Danish Trial of Beta Blocker Treatment After Myocardial Infarction Without Reduced Ejection Fraction (DANBLOCK)
Phase: PHASE4
Conditions: Acute Myocardial Infarction, Non-ST Elevation Myocardial Infarction (nSTEMI), ST Elevation Myocardial Infarction
Sponsor: Bispebjerg Hospital

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Danish trial of beta blocker treatment after myocardial infarction without 
reduced ejection fraction (DANBLOCK) 
 
Protocol Identification Number:  
DANBLOCK 
EudraCT Number:  
2018-002699-42 
 
SPONSOR:  
Professor Eva Prescott 
 
Department of Cardiology, Y  
 
Bispebjerg Frederiksberg University Hospital 
 
Bispebjerg Bakke 23, 2400 NV, København, Denmark 
 
Primary investigator: 
Professor, Eva Prescott 
 
Email: Eva.Irene.Bossano.Prescott@regionh.dk 
 
Tel:  +45 22 57 26 14 
 
 
Protocol version 2.1 (15.11.2023) 
 
 

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TABLE OF CONTENTS 
Generelle oplysninger til brug for lægemiddelstyrelsen: ............................................................. 5 
Contact details of steering committee, DSMB and CEAC ............................................................. 6 
Signature page ........................................................................................................................... 7 
Local investigators/MD responsible for conducting the trial........................................................ 7 
Protocol synopsis ....................................................................................................................... 8 
List of abbreviation and definitions of terms ............................................................................. 11 
Introduction ............................................................................................................................. 12 
Prognostic benefit of betablocker treatment after MI ....................................................................... 12 
The patient perspective .................................................................................................................... 12 
Study Hypothesis ..................................................................................................................... 12 
Study objectives ....................................................................................................................... 13 
Primary objective and endpoints: ..................................................................................................... 13 
Secondary objective and endpoints:.................................................................................................. 13 
Study endpoints ....................................................................................................................... 13 
Primary endpoint ............................................................................................................................. 13 
Adjudication of endpoints ....................................................................................................................... 13 
Secondary endpoints and their justification ...................................................................................... 14 
Study design ............................................................................................................................ 14 
Overall study design ......................................................................................................................... 14 
Treatment responsibility during the trial ........................................................................................... 15 
Recruitment plan and time frame ..................................................................................................... 15 
Study population ...................................................................................................................... 15 
Selection of Study population ........................................................................................................... 15 
Inclusion Criteria .............................................................................................................................. 15 
Exclusion Criteria .............................................................................................................................. 15 
Original sample size and power calculation .............................................................................. 16 
Pilot work on Danish data ................................................................................................................. 16 
Sample size ...................................................................................................................................... 16 
Power calculation ............................................................................................................................. 16 
Amendment 2022 .................................................................................................................... 17 
Treatment ................................................................................................................................ 18 
Type, dosage and administration of drug .......................................................................................... 18 
Duration of treatment ...................................................................................................................... 18 
Costs of medication .......................................................................................................................... 18 
Drug accountability and labelling ...................................................................................................... 18 
Patient compliance and concomitant medication .............................................................................. 18 
Criteria for interruption of study medication ..................................................................................... 19 
Study procedures ..................................................................................................................... 20 
Study Flowchart ............................................................................................................................... 20 
Screening ......................................................................................................................................... 20 

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Randomization and datahandling ..................................................................................................... 20 
Subject identification........................................................................................................................ 21 
Data Sources .................................................................................................................................... 21 
Patient records ........................................................................................................................................ 21 
Registries ................................................................................................................................................. 21 
Electronic-questionnaires ........................................................................................................................ 21 
Data collected .................................................................................................................................. 22 
Screening data ......................................................................................................................................... 22 
Baseline data ........................................................................................................................................... 22 
Registry data ............................................................................................................................................ 22 
Table 1. Overview of activities................................................................................................................. 23 
Biological material ................................................................................................................................... 24 
Procedures for discontinuation ......................................................................................................... 24 
Patient discontinuation or withdrawal .................................................................................................... 24 
Trial discontinuation ................................................................................................................................ 24 
End of patient inclusion and end of study ................................................................................. 24 
Patient involvement ................................................................................................................. 25 
Safety monitoring and reporting .............................................................................................. 25 
Adverse events ................................................................................................................................. 25 
Monitoring of safety ......................................................................................................................... 25 
Serious Adverse Events (SAE) and Serious Adverse Reactions (SAR) ................................................... 26 
Suspected Unexpected Adverse Events (SUSARs) .............................................................................. 27 
Safety and reporting ......................................................................................................................... 27 
Study Organization ................................................................................................................... 27 
Sponsor ............................................................................................................................................ 27 
Steering Committee: ........................................................................................................................ 27 
Project management: Project leader, project manager and assisting project managers ...................... 28 
Participating Centres/investigators ................................................................................................... 28 
Data Safety Monitoring Board (DSMB) .............................................................................................. 28 
Statistical analysis plan and supervision ............................................................................................ 28 
GCP -Good Clinical Practice ............................................................................................................... 28 
Danish Medicines Agency (Lægemiddelstyrelsen - DMA) ................................................................... 28 
The Committee on Health Research Ethics (Videnskabsetiske Komitéer) ............................................ 28 
The Danish Data Protection Agency (DDPA) ...................................................................................... 29 
International collaboration ............................................................................................................... 29 
Ethical and regulatory requirements ......................................................................................... 29 
Ethical considerations ....................................................................................................................... 29 
Informed consent ............................................................................................................................. 29 
Trial sponsorship and financing ................................................................................................ 30 
Communication ........................................................................................................................ 30 
Publication policy ..................................................................................................................... 30 
Time line .................................................................................................................................. 30 
Reference list ........................................................................................................................... 31 
Appendix 1: Patient information .............................................................................................. 34 

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Appendix 2: eCRF and eQuestionnaires .................................................................................... 34 
Appendix 3: Definition of endpoints and adjudication .............................................................. 34 
Appendix 4: Data Safety Monitoring Board ............................................................................... 34 
Appendix 5: DSMB contract ...................................................................................................... 34 
Appendix 6: Product resume for beta blockers.......................................................................... 34 
Appendix 7: Budget .................................................................................................................. 34 
Appendix 8: List of PI’s (Updated 22.12.2021) ............................................................................. 35 
 

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Generelle oplysninger til brug for lægemiddelstyrelsen: 
• Navn og titel på person/personer, som er autoriseret til at underskrive protokollen og 
protokolamendment(s) for Sponsor:  
 
Eva Prescott, Professor 
Thomas Sehested, Læge 
• Navn og titel på de forsøgsansvarlige investigatorer, samt adresse og tlf.nr. på de pågældende 
forsøgscentre: 
 
Alle kardiologiske afdelinger i Danmark inviteres til at deltage i forsøget. Nedenfor er angivet 
oplysninger for de 5 regionalt ansvarlige: 
Navn & titel 
Repræsenterer  
Adresse 
Telefon & e-mail 
Ida Gustafsson, 
klinikchef 
Region H 
Bispebjerg Frederiksberg Hospital, 
Bispebjerg Bakke 23, 2400 NV, 
København, Denmark 
23113596 
Ida.gustafsson@regionh.dk 
Michael Hecht Olsen, 
professor 
Region Sjælland 
Kardiologisk afdeling, Holbæk 
Sygehus, OUH 
61304904 
Michael.olsen@dadlnet.dk 
Kristian Korsgaard 
Thomsen, overlæge 
Region Syd 
Kardiologisk afdeling, Esbjerg 
Sygehus 
Kristian.thomasen@svs.regionsyddanmark.dk 
Michael Mæng, 
professor 
Region Midt 
Kardiologisk afdeling, Aarhus 
Universitetshospital 
michael.maeng@clin.au.dk 
Svend Eggert Jensen, 
lektor, overlæge 
Region Nord 
Kardiologisk afdeling, Aalborg 
Universitetshospital 
svend.eggert.jensen@rn.dk 
 
• Forsøget udføres i overensstemmelse med protokollen og gældende myndighedskrav/lovgivning 
på området 
• For tidsplan, herunder datoer for forsøgets påbegyndelse, forsøgsperiode og afslutning henvises 
venligst til punktet timeline i indholdsfortegnelsen 
 
 
 

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Contact details of steering committee, DSMB and CEAC 
 
