point only, when
different projections were used for evaluation of TIMI flow. These data
suggest that TIMI flow definitions for both core laboratories were
identical.
Randomization and Treatment
This study was a multicenter,
open-label, parallel group study
in which patients were randomized to receive 15 MU of r-PA as a single
bolus, a 10-MU bolus of r-PA followed by 5 MU 30 minutes later (15 MU
total dose), a 10-MU bolus followed by a 10-MU bolus 30 minutes later
(20 MU total dose), or TPA 60 mg over the first hour, with 6 to 10 mg
being administered as an initial bolus followed by 20 mg/h for an
additional 2 hours (total dose, 100 mg). Individual study sites were
supplied with patient-specific sealed randomization envelopes that
contained the treatment group assignment and drug identification label.
Immediately before administration of the thrombolytic agent, soluble
aspirin was given at a dose of 200 to 325 mg and then was continued on
a daily basis through hospital discharge. Additionally, a 5000-U bolus
of heparin followed by 1000 U/h for at least 24 hours was initiated,
with the heparin bolus given just before initiation of thrombolytic
therapy. The activated partial thromboplastin time was followed, and
the heparin dose was adjusted to maintain a value between 1.5 and 2
times the control value. After treatment with r-PA or TPA was
initiated, the patient was taken to the cardiac catheterization
laboratory, and coronary arteriography was performed at 30 and 60
minutes (if possible) as well as 90 minutes (mandatory) after the
initiation of thrombolytic therapy. Left ventriculography was also
performed after coronary angiography. TIMI flow was estimated by the
investigator at 90 minutes, and if TIMI grade 2 or 3 flow was
present, mechanical or medical interventions were not performed
unless there was clear evidence of ongoing ischemia.
Angiography, including coronary arteriography and left
ventriculography, was repeated between 5 days after hospital admission
and hospital discharge for assessment of TIMI flow in the
infarct-related artery as well as determination of global and regional
LV function.
Blood samples for assessment of fibrinogen, plasminogen,
fibrin
degradation products, and 
2-antiplasmin were obtained
before thrombolysis and at 2, 4, 8, 12, 24, and 48 hours after
initiation of thrombolytic therapy. Follow-up visits were performed 1
and 6 months after the initial admission to assess clinical status
after hospital discharge.
End Points
The primary end point was TIMI grade 2 or 3
patency at coronary
arteriography 90 minutes after initiation of thrombolytic therapy. The
secondary end points included TIMI 2 or 3 patency at 30 and 60 minutes
and 5 to 14 days after initiation of thrombolytic therapy, as well as
reocclusion within 5 to 14 days after administration of thrombolytic
therapy and global (ejection fraction, EF) and regional (infarct zone)
function at hospital admission and discharge. Clinical end points
(including stroke, reinfarction, heart failure, and
angina/ischemia) and coronary artery interventions (including
PTCA, bypass surgery, and intracoronary thrombolysis) were evaluated.
Bleeding episodes were characterized during the 1-month period after
administration of thrombolytic therapy. Significant bleeding was
defined as any bleeding requiring transfusion. Additional secondary end
points included mortality at 30 days and 6 months after administration
of therapy.
The TIMI grade of the infarct-related artery was determined by core laboratories (see "Appendix") blinded to therapy. The first coronary injection, at the beginning of each time period, was used for evaluation of TIMI flow.
Statistical Analysis and Sample Size Calculation
The study
was to be performed with 150 patients per group. This
sample size provided 98% power to identify a dose of r-PA that had a
90-minute patency rate that was at least equivalent to that of TPA
within 15 percentage points. In addition, this sample size provided
90% power to detect a 12.6–absolute percentage point difference in
patency rates between r-PA and TPA, assuming an underlying patency rate
of 80% with TPA.
Differences in patency (TIMI 2 and 3), TIMI 3 rates,
and all
clinical end points except stroke and intracranial hemorrhage were
tested by Pearson's 
2 test. Differences in
strokes and intracranial hemorrhage were tested by Fisher's exact
test. All tests were performed at the nominal P=.05 level of
significance. Continuous variables are presented as mean±SD except
as noted. Patency data are presented with 95% confidence intervals
in parentheses. Two patients who received therapy but were determined
not to have had an acute MI by lack of enzymatic confirmation were
excluded from patency analysis. Patients were included in the
analysis of 90-minute patency if they had an angiogram performed
within a 75- to 120-minute time window.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Patient Characteristics
A total of 606 patients were enrolled between August 17, 1991, and June 30, 1993. As listed in Table 1
, there
were no significant differences among the groups in baseline
characteristics, including age, weight, height, sex, prior history of
myocardial infarction, heart failure, angina, or prior PTCA. There was
essentially an equal incidence of patients with acute anterior
myocardial infarction, and the time to treatment was similar in all
groups.
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Infarct-Related Artery Patency
At 60 minutes, the total
patency (TIMI 2 and 3 flow) was 78% (CI,
69% to 86%) in the r-PA 10+10 group, compared with 66% (57% to
76%) in the TPA group (P=.079) (Table 2 and
Fig 1a and 1b). At 90 minutes, the r-PA
10+10 and the
TPA groups had similar TIMI 2 and 3 flow (85% versus 78%,
P=.084). Late patency was highest in the r-PA 10+10 group
at
95% (91% to 99%) versus 88% (82% to 94%) (P=.04
compared with TPA). Importantly, TIMI 3 flow was significantly higher
in the r-PA 10+10 group than the TPA group at 60 minutes (51% [41%
to 61%] versus 33% [24% to 42%], P=.009), at 90
minutes (63% [55% to 71%] versus 49% [41% to 57%],
P=.019), and at hospital discharge (88% [82% to 94%]
versus 71% [63% to 79%], P<.001). Interestingly, the
60-minute TIMI 3 flow in the r-PA 10+10 group was slightly, but not
significantly, higher than the 90-minute TIMI 3 flow in the TPA group.
The 15-MU and 10+5-MU r-PA patency and left ventricular function
results were similar to those for TPA and inferior to those of the
10+10-MU r-PA group.
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Effect of Thrombolysis on Ventricular Function
The relation
between TIMI flow at 90 minutes and global
ventricular function in all patients evaluated was dramatic both at the
acute study and at follow-up, as illustrated in Fig 2.
There was a significant difference in EF between patients with TIMI 0
to 1 flow (48±1.4%) and patients with TIMI 3 flow (54±1.0%,
P=.0007) at the initial study. There was a similar
difference in EF between patients with TIMI 2 and TIMI 3 flow. These
differences were maintained at the follow-up study.
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Global ventricular
function in the acute study was similar in the TPA
and 10+10-MU r-PA groups, as illustrated in Fig 3A.
There was a slight (not significant) deterioration in the TPA group at
hospital discharge compared with an increase in EF in the r-PA 10+10-MU
group. The net result was a significant difference in EF in the TPA
compared with the r-PA group (49±1.3% versus 53±1.3%,
P=.034). Similar findings were seen in the analysis of
infarct zone regional function, as illustrated by Fig 3B. In
the TPA
group, there was no significant improvement in regional function from
hospital admission to discharge. The 10+10-MU r-PA group did improve
and had better function than the TPA group (-2.19±0.12 versus
-2.61±0.13, P=.02).
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Need for Additional Interventions
The need for additional
interventions to restore normal blood flow
in the infarct-related artery seemed to be inversely correlated with
success in reperfusion. As illustrated in Table 3, there
was a trend toward less rescue PTCA and need for intracoronary lytics
in the 10+10-MU r-PA group compared with the TPA group. These
differences, however, did not achieve statistical significance
(P=.11). Interestingly, when patients with rescue
angioplasty were excluded from the analysis, the TIMI 3 patency in
the r-PA group was 87% compared with 75% in the TPA group
(P=.03).
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Bleeding Complications
Animal investigations have shown that
r-PA has less high-affinity
fibrin binding but equal fibrin specificity compared with TPA at
equipotent doses.8 However, as demonstrated by Fig
4, with the doses used in this study, the median plasma
fibrinogen concentrations in the r-PA patients were significantly less
than in the TPA patients. Interestingly, the bleeding complications did
not seem to parallel the hypofibrinogenemia. The need for transfusions
in the 10+10-MU group and the TPA group was similar, as illustrated in
Table 4.
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Adverse Clinical Events
The incidence of reocclusion was not
different between the groups.
The standard-dose TPA group experienced a 7.8% reocclusion rate
compared with 2.9% in the 10+10-MU r-PA group (P=NS).
Since the trial was designed to detect differences in patency, it did
not have sufficient power to detect differences in mortality among the
groups. Nonetheless, adverse clinical outcomes are listed in Table
5 for interest. The 30-day mortality rate in the
10+10-MU group was 1.9% compared with 3.9% in the TPA group. There
was only one stroke in the r-PA groups (1/452) compared with six in the
TPA group (6/154). The incidence of stroke in the 10+10-MU r-PA group
was less than that observed in the TPA group (P=.03). The
reinfarction rate and the incidence of congestive heart failure were
similar between the groups.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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Effect of Thrombolysis on Patency
Very early administration of thrombolytics, within 70 to 90 minutes of onset of chest pain, is associated with improved survival and left ventricular function.2 11 Completeness of thrombolysis is also critical for achieving optimal outcomes,3 4 5 12 as well as for prevention of late reocclusions.5 6 7 A dose-ranging study with r-PA in a canine model of coronary artery thrombosis showed an apparently optimal thrombolysis with an equivalent clinical dose of 15 MU.13 As demonstrated by Neuhaus et al,10 the 15-MU single dose in humans was associated with relatively high rates of occlusion. Further animal experiments suggested that a 10+10-MU regimen would be most effective in achieving an early and sustained patency. This study was designed to find an optimal dose of r-PA compared with TPA in humans.
The original TIMI investigators suggested that intravenous standard-dose TPA was superior to intravenous streptokinase in achieving early reperfusion,14 and this has been confirmed by the GUSTO angiographic substudy5 using accelerated administration of TPA. The RAPID trial used a standard (FDA-approved) dose of TPA15 that was universally accepted at the time of initiation of the study. Although relatively small trials had suggested that a more rapid administration of TPA was associated with improved 90-minute patency,16 17 the accelerated TPA regimen was not used because the true incidence of intracranial bleeding with it was not well substantiated at the time the RAPID trial began. For comparison, the patient baseline characteristics in the GUSTO angiographic substudy were virtually identical to those in the RAPID trial.5 The 90-minute TIMI 3 flow rate in the GUSTO angiographic substudy was 54% with accelerated TPA administration, which was slightly higher than the 90-minute TIMI 3 flow rate with standard-dose TPA in this trial (49.0%). The 90-minute TIMI 3 flow rate with the 10+10-MU r-PA regimen was 62.7%, which was an improvement over that of standard-dose TPA and may be an improvement over that of accelerated TPA. Interestingly, infarct-related artery TIMI 3 flow in the GUSTO substudy at 5 to 7 days was only 58%, compared with 70.7% in the RAPID trial in patients treated with standard-dose TPA. Once again, the r-PA 10+10-MU dose resulted in a higher TIMI 3 patency rate compared with standard-dose TPA (87.8% versus 70.7%, P<.01). To be certain that bolus administration of r-PA results in a higher patency rate than accelerated-dose TPA will require a separate randomized trial (RAPID II), which is nearing completion.
Left Ventricular Function
While many investigators have
reported that reperfusion is
positively correlated with improved ventricular function at follow-up,
the GUSTO angiographic substudy5 has provided the most
convincing evidence for this hypothesis. The higher dose of r-PA (10+10
MU) produced superior TIMI 3 flow compared with the other dosing
regimens of r-PA and standard-dose TPA. This was associated with
improved global and regional function at the follow-up study, as
illustrated in Fig 3A
and 3B. The magnitude of
this difference was
probably related to the relatively high incidence of patients with
anterior MI (
50%) in addition to the relatively large differences
in TIMI 3 flow rates between the r-PA 10+10 group and the other groups
at 90 minutes. Unfortunately, not all patients had left
ventriculography at both admission and discharge. Table 6 lists
left ventricular function data in patients with
paired samples. The results are similar to those in Fig 3A and
3B;
however, because of the small numbers, they do not achieve statistical
significance.
