BEtablocker Treatment After Acute Myocardial Infarction in Patients Without Reduced Left Ventricular Systolic Function (BETAMI)
Phase: PHASE4
Conditions: Acute Myocardial Infarction, Non-ST Elevation Myocardial Infarction, ST Elevation Myocardial Infarction
Sponsor: Oslo University Hospital

 
 
 
 
 
 
Protocol Identification Number:  BETAMI 
EudraCT Number:  2018-000590-75 
 
 
SPONSOR: 
Oslo University Hospital  
 
Head of Division, Morten Mowe 
 
Postboks 4950 Nydalen 
                                                                                                0424 OSLO 
 
Tel : +47 23 02 75 10 
 
E-mail: mormow@ous-hf.no 
 
 
 
 
 
 
 
 
 
 
 
 
 
BEtablocker Treatment After Acute Myocardial Infarction in Patients 
Without Reduced Left Ventricular Systolic Function (BETAMI) 
 
PROTOCOL VERSION NO. 10.0 – 22 NOV 2023 

Protocol BETAMI Version no. 10.0 22 NOV2023 
 
 
CONTACT DETAILS 
 
Sponsor: 
Oslo University Hospital, Ullevaal 
Head of Division, Morten Mowe 
Address: Postboks 4950 Nydalen 
0424 Oslo 
Tel: +47 23 02 75 10 
E-mail: mormow@ous-hf.no 
Study Chair 
Oslo University Hospital, Ullevaal 
Prof. Dan Atar 
Address: Postboks 4950 Nydalen 
0424 Oslo 
Tel: +47 22 11 91 87 
E-mail: dan.atar@medisin.uio.no 
Principal investigator at Site 1: 
Oslo University Hospital Ullevaal, Dept. of Cardiology 
Prof. Sigrun Halvorsen 
Address: Postboks 4950 Nydalen 
0424 Oslo 
Tel: +47 22 11 91 00 
E-mail: sigrun.halvorsen@online.no 
Principal investigator at Site 2: 
Oslo University Hospital Rikshospitalet, Dept.of Cardiology 
Prof. Thor Edvardsen 
Address: Postboks 4950 Nydalen 
0424 Oslo 
Tel: + 47 23 07 13 93 
E-mail: thor.edvardsen@medisin.uio.no 
Principal investigator at Site 3: 
Akershus universitetssykehus HF 
Prof.Henrik Schirmer 
Address: Postboks 1000, 1478 Lørenskog 
Tel: +47 992 64 338 
E-mail: henrik.schirmer@medisin.uio.no 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
 
 
Principal investigator at Site 4: 
St. Olavs Hospital NTNU 
Prof. Rune Wiseth 
Address: Postboks 8905 
7491 Trondheim 
Tel: +47 
E-mail: rune.wiseth@ntnu.no 
Principal investigator at Site 5: 
Haukeland Universitetssykehus,  
Attending Physician, dr. Vegard Tuseth 
Address: Postboks 7804 
5020 Bergen 
Tel: +47 90 15 11 48 
E-mail: vegard.tuseth@helse-bergen.no 
Principal investigator at Site 6: 
Universitetssykehuset Nord-Norge, UNN 
Assoc. Prof. Dr. Terje Steigen 
Address: 9038 Tromsø 
Tel: +47 99 40 38 60 
E-mail: Terje.Steigen@unn.no 
Principal investigator at Site 7: 
Stavanger Universitetssjukehus 
Prof. Alf Inge Larsen 
Address: Postboks 8100 
4068 Stavanger 
Tel: + 47 51 54 38 78 
E-mail: alf.inge.larsen@sus.no 
Principal investigator at Site 8: 
Sørlandet Sykehus HF Arendal 
Head of Dept. of Cardiology, dr. Jarle Jortveit 
Address: Postboks 416 
4604 Kristiansand S 
Tel: +47 99 45 07 14 
E-mail: Jarle.Jortveit@sshf.no 
Principal investigator at Site 9 and 
Study Co-Chair: 
Vestre Viken HF, Drammen Sykehus  
Attending Physician, dr. John Munkhaugen 
Address: Postboks 800 
3004 Drammen 
Tel: +47 975 24 194 
E-mail: johmun@vestreviken.no 

Protocol BETAMI Version no. 10.0 22 NOV2023 
 
 
 
Principal   investigator   at   Site   10   and 
Scientific Secretary: 
Sykehuset i Vestfold 
Attending Physician, dr. Vidar Ruddox 
Address Postboks 2168 
3103 Tønsberg 
Tel: + 47 918 84 818 
E-mail: vidar.ruddox@siv.no 
Principal investigator at Site 11 
LHL Gardermoen 
Attending Physician, dr. Olaf Rødevand 
Postboks 103 Jessheimbyen, 2051 Jessheim 
Tel: +47 67 02 30 00 
E-mail: Olaf.Rodevand@lhl.no 
Principal investigator at Site 12 
Sykehuset Østfold Kalnes 
Attending Physician, dr. Peter Stefan Deeg 
Postboks 300, 1714 Grålum 
E-mail: Peter.Stefan.Deeg@so-hf.no 
Principal investigator at Site 13 
Sykehuset Innlandet Lillehammer 
Attending Physician, dr. Ellen Bøhmer 
Postboks 104, 2381 Brummundal 
E-mail: Ellen.Bohmer@sykehuset-innlandet.no 
Principal investigator at Site 14 
Sykehuset Innlandet Hamar 
Attending Physician, dr. Anja Otrebska Brattrud 
Postboks 104, 2381 Brummundal 
E-mail: Anja.Otrebska.Brattrud@sykehuset-innlandet.no 
Principal investigator at Site 15 
Vestre Viken HF, Bærum Sykehus 
Attending Physician, dr. Guro Storsul 
Postboks 800, 3004 Drammen 
E-mail: Guro.Storsul@vestreviken.no 
Principal investigator at Site 16 
Vestre Viken HF, Ringerike Sykehus 
Attending Physician, dr. Alf-Åge Reistad Pettersen  
Postboks 800, 3004 Drammen 
E-mail: ALFPET@vestreviken.no 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
 
Principal investigator at Site 17 
Diakonhjemmet Sykehus 
Attending Physician, dr. Erik Harald Øie 
Postboks 23 Vinderen, 0319 Oslo 
E-mail: Erik.Oie@diakonsyk.no 
Principal investigator at Site 18 
Sykehuset Innlandet HF, Gjøvik Sykehus 
Attending Physician, dr. Eva Bostad Borg 
Postboks 104, 2381 Brummundal 
E-mail: Eva.Bostad.Borg@sykehuset-innlandet.no 
Principal investigator at Site 19 
Lovisenberg Diakonale Sykehus 
Attending Physician, dr. Tobias Erik Herrscher 
Postboks 4970 Nydalen, 0440 Oslo 
E-mail: Tobias.Erik.Herrscher@lds.no 
Principal investigator at Site 20 
Nordlandssykehuset HF Bodø 
Attending Physician, dr. Ståle Haugset Nymo 
Postboks 1480, 8092 Bodø 
E-mail: stale.haugset.nymo@nordlandssykehuset.no 
Coordinating monitoring unit: 
Clinical Trial Unit, Oslo University Hospital 
Address: Oslo universitetssykehus HF, Sogn Arena, Postboks 
4950 Nydalen, 0424 Oslo 
Tel: +47 415 44 583 
Data Safety Monitoring Board: 
Prof. Cardiologist David Erlinge, Lund University,  
Sweden (Head) 
Prof. Cardiologist Lars Køber, København, Denmark 
Associate Professor, statistician Theis Lange, København, 
Denmark 
Sponsor’s Medical Officer 
Dan Atar 
Clinical Endpoint Committee: 
Prof.  Cardiologist  Finn  Gustafsson,  København,   
Denmark (Head) 
PhD   Cardiologist   Harald   Thune   Jørstad,   Amsterdam, 
Netherlands 
Prof. Cardiologist Tord Juhlin, Malmö, Sweden 

Protocol BETAMI Version no. 10.0 22 NOV2023 
 
 
Steering Committee 
Norway 
Dan Atar (Chair) (OUS/UiO) 
John Munkhaugen (co-Chair, Drammen / VV) 
Vidar Ruddox (Scientific Secretary, Tønsberg / SiV) 
Sigrun Halvorsen (OUS/UiO) 
Thor Edvardsen (OUS/UiO) 
Toril Dammen (UiO) 
Nils Tore Vethe (OUS) 
Morten Wang Fagerland (OUS) 
Rune Wiseth (St.Olav / NTNU) 
Kjell Vikenes (Haukeland / UiB) 
Terje Steigen (Tromsø / UNN) 
Henrik Schirmer (AHUS) 
Rune Wiseth (St.Olav / NTNU) 
Olaf Rødevand (LHL Gardermoen) 
Jarle Jortveit, (Arendal / SSHF)  
Denmark 
Lars Køber (RH - København, Danmark) 
Hans Erik Bøtker (AUH - Århus, Danmark) 
Svend Eggert Jensen (AUH - Aalborg, Danmark) 
Eva Prescott (Bispebjerg Hospital - København, Danmark) 
Executive Steering Committee 
Dan Atar (Chair) (OUS/UiO) 
John Munkhaugen (co-Chair, Drammen / VV) 
Vidar Ruddox (Scientific Secretary, Tønsberg / SiV) 
Sigrun Halvorsen (OUS/UiO) 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
 
SIGNATURE PAGE 
 
 
 
Title: 
BEtablocker Treatment after Acute Myocardial Infarction in patients without reducedleft 
ventricular ejection fraction (BETAMI). 
Protocol ID no: 
BETAMI 
EudraCT no: 
2018-000590-75 
 
 
 
 
I hereby declare that I will conduct the study in compliance with the Protocol, ICH GCP and the 
applicable regulatory requirements: 
 
 
 
Name 
Title 
Role 
Signature 
Date 
Dan Atar 
MD PhD 
Principal 
Investigator and 
Study Chair 
(e-sign) 
22.11.23 
John Munkhaugen 
MD PhD 
Study Co-Chair 
WP leader, 
secondary 
prevention and 
biobank 
(e-sign) 
22.11.23 
Vidar Ruddox 
MD PhD 
Scientific Study 
Secretary 
(e-sign) 
22.11.23 
Sigrun Halvorsen 
MD PhD 
Member of 
Executive 
Steering Group 
(e-sign) 
22.11.23 
Morten Wang 
Fagerland 
PhD 
Study statistician 
(e-sign) 
  22.11.23 
Toril Dammen 
MD PhD 
WP leader, 
psychosocial 
factors 
(e-sign) 
22.11.23 

Protocol BETAMI Version no. 10.0 22 NOV2023 
 
 
SIGNATURE PAGE, PRINCIPAL INVESTIGATOR / COORDINATING 
INVESTIGATOR 
 
 
 
Title: 
BEtablocker Treatment after Acute Myocardial Infarction in patients without reduced left 
ventricular ejection fraction (BETAMI). 
Protocol ID no: 
BETAMI 
EudraCT no: 
2018-000590-75 
 
 
 
 
I hereby declare that I will conduct the study in compliance with the Protocol, ICH GCP and the 
applicable regulatory requirements: 
 
Dan Atar 
Prof. 
 
22.11.2023 
Name 
Title 
Signature 
Date 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
 
PROTOCOL SYNOPSIS 
 
Protocol title: BEtablocker Treatment after Acute Myocardial Infarction in patients without reduced left 
ventricular ejection fraction (BETAMI). 
 
 
 
Sponsor 
Oslo University Hospital 
Phase and study type 
Prospective, randomized, open, blinded end-point (PROBE) study. 
Investigational Medical 
Product (IMP) (including 
active comparator and 
placebo): 
The study aims to investigate whether oral betablocker (BB) therapy is 
superior to no such treatment following an acute myocardial infarction 
(AMI). 
Centers: 
20 hospitals in Norway 
Study Period: 
Actual date of first patient enrolled: 2-OCT-2018  
Anticipated recruitment period: 5.4 years 
Estimated date of last patient completed: 10-DEC-2024 
 
Follow-up period at end of inclusion at least 0.5 years 
Treatment Duration: 
Estimated (non) treatment duration per patient:  range 0.5 –6 years 
Follow-up: 
Subjects will be followed up for at least 0.5 –6 (mean 3) years for 
the primary and secondary endpoints. 

Protocol BETAMI Version no. 10.0 22 NOV2023 
 
 
Collaboration with the 
DANBLOCK trial from 
Denmark 
 
 
 
 
 
Objectives 
In all, 2250 patients have been included during a 3.5 years months period 
(per April 2022) indicating a total inclusion period of >10 years to enroll 10 
000 patients. After careful discussions, the BETAMI steering committee 
consider such a long recruitment period not feasible neither from scientific 
or an ethical point of view. Therefore, negotiations with the parallel 
DANBLOCK (NCT03778554)study Steering Committee, featuring an almost 
identical study design, has led to decision to merge the two final databases 
for endpoint analysis. However, each country (Norway and Denmark), 
respectively, retain their responsibility and financial plan for execution of 
their respective original studies.    
 
The primary objective is to test whether oral BB therapy reduces the risk of 
major adverse cardiovascular event (MACE; i.e. all-cause death, non-fatal 
MI, ischemic stroke, malignant ventricular arrhythmias, coronary 
revascularization, cardiac arrest with successful resuscitation due to 
cardiac cause, and incident heart failure compared to no such therapy, in 
post-AMI patients treated with PCI or thrombolysis without reduced LVEF. 
The key secondary objectives are: 
 
To study whether oral BB therapy reduces the risk of each of the 
components of the primary end-point separately, compared to no 
such therapy 
To assess clinical outcomes linked BB therapy including outcomes in 
the following subgroups: age (tertiles), gender (men vs. women), BB 
dosage tertiles (dosage at randomization) and, LVEF subgroups 
(preserved LVEF: 
≥50% vs. mid-range LVEF: 40-49%) 
 
The key secondary objectives are: 
 
To study whether oral BB therapy reduces the risk of cardiovascular 
death compared to no such therapy 
 
To study whether oral BB therapy reduces the risk of stable and 
unstable angina compared to no such therapy 
 
To study whether oral BB therapy reduces the risk of atrial 
fibrillation, atrial flutter or other atrial tachyarrhythmias compared 
to no such therapy 
 
To study whether oral BB therapy increases the risk of 
hospitalization for bradycardia, syncope, AV-block, implantation of 
pacemaker, ICD, or CRT. 
 
To study whether oral BB therapy increases the risk of 
hospitalization for chronic obstructive pulmonary disease, asthma 
or peripheral artery disease. 
 
