23, 2016
ORIGINAL INVESTIGATIONS
ABSTRACT
BACKGROUND The impact of intravenous (IV) beta-blockers before primary percutaneous coronary intervention (PPCI)
on infarct size and clinical outcomes is not well established.
OBJECTIVES This study sought to conduct the rst double-blind, placebo-controlled international multicenter study
testing the effect of early IV beta-blockers before PPCI in a general ST-segment elevation myocardial infarction (STEMI)
population.
METHODS STEMI patients presenting <12 h from symptom onset in Killip class I to II without atrioventricular block were
randomized 1:1 to IV metoprolol (2 5-mg bolus) or matched placebo before PPCI. Primary endpoint was myocardial
infarct size as assessed by cardiac magnetic resonance imaging (CMR) at 30 days. Secondary endpoints were enzymatic
infarct size and incidence of ventricular arrhythmias. Safety endpoints included symptomatic bradycardia, symptomatic
hypotension, and cardiogenic shock.
RESULTS A total of 683 patients (mean age 62 12 years; 75% male) were randomized to metoprolol (n 336) or
placebo (n 346). CMR was performed in 342 patients (54.8%). Infarct size (percent of left ventricle [LV]) by CMR did not
differ between the metoprolol (15.3 11.0%) and placebo groups (14.9 11.5%; p 0.616). Peak and area under the
creatine kinase curve did not differ between both groups. LV ejection fraction by CMR was 51.0 10.9% in the metoprolol
group and 51.6 10.8% in the placebo group (p 0.68). The incidence of malignant arrhythmias was 3.6% in the
metoprolol group versus 6.9% in placebo (p 0.050). The incidence of adverse events was not different between groups.
From the aDepartment of Cardiology, Isala Hospital, Zwolle, the Netherlands; bDepartment of Cardiology, Centro Nacional de
Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; cDepartment of Cardiology, IIS-Fundacion Jimenez Daz Hos-
pital, Madrid, Spain; dDepartment of Cardiology, Hospital Universitario Quirn, Universidad Europea de Madrid & Hospital Ruber-
Quirnsalud, Madrid, Spain; eDepartment of Cardiology, VU University Medical Center, Amsterdam, the Netherlands; fDepartment
of Cardiology, Servicio de Urgencia Medica de Madrid (SUMMA 112), Madrid, Spain; gDepartment of Cardiology, University Medical
Center Groningen, Groningen, the Netherlands; hDepartment of Cardiology, Codigo Infarto, Madrid, Spain; iDepartment of Car-
diology, Hospital 12 de Octubre, Madrid, Spain; jDepartment of Cardiology, Hospital Clnico San Carlos, Madrid, Spain; kDepartment
of Cardiology, Hospital Gregorio Maran, Madrid, Spain; lDepartment of Cardiology, Hospital Puerta de Hierro, Madrid, Spain;
m
Department of Cardiology, Hospital Fundacin Alcorcn, Madrid, Spain; nDepartment of Cardiology, Hospital Ramn y Cajal,
Madrid, Spain; oDepartment of Cardiology, Hospital de La Princesa, Madrid, Spain; pDepartment of Cardiology, Hospital Prncipe de
Asturias, Alcal de Henares, Madrid, Spain; qDepartment of Cardiology, Hospital de Getafe, Madrid, Spain; rDiagram, Diagnostic
Research and Management, Zwolle, the Netherlands; sDepartment of Cardiology, Meander Medisch Centrum, Amersfoort, the
Netherlands; tDepartment of Cardiology, Maastricht University Medical Center, Maastricht, the Netherlands; uDepartment of
Cardiology, Academic Medical Center, Amsterdam, the Netherlands; and vThe Zena and Michael A Wiener Cardiovascular Institute,
Icahn School of Medicine at Mount Sinai, New York, New York. The Early-BAMI trial was an investigator-initiated, noncommercial
trial. The trial was funded by a research grant from the Dutch Heart Foundation (Utrecht, the Netherlands) (no. 2010B125) and an
unrestricted grant of Medtronic Inc. (Heerlen, the Netherlands). QMass software version MR 7.6 was partially supported by a
scientic collaboration between CNIC and Medis. Dr. Botas has been a consultant for Terumo. Dr. van t Hof has received speakers
fees from AstraZeneca, Iroko, and Daiichi-Sankyo; has received nonpersonal grants from Medtronic and Daiichi-Sankyo to his
research institution. All other authors have reported that they have no relationships relevant to the contents of this paper to
disclose. Christopher Granger, MD, served as Guest Editor for this paper.