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Bleeding Risks
The improved patency results with the
10+10-MU r-PA dose
were not associated with an increased risk of bleeding (Table
4).
Although the incidence of intracranial hemorrhage with r-PA seemed to
be less than that associated with TPA, the trial was definitely not
large enough to make any conclusive statements regarding risk of
intracranial bleeding. A larger 6000-patient trial comparing r-PA 10+10
MU and intravenous streptokinase has recently been completed in Europe
(the INJECT trial), which will better define the risk of intracranial
hemorrhage with r-PA. It has been suggested that r-PA, by virtue of
decreased high-affinity fibrin binding compared with TPA, may be less
effective on older, fibrin-rich thrombi. This reduced high-affinity
fibrin binding may result in reduced lysis of old fibrin plugs in the
cerebral circulation and, hence, a lower incidence of intracranial
hemorrhage.
Mode of Administration
An attractive feature of the r-PA
10+10-MU regimen is the ease of
bolus administration compared with the relative complexity of infusions
of varying doses of TPA. A high bolus dose of TPA followed by an
infusion has been reported to achieve TIMI 3 flow rates at 90 minutes
of approximately 55%.18 Nonetheless, the cumbersome
accelerated TPA dosing regimen remains the gold standard at
present. Purvis and colleagues19 have reported
encouraging results in a nonrandomized pilot trial using a double-bolus
regimen of 100 mg TPA. The TIMI flow rate was 86% at 60 minutes after
injection and 88% at 90 minutes. If these results are confirmed by
larger randomized trials with acceptable bleeding complications, then
an additional trial of double-bolus r-PA versus TPA should be
performed.
Mechanical Interventions
Direct PTCA performed early in the
course of myocardial
infarction has been associated with a low in-hospital mortality rate of
0 to 2.6% without apparent risk for cerebral vascular
accident.20 21 The mortality with direct PTCA in the
PAMI20 and Zwolle21 trials appeared to be
better than that achieved with thrombolytic therapy. Subsequently, this
apparent difference has been ascribed to the improved incidence of TIMI
3 flow achieved by PTCA compared with intravenous thrombolysis.
Obviously, it will not be possible to treat all acute myocardial
infarction patients with direct coronary angioplasty. We were
encouraged to find a low mortality rate with bolus administration of
r-PA, which was comparable to that achieved by direct angioplasty in
the PAMI trial. Clearly, larger trials will be necessary to confirm the
low mortality rates with each form of therapy.
Adjunctive Therapy
Adjunctive therapies for thrombolysis have
been reported,
including direct thrombin inhibitors such as hirudin, as well as
antiplatelet antibodies such as 7E3-Fab. The TIMI 5 trial demonstrated
that hirudin plus TPA appeared to be superior to heparin plus TPA in
achieving patency assessed at 18 to 36 hours, as well as inhibiting
reocclusion.22 The 90-minute TIMI 3 flow rate in
hirudin-treated patients was 65%, compared with 57% in the
heparin-treated patients. Reocclusion by 18 to 36 hours occurred in
1.6% of the hirudin-treated patients, compared with 6.7% of the
heparin-treated patients. For comparison, in this study, reocclusion by
hospital discharge occurred in 2.9% of the r-PA 10+10 group, compared
with 7.8% of the TPA group (P=NS). Subsequent to the
encouraging results reported in TIMI 5, additional information
suggested that hirudin may increase bleeding risk with either
streptokinase or TPA.23 24 A preliminary trial using
the
monoclonal antibody 7E3-Fab suggested that platelet inhibition may
improve infarct-related artery patency as well as reduce episodes of
recurrent ischemia.25 However, the trial was too
small and lacked sufficient angiographic control to clearly assess the
impact of the 7E3-Fab antibody.
Limitations of the Trial
The trial was open label and single
blinded with envelope
randomization. Given the differences in thrombolytic administration,
double blinding would have been difficult but desirable. Perhaps, for
multiple treatment groups, the nominal level of significance for each
r-PA group compared with the TPA group might be more correctly stated
as P=.05/3=.0167. Not all patients had left
ventriculography
at the prescribed times, for a multiplicity of reasons, as previously
described.
