Context No specifically designed studies have addressed the role of primary
percutaneous coronary intervention in patients with acute ST-segment elevation
myocardial infarction (STEMI) presenting more than 12 hours after symptom
onset. Current guidelines do not recommend reperfusion treatment in these
patients.
Objective To assess whether an immediate invasive treatment strategy is associated
with a reduction of infarct size in patients with acute STEMI, presenting
between 12 and 48 hours after symptom onset, vs a conventional conservative
strategy.
Design, Setting, and Patients International, multicenter, open-label, randomized controlled trial
conducted from May 23, 2001, to December 15, 2004, of 365 patients aged 18
to 80 years without persistent symptoms admitted with the diagnosis of acute
STEMI between 12 and 48 hours after symptom onset.
Interventions Random assignment to either an invasive strategy (n=182) based predominantly
on coronary stenting with abciximab or a conventional conservative treatment
strategy (n=183).
Main Outcome Measures The primary end point was final left ventricular infarct size according
to single-photon emission computed tomography study with technetium Tc 99m
sestamibi performed between 5 and 10 days after randomization in 347 patients
(95.1%). Secondary end points included composite of death, recurrent MI, or
stroke at 30 days.
Results The final left ventricular infarct size was significantly smaller in
patients assigned to the invasive group (median, 8.0%; interquartile range
[IQR], 2.0%-15.8%) vs those assigned to the conservative group (median, 13.0%;
IQR, 3.0%-27.0%; P<.001). The mean difference
in final left ventricular infarct size between the invasive and conservative
groups was −6.8% (95% confidence interval [CI], −10.2% to −3.5%).
The secondary end points of death, recurrent MI, or stroke at 30 days occurred
in 8 patients in the invasive group (4.4%) and 12 patients in the conservative
group (6.6%) (relative risk, 0.67; 95% CI, 0.27-1.62; P = .37).
Conclusion An invasive strategy based on coronary stenting with adjunctive use
of abciximab reduces infarct size in patients with acute STEMI without persistent
symptoms presenting 12 to 48 hours after symptom onset.
In patients with acute ST-segment elevation myocardial infarction (STEMI),
numerous studies have demonstrated that early reperfusion within 12 hours
of symptom onset is associated with increased myocardial salvage, preservation
of left ventricular function, and improved survival.1 Due
to time-dependent attenuation of the efficacy of thrombolysis,2 the
application of this reperfusion modality after 12 hours from symptom onset
of acute myocardial infarction (MI) offers no benefit and may be even harmful.1,3,4 Between 8.5% and 40%
of patients with acute MI present late after symptom onset, no longer being
eligible for thrombolysis.5-9 Despite
efforts to reduce time to presentation, recent studies have demonstrated that
time-to-arrival has not changed10 or has even
increased.6 The lack of efficacy of thrombolysis
in patients with acute MI presenting more than 12 hours after symptom onset
may be a reason why current guidelines oppose reperfusion therapy in this
setting.11
Several findings suggest, however, that reperfusion therapy may be beneficial
even among patients with acute MI who present late after symptom onset. First,
recent studies have shown that viable salvageable myocardium exists even after
more than 12 hours of severe ischemia.12-14 Second,
previous studies have not only demonstrated that percutaneous coronary intervention
(PCI) is better than thrombolysis in patients with acute MI,15-17 but
also that the time window of efficacy for PCI may be wider than that for thrombolysis.18-20 Third, observational
studies suggest that PCI is effective even when performed after 12 hours from
symptom onset in patients with acute MI.21,22
The goal of our trial was to assess whether an invasive strategy based
on PCI with stenting is associated with reduction of infarct size in patients
with acute STEMI presenting more than 12 hours after symptom onset compared
with a conventional conservative treatment strategy.
Patients aged 18 to 80 years who had at least 1 chest pain episode lasting
at least 20 minutes between 12 and 48 hours before presentation and unequivocal
changes (≥0.1 mV of ST-segment elevation in ≥2 adjacent limb leads or
≥0.2 mV in ≥2 contiguous precordial leads or new pathological Q waves)
on surface electrocardiogram on admission were eligible for the Beyond 12
hours Reperfusion AlternatiVe Evaluation (BRAVE-2) trial. Exclusion criteria
included persistent anginal chest pain, cardiogenic shock (systolic blood
pressure <80 mm Hg, unresponsive to fluids, or necessitating catecholamines),
electrical instability, severe congestive heart failure and/or pulmonary edema,
or previous stroke (within the last 3 months); prior thrombolysis for index
infarction; active bleeding or bleeding diatheses; recent trauma or major
surgery (during the last month); relevant hematologic deviations (hemoglobin
<10 g/dL or hematocrit <34%, platelet cell count of <100 × 103/μL, white blood cell count <3 × 103/μL)
or malignancies; recent PCI (within the last 30 days); known or suspected
pregnancy; inability to comply with study procedures; and unwillingness or
inability to provide written informed consent for participation. Written informed
consent was obtained from all included patients. Institutional ethics committee
approval was obtained in all participating centers.
A computer-generated randomization sequence was used to assign patients
to either an invasive or a conservative treatment group. The sequence was
set in blocks of 10. Allocation concealment was implemented using sealed,
sequentially numbered envelopes. The individual who created the randomization
sequence and filled and labeled the study envelopes was not involved in any
other study procedures or analyses.
All patients received an initial dose of clopidogrel (300-600 mg) or
ticlopidine (500 mg) and 500 mg of aspirin as well as an intravenous bolus
of 70 U/kg of body weight of heparin (up to 5000 U). Patients assigned to
the conservative group received an intravenous infusion of unfractionated
heparin (12 U/kg per hour, maximum 1000 U/h) or subcutaneous low-molecular-weight
heparin in the dose appropriate for the specific agent for at least 24 hours.
Patients assigned to the invasive group were taken to the catheterization
laboratory immediately. The decision whether to perform a PCI procedure (with
or without stenting) or to send the patient for aortocoronary graft surgery
was made by the operator on the basis of flow status, lesion severity, and
anatomy of the infarct-related artery. Multilink stents (Guidant Advanced
Cardiovascular Systems Inc, Santa Clara, Calif) were used for coronary stenting
and adjunctive abciximab (ReoPro, Lilly Pharma Produktion GmbH & Co, Hamburg,
Germany) was administered during and after the procedure (as an intravenous
bolus of 0.25 mg/kg of body weight followed by a 12-hour infusion of 0.125
μg/kg per minute up to a maximal dose of 10 μg/min). Abciximab therapy
was started immediately after diagnostic angiography was performed and a decision
to intervene was taken.
In the conservative group, a symptom-limited exercise test was scheduled
to be performed before discharge. Patients were sent for unplanned invasive
evaluation and treatment if they developed recurrent severe angina, hemodynamic
and electrical instability, severe congestive heart failure and/or pulmonary
edema, mechanical complications, new relevant electrocardiographic changes
(new or reelevation of ST-segments of 0.2 mV in 2 contiguous precordial leads
or 0.1 mV in 2 adjacent limb electrocardiographic leads), reelevation of creatine
kinase or creatine kinase-MB by at least 50% above the trough level after
documentation that the level was decreasing prior to this reelevation, or
signs of induced ischemia during exercise testing.
Patients of both treatment groups were admitted to a monitored bed for
at least 48 hours after enrollment. All patients received 75-mg/d clopidogrel
or 500-mg/d ticlopidine for at least 4 weeks and 200 to 325 mg/d of aspirin,
indefinitely. Recommended concomitant drugs included β-blockers, angiotensin-converting
enzyme inhibitors, and statins.
A resting single-photon emission computed tomography (SPECT) study was
performed between 5 and 10 days after randomization using technetium Tc 99m
sestamibi to measure infarct size as a percentage of the left ventricle. All
studies were processed and measured in a Scintigraphic Core Laboratory by
experienced operators who were unaware of assigned therapy. Methods of data
acquisition and processing as well as infarct size measurement have previously
been described in detail.23
Angiographic parameters of patients assigned to the invasive treatment
group were assessed off-line in the Angiographic Core Laboratory by personnel
unaware of study allocation. Classification of anterograde coronary flow in
the infarct-related artery was performed according to Thrombolysis in Myocardial
Infarction (TIMI) classification.24 Collateral
circulation was quantified according to criteria of Rentrop et al.25 Quantitative assessment was performed with the use
of an automated edge detection system (CMS, Medis Medical Imaging Systems,
Nuenen, the Netherlands).
In-hospital follow-up protocol consisted of electrocardiographic recordings,
determination of creatine kinase, creatine kinase-MB, hemoglobin content,
and platelet cell count before and 8, 16, and 24 hours after the randomization
as well as daily thereafter. After discharge, trained personnel blinded to
patient’s allocation performed detailed telephone interviews at 30 and
90 days after randomization. For each event reported, evidence was sought
from hospital case records or the family physician. The local research coordinators
collected the data and forwarded them to the data coordinating center. A high
quality of data was ensured by checking source documentation. An event adjudication
committee blinded to the randomization status of the patients adjudicated
adverse clinical events.
The primary end point was final left ventricular infarct size determined
by SPECT. The secondary end points were a composite of all-cause death, recurrent
MI, or stroke within 30 days after randomization. Diagnosis of recurrent MI
was based on the presence of at least 2 of the following criteria: typical
chest pain, new ST-segment changes, and an increase in creatine kinase and
creatine kinase-MB of at least 50% above the previous trough level in at least
2 samples reaching at least 3 times the upper limit of normal. The diagnosis
of stroke required confirmation by computed tomography or magnetic resonance
imaging of the head in the presence of a new onset focal or global neurological
deficit lasting more than 24 hours.
The incidence of major bleeding complications as well as severe thrombocytopenia
was also monitored. Major bleeding was defined as an intracranial bleeding
or clinically significant overt signs of hemorrhage associated with a decrease
of more than 5 g/dL in hemoglobin or, when hemoglobin was not available, an
absolute decrease of at least 15% in hematocrit.26 Severe
thrombocytopenia was defined as true decrease of thrombocytes to less than
20 × 103/μL.
Sample size calculation was performed on the basis of the primary end
point of the trial. In a previous series of patients with acute MI presenting
more than 12 hours after symptom onset and treated conservatively in Deutsches
Herzzentrum, Munich, Germany, the mean (SD) left ventricular infarct size
was 20% (16%). In patients assigned to the invasive strategy, we expected
to achieve at least 30% reduction of infarct size. Choosing a 2-sided α=.05
and power of 90%, 150 patients in each group were needed. The overall number
of patients enrolled was expanded to 365 to accommodate for possible missing
scintigraphic studies.
All analyses were performed on the basis of the intention-to-treat principle
by using data from all patients as randomized. Because most continuous data
were not normally distributed, they are presented as median (interquartile
range [IQR]). Categorical data are presented as counts or proportions. Differences
between the groups were assessed using Fisher exact test for categorical data
and the nonparametric Wilcoxon rank sum test for continuous data. Kaplan-Meier
method was used to assess event-free survival with differences checked by
means of the log-rank test. Multiple linear regression modeling was used to
identify independent predictors of final infarct size. A 2-tailed P<.05 was considered statistically significant. S-PLUS version 4.5
(Insightful Corp, Seattle, Wash) was used for all statistical analyses.
Between May 23, 2001, and December 15, 2004, a total of 365 patients
were enrolled; 182 patients were randomly assigned to the invasive group and
183 patients to the conservative group (Figure
1). Baseline clinical and infarct characteristics of the patients
are shown in Table 1. Angiographic and
procedural characteristics of patients assigned to the invasive group are
shown in Table 2.