To study whether oral BB therapy increases the risk of 
hospitalization or outpatient visit for new-onset or dysregulated 
diabetes 
 
 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
 
 
 
To study whether oral BB therapy affects the following patient 
related outcomes: quality of life, angina, dyspnoea, anxiety, 
depression, sexual dysfunction or sleep disorders 
 
To conduct a cost-utility analysis in relation to quality of life and a 
health economic evaluation including drug use, health care 
utilization, employment, income, and benefit take-up 
 
To assess study safety 
Exploratory biobanking objectives: 
 
To study the proportion and predictors of non-adherence with BB, 
statins and other cardiovascular drugs assessed by direct methods 
quantifying drug concentrations in blood 
 
Identify pharmacokinetic, pharmacogenetic and pharmacodynamic 
markers associated with side-effects and suboptimal response to 
treatment with cardiovascular drugs 
Post-trial objective: 
 
To perform a joint analysis of the data from the BETAMI/ 
DANBLOCK (Denmark) study and the REDUCE (NCT03278509) and 
REBOOT (NCT03596385) trials. This analysis will increase power and 
precision for clinical decisions on both primary and secondary 
endpoints. 
Endpoints: 
Primary endpoint: 
Time to all-cause mortality, non-fatal MI, ischemic stroke, malignant 
ventricular arrhythmias, coronary revascularization, cardiac arrest with 
successful resuscitation due to cardiac cause, and incident heart failure 
since randomization  
 
Key secondary endpoints: 
 Each of the components of the primary study end-point. 
 Subgroup analyses as elaborated above. 

Safety endpoint: 
 
A composite of malignant ventricular arrhythmias, incident heart failure, 
new MI or all-cause death a t 30 days after randomization assessed after 
18 months follow-up and at study end. 
 
All-Cause Mortality: obtained from the Norwegian Population Registry at 
study end.  
 
Suspected Unexpected Serious Adverse Reaction (SUSARs) reported 
continuously by local investigators obtained from the study database. 
Assessment of primary study 
end points 
The primary study end-points will be obtained through linkage to the 
Norwegian Cardiovascular Disease Registry and the Population Registry. 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
 
 
Assessment of safety end 
points 
 
The safety endpoints will be under the responsibility of the 
primary investigators at all participating centers and collected 
at day 30 through direct telephone contact with the patient and 
from hospital medical records. A safety analysis will be 
performed 18 months after study start and at study end through 
linkage to the Norwegian Cardiovascular Disease Registry and 
the Norwegian Population Registry. 
 
All serious adverse events, including potential endpoints will be 
collected from the Norwegian Cardiovascular Disease Registry 
and the Norwegian Population Registry at study end. 
 
Assessment of secondary 
registry-based study end 
points 
In addition to SAE reporting, data will be collected through linkage to the 
following national registries: The Norwegian Population Registry 
(Folkeregisteret), the Cause of Death Registry, the Norwegian Patient 
Registry, the Norwegian Cardiovascular Disease Registry, the Norwegian 
Prescription Database, the Norwegian registry for income, the FD-Trygd 
database (social security micro data for research) and the Control and 
payment of reimbursements to health service providers (KUHR) database 
Study Design: 
This is a prospective, randomized, open blinded end-point (PROBE) study. 
Patients with AMI will be randomized 1-8 days following PCI or 
thrombolysis, and allocated to either prescription of a BB or to no such 
prescription 
Main Inclusion Criteria: 
 
An AMI diagnosis verified according to the "Universal Definition of AMI" 
and treatment with PCI and/or thrombolysis during the AMI 
hospitalization 
Main Exclusion Criteria 
 
No clinical diagnosis of heart failure. 
 
LVEF < 40% or significant LV akinesia in ≥ 3 segments regardless of LVEF 
by visual assessment 
 
Conditions requiring BB therapy 
 
Contraindications to BB treatment 
 
End-stage somatic disease, dementia, psychosis and other conditions 
could put the subject at significant risk, confound the study results, 
interfere significantly with the subject participation in the study, or 
rendering informed consent unfeasible 
 
Women of childbearing potential 
Sample Size: 
Estimated 5600 patients in Norway (N=2900)  and Denmark (N=2700) 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
 
Power Calculation 
Incident rates obtained from the subpopulation with AMI as the indication for 
treatment with PCI in the NORSTENT trial provided the background for sample 
size considerations indicating a 5-year event rate of 17% for the initial primary 
endpoint (Mortality 6.9% and AMI 10.1%). With a randomization ratio of 1:1, a 
sample size of 4671 patients (794 events) will provide a power of 80% to 
detect a difference of 18.7% primary endpoints with no BB treatment and 
15.3% primary endpoints with BB treatment. This corresponds to a hazard 
ratio of approximately 1.22. To allow for a slightly lower overall event rate and 
some information loss due to drop-outs and crossover between groups the 
total sample size of the trial will be 5000 patients.                                                     
However, preliminary data from Denmark indicates that the prevalence of the 
initial primary endpoint is significantly lower than estimated. A new power 
calculation for the joint BETAMI – DANBLOCK trial has therefore been made. 
The analysis is based on a time-to-event outcome. We aim to have sufficient 
power to detect a true treatment effect with a hazard ratio of 1.2. It is 
observed that 80 % power is obtained with around 950 events in total.  Only 
one analysis of the primary endpoint on the combined BETAMI and DANBLOCK 
sample will be performed.  
 
Efficacy Assessments: 
Not applicable 
Safety Assessments: 
Subjects will be interviewed by phone after a standardized protocol by a 
specially trained study nurse after 30 days for the assessment of the 
composite safety endpoints. A safety analysis will be performed as soon 
as data from 1667 patients (1/3 of the population) at 30 days are 
available. Data on the 30 days safety endpoint will also be collected at 
end-of follow-up from Norwegian Cardiovascular Disease Registry and 
the Population Registry.  

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
 
 
Type and Dosage of BB 
Treatment 
Information will be collected from a telephone interview with the patients 
at day 30, from the Norwegian Prescription Registry at study end 
Statistical Analysis 
Statistical analyses will be conducted according to the intention-to-treat 
principle. Clinical endpoints will be assessed by using Cox-regression and 
Kaplan-Meier curves 
Oslo Centre for Biostatistics and Epidemiology (OCBE) is responsible for all 
statistics. A statistical analysis plan (SAP) describing all details in this respect 
will be produced prior to database lock together with the study statistician 
from the DANBLOCK trial.  
Clinical Endpoint Committee 
(CEC) 
Data Safety Monitoring 
Board 
Adjudication of all end-points according to pre-specified and standardized 
criteria will be performed by a CEC blinded to study assignment. 
This committee consisting of two senior cardiologists and one trial-science 
statistician will overview safety and will have access to unblinded data. 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
3 
TABLE OF CONTENTS 
Innhold 
Protocol Identification Number:  BETAMI ................................................................................................... 1 
CONTACT DETAILS ...................................................................................................................................... 2 
SIGNATURE PAGE ....................................................................................................................................... 7 
SIGNATURE PAGE, PRINCIPAL INVESTIGATOR / COORDINATING INVESTIGATOR ........................................... 8 
PROTOCOL SYNOPSIS .................................................................................................................................. 9 
TABLE OF CONTENTS ................................................................................................................................. 12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................................................ 16 
1 
INTRODUCTION ............................................................................................................................... 17 
1.1 Background – Myocardial Infarction ................................................................................................. 17 
1.2 Background - Therapeutic Information ............................................................................................. 17 
1.3 eHealth ........................................................................................................................................... 18 
1.4 Study Rationale ............................................................................................................................... 19 
1.5 Risk/Benefit .................................................................................................................................... 19 
1.6 Secondary coronary prevention, biomarkers and drug adherence ..................................................... 19 
1.7 Health Economic Aspects ................................................................................................................. 19 
1.8 Study Hypothesis ............................................................................................................................ 20 
2 
STUDY OBJECTIVES AND RELATED ENDPOINTS .................................................................................. 21 
3 
OVERALL STUDY DESIGN .................................................................................................................. 24 
3.1 Recruitment Plan ............................................................................................................................ 24 
4 
STUDY POPULATION ........................................................................................................................ 25 
4.1 Selection of Study Population .......................................................................................................... 25 
4.2 Number of Patients ......................................................................................................................... 26 
4.3 Inclusion Criteria ............................................................................................................................. 26 
4.4 Exclusion Criteria............................................................................................................................. 26 
5 
TREATMENT .................................................................................................................................... 27 
5.1 Drug Identity, Supply and Storage .................................................................................................... 27 
5.2 Dosage and Drug Administration ..................................................................................................... 27 
5.3 Concomitant Medication ................................................................................................................. 27 
5.4 Subject Compliance ......................................................................................................................... 28 
5.5 Drug Accountability ......................................................................................................................... 28 
5.6 Subject Numbering.......................................................................................................................... 28 
6 
STUDY PROCEDURES ........................................................................................................................ 29 
6.1 Data collected at baseline: .............................................................................................................. 30 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
 
6.2.1 Informed Consent and Randomization .................................................................................................. 30 
6.2.2 Data registered from the hospital medical records ............................................................................... 30 
6.2.3 Patient  self-report  using  commonly  used  and  mainly  validated  questionnaires   ......................... 30 
6.2.4 Laboratory evaluations and biobanking ................................................................................................. 31 
6.3 Data Collected During Treatment and Follow-up .............................................................................. 31 
6.3.1 Safety data and online self-reported questionnaires ............................................................................. 31 
6.3.2 Clinical follow-up with laboratory evaluations, biobanking and completion of the baseline self-reported 
questionnaire ........................................................................................................................................ 32 
6.4 Linkage to National Registries .......................................................................................................... 32 
6.4.1 The Norwegian Prescription Database .................................................................................................. 32 
6.6.2 Administrative registries for income and social security programs (FD-Trygd) ..................................... 33 
6.6.3 Health care utilization - the Norwegian Patient Registry and the KUHR database ................................. 33 
6.4.4      The Cause of Death Registry .............................................................................................................. 33 
6.5 Withdrawals and Procedures for Stopping Data Collection ................................................................ 33 
6.6 Procedures for Discontinuation ........................................................................................................ 33 
6.6.1 Patient Discontinuation ......................................................................................................................... 33 
6.6.2 Trial Discontinuation .............................................................................................................................. 33 
6.7 End of Study ................................................................................................................................... 34 
7 
ASSESSMENTS ................................................................................................................................. 34 
7.1 Primary and Secondary Endpoint Assessments ................................................................................. 34 
7.2 Safety Assessments ......................................................................................................................... 34 
7.3 Health Economic Assessments ......................................................................................................... 34 
7.4 Traditional cardiovascular risk factors and drug related side-effects .................................................. 35 
7.5 Adherence Assessments .................................................................................................................. 35 
8 
SAFETY MONITORING AND REPORTING ............................................................................................ 35 
8.1 Adverse Events ............................................................................................................................... 35 
8.2 Serious Adverse Events (SAEs) ......................................................................................................... 35 
8.3 Suspected Unexpected Adverse Events (SUSARs) .............................................................................. 36 
8.4 Safety and Reporting ....................................................................................................................... 36 
8.4.1 Annual Safety Report ............................................................................................................................. 36 
8.4.2 Clinical Study Report .............................................................................................................................. 36 
8.5 Data Safety Monitoring Board (DSMB) ............................................................................................. 36 
9 
DATA MANAGEMENT AND MONITORING ......................................................................................... 37 
9.1 Case Report Forms .......................................................................................................................... 37 
9.1.1 Electronic Case Report Forms (eCRFs) ................................................................................................... 37 
9.1.2 Paper Case Report Forms (pCRF) ........................................................................................................... 37 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
3 
9.2 Source Data .................................................................................................................................... 37 
9.3 Study Monitoring ............................................................................................................................ 38 
9.4 Confidentiality ................................................................................................................................ 38 
9.5 Database management .................................................................................................................... 39 
9.6 Determination of Sample Size and Power Calculation ....................................................................... 39 
9.6.1 Sample Size ............................................................................................................................................ 39 
9.7 Randomization ................................................................................................................................ 40 
9.7.1 Allocation- sequence generation ........................................................................................................... 40 
9.7.2 Blinding and emergency unblinding ...................................................................................................... 40 
9.8 Population for Analysis .................................................................................................................... 40 
9.9 Planned analyses............................................................................................................................. 40 
9.10 Statistical Analysis ........................................................................................................................... 42 
9.10.1 Statistical hypothesis (superiority test) .................................................................................................. 42 
9.10.2 Primary analysis ..................................................................................................................................... 42 
9.10.3 Secondary analyses ................................................................................................................................ 42 
9.10.4 Safety analyses ...................................................................................................................................... 42 
9.10.5 Exploratory analyses using biobanking .................................................................................................. 42 
9.10.6 Other analyses ....................................................................................................................................... 42 
9.10.7 Post-trial joint analysis ........................................................................................................................... 42 
10 
STUDY MANAGEMENT ..................................................................................................................... 42 
10.1 Investigator Delegation Procedure ................................................................................................... 42 
10.2 Protocol Adherence ......................................................................................................................... 42 
10.3 Study Amendments ......................................................................................................................... 42 
10.4 Audit and Inspections ...................................................................................................................... 43 
11 
ETHICAL AND REGULATORY REQUIREMENTS .................................................................................... 43 
11.1 Ethics Committee Approval ............................................................................................................. 43 
11.2 Other Regulatory Approvals ............................................................................................................ 43 
11.3 Informed Consent Procedure ........................................................................................................... 43 
11.3.1 Informed Consent Form Registry – Medinsight ..................................................................................... 44 
11.4 Subject Identification ...................................................................................................................... 44 
11.5 User involvement ............................................................................................................................ 44 
12 
TRIAL SPONSORSHIP AND FINANCING .............................................................................................. 44 
13 
TRIAL INSURANCE ............................................................................................................................ 45 
14 
PUBLICATION POLICY ....................................................................................................................... 45 
15 
APPENDICES .................................................................................................................................... 46 
15.1 APPENDIX A – Background secondary coronary prevention (clinical, registry and biobank) ............... 46 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
 
15.2 APPENDIX B – Background Health Economic Aspects ........................................................................ 50 
15.3 Protocol amendment on safety issues and follow-up of primary and safety endpoints ................... 58 
16 
REFERENCES ................................................................................................................................... 59 
 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
 
Abbreviation or special term 
Explanation 
AMI 
Acute myocardial infarction 
BB 
Betablocker 
CAD 
Coronary artery disease 
CAG 
Coronary angiogram 
CEC 
Clinical Endpoint Committee 
CV 
Cardiovascular 
DSMB 
Data Safety Monitoring Board 
ESC 
European Society of Cardiology 
GP 
General Practitioner 
IeCRF 
Electronic Case Record Form 
IMP 
Investigational medicinal product 
LVEF 
Left ventricular ejection fraction 
NORMI 
Norwegian myocardial infarction Registry 
NORSTENT 
Trial  of  Drug  Eluting  Stent  Versus  Bare  Metal  Stent  to  Treat 
Coronary Artery Stenosis 
NSTEMI 
Non-STEMI (Non-ST-elevation myocardial infarction) 
PCI 
Percutaneous coronary intervention 
PROBE 
Prospective, randomized, open label, blinded endpoint evaluation 
PROMS 
Patient-reported   outcome   measures   (on   sociodemographic, 
clinical and psychosocial factors) 
STEMI 
ST-elevatiom myocardial infarction 
UAP 
Unstable angina pectoris 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
 
1 
INTRODUCTION 
 
1.1 
Background – Myocardial Infarction 
Acute Myocardial Infarction (AMI) remains one of the leading causes of heart failure, sudden cardiac death 
all-cause mortality and disability-adjusted life-years (DALY) globally(1-3). Furthermore, costs related to MI 
management represent a significant economic burden to healthcare systems(4). Treatment for an AMI aims 
to reduce initial and late events and disease progression. Although separate guidelines have been developed 
for different presentations of the AMI, ST-segment elevation (STE) MIs and non (N)-STEMIs, the two have in 
common that a coronary angiogram (CAG) is recommended during hospital admission. The CAG will, with 
certain exceptions, reveal one or more occluded/stenotic coronary arteries as a result of an atherosclerotic 
process, termed coronary artery disease (CAD). CAD remains the single most frequent cause of death in 
Europe, whatever the severity, is estimated to account for >12% of all deaths(2). 
 
