Danish Trial of Beta Blocker Treatment After Myocardial Infarction Without Reduced Ejection Fraction (DANBLOCK)

Danish Trial of Beta Blocker Treatment After Myocardial Infarction Without Reduced Ejection Fraction (DANBLOCK)

Amager Hospital, Bispebjerg Frederiksberg Hospital, Bornholm Hospital, Gentofte Hospital, Glostrup University Hospital, Copenhagen, Herlev Hospital, Hvidovre University Hospital, Nordsjaelland Hospital, Holbaek Hospital, Nykoebing Hospital, Naestved Hospital, Nordsjaellands Hospital, Zealand University Hospital, Slagelse Hospital, Odense University Hospital, Svendborg Hospital, Sydvestjysk Sygehus, Hospital of Southern Jutland, Sygehus Lillebaelt (Vejle and Kolding), Aarhus Universitetshospital, Hospitalsenheden Midt, Hospitalsenheden Vest, Regionshospitalet Horsens, Silkeborg Sygehus, Aalborg University Hospital

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 non-fatal MI, all-cause mortality, revascularisation with percutaneous coronary intervention or coronary artery bypass graft, stroke, ventricular arrhythmia, cardiac arrest with successful resuscitation or heart failure.

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, revascularisation with percutaneous coronary intervention or coronary artery bypass graft, stroke, ventricular arrhythmia, cardiac arrest with successful resuscitation due to cardiac cause or heart failure. 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 non-fatal MI, revascularisation with PCI or CABG, stroke, ventