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The BEtA-Blocker Therapy in Patients with Acute Myocardial Infarction with ST-Segment
Elevation
BEAT-AMI Trial
Randomized Controlled Trial
Study Protocol
Version 1.0
October, 2010
EudraCT: 2011-000911-26
Sponsor-ID: Uni-Koeln-1392
Local ethics approval: 11-080
German Clinical Trials Register: DRKS00000766
Investigator Initiated Study
Responsible:
Fikret Er, MD
Assistant Professor of Cardiology
Department of internal Medicine I
Klinikum Guetersloh
Reckenberger Str. 18
33332 Guetersloh, Germany
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Content
Page
1. Study Design .......................................................................................................................... 3
1.1 Overview ................................................................................................................... 3
1.2 Study Objective ......................................................................................................... 4
1.3 Study Population ....................................................................................................... 4
1.4 Use of Esmolol .......................................................................................................... 4
2. Selection Criteria .................................................................................................................. 5
2.1 Inclusion Criteria ....................................................................................................... 5
2.2 Exclusion Criteria...................................................................................................... 5
2.3 Study Endpoints ........................................................................................................ 5
3. Study Methodology ............................................................................................................... 6
3.1 Screening and Enrollment ......................................................................................... 6
3.2 Baseline Procedures .................................................................................................. 8
3.3 Randomization .......................................................................................................... 8
3.4 Standard Care Procedures: ........................................................................................ 8
3.5 Control Group Procedures ........................................................................................ 8
3.6 Treatment Group Procedures .................................................................................... 9
3.7 Esmolol-infusion ....................................................................................................... 9
3.8 Safety Guard............................................................................................................ 10
4. Follow-Up Procedures ........................................................................................................ 11
5. Data Management ............................................................................................................... 12
5.1 Data Collection........................................................................................................ 12
5.2 Data Monitoring ...................................................................................................... 12
6. Statistical Analysis Plan Summary.................................................................................... 12
6.1 Primary Endpoint .................................................................................................... 12
6.2 Sample Size Calculation ......................................................................................... 13
6.3 Intent-to-Treat (ITT) Analysis ................................................................................ 15
6.4 General Analysis ..................................................................................................... 15
7. References ............................................................................................................................ 16
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1. Study design
1.1 Overview
Beta-blocker (BB) therapy is of proven value in the treatment of arrhythmias and hypertension,
as well as for long-term secondary prevention after acute myocardial infarction (AMI) (1,2). The
impact of BB therapy in the acute phase of a myocardial infarction is a matter of discussion.
While oral BBs are widely recommended in AMI (evidence class and level of recommendation IA), the administration of intravenous (i.v.) BBs is controversially discussed (evidence class and
level of recommendation IIb-A) (2).
The concerns linked to i.v. BB treatment are based on historical or pre-percutaneous
coronary intervention (PCI) trials. During the pre-reperfusion era intensified usage of i.v. BB
showed mortality reduction in patients with AMI (3,4). Contrary, studies with thrombolysis
therapy in patients with AMI uncovered more cardiogenic shocks in patients receiving i.v. BB.
The elevated risk of cardiogenic shocks in the i.v.-BB group was explained by severe cases of
AMI, reflected by higher Killip classes in these patients (5). The impact of i.v. BB in patients
with AMI and PCI has not been assessed.
Several studies demonstrated that BB can improve cardiac function and reduce brain
natriuretic peptide (NT-proBNP) (6-8). In particular, a high value NT-proBNP is well known to
be associated with poor outcome (9-12). The coronary blood flow is heart rate (HR) dependent
and is associated with overproportional reduction with increasing heart rate (13). Thus, coronary
