Clinical trial NCT03778554: Danish Trial of Beta Blocker Treatment After Myocardial Infarction Without Reduced Ejection Fraction
Official title: Danish Trial of Beta Blocker Treatment After Myocardial Infarction Without Reduced Ejection Fraction (DANBLOCK)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Acute Myocardial Infarction
Non-ST Elevation Myocardial Infarction (nSTEMI)
ST Elevation Myocardial Infarction
Lead sponsor: Bispebjerg Hospital
Sponsor class: OTHER
Collaborators: name: Amager Hospital
name: University Hospital Bispebjerg and Frederiksberg
name: Bornholm Hospital
name: Gentofte Hospital
name: Glostrup University Hospital, Copenhagen
name: Herlev Hospital
name: Hvidovre University Hospital
name: Nordsjaelland Hospital
name: Holbaek Hospital
name: Nykoebing Hospital
name: Naestved Hospital
name: Nordsjaellands Hospital
name: Zealand University Hospital
name: Slagelse Hospital
name: Odense University Hospital
name: Svendborg Hospital
name: Sydvestjysk Sygehus
name: Hospital of Southern Jutland
name: Sygehus Lillebaelt (Vejle and Kolding)
name: Aarhus University Hospital
name: Hospitalsenheden Midt
name: Hospitalsenheden Vest
name: Regionshospitalet Horsens
name: Silkeborg Sygehus
name: Aalborg University Hospital
First posted: 2018-12-19
Enrollment: 2760
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective, randomized, controlled, open-label, blinded endpoint (PROBE design)
Primary purpose: TREATMENT

Brief summary: To determine whether long-term treatment with oral betablocker therapy after myocardial infarction in patient with no heart failure reduces the composite outcome of recurrent MI, all-cause mortality, revascularisation with percutaneous coronary intervention or coronary artery bypass graft, ischemic stroke, incident heart failure, or malignant ventricular arrhythmia including resuscitated cardiac arrest of cardiac origin.

Detailed description: 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 MI, all-cause mortality, revascularisation with percutaneous coronary intervention or coronary artery bypass graft, ischemic stroke, incident heart failure, or malignant ventricular arrhythmia including resuscitated cardiac arrest of cardiac origin.

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. To enhance feasibility, the decision was made by the Steering Committees to combine the data from DANBLOCK with the data from the Norwegian BETAMI (NCT03646357) and publish the primary endpoint, key secondary endpoints and most other secondary endpoints together (presented below).

The trials have similar designs, only minor differences in study entry criteria, and were, from the very beginning, coordinated with the aim of conducting sub-studies on pooled data. The primary endpoint has been harmonized without knowledge of the distribution of events. BETAMI and DANBLOCK will remain separate trials until the end of follow-up, where data from the trials will be combined and main results published together.

Intervention: BB therapy versus no therapy.

Main Inclusion Criteria: Patient that have suffered a MI, both Non-ST elevation MI and ST elevation MI and can be randomized within 14 days of MI with no signs of heart failure and a left ventricular ejection fraction\>40%.

Main Exclusion Criteria: Any indication or contraindication for BB treatment other than secondary prevention according to the treating cardiologist

Primary study endpoint:

• The composite of all-cause mortality, recurrent MI, revascularisation with PCI or CABG, ischemic stroke, incident heart failure, or malignant ventricular arrhythmia including resuscitated cardiac arrest of cardiac origin.

Key secondary endpoints to be included in the main publication:

* Each of the components of the primary endpoint, i.e.: All-cause mortality, recurrent MI, revascularisation with PCI or CABG, ischemic stroke, incident heart failure, malignant ventricular arrhythmia including resuscitated cardiac arrest of cardiac origin.
* To study whether oral beta-blocker therapy increases the risk of hospitalization for 2 or 3rd degree AV-block, or implantation of pacemaker
* To assess clinical outcomes linked to beta-blocker therapy in the following subgroups:

age (\> vs \<70 years), sex (men vs. women), beta-blocker dosage, STEMI vs. NSTEMI, LVEF subgroups (preserved vs. mid-range), country, hypertension and diabetes.

Other secondary endpoints are described in the Statistical Analysis Plan and under "Outcome Measures".

Other secondary objectives (for BETAMI-DANBLOCK substudies unless specified otherwise):

* To study whether oral beta-blocker therapy reduces the risk of cardiovascular death compared to no such therapy
* To study whether oral beta-blocker therapy reduces the risk of stable and unstable angina compared to no such therapy
* To study whether oral beta-blocker therapy reduces the risk of atrial fibrillation, atrial flutter or other tachyarrhythmias compared to no such therapy
* To study whether oral beta-blocker therapy increases the risk of hospitalization for chronic obstructive pulmonary disease, asthma or peripheral artery disease.
* To study whether oral beta-blocker therapy increases the risk of hospitalization or outpatient visit for new-onset or dysregulated diabetes (DANBLOCK only)
* To study whether oral beta-blocker therapy affects the following patient related outcomes: Quality of life, angina, dyspnoea, anxiety, depression, sexual dysfunction or sleep disorders.
* To conduct 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 describe beta-blocker dosage and adherence
* To assess study safety

Safety endpoints:

The following safety endpoints will be reported in the main publication:

* Primary safety endpoint: A composite of all-cause mortality, recurrent MI, incident HF, malignant ventricular arrhythmia including resuscitated cardiac arrest of cardiac origin at 30 days following randomization
* Other safety endpoint: All-Cause Mortality: A table of all deaths within the follow-up period
* Other safety endpoint: Suspected Unexpected Serious Adverse Reaction (SUSARs): A table of all SUSARs within the follow-up period with number and frequency in each group. Reported by local investigators and obtained from the study databases.

All serious adverse events, including potential endpoints, are captured in the study database to be used for safety assessments and are reported continuously to regulatory authorities.

Sample Size: A total of approximately 2760 patients 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.

Sample size considerations: The study is event driven and a power calculation for the combined DANBLOCK-BETAMI trial has been performed in which 950 events will provide a power of 80% to detect a true treatment effect equal to a hazard ratio of 1.2 for no beta-blocker therapy.

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.

Treatment Duration: Estimated (non) treatment duration of a minimum of 6 months and a maximum of 6.25 years (anticipated).

Follow-up: Patients will be followed from the randomization date until end of follow-up.

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.

Original sample size considerations: Assuming a hazard ratio of 1.2 for the non-treated group compared to the treated the DANBLOCK trial has 80% power to detect this effect with an accumulation of 900 events of the primary endpoint. With approximately 3570 patients randomized the investigators expect to reach 900 events within the study period.

Statistical Analysis: Please see the Statistical Analysis Plan.

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.

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.

Furthermore, a joint analysis of the data from BETAMI-DANBLOCK with the REDUCE (NCT03278509), CAPITAL-RCT (NCT01155635), and REBOOT (NCT03596385) trials will be performed.

Eligibility criteria: Inclusion Criteria:

* Left ventricular ejection fraction \> 40%
* Myocardial infarction (MI) within previous two weeks

The diagnosis of acute MI must meet the Universal European Society of Cardiology (ESC) definition of MI

Exclusion Criteria:

* Clinical evidence of heart failure at the time of discharge
* Pregnancy or of child bearing age not using safe anticonception throughout the study period
* Lack of signed informed consent and expected cooperation during follow-up
* Any medical condition where beta blocker treatment is indicated according to the treating physician