Sponsor 
Department of Cardiology, Y.  
Bispebjerg & Frederiksberg, University Hospital. 
Bispebjerg Bakke 23, 2400 NV, København, Denmark 
Principal investigator, 
SC member 
Professor Eva Prescott, MD, DMSc, Department of Cardiology, Bispebjerg 
Frederiksberg Hospital 
Project manager, SC 
member 
Thomas S. G. Sehested, MD, Department of Cardiology, Copenhagen, 
University Hospital, Herlev and Gentofte, Denmark 
Project assistant 
Anna Meta D. Kristensen, Stud. Med, Department of Cardiology, Bispebjerg 
Frederiksberg Hospital 
SC member 
Professor Ann Dorthe Zwisler, MD, PhD, Danish Centre for Rehabilitation 
and Palliative Care, Odense University Hospital and University of Southern 
Denmark 
SC member 
Professor Svend Eggert Jensen, Department of Cardiology, Aalborg 
University Hospital 
SC member 
Kristian Korsgaard Thomsen, MD, PhD, Department of Cardiology, Esbjerg 
Hospital  
SC member 
Professor Mogens Lytken Larsen, MD, DMSc, Department of Cardiology, 
Aalborg UniversityHospital 
SC member 
Ida Gustafsson, MD, PhD, Department of Cardiology, Bispebjerg 
Frederiksberg Hospital 
SC member 
Professor Michael Hecht Olsen, Department of Cardiology, Holbæk 
Sygehus, region Seeland 
SC member 
Ann Bovin, MD, PhD, Department of Cardiology, Regional Hospital West 
Jutland 
SC member 
Professor Hans Erik Bøtker, MD, DMSc, Department of Cardiology, Aarhus 
University Hospital 
SC member 
Karsten Veien, MD, PhD, Department of Cardiology, Odense University 
Hospital 
SC member 
Professor Christian Torp-Pedersen, MD, DMSc, Ålborg University Hospital, 
Department of Health Science and Technology  
SC member 
Sussie Foghmar, Hvidovre Amager Hospital, Representative of Cardiac 
Rehabilitation Nursing 
SC member 
Charlotte Cerquira, MD, PhD, Department Manager, The regional clinical 
quality development program 
SC member 
Theis Lange, biostatistician, Section of Biostatistics, University of 
Copenhagen 
Data Safety Monitoring 
Board 
Kristian Thygesen (cardiologist) 
Chris Gale (cardiologist) 
Biostatistician TBD 
Furthermore, all primary investigators have been invited to the steering committee to ensure that all sites 
are represented.  
 

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Signature page 
Title: Danish trial of beta blocker treatment after myocardial infarction without reduced ejection fraction 
(DANBLOCK) 
Protocol ID no:  
EudraCT no:  2018-002699-42 
I hereby declare that I will conduct the study in compliance with the Protocol, ICH-GCP and the relevant 
governing requirements and law: 
Name 
Role 
Signature 
Date 
Eva Prescott 
Principal investigator & 
sponsor 
 
 
Thomas S. G. Sehested 
Project manager 
 
 
Ann Dorthe Zwisler 
Representing the Working 
group on Cardiovascular 
Prevention and Rehabilitation  
 
 
Mogens Lytken Larsen 
Representing the Working 
group on Cardiovascular 
Prevention and Rehabilitation 
 
 
Ann Bovin 
Representing the Working 
group on Cardiovascular 
Prevention and Rehabilitation 
 
 
Ida Gustafsson 
Regional PI, 
Eastern Denmark (Region H) 
 
 
Michael Hecht Olsen 
Regional PI, 
Sealand (Region Sjælland) 
 
 
Svend Eggert Jensen 
Regional PI,  
Northern Denmark (Region 
Nord) 
 
 
Kristian Korsgaard 
Thomsen 
Representing the Danish 
cardiac rehabilitation database 
(MD part) and Regional PI 
Southern Denmark (Region 
Syd) 
 
 
Michael Mæng 
Regional PI, 
Middle Denmark (Region Midt) 
 
 
Karsten Veien 
Representing the Danish 
society of cardiology working 
group of ACS & PCI 
 
 
Christian Torp-Pedersen 
Expert trialist 
 
 
Sussie Foghmar 
Representing the DHRD 
(nursing part) 
 
 
Charlotte Cerquira 
Representing RKKP & DHRD 
 
 
Theis Lange 
Expert biostatistician 
 
 
Local investigators/MD responsible for conducting the trial 
Please see appendix 8. This will be kept updated and any changes reported to EC and DMA/EudraCT 

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Protocol synopsis  
Protocol title: Danish trial of betablocker treatment after myocardial infarction without reduced ejection 
fraction (DANBLOCK) 
Primary investigator and sponsor: Professor, Eva Prescott. Bispebjerg & Frederiksberg, University Hospital, 
Department of Cardiology, Y, Bispebjerg Bakke 23, 2400 NV, København, Denmark 
Aim: To determine whether long-term treatment with oral betablocker (BB) therapy after myocardial 
infarction (MI) in patient with no heart failure reduces the composite outcome of recurrent non-fatal MI, 
all-cause mortality, revascularization with percutaneous coronary intervention or coronary artery bypass 
graft, stroke, heart failure, malignant ventricular arrhythmia, or resuscitated cardiac arrest. 
Intervention: BB therapy versus no therapy. 
Study Design: Prospective, randomized, controlled, open-label, blinded endpoint (PROBE 
design) clinical trial testing the benefits of long-term oral BB therapy in patients discharged 
after an acute MI.  
Main Inclusion Criteria: Patient that have suffered a MI, both Non-ST elevation MI and ST elevation MI, can 
be randomized within 14 days of MI with no signs of heart failure and a LVEF>40%.  
Main Exclusion Criteria: Any indication or contraindication for BB treatment other than secondary 
prevention according to the treating cardiologist 
Sample Size: A total of approximately 2760 patients (the trial is event driven) will be recruited and 
randomized 1:1 to BB treatment (type and dosage according to treating physician) or no BB treatment. 
Treatment must be initiated within 14 days of MI. 
Location: All departments of cardiology in Denmark are invited to participate. All patients admitted to 
hospital for MI will be screened for in- and exclusion criteria and contacted if eligible. 
Study Period: Anticipated recruitment period: 6 years. Estimated date of first patient enrolled: December 
2018. Estimated end of follow-up December 2024. 
Treatment Duration: Estimated (non) treatment duration of 11 months-6 years.  
Follow-up: Patients will be followed from the randomization date until end of follow-up with respect to the 
primary and most secondary endpoints.   
Endpoints:  
1. Primary:  
• 
All-cause mortality, recurrent non-fatal MI, revascularization with PCI or CABG, stroke, heart 
failure, malignant ventricular arrhythmia, or resuscitated cardiac arrest.  
2. Secondary:  
• 
To determine whether long-term treatment with BB therapy reduces: 
• 
Each of the components of the primary outcome 
• 
CV mortality 
• 
Atrial fibrillation/atrial flutter and other tachyarrhythmia 
• 
Unstable angina 
• 
Angina symptoms 
• 
Exercise capacity 
• 
To determine whether long-term treatment with BB therapy increases: 
• 
Bradycardia, syncope or need for pacemaker 

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• 
Asthma and COPD symptoms 
• 
Stroke 
• 
Blood pressure control 
• 
Diabetes (new diagnosis and dysregulation) 
• 
Peripheral artery disease 
• 
To determine whether long-term treatment with BB affects the following patient reported 
outcome (PRO): 
• 
 Quality of life, depression, sexual dysfunction and sleep disorders 
3. Safety endpoint: 
• 
A composite of recurrent MI, heart failure, all-cause mortality, malignant ventricular 
arrhythmia, or resuscitated cardiac arrest 30 days after randomization. 
Assessment of primary study and safety end points: The primary and safety endpoints will be obtained 
through individual-level linkage between data obtained at inclusion and nationwide administrative 
registries: 1. The Danish Cause of Death Registry,  2. The Danish National Patient Register that holds 
information on all hospital admissions with registration in accordance with the international classification 
of disease 10th revision (ICD-10), 3. The Danish Register of Medical Product Statistics holds information 
concerning redeemed prescription medication in accordance with the anatomical therapeutic chemical 
(ATC) classification system and 4. The Central Person Registry (CPR-registeret) which holds information on 
whether the person is alive and living in Denmark. Serious adverse events (SAE) will be monitored through 
patient reported hospital admission by surveys every 3 months combined with local follow-up on patients 
that do not respond to surveys.  
Assessment of secondary study end points: Secondary endpoints will be assessed through individual-level 
linkage between administrative registries, clinical registries on cardiac rehabilitation (DHRD), e-
questionnaires for PRO and hospital admissions as described above every 3 months.  
Intervention and dosage of BB treatment: The intervention will be active treatment with BB, type and 
dosage according to treating cardiologist choice and control will be standard care (without BB treatment). 
The treating cardiologist is recommended to use the highest dose deemed tolerable for the patient at the 
time of randomization. Dosage, adherence and cross-over will be monitored through linkage to the Danish 
Register of Medical Product Statistics. 
Sample size considerations: Assuming a hazard ratio of 1.2 for the non-treated group compared to the 
treated the trial has 80% power to detect this effect with an accumulation of 950 events of the primary 
endpoint. As the study is event-driven linking the study data to the registries will be crucial for providing an 
estimate of the event rate of the new composite endpoint and thus the number of study participants and 
follow-up length needed. 
Statistical Analysis: Intention-to-treat analysis will be carried out. Additionally, a secondary per-protocol 
analysis will be performed, where compliant BB-users are considered exposed during follow-up. Outcome 
analysis will be assessed by Cox-regressions.  
Data Safety Monitoring Board (DSMB): This committee consisting of two senior cardiologists and one trial-
science statistician will overview safety and will have access to unblinded data. They will formally review 
the accumulating data every 6 months throughout the study period to ensure there is no avoidable 
increased harm to patients.  The DSMB may recommend trial termination due to excess risk associated with 
no treatment with BB. 
Economic conditions: Payment of study expenses will follow patient inclusion: Each participating centre will 
be re-imbursed for the time spent on screening and patient inclusion, in addition to a set-up investigators 
fee. Costs of medication is by the patient (exempted from Paragraph 13 by DMA) 

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Recruitment: All patients admitted to hospital for MI will be screened for in- and exclusion criteria and 
contacted if eligible. Logistics of identifying and contacting the patients will be organized locally; some 
hospitals will randomize patients before discharge, others will contact patients after discharge. Patients will 
be randomized 1:1. 
Publication policy: On study completion the results will be submitted for publication in an international 
medical journal. The results of this study will also be submitted to the Competent Authority and the Ethics 
Committee according to EU and Danish regulations. 
 
