Clinical trial NCT03646357: BEtablocker Treatment After Acute Myocardial Infarction in Patients Without Reduced Left Ventricular Systolic Function
Official title: BEtablocker Treatment After Acute Myocardial Infarction in Patients Without Reduced Left Ventricular Systolic Function (BETAMI)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Acute Myocardial Infarction
Non-ST Elevation Myocardial Infarction
ST Elevation Myocardial Infarction
Keywords: Infarction
Myocardial Infarction
ST Elevation Myocardial Infarction
Non-ST Elevated Myocardial Infarction
Ischemia
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Metoprolol
Bisoprolol
Betablocker
Anti-Arrhythmia Agents
Physiological Effects of Drugs
Beta-blocker
Beta blocker
Lead sponsor: Oslo University Hospital
Sponsor class: OTHER
Collaborators: name: Vestre Viken Hospital Trust
name: The Hospital of Vestfold
name: University of Oslo
name: Helse Stavanger HF
name: Haukeland University Hospital
name: St. Olavs Hospital
name: University Hospital of North Norway
name: Sorlandet Hospital HF
name: Norwegian University of Science and Technology
name: Sykehuset Innlandet HF
name: Nordlandssykehuset HF
name: Lovisenberg Diakonale Hospital
name: Diakonhjemmet Hospital
name: Ostfold Hospital Trust
First posted: 2018-08-24
Enrollment: 2895
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: PROBE - prospective, randomized, open blinded end-point
Primary purpose: TREATMENT

Brief summary: The study aims to investigate whether oral betablocker (BB) therapy is superior to no such treatment following an acute myocardial infarction (AMI).

Detailed description: This is a prospective, randomized, open blinded end-point (PROBE) study. Patients with AMI will be randomized 1-8 days following PCI or thrombolysis, and allocated to either prescription of a BB or to no such prescription. Subjects will be followed up for at least 6 months (median 3 years) with respect to the primary and secondary endpoints. The primary end point, the key secondary end points, and most other secondary end points will be analysed and published jointly with data from the 'Danish Trial of Beta-blocker therapy after myocardial infarction without heart failure' (DANBLOCK) (NCT 03778554) (please see below).

The primary objective is to test whether oral BB therapy reduces the risk of all-cause death, recurrent MI, incident heart failure, unplanned coronary revascularization, ischemic stroke, or malignant ventricular arrhythmia including resuscitated cardiac arrest of cardiac origin compared to no such therapy, in patients with AMI treated with PCI or thrombolysis without reduced LVEF.

The key secondary objectives (planned for the main study) are:

* To study whether oral BB therapy reduces the risk of each of the components of the primary end-point separately, compared to no such therapy
* To assess clinical outcomes linked BB therapy in the following subgroups: age (tertiles\< 70 years vs. ≥70 years), gender sex (men vs. women), country (Denmark vs Norway), BB dosage tertiles (dosage at randomization (\<50 mg vs. ≥50 mg), hypertension (yes vs. no), diabetes (yes vs. no), diabetes (yes vs no), type of MI (STEMI vs. NSTEMI), and LVEF subgroups (preserved LVEF: ≥50% vs. mid-range LVEF: 40-49%).
* To study whether oral BB therapy increases the risk of hospitalization for second or third-degree atrioventricular block or implantation of pacemaker.
* To describe BB dosage and adherence at six months following randomization obtained from the national prescription registries
* To assess study safety

Other secondary objectives (for joint BETAMI-DANBLOCK sub-studies) are:

* To study whether oral BB therapy reduces the risk of cardiovascular death compared to no such therapy
* To study whether oral BB therapy reduces the risk of stable and unstable angina compared to no such therapy
* To study whether oral BB therapy reduces the risk of atrial fibrillation, atrial flutter or other atrial tachyarrhythmias compared to no such therapy
* To study whether oral BB therapy increases the risk of hospitalization for bradycardia or syncope.
* To study whether oral BB therapy increases the risk of hospitalization for chronic obstructive pulmonary disease, asthma or peripheral artery disease.
* To study whether oral BB therapy affects the following patient related outcomes:

quality of life, angina, dyspnoea, anxiety, depression, sexual dysfunction or sleep disorders

* To describe long term BB adherence obtained from the national prescription registries
* To study sociodemographic, clinical, and psychosocial characteristics (PROMS and clinical data) between the two study arms and in the total sample
* 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

Exploratory objectives (based on BETAMI data, only):

* To study the proportion and predictors of non-adherence with BB, statins and other cardiovascular drugs assessed by direct methods quantifying drug concentrations in blood
* Identify pharmacokinetic, pharmacogenetic and pharmacodynamic markers associated with side-effects and suboptimal response to treatment with cardiovascular drugs

The primary study end-points will be obtained through linkage to the Norwegian Cardiovascular Disease Registry and The Norwegian Population Registry (Folkeregisteret)

Secondary endpoints will be obtained by linkage to the following national registries: The Norwegian Population Registry (Folkeregisteret), the Cause of Death Registry, the Norwegian Patient Registry, the Norwegian Cardiovascular Disease Registry, the Norwegian Prescription Database, the Norwegian registry for income, the FD-Trygd database (social security micro data for research) and the Control and payment of reimbursements to health service providers (KUHR) database. Further by collecting self-reported questionnaires and a clinical examination with blood sample collection.

Primary safety endpoints:

• To describe the composite endpoint of malignant ventricular arrhythmias including resuscitated cardiac arrest of cardiac origin, incident heart failure, new MI or all-cause death at 30 days after randomization collected from i. direct telephone contact with the patient and from hospital medical records, ii. linkage to the Norwegian Cardiovascular Disease Registry and The Norwegian Population Registry at study end.

Other safety endpoints:

* To describe all-cause death at study end
* To describe Suspected Unexpected Serious Adverse Reaction (SUSARs) during the follow-up period from the study database (continously reported by local investigators).

Rationale for combining data from the BETAMI study with the DANBLOCK (NCT03778554) study from Denmark: 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. However, the inclusion- and event rates have been lower than expected in both studies. To enhance feasibility, the final decision was made from both Steering Committees in May 2021 to combine the trials and publish initial results jointly. 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.

Sample size: A total of approximately 2900 patients from BETAMI will be recruited and randomized 1:1 to BB treatment (type and dosage according to treating physician) or no BB treatment within 8 days of MI. 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. Follow-up: Patients will be followed from the randomization date until end of follow-up. The last patient included will be followed for a minimum of 6 months. Estimated mean (non) treatment duration is 3 (0.5-6) years.

Post-trial objective:

• To perform a joint analysis of the data from BETAMI-DANBLOCK with the REDUCE (NCT03278509), CAPITAL-RCT (NCT01155635) and REBOOT (NCT03596385) trials. This analysis will comprise approximately 19000 patients, giving increased power and precision for clinical decisions on both primary and secondary endpoints.

Eligibility criteria: Inclusion Criteria

To be eligible for inclusion in the study, subjects must fulfill the following criteria at inclusion:

* 18 years or older
* Diagnosed with an acute MI type I according to the "Universal Definition of MI" (Defined as a detection of a rise and/or fall of cardiac biomarker value, preferably troponin, with at least one value above the 99th percentile upper reference limit and with at least one of the following; a) symptoms of ischemia, b) new or presumed new significant ST-segment-T wave changes or new left bundle branch block, c) development of pathological Q waves, d) imaging evidence of new loss of viable myocardium or e) identification of an intracoronary thrombus by coronary angiogram)
* Must have been treated with PCI or thrombolysis during current hospitalization
* Signed informed consent and expected cooperation of the patient according to ICH/GCP and national/local regulations
* Have a national personal identification number and not be expected to emigrate during study

Exclusion Criteria

Study subjects must not meet any of the following criteria:

* Having a condition where betablocker-therapy is required, including but not limited to:

  * Arrhythmias
  * Hypertension
  * Cardiomyopathies
  * Clinical diagnosis of heart failure
  * LVEF \< 40% by echocardiography (by measurement and not only visual assessment for STEMI patients)
  * Left ventricular akinesia in ≥ 3 segments regardless of the LVEF
* Contraindications to betablocker-therapy, including but not limited to:

  * Bradyarrhythmias
  * Hypotension
  * Severe peripheral artery disease
  * Previously known side-effects causing withdrawal
  * Severe chronic obstructive pulmonary disease
  * • Women of childbearing potential (a woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile)
* Known hypersensitivity to any ingredient of the IMP
* Other, according to the responsible investigator
* End-stage somatic disease with short life expectancy, dementia, psychosis and other conditions could put the subject at significant risk, confound the study results, interfere significantly with the subject participation in the study, or rendering informed consent unfeasible

Previous treatment with a betablocker is not an exclusion criterion for enrollment into the BETAMI study. Enrolled patients can participate in any other study that does not directly alter the effect betablocker treatment

