BEtablocker Treatment After Acute Myocardial Infarction in Patients Without Reduced Left Ventricular Systolic Function (BETAMI)

• ClinicalTrials.gov Identifier: NCT03646357
• Recruitment Status: Active, not recruiting
• First Posted: August 24, 2018
• Last Update Posted: March 1, 2024
• Sponsor: Oslo University Hospital
• Collaborators: Vestre Viken Hospital Trust; The Hospital of Vestfold; University of Oslo; Helse Stavanger HF; Haukeland University Hospital; St. Olavs Hospital; University Hospital of North Norway; Sorlandet Hospital HF; Norwegian University of Science and Technology; Sykehuset Innlandet HF; Nordlandssykehuset HF; Lovisenberg Diakonale Hospital; Diakonhjemmet Hospital; Ostfold Hospital Trust
• Information provided by (Responsible Party): Dan Atar, Oslo University Hospital

Tracking Information

• First Submitted Date: May 14, 2018
• First Posted Date: August 24, 2018
• Last Update Posted Date: March 1, 2024
• Actual Study Start Date: October 1, 2018
• Estimated Primary Completion Date: December 10, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 2, 2024)

A composite of death of any cause, recurrent myocardial infarction, incident heart failure, coronary revascularization, ischemic stroke, malignant ventricular arrhythmia or resuscitated cardiac arrest [ Time Frame: 6 months (minimum) to 6 years (maximum) ]

Incidence of combined endpoint from randomization. Estimated maximal follow-up for each patient for this outcome is 6 months to 6 years

Original Primary Outcome Measures (submitted: August 23, 2018)

Time to the composite of death of any cause and non-fatal myocardial infarction [ Time Frame: 2 years minimum ]

Incidence of combined endpoint from randomization. Estimated maximal follow-up for each patient for this outcome is 1-3 years

Current Secondary Outcome Measures (submitted: January 2, 2024)

• Recurrent MI [ Time Frame: 6 months (minimum) to 6 years (maximum) ]
  Time to recurrent MI from randomization. Estimated maximal follow-up for each patient for this outcome is 6 months to 6 years
• All-cause death [ Time Frame: 6 months (minimum) to 6 years (maximum) ]
  Time to a-cause Death from randomization. Estimated maximal follow-up for each patient for this outcome is 6 months to 6 years
• Malignant ventricular arrhythmia [ Time Frame: 6 months (minimum) to 6 years (maximum) ]
  Time to malignant ventricular arrhythmia from randomization. Estimated maximal follow-up for each patient for this outcome is 6 months to 6 years
• Hospitalization or outpatient consultation for incident heart failure [ Time Frame: 6 months (minimum) to 6 years (maximum) ]
  Time to hospitalization or outpatient consultation for heart failure from randomization. Estimated maximal follow-up for each patient for this outcome is 6 months to 6 years
• Unplanned coronary revascularization [ Time Frame: 6 months (minimum) to 6 years (maximum) ]
  Time to unplanned coronary revascularization from randomization. Estimated maximal follow-up for each patient for this outcome is 6 months to 6 years
• Ischemic stroke [ Time Frame: 6 months (minimum) to 6 years (maximum) ]
  Time to ischemic stroke from randomization. Estimated maximal follow-up for each patient for this outcome is 6 months to 6 years
• Resuscitated cardiac arrest [ Time Frame: 6 months (minimum) to 6 years (maximum) ]
  Time to resuscitated cardiac arrest from randomization. Estimated maximal follow-up for each patient for this outcome is 6 months to 6 years
• Cardiovascular death [ Time Frame: 6 months (minimum) to 6 years (maximum) ]
  Time to cardiovascular death from randomization. Estimated maximal follow-up for each patient for this outcome is 6 months to 6 years
• Hospitalization for stable and unstable angina [ Time Frame: 6 months (minimum) to 6 years (maximum) ]
  Time to hospitalization for stable and unstable angina from randomization. Estimated maximal follow-up for each patient for this outcome is 6 months to 6 years
• Hospitalization for atrial fibrillation, atrial flutter or other atrial tachyarrhythmias [ Time Frame: 6 months (minimum) to 6 years (maximum) ]
  Time to hospitalization for atrial fibrillation, atrial flutter or other atrial tachyarrhythmias from randomization. Estimated maximal follow-up for each patient for this outcome is 6 months to 6 years
• Hospitalization for bradycardia, syncope or implantation of pacemaker [ Time Frame: 6 months (minimum) to 6 years (maximum) ]
  Time to hospitalization for bradycardia, syncope or implantation of pacemaker from randomization. Estimated maximal follow-up for each patient for this outcome I 6 months to 6 years
• Hospitalization for chronic obstructive pulmonary disease, asthma or peripheral artery disease [ Time Frame: 6 months (minimum) to 6 years (maximum) ]
  Time to hospitalization for chronic obstructive pulmonary disease, asthma or peripheral artery disease from randomization. Estimated maximal follow-up for each patient for this outcome is 6 months to 6 years
• Hospitalization or outpatient visit for new-onset or dysregulated diabetes [ Time Frame: 6 months (minimum) to 6 years (maximum) ]
  Time to hospitalization hospitalization or outpatient visit for new-onset or dysregulated diabetes from randomization. Estimated maximal follow-up for each patient for this outcome is 6 months to 6 years
• Angina symptoms [ Time Frame: Through self-report questionnaires administered at inclusion, 30 days, 3,6 and 18 months ]
  Canadian Cardiovascular Society (CCS) grading of angina pectoris.
• Health-related quality of life [ Time Frame: Through self-report questionnaires administered at inclusion, 30 days, 3,6 and 18 months ]
  Health-related quality of life measured by the Short Form (SF) 12
• Measures of depression and anxiety [ Time Frame: Through self-report questionnaires administered at inclusion, 30 days, 3,6 and 18 months ]
  HADS (Hospital Anxiety and Depression Scale)
• Measures of sexual dysfunction [ Time Frame: Through self-report questionnaires administered at inclusion, 30 days, 3,6 and 18 months ]
  The International Index of Erectile Function (IIEF) and Female Sexual Function Index (FSFI)
• Measures of sleep disorders [ Time Frame: Through self-report questionnaires administered at inclusion, 30 days, 3,6 and 18 months ]
  Bergen insomnia Scale
• Measures of sleep disorders [ Time Frame: Through self-report questionnaires administered at inclusion, 30 days, 3,6 and 18 months ]
  Bergen insomnia Scale and sleep duration
• Measures of Nightmare Frequency [ Time Frame: Through self-report questionnaires administered at inclusion, 30 days, 3,6 and 18 months ]
  Nightmare Frequency Questionnaire