 

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List of abbreviation and definitions of terms 
Abbreviations 
Explanations 
AHA/ACC 
American Heart Association/American College of Cardiology 
BB 
Beta blockers  
CABG 
Coronary artery bypass graft 
CEAC 
Clinical Events Adjudication Committee 
DCS 
Danish Society of Cardiology 
DHRD 
Danish Cardiac Rehabilitation database 
DMA 
Danish Medicines Agency (Lægemiddelstyrelsen) 
eCRF 
Electronic case record form 
ESC 
European Society of Cardiology 
GP 
General practitioner  
HF 
Heart failure 
LVEF 
Left ventricular ejection fraction 
MI 
Myocardial infarction 
NSTEMI 
Non-ST elevation myocardial infarction 
PCI 
Percutaneous coronary intervention 
PRO 
Patient reported outcome 
PROBE 
Prospective, randomized, open label, blinded endpoint 
evaluation 
QoL 
quality of life 
REDCap  
Research electronic data capture 
RKKP 
The regional clinical quality development program 
STEMI 
ST-elevation myocardial infarction  
UAP 
Unstable angina pectoris 
 
 

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Introduction 
Prognostic benefit of betablocker treatment after MI 
Beta-blockade has been a cornerstone in the treatment after acute myocardial infarction (MI) for decades. 
Beta blockers (BBs) competitively inhibit the myocardial effects of catecholamines and reduce myocardial 
oxygen consumption by reducing blood pressure, heart rate and myocardial contractility. Trials have shown 
benefit of acute treatment with BB in hemodynamically stable patients 1,2, solid evidence of survival benefit 
in patients with reduced left ventricular ejection fraction (LVEF)3–6 and a 23% reduction in mortality in early 
long term post-MI trials.7 
Most BB trials were conducted before reperfusion was standard treatment and before efficient secondary 
prevention with statins and antiplatelet agents reduced case-fatality. In contemporary post MI patients, the 
ischemic substrate is small, risk of arrythmias reduced and the outlook much improved.8,9 Additionally, in 
hypertension, BBs are no longer first line treatment due to their inferior effect on reduction of coronary 
heart disease, stroke and mortality compared to alternative treatment options.10 Therefore, studies have 
called the current role of BB after MI with preserved LVEF into question.11  
A meta-analysis of randomized trials that compared effect of BB treatment in pre- and reperfusion era 
concluded that the reduction in mortality with BB treatment was only documented in the pre-reperfusion 
era.12,13 In a meta-analysis of more recent trials and observational studies, including only patients with 
acute MI who underwent PCI, all-cause mortality was not significantly reduced in patients with preserved 
LVEF.14 Long-term BB treatment has not been investigated in patients with non-ST-segment elevation MI 
and preserved LVEF.15 Large registry based studies have given mixed results on the effect of long-term 
treatment with BBs11,14,16–25 and are likely to be biased. A meta-analysis of randomized trials of BB in heart 
failure (HF) recently reported an insignificant mortality reduction in the patients with LVEF 40-49% but was 
based on only 575 randomized patients.26 Thus, the beneficial effect of long-term treatment with beta-
blockade after MI for patients with preserved and midrange LVEF is controversial. The lack of evidence in 
the reperfusion era has resulted in divergence between guideline recommendations: the AHA/ACC 
guidelines strongly recommend BB in patients with STEMI (Class I recommendation) and less strongly in 
patients with NSTEMI (IIa) while the ESC guidelines recommend treatment in STEMI (Class IIa) but have no 
recommendations in NSTEMI.15,27–29 Danish guidelines recommend routine treatment for a minimum of two 
years following MI. Consequently, most patients in Denmark are treated with BB after MI.30 
The patient perspective 
Despite wide-spread use and tolerability, side-effects are well-known and common. They include 
depressive symptoms, sexual dysfunction, vivid dreams, cold hands and feet, weight gain and fatigue. Not 
all of these side effects are supported by evidence from randomized trials, e.g., the association between BB 
and depression has yet to be proven. BBs also reduce maximal heart rate and recent evidence indicates 
that patients treated with BBs have lower maximal exercise capacity, an indicator of daily function capacity 
and a strong prognostic marker. Patients participating in cardiac rehabilitation often complain of side 
effects and upon discontinuation many patients feel relief. The lower compliance with BB treatment 
compared to other cardiovascular medications is thought to be related to side effects.30 On the other hand, 
BB treatment reduces angina symptoms, which has profound effects on quality of life (QoL). Thus, the 
benefit of BB treatment on survival outlook needs to be weighed against the impact on side-effects as well 
as QoL. 
Study Hypothesis 
Treatment with beta blockers is superior to not treating with beta blockers following myocardial infarction 
in patients without heart failure (LVEF of >40%) in terms of all-cause mortality, recurrent myocardial 

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infarction, stroke, revascularization with percutaneous coronary intervention (PCI) or coronary bypass 
intervention graft (CABG), heart failure, malignant ventricular arrhythmias or resuscitated cardiac arrest. 
Study objectives 
Primary objective and endpoints: 
To determine whether long-term treatment with BB therapy after MI with no signs of HF reduces the 
composite outcome of: 
• 
Death from any cause 
• 
Recurrent acute myocardial infarction  
• 
Stroke  
• 
Revascularization with PCI or CABG  
• 
Malignant ventricular arrhythmias or resuscitated cardiac arrest 
• 
Heart failure 
 
Secondary objective and endpoints: 
To determine whether long-term treatment with BB therapy reduces: 
• 
Each of the components of the primary outcome 
• 
Cardiovascular mortality  
• 
Atrial fibrillation/atrial flutter and other tachyarrhythmias 
• 
Angina symptoms 
• 
Exercise capacity 
• 
Unstable angina 
To determine whether long-term treatment with BB therapy increases: 
• 
Bradycardia, syncope or need for pacemaker 
• 
Asthma and COPD symptoms 
• 
Blood pressure control 
• 
Diabetes (both newly diagnosed and dysregulation of existing diabetes 
• 
Peripheral artery disease (PAD) 
To determine whether long-term treatment with BB affects the following patient reported outcome (PRO) 
•  
Quality of life (including angina and dyspnea), depression, sexual dysfunction and sleep disorders 
In case of effect of BB treatment on primary outcome to investigate the cost-effectiveness of long-term 
treatment with BB in relation to health-related QoL. 
Study endpoints 
Primary endpoint 
The composite endpoint of all-cause mortality, recurrent non-fatal MI, revascularization with PCI or CABG, 
stroke, heart failure, malignant ventricular arrhythmia, or resuscitated cardiac arrest will be assessed 
through registries and adjudication. All primary and safety endpoints are monitored and adjudicated as 
described below and under safety while the study is ongoing. The final primary endpoint will be through a 
combination of adjudicated endpoints and registry linkage.  
Adjudication of endpoints 
Adjudication of endpoints will be through review of hospital records, a clinical endpoint adjudication 
committee (CEAC), local adjudication and rigorous application of endpoint-definitions following the 
objective criteria in the 2017 Cardiovascular and Stroke Endpoint Definition for Clinical Trials. 31 (Please see 