Initial treatment during the first phase of an AMI, being partial or total occlusion, is to restore coronary blood 
flow in the diseased vessel and thus myocardial perfusion. This can be done either by pharmacologic 
reperfusion or by percutaneous coronary intervention (PCI), or, in some cases by surgery (coronary artery 
bypass grafting, CABG). Further treatment, including secondary prophylaxis depends on individual risk 
assessment. 
 
The comprehensive AMI registry in Sweden (SWEDEHEART) reported in 2015 the yearly incidence of STEMI 
to be 66/100000 and of NSTEMI to be 132/100000 individuals. In the Norwegian Myocardial Infarction 
Registry (NORMI) report from 2015, these incidence figures were 64 / 100 000 and 184 / 100 000, 
respectively. The higher Norwegian incidence of NSTEMI is due to the fact that SWEDEHEART does not 
include small AMIs treated in other hospitals than major intensive care units. In Norway 12 612 individuals 
were registered with at least one AMI, and the total number was 13 397. NSTEMIs constituted 75% of all 
AMIs, and 30 days survival rate was 90 %(6). The rate of STEMI patients < 80 years treated with primary PCI 
was 80%, and of NSTEMI patients < 80 years undergoing early CAG was 76%, of whom about the half also 
underwent PCI. Based upon these figures it is reasonable to assess that 65% of AMI patients at present are 
being treated with PCI or thrombolysis during their index hospitalization in Norway(6). 
 
Appropriate secondary preventive treatment and high adherence with recommended drug treatment and 
lifestyle changes are crucial to prevent disease progression after hospital discharge(5). The general 
practitioners (GPs) are the key actors to initiate, coordinate, and provide long-term secondary preventive 
management as they deliver most of the preventive consultations(5). Efforts to support their clinical work 
with secondary prevention is apparently needed as we have recently demonstrated that a majority of post- 
MI patients in Norway has an unfavourable lifestyle and poor coronary risk factor control(7). We have also 
shown that 65% were on social disability benefits, whereas the prevalence of comorbid depression, anxiety, 
type D (distressed) personality, and insomnia ranged 18-45%(8). Long-term follow-up data on lifestyle 
behaviour, risk factor management and the mediating socio-economic, clinical and psychosocial predictors 
are strongly requested in guidelines(5). Such knowledge is of utmost importance to i. determine quality and 
outcome of care, ii. develop empirically-based interventions, and  iii. develop psychosocial and  clinical 
screening instruments and risk prediction models that help clinicians to individualize lifestyle, drug 
management and follow-up care(5, 9). Comprehensive datasets in large populations are required for such 
analyses(10). 
 
 
1.2 
Background - Therapeutic Information 
BBs have been a part of secondary prophylaxis following AMI irrespective of its severity for decades. Three 
studies published in the early eighties are credited for the introduction of secondary prophylactic BB 
treatment; the BHAT trial (11), the Norwegian Timolol study (12) and the Gothenburg Metoprolol trial (13). 
In the European Society of Cardiology (ESC) guidelines from 2013 on treatment of stable coronary disease, it 
is argued that the present efficacy of BBs is uncertain because the studies on post-MI patients were 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
3 
conducted prior to the implementation of acute coronary revascularization and modern secondary 
prophylactic treatment(14). Similar ESC guidelines on STEMI assert long-term BB therapy as well established, 
but recognize the uncertainties referred to above(2). In the 2015 guidelines for NSTEMI, early BB therapy is 
recommended for patients with persistent ischemic symptoms, provided this is not contraindicated, and that 
patients without severe heart failure can be offered long-term therapy(15). In the American guidelines for 
management of stable ischemic disease from 2012, it is pointed out that BBs are efficacious in patients who 
have suffered myocardial infarction in the last three years (16, 17). Notwithstanding, patients experiencing 
heart failure or arrhythmias following an AMI have an unquestionable indication for treatment with BBs (14, 
18). 
 
In a large meta-analysis of randomized trials, BBs did not show effect post-AMI in the contemporary 
revascularization period (1991-2013) as opposed to the mortality reduction seen in the pre-revascularization 
period (1966-1991) (19). Recently, Puymirat et al (20) reported that early BB use in post AMI patients was 
associated with reduced 30-days mortality based upon propensity score matched cohorts comprising 502 
patients in each group. However, discontinuation of BBs after one year was not associated with different 
five-year survival. In a large registry study of post-AMI patients without heart failure, Dondo et al (21) did not 
observe any mortality benefit from BB versus non-BB after 30 days, 6 or 12 months in a propensity analysis 
comprising 16 683 patients, regardless of their LVEF level (Tatendashe Bernadette Dondo, personal 
communication). Reduced mortality with BB treatment is still evident in study populations with reduced left 
ventricular ejection fraction (LVEF)(22). 
 
In the last two decades BBs have been shown to reduce mortality and morbidity for a broad range of patients 
with a reduced LVEF in sinus rhythm. Recently, the ESC suggested there should be a third intermediate 
prototype of LVEF distribution, called mid-range LVEF (40-49%), thereby creating a clear separation between 
reduced LVEF (< 40%) and preserved LVEF ≥ 50% (23). In a recent meta-analysis of double blind, placebo- 
controlled randomized trials, Cleland et al (24) could show that for patients with heart failure in sinus rhythm 
and LVEF < 40% (n = 13442 patients) BB reduced all cause mortality (log rank p<0.001). These benefits, 
although less pronounced, also applied to the much smaller subgroup of patients with LVEF 40-49% (n = 575, 
log rank p = 0.042), whereas no benefit was seen the small group of patients with LVEF ≥ 50% (n= 244). The 
smaller number of patients with LVEF > 40% may not allow any firm conclusion on the efficacy of safety of 
BBs for mid-range and preserved LVEF. 
 
BBs are still frequently prescribed in clinical practice to CAD patients even if cardiac function is preserved: In 
the study by Puymirat et al (20), BBs were given to 76.5% which dropped by 11% after one year. In an 
observational study of patients hospitalized for CAD events (80% AMI, 10% with heart failure) in two 
Norwegian Hospitals, the use of BBs among patients without heart failure was 83% at discharge and 70% 
after a median follow-up period of 1.7 years (range 6 months – 3 years) (25). 
 
BB treatment introduces side effects that may have deteriorating effect on quality of life, functional status 
and health economic aspects such as the ability to work. Looking back to the pioneering BB trials, more 
patients in the BB group of the BHAT trial (11) reported tiredness, bronchospasm, diarrhea, and cold hands 
or feet. The excessive withdrawal rate in the BB group during the first month of the Norwegian Timolol study 
(12) was mainly due to bradycardia and hypotension. Finally, in the Gothenburg Metoprolol trial(13), more 
patients were withdrawn from treatment in the BB group because of suspected cardiovascular reactions. In 
a more recent review, Messerli et al (26) pointed out that acquisition cost of BBs is minimal, but certainly 
adverse events with this drug class is not. 
 
 
1.3 
eHealth 
The Norwegian Directorate of eHealth (NDE) uses eHealth as a term to describe healthcare practice 
supported by electronic processes and communication. eHealth refers to tools and services using 
information- and communication-technologies that can improve the healthcare system as a whole, including 
prevention and monitoring of medical conditions and diseases. eHealth has been recognized as important in 
the development of patient centered health care. This study will, by the regular questionnaires that are 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
 
planned, be able to explore if certain standardized instruments for measuring generic health status might 
predict unfavorable disease progression in the follow up of patients with established CHD. 
 
 
1.4 
Study Rationale 
The landmark studies which established the rationale for the routine use of oral betablocker after AMI were 
published more than thirty years ago (11-13). Since then, the implementation of acute coronary 
revascularization (the term ‘revascularization’ is in this protocol defined as primary PCI or thrombolysis for 
STEMI and with “early” PCI (i.e. during index hospitalization) for NSTEMI), and the use of modern secondary 
preventive treatments have changed the short and long-term prognosis for MI patients substantially. It is 
therefore possible that in this context BBs may have lost some of their effectiveness. 
 
Based on contemporary studies there is at present a questionable rationale for a treatment which may 
influence quality of life and cause treatment withdrawal of both BBs and other secondary prophylactic drugs. 
Therefore, the important question arises whether BB treatment gives a net health benefit in patients who 
have received revascularization therapy post-AMI and who do not have clinical heart failure and/or evidence 
of LV systolic dysfunction. 
 
 
1.5 
Risk/Benefit 
The BETAMI study has been designed as a multi-center, prospective, randomized, open blinded end-point 
(PROBE) study to provide definite evidence on the effects of oral BB therapy on all-cause mortality and 
recurrent MI in AMI patients treated with early revascularization and no clinical signs of heart failure and/or 
LVEF ≥ 40% by visual estimation or the Simpron`s biplane method.. The choice of a combined endpoint is 
explained by the high number of re-infarctions and by the importance of these two clinical endpoints (death 
and re-MI). Moreover, a meta-analysis using data from BETAMI and the similar REDUCE study conducted in 
Sweden, will provide evidence on the effects of oral BB therapy on all-cause mortality. Detailed information 
on the rationale for the study doses is provided in Section 5.1. 
 
The greatest risk in this study is related to the risk of adverse cardiovascular events in the study group that 
does not receive beta blockers. This also includes patients with established CAD who were taken off their 
beta blocker at study inclusion. Strict study inclusion and exclusion criteria are pursued in order to mitigate 
that risk. Safety monitoring procedures further seek to minimize the risk of study participation. The study will 
have predefined termination criteria at predefined point in the study timeline. The use of BBs is associated 
with a risk to develop side effects which are well known to medical practitioners and are handled as a part of 
routine practice. Thus, these issues are not within the scope of this study as they are already known and 
present in everyday practice. 
 
The greatest benefit will be to answer the question whether or not all AMI patients without heart failure or 
reduced LVEF should be given a betablocker, or if it certain subpopulations should not. 
 
 
1.6 
Secondary coronary prevention, biomarkers and drug adherence 
Background and rationale for the work package (WP) covering secondary prevention, biomarkers and drug 
adherence is presented in Appendix A. 
 
 
1.7 
Health Economic Aspects 
Background and rationale for the WP covering health economic aspects is presented in Appendix B. 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
 
1.8 
Study Hypothesis 
 'BB treatment’ is superior to 'No BB treatment' in patients who have received 
revascularization therapy for AMI (either PCI or, in some cases, thrombolysis), in terms of 
re-infarction, ischemic stroke, malignant ventricular arrhythmias, coronary revascularization, 
incident heart failure, cardiac arrest with successful resuscitation due to cardiac cause or all-
cause death, over a mean of 3 years of follow-up period. 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
 
2 
STUDY OBJECTIVES AND RELATED ENDPOINTS 
 
Objectives 
Endpoints 
Assessments 
Primary 
To study whether oral BB therapy 
reduces the risk of all-cause death, 
non-fatal MI, ischemic stroke, 
malignant ventricular arrhythmias, 
coronary revascularization, cardiac 
arrest with successful resuscitation 
due to cardiac cause, and incident  
heart failure  since randomization  
compared to no such treatment, in 
patients with acute MI treated with 
PCI or thrombolysis without reduced 
LVEF 
Time to all-cause death, non-fatal 
MI, ischemic stroke, ventricular 
arrhythmias, coronary 
revascularization, cardiac arrest 
with successful resuscitation due to 
cardiac cause, and incident  heart 
failure * 
Ref. Section 7.1. Obtained from Norwegian 
Cardiovascular Disease Registry at study end 
Secondary 
To study whether oral BB therapy 
reduces the risk of each of the 
components of the primary end-point 
separately, compared to no such 
therapy 
Time to all-cause death, re-
infarction, ischemic stroke, 
ventricular arrhythmias, coronary 
revascularization, cardiac arrest 
with successful resuscitation due 
to cardiac cause or incident heart 
failure* 
Ref. Section 7.1. Obtained from the Norwegian 
Cardiovascular Disease Registry at study end 
To study whether oral BB therapy 
reduces the risk of cardiovascular 
death compared to no such therapy 
Time to cardiovascular death* 
Ref. Section 7.1. Obtained from the Norwegian 
Cause of Death Registry at study end 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
 
Objectives 
Endpoints 
Assessments 
To study sociodemographic, clinical, 
and 
psychosocial 
characteristics 
(PROMS and clinical data) between the 
two study arms and in the total sample 
Time to non-fatal MI, all-cause 
mortality, ventricular arrhythmias, 
ischemic stroke, coronary 
revascularization, cardiac arrest 
with successful resuscitation due 
to cardiac cause, hospitalization 
for heart failure, and 
cardiovascular death* 
Ref. Section 7.1. Obtained from the Norwegian 
Cause of death  Registry and the  Norwegian 
Cardiovascular Disease Registry at study end 
To assess study safety 
1.Rate of ventricular arrhythmias, 
heart failure, new MI or all-cause 
death 30 days after randomization 
analysed at 18 months follow-up 
and at study end.                                      
2. All-cause death analyzed at study 
end  
Ref. Section 7.2. Collected by direct telephone 
contact at 30 days and from hospital medical 
records at local hospitals throughout the study 
analysed at 18 months follow-up. Obtained from 
the Norwegian Population Registry and 
Norwegian Cardiovascular Disease Registry 
at study end  
To assess clinical outcomes linked BB 
therapy including outcomes in the 
following supbgroups: age (tertiles), 
gender (men vs. women), treatment 
subgroups (i.e. BB doses), LVEF 
subgroups (preserved LVEF: 
≥50% vs. mid-range LVEF: 40-49%), 
quality of life, anxiety, depression, 
symptom burden (angina, dyspnea), 
sexual dysfunction and sleep 
disturbances. 
Time to non-fatal MI, all-cause 
mortality, malignant ventricular 
arrhythmias, ischemic stroke, 
coronary revascularization, 
cardiac arrest with successful 
resuscitation due to cardiac cause, 
and incident heart failure* 
Ref. Section 7.1. Obtained from the Norwegian 
Cardiovascular Disease Registry at study end 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
To conduct a cost-utility analysis in 
relation to quality of life and a health 
economic evaluation including drug 
use, 
health 
care 
utilization, 
employment, income, and benefit 
take-up, controlling for death and 
relevant demographic variables. 
Costs and benefits from a societal 
perspective, and net gain for public 
budgets. 
Ref. Section 7.3. Obtained by patient self-report (SF- 
12) and from the Norwegian registry for income, the 
FD-Trygd (social security micro data for research) 
database, the Norwegian Prescription Database, the 
KUHR (control and payment of reimbursements to 
health    service    providers)    database    and    the 
Norwegian  Patient  Registry.  These  data  will  be 
retrieved after patient enrollment is completed 
 
Exploratory 
biobanking 
objectives: 
To study the proportion and 
predictors of non-adherence with BB, 
statins and other cardiovascular drugs 
assessed by quantifying drug 
concentrations in blood 
Identify pharmacokinetic, 
pharmacogenetic and direct drug- 
related markers associated with side- 
effects and suboptimal response to 
treatment with cardiovascular drugs 
Association with traditional 
cardiovascular risk factors, drug 
adherence, self-reported side- 
effects, and the primary and 
secondary study end-points 
Association with traditional 
cardiovascular risk factors, drug 
concentration measurements, self- 
reported side-effects, and the 
primary and secondary study end- 
points 
Ref. Section 7.1-7.5 Obtained from the Norwegian 
Population Registry, the Norwegian Cardiovascular 
Disease Registry, the Norwegian 
Prescription 
Database 
and 
collected 
from 
self-reported 
questionnaires, and a clinical examination with 
blood sample collection and biobanking at baseline 
(all patients) and after 6 months follow-up (sub- 
sample). 
Post-trial 
objective: 
To perform a joint analysis of the data 
from this study with that of the 
REDUCE (NCT03278509) and REBOOT 
(NCT03596385) trials. This analysis 
will comprise >19000 patients, giving 
increased power and precision to 
make clinical decisions on both 
primary and secondary endpoints.  
Time to non-fatal MI, all-cause 
mortality,  ischemic stroke, 
ventricular arrhythmias, coronary 
revascularization, cardiac arrest 
with successful resuscitation due 
to cardiac cause , hospitalization 
for heart failure, and 
cardiovascular death* 
Ref. Section 7.1. Obtained from the Norwegian 
Cardiovascular Disease Registry at study end 
*time since randomization 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
 
3 
OVERALL STUDY DESIGN 
This is a multi-center, prospective, randomized, open label, blinded endpoint evaluation (PROBE) multicenter 
superiority study. It will include a total of 3000 patients in Norway with AMI who are treated with early 
coronary revascularization therapy (primary PCI or thrombolysis for STEMI and with “early” PCI (i.e. during 
index hospitalization) for NSTEMI). Patients will be electronically randomized to open prescription of a BB or 
no such treatment. All other documented secondary prophylactic drugs will be prescribed according to 
existing guidelines. 
 
 
3.1 
Recruitment Plan 
In Norway, approximately 12.600 patients have an AMI each year, of which 65% are treated with a 
revascularization procedure, and hence theoretically eligible for study participation(6). Based on the study 
inclusion and exclusion criteria and previous experience with patient inclusion in recent similar randomized 
trials in Norway(27), we estimated that that some 4500-5000 patients may be included per year, indicating a 
recruitment period of 2 ½ to 3  years to enrol 10 000 patients in Norway. However, after an inclusion period 
of 8 months, we have experienced that the true inclusion rate is significantly lower.  
 
 
 
In all, 2250 patients have been included during a 3.5 years period (per March 2022) indicating a total 
inclusion period of >10 years to enroll 10 000 patients. After careful discussions, the BETAMI steering 
committee consider such a long recruitment period not feasible neither from scientific nor an ethical point of 
view. Therefore, negotiations with the parallel  DANBLOCK (NCT03778554) study  Steering Committee, 
featuring an almost identical study design, has led to decision to merge the two final databases for endpoint 
analysis. However, each country (Norway and Denmark), respectively, retain their responsibility and financial 
plan for execution of their respective original studies.   Further, we have decided to reduce the number of 
patients to be enrolled from 10 000 to aprox. 5 600. To maintain statistical power, we also increase the primary 
composite end-point, so that the same number of events will be observed (see updated sample size calculation 
in Section 9.6.1). 
 
The first patient was enrolled October 2nd 2018. With an inclusion duration of 5.5 years, the mean/median 
follow-up period at end of inclusion is approximately 0.5 year; hence, the subsequent mean follow-up period 
will be 3 years or even longer in case of fewer primary end points occurring than expected. The total study 
duration from inclusion of the first patient to completion of the last included is estimated to 6 years. 
 
Study Period 
Actual date of first patient enrolled: 2-OCT-2018 
Anticipated recruitment period: 5.5 years 
Estimated date of last patient completed: 10 DEC 2024 
 
Estimated follow-up period at end of inclusion 0.5  years  
 
Treatment Duration: 
Until end of study period (mean 3 years after randomization) 
Follow-up: 
Expected range of follow-up is 0.5-6 years after randomization. 
 
 
 
 
 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
4 
STUDY POPULATION 
 
4.1 
Selection of Study Population 
PCI procedures will be performed according to generally accepted techniques, and is anticipated that most 
patients will have drug-eluting stents. The term PCI includes patients who are treated with balloon dilatation 
only. Subsequent antiplatelet and eventual triple therapy will be performed according to recommendations 
given by the respective PCI-centers. 
 
All AMI patients who have been treated with a revascularization procedure will be screened for eligibility. 
Patients should be considered for inclusion in the study in the general ward / intensity care unit when 
stabilized the first days following PCI or thrombolysis, under the responsibility of the investigator in charge 
of patients` visits in the PCI center acting as the patients` local hospital as well, or at local hospitals after 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
discharge, at the latest within 8 days following PCI or thrombolysis. This recruitment strategy will allow a 
clinical and, in most cases, an echocardiographic evaluation with measurement of LVEF. In a pilot study of 
159 consecutive post-AMI patients treated with primary PCI for STEMI or NSTEMI who underwent an 
echocardiographic examination after 3-7 days, 11% had LVEF <40%(28). Thus, nearly 90% of these patients 
may be potentially eligible for a trial like BETAMI. However, our experiences after trial commencement is 
that only half of these population are actually enrolled. Enrolled patients can participate in any other study 
that does not directly alter the effect of BB treatment. A prerequisite for participation is that patients 
fulfill all inclusion and exclusion criteria according to the assessment of the responsible physician 
performing the randomization procedure. 
 
 
4.2 
Number of Patients 
2 900 patients will be included in the Norway part of this trial and 2 700 patients will be included in the Danish 
part of the trial. 
 
 
4.3 
Inclusion Criteria 
To be eligible for inclusion in the study, subjects must fulfill the following criteria at inclusion: 
 
18 years or older 
 
Diagnosed with an acute MI type I according to the "Universal Definition of MI" (Defined as a detection 
of a rise and/or fall of cardiac biomarker value, preferably troponin, with at least one value above the 
99th percentile upper reference limit and with at least one of the following; a) symptoms of ischemia, b) 
new or presumed new significant ST-segment-T wave changes or new left bundle branch block, c) 
development of pathological Q waves, d) imaging evidence of new loss of viable myocardium or e) 
identification of an intracoronary thrombus by CAG) (18) 
 
Must have been treated with PCI or thrombolysis during current hospitalization 
 
Signed  informed  consent  and  expected  cooperation  of  the  patient  according  to  ICH/GCP  and 
national/local regulations 
 
Have a national personal identification number and not be expected to emigrate during study 
 
4.4 
Exclusion Criteria 
Study subjects must not meet any of the following criteria: 
 
 
Having a condition where BB-therapy is required, including but not limited to: 
o Arrhythmias 
o Hypertension 
o Cardiomyopathies 
o Clinical diagnosis of heart failure 
o LVEF < 40% by echocardiography (by measurement and not only visual assessment for STEMI 
patients) 
o Left ventricular akinesia in ≥ 3 segments regardless of the LVEF 
 
 
 
Contraindications to BB-therapy: 
o Bradyarrhythmias 
o Hypotension 
o Severe peripheral artery disease 
o Previously known side-effects causing withdrawal 
o Severe chronic obstructive pulmonary disease 
o Women of childbearing potential (a woman is considered of childbearing potential, 
i.e. fertile, following menarche and until becoming post-menopausal unless permanently 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
sterile) 
o Known hypersensitivity to any ingredient of the IMP 
o Other, according to the responsible investigator 
 
 
End-stage somatic disease with short life expectancy, dementia, psychosis and other conditions could 
put the subject at significant risk, confound the study results, interfere significantly with the subject 
participation in the study, or rendering informed consent unfeasible 
 
Previous treatment with a BB is not an exclusion criterion for enrollment into the BETAMI study. 
Enrolled patients can participate in any other study that does not directly alter the effect of BB 
treatment 
 
5 
TREATMENT 
Patients will be electronically randomized to open prescription of either a BB or no such treatment in a 1:1 
fashion within 1 – 8 days following the invasive procedure and after written, informed consent. Block 
randomization (with block sizes 4, 6, and 8 in random order), stratified by study centre and LVEF above vs. 
below 50% (preserved vs. mid-range), will be conducted through a web-based application (Viedoc™). All 
other documented secondary prophylactic drugs will be prescribed according to existing guidelines as judged 
by the responsible investigator. 
 
 
5.1 
Drug Identity, Supply and Storage 
Drugs will be prescribed to the BB group as per clinical practice. Patients will upon discharge from the ward 
receive standard reimbursed prescriptions either on paper or electronically (so-called “blåresept”), hence no 
trial specific labelling of trial drugs will be performed. Excemption to requirements of trial specific labelling 
and batch registration has been given by Norwegian Medicines Agency (NoMA). 
 
 
5.2 
Dosage and Drug Administration 
BB is administered orally. Dosages used in the pivotal BB trials described above [12-14] were very high, and 
do not reflect contemporary management. Pilot data from 80 consecutive AMI patients treated with PCI over 
a 3 months period in Drammen, Norway (dr. Elise Sverre, personal communication) shows that the majority 
of coronary patients was discharged with metoprolol succinate ranging from 25 to 100 mg OD (mean 75 mg 
OD). Nationwide mean dosage is 60mg daily. 
 
To reflect contemporary management, for which this study is designed to test, there will not be a defined 
minimum dosage. The type and dose of BB will be left at the discretion of the PI. Generic drug and accepted 
dosages will be: 
 
Metoprolol succinate up to a total dose of 200mg daily 
 
Bisoprolol up to a total dose of 10mg daily 
 
Carvedilol up to a total dose of 50mg daily 
 
5.3 
Concomitant Medication 
All concomitant medication will be registered at baseline. Information about drug use during follow up will 
be obtained by linkage to the NorPD. 
 
All other drugs with documented secondary prophylactic effect are permitted (e.g. statins, platelet inhibitors, 
oral anticoagulants, antihypertensive medication including ACE inhibitors / aniogtensin receptor 
antagonists). In fact, there are no prohibited medications unless for patients randomized to BBs, the use of 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
verapamil or diltiazem are considered to be prohibited, and patients who require such therapy will be 
withdrawn. 
 
 
5.4 
Subject Compliance 
Patients will be asked to report BB use to the study nurse at 30 days and in the self-report system every 6 
months until study end. 
 
 
5.5 
Drug Accountability 
Drug accountability is not applicable (ref. section 5.1), but BB type and doses will be registered from the self- 
report system 
 
 
5.6 
Subject Numbering 
Each subject is identified in the study by a unique subject number, which is assigned electronically after the 
subject has signed the Informed Consent Form. Once assigned the subject number cannot be re-used for any 
other subject. 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
6 
STUDY PROCEDURES 
 
Table 1.  Schedule of activities 
 
Baseline 
Treatment period (0-2 years following randomization) 
Time and assessments 
1-8 days 
following 
randomiza 
tion 
Day 30 
Every 6th 
month 
Six months 
study 
end 
Recruitment, inclusion/exclusion 
evaluation1) 
X 
Informed consent and 
randomization2) 
X 
Collection of relevant hospital 
record data3) 
X 
X 
     x 
Self-reported questionnaires 
(PROMs)4) 
X 
X 
        
          X*  
X* 
    
       
Other self-reported 
questionnaires5) 
X 
X 
Collection of fasting blood samples 
for analyses and biobanking6) 
X 
 
X* 
Safety assessment obtained from 
medical records and national 
registries7) 
X 
 
X 
1. 
Recruitment and inclusion/exclusion evaluation will be performed at baseline by a dedicated study nurse or 
the treating physician at PCI centers or community hospitals. 
2. 
Randomization and collection of informed consent will be performed at baseline by the site-PI or delegated staff. 
3. 
Relevant hospital record data at baseline will be registered in an eCRF by specially trained study nurses at each 
site. The following variables will be recorded: Age, gender, ethnicity, medical history, index cardiac event   
(NSTEMI, STEMI), angiographic findings, coronary treatment (PCI with or without stent implantation, thrombolysis)   
and echocardiographic findings (if performed) with emphasis on LVEF (40-49% and >=50%), a                        
standard 12-lead ECG, prescribed medical treatment at hospitalization and at discharge, cardiac rehabilitation 
(content, duration, referral rate) and relevant information about cardiovascular risk factors (blood pressure, pulse, 
weight, height) provided in hospital discharge letters. The following blood sample will be recorded from the 
hospital record: HbA1c, haemoglobin, hsCRP, creatinine, cardiac biomarkers (max. CK-MB and/r Troponin-T/I,  
Brain Natriuetic Peptide), ALT, lipid profile (total cholesterol, HDL cholesterol, and LDL cholesterol. 
4. A self-report questionnaire will be completed by all patients at baseline and after 6, 12, and 18 months follow-
up. The questionnaire comprises lifestyle behaviour (smoking history, diet, alcohol, physical activity), 
generalized muscle pains (the Brief Pain Inventory Questionnaire), anxiety and depression (the Hospital Anxiety 
and Depression Scale and Patient Healthg Questionnaire-2), Type D personality (DS-14 questionnaire), insomnia 
(Bergen Insomnia scale), Nightmare Frequency Questionnaire, and average sleep length,  health-related quality 
of life (Short Form-12), sexual dysfunction (Female Sexual Function Index and The International Index of Erectile 
Function ) and symptom burden (New Your Heart Association functional, Canadian Cardiovascular Society 
functional classification of angina). 
5. 
All patients will complete an electronic questionnaire at day 30 following randomization and at 6, 12 and 18 
months 
follow-up. The online forms will include brief screening questions covering i. status on BB 
treatment,treatment with statins, ii. lifestyle behaviour (smoking, physical activity), drug adherence, and perceived 
drug related side- effects, iii. secondary preventive follow-up visits, iv. screening questions on generic health status, 
angina, dyspnoa, depression, anxiety, muscle pains, sexual dysfunction, fatigue and insomnia. 
6. 
Biobanking for biomarker analyses and pharmacokinetic, pharmacodynamics and pharmacogenetic markers will be 
collected at baseline and after 6 months from both treatment arms on a subgroup of 500 patients.  
7. 
Safety data after 30 days will be collected from a standardized telephone interview with all patients. The screening 
questions include: i. occurrence of events since discharge, particularly hospitalizations for subsequent 
cardiovascular events or reiteration of study procedures, ii. current medication, particularly BB treatment including 
dosages. The hospital records will be reviewed by the site PI if patients report hospitalization for subsequent 
cardiovascular events on the telephone interview. Safety data will also be collected from registries at study end. 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
6.1 
Data collected at baseline: 
 
6.2.1 
Informed Consent and Randomization 
Informed consent must have been given voluntarily by each subject before any study specific procedures are 
initiated, ref. Section 11.3. The informed consents will be systematized in a secure IT solution provided by 
Medinsight (Informed Consent Form Registry), ref. Section 11.3.1 
 
A subject who has signed the informed consent form and has been assigned a subject identification number 
generated by Viedoc™ is considered registered (but not yet randomized). A subject who has been assigned 
to one of the two groups and has been assigned a randomization number is considered randomized. 
 
All subjects will receive a study specific ID card stating that they participate in a clinical trial, containing 
information about the sponsor and contact information to the local PI/study nurse as well as the treatment 
allocation. This ID card will also include information that states that the patient, next of kin or the patient`s 
treating physician at the hospital and/or family doctor must inform the BETAMI investigators as soon as 
possible, when a diagnosis is established, about relevant cardiovascular events, for example stable angina 
pectoris , UAP, new AMI, ventricular arrhythmias, heart failure or death. The card will explain that the BETAMI 
investigators will not be made aware of this information unless specifically informed. 
 
 
6.2.2 
Data registered from the hospital medical records 
 
Age, gender, ethnicity 
 
 
Medical history, current cardiac status (NSTEMI, STEMI), angiographic findings, coronary treatment 
and echocardiographic findings (if performed), with emphasis on LVEF, and standard 12-lead ECG. 
 
 
Prescribed medical treatment at hospitalization and at discharge, content, duration and referral rate 
to cardiac rehabilitation programs. This information should be exchanged between PCI centers, local 
hospitals and the patient’s treating physician, as per normal practice. 
 
 
Information about cardiovascular risk factors including blood pressure, pulse, height and weight. 
 
 
For subjects who have undergone an echocardiography before trial inclusion, where the images are 
available, these images may later be collected and analyzed by a central facility. 
 
 
6.2.3 
Patient  self-report  using  commonly  used  and  mainly  validated  questionnaires  (See 
Appendix C) 
 
Lifestyle behaviour: Smoking history, diet, physical activity and alcohol addiction measured by 
AUDIT (Alcohol Use Disorders Identification Test). 
 
 
Medication with emphasis on BB and dose and secondary prophylactic treatment 
 
 
Generalized muscle pains (Brief Pain Inventory) 
 
 
Psychosocial factors: 
 
o Anxiety and depression: The Hospital Anxiety and Depression Scale (HADS)(29), contain 14 
item covering symptoms of anxiety (HADS-A) and depression (HADS-D). It focuses on 
affective and cognitive symptoms and there are no somatic symptoms. Cut-off scores >8 on 
each subscale define doubtful cases and >11 define definite cases(29). Patient Health 
Questionnaire-2 (PHQ-2) a 2-item screening questionnaire for depression. 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
o Type D personality: DS-14 questionnaire(30), contains 14 items, with  7 items each  on 
subscales of negative affectivity and social inhibition. To be categorized with type D 
personality a score ≥10 points on both subscales is required. 
 
o Bergen Insomnia scale(31): Contains 6 items about sleep onset, maintenance of sleep and 
early morning wakening.  In addition the average sleep duration will be measured 
 
o Short Form-12 (SF-12)(32): Provides information on mental and physical health status and 
may be used for measurement of the patients quality of life and for health economic 
evaluation. 
 
o Sexual dysfunction (Female Sexual Function Index and The International Index of Erectile 
Function) 
 
o Symptom burden (New Your Heart Association functional, Canadian Cardiovascular Society 
functional classification of angina).) 
 
 
6.2.4 
Laboratory evaluations and biobanking 
Standard blood samples (i.e. haematology, clinical chemistry and lipids) will be analysed at local hospitals 
and recorded from the hospital medical records. In addition, blood samples from a subsample of 500 
patients from selected study centers at the south-eastern part of Norway (mainly OUS Ullevål, Akershus, 
Haukeland and Sykehuset i Østfold Kalnes ) that are previously not treated with BBs or statins. Blood 
samples will be sent to the central laboratory at OUS for analyses of cardiovascular and drug-related 
biomarkers and biobanking. Details on the collections, shipment of samples and reporting of results will be 
prepared in a laboratory manual. 
 
Hematology 
The following tests are included in the haematology: HbA1c and haemoglobin, 
 
Clinical chemistry 
The following tests are included in the chemistry: hsCRP creatinine, CK, cardiac biomarkers (max. CK-MB 
and/r Troponin-T/I), and ALTwill be measured. 
 
Fasting lipid profile 
The following tests are included in the non-fasting lipid profile including total cholesterol, HDL cholesterol, 
LDL cholesterol and non-HDL cholesterol. 
 
Pharmacological biomarker analyses 
Concentrations of BBs in blood will be quantified by a direct liquid chromatography-tandem mass 
spectrometry (LC-MS/MS) methods and pharmacokinetic (concentrations), pharmacogenetic (known CYP 
enzymes) and direct drug-related markers (drug related metabolites) associated with side-effects and 
suboptimal response to treatment with BBs and other cardiovascular drugs will be explored. 
 
 
6.3 
Data Collected During Treatment and Follow-up 
 
6.3.1 
Safety data and online self-reported questionnaires 
For this trial, NoMA has accepted that safety reporting will be limited to a selected number of safety 
parameters, i.e. the investigators do not have to report all adverse events occurring during the course of the 
trial. 
 
The  Steering  Committee  has  chosen  the  following  events  considered  important  for  safety  reasons: 
Hospitalizations  for  heart  failure,  serious  heart  rhythm  disturbances  (ventricular  tachycardia),  new 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
myocardial infarction and death. With the present design and safety conduct, all these adverse events of 
special interest (AESI) will be included and handled as SAEs. 
 
All patients will be contacted by telephone regarding the safety parameters malignant ventricular 
arrhythmias, incident heart failure, new myocardial infarction and all-cause death, as well as BB treatment 
including dosages, 30 days after randomisation. The interviews will be performed by trained site staff 
according to a standardised written protocol (ref. Appendix E). 
 
Hospital records will be checked by trial staff for all patients who report such events and for all patients not 
reached. In addition, the ID card (ref. section 6.2.1 and Appendix D) will contain information encouraging 
reporting of relevant cardiovascular events to the site staff. 
 
Further safety monitoring will be based on rates of all-cause death and the composite end-point of malignant 
ventricular arrhythmias, incident heart failure, new myocardial infarction and all-cause death from the 
Norwegian CVD Registry at study end. 
 
During the follow-up visits, all study patients will be asked to complete electronic questionnaires at 30 days 
after randomization and every 6 months thereafter until the end of study. The system (ViedocMe) will be set 
up to issue a reminder if the online forms are not completed. Paper version of the questionnaires will be 
available. 
 
Online forms (Appendix C) will include brief screening questions covering the following information: 
 
Status on BB treatment 
 
Concomitant treatment with statins. 
 
Lifestyle behaviour, drug adherence and perceived drug related side-effects 
 
Participation in cardiac rehabilitation programs and visits to primary care physicians 
 
Screening questions on generic health status, depression, anxiety, muscle pains, symptoms (dyspnoa 
and angina), sexual dysfunction, fatigue and insomnia 
 
 
6.3.2 
Clinical follow-up with laboratory evaluations, biobanking and completion of the baseline 
self-reported questionnaire 
A subsample of 500 study patients will be invited to a visit at the local hospitals 6 months after 
randomization. Study data collected during the follow-up visit will be registered from a self-report 
questionnaire and from blood sample collections with biobanking. The study variables and procedures 
include those described above (see 6.2.). 
 
 
6.4 
Linkage to National Registries 
 
6.4.1 
The Norwegian Prescription Database 
The Norwegian Prescription Database (NorPD) registers all pharmacy dispenses in Norway. Actual drug use 
is not registered, thus we will follow an intention-to-treat principle. For the individual patient, information 
on the Anatomical Therapeutic Chemical code, the date of dispensation, the quantity and dosage dispensed, 
and reimbursement codes will be retrieved. A dataset including the patients’ unique personal identifiers, 
clinical data, treatment allocation and study end-points will be sent to NorPD who pseudonymize the dataset 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
prior to linkage. Importantly, the pseudonymized dataset which is returned to the researchers, still includes 
prescription data on the individual patient. 
 
6.6.2 Administrative registries for income and social security programs (FD-Trygd) 
 
Data on income, employment and benefit take-up will be retrieved from the FD-trygd database (social 
security micro data for research) and tax-return data (income registry), together with demographic variables 
such as marital status, place of residence (bosted) and education. 
 
 
6.6.3 Health care utilization - the Norwegian Patient Registry and the KUHR database 
Data on health care utilization, with primary focus on cardiovascular vs. non-cardiovascular events, will be 
retrieved from the KUHR database (control and payment of reimbursements to health service providers) and 
from the Norwegian Patient Registry (NPR). Together KUHR and NPR will give a detailed description of health 
care utilization for the patients included in this study. 
 
 
6.4.4      The Cause of Death Registry 
Cause of death, which is relevant for the long-term follow-up, will be retrieved from the Cause of Death 
Registry. 
 
 
6.5 
Withdrawals and Procedures for Stopping Data Collection 
Once randomized into the study, all patients will be assessed until study closure unless informed consent is 
withdrawn for study participation. Patients can withdraw their consent to participate at any time during 
follow-up without prejudice to further treatment. Data collection will stop at the time of withdrawal. 
 
All randomized patients will be included in the study population. Patients who withdraw or are withdrawn 
from the study after randomization will not be replaced. 
 
 
6.6 
Procedures for Discontinuation 
 
6.6.1 
Patient Discontinuation 
Subjects will not be discontinued from the trial, but cross over from one arm to the other will be recorded. 
BB prescription to subjects in the “non BB” arm will be done at the discretion of the treating physicians. 
 
6.6.2 
Trial Discontinuation 
The whole trial may be discontinued upon DSMB recommendation. After 1/3 (1667) of the patients have 
completed 30 days follow-up, the DSMB will analyze the safety endpoint (rate of ventricular arrhythmias, 
heart failure, new MI). The DSMB will recommend to the executive steering committee that the trial is stopped 
if one of the treatment arms has 50% more events than the other. A 95% Koopman confidence interval for the 
ratio of probabilities, defined such that the ratio is above 1.0, will be estimated. If the lower confidence limit 
exceeds 1.5, the stopping criteria will be deemed to have been met. The recommendation to either continue 
or stop the trial because of an unbalance in event rates between the treatment arms will be at the discretion 
of the DSMB. 
 
The DSMB may also recommend that the trial is stopped if the committee at any time is of the conviction 
that the risk to current and future trial patients outweighs the potential impact of premature termination 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
on future clinical practice, and should be based on emergent data on patient safety or trial conduct 
inconsistent with pre-trial assumptions available at ethics committee approval. 
 
 
6.7 
End of Study 
The Steering Committee is responsible for the decision to end the study, either due to safety reasons or 
when a sufficient number of patients is deemed to have been followed up for a sufficient time period. We 
estimate that study closure will happen in Dec 2024. Upon trial end, patients will be sent a letter (ref. 
Appendix F) describing that the study has been closed, and that all further treatment(s) with betablockers 
(or no betablocker treatment) and other concomitant medications will be fully up to the preferences and 
choices of the patient’s physician and the patient based on prevailing national and international guidelines. 
 
The sponsor and principal investigator(s) will inform all investigators, the relevant Competent Authorities 
and Ethics Committees in the event of an early termination of the trial along with the reasons for such action. 
If the study is terminated early on grounds of safety, the Competent Authorities and Ethics Committees will 
be informed within 15 days. 
 
7 
ASSESSMENTS 
 
7.1 
Primary and Secondary Endpoint Assessments 
Assessment of t h e  p r im a r y  e n d po i n t s  ( M A C E ;  all-cause mortality, non-fatal MI, ischemic stroke, 
ventricular arrhythmias, coronary revascularization, cardiac arrest with successful resuscitation due to cardiac 
cause , and incident heart failure since randomization) and the other secondary cardiovascular study end-
points will be obtained from the Cardiovascular Disease Registry of Norway and the Norwegian Population 
Registry at study end except for cardiovascular death which will be retrieved from the Cause of Death Registry.  
 
 
7.2 
Safety Assessments 
Assessment of safety will be obtained from hospital medical records at the participating hospitals after 30 
days, follow-up. All patients will be contacted by telephone by a specially trained study nurse and interviewed 
after a standardized written procedure. Hospital records will be screened for safety end-points by the local 
study nurse or site-investigator if patients a) report hospitalization for cardiovascular events or b) if the 
patients do not respond to the phone call. 
 
Assessment of safety at study end will be based on rates of all-cause death and the composite end-point of  
malignant ventricular arrhythmias or resuscitated cardiac arrest, incident heart failure, new MI , and all-cause 
death obtained from the Norwegian CVD Registry. 
 
The CSC will, in cooperation with the Department of Research Support (DRS) conduct a control of all safety 
end points as provided from the SAE and SUSAR reports at 30 days and provide it for the data and safety 
monitoring board (DSMB) 
 
 
7.3 
Health Economic Assessments 
Assessment of income and employment will be obtained from adminstrative registries for income and social 
security programs (FD-Trygd) at study end. Assessment of drug use will be obtained from the Norwegian 
Prescription Database at study end. Assessment of health care utilization will be obtained from the KUHR 
(control and payment of reimbursements to health service providers) database and from the Norwegian 
Patient Registry at study end. Cause of death in the long-term health economic follow-up will be obtained 
from the Cause of Death Registry. In addition a health economic analysis in terms of quality of life will be 
performed based on self-reported data (SF-12). 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
7.4 
Traditional cardiovascular risk factors and drug related side-effects 
Assessment of traditional cardiovascular risk factors and side-effects will be obtained from hospital records 
and the self-report questionnaires at baseline and from the eCRF after 30 days, 6, 12 and 18 months follow-
up. 
 
7.5 
Adherence Assessments 
Assessment of drug adherence will be obtained by patient self-report from the eCRF during follow-up and 
from the Norwegian Prescription Database at study end. 
 
 
8 
SAFETY MONITORING AND REPORTING 
 
8.1 
Adverse Events 
Traditional Adverse Event reporting, i.e. reporting side effects of the IMP to the sponsor is not within the 
scope of this trial. Prophylactic treatment with BBs following an AMI has been standard of care since the 
seventies, and the side effects are well known, as described in Section 1. 
 
The main objective of this trial is to assess whether treatment with BB in the selected patient population 
reduces the risk of death or new MI, compared to no such treatment. Side effects of BB treatment are mainly 
relevant in terms of investigating their effect on the subjects’ general condition with regard to quality of life, 
health care utilization, employment and benefit take up. 
 
 
8.2 
Serious Adverse Events (SAEs) 
A Serious Adverse Event is defined as any untoward medical occurrence that at any dose: 
 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital abnormality or birth defect 
• 
Is an important medical event that may jeopardize the subject or may require medical intervention to 
prevent one of the outcomes listed above. 
 
Medical and scientific judgment is to be exercised in deciding on the seriousness of a case. Important medical 
events may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the 
subject or may require intervention to prevent one of the listed outcomes in the definitions above. In such 
situations, or in doubtful cases, the case should be considered as serious. Hospitalization for administrative 
reason (for observation or social reasons) is allowed at the investigator’s discretion and will not qualify as 
serious unless there is an associated adverse event warranting hospitalization. 
 
A pre-planned hospitalization admission (ie, elective or scheduled surgery arranged prior to the start of 
treatment) for pre-existing condition is not considered to be a serious adverse event. 
 
All serious adverse events (SAEs) will be reported according to GCP. SAEs will be reported by the Investigator 
via the eCRF system (Viedoc™) as soon as possible, and no more than 24 hours following the knowledge of 
such an event. 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
8.3 
Suspected Unexpected Adverse Events (SUSARs) 
The Sponsor’s Medical Officer will review all SAEs reported as related to the trial drug and evaluate whether 
the  event  is  expected  according  to  the  Reference  Safety  Information  (RSI).     The SPC (section  4.8 
«Bivirkninger») of the IMPs is used as Reference Safety Information (RSI) in this trial. 
 
SUSARs will be reported to the Competent Authority according to national regulation. The following timelines 
should be followed: 
 
The sponsor will ensure that all relevant information about suspected serious unexpected adverse reactions 
that are fatal or life-threatening is recorded and reported as soon as possible to the Competent Authorities 
in any case no later than seven (7) days after knowledge by the sponsor of such a case, and that relevant 
follow-up information is subsequently communicated within an additional eight (8) days. 
 
All other suspected serious unexpected adverse reactions will be reported to the Competent Authority 
concerned concerned as soon as possible but within a maximum of fifteen (15) days of first knowledge by 
the sponsor. 
 
SUSARs will be reported using the CIOMS form. 
 
 
8.4 
Safety and Reporting 
Clinical end- points and safety items are similar and safety end points new MI, m a l i g n a n t  ventricular 
arrhythmias, hospitalization for heart failure, and all-cause mortality. They will all be validated by the 
Clinical Endpoint Committee (CEC). In addition, the Data Safety Monitoring Board (DSMB) will overview the 
outcomes throughout the study. Please see Section 6.3and 7.2were this is described in detail. 
 
 
8.4.1 
Annual Safety Report 
A yearly safety report to the Competent Authority is not relevant in this trial. The Competent Authority will 
receive reports from the Data Safety Monitoring Board (ref. Section 8.5). 
 
 
8.4.2 
Clinical Study Report 
The adverse events and serious adverse events occurring during the study will be discussed in the safety 
evaluation part of the Clinical Study Report. 
 
 
8.5 
Data Safety Monitoring Board (DSMB) 
The DSMB consists of three international experts who will review all safety parameters death, hospitalization 
for heart failure, ECG-documented ventricular arrhythmia and recurrent AMI at day unblinded as well as 
the rate. This review will take place after the first 30 days of follow up, and at study end. The DSMB members 
will not be a part of the study organization and must not have any competing interests as judged by the 
Executive Steering Committee. 
 
A DSMB charter, detailing the committee’s activities and responsibilities, will be created prior to the 
inclusion of the first patient. 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
9 
DATA MANAGEMENT AND MONITORING 
 
9.1 
Case Report Forms 
 
9.1.1 
Electronic Case Report Forms (eCRFs) 
The Clinical Data Management System (CDMS) used for the eCRF in this study is Viedoc™. The setup of the 
study specific eCRF in the CDMS will be performed by the Clinical Trial Unit at Oslo University Hospital. The 
eCRF system will be FDA Code of Federal Regulations 21 Part 11 compliant. 
 
The designated investigator staff will enter the data required by the protocol into the eCase report forms 
(eCRF). The Investigator is responsible for assuring that data entered into the eCRF is complete, accurate, 
and that entry is performed in a timely manner. The signature of the investigator will attest the accuracy of 
the data on each eCRF. If any assessments are omitted, the reason for such omissions will be noted on the 
eCRFs. Corrections, with the reason for the corrections will also be recorded. 
 
At 30 days and at 6, 12 and 18 months thereafter, eCRFs/PROMs will be made available for the patients to 
fill in electronically, using the web-based application ViedocMe. An SMS reminder will be issued in case of 
missing responses. The patient accesses ViedocMe from any web-browser enabled platform, i.e. using their 
smartphone, tablet computer or PC. This accounts for eCRFs used for eHealth assessments as well. 
 
After database lock, the investigator will receive a digital copy of the subject data for archiving at the 
investigational site. 
 
 
9.1.2 
Paper Case Report Forms (pCRF) 
Paper forms are only relevant for patient reported data (questionnaires), which will be produced by the 
Clinical Trial Unit, Oslo University Hospital. 
 
The data will be entered into Viedoc™ by the study staff. 
 
 
9.2 
Source Data 
Source data are all information in original records and certified copies of original records of clinical findings, 
observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Source data are contained in source documents (original records or certified copies). 
 
The medical records for each patient should contain information which is important for the patient’s safety 
and continued care, and to fulfill the requirement that critical study data should be verifiable. 
 
To achieve this, the medical records of each patient should clearly describe at least: 
 
 
That the patient is participating in the study, e.g. by including the enrollment number and the study code 
or other study identification; 
 
 
Date when Informed Consent was obtained from the patient and statement that patient received a copy 
of the signed and dated Informed Consent; 
 
 
Results of all assessments confirming a patient’s eligibility for the study; 
 
 
Diseases (past and current; both the disease studied and others, as relevant); 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
 
Surgical history, as relevant; 
 
 
Treatments withdrawn/withheld due to participation in the study; 
 
 
Results of assessments performed during the study; 
 
 
Treatments given, changes in treatments during the study and the time points for the changes; 
 
 
Visits to the clinic / telephone contacts during the study, including those for study purposes only; 
 
 
Non-Serious Adverse Events and Serious Adverse Events (if any) including causality assessments; 
 
 
Date of, and reason for, discontinuation from study treatment, and vice-versa crossover from no-BB arm 
to BB-treatment; 
 
 
Date of, and reason for, withdrawal from study; 
 
 
Date of death and cause of death, if available; 
 
 
Additional information according to local regulations and practice. 
 
Specify and provide details if any source data will be recorded directly into the Case Report Form (meaning 
that for the defined parameters, CRF is source data and not the hospital records). 
 
A source data list will be agreed upon for each site specifying the source at a module or a variable level. 
 
 
9.3 
Study Monitoring 
The investigators at local hospitals will be visited on a regular basis by the Clinical Study Monitor, who will 
check the following: 
 
 
Informed consent process 
 
 
Reporting of safety data 
 
 
Adherence to protocol 
 
 
Maintenance of required regulatory documents 
 
 
Facilities and equipment’s (example: pharmacy, BP devices, etc.) if applicable 
 
 
Data completion on the CRFs including source data verification (SDV). 
 
The monitor will review the relevant CRFs for accuracy and completeness and will ask the site staff to adjust 
any discrepancies as required. 
 
Sponsor’s representatives (e.g. monitors, auditors) and/or competent authorities will be allowed access to 
source data for source data verification in which case a review of those parts of the hospital records relevant 
to the study will be required. 
 
 
9.4 
Confidentiality 
The investigator shall arrange for the secure retention of the patient identification and the code list. Patient 
files shall be kept for the maximum period of time permitted by each hospital. The study documentation 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
(CRFs, Site File etc) shall be retained and stored during the study and for 25 years after study closure). All 
information concerning the study will be stored in a safe place inaccessible to unauthorized personnel. 
 
 
9.5 
Database management 
Data management will be performed by the Clinical Trial Unit, Oslo University Hospital. The Data 
management procedures will be performed in accordance with the department’s SOPs and ICH guidelines. 
The data management process will be described in the study specific data handling plan and the study specific 
data handling report after database closure. 
 
Data entered into the eCRF will be validated as defined in the data validation plan. Validation includes, but is 
not limited to, validity checks (e.g. range checks), consistency checks and customized checks (logical checks 
between variables to ensure that study data are accurately reported) for eCRF data and external data (e.g. 
laboratory data). A majority of edit checks will be triggered during data entry and will therefore facilitate 
efficient ‘point of entry’ data cleaning. 
 
Data management personnel will perform both manual eCRF review and review of additional electronic edit 
checks to ensure that the data are complete, consistent and reasonable. The electronic edit checks will run 
continually throughout the course of the study and the issues will be reviewed manually online to determine 
what action needs to be taken. 
 
Manual queries may be added to the system by clinical data management or study monitor. Clinical data 
managers and study monitors are able to remotely and proactively monitor the patient eCRFs to improve 
data quality. 
 
All updates to queried data will be made by authorized study center personnel only and all modifications to 
the database will be recorded in an audit trail. Once the queries have been resolved, eCRFs will be signed by 
electronic signature Any changes to signed eCRFs will be approved and resigned by the Investigator. 
 
Once the full set of eCRFs have been completed and locked, the Sponsor will authorize database lock and all 
electronic data will be sent to the designated statistician for analysis. Subsequent changes to the database 
will then be made only by written agreement. 
 
The data will be stored in a dedicated and secured area at Oslo University Hospital. Data will be stored in a 
de-identified manner, where each study participant is recognisable by his/her unique trial subject number. 
The data will be stored until 31.12.2038. 
 
Adverse events and medical history will be coded from the verbatim description (Investigator term) using the 
Medical Dictionary for Regulatory Activities, MedDRA. Prior and concomitant medications and therapies willbe 
coded according to <name of dictionary>. 
 
Once the database has been completed and locked, the Sponsor will authorise database lock and all 
electronic data will be sent to the designated statistician for analysis. Subsequent changes to the database 
will then be made only by written agreement. 
 
 
9.6 
Determination of Sample Size and Power Calculation 
 
9.6.1 
Sample Size 
The trial will include a total of 2900 patients from Norway with AMI who are revascularized. As previously 
described the remaining 2700 patients will be included from the Danish DANBLCOCK trial.  
 
Incident rates obtained from the subpopulation with AMI as the indication for treatment with PCI in the 
NORSTENT trial [16] provide the background for sample size considerations and indicate a 5-year event rate 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
of 17% for the primary endpoint (Mortality 6.9% and AMI 10.1%). Assuming a recruitment (5.5 years) and 
post-trial follow-up (0.5 years) period of 6 years, a 3-year mean follow-up period, and a randomization 
ratio of 1:1, a sample size of 4671 patients (794 events) will provide a power of 80% to detect a difference 
of 18.7% primary endpoints with no BB treatment and 15.3% primary endpoints with BB treatment. This 
corresponds to a hazard ratio of approximately 1.22. To allow for a slightly lower overall event rate and 
some information loss due to drop-outs and crossover between groups the total sample size of the trial 
will be 5 000 patients. 
After careful discussions in the common BETAMI-DANBLOCK executive steering committee and with the 
study statisticians, it has been decided that the primary composite study endpoint by the elements 
mentioned in 2.0 and in the synopsis (all-cause mortality, non-fatal MI, coronary revascularization, 
ischemic stroke, malignant ventricular arrhythmia, cardiac arrest with successful resuscitation due to 
cardiac cause, and incident heart failure since randomization) will be a time-to-event outcome. A new 
power calculation for the joint BETAMI - DANBLOCK trial has therefore been made based on a time-to-
event outcome. We aim to have sufficient power to detect a true treatment effect with a hazard ratio of 
1.2. It is observed that 80 % power is obtained with around 950 events in total.  Only one analysis of the 
primary endpoint on the combined BETAMI and DANBLOCK sample will be performed. 
 
 
9.7 
Randomization 
 
9.7.1 
Allocation- sequence generation 
Eligible patients will be allocated in a 1:1 ratio between BB and no BB, using a computer randomization 
procedure stratified by centre. Block randomization with block sizes 4, 6, and 8 in random order will be used. 
 
Details of block size and allocation sequence generation will be provided in a separate document that is 
unavailable to those who enroll patients or assign treatment. 
 
 
9.7.2 
Blinding and emergency unblinding 
Not applicable. 
 
 
9.8 
Population for Analysis 
The following populations will be considered for the analyses: 
 
- 
The primary statistical analyses will be conducted according to the intention-to-treat (ITT) principle. 
 
 
- 
Safety population: Includes all subjects who have received at least one dose of study medication. 
Subjects who withdraw from the study will be included in the safety analysis. A list of withdrawn 
subjects, preferably with the reasons for withdrawal, will be established. 
 
 
9.9 
Planned analyses 
The main statistical analysis is planned when all patients have been followed for a minimum of 0.5 years, 
all data have been entered, verified and validated, and the database has been locked. 
 