Manuscript received March 17, 2016; revised manuscript received March 24, 2016, accepted March 24, 2016.
JACC VOL. 67, NO. 23, 2016 Roolvink et al. 2707
JUNE 14, 2016:270515 The EARLY-BAMI Trial
no. 2010B125) and an unrestricted grant by Medtronic aspiration and glycoprotein IIb/IIIa inhibitors was left
Inc. (Heerlen, the Netherlands), which was used for to operator discretion. Stenting was performed with a
additional analyses. second-generation drug-eluting stent. After PCI, pa-
tients received detailed written study information
STUDY PROTOCOL. Patients >18 years of age with detailing the protocol and the CMR follow-up,
symptoms of acute STEMI for >30 min but <12 h, whereafter written informed consent was obtained.
plus ST-segment elevation >1 mV in 2 adjacent Plans were for all patients to receive oral metoprolol
electrocardiogram leads or new left bundle branch within 12 h post-PCI, according to current guidelines,
block were eligible for enrollment. The diagnosis during hospitalization. At discharge, all patients
of STEMI was made by the ambulance medical received oral metoprolol at a dose recommended by
personnel. Electrocardiogram transmission to a their treating physician. Follow-up included outpa-
physician at the PCI center was allowed to conrm tient clinic visits to obtain follow-up data.
the diagnosis. After the in-ambulance diagnosis of The primary endpoint was myocardial infarct size
STEMI, medical treatment proceeded per current (percent infarcted myocardium, percentage of LV) as
guidelines: administration of 500 mg of IV aspirin, measured by CMR at 30 days (10 days). The sec-
600 mg of clopidogrel or 180 mg of ticagrelor orally, ondary efcacy endpoints were peak creatine kinase
and 5,000 international units of IV unfractionated (CK), peak CK-MB, troponin at 24 h, the CK and CK-
heparin. Exclusion criteria were Killip class III and IV, MB area under the curve during the rst 24 h, resid-
systolic blood pressure (BP) <100 mm Hg, heart ual ST-segment deviation 1 h after PCI/coronary
rate <60 beats/min, type II and III atrioventricular angiogram, ventricular arrhythmias requiring de-
block, history of previous myocardial infarction (MI), brillation during transportation and hospitalization,
known asthma bronchiale, pacemaker or implanted and major adverse cardiac event (MACE) rate, dened
cardioverter-debrillator (no cardiac magnetic reso- as cardiac death, nonfatal reinfarction, or target
nance imaging [CMR] possible), pregnancy or breast- vessel revascularization at 30 days. The secondary
feeding, or inability to provide informed consent. If safety endpoints included symptomatic bradycardia,
patients fullled the inclusion/exclusion criteria, symptomatic hypotension, and cardiogenic shock.
verbal informed consent was obtained. The following subgroups were prespecied for anal-
The trained ambulance paramedic completed the ysis: anterior versus nonanterior infarctions, patients
administration/enrollment procedure. After informed presenting <6 h after symptom onset versus patients
consent, a blinded study medication box was opened. presenting $6 h, and occluded (Thrombolysis
This box contained 2 vials of metoprolol 5 mg or In Myocardial Infarction [TIMI] ow grade 0 and
matching placebo and labeled with a number that 1) infarct-related vessel at time of PCI versus open
corresponded with the randomization list. Randomi- (TIMI ow grade 2 and 3) infarct-related vessel.