Primary outcomes:
measure: A composite of all-cause mortality, recurrent MI, revascularisation with PCI or CABG, ischemic stroke, incident heart failure, or malignant ventricular arrhythmia including resuscitated cardiac arrest of cardiac origin.
timeFrame: Estimated follow-up min 6 months - max 6.25 years
Secondary outcomes:
measure: Recurrent myocardial infarction
timeFrame: Estimated follow-up min 6 months - max 6.25 years
measure: All-cause mortality
timeFrame: Estimated follow-up min 6 months - max 6.25 years
measure: Malignant ventricular arrhythmias
timeFrame: Estimated follow-up min 6 months - max 6.25 years
measure: Incident heart failure (diagnosed at hospitalization or at out-patient visits)
timeFrame: Estimated follow-up min 6 months - max 6.25 years
measure: Unplanned coronary revascularization
timeFrame: Estimated follow-up min 6 months - max 6.25 years
measure: Ischemic stroke
timeFrame: Estimated follow-up min 6 months - max 6.25 years
measure: Resuscitated cardiac arrest of cardiac origin
timeFrame: Estimated follow-up min 6 months - max 6.25 years
measure: Cardiovascular mortality
timeFrame: Estimated follow-up min 6 months - max 6.25 years
measure: Hospitalization for stable and unstable angina pectoris
timeFrame: Estimated follow-up min 6 months - max 6.25 years
measure: Hospitalization for atrial fibrillation, atrial flutter or other tachyarrhythmias
timeFrame: Estimated follow-up min 6 months - max 6.25 years
measure: Hospitalization for bradycardia, AV-block, syncope, or need for pacemaker
timeFrame: Estimated follow-up min 6 months - max 6.25 years
measure: Hospitalization for asthma and chronic obstructive pulmonary disease symptoms
timeFrame: Estimated maximal follow-up 6 months - 6.25 years
measure: Hospitalization or outpatient visit for peripheral artery disease
timeFrame: Estimated follow-up min 6 months - max 6.25 years
measure: Hospitalization or outpatient visit for new-onset or dysregulated diabetes (DANBLOCK only)
timeFrame: Estimated follow-up min 6 months - max 6.25 years
measure: Angina symptoms
timeFrame: E-questionnaires will be administered at inclusion, 3, 12 and 24 months
measure: Exercise capacity (DANBLOCK only)
timeFrame: At the beginning of cardiac rehabilitation (within approximately 4 weeks after randomization) and at the end of cardiac rehabilitation (approximately 6-12 weeks after beginning of rehabilitation)
measure: Blood pressure control (DANBLOCK only)
timeFrame: At the beginning of cardiac rehabilitation (within approximately 4 weeks after randomization) and at the end of cardiac rehabilitation (approximately 6-12 weeks after beginning of rehabilitation)
measure: Quality of life measure
timeFrame: E-questionnaires will be administered at inclusion, 3, 12 and 24 months
measure: Measures of depression and anxiety
timeFrame: E-questionnaires will be administered at inclusion, 3, 12 and 24 months
measure: Measures of sexual dysfunction
timeFrame: E-questionnaires will be administered at inclusion, 3, 12 and 24 months
measure: Measures of sleeping disorder
timeFrame: E-questionnaires will be administered at inclusion, 3, 12 and 24 months
measure: Adherence to the prescribed dosage of beta-blocker
timeFrame: Estimated follow-up min 6 months - max 6.25 years
measure: 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
timeFrame: Estimated follow-up min 6 months - max 6.25 years
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Bispebjerg Hospital, Dept. of Cardiology Y builing 67, 1.floor, Bispebjerg Bakke 23
Study officials:
affiliation: Bispebjerg Frederiksberg University Hospital
name: Eva IB Prescott, MD, DMsC
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital Bispebjerg and Frederiksberg
name: Anna Meta D Kristensen, MD
role: STUDY_CHAIR
References:
citation: Kristensen AMD, Bovin A, Zwisler AD, Cerquira C, Torp-Pedersen C, Botker HE, Gustafsson I, Veien KT, Thomsen KK, Olsen MH, Larsen ML, Nielsen OW, Hildebrandt P, Foghmar S, Jensen SE, Lange T, Sehested T, Jernberg T, Atar D, Ibanez B, Prescott E. Design and rationale of the Danish trial of beta-blocker treatment after myocardial infarction without reduced ejection fraction: study protocol for a randomized controlled trial. Trials. 2020 May 23;21(1):415. doi: 10.1186/s13063-020-4214-6.