Primary outcomes:
measure: A composite of death of any cause, recurrent myocardial infarction, incident heart failure, coronary revascularization, ischemic stroke, malignant ventricular arrhythmia including resuscitated cardiac arrest of cardiac origin
timeFrame: 6 months (minimum) to 6 years (maximum)
Secondary outcomes:
measure: Recurrent MI
timeFrame: 6 months (minimum) to 6 years (maximum)
measure: All-cause death
timeFrame: 6 months (minimum) to 6 years (maximum)
measure: Malignant ventricular arrhythmias including resuscitated cardiac arrest of cardiac origin
timeFrame: 6 months (minimum) to 6 years (maximum)
measure: Hospitalization or outpatient consultation for incident heart failure
timeFrame: 6 months (minimum) to 6 years (maximum)
measure: Unplanned coronary revascularization
timeFrame: 6 months (minimum) to 6 years (maximum)
measure: Ischemic stroke
timeFrame: 6 months (minimum) to 6 years (maximum)
measure: Cardiovascular death
timeFrame: 6 months (minimum) to 6 years (maximum)
measure: Hospitalization for stable and unstable angina
timeFrame: 6 months (minimum) to 6 years (maximum)
measure: Hospitalization for atrial fibrillation, atrial flutter or other atrial tachyarrhythmias
timeFrame: 6 months (minimum) to 6 years (maximum)
measure: Hospitalization for bradycardia, syncope or implantation of pacemaker
timeFrame: 6 months (minimum) to 6 years (maximum)
measure: Hospitalization for chronic obstructive pulmonary disease, asthma or peripheral artery disease
timeFrame: 6 months (minimum) to 6 years (maximum)
measure: Angina symptoms
timeFrame: Through self-report questionnaires administered at inclusion, 30 days, 3,6 and 18 months
measure: Health-related quality of life
timeFrame: Through self-report questionnaires administered at inclusion, 30 days, 3,6 and 18 months
measure: Measures of depression and anxiety
timeFrame: Through self-report questionnaires administered at inclusion, 30 days, 3,6 and 18 months
measure: Measures of sexual dysfunction
timeFrame: Through self-report questionnaires administered at inclusion, 30 days, 3,6 and 18 months
measure: Measures of sleep disorders
timeFrame: Through self-report questionnaires administered at inclusion, 30 days, 3,6 and 18 months
measure: Measures of sleep disorders
timeFrame: Through self-report questionnaires administered at inclusion, 30 days, 3,6 and 18 months
measure: Measures of Nightmare Frequency
timeFrame: Through self-report questionnaires administered at inclusion, 30 days, 3,6 and 18 months
Other outcomes:
Locations:
city: Arendal
country: Norway
facility: Sørlandet Sykehus
city: Bergen
country: Norway
facility: Haukeland Universitetssykehus
city: Bodø
country: Norway
facility: Nordlandssykehuset HF Bodø
city: Drammen
country: Norway
facility: Drammen Hospital
city: Fredrikstad
country: Norway
facility: Sykehuset Østfold Kalnes
city: Gjøvik
country: Norway
facility: Sykehuset Innlandet HF, Gjøvik Sykehus
city: Hamar
country: Norway
facility: Sykehuset Innlandet Hamar
city: Hønefoss
country: Norway
facility: Vestre Viken HF, Ringerike Sykehus
city: Lillehammer
country: Norway
facility: Sykehuset Innlandet Lillehammer
city: Lørenskog
country: Norway
facility: AHUS
city: Lørenskog
country: Norway
facility: LHL Gardermoen
city: Oslo
country: Norway
facility: Diakonhjemmet Sykehus
city: Oslo
country: Norway
facility: Lovisenberg Diakonale Sykehus
city: Oslo
country: Norway
facility: Oslo University Hospital Rikshospitalet, Dept.of Cardiology
city: Oslo
country: Norway
facility: Oslo University Hospital Ullevaal, Dept. of Cardiology
city: Sandvika
country: Norway
facility: Vestre Viken HF, Bærum Sykehus
city: Stavanger
country: Norway
facility: Stavanger Universitetssjukehus
city: Tromsø
country: Norway
facility: Universitetssykehuset Nord-Norge, UNN
city: Trondheim
country: Norway
facility: St. Olavs University Hospital
city: Tønsberg
country: Norway
facility: Vestfold hospital
Study officials:
affiliation: Oslo University Hospital
name: Dan Atar, MD Prof
role: STUDY_CHAIR
References: