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

Acute Myocardial Infarction Clinical Trial

— BETAMI  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03646357
• Other study ID #: 2018-000590-75
• Status: Active, not recruiting
• Phase: Phase 4
• Start date: October 1, 2018
• Est. completion date: December 10, 2034

Study information

• Verified date: February 2024
• Source: Oslo University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 2895
• Est. completion date: December 10, 2034
• Est. primary completion date: December 10, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Myocardial Infarction
• Infarction
• Myocardial Infarction
• Non-ST Elevated 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.

Locations

Country	Name	City	State
Norway	Sørlandet Sykehus	Arendal
Norway	Haukeland Universitetssykehus	Bergen
Norway	Nordlandssykehuset HF Bodø	Bodø
Norway	Drammen Hospital	Drammen
Norway	Sykehuset Østfold Kalnes	Fredrikstad
Norway	Sykehuset Innlandet HF, Gjøvik Sykehus	Gjøvik
Norway	Sykehuset Innlandet Hamar	Hamar
Norway	Vestre Viken HF, Ringerike Sykehus	Hønefoss
Norway	Sykehuset Innlandet Lillehammer	Lillehammer
Norway	AHUS	Lørenskog
Norway	LHL Gardermoen	Lørenskog
Norway	Diakonhjemmet Sykehus	Oslo
Norway	Lovisenberg Diakonale Sykehus	Oslo
Norway	Oslo University Hospital Rikshospitalet, Dept.of Cardiology	Oslo
Norway	Oslo University Hospital Ullevaal, Dept. of Cardiology	Oslo
Norway	Vestre Viken HF, Bærum Sykehus	Sandvika
Norway	Stavanger Universitetssjukehus	Stavanger
Norway	Vestfold hospital	Tønsberg
Norway	Universitetssykehuset Nord-Norge, UNN	Tromsø
Norway	St. Olavs University Hospital	Trondheim

Sponsors (15)

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

Country where clinical trial is conducted

Norway, 

Outcome

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