flow volume per heart beat decreases and causes a dramatic decline of myocardial cells in
ischemic area during AMI (13). Due to emotional stress and increased endogenous
catecholamines HR is elevated in patients with AMI. Consequently, complete regeneration of
cardiomyocytes may fail. It is a matter of interest in patients with acute MI whether elevated
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heart rate reflects the severity of myocardial injury (Killip III, IV) or is an adjustable value which
influences final infarct size. The present BEAT-AMI trial hypothesize that during the vulnerable
period of first hours after successful PCI in STEMI depression of sympathetic activity reflected
by tight heart rate control with esmolol is effective in prevention of detrimental sympathetic
impact and limitation of myocardial damage.
1.2 Study Objective
To demonstrate that depression of sympathetic activity by tight heart rate control with beta
blocker infusion is an effective therapy to limit Troponin T, Creatine kinase and NT-proBNP
release as surrogate parameter for myocardial damage during acute STEMI.
1.3 Study Population
The target enrollment size is 100 randomized patients. Prior to randomization, eligible subjects
will be consented. Only patients who meet all inclusion criteria will be included. Enrollment will
continue until 100 patients are randomized. It is estimated that approximately 350 patients will
be screened.
Eligible patients will be randomized at a 1:1 ratio to:
Treatment Group:
Patients receive continuous intravenous esmolol infusion for 24 hours after
successful PCI for STEMI additional to standard care
Control Group:
Patients receive continuous intravenous placebo infusion after successful
PCI for STEMI additional to standard care
1. 4 Use of esmolol
Most dreaded effect of intravenous beta blockade in acute phase of myocardial infarction is a
potentially overemphasized effect on heart rate and blood pressure. We identified esmolol to be
suitable due to the facts that it’s titratable and dosage is weight-adjustable. A short half-time of
6-9 minutes prevents long lasting side-effects.
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2. Selection Criteria
Participants will be screened to the following inclusion and exclusion criteria. All inclusion
criteria must be fulfilled before patient can be screened for randomization. The presence of any
exclusion criteria disqualifies participants from inclusion.
2.1 Inclusion Criteria
1. Subject has been admitted for invasive coronary angiography and percutaneous intervention
for acute STEMI with symptom onset less than 6 hours
2. Successful PCI with TIMI III flow
3. Subject is ≥ 18
4. Heart rate ≥ 60 bpm after PCI documented by ECG
5. Killip class I and II
6. Mean invasive arterial blood pressure > 65 mmHg and systolic blood pressure > 90 mmHg
7. Administration of Aspirin, Heparin, Clopidogrel or Prasugrel before PCI
8. Oxygen saturation (SO2) > 90 %
9. Written informed consent
2.2 Exclusion Criteria
Symptomatic AV-Block II and III
Contraindication for beta blocker or esmolol
Potential pregnancy
2.3 Study Endpoints
Primary:
The primary effectiveness endpoint is the maximum change in troponin T during first 48 hours
after successful PCI (peak troponin T minus baseline troponin T).
Secondary:
Secondary endpoints include:
Changes of NT-proBNP at 24h, 48h, 6 weeks and 6 months time points.
Changes of creatine kinase with MB fraction in 48 hours after index PCI.
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Circulating endothelial progenitor cells at 24 hours.
6-minutes-walk test
Neuropsychological testing (Visual analog scale)
Quality of life assessment with EQ5-D
Safety endpoints
Cardiogenic shock during index hospitalization
Symptomatic bradycardia
Hypotension during treatment (SPB<90 mmHg or MAP<65 mmHg)
Re-Angina pectoris
Re-Coronary angiography with or without target vessel revascularization
Re-Hospitalization
Re-Infarction
Cerebral insult
Mortality
3. Study Methodology
3.1 Screening and Enrollment
The ordered enrollment process consists of screening, obtaining written consent, completing the
baseline evaluation procedures, randomization, and treatment with remote ischemic
preconditioning (if randomized to treatment). A study flowchart demonstrating the enrollment
process is provided in figure 1.
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Eligible subjects with STEMI
and succesful PCI
Evaluation of in- and exclusion criteria
Written informed consent
Randomization
(numbered, sealed envelopes)
Esmolol-Group
Continous intravenous esmololinfusion targeting heart rate <60
bpm for 24 hours after PCI
N=50
Placebo-Group
Continous saline infusion of
similar esmolol-infusion amount
for 24 hours without heart rate
control
N=50
Figure 1. Flow-chart demonstrating enrollment process.
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All patients referred to the Cardiology Department of the University Hospital of Cologne for
acute PCI due to ST elevation myocardial infarction. elective invasive CA are screened for
eligibility. The trial will be explained to the individual patient for consideration. The potential
participant will be given adequate time to have all their questions answered and to carefully
consider participation. In case of participation written informed consent will be obtained.
3.2 Baseline Procedures
Prior to enrollment, patients referred for acute STEMI undergo percutaneous intervention. When
symptom onset was less than 6 hours and PCI was successful with TIMI III flow patients will be
asked for participation. Table 1 reflects the obtained procedures.
3.3 Randomization
Randomization with allocation ratio 1:1 is based on permuted blocks of varying length and is
implemented using sequentially numbered, opaque and sealed envelopes.