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appendix 5). Local end-point adjudication will be monitored by the GCP/sponsor. The original primary 
endpoints (death, unstable angina, acute myocardial infarction, heart failure and stroke) will continuously 
be adjudicated locally. There will an independent event adjudication committee consisting of 3 
Scandinavian cardiologists. All primary endpoints will be adjudicated by the CEAC:  
Secondary endpoints and their justification 
• 
The endpoints cardiovascular mortality, atrial fibrillation/atrial flutter, other tachyarrhythmia, 
bradycardia, syncope, need for pacemaker, worsening of asthma/CODP and PAD will be assessed 
through registry linkage for hospital admission and through review of hospital admission as described 
under ‘Safety Monitoring and Reporting’. 
• 
Common side-effects to BB: Quality of life measures (EQ5D), depressive and anxiety symptoms (HADS), 
sexual dysfunction in men and women (IIEF, FSFI, short versions) and sleep disorders (Bergen insomnia 
scale) 
• 
Symptom-burden after MI (NYHA, CCS, Seattle Angina questionnaire): Despite complete 
revascularization a significant proportion of patients still have angina symptoms. Continued angina 
affects QoL and is associated with anxiety and depression. BBs are first-line treatment of angina 
pectoris but whether this effect of BB is clinically relevant in a contemporary post-MI population is 
unknown. 
• 
Benefit from cardiac rehabilitation on VO2peak: BB treatment leads to reduced maximal heart rate 
and increased muscle fatigue. Early trials have indicated that exercise capacity is not affected by 
treatment, but this has never been tested in a randomized trial of patients with no HF. We wish to 
determine whether VO2peak, an objective indicator of physical functioning and an important predictor 
of prognosis, is affected by BB treatment. 
• 
Blood pressure control: Any beneficial effect of BB treatment in this pragmatic design, where blood 
pressure is not controlled as part of the study protocol, may be due to better blood pressure control. 
BB treatment will also increase pulse pressure which might increase the risk of stroke32 and counteract 
any beneficial effect of BB treatment. We plan substudies to test the hypothesis that BB treatment is 
most beneficial in patients with high heart rate or diastolic hypertension and the least beneficial in 
patients with isolated systolic hypertension33, prediabetes34, diabetes32 or new onset diabetes during 
follow-up. Blood pressure will be monitored during cardiac rehabilitation and use of blood pressure 
lowering medication will be assessed through the National Prescription Registry. 
• 
Diabetes control: The use of BBs in patients with diabetes may reduce insulin sensitivity35, increase 
plasma glucose, mask hypoglycaemic symptoms and increase the risk of new onset diabetes36–38 but 
limited data is available. We will assess the metabolic control among patients with established 
diabetes and the incidence of new onset diabetes. 
Study design 
Overall study design 
The trial will be a prospective, randomized, controlled, open-label, blinded endpoint (PROBE design39) 
clinical trial testing the benefits of long-term oral BB therapy in patients discharged after an acute MI. A 
total of approximately 2760 patients with MI, both NSTEMI and STEMI, with no signs of HF during hospital 
admission and with a LVEF of >40% will be recruited and randomized 1:1 to BB treatment (type and dosage 
according to treating cardiologist) or no BB treatment. Treatment will be initiated within 14 days of MI. 
Pragmatic clinical trials are performed under normal conditions with the intention of providing results that 
are more applicable to clinical practice and decision making. Outcomes will be from hospital records, 
clinical registry data and e-questionnaires keeping costs at a minimum. Bias will be reduced through 1) 
Randomization, 2) Since the design is open label, rigorous endpoint adjudication is essential and hard, 
clinical meaningful endpoints have been selected as primary endpoints, 3) To address multiplicity concerns 
the primary endpoint is a composite endpoint, and 4) The pragmatic design of this trial increases the 
generalizability of its conclusions to real daily clinical practice. 

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Treatment responsibility during the trial 
After the patient has been included in the trial, randomized and BB has been prescribed in the active 
treatment group, further follow-up and treatment responsibility for the patient is not with the investigator, 
but is according to the local cardiology clinical practice: This can be cardiologist out-patient care in the 
department of cardiology, in the cardiac rehabilitation or by the patient’s GP. The patient receives a card 
with information on participation in the trial, website with description of the trial (hosted by OPEN), 
contact information on local MD responsible for the DANBLOCK trial and a reminder to report any hospital-
admission in the e-questionnaire every 3 months. 
Recruitment plan and time frame 
Patients can potentially be recruited from all 36 departments of Cardiology in Denmark. All patients 
admitted to hospital for MI will be screened for in- and exclusion criteria and contacted if eligible. Logistics 
of identifying and contacting the patients will be organized locally; some hospitals will randomize patients 
before discharge, others will contact patients after discharge. 
• 
Study period: From December 2018 to December 2024 
• 
Recruitment period: Between December 2018 and January 2024 
• 
Treatment duration: Minimum 6 months from randomization  
• 
Follow-up: Patients will be followed until December 2024 
• 
Anticipated publication of results will be June 2025 
Study population 
Selection of Study population 
Patients that have suffered a first-time or recurrent MI (both non-ST elevation MI and ST elevation MI are 
eligible). Patients will be screened for in- and exclusion criteria and contacted (if eligible) before discharge 
or during cardiac rehabilitation. Randomization must be no later than two weeks after myocardial 
infarction.   
Inclusion Criteria 
To be eligible for this study the following inclusion criteria must be meet: 
• 
18 years or older 
• 
LVEF > 40%  
• 
Myocardial infarction (MI) within previous two weeks 
The diagnosis of acute MI must meet the Universal ESC definition of MI40: Detection of a rise and/or fall of 
cardiac biomarker values with at least one value above the 99th percentile upper reference limit and with at 
least one of the followings:  
o Symptoms of ischaemia. 
o New or presumed new significant ST-segment–T wave (ST–T) changes or new left bundle 
branch block (LBBB). 
o Development of pathological Q waves in the ECG. 
o Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality. 
Exclusion Criteria 
Patient will be excluded if they meet any of the following criteria:  
• 
Clinical evidence of heart failure at the time of discharge  
• 
Pregnancy or of childbearing age not using safe anticonception throughout the study period** 
• 
Lack of signed informed consent and expected cooperation during follow-up 

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** The BB used in the trial have not documented safety during pregnancy. The following is considered safe anticonception: 
Hormonal anticonception, encompassing (p-piller, implantat, transdermal depotplastre, vaginalring eller depotinjection) 
Any medical condition where BB treatment is indicated according to the treating physician, which may 
include: 
• 
BB treated arrhythmias 
• 
BB treated hypertension 
• 
Reduced left ventricular ejection fraction 
• 
Cardiomyopathies 
Any contraindication to BB treatment according to the treating physician, which may include:  
• 
Hypotension 
• 
Brady-arrhythmias 
• 
Severe peripheral artery disease 
• 
History of not able to tolerate BB-therapy 
• 
Severe COPD or asthma 
• 
Severe valvular heart disease 
• 
Any condition (i.e. dementia) that could lead to increased risk for the patient when treated with BB-
therapy 
 
The exclusion is not limited to this list and the responsible treating physician will need to consider if any 
other contraindication might exist for the patient. Both patients treated with a BB before their MI and 
patients in whom BB was initiated during the hospital admission are eligible for the trial. Patients are 
allowed to participate in other contemporary studies. 
Original sample size and power calculation 
In Denmark annually 9100 patients suffer a first-time or recurrent MI with a NSTEMI-STEMI ratio of approx. 
3:1.41,42 
Pilot work on Danish data 
We used the Danish nationwide registry (2010-2015) to identify a population of patients with MI, but 
without a previous diagnosis of HF. The monthly risk of the primary endpoint (the composite of all-cause 
mortality, recurrent MI, stroke, heart failure and unstable angina pectoris) was 1.62 % and the monthly risk 
of all-cause mortality was 0.06 %. These values formed the basis for the presented power analysis. 
Sample size  
Some patients need BB therapy for other indications such as HF, atrial fibrillation or continued angina 
pectoris and will be excluded after the judgment of the attending cardiologist. A conservative estimate is 
that 65% of MI patients will be eligible for the study and the number of eligible MI patients per year 
approximately 5950.43 We conservatively estimate 30% will be included in the trial, equivalent of 3570 
patients over the 2-year inclusion period (2*5950*0.3). We thus plan to screen approximately 10000 
patients and include 3570 subjects and we expect that 2500 patients will provide data from participation in 
a full cardiac rehabilitation program. 
Power calculation 
Analysis will be intention to treat (ITT) i.e. patients will be analysed in the group to which they were 
randomized. We expect some cross-over between groups but aim to keep this at a minimum primarily by 
informing the participating investigators of medical alternatives to change in BB treatment (e.g. alternative 
medical treatment for blood pressure control and alternative medication for angina). Cross over will be 

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monitored through patient-report (every 3 months) and if excessive may lead to decisions regarding futility 
of the trial.   
From the arguments in the previous section we deduce that a monthly event rate of the primary outcome 
for the care as usual group of 1.6 % can be presumed and that around 150 patients can be included per 
month. These patients will be randomized 1:1 to the two groups. 
We will analyze the power of an ordinary superiority trial. The trial will be designed to achieve a pre-
specified number of events. Assuming a hazard ratio of 1.2 for the non-treated group compared to the 
treated the DANBLOCK trial alone has 80% power to detect this effect with an accumulation of 900 events 
of the primary endpoint. However, for logistic reasons inclusion will be stopped substantially before this 
number of events is achieved. This is because events will keep accumulating for 2 years after last-patient-
randomized. We estimate that we will reach that number of events in around 30 months after including the 
first patient. With two years inclusion and further two years follow-up the trial would have 90% power. 
However, the true event rate of this study might be lower than what is found in the registers because of 
difficulty with including and obtaining informed consent from the sickest patients. This will lower power in 
an unpredictable way. In summary we feel confident that the planned study has at least 80% power. 
After one year of patient inclusion, we will assess the actual event-rate and re-assess whether the goal of 
900 events can be achieved with the planned inclusion period. Based on this information the Steering 
Committee will decide on whether patient inclusion should be extended or stopped early due to efficacy. 
This does not change the sample size planned for, which remains at 900. It is merely a logistic 
consideration. 
The study data from DANBLOCK will be pooled with results from BETAMI and will be initially published 
together. Furthermore, a meta-analysis will be carried out in collaboration with REDUCE. The combined 
power of the meta-analysis will be calculated.  
For the secondary outcomes (except hospital admissions) the DANBLOCK trial has ample power, e.g. with 
V02peak assessed on 2000 patients we will have 80% power to detect a difference in improvement in 
VO2peak between the two groups of 0.5 ml/kg/min conservatively assuming a mean improvement of 2.4 
and a SD of 4.3 (from existing registry data). 
Amendment 2022 
The inclusion- and event rate in DANBLOCK have been continuously assessed since the first patient was 
randomized in December 2018. The inclusion- and event rate have been lower than expected, in part due 
to COVID-19. In July 2022, 3.5 years since the first patient was randomized, approximately 2000 patients 
have been randomized and the steering committee has been compelled to apply for changes in addition to 
the already approved prolongation to ensure the completion of the study. The composite primary endpoint 
has been expanded from all-cause mortality, heart failure, recurrent MI, stroke and unstable angina to all-
cause mortality, heart failure, recurrent MI, stroke, revascularization with PCI or CABG, malignant 
ventricular arrhythmia or resuscitated cardiac arrest. Furthermore, the follow up period for the last patient 
randomized has been changed from 2 years to a minimum of 6 months and the study will be event driven. 
The decision to change the primary endpoint was done prior to registry linkage and with no knowledge of 
the distribution of endpoints. As stated above, at study end results from DANBLOCK will be pooled with 
results from BETAMI and will be initially published together. A new power calculation 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 approximately 
950 events in total. Completion of DANBLOCK and BETAMI is therefore based on the total number of events 
(approximately 950) in the two trials. Study inclusion will be terminated when the observed number of 
events and the observed event rate indicate that a total number of events will be accumulated within 6 
months, to fulfil the criteria of a minimum follow-up of 6 months for all subjects randomized in the trial. 

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Linking the study data to the registries will be crucial for providing an estimate of the event rate of the new 
composite endpoint and thus the number of study participants and/or follow-up length needed. A 
statistical analysis plan describing all the statistical methods will be produced prior to database lock in close 
collaboration with the BETAMI study group including statisticians. The SAP will also describe the analyses 
set and all endpoints in detail. 
Treatment 
Patients will be randomized 1:1. The intervention will be active treatment with BB, type and dosage 
according to treating cardiologist choice and control will be standard care without BB treatment. The study 
is open label. The treating cardiologist is recommended to use the highest dose deemed tolerable for the 
patient. The patient will be randomized within 14 days during admission or after discharge but no more 
than 14 days after myocardial infarction. All other standard of care therapy will be prescribed according to 
guidelines. Concomitant medication will be ascertained through linkage to the Danish Prescription Registry. 
Type, dosage and administration of drug 
If the patient is randomized to BB therapy the treatment will be given orally. Dosage used will reflect 
contemporary management and will be according to the treating cardiologist. The highest tolerated dose is 
recommended. The following list is on the generic BB drugs and common dosage 
• 
Bisoprolol up to a total dose of 10 mg daily 
• 
Carvedilol up to a total dose of 50 mg daily 
• 
Metoprolol succinate up to a total dose of 200 mg daily 
• 
Nebivolol up to a total dose of 10 mg daily 
Duration of treatment 
Treatment is planned from enrolment to study end, i.e. a minimum of 6 months from randomization. After 
study end continued BB treatment, discontinuation or uptake of BB treatment is according to the treating 
cardiologist/GP. 
Costs of medication 
The costs of medication for patients randomized to BB treatment will be covered by the patients. The study 
has been exempted from paragraph 13 in ‘Bekendtgørelse om god klinisk praksis I forbindelse med kliniske 
forsøg med lægemidler på mennesker’ by the Danish Medicines Agency.  
Drug accountability and labelling 
BB use will be ascertained through the prescription registry and through information in e-questionnaires 
every 3 months throughout the study period. There will be no labelling and batch registration of the 
prescribed medication following an exemption from the DMA because a) The IMPs have marketing 
authorization. b) The IMPs have been in extensive clinical use for decades, hence the safety profile of these 
drugs is very well established and new information in this regard is unlikely to emerge, c) The patients who 
are randomized to receive the IMP would have received the IMP regardless of the inclusion in the trial, at 
the same doses and duration as in the trial, i.e. the treatment will be in accordance with current clinical 
practice,  d) The safety of the patients who are randomized to receive the IMP will not be altered because 
of inclusion in the trial and e) The suggested exemption will not alter the safety of the subjects. 
Patient compliance and concomitant medication 
Information on compliance, dosage and crossover during follow-up and concomitant medication will be 
monitored through linkage to the Danish Prescription Registry and through the e-questionnaire as 
described above. 

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Criteria for interruption of study medication  
BB can be stopped in the intervention arm and taken up in the control arm at the discretion of the 
attending cardiologist or GP. Criteria for stopping medication include but are not limited to: 
• 
Pregnancy or wish to become pregnant  
• 
Safety issues as judged by the investigator 
• 
Withdrawal of consent  
• 
Adverse events and adverse reactions related to BB treatment 

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Study procedures 
Study Flowchart 
 
 
Screening 
Patients admitted to hospital for MI will be screened for in- and exclusion criteria in the participating sites. 
Patients fulfilling the inclusion criteria will be registered in the eCRF with information on reasons for not 
being included in the trial. 
Randomization and datahandling 
Randomization and eCRF (electronic case record forms) will be by the REDCap (Research Electronic Data 
Capture) system through OPEN. This is an open-label trial and both patient and the local investigator will be 
aware of treatment allocation. Data will be stored in a secure server and will be kept confidential according 
to legal regulations for data protection. After randomization, each patient will receive a card identifying the 
N ~  2760 
N ~  1380 
N ~  1380 
N ~  1500 

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clinical trial that will contain a brief explanation of the aims of the trial. In the trial card, the arm in which 
the patient was included (BB yes or no) will be stated, together with address of the website with 
information on the trial, a reminder to report hospital admissions in the e-questionnaire every 3 months 
and contact information to the MD responsible for the trial locally (‘local investigator’) and study nurse. The 
patient will be encouraged to contact him/her for any question related to the trial either from the patient 
or from any physician seeing the patient. The patients’ GP will be informed of the trial in the discharge 
letter. No other incentives will be established for participating in the study.  
Subject identification 
Once patients have signed the informed consent form, the REDCap system will assign an electronically 
identification number that can be linked to the nationwide administrative personal identification number 
(CPR).  
Data Sources 
Data sources are patient records, e-questionnaires and administrative and clinical registries. All outcome is 
registry based or from e-questionnaires. We anticipate that >80% of the patients will have a least one 
consultation by a nurse/cardiologist as part of introduction to cardiac rehabilitation. This will enable us to 
monitor a number of outcomes that are routinely collected and entered into the nationwide Danish Cardiac 
Rehabilitation database (DHRD). 
Patient records 
Patient records will be consulted for baseline information, information in relation to SAE and for 
adjudication of outcomes.  
Registries 
The following registries will be used (please see below and Table 1 for description of the data extracted): 
• 
The Danish National Patient Register (Landspatientregistret) that holds information on all hospital 
admissions with registration in accordance with the international classification of disease 10th revision 
(ICD-10) 
• 
The National Death Registry (Dødsårsagsregisteret), which holds information on cause of death 
• 
The Central Person Registry (CPR-registeret) which holds information on whether the person is alive 
and living in Denmark 
• 
The National Prescription Register (Lægemiddelstatistikregisteret), which holds information on 
medication deemed by the patient 
• 
The National Register of Laboratory Results (Laboratoriedatabasen), which holds information on 
laboratory results 
• 
The clinical registries on cardiac rehabilitation (DHRD) that holds information on type of MI, left 
ventricular ejection fraction (LVEF), clinical data, risk factor controls, laboratory data as well as results 
from functional testing at baseline and after completion of cardiac rehabilitation.  
Electronic-questionnaires 
E-questionnaires are used for monitoring of safety/outcomes and for monitoring of patient reported 
outcomes on quality of life, symptoms, etc. E-questionnaires on safety are dispatched every 3 months and 
described further below. For the expected 10-20% non-responders safety/outcome data is ascertained 
through electronic health records. 
Patient reported outcome (PRO) will be collected regularly (see table 1) by e-questionnaires from the 
REDCap system (OPEN), which fulfils all requirements for data security and is recommended for research 
data-management (data-entry and storage) of research data in the Danish Regions. All questionnaires used 
are validated and commonly used. The e-questionnaire will be administered by e-mail. For patients who do 