Oslo Centre for Biostatistics and Epidemiology (OCBE) will be responsible for the statistical quality of the trial. 
Prior to the main statistical analysis, the data base will be locked for further entering or altering of data. A 
statistical analysis plan (SAP) describing all the statistical methods will be produced prior to database lock in 
close collaboration with the DANBLOCK statistician. The SAP will also describe the analyses set (ITT and PP) 
and all endpoints in detail. The treatment allocation will be revealed after the database lock and used in the 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
statistical analysis. 
 
Deviation from the original statistical plan will be described and justified in the Clinical Study Report. 
Amendments to plan can be done until day of DB lock. 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
9.10 
Statistical Analysis 
 
 
9.10.1 
Statistical hypothesis (superiority test) 
Null hypothesis: The rate of the primary composite MACE endpoint in the group with prescription to BB 
is equal to the rate of MACE in the group without prescription to BB. 
 
Alternative hypothesis (two-sided): the rate of MACE in the group with prescription to BB is greater than or 
smaller than the rate of MACE in the group without prescription to BB. 
 
 
9.10.2 
Primary analysis 
The primary endpoint is time to MACE, assessed after all patients have completed a minimum of 0.5 
years follow-up. A Cox regression model with prescription of BB (yes/no) and study site as covariates will 
be used. A hazard ratio for prescription of BB vs no BB with a 95% confidence interval will be estimated, 
and a test of a hazard ratio equal to one will be performed. 
 
The survival curves for the two groups (BB vs no BB) will be estimated and plotted with the Kaplan-Meier 
estimator and the equality of the survival curves will be tested with the log-rank test. 
 
The primary analysis will be performed on the ITT population.  
 
 
9.10.3 
Secondary analyses 
Secondary endpoints will be analyzed in a similar manner as the primary endpoints, with Cox regression 
models and Kaplan-Meier survival curve estimation – or other suitable statistical methods – as detailed in 
the SAP, to be completed before database lock. 
 
 
9.10.4 
Safety analyses 
After 1/3 (1667) of patients have completed 30 days follow-up, the DSMB will analyze the safety endpoint 
(rate of ventricular arrhythmias, heart failure, new MI or all-cause death 30 days after randomization). 
The DSMB will recommend to the executive steering committee that the trial is stopped if one of the 
treatment arms has 50% more events than the other A 95% Koopman confidence interval for the ratio of 
probabilities, defined such that the ratio is above 1.0, will be estimated. If the lower confidence limit exceeds 
1.5, the criteria for such a recommendation is deemed to have been met. The recommendation to either 
continue or stop the trial because of an unbalance in event between the treatment arms will be at the 
discretion of the DSMB.  The composite safety endpoint as well as all-cause mortality will also be assessed 
at study end. 
 
Other safety analysis may be performed by the DSMB during the course of the trial, and include descriptive 
statistics and tabulations of safety parameters. 
 
The DSMB charter, to be completed before inclusion of the first patient, will contain more details of the 
committee’s activities and responsibilities. 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
9.10.5 
Exploratory analyses using biobanking 
1. 
To study the proportion of post MI patients that is non-adherent with BBs, statins and other 
cardiovascular drugs assessed by indirect (self-report and pharmacy registry) and novel direct methods 
quantifying drug concentrations in blood. 
2. 
To study the association between clinical and psychosocial predictors of drug non-adherence 
measured with direct and indirect methodology. 
3. 
To identify direct drug-related markers that predict statin-associated muscle symptoms and 
validate these against self-reported symptoms. 
4. 
To explore the association between side-effects of cardiovascular drugs, clinical factors, cardiovascular 
drug concentrations and pharmacogenetic factors. 
 
9.10.6 
Other analyses 
Other exploratory analyses of primary, secondary, and exploratory variables, on the whole trial sample or in 
selected subgroups, may be performed if appropriate. The decision to perform such analyses will be made 
by the executive steering committees on basis of the collected data. 
 
 
9.10.7 
Post-trial joint analysis  
After completion of the primary analysis of the trial, a joint analysis of the data from this trial with that of the 
REDUCE trial in Sweden – provided this trial is completed – will be performed. In this analysis, a larger 
population from Norway/Denmark and Sweden will be available, giving increased power and precision to 
make clinical decisions on both primary and secondary endpoints, including total mortality, in addition to 
increased generalizability through a broader patient population. 
 
10 
STUDY MANAGEMENT 
 
10.1 
Investigator Delegation Procedure 
The principal investigator is responsible for making and updating a “delegation of tasks” listing all the involved 
co-workers and their role in the project. He will ensure that appropriate training relevant to the study is given 
to all of these staff, and that any new information of relevance to the performance of this study is forwarded 
to the staff involved. 
 
 
10.2 
Protocol Adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. 
All significant protocol deviations will be recorded and reported in the Clinical Study Report (CSR). 
 
 
10.3 
Study Amendments 
If it is necessary for the study protocol to be amended, the amendment and/or a new version of the study 
protocol (Amended Protocol) must be notified to and approved by the Competent Authority and the Ethics 
Committee according to EU and national regulations. 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
10.4 
Audit and Inspections 
Authorized representatives of a Competent Authority and Ethics Committee may visit the study centers to 
perform inspections, including source data verification. Likewise the representatives from sponsor may visit 
the center to perform an audit. The purpose of an audit or inspection is to systematically and independently 
examine all study-related activities and documents to determine whether these activities were conducted, 
and data were recorded, analyzed, and accurately reported according to the protocol, Good Clinical Practice 
(ICH GCP), and any applicable regulatory requirements. The principal investigator will ensure that the 
inspectors and auditors will be provided with access to source data/documents. 
 
 
11 
ETHICAL AND REGULATORY REQUIREMENTS 
The study will be conducted in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and are consistent with ICH/Good Clinical Practice and applicable regulatory requirements. 
Registration of patient data will be carried out in accordance with national personal data laws. 
 
 
11.1 
Ethics Committee Approval 
The study protocol, including the patient information and informed consent form to be used, must be 
approved by the regional ethics committee before enrolment of any patients into the study. 
 
The investigator is responsible for informing the ethics committee of any serious and unexpected adverse 
events and/or major amendments to the protocol as per national requirements. 
 
 
11.2 
Other Regulatory Approvals 
The protocol will be submitted and approved by the applicable competent authorities before 
commencement of the study. 
 
The protocol will also be registered in www.clinicaltrials.gov and the European Clinical Trials Database 
(EudraCT) as before inclusion of the first patient. 
 
 
11.3 
Informed Consent Procedure 
The investigator is responsible for giving the patients full and adequate verbal and written information about 
the nature, purpose, possible risk and benefit of the study. They will be informed as to the strict 
confidentiality of their patient data, but that their medical records may be reviewed for trial purposes by 
authorized individuals other than their treating physician. 
 
It will be emphasized that the participation is voluntary and that the patient is allowed to refuse further 
participation in the protocol whenever she/he wants. This will not prejudice the patient’s subsequent care. 
Documented informed consent must be obtained for all patients included in the study before they are 
registered in the study. This will be done in accordance with the national and local regulatory requirements. 
The investigator is responsible for obtaining signed informed consent. 
 
A copy of the patient information and consent will be given to the patients. The signed and dated patient 
consent forms will be filed in the Investigator Site File binder. 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
11.3.1 Informed Consent Form Registry – Medinsight 
The consent forms will be scanned and stored in a secure, encrypted, and access controlled database at OUH 
(Medinsight). 
 
The “Informed Consent Form Registry” in Medinsight is approved by the Information Security Manager 
(Personvernombud) at OUH. 
 
Site staff will, on an ongoing basis, send validated paper copies of the informed consent (IC) signature pages 
by post/courier to the Sponsor. The signature pages must contain the subject’s trial ID and 11-digit personal 
ID. Dedicated staff will scan the signature pages into the Informed Consent Form Registry and record the 
subject’s corresponding ID information, as well as information regarding what the subject has consented to 
(participation in the trial, genetic analyses, information regarding use of certain medications). The data will 
be verified by a second person and the verification documented. The paper copies at OUH will be destroyed 
after verification. 
 
For every version of the IC forms, the full text will be scanned into the registry. In case of amendments to the 
IC forms, all versions will be available, as well as information regarding which version each subject has signed. 
 
 
11.4 
Subject Identification 
The investigator is responsible for keeping a list of all patients (who have received study treatment or 
undergone any study specific procedure) including patient’s date of birth and personal number, full names 
and last known addresses. 
 
The patients will be identified in the CRFs by patient number, initials and date of birth (define as applicable). 
 
 
11.5 
User involvement  
The BETAMI user group has been established with coronary patients (n=2), user group representatives (n=2), 
primary physicians (n=4), cardiac nurses (n=3), and clinical cardiologists (n=2). The research group will choose 
a representative from this group that will be a member of the Study Steering Committee and participate at 
their meetings. 
 
The user group has discussed BB treatment in clinical practice together with members of the BETAMI research 
group during the planning phase. The group has also provided valuable input on the practical study 
implementation and the development and revision of the PROMS. The user group will participate in the 
development of written study information to patients, primary physicians and clinical cardiologists at the 
local hospitals. The user group will include central members of the major CAD patient organizations in 
Norway (Nasjonalforeningen for folkehelsen and Landsforeningen for Hjerte og Lungesyke). They will be 
pivotal in disseminating the BETAMI trial design, the importance of high compliance with the study protocol 
and the future study results to to patients, healthcare providers, authorities and the lay public. The BETAMI 
website (wwe.betami.no/wwwbetami.org) is about to be established. 
 
 
12 
TRIAL SPONSORSHIP AND FINANCING 
Oslo University Hospital is the sponsor of the trial, which is funded by KLINBEFORSK (South-Eastern Norway 
Regional Health Authority) and the Norwegian Research Council. Further applications for funding for sub-
studies and researchers will be submitted in due course. 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
13 
TRIAL INSURANCE 
The Principal investigator has insurance coverage for this study through membership of the Drug Liability 
Association (see http://www.laf.no for more details). This coverage harmonizes with the time period from 
randomization until end-of-study. In case of data collection and analysis after 5 and 10 years this will be 
performed in a separate trial. 
 
 
14 
PUBLICATION POLICY 
Upon study completion and finalization of the study report the results of this study will either be submitted 
for publication and/or posted in a publicly assessable database of clinical study results. 
 
The results of this study will also be submitted to the Competent Authority and the Ethics Committee 
according to EU and national regulations. 
 
All personnel who have contributed significantly with the planning and performance of the study (Vancouver 
convention 1988) may be included in the list of authors. 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
15 
APPENDICES 
 
15.1 
APPENDIX A – Background secondary coronary prevention (clinical, registry 
and biobank) 
Burden, temporal trends, and cardiovascular risk factor control in CHD patients 
Coronary heart disease (CHD) is the single leading cause of disability-adjusted life-years (DALY)(3) and 
premature death globally(1). Costs related to CHD management represent a significant economic burden to 
the healthcare system in Europe(4). Population aging and reduction in short-term mortality due to 
widespread use of coronary revascularization and effective medical treatment(4), have contributed to 
worldwide increases in the number of patients in need for optimal secondary prevention. Appropriate 
treatment and high adherence with secondary preventive drug treatment to obtain lipids and blood pressure 
(BP) at targets, metabolic control in diabetic patients, and appropriate lifestyle changes after AMI are crucial 
to prevent disease progression and recommended with the highest level of evidence in clinical practice 
guidelines(5). 
However, cardiovascular risk factor control after CAD events in clinical practice today is poor (33)with 
an unfavourable trend over time has been  documented(34) .  Since the mid-1990s, the proportion of 
European CAD patients with obesity increased by 13% and with diabetes increased by 11%, while the 
proportion of daily smokers and patients with elevated BP remained nearly unchanged (34). Only cholesterol 
management has improved due to the increased prescription of statins (34). Norway did not participate in 
these multi-centre studies, but a recent cross-sectional study in 1127 patients (NORwegian CORonary [NOR- 
COR] Prevention Project) documented that cardiovascular risk factor control in CHD patients in two 
Norwegian counties was in line with European data(7). Unpublished NOR-COR data from the sub-group (i.e. 
65% of the NOR-COR sample population) treated with percutaneous coronary intervention (PCI) without 
clinical heart failure reveals a similar prevalence of cardiovascular risk factors as in the total study group (John 
Munkhaugen, personal communication). 
Unfavourable lifestyle and risk factor management contribute significantly to the high (18-20%/year) 
arisk of subsequent cardiovascular events in patients surviving an AMI(35, 36).Twenty-eight percent of the 
registered MIs in 2013 Norway were recurrent events(37) and even though the risk of recurrent MI has 
declined in patients older than 65 years between 2001 and 2008, it is concerning that no decline was 
observed in younger patients(38). These data are concerning and encourage further studies on temporal 
trends and cardiovascular risk factors in clinical CHD populations (39-41). 
The reasons for unfavourable lifestyle behaviour and risk factor control after MIs are complex and the 
mechanisms are not yet well understood. The factors are often categorised as related to the patient, the 
treatment, the healthcare provider, and healthcare system (42). Examples of patient and treatment related 
factors are demographic background(40), socio-economic status(43-45), factors related to the CHD and other 
somatic comorbidities(46-48), psychological distress(49, 50) , personality(51, 52), complex treatment, 
treatment non-adherence and side-effects(48, 53). Poor discharge information and transition of patients 
between the hospital wards and primary physicians, the content and the duration and structure of CR 
programs are examples of healthcare and system factors of relevance (49, 54). 
The cross-sectional NOR-COR study have identified several potentially modifiable clinical and 
psychosocial factors associated with (a) persistent smoking(8), (b) unfavourably elevated blood pressure(55), 
(c) unfavourably elevated LDL-cholesterol(56), (d) subclinical inflammation (Munkhaugen et al, resubmitted 
Eur J of Prev Cardiology after revision in January 2017) and (e) poor metabolic control in diabetes 
(Munkhaugen et al, under review BMC Cardiovascular Disorders), respectively. Suboptimal secondary 
preventive drug prescription, low drug adherence, drug-related side-effects, low participation rate in CR, 
and high level of psychosocial distress were among the most frequently potentially modifiable factors 
identified. 
Identification of potentially modifiable factors of importance for risk profile and prognosis remains a 
public health priority(39, 40). In most previous large-scale studies in CHD populations, cardiovascular risk 
factors and clinical and demographic factors for the individual patient are measured one point in time (34, 
36). The natural course of coronary risk factors and the mediating predictors of risk factor control over time 
on  cardiac  prognosis  needs  to  be  better  clarified   for  the  development  of  i.   empirically-based 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
interventions(25), ii. risk prediction models that help clinicians to individualize drug management and 
select patients for treatment with novel and more expensive drug therapy(9), iii. psychosocial and clinical 
screening instruments for early identification of  subgroups  of  CHD patients  in need of personalized 
management and extended follow-up care. Comprehensive datasets in large populations are required for 
such analyses(10). 
 