In the invasive treatment group, 90 patients (49.5%) had an initial
TIMI flow grade of 0. Of these patients, 50 (56%) had collateral grade 0,
25 (28%) grade 1, 11 (12%) grade 2, and 4 (4%) grade 3. The median time of
randomization to angiography (defined as the time of angiographic visualization
of the infarct-related artery) was 1.5 hours (IQR, 0.9-3.3 hours). Following
diagnostic angiography, 159 patients (87.4%) underwent coronary stenting,
13 patients (7.2%) plain balloon angioplasty, 7 patients (3.8%) received aortocoronary
bypass graft surgery, and 3 patients (1.6%) received no interventional treatment
because of an open infarct-related artery without significant residual stenosis.
The median time from randomization to first balloon inflation among patients
who underwent either stenting or balloon angioplasty was 1.7 hours (IQR, 1.1-3.6
hours).
SPECT imaging was performed in 347 patients (95.1%) after a median of
7.1 days (IQR, 6.2-8.7 days) after randomization in the invasive group and
7.3 days (IQR, 5.8-8.4 days) in the conservative group (P = .56). Eight patients in the invasive group and 10 patients
in the conservative group did not undergo SPECT imaging (Figure 1).
Among the 173 patients who had SPECT imaging in the conservative group,
15 patients (8.7%) underwent unplanned PCI before performing the follow-up
SPECT imaging, which was due to recurrent angina in 7 patients, congestive
heart failure in 4 patients, malignant arrhythmia in 1 patient, patient’s
preference in 1 patient, and attending physician’s decision in 2 patients.
The final left ventricular infarct size was significantly smaller in
patients assigned to the invasive group (median, 8.0%; IQR, 2.0%-15.8%) vs
those assigned to the conservative group (median, 13.0%; IQR, 3.0%-27.0%; P<.001). If expressed as mean (SD), left ventricular
infarct size was 11.6% (13.4%) in the invasive group and 18.4% (18.0%) in
the conservative group. The mean difference in final left ventricular infarct
size between the invasive and conservative groups was −6.8% (95% confidence
interval [CI], −10.2% to −3.5%). When the analysis was confined
to only those patients in the conservative group who did not undergo unplanned
PCI before SPECT imaging, the final left ventricular infarct size was 12.0%
(IQR, 3.0%-26.8%), which was significantly smaller than the final infarct
size in the invasive group (P<.001). When the
analysis was confined to only patients without a history of MI, the final
left ventricular infarct size was 7% (IQR, 2.0%-14.0%) in the invasive group
vs 12.0% (IQR, 3.0%-26.7%) in the conservative group (P<.001). Among patients presenting between 12 and 24 hours, the final
left ventricular infarct size was 9.0% (IQR, 2.0%-14.0%) in the invasive group
vs 10.5% (IQR, 3.0%-23.0%) in the conservative group (P = .06). Among patients presenting between 24 and 48 hours,
the final infarct size was 6.5% (IQR, 2.0%-20.5%) in the invasive group vs
15.0% (IQR, 7.0%-35.0%) in the conservative group (P<.001).
We constructed 2 multiple linear regression models aimed at the identification
of predictors of final infarct size in the invasive group. The variables included
in the first model were initial TIMI flow grade, collateral grade, left anterior
descending artery as an infarct-related artery, and time of onset of pain
to angiography. The second model included final TIMI flow grade in addition
to the variables included in the first model. The only independent predictor
of final infarct size that emerged from both models was initial TIMI flow
grade (P = .04).
No patients were lost to 30-day follow-up. During this interval, 3 patients
(1.6%) in the invasive group and 7 patients (3.8%) in the conservative group
died (P = .21). Five patients (2.7%) in
the invasive group and 8 patients (4.4%) in the conservative group experienced
recurrent MI. The combined incidence of death or recurrent MI was 4.4% (n=8
patients) in the invasive group and 6.0% (n=11) in the conservative group
(P = .49). Only 1 patient in the conservative
group incurred disabling ischemic stroke. The cumulative incidence of the
secondary end points, the composite of death, recurrent MI, or stroke within
30 days, was 4.4% (n=8) in the invasive group and 6.6% (n=12) in the conservative
group (relative risk, 0.67; 95% CI, 0.27-1.62; P = .37).
If the composite end point is presented in an information preserving form,
the number of patients in each of the 4 categories (death, nonfatal recurrent
MI, nonfatal stroke, or none of these events) was 3, 5, 0, 174, respectively,
in the invasive group and 7, 4, 1, 171, respectively, in the conservative
group. Two patients (1.1%) in the invasive group and 60 patients (32.8%) in
the conservative group underwent unplanned PCI during the 30-day period.
Major bleeding complications were observed in 6 patients (3.3%) in the
invasive group and 2 patients (1.1%) in the conservative group (P = .28). Severe thrombocytopenia was observed in 2 patients
(1.1%) in the invasive group and none (0%) in the conservative group (P = .50).
The 90-day follow-up was completed in 350 (95.9%) of 365 patients, and
the cumulative incidence of the composite of death, recurrent MI, or stroke
was 4.9% (n=9) in the invasive group and 7.1% (n=13) in the conservative group
(log-rank P = .39) (Figure 2). In an information preserving form, the number of patients
in each of the 4 categories (death, nonfatal recurrent MI, nonfatal stroke,
or none of these events) was 4, 5, 0, 173, respectively, in the invasive group
and 8, 4, 1, 170, respectively, in the conservative group.
The optimal therapeutic approach to patients with acute MI arriving
to hospital more than 12 hours after symptom onset represents a challenging
and as yet unresolved problem. This is due to the large number of these patients,5-7,9 dramatic
time-dependent reduction in thrombolysis efficacy,3,4 and
their unfavorable clinical course.27 Currently,
there is no evidence to our knowledge in support of a reperfusion strategy
in the majority of patients presenting more than 12 hours after symptom onset,
a situation that is also reflected in current treatment guidelines for patients
with acute MI.11
In an earlier nonrandomized study, Ellis et al28 reported
an in-hospital mortality rate of 13.7% in patients with acute MI who underwent
balloon angioplasty 6 to 48 hours after symptom onset (5.5% in those patients
with a successful procedure and 43.3% in those with a failed procedure). Subsequently,
3 randomized studies investigated the value of balloon angioplasty in 44 to
212 patients with acute MI presenting late after symptom onset.29-31 The
results of these studies are less relevant with respect to the definition
of an appropriate immediate treatment strategy for patients with acute MI
presenting late because mechanical recanalization was performed between 8
and 21 days after MI.29-31 Other
recent randomized controlled trials have addressed the issue of “late
comers” only in the context of patients ineligible for thrombolysis
and have demonstrated a clinical benefit of PCI.32,33 Conversely,
although results of large registries have demonstrated a mortality benefit
of balloon angioplasty in patients presenting more than 12 hours after symptom
onset, selection bias favoring lower-risk patients among those treated with
mechanical reperfusion vs those receiving conservative treatment might have
influenced the gradient in clinical outcome.21,22 Isolated
modification and potentiation of antithrombotic regimen cannot produce a measurable
benefit in patients ineligible for thombolysis who do not undergo PCI.34 Currently, we lack clear evidence that could help
guide the treatment of patients with acute MI presenting more than 12 hours
after symptom onset.