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not have an e-mail the questionnaire will be sent by ordinary mail. Instructions on how to fill in the 
questionnaire will be forwarded as part of the e-questionnaires. 
Data collected 
(see table 1 for details) 
All data will be entered into an eCRF using the REDCap system and monitored through OPEN. 
Screening data 
• 
Patient identity (CPR) 
• 
Age, gender 
• 
Inclusion criteria including type and date of index event (STEMI/NSTEMI) and LVEF-value 
• 
Exclusion criteria 
• 
Reasons for not being included in trial 
Baseline data 
• 
Demographics 
• 
Cardiovascular risk factors 
• 
Major comorbidities 
• 
Procedures performed during index event (CAG, PCI, CABG) 
• 
Laboratory data, including eGFR, Hba1c and lipids 
• 
Exercise capacity measured by VO2peak (only in patients attending cardiac rehabilitation) 
• 
Patient reported outcomes (PRO) on symptoms and quality of life measures (as described under 
secondary outcomes) 
a. Measures for quality of life: EQ5D (a measure of health-related quality of life that can be used 
in a wide range of health conditions and treatments) 
b. Measures of depression and anxiety: HADS (Hospital Anxiety and Depression Scale) 
c. Measures of sexual dysfunction one year after MI: IIEF (The International Index of Erectile 
Function), FSFI (Female Sexual Function Index) (short versions) 
d. Measures of sleeping disorder: Bergen insomnia Scale 
e. Angina burden following MI: NYHA (New York Heart Association); CCS (Canadian 
Cardiovascular Society grading of angina pectoris); Seattle Angina questionnaire (SAQ) (for 
those who report angina symptoms).  
Data Collected during follow-up: Primary, most secondary and safety endpoints are monitored through e-
questionnaires, registry linkage and electronic health records throughout the trial. Follow-up also includes 
DHRD data and PRO from e-questionnaires described above.  Patient reported SAE will be administered 
every 3 months. PRO through e-questionnaires will be administered at 3, 12 and 24 months. 
Registry data 
The primary endpoints and all secondary endpoints will be ascertained through registry linkage, e-
questionnaires and patient records. Adherence to BB and other medication is ascertained through The 
Danish Register of Medical Product Statistics, which holds information concerning redeemed prescription 
medication in accordance with the anatomical therapeutic chemical (ATC) classification system. From this 
register we will be able to determine compliance, discontinuation, type and estimate dose of BB therapy. 
  

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Table 1. Overview of activities 
 
Screening 
population 
Patients included in the trial 
 
Screening 
Baseline 
Treatment period following 
randomization 
Study 
end 
Time and 
assessment 
0-14 days 
following 
MI 
At 
randomization 
3 
mo 
6 
mo 
1 
year 
24 
months 
Every 3 mo 
thereafter 
 
In/exclusion criteria, 
basic information 
and reasons for not 
entering the trial 1 
x 
 
 
 
 
 
 
 
Informed consent, 
randomization and 
collection of 
baseline data2 
 
x 
 
 
 
 
 
 
Self-reported e-
questionnaires on 
QOL and 
symptomburden3 
 
x 
x 
 
x 
x 
 
 
Risk factor control 
and benefit from 
cardiac 
rehabilitation4 
 
 
 
 
 
 
 
x 
Adherence to 
medication5 
 
 
 
 
 
 
 
x 
Adherence to 
medication – 
selfreported6 
 
 
x 
x 
x 
x 
X 
Every 3 months 
until study end 
x 
Patient reported of 
SAE in e-
questionnaire every 
3 months8 
 
 
x 
X 
+ at 
9 mo 
X 
+ at 
15, 18 
and 21 
mo 
X 
 
X 
Every 3 months 
until study end  
x 
Endpoints from 
registry data7 
 
 
 
 
 
 
 
During 
follow up 
1 All patients with MI who fulfil inclusion criteria should be screened and entered in the eCRF. Data is 
collected during hospital admission.  
2 Data collected during hospital admission from patient and hospital records 
3 The following e-questionnaires on symptoms and quality of life will be administered: EQ5D, HADS, 
IIEF/FSFI (short versions), Bergen Insomnia Scale, NYHA, CCS, SAQ (for those reporting symptoms of 
angina). Adherence to medication will also be assessed.  
4 Data on blood pressure, serum lipids, diabetes, hba1c and VO2peak before and after rehabilitation will 
be through registry linkage to DHRD at study end. This data is only available for patients participating in 
cardiac rehabilitation.  
5 Adherence to treatment group as well as other medication will be from the National Prescription 
Register at study end. All primary analysis will be by the intention-to treat principle. 
6 Self-reported continued adherences to treatment group will be gathered every 3 months  
7 Hospital admission or death from a primary or secondary outcome be ascertained from the Danish 
National Registers, e-questionnaires and patient records. 
8 An e-questionnaire on SAE will be sent to patients every 3 months throughout the study period with a 
reminder after 5 and 10 days to non-responders. The patient will be given a trial card describing the trial 
name, website for description of the trial, contact information on investigator and a reminder to report 
hospital admissions in the e-questionnaires every 3 months. All patient-reported hospital admissions 

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(SAEs) will be evaluated by the sponsor/investigator for relationship with BB treatment or lack of BB 
treatment. This will be the data for biannual safety evaluation by the DSMB 
 
Biological material 
No separate blood samples or other biological material will be specifically collected for this trial and no 
biobank will be constructed. All blood sample assessed and used in the analysis will be from routine blood 
samples collected.  
Procedures for discontinuation 
Patient discontinuation or withdrawal 
Patients will not be discontinued from the trial if they cross over from the allocated treatment arm. Patient 
consent withdrawals can be done at any time during follow-up with no consequence on other treatment 
options. Cross-over will be registered through prescription registry and through the e-questionnaires 
administered at baseline, after 3 months, and every 3 months thereafter. The primary statistical analysis 
will be intention to treat, i.e. without taking cross-over into account. 
Trial discontinuation 
It is important to ensure that there is no avoidable increased harm to patients in both the active and 
inactive group. The Data Safety Monitoring Board (DSMB) consisting of two senior cardiologists and one 
experienced trial-statistician will overview safety and will have access to unblinded data. The DSMB 
members will be independent and will not be involved otherwise in the trial. The DSMB will formally review 
the accumulating data to ensure there is no avoidable increased harm to patients.  The data will include 
incidence of ventricular arrhythmias, heart failure, stroke, recurrent MI and all-cause mortality. The first 
data safety analysis will be made 3 months after inclusion of the first patient and biannually thereafter.  
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. All final decisions regarding trial 
modifications rest with the Steering Committee and is not subject to a pre-defined stopping criterion. 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 
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. 
In the event of a decision to terminate the study, the principle investigator will inform all investigators, 
relevant authorities and ethics committees of the termination within two weeks.  
The trial may be discontinued for futility if the inclusion rate is such that the study cannot reach the desired 
number of patients within a reasonable time frame. This decision lies with the Steering Committee 
End of patient inclusion and end of study 
The steering Committee is responsible for decision of modification of patient inclusion based on interim 
analyses as described in the section ‘Sample size and power calculation’. 
The Steering committee is responsible for decision to end the study either due to safety reasons or futility, 
as described above or due to achievement of the desired number of primary endpoints.  

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The sponsor and principal investigator will inform all investigators, the relevant competent authorities and 
the 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 the Ethics 
Committees will be informed within 15 days. 
All patients will be informed of study end. Continued treatment/discontinuation or uptake of BB will be at 
the discretion of the treating physician. The study group will provide written guidance for the patient and 
the treating physician. 
Patient involvement  
Because of the central role of patient reported outcomes, user involvement is an important part of the 
DANBLOCK trial, and will be organised in collaboration with REHPA, knowledge-centre of rehabilitation and 
palliative care. Patient expert groups that reflect the patients eligible for inclusion in the study will be set 
up containing 4-8 members ideally representing patients recruited from hospital and cardiac rehabilitation. 
The patient expert groups will meet to share their experiences with BB treatment, development of patient 
material, e-questionnaires and how to best set up the patient recruitment seen from a patient perspective. 
Further meetings of the patient expert group will be undertaken during the project to ensure patient 
involvement in the process of interpretation and dissemination of results and ensure patient recruitment. 
We strive to recruit patients from different backgrounds. All participants in the expert patient group will be 
provided with travel expenses and food and beverage during meetings. There will be a closing event at the 
end of the project where all stakeholders, study participants, and carers will be invited to hear the results 
of the project and give their input into the next steps for use of BB following acute coronary syndrome. 
We will ensure all patient experts; trial participants; research collaborators and stakeholders involved in the 
project are kept informed at all stages via the DANBLOCK project website and a newsletter by post.  
Safety monitoring and reporting 
Adverse events 
BBs have been widely used for more than 40 years and treatment with BB is currently standard of care after 
MI. Any safety concerns are therefore primarily related to lack of treatment with BB after MI. The potential 
serious consequences of NOT being treated with a BB after MI are the following: Increased risk of MI, 
ventricular arrhythmia, development of heart failure and cardiac death. The possible non-serious 
consequences of NOT being treated with a BB after MI are: poorer angina control and risk of 
supraventricular arrhythmia.  
The main objective of the trial is to assess whether treatment with BB in the selected patients (i.e. who 
have received todays standard of care and who do not have heart failure) reduces the risk of death, heart 
failure and new MI compared to no such treatment. Non-serious consequences (supraventricular 
arrhythmia) and side-effects are mainly relevant in terms of impact on quality of life, health care utilization 
and employment and are part of the secondary endpoints of the trial. 
Monitoring of safety 
In each case safety is ensured by  
1) The original primary endpoints recurrent MI, unstable angina, stroke, heart failure, and death will 
be monitored through repeated assessment of hospital admission. Participants receive E-
questionnaires asking about hospital admission every 3 months. Orignial endpoints will be 
adjudicated locally in the eCRF and summarized by group assignment after 3 months and every 6 
months thereafter. This ensures that any difference between groups in rates of the primary 
endpoints are repeatedly assessed. 