Treatment group (blinded):
Patients receive standard care plus intravenous esmolol

Control group (blinded):
Patients receive standard care plus intravenous infusion of sodium-chloride (0.9%)
3.4 Standard Care Procedures:
All patients with STEMI receive guideline recommended treatment after successful PCI. This
treatment is located in the intensive care unit and consists:

Intake of aspirin 100 mg per os after initial intravenous administration of 250 mg to 500
mg

Administration of clopidogrel 75 mg per os after loading with 600 mg or prasugrel 10 mg
per os after loading with 60 mg or ticagrelor 90 mg twice daily after loading with 180 mg

Administration of a statin

Administration of oral beta-blocker

No limitation of any other indicated therapy
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Randomization and administration of study medication starts immediately after transfer of
patient from catheter laboratory to intensive care unit with target delay of infusion start of less
than 60 minutes after successful PCI.
3.5 Control Group Procedures

24 hour continuous placebo infusion without target heart rate plus standard care
Patients in the control group are blinded for study medication. To maintain blinding procedure
bedside monitors are moved beside to prevent active monitoring of heart rate and blood pressure
by subject.
3.6 Treatment Group Procedures

24 hour continuous esmolol infusion targeting heart rate of 60 bpm plus standard care
Patients in the treatment group are blinded for study medication. To maintain blinding procedure
bedside monitors are moved beside to prevent active monitoring of heart rate and blood pressure
by subject.
3.7 Esmolol-infusion
Esmolol is used in ready-to-use bags of 250 ml with a concentration of 10 mg per ml.
Subjects assigned to esmolol receive weight-adjusted continuous infusion and intermittent bolus
infusion (Table 1). In contrast to manufacturers recommendation to start with a bolus injection,
due to safety reasons subjects in BEAT-AMI trial will receive low concentration of continuous
infusion, first. Over a period of 20 minutes every five minutes a bolus injection of esmolol
followed by increased infusion concentration is administered targeting heart rate of 60 bpm.
Final concentration is maintained for 23.5 hours and reduced over 30 minutes.
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Time (minutes)
Bolus
Continous infusion rate
μg/kg KG/min
μg/kg KG/min.
0–1
1–5
50
500
5–6
6 – 10
100
500
10 – 11
11 – 15
150
500
15 – 16
16 – 20
200
500
Table 1. Infusion schema of esmolol.
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3.8 Safety Guard
During Esmolol Infusion heart rate and blood pressure are monitored. The infusion will be
started when HR is > 60 bpm, systolic blood pressure (SBP) is > 90 mmHg and mean arterial
blood pressure (MBP) is > 65 mmHg (Figure 2). In case of HR decreases the 55 bpm limit the
Esmolol infusion rate will be reduced by 50 µg/kg/min or stopped when the actual dosage is 50
µg/kg/min. Between HR of 55-60 bpm infusion rate will not changed, bolus infusion will not
given. When SPB is decreased (< 90 mmHg) or MBP is decreased (< 65 mmHg) Esmolol
infusion will be stopped until SPB and MBP are above inclusion limits. In case of restarting the
Esmolol infusion, the initial administration protocol will be used with continuous infusion of 50
µg/kg/min.
If significant tachycardia, bradycardia, hypotension or hypertension occurs, then per physicians’
discretion rescue therapy may be implemented.
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HR > 60 bpm
SBP > 90 mmHg
MBP > 65 mmHg
Continue Esmolol
infusion up to
max. dose
HR < 55 bpm
Reduce Esmolol
infusion rate
by 50 µg/kg/min or
interrupt infusion
SBP < 90 mmHg or
MBP < 65 mmHg
Stopp Esmolol
infusion