Our trial included 365 patients with acute STEMI, who according to current
guidelines, were not eligible for reperfusion treatment. Half of the patients
were randomly assigned to an invasive strategy consisting of immediate diagnostic
angiography followed predominantly by percutaneous coronary recanalization
and the other half to the conservative, medical treatment strategy. Being
the first prospective study to our knowledge to address this issue, we provided
unique information useful for the characterization of this population. Complementary
information relative to infarct size and angiographic features of these patients
was also obtained. Scintigraphic infarct size measured in the conservative
group appears to be smaller than that measured in patients with acute MI presenting
within 12 hours after symptom onset.16,17,35 Correspondingly,
the proportion of patients with a TIMI flow grade of 0 or 1 in the invasive
group seems to be lower than that observed in previous trials that included
patients with acute MI presenting within 12 hours after symptom onset.16,36
We found that an invasive strategy based predominantly on mechanical
reperfusion with coronary stenting and adjunctive abciximab in patients with
acute STEMI presenting after 12 hours from symptom onset is associated with
a reduction of infarct size compared with the currently recommended conservative
strategy. The trend observed toward a better clinical outcome in the invasive
group should be interpreted with caution due to the limited number of patients
and insufficient power for the assessment of clinical events. Scintigraphic
infarct size, however, contains useful prognostic information and is recognized
for its accuracy as a marker of reperfusion efficacy in trials of patients
with acute MI.37,38 Therefore,
our findings show that a significant reduction of infarct size is achievable
if an invasive reperfusion strategy is also offered to patients presenting
later than 12 hours, promptly upon arrival to hospital.
We do not know to what extent the systematic administration of abciximab
influenced the results obtained in the invasive group. Glycoprotein IIb/IIIa
inhibitors have shown a beneficial additive effect when used in conjunction
with PCI in patients with acute MI presenting within 12 hours39-41 and
may also enhance the effectiveness of mechanical recanalization performed
more than 12 hours after symptom onset.
Several mechanisms may explain our main finding. Experimental42 and clinical studies12-14 have
demonstrated that viable myocardium can persist after 12 hours of coronary
occlusion or symptom onset. Apart from stuttering course with intermittent
occlusion and recanalization,43 other factors
such as ischemic preconditioning,44 persistence
of residual blood flow in the infarct-related artery,14 or
recruitment of collaterals45 may prevent complete
necrosis and preserve some degree of myocardial viability. The presence of
anterograde and/or collateral flow before PCI in patients with evolving MI
is associated with reduced infarct size.46 Furthermore,
stunned and/or hibernating myocardium may exist within the area at risk with
a delicate balance between survival and apoptosis.47-49 All
these studies lend credit to the theory that viable myocardium can be found
late after symptom onset and that this myocardium may be salvaged if an effective
reperfusion strategy is applied.
In conclusion, our randomized controlled trial demonstrates that an
invasive strategy based on coronary stenting with adjunctive use of abciximab
reduces infarct size in patients with acute STEMI without persistent symptoms
presenting 12 to 48 hours after symptom onset. This finding increases the
level of evidence in support of the invasive strategy and deserves consideration
when current treatment guidelines for this category of patients will be reassessed.
Corresponding Author: Albert Schömig,
MD, Deutsches Herzzentrum, Technische Universität München, Lazarettstrasse
36, 80636 Munich, Germany (aschoemig@dhm.mhn.de).
Author Contributions: Dr Schömig had full
access to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Schömig, Antoniucci,
Schwaiger, Kastrati.
Acquisition of data: Schömig, Mehilli,
Antoniucci, Markwardt, Di Pede, Nekolla, Schlotterbeck, Schühlen, Pache,
Seyfarth, Martinoff, Benzer, Schmitt, Dirschinger, Schwaiger, Kastrati.
Analysis and interpretation of data: Schömig,
Mehilli, Ndrepepa, Kastrati.
Drafting of the manuscript: Schömig, Mehilli,
Ndrepepa, Kastrati.
Critical revision of the manuscript for important
intellectual content: Antoniucci, Markwardt, Di Pede, Nekolla, Schlotterbeck,
Schühlen, Pache, Seyfarth, Martinoff, Benzer, Schmitt, Dirschinger, Schwaiger.
Statistical analysis: Ndrepepa, Kastrati.
Obtained funding: Schömig, Kastrati.