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2) In the E-questionnaire to the patient every 3 months the patient will report on continued use of BB 
and any hospital admission (i.e. SAE). After 5 and 10 days a reminder will be sent for patients that 
have not responded. Data on any non-endpoint SAE thus reported will be reviewed for possible 
causal relation to the treatment/non-treatment with betablocker (SAE/SAR/SUSAR) by the MD 
responsible for the trial locally after acquiring additional information from hospital records. Any 
hospital admission/SAE considered related to treatment/no-treatment with BB that is not included 
on the list of SARs will be reported to the sponsor, who will consider whether the hospital 
admission is a SUSAR. Any SUSAR will be reported to the DMA. 
3) Patients who do not respond to the e-questionnaire will be assessed through electronic health 
records for hospital admission/death in the latest 3-month period.1 Any hospital admission will be 
assessed for SAE locally as described above. 
4) The patients GP will be informed that the patient has been included in the trial in the discharge 
letter. This information will include the title of the trial, EudraCT identification and web-address for 
more information (hosted by OPEN).  
5) Each participating patient receives a trial card with the following information: Trial-name, website 
describing the trial (hosted by OPEN), contact information on the MD responsible for the trial 
locally and information on reporting of hospital-admissions via e-questionnaires every 3 months. 
This ensures that all professionals in contact with the patient know how SAEs/SARs will be 
reported. 
It is the opinion of the steering committee of the trial that this monitoring ensures the safety of each 
participant included in the trial.  
Serious Adverse Events (SAE) and Serious Adverse Reactions (SAR) 
A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that results in death or 
requires in-patient hospitalization or prolongation of existing hospitalization or results in persistent or 
significant disability or incapacity or is a congenital anomaly or birth defect. BB treatment is standard of 
care and has been widely prescribed for decades. The treatment with BB after MI has the aim of reducing 
cardiovascular mortality, recurrent MI and serious heart rhythm disturbances. For the BB treated group any 
SAE judged to be related to drug therapy is a serious adverse reaction (SAR). For the non-BB treated group 
focus is on SAE that may be related to NOT being treated with BB.  
In both groups, safety reporting will be based on rates of all hospital admission reported by the patients 
and ascertained through electronic health records. Additionally, each patient will report all hospital 
admissions, and these will be assessed by the sponsor/investigator through review of hospital records for 
relation to treatment/no treatment with betablocker and reported in the eCRF. Secondary endpoints 
leading to hospital admission (i.e. ventricular arrhythmia, atrial fibrillation, angina symptoms, bradycardia, 
syncope or need for a pacemaker, asthma, stroke and hypertension) will be included in the SAE/SAR 
reporting. Patients that do not respond to the e-questionnaire will be checked through electronic health 
records for hospital admissions in the intermittent 3-month period. Any hospital admissions will be 
assessed for whether this is an original primary endpoint, secondary endpoint or SAR as described above. 
Monitoring will be based on rates of hospital admission derived from patient reports and other sources of 
entry into the eCRF and will be assessed and reported 3 months after the first patient is randomized and 
biannually thereafter throughout the trial period. 
 
1 Lovhjemmel: LOV nr 620 af 08/06/2016, paragraf 21, stk 1: ’ Et samtykke afgivet efter kapitel V i forordningen giver sponsor og sponsors repræt 
samtykke a investigator direkte adgang til at indhente oplysninger i patientjournaler m.v., herunder i elektroniske journaler, med henblik på at se 
oplysninger om forsøgspersonens helbredsforhold, som er nødvendige som led i egenkontrol med forskningsprojektet, herunder kvalitetskontrol og 
monitorering, som disse er forpligtet til at udføre.’ 

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Suspected Unexpected Adverse Events (SUSARs) 
Since BB’s have been standard of care in MI patients for several decades, we expect no SUSARs in patients 
treated with BB. Any SUSAR in patients not treated with BB will be related to the indication for treatment, 
i.e. MI. 
The SAEs MI, heart failure, hospital admission for unstable angina, stroke and death will be monitored 
repeatedly as described. SAEs will be monitored as described above through e-questionnaires to study 
participants every 3 months and through electronic health records in patients who do not respond to the e-
questionnaire. Any report of an SAE by a patient will be assessed by sponsor/investigator to determine 
whether this is an original primary endpoint, secondary endpoint, SAE and whether this is a possible SAR. In 
the event of death the MD responsible for the trial locally will investigate the cause of death and report it in 
the eCRF as soon as possible and no more than 24 hours following the knowledge of such an event. The 
sponsors Medical Officer will review all SAEs reported as related to the trial drug (or lack of trial drug) and 
evaluate whether the event is expected according to the Reference Safety Information (RSI) for patients 
under treatment or related to lack of BB treatment post MI in the untreated group. The following are 
regarded as possibly related to treatment or lack of BB treatment and will not be reviewed independently 
by the sponsors Medical Officer: Ventricular arrhythmia, supraventricular arrhythmia (including atrial 
fibrillation and atrial flutter), any tachycardia leading to hospital admission and angina pectoris leading to 
hospital admission, brady-arrhythmias, syncope, pacemaker implantation, hypertension, hypotension, 
dysregulated or incident case of diabetes, PAD and constipation.  These events will be reported to the 
DSMB biannually and to the DMA annually. The product information for the IMPs is used as 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 (SUSAR) that are fatal or life-threatening is recorded and reported as soon as 
possible to the Competent Authorities in any case no later than 7 days after knowledge by the sponsor and 
that relevant follow-up information is subsequently communicated within and additional 8 days.  
Safety and reporting 
Accumulated data on the primary outcomes as well as SAE and SAR based on patient reports and hospital 
records every 3 months for both patients on BB treatment and not on treatment will be made available to 
the Data Safety Monitoring Board (DSMB). This process ensures that accumulated events/SAE/SAR in both 
the treatment group and the non-treatment group are evaluated and will form the basis of safety 
assessment. The DSMB will first assess the outcomes 3 months after the first patients is included and 
thereafter biannually throughout the study period.  The Competent Authority will receive annual reports 
from the DSMB. 
Study Organization 
Sponsor 
The study sponsor is Eva Prescott, Department of Cardiology, Bispebjerg Frederiksberg Hospital 
The initiative to the present study was taken by members of the Working Group on Cardiac Prevention and 
Rehabilitation under the Danish Society of Cardiology 
Steering Committee: 
The steering committee (SC) is responsible for conducting the trial. The role of the SC is to define the study, 
write the protocol, ensure funding, oversee the scientific content and integrity of the study and monitor 
the study economy. The SC is also responsible for reporting of the trial results. The study will be managed 
by a senior researcher and a project coordinator (study nurse). Payment of study expenses will follow 
patient inclusion: Each participating centre will be re-imbursed for the time spent on screening and patient 
inclusion, in addition to a set-up investigators fee. All members of the steering committee are voting 

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members. The steering committee (SC) will convene when necessary (in person or video conference) to 
monitor study progress. 
Project management: Project leader, project manager and assisting project managers 
Eva Prescott is project leader (PL) and responsible for the coordinating center at the department of 
Cardiology at Bispebjerg Frederiksberg Hospital. The PL has the overall responsibility of conducting the trial 
according to good clinical practice. The PL will refer directly to the SC. 
A project manager (PM) Thomas S G Sehested has been appointed. The primary task of the project 
manager is to promote the study, give advice to the participating centres, monitor safety in the study and 
follow-up on decisions made by the steering committee and serve as datamanager in collaboration with 
OPEN and assistant project manager. The PM will refer directly to the PL.  
A PhD student will act as assistant project manager. He/she will handle safety issues, communication with 
authorities, GCP, eCRF, economy, etc, promote the study and give advice to participating centres and assist 
the project manager/project leader in their responsibilities.  
PL, PM and assisting PM’s will work closely together and be situated at Bispebjerg Frederiksberg Hospital 
Participating Centres/investigators 
The study is open to all departments of Cardiology in Denmark, most of which have already agreed to 
participate. A representative of each of the five Danish regions is a member of the Steering Committee. 
Each center will appoint an investigator who will be responsible for the conduct of the study at the 
department and for communication with the project management. One representative from each 
participating center is invited to participate in a writing group. 
Data Safety Monitoring Board (DSMB) 
This independent committee consisting of three international specialists, two senior cardiologists and one 
experienced trial-statistician, will overview safety and will have access to unblinded data. The DSMB 
members will be independent and will not be involved otherwise in the trial. They will formally review the 
accumulating data after 3 months and every 6 months thereafter to ensure there is no avoidable increased 
harm to patients.  The DSMB may recommend trial termination due to excess risk associated with no 
treatment with BB as described above. All final decisions regarding trial modifications rest with the Steering 
Committee. The responsibilities of the DSMB are described in a contract (appendix 5).  
Statistical analysis plan and supervision 
The primary analysis will be intention-to-treat analysis, i.e. patients will be counted in the group to which 
they were assigned at randomization regardless of later cross-over. Additionally, a secondary per-protocol 
analysis will be performed, where compliant BB-users are considered exposed during follow-up. Outcome 
analysis will be assessed by using cumulative incidence and Cox-regressions. Level of significance will be 
0.05. No interim analyses are planned. A detailed statistical analyses plan will be developed by the project 
management and SC and will be published through clinicaltrials.gov and EudraCT. Statistical analysis will be 
supervised by Theis Lange, Institute of Biostatistics, University of Copenhagen. 
GCP -Good Clinical Practice  
The study will be performed according to the most recent approved study protocol, ICH-GCP guidelines and 
applicable regulatory requirements and legislation. The study will be monitored by the Danish GCP-unit.  
Danish Medicines Agency (Lægemiddelstyrelsen - DMA) 
The study has been approved by the Danish Health and Medicines Authority.  
The Committee on Health Research Ethics (Videnskabsetiske Komitéer) 
The study has been approved by the regional Ethics Committee 