Summary
We conclude that bolus administration of a dose of 10
MU of r-PA
followed by an additional 10 MU 30 minutes later results in a superior
TIMI 3 flow rate, both at 90 minutes and before hospital discharge,
compared with standard-dose TPA. Additionally, TIMI 3 flow appears to
occur earlier after bolus administration of r-PA than with
standard-dose TPA. This early and improved infarct-related artery
patency was associated with improved global and regional function at
hospital discharge. The bleeding risks with all doses of r-PA were
comparable to those associated with standard-dose TPA. The encouraging
trend toward lower mortality and lower incidence of intracranial
bleeding with r-PA will have to be confirmed by larger randomized
trials.
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Acknowledgments |
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This study was supported in part by a grant from the Boehringer Mannheim Co.
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Footnotes |
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Reprint requests to Richard W. Smalling, MD, PhD, Division of Cardiology, University of Texas Medical School at Houston, 6431 Fannin, Room 1.246 MSB, Houston, TX 77030.
Guest editor for this article was Robert A. O'Rourke, MD, University of Texas Health Science Center at San Antonio.
The following investigators collaborated in the RAPID trial.
Steering Committee: R. Smalling, The University of Texas Medical School, Houston; C. Bode, Universität Heidelberg, Germany.
Safety Committee: R. Califf, Duke University, NC; A. Guerci, St Francis Hospital, Roslyn, NY; R. Schroeder, Universitätsklinikum Benjamin Franklin, Berlin, Germany.
Core Angiographic Laboratory (United States): E. Topol, D. Debowey, The Cleveland Clinic Foundation, Cleveland, Ohio.
Core Angiographic Laboratory (Europe): T. Linderer, Universitätsklinikum Benjamin Franklin, Berlin.
Hemostatic Core Laboratory: J. Loscalzo, West Roxbury VA Medical Center, Boston, Mass.
Sponsor Clinical Monitors: D. Odenheimer, E. Boem, Boehringer Mannheim.
European Study Centers Listed in Order of Patient Enrollment:
Klinikum der Universität Heidelberg; Principal Investigator (PI) C. Bode; H. Baumann, A. Gries, B. Kohler, M. Freitag.
Medizinische Universitätsklinik Homburg/Saar; PI S. Sen; G. Berg.
Krankenhaus Neukoelln; PI F. Forycki; P. Schreiber.
Stadtkrankenhaus Worms; PI P. Limbourg; E. Roth, W. Schmalz, R. Dick.
Klinikum der Universität Freiburg; PI S. Hohnloser; T. Klingenheben.
Universitätsklinik Marburg; PI B. Maisch; D. Gehrke.
Krankenhaus der Barmherzigen Brüder, Trier; PI K. Hauptmann; F. Schwarzbach, P. Albrecht.
Klinikum Grosshadern; PI G. Steinbeck; M. Blumenstein, D Beuckelmann, R. Reith, H. Neuhold, H. Berger, M. Kasel.
St George's Medical School, London; PI J. Kaski.
Klinikum Ludwigshafen; PI J. Rustige; Y. Schreiber, M. Sekkal, Lehmkuhl, M. Zander, R. Zahn, R. Koser, H. Seidl, W. Astheimer, B. Hauer, R. Lotter, Zimmer, A. Schwarz.
Herz-Kreislauf-Klinik Berlin-Buch; PI H. Fiehring; H. Pech, O. Schulz, J. Menger, F. Zimmermann, W. Goedicke.
Universitätsklinik Göttingen; PI H. Kreuzer; B. Buchwald, J. Rab.
St Mary's Hospital, London; PI R. Foale.
Allgemeines Krankenhaus der Stadt Wien; PI P. Probst; C. Kratochwill, A. Laggner, W. Schreiber.
Städtisches Klinikum Friedrichstadt; PI E. Altmann; A. Graf, C. Spranger.
Medizinische Hochschule Hannover; PI D. Gulba; C. Gunther. United States Study Centers Listed in Order of Enrollment:
St Francis Hospital, Tulsa, Okla; PI J. Kalbfleisch; R. Slagle, D. Brewer, C. McEntee, R. Okada, M. Spain, J. Waters, B. Lucenta, W. Ross, J. Cooper, A. Ghitis, M. Friedman, J. Higgins, M. Lim, V. Wagner, S. Black, S. DeWald.