Figure 2. Rules for maintaining of infusion, rate reduction, interruption and discontinuation.
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4. Follow-up Procedures
Follow-up procedures are same in the treatment and control group. Table 2 lists the testing and
procedures required at baseline and follow-up time points.
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0h 6h 12h
18h
24h
48h
6 weeks
6 months
Heart rate
X
X
X
X
X
X
X
Blood pressure
X
X
X
X
X
X
X
ECG
X
Troponin T
X
CK
X
CK-MB
X
Circulating endothelial
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
progenitor cells
Transthoracic
X
echocardiography
6-minute-walk test
EQ5D; VAS
X
Table 2. Required testing procedures and time-points.
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5. Data Management
5.1 Data Collection
All study data will be recorded onto electronic case report forms (eCRFs). All eCRFs will be
completed using pseudonymized data.
eCRF completion may be delegated to other study personnel but the principle investigator
remains responsible for the accuracy and integrity of all data entered on eCRFs.
5.2 Data Monitoring
Data will be monitored periodically by independent monitors of the Clinical Trials Center
Cologne (CTC Cologne, Gleueler Str. 269, 50935 Cologne). During site visits, the monitor will
review participant records, general study procedures, and will discuss any problems with the
investigator. Monitors will audit data collected on eCRFs and verify it against source
documentation. Monitors will confirm that written informed consent was properly obtained prior
to enrollment of all participants. Any evident pattern of non-compliance will be addressed with
the principal investigator.
6. Statistical Analysis Plan Summary
This is a single-center, prospective, randomized, blinded two-arm phase IV clinical trial designed
to compare the effectiveness of heart rate control with esmolol during the first 24 hours after
acute STEMI.
6.1 Trial populations
The full-analysis set for the primary analysis will be derived from the intention-to-treat (ITT)
principle. This dataset includes all trial subjects enrolled and randomized. Only patients with
sub-acute myocardial infarction will be excluded after randomization (lactate dehydrogenase
>280 U/L without other explanation).
The per-protocol (PP) set includes all trial subjects who are essentially treated according to
protocol (e.g. received study medication for 24 hours +/- 1 hour, performed follow-up visits after
six weeks +/-7 days and six months +/-10 days in accepted time windows allowing a complete
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and
meaningful
documentation
of
clinical
outcome).
PP
analyses
are
treated
secondary/supportive.
The valid for safety (VFS) set included all trial subjects who receive any trial medication.
The analysis sets will be defined in a blinded manner.
6.2 Primary Endpoint
The primary efficacy outcome is the maximum change in Troponin T level from baseline to 48
hours. The null hypothesis that Troponin T increase is equal in patients with esmolol therapy and
placebo will be tested using the Mann-Whitney U test. A difference is seen to be statistically
significant if the two-sided p-value is <0.05.
6.3 General Analysis
Baseline characteristics and secondary endpoints will be described using mean, standard
deviation and percentiles (0, 25, 50, 75, 100) for continuous variables, count and percentage for
categorical variables. We will use unpaired t-tests, Mann-Whitney U tests and Fisher’s exact
tests to perform pairwise treatment comparisons. Subgroup analyses will be performed by gender
(expected ratio male:female is 7:3). An interim analysis will not be performed.
All statistical analyses will be performed using SPSS for windows (Version 18 or higher). Unless
otherwise specified, a two-sided 0.05 level of significance will be used to declare treatment arms