zation took place without stratication and in blocks STATISTICAL METHODS. Initially, the study was
of 4. The rst bolus of study medication was given in designed and initiated with enzymatic infarct size as
the ambulance, the second bolus was given at the the primary endpoint. However, after inclusion of 164
catheterization laboratory pre-PCI but only if systolic patients, the primary endpoint was changed into a
BP was >100 mm Hg and heart rate >60 beats/min. CMR-based endpoint (at July 3, 2013), which was
Given that the COMMIT CC2 study (Clopidogrel and approved by the steering committee and the medical
Metoprolol in Myocardial Infarction Trial/Second ethics committee. The original primary outcome
Chinese Cardiac Study) (12) showed that 15 mg of measure was enzymatic infarct size assessed by car-
metoprolol administered in a short interval was diac troponin T, and required 770 patients, based on
associated with a slight increase in cardiogenic shock the assumption that pre-hospital administration of
(although this was restricted to Killip III patients), the 2 5-mg metoprolol IV would give a relative 20%
reference ethics committee suggested reducing reduction in infarct size (alpha 0.05; power: 80%;
the dose to 10 mg separated into two 5-mg boluses: mean troponin T: 3.34 ng/l; SD 3.30). This original
the rst 5-mg bolus during ambulance transit and the primary outcome became a secondary outcome after
second 5-mg bolus on arrival at the catheterization the protocol change. This change in primary outcome
laboratory (i.e., immediately before initiating PCI). was mostly made to reduce the necessary sample size
The METOCARD-CNIC trial results (using 15 mg of and accommodate a time limitation on funding. Also,
metoprolol) were not known at the time of the study infarct size could be studied more precisely with CMR.
design. Patients participating in the trial were treated The change occurred while the investigators were still
during hospital admission and thereafter according to entirely blinded to trial results and without any
current guidelines. During PCI, the use of thrombus interim analysis performed. The sample size was than
2708 Roolvink et al. JACC VOL. 67, NO. 23, 2016
F I G U R E 1 Patient Flow
Included
N=684
No MRI No MRI
44 Inclusion before amendment 1 patient randomization 47 Inclusion before amendment
1 CABG unknown 3 CABG
25 Claustrophobia 15 Claustrophobia
11 Comorbidity 14 Comorbidity
3 Distance Metoprolol placebo 5 Distance
1 ICD N=336 N=347 2 ICD
9 No infarction criteria (enzymes) 9 No infarction criteria (enzymes)
4 Previous MI 6 Previous MI
14 No written informed consent 15 No written informed consent
15 Out of window 20 Out of window
8 Died 4 Died
17 Refused 18 Refused
7 Unable to plan appointment Underwent cardiac MRI Underwent cardiac MRI
10 Unable to plan appointment
8 Other N=169 N=173
6 Other
MRI analyzed
MRI analyzed
N=169
N=162
Excluded (n = 4)
Excluded (n = 7)
1 Previous MI
3 Acquisition problem
2 Acquisition problem
4 No infarction criteria (enzymes)
1 No infarction criteria (enzymes)
Reasons as to why patients did not undergo cardiac magnetic resonance imaging (CMR) are shown for both groups. CABG coronary artery bypass graft surgery;
ICD implantable cardioverter-debrillator; MI myocardial infarction; MRI magnetic resonance imaging.
determined for the revised primary endpoint by a respectively. For quantitative variables, data were
power analysis with reasonable clinical and statistical expressed as mean SD, and median with rst and
assumptions. With an expected infarct size of 28% (18) third quartiles. Non-normal data were compared by
in a population under standard treatment (no nonparametric methods (Wilcoxon rank sum test) and
beta-blocker pre-PCI), we considered a reduction in normal data by parametric methods. Categorical data
infarct size from 28% to 23.5% clinically relevant. were expressed as percentages and compared by chi-
Assuming an SD of the MI size measured by CMR equal square test (or Fisher exact test when appropriate).
to 10% (19), the power analysis indicated a total sam- For all analyses, statistical signicance was assumed
ple size of 326 patients (163 subjects in each group) was when the 2-tailed p < 0.05.