Original Secondary Outcome Measures (submitted: August 23, 2018)

• Non-fatal MI [ Time Frame: 2 years minimum ]
  Time to non-fatal MI from randomization. Estimated maximal follow-up for each patient for this outcome is 1-3 years
• All-cause death [ Time Frame: 2 years minimum ]
  Time to a-cause Death from randomization. Estimated maximal follow-up for each patient for this outcome is 1-3 years
• Ventricular arrhythmia [ Time Frame: 2 years minimum ]
  Time to ventricular arrhythmia from randomization. Estimated maximal follow-up for each patient for this outcome is 1-3 years
• Hospitalization for heart failure [ Time Frame: 2 years minimum ]
  Time to hospitalization for heart failure from randomization. Estimated maximal follow-up for each patient for this outcome is 1-3 years
• Cardiovascular death [ Time Frame: 2 years minimum ]
  Time to cardiovascular death from randomization. Estimated maximal follow-up for each patient for this outcome is 1-3 years

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

The key secondary objectives are:

• To study whether oral BB therapy reduces the risk of each of the components of the primary end-point separately, compared to no such therapy
• To assess clinical outcomes linked BB therapy in the following subgroups: age (tertiles), gender (men vs. women), BB dosage tertiles (dosage at randomization, STEMI vs. NSTEMI, and LVEF subgroups (preserved LVEF: ≥50% vs. mid-range LVEF: 40-49%).

Other secondary objectives are:

• To study whether oral BB therapy reduces the risk of cardiovascular death compared to no such therapy
• To study whether oral BB therapy reduces the risk of stable and unstable angina compared to no such therapy
• To study whether oral BB therapy reduces the risk of atrial fibrillation, atrial flutter or other atrial tachyarrhythmias compared to no such therapy
• To study whether oral BB therapy increases the risk of hospitalization for bradycardia, syncope, implantation of pacemaker.
• To study whether oral BB therapy increases the risk of hospitalization for chronic obstructive pulmonary disease, asthma or peripheral artery disease.
• To study whether oral BB therapy increases the risk of hospitalization or outpatient visit for new-onset or dysregulated diabetes
• 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 BB dosage and 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
• To assess study safety

Exploratory objectives:

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

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 or resuscitated cardiac arrest, 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 safery 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 March 2022 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) 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.

• Study Type: Interventional
• Study Phase: Phase 4

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

PROBE - prospective, randomized, open blinded end-point

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• Acute Myocardial Infarction
• Non-ST Elevation Myocardial Infarction
• ST Elevation Myocardial Infarction

Intervention

• Other: Non-betablocker
  No betablocker will be administered. Patients randomized to no beta-blockade will be discouraged to use beta-blockade as long as there is no other indication than strictly secondary prevention after myocardial infarction. Any other treatment or management is to be given as per usual care.
• Drug: Betablocker

  A betablocker will be administered. To reflect contemporary management, for which this study is designed to test, there will not be a defined minimum dosage. The type and dose of BB will be left at the discretion of the PI. Generic drug and accepted dosages will be:

  • Metoprolol succinate up to a total dose of 200mg daily
  • Bisoprolol up to a total dose of 10mg daily
  • Carvedilol up to a total dose of 50mg daily

  The treating physician will be encouraged to aim for an equipotent dose of 100 mg metoprolol succinate or higher. Any other treatment or management is to be given as per usual care.

Study Arms

• Active Comparator: Betablocker
  Patients receiving a betablocker. Any other treatment or management is to be given as per usual care.
  Intervention: Drug: Betablocker
• Experimental: Non-Betablocker
  No betablocker is given to this arm. Any other treatment or management is to be given as per usual care.
  Intervention: Other: Non-betablocker

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: February 29, 2024): 2895
• Original Estimated Enrollment (submitted: August 23, 2018): 10000
• Estimated Study Completion Date: December 10, 2034
• Estimated Primary Completion Date: December 10, 2024 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Norway

Administrative Information

• NCT Number: NCT03646357
• Other Study ID Numbers: 2018-000590-75
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Dan Atar, Oslo University Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: Oslo University Hospital
• Original Study Sponsor: Same as current

Collaborators

• Vestre Viken Hospital Trust
• The Hospital of Vestfold
• University of Oslo
• Helse Stavanger HF
• Haukeland University Hospital
• St. Olavs Hospital
• University Hospital of North Norway
• Sorlandet Hospital HF
• Norwegian University of Science and Technology
• Sykehuset Innlandet HF
• Nordlandssykehuset HF
• Lovisenberg Diakonale Hospital
• Diakonhjemmet Hospital
• Ostfold Hospital Trust

Investigators

• Study Chair: Dan Atar, MD Prof; Oslo University Hospital

• PRS Account: Oslo University Hospital
• Verification Date: February 2024