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The Danish Data Protection Agency (DDPA) 
The study will adhere to ’Databeskyttelsesforordningen’ and ’Databeskyttelsesloven’ and will be approved 
by the Danish Data Protection Agency. 
International collaboration 
To resolve the question of BB treatment after MI an adequately powered trial is needed. Two Scandinavian 
and one Spanish/Italian trial have been funded and initiated: The Swedish REDUCE trial the Norwegian 
BETAMI, and the Spanish/Italian REBOOT. Similar trials in the UK (REDUCE-UK) are planned but have not yet 
acquired funding. Both the BETAMI and the REDUCE trial are powered for a conventional superiority trial to 
detect a HR of >1.20 with a combined outcome of recurrent MI and death. However, more patients are 
needed to identify smaller but clinically relevant benefits of BB treatment and resolve the question of 
mortality. With a total number of events of 2800 between the tree trials, we will have 80% power to detect 
a 10% reduction in the primary outcome. This will also allow for subgroup analyses including midrange 
LVEF40-49/>=50%, men/women, young/elderly, NSTEMI/STEMI and MI with vs. without significant lesions 
(MINOCA). The trials are collaborating closely on design to ensure that an international individual patient 
meta-analysis can be performed.  
A formal collaboration with the Swedish REDUCE trial (PI Thomas Jernberg) and the Norwegian BETAMI trial 
(PI Dan Atar) has been established to coordinate the studies. A Scandinavian collaborative committee will 
be formed and there will be mutual representation in the national steering committees. The DANBLOCK 
trial will include patients with MINOCA, i.e. MI patients with no obstructive CAD. An international 
(Swedish/Norwegian/Australian/US/UK) trial is being undertaken to test the effect of BB (and ACE/ARB) on 
patients with MINOCA – the MINOCA BAT trial. A formal collaboration with the PI Bertil Lindahl has been 
established to ensure that the DANBLOCK study results can be pooled in a similar manner. 
Ethical and regulatory requirements 
Ethical considerations 
The project requires approval by the Danish Health Data Board, the Danish Data Protection Agency and the 
National Ethics Committee. All legislation on handling of personal data will be adhered to. 
The aim of the present study is to evaluate the effectiveness and the risk-benefit balance of BBs after MI in 
real-life practice. Treatment with BBs will be used according to summary of product characteristics and 
therefore it is not necessary to distribute the BBs free of charge to patients. This is according to the Danish 
Board of Health rules since section 3 paragraph 13, no. 2 is fulfilled and we have been exempted from the 
general rule by the DMA.   
The treatment with beta BB is current standard and we see no risk in participating in this arm of the trial. 
For the control group who receive no beta-blocker treatment there may be an increased risk of adverse 
outcome. This is monitored by the DSMB with the process described above. Side-effects will be reported 
according to the reference documents for the BB’s used. 
The study has been registered at EudraCT and will be registered at clinicaltrials.gov once approvals have 
been obtained. 
Informed consent 
Patients are recruited on the basis of in- and exclusion criteria. The first contact can be during hospital 
admission for MI, shortly thereafter by telephone or mail or at their first appointment at the cardiac 
rehabilitation. They will be informed about the background and design of the trial. If they are interested in 
participating, a consultation at the hospital or by telephone (if the patient prefers this option) will be 
scheduled and they will be provided with oral and written information about the trial along with the 
brochure ‘Your rights as a participant in biomedical research’. They are encouraged to bring a companion 

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and ask questions. Before signing the consent form the patient will be given ample time to re-consider. 
Should the patient need further time, a follow-up meeting will be scheduled. If the patient consents, the 
form is signed (“Samtykkeerklæring”) either by mail or in person and the patient receives a copy of the 
informed consent. 
Patients are informed that they may at any time withdraw their consent to participate in the trial without 
consequences for their treatment in the department of cardiology. The patients are informed that 
information from their patient records will be retried by study personnel and used in this study. The 
patients are specifically informed and asked about their consent to this in the patient information. This 
information will be used to assess AEs, SAEs, SUSARs, endpoints, etc. 
All study personnel will undergo training by the local principal investigator in study design, patient 
treatment, safety and other study related issues before they are involved in patient contact. The study 
personnel involved will be doctors and nurses employed at the department of cardiology or the cardiac 
rehabilitation. 
Compensation for any treatment injury to the participants will be through ’Patienterstatningen’.  
Trial sponsorship and financing  
The study is investigator initiated by the principal investigator and members of the working group on 
cardiovascular prevention and rehabilitation under the DCS. The study has received support from the 
Danish Heart Foundation covering costs for the first year of the trial and the Novo Nordisk Foundation. 
There are no financial interests in the trial. 
Communication 
A website will be developed for information on study rationale and description of the trial. An e-mail and 
telephone number will be dedicated to questions on the trial and answered 24/7. 
Publication policy 
When the study is completed, and results are analysed and reported the study will be submitted for an 
international journal and results will be made publicly available. The results will also be reported at 
EUDRACT and ClinicalTrials.gov. Both positive, negative and inconclusive results will be published. 
All individuals who have contributed significantly to the study, including local MD s responsible for the trial 
conductance, will be acknowledged and if they fulfil the requirements of co-authorship in accordance with 
the Vancouver convention they will be invited to participate in the process of publication.  
Time line 
Approval from the Committee on Health Research Ethics  
December 2018 
Approval from the Danish Data Protection Agency 
 
December 2018 
Approval from the Danish Medicines Agency 
 
December 2018 
First patient randomized 
 
 
 
December 2018 
Last patient randomized 
 
 
 
January 2024 
End of follow up 
 
 
 
December 2024 
Data analysis complete (+4 months) 
 
 
April 2025 
Publication of study results (+3-8 months)  
 
October 2025 

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Appendix 1: Patient information 
Appendix 2: eCRF and eQuestionnaires 
Appendix 3: Definition of endpoints and adjudication 
Appendix 4: Data Safety Monitoring Board  
Kristian Thygesen, Independent Cardiologist, Denmark 
Chris Gale, Independent Cardiologist, UK 
Biostatistician TBD 
Appendix 5: DSMB contract 
Appendix 6: Product resume for beta blockers  
Has been forwarded separately to DMA 
Appendix 7: Budget 
 
 

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Appendix 8: List of PI’s (Updated 22.12.2021) 
  
Region Hovedstaden 
 
Amager Hospital 
Jens Brønnum Schou 
Bispebjerg Hospital  
Eva Prescott  
Bornholms sygehus 
Kjeld Skødebjerg Kristensen 
Frederiksberg Hospital  
Eva Prescott  
Gentofte Hospital  
Gunnar Gislasson 
Glostrup Hospital 
Jawdat Abdulla 
Herlev Hospital 
Mette Mouridsen 
Hvidovre Hospital 
Jens Hove 
Nordsjællands Hospital  
Louise Schierbeck  
  
Sjælland 
 
Holbæk Sygehus  
Michael Hecht Olsen 
Nykøbing F. Sygehus 
 
Næstved Sygehus 
John Larsen 
Roskilde Sygehus 
Martin Snoer  
Slagelse Sygehus  
Jens Lomholdt 
  
Syddanmark 
 
OUH Odense Universitetshospital 
Gro Egholm  
OUH Svendborg Sygehus 
Jess Lambrechtsen 
Sydvestjysk Sygehus 
Kristian Korsgaard Thomsen 
Sygehus Sønderjylland 
Ghassan Jadou 
Sygehus Lillebælt  
Ann Bovin 
Sygehus Lillebælt, Kolding 
Monica Poenaru 
  
Midtjylland 
 
Aarhus Universitetshospital 
Michael Mæng 
Hospitalsenhed Midt 
Nikolaj Thure Krarup 
Hospitalsenhed Vest 
Morten Bøttcher 
Regionshospitalet Horsens 
Morten Krogh Christiansen 
Silkeborg Hospital 
Lars Frost (inkluderer ikke længere) 
  
Nordjylland 
 
Aalborg Universitetshospital 
Svend Eggert Jensen  
Regionshospital Nordjylland 
Peter Bisgaard Stæhr