needed to achieve 80% power with signicance level CMR ANALYSIS. All CMR studies were performed
of 0.05 to detect a difference in infarct size. blinded to treatment allocation and according to a
Patients who died after completing the CMR study centralized protocol. Dedicated sequences evaluating
were included in the primary outcome analysis. Pa- cardiac function, myocardial edema, myocardial
tients who died before performance of the CMR were perfusion, and myocardial necrosis/brosis were per-
not included in the primary outcome analysis; how- formed. All CMR studies were stored and further
ever, they were included in the secondary outcome analyzed in a central core laboratory at the Centro
analysis because death within 1 year is a secondary Nacional de Intervestigaciones Cardiovasculares
endpoint. Statistical analysis was performed with Carlos III in Madrid, Spain. CMR study analyses were
SAS, version 9.3 (SAS Institute, Cary, North Carolina) performed in a random manner by expert observers
and SPSS Statistics for Windows, version 22.0 (IBM blinded to treatment allocation. Quantication was
Corp, Armonk, New York). Continuous data were performed on a separate workstation using a dedicated
expressed as mean SD, and categorical data as software package (QMass MR 7.6, Medis, Leiden, the
percentage, unless otherwise denoted. The analysis Netherlands). In all CMR studies, the following infor-
of variance and the chi-square tests were appropri- mation was determined: LV volumes, LV function,
ately used for continuous and categorical variables, and myocardial delayed enhancement. Myocardial
JACC VOL. 67, NO. 23, 2016 Roolvink et al. 2709
JUNE 14, 2016:270515 The EARLY-BAMI Trial
complaints until rst medical contact was comparable Diastolic BP, mm Hg 82.25 14.67 82.83 16.16 82.54 15.43 0.702
Heart rate, beats/min 74.35 13.71 78.68 15.69 76.53 14.89 <0.001
between the 2 groups, early presenters (<6 h after
Discharge medication
complaint onset) were more often present in the
ACE inhibitors 215/333 (64.6) 209/341 (61.3) 424/674 (62.9) 0.379
metoprolol group. At inclusion (before randomiza-
Angiotensin II blockers 14/333 (4.2) 23/341 (6.7) 37/674 (5.5) 0.148
tion), mean BP on admission was comparable be- beta-blocker 260/333 (78.1) 249/341 (73.0) 249/341 (73.0) 0.127
tween the 2 groups, whereas mean heart rate was Angiographic ndings
not signicantly lower in the metoprolol group 1-vessel disease 175/330 (53.0) 201/339 (59.3) 376/669 (56.2)
(78.6 beats/min vs. 80.5 beats/min; p 0.09). A total 2-vessel disease 100/330 (30.3) 71/339 (20.9) 171/669 (25.6)
of 20 patients (2.9%) were enrolled at the emergency 3-vessel disease 39/330 (11.8) 46/339 (13.6) 85/669 (12.7)
Primary PCI 306/315 (97.1) 306/322 (95.0) 612/637 (96.1) 0.164
department of the PCI center, mainly because patient
Additional PCI during 16/334 (4.8) 15/345 (4.3) 31/679 (4.6) 0.782
transport to the PCI center was very short. In these admission
patients, the rst study bolus was given as soon as CABG during admission 12/335 (3.6) 24/345 (7.0) 36/680 (5.3) 0.049
possible at the emergency department with the sec-
Values are mean SD or n/N (%).
ond bolus at catheterization laboratory arrival.
ACE angiotensin-converting enzyme; BMI body mass index; BP blood pressure; CABG coronary artery
Of the 336 patients allocated to pre-reperfusion bypass graft surgery; PCI percutaneous coronary intervention.
Infarction) trial tested the effect of pre-reperfusion Mean SD 276 243 232 254 254 248
Median (IQR) 188 (97450) 133 (49282) 152 (60440)
metoprolol (3 5 mg IV) versus placebo in STEMI
Min-max 3880 0969 0969
patients (N 5,778) treated by thrombolysis and
(n 52) (n 54) (n 106)
demonstrated no effect of metoprolol (11). In the Maximal CK (total), U/l 0.880
COMMIT CC2 trial with 45,825 patients, IV metoprolol Mean SD 2,102 2,029 2,072 2,018 2,087 2,022
3 5 mg followed by oral administration up to 4 Median (IQR) 1,370 (5383,050) 1,411 (4662,980) 1,376 (5043,050)
weeks did not improve survival in STEMI patients Min-max 479,857 308,769 309,857
(12). However, this was mainly caused by a higher (n 298) (n 293) (n 591)
24-h hs-cTn T, ng/l 0.103
incidence of cardiogenic shock in patients treated by
Mean SD 3,711 3,587 3,166 3,998 3,451 3,790
early beta-blocker therapy, possibly due to inclusion
Median (IQR) 2,530 1,994 2,224
of patients with heart failure. In the current era of (1,2005,450) (962.53,800) (1,0594,800)
PPCI, the METOCARD-CNIC trial showed reduced Min-max 22.4019,480 1.2531,700 1.2531,700
infarct size and increased LVEF in STEMI patients (n 114) (n 104) (n 218)
without signs of heart failure treated with early IV 24-h cTn I, mg/l 0.948
Mean SD 42.37 39.85 53.04 56.49 48.26 49.19
metoprolol (14,23). However, this study had a rela-
Median (IQR) 32.60 (13.3058.99) 32.83 (9.2874.71) 32.60 (9.7058.99)
tively small sample size (N 270), was not blinded
Min-max 0.65136.5 0.07177.1 0.07177.1
or placebo controlled, and included a select (n 13) (n 16) (n 29)
patient group (anterior STEMI presenting <6 h from
symptom onset). CK creatine kinase; cTn cardiac troponin; hs high sensitivity; other abbreviations as in Table 2.