Administrative, technical, or material support:
Schömig, Mehilli, Antoniucci, Markwardt, Di Pede, Nekolla, Schlotterbeck,
Schühlen, Pache, Seyfarth, Martinoff, Benzer, Schmitt, Dirschinger, Schwaiger,
Kastrati.
Study supervision: Schömig, Mehilli, Antoniucci,
Di Pede, Schlotterbeck, Benzer, Schmitt, Dirschinger, Schwaiger, Kastrati.
Financial Disclosures: None reported.
Centers and Investigators of the BRAVE-2 Trial:Steering Committee: A. Schömig (chairman), A. Kastrati
(principal investigator), D. Antoniucci, M. Schwaiger; Data Coordinating Center: J. Mehilli, C. Markwardt, H. Holle, A. Barth; Scintigraphic Core Laboratory: S. Nekolla, J. Neverve,
A. Claus, A. Funk, Klinik und Poliklinik für Nuklearmedizin rechts der
Isar, Munich, Germany; Angiographic Core Laboratory:
A. Dibra, A. Redl, S. Piniek, S. Mayer, Deutsches Herzzentrum, Munich, Germany; Clinical Follow-Up Center: K. Hösl, F. Rodrigues;
C. Peterle, Deutsches Herzzentrum, Munich, Germany.
Participating Centers and Investigators:Deutsches Herzzentrum, Munich, Germany: C. Schmitt (principal
investigator), H. Schühlen, J. Pache, N. von Beckerath, R. Wessely; Klinikum rechts der Isar, Munich, Germany: J. Dirschinger
(principal investigator), M. Seyfarth, M. Karch; Azienda
Ospedaliera Careggi, Florence, Italy: D. Antoniucci (principal investigator),
A. Conti, A. Pupi, G. Parodi; Klinikum Traunstein, Traunstein,
Germany: K. Schlotterbeck (principal investigator), G. Clermont, S.
Mang, O. Bosse, J. Fraunhofer, M. Barth, W. Moshage; Ospedale,
“Umberto I”, Mestre, Italy: F. di Pede (principal investigator),
G. Zuin, M. Sicolo; Landeskrankenhaus Feldkirch, Austria: W. Benzer (principal investigators), W. Fuchs; Klinikum Garmisch-Partenkirchen, Germany: F. Dotzer (principal investigator),
C. Glatthor, M. Fleckenstein; Sana-Herzzentrum Cottbus,
Germany: C. Kalina (principal investigator), U. Grelke; Asklepios Stadtklinik Bad Tölz, Germany: H. W. Gerbig (principal
investigator), W. Rothenberger; Kreisklinik Fürstenfeldbruck,
Germany: P. Permanetter (principal investigator), P. Seufert; Kreiskrankenhaus Erding/Dorfen, Germany: J. Leiss (principal
investigator), H. P. Emslander; Kreisklinik Trostberg, Germany: H. Bruckmayer (principal investigator), H.-G. Biedermann; Städtisches Krankenhaus Bad Reichenhall, Germany: H. Tanzer (principal
investigator), R. W. Hauck; Krankenhaus Vinzentinum Ruhpolding,
Germany: H. Fischer (principal investigator), T. Koch; Kreiskrankenhaus Freilassing, Germany: F. C. Himmler (principal investigator); Krankenhaus Schongau, Germany: V. Mayer (principal investigator).
Funding/Support: This work was supported by
grants KKF 10-02 and KKF 04-03 from Deutsches Herzzentrum, Munich, Germany,
as well as by unrestricted research grants from Lilly Deutschland GmbH, Bad
Homburg, Germany, and Guidant Advanced Cardiovascular Systems Inc, Santa Clara,
Calif.
Role of the Sponsor: The funding sources had
no role in the design and conduct of the study, in the collection, analysis,
and interpretation of the data, or in the writing of the manuscript and decision
to publish the findings.
Acknowledgment: We appreciate the invaluable
contribution of the medical and technical staffs operating in the coronary
care units, nuclear medicine, and catheterization laboratories of the participating
institutions.
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