significantly different.
6.4 Sample Size Calculation
Quartile construction for sample size calculation is based on pilot data and the work by a study
on BNP in STEMI (14). For a reduction in mean heart rate of 10 beats/min we expect a reduction
in mean troponin T max (primary variable) of about 3≈0.5*5.87 µg/l, based on the hypothesis
that heart rate reduction is responsible for troponin T decrease for at least for 50%. Assuming a
coefficient of variation of 1, such a troponin T max reduction may be detected with 92% power,
obtained by simulation, using the Welch-modified t-test with 50 patients per treatment group (at
5% two-sided significance level). In a non-simulation-based approach this roughly corresponds
to a delta/sigma of 0.67 (=3/4.5) assuming equal within-group variances. Note, we found
differences of 11.2 beats/min (85.6 beats/min in quartile 4 and 74.3 beats/min in quartile 1) and
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5.87 µg/l (>6.95 µg/l in quartile 4 and ≤1.08 in quartile 1 µg/l), see tables 3 to 6 below.
Likewise, for a reduction in mean heart rate of 10 beats/min we expect a reduction in mean BNP
(secondary variable) of 137≈0.5*274.9 pg/ml. Again, assuming a coefficient of variation of 1,
such a BNP reduction may be detected with 90% Power (obtained by simulation) using the
Welch-modified t-test with 50 patients per treatment group (5% two-sided significance level). In
a non-simulation-based approach this corresponds to a delta/sigma of 0.66 (=137/209) assuming
equal within-group variances. Note, Grabowski et al. report differences of 7.7 beats/min (84.8
beats/min in quartile 4, 77.1 beats/min in quartile 1) and 274.9 pg/ml (>334 pg/ml in quartile 4,
≤59.1 pg/ml in quartile 1), respectively. Our pilot data show very similar differences of 7.7
beats/min and 230.2 pg/ml, see tables 1 and 2 below. Although in this study BNP and not the
prohormone NT-proBNP was assessed, similar properties and relations between BNP and NTproBNP are expected (15,16). Thus a sample size of 50 patients per treatment group (i.e. 100 in
total) seems required and sufficient to assess presumably relevant effects of study treatment on
cTnT, BNP and EPCs in an explorative manner. Due to the sufficient power we did not account
for drop-outs and non-parametric analysis.
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Minimum
Percentile 25
Median
Percentile 75
3235
6008
135
788
1585
3090
34629
Troponin T 24h
39
3.04
2.60
.01
.99
2.14
4.99
9.22
Troponin T max
39
4.11
3.54
.01
1.08
3.65
6.95
15.70
Maximum
Mean
39
Standard
Deviation
Valid N
NT-proBNP
Table 3.
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Maximum
Percentile 75
Median
Percentile 25
Minimum
Standard
Deviation
Mean
Valid N
NT-proBNP
Q1*
HR
9
77.33
15.83
56.00
66.00
73.00
90.00
103.00
Q2
HR
10
74.80
8.08
61.00
69.00
76.50
82.00
85.00
Q3
HR
10
79.00
9.61
55.00
77.00
80.00
83.00
90.00
Q4
HR
9
85.00
27.88
52.00
59.00
84.00
98.00
130.00
Table 4. * Q ‘quartile’
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T 24h
Maximum
Percentile 75
Median
Percentile 25
Minimum
Standard
Deviation
Mean
Valid N
Troponin
Q1* HR
9
72.56 18.30 52.00 66.00 69.00 75.00 116.00
Q2
HR
10
78.70 14.17 52.00 70.00 79.50 89.00 103.00
Q3
HR
10
77.30 14.06 55.00 61.00 80.00 86.00
Q4
HR
9
86.67 19.31 59.00 79.00 83.00 90.00 130.00
98.00
Table 5. * Q ‘quartile’
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Maximum
Percentile 75
Median
Percentile 25
Minimum
Standard
Deviation
Mean
Valid N
Troponin T max Q1* HR
9
74.33 12.93 56.00 69.00 73.00 77.00 103.00
Q2
HR
10
73.70 18.22 52.00 61.00 73.00 80.00 116.00
Q3
HR
10
84.60
Q4
HR
9
85.56 20.79 59.00 81.00 84.00 89.00 130.00
7.43
76.00 77.00 83.50 90.00
98.00
Table 6. * Q ‘quartile’
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