A 3000 B 2500
p value = 0.88 P value = 0.6416
2500
2000 Placebo
Metoprolol
Infarct Size (Peak CK, U/L)
1500
1000
1000
500
500
0 0
Metoprolol Placebo 0 3 6 9 12 18 24 36 48 72
Time After Admission (Hrs)
There was no signicant difference in infarct size estimated by (A) peak creatine kinase (CK) or (B) area under the CK curve.
after the rst bolus of medication (i.e., before the reduction of acute malignant arrhythmias seen in
second bolus) was no different between metoprolol this trial encourage the performance of additional
and placebo arms in this trial, supporting the low- larger trials.
dosing hypothesis. In most randomized trials, in which infarct size or
Based on these data, and the conicting results LVEF was measured with CMR, CMR was performed
with the METOCARD-CNIC trial, additional random- at 1 month (25,26). This was the main reason why we
ized trials are needed to clarify whether early chose 1 month in our trial. All participating PCI cen-
beta-blocker treatment has any effect in these pa- ters and ambulance services had a longstanding
tients. We advocate that future studies test the car- experience in pre-hospital triage and treatment of
dioprotective effects of IV metoprolol in STEMI STEMI patients. Regional differences in systems of
patients using a target dose of 15 mg and administer care in which prehospital drug administration in the
medication immediately after STEMI diagnosis to ambulance differ (Europe vs. United States) can lead
allow a maximum on-board metoprolol time before to different application of these study results to daily
reperfusion. Given the reduced observed infarct size practice.
with a trial of our sample size, the reduction in STUDY LIMITATIONS. During the course of the trial,
infarct size by metoprolol should be at least 3.5% the primary endpoint was changed from enzymatic
to demonstrate a signicant difference between infarct size to infarct size measured by CMR, to
the groups. The safety prole, low cost, and the reduce the necessary sample size and because infarct
Metoprolol Placebo Metoprolol Placebo Difference in Delayed Enhancement Infarct (95% CI) P for interaction
All patients 159 167 15.29 10.97 14.91 11.52 -0.38 (-2.84 - 2.07)
Location of MI
Anterior infarction 78 88 18.81 12.20 19.30 12.65 0.49 (-3.33 - 4.31) 0.33
Non anterior infarction 75 71 12.24 8.01 10.41 7.78 -1.83 (-4.42 - 0.75)
Presentation
Early 135 129 15.11 10.69 14.56 11.09 -0.55 (-3.19 - 2.09) 0.72
Initial 0,1 98 97 17.78 10.81 18.12 11.81 0.35 (-2.85 - 3.54) 0.74
-10 -5 0 5 10
Favors Placebo Favors Metoprolol
Compared with placebo, metoprolol exhibited no signicant effects on delayed enhancement infarction (percent of left ventricle) in pre-specied subgroups.
CI condence interval; MI myocardial infarction; TIMI Thrombolysis In Myocardial Infarction; other abbreviations as in Figure 1.
size could be studied more precisely with CMR. The was no observed effect. Also, patients who died
results from enzymatic infarct size analysis, howev- before CMR was performed, meaning they probably
er, were completely in line with the results from the had larger infarctions, may have caused a selection
primary CMR endpoint. of patients with smaller infarctions undergoing
The trial was powered with a reduction of infarct CMR.
size from 28% to 23.5%. The smaller-than-estimated Although we dened several subanalyses, these
infarct size in this trial (15.1%) could affect the analyses should be interpreted with caution, since the
neutral effect seen (the smaller the infarct size, included number of patients in several subgroups
the less probability a difference could be found). were small. Also, we could not blind physicians and
However, in the larger anterior infarctions, there nurses to heart rate and BP; however, CMR analyses
Early Beta-blocker Administration before primary PCI in patients with ST-elevation Myocardial Infarction (EARLY-BAMI) trial
Baseline characteristics
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