The University of Texas Medical School, Hermann Hospital and LBJ Hospital, Houston; PI R. Smalling; F. Fuentes, H. Anderson, J. Heibig, G. Li, G. Schroth, A. Adyanthaya, J. Willerson, M. Hess, K. Molke, C. Underwood, L. Weigelt.
Baylor College of Medicine and VA Medical Center, Houston, Tex; PI G. Habib; D. Mann, B. Stein, J. Cheirif, M. Jeroudi, J. Mickelson, R. Rodriquez.
Munroe Regional Medical Center, Ocala, Fla; PI R. Feldman; F. Hildner, M. Standley, L. Craggs.
Memorial Medical Center, Jacksonville, Fla; PI A. Seals; S. Baker, K. Gilmour, R. Baker, J. Hartley.
University of California, Davis, Medical Center; PI E. Amsterdam; R. Martschinske, K. Krstich, R. Martschinske.
Brotman Medical Center, Culver City, Calif; PI R. Karlsberg; S. Bhatia, F. Murphy, J. Stone.
Taylor Hospital, Ridley Park, Pa; PI R. Chernoff; R. Weiner; P. Bhark, S. Rudy, C. Donahue.
Community Hospitals, Indianapolis, Ind; PI E. Harlamert; W. Bugni, R. Edmands, R. Hahn, S. Hazlett, B. MacPhail, J. McGoff, E. Manalo, R. Meldahl, S. Peskoe, S. Sharp, K. Stanley, M. Venturini, B. Weinberg, D. Ziperman, C. Adams, B. Fisher.
University of Oklahoma Health Science Center, Oklahoma City; PI U. Thadani; E. Olson, J. Harvey, E. Schechter, D. Schmidt, J. Turner.
Memorial Hospital Northwest, Houston, Tex; PI R. Morris; P. Berman, A. Ali, M. Baig, D. Reddy, D. Gonzalez, D. Lipetz.
Deaconess Medical Center, Spokane, Wash; PI P. Leimgruber; K. Sutherland, T. Judge, M. Hinnen, G. Goodman, H. Goldberg, B. Fuhs, G. Katz, S. Savran, M. Fisher, S. Vanvig, S. Kirchoff.
St Elizabeth's Hospital of Boston (Mass); PI K. Ramaswamy; D. Losordo, S. Keane.
Houston Northwest Medical Center, Houston, Tex; PI V. Aquino; H. Bhatia, G. Coleman, R. Agusala, J. Amell, I. Lieber, C. Moore, W. Pollo, G. Perez, M. Rao, V. Shenoy, J. Dippel.
Highline Hospital, Seattle, Wash; PI D. Gottlieb; B. Green, D. Hansen, T. Williams, C. Burnett, K. Kreisman, T. Brown, T. Williams.
Hospital of the University of Pennsylvania, Philadelphia; PI W. Laskey, H. Herrmann, W. Kussmaul; J. Hirshfeld, Jr; J. Krol.
St Joseph Hospital, Lancaster, Pa; PI S. Worley; J. Gault, R. Gentzler, I. Smith, J. Slovak, E. Supple, R. Anderson, R. Small, N. Clark, J. Ibarra, R. Canosa, F. Corbally, S. Deron, D. Loss, K. Clark, J. Damiano, P. Leaman, R. Lucas, J. Mayberry, R. Mazda, G. Winiarski, J. Tuzi.
Sequoia Hospital, Redwood City, Calif; PI E. Anderson; R. Mead, N. Smith, R. Winkle, M. Ruder, C. Titus.
St Vincent Hospital, Worcester, Mass; PI J. Benotti; R. Dave, J. Pendleton.
Brockton/West Roxbury VAMC, Boston, Mass; PI G. Sharma; J. Vita, W. Daley, D. Lapsley.
Hines VA Hospital, Hines, Ill; PI M. Hwang; R. Carroll, C. Sumida, J. Callahan.
VA Medical Center, Brooklyn, NY; PI N. El-Sherif; S. Bekheit, R. Khan, J. Sills.
Received December 28, 1994; revision received March 15, 1995; accepted March 27, 1995.
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