Risk prediction in patients with established CHD 
The assessment of CVD risk and the prevention of recurrent events in patients suffering from cardiovascular 
disease represent an opportunity for major public health gains (57). Informal methods of risk prediction have 
traditionally been used to guide which individuals may benefit from therapy (58). However, due to variation 
in the observed and unobserved risk factors and the fact that clinicians are not good at estimating the 
likelihood of an outcome, risk assessment based on informal methods is not optimal(59, 60). Multivariable 
risk models in the setting of primary prevention have been intensely studied, in contrast to patients with 
established cardiovascular disease, where  much less data are available(58). The SMART  (Second 
Manifestations of Arterial disease) risk score for 10-year risk of myocardial infarction, stroke, or vascular 
death is among the very few risk prediction models developed for patients with established cardiovascular 
disease(9). The variables included in the model were age, sex, current smoking, diabetes, blood pressure, 
cholesterol, coronary artery disease, cerebrovascular disease, peripheral artery disease, creatinine, and high- 
sensitivity C-reactive protein. The present project will include a large number of patient related variables 
that may be used for the development prediction models for CHD patients. 
 
Non-adherence with cardiovascular drug therapy 
Drug adherence is defined as the extent to which a patient takes medications as prescribed by their 
healthcare providers12,13. While significant resources are allocated to develop  new  CV  drug treatments, 
‘simple’ non-adherence to existing medications has become well-recognized, but yet an undermanaged 
challange(61). In a secondary care settings, non-adherence undermines evidence-based therapy, 
contributing to hundreds of thousands of deaths annually and unnecessary healthcare expenditures exceeding 
hundreds of billions of dollars in the US and Europe alone (62). International data indicate that only 50-60% of 
patients remain adherent with CV (i.e. antiplatelets, statins and antihypertensive) drugs within one year of 
initial prescription10,25. Non-adherence is associated with a significant increased risk of long-term adverse 
events and mortality in patients with established CHD12,13. Adherence has traditionally been monitored by 
patient self-report questionnaires22. Pill counts, prescription fill rates, and electronic pillboxes24 are other 
indirect methods that all may overestimate drug intake, due to recall bias and/or patient overestimation9. 
Rates of prescription refill obtained from pharmacy registries, provide the most accurate data on adherence 
with cardiovascular drugs today9. In a recent Norwegian study, guideline- recommended secondary 
preventive drugs were   prescribed   to   most   patients   discharged   from hospital after MI and 12 months 
after the index MI, 84 % of patients were still on aspirin, 84 % on statins, 77 
% on BBs and 57 % on ACEI/ARB(63). However, few drug and dose adjustments were made during follow- 
up. 
However, pharmacy registry data also have their limitations since they cannot document tablet 
intake9. Furthermore, assessment of refill compliance from registries is laborious, and not feasible in daily 
clinical practice. Hence, drug adherence is rarely monitored in routine clinical practice9, and when performed, 
the outcome is uncertain. Directly observed therapy with subsequent measurement of the active drug or its 
biological markers, and spot measurements of drug and/or metabolites in blood are regarded the most 
objective and accurate measurements of drug adherence9. Liquid chromatography-tandem mass 
spectrometry (LC-MS/MS) is the reference methodology for quantitative bioanalysis of cardiovascular 
drugs26. In a study of 84 patients with apparent treatment resistant hypertension who were taking on average 
five antihypertensive drugs, there were no detectable drug concentrations in serum samples from 35% of 
the patients, and 66% of the patients fulfilled the criteria of non-adherence27. Measurements of active drug 
or metabolites of antihypertensive drugs have recently been shown effective in improving blood pressure 
control in patients with resistant hypertension in a small pilot study28. LC-MS/MS methodology for measuring 
the blood levels of several clinical relevant secondary preventive drugs in blood is available(64). Recently, LC-
MS/MS methodology  for  blood  concentration 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
measurements of several cardiovascular drugs has also been established in Norway (NT Vethe and Mimi 
Opdal, Oslo University Hospital, Personal communication). 
The reasons for non-adherence to cardiovascular medications are complex, multifactorial and 
probably related to both patient factors (composed treatment, side-effects, demographic and social factors, 
psychological distress9), and the healthcare provider9. The frequency, duration and structure of follow-up 
care are factors of relevance9. 
The main requirements challenges to improve drug adherence are3,11:i. identifying patients who do 
not take their prescribed cardiovascular drugs measured with direct and indirect tests, ii elucidating causes 
of non-adherence, measured with reliable measures of adherence, and ii. exploring the relative importance 
of drug non-adherence in risk of subsequent cardiovascular events. 
 
Individual variations in cardiovascular drug therapy and drug related side-effects 
The blood level of cardiovascular drugs is individual and determined by dosage, absorption, distribution, 
metabolism, excretion, drug-interactions and the liver and kidney function (65). Altered drug metabolism of 
CV drugs in the individual patient may be due to genetic polymorphisms or other drug and non-drug related 
biomarkers(65-69), which can lead to reduced or increased effect of consumed medication leading to side 
effects or poor treatment response. The prevalence of statin intolerance in clinical practice, including mainly 
side-effects from the musculoskeletal system, reaches 30% in observational studies (70, 71) and is an 
independent predictor of failure to reach the therapeutic target for LDL-C in CHD patients (72). Furthermore, 
side-effects with antihypertensive drug therapy is a common barrier to patients’ adherence to BP lowering 
medication (73). Patients experiencing many side-effects might therefore have stopped their medication 
themselves resulting in poor risk factor control and cardiac prognosis. Knowledge on how pharmacokinetic, 
pharmacogenetic, pharmacogenomic and other drug related biomarkers influence individual drug 
metabolism and contributes to drug-related side-effects is needed to personalize drug treatment, reduce 
the burden of side-effects and thereby may improve drug adherence, risk factor control and cardiac 
prognosis. 
 
 
Biomarkers and novel personalized drug therapy 
Even though the current challenge in combating CHD(39, 40) is to efficiently target the established CV risk 
factors that account for most of the CHD events(74, 75), a complex array of genetic, inflammatory and non- 
inflammatory biomarkers also contributes to the development and progression of CHD(76-78). Recently, 
specific drug therapy to target residual inflammatory (e.g. interleukin-beta antagonist)(79) and lipid risk (e.g. 
proprotein convertase subtilisin kexin 9 antibodies)(80) have reduced the risk of cardiovascular events in MI 
patients, while the sodium–glucose transport inhibitors reduce the risk of cardiovascular death and heart 
failure hospitalizations in patients with type 2 diabetes and established cardiovascular disease(81). 
Furthermore, cholesteryl ester transfer protein (CETP) inhibition(82), anti-thrombotic therapy with low-dose 
factor Xa antagonism in addition to platelet inhibition, and RNA interference which is a novel genetic 
treatment strategy(83), appear promising in the prevention of CHD(84). These novel drugs provide unique 
opportunities to personalize secondary prevention(85), but could also potentially increase the healthcare 
costs related to secondary preventive management markedly(86). Moreover, these drugs are hampered by 
potentially fatal side-effects(79). In the forthcoming years, several new therapeutic agents that target 
residual inflammatory, lipid and thrombotic risk will be available.Since these novel treatments have not yet 
been tested in combination and because of the practical and economic limitations(87), an important 
challenge is patient selection. New knowledge of the relative importance of the genetic, inflammatory and 
non-inflammatory biomarkers on cardiovascular prognosis and their associations with established 
cardiovascular, clinical and psychosocial risk factors may be important for the development of risk 
prediction models that may guide selection of patients for novel drug therapy. 
 
Psychosocial factors, drug treatment and cardiac prognosis 
Comorbid psychosocial distress is prevalent after MI. The rate of clinically significant depressive symptoms 
has been estimated to be 40-65%, while 15-25% meet the criteria for major depression(49). The prevalence 
of anxiety symptoms has been estimated to be 25-40%, while type D (i.e. distressed) personality is estimated 
to be 18-28%(49). Unpublished NOR-COR data reveals a similar prevalence of psychosocial risk factors in the 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
sub-group (i.e. 65% of the NOR-COR sample population) treated with PCI without clinical heart failure. In 
observational studies, depression(88, 89), anxiety(88, 90), type D personality(91) and insomnia(92) increase 
the risk of coronary events(39, 93)  and deteriorate the prognosis and quality of life of patients with 
established CHD(39, 49). The mechanisms by which psychosocial factors influence prognosis in CHD patients 
are not completely understood, but it is hypothesized that they are mediated through both direct 
pathophysiological (as autonomic nervous system dysfunction, genetics, epigenetics inflammatory and non- 
inflammatory markers) and bio-behavioural (i.e. unhealthy lifestyle, low adherence with medication, low 
participation in CR) pathways(39, 49, 94).  Great variations in  levels of psychosocial  distress by socio- 
demographic and somatic background factors make the picture even more complex(49, 95). Available 
psychological treatments have only small effects on symptoms and quality of life, and no effects on cardiac 
prognosis have been found(96). 
Evidence based pharmacotherapies that potentially modify the symptoms of anxiety, depression and 
insomnia are available(96, 97). Therefore, knowledge of the proportion of patients with psychosocial distress 
who was under concomitant active psychotropic drug treatment and the relative influence of drug treatment 
on cardiac prognosis is needed(96, 97). Moreover, psychotropic drug treatment gives an indication of the 
proportion of patients with psychosocial distress or psychological diseases prior to the study participation. 
Better insight into the mechanisms linking psychosocial factors to cardiac prognosis and the 
relative influence of concomitant psychotropic drug treatment is required for the development of more 
efficient and sustained psychosocial interventions(96). 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
15.2 
APPENDIX B – Background Health Economic Aspects 
 
 
The health economic aspects of this study cover impacts on drug use, health care utilization, employment, 
and benefit take-up, all of which will be studied separately as well as jointly in the health economic 
evaluation. 
 
The analysis will exploit rich and detailed administrative data, virtually attrition free, merged together using 
unique personal identifiers. For drug use we make use of the Drug Prescription database, covering all 
prescriptions in Norway. It does however not contain information on actual drug use and the analysis will 
thus follow an “intention to treat” strategy (as we do in the randomization of BB as well). 
 
We will study health care utilization using the KUHR database (control and payment of reimbursements to 
health service providers), covering all visits to primary health care and private specialists, as well as NPR (the 
Norwegian Patient Registry), covering all visits to hospitals. Together KUHR and NPR will give a detailed 
description of health care utilization for the patients included in this study. Health care utilization will be 
measured in monetary terms. For KUHR this is straightforward since the database contains billing 
information. For NPR this can be estimated using DRG points. 
 
The FD-Trygd database and tax-return data will be used to study employment, benefit take-up (Disability 
Insurance (DI), Temporary Disability Insurance (TDI), Unemployment Insurance (UI), Sick Leave (SL) and Social 
Assistance (SA)) and income from annual labour earnings, earnings from taxable benefits (disability, 
unemployment) and non-taxable benefits (social assistance etc.). Certain demographic variables, such as 
marital status, place of residence (bosted) and education, will be used as background variables in these 
analyses. By using data for the years prior to the AMI, we can characterize patients’ labour supply before and 
after the event. Cause of death will be retrieved from the Cause of Death Registry (CDR) or the National 
Population Registry. 
 
A follow-up of the patients using data from the above mentioned registries is planned for 5 and 10 years after 
completing patient enrollment. 
 
All together these data provide insight into the costs and benefits for post-AMI patients, with and without 
BB treatment, in the short and long term. Firstly, we will try to evaluate costs and benefits from a societal 
perspective. We then assume that value added from employment equals labour income, and subtract the 
deadweight loss from raising taxes to cover all public costs (drug subsidies, subsidized treatment and 
benefits). Secondly, we will try to estimate net gain for public budgets by comparing changes in tax-revenues 
with total changes in public costs. We believe this may provide valuable insight into future treatment 
decisions. The study also includes self-reported data on quality of life, as measured by SF-12, which allows 
for an estimation of costs per quality-adjusted life year (QALY). 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
15.3 
Protocol amendment on safety issues and follow-up of primary and safety 
endpoints 
 
 
This document describes in further detail the handling of safety issues and follow-up of primary and safety 
endpoints in accordance with requirements from the Norwegian Medicines Agency (NoMA), and it 
complements the Protocol v4.0. 
 
After 30 days, all patients will be contacted by telephone from the site staff and/or Central Study Coordinator 
to record Adverse Events of Special Interest (AESI): 
 
 
Hospitalizations for recurrent MI 
 
Heart failure 
 
Malignant cardiac arrhythmias (ventricular tachycardia/fibrillation) 
 
 
In the instances where telephone contact were unsuccessful, hospital records will be scrutinized for all AESIs 
 
In case of rehospitalizations, hospital records will be scrutinized for all AESIs and other relevant events leading 
to hospitalization 
 
ASEIs shall be reported to the sponsor similarly to all Serious Adverse Events (SAE)s. Most probably all ASEIs 
will represent an SAE. 
 
At the end-of-study the Norwegian Cardiovascular Registry and the Norwegian Population Registry will be 
scrutinized for the occurrence of the combined primary endpoint recurrent myocardial infarction or all 
cause death. In addition, patients alive at the end-of-study will be contacted by telephone with a question 
about having been hospitalized for a new myocardial infarction. 
 
The patients and their closest relatives will, through the BETAMI study patient-ID card be informed that all 
hospitalizations including relevant cardiovascular events (including AESI) should be continuously, and as soon 
as possible, reported to the Sponsor. A list of the AESIs has to be included in the ID card. In addition, the card 
will point out that the Sponsor will not receive this information unless it is reported as requested. 
 
In case of a rehospitalization the event has to be reported to the treating physician and then further on to 
the Sponsor if the event qualifies as an SAE. Most rehospitalizations will represent an SAE (see chapter 8.2 
for exceptions). SAEs (in both study-arms) should be reported to the Sponsor as soon as possible and not 
later than 24 hours after being aware of the event. 
 
The Sponsor shall record all SAEs, including ASEIs at the earliest possible time, and within 24 hours of 
becoming aware of the event. 
 
The Sponsor shall report all SAEs which, according to the opinion of the PI or Sponsor represent a Suspected 
Unexpected Serious Adverse Reaction (SUSAR), to the NMA via CIOMS. A SUSAR considered fatal or life- 
threatening shall be reported to NMA within 7 days, all others within 15 days. 
 
DSMB shall use data from all recorded ASEIs and other SAEs in their safety evaluations. Details of these safety 
evaluations are provided in the protocol. 

Protocol BETAMI Version no. 10.0 22 NOV 2023 
 
16 
REFERENCES 
 
1. Ford ES, Zhao G, Li C. Pre-diabetes and the risk for cardiovascular disease: a systematic review of the 
evidence. J Am Coll Cardiol. 2010;55(13):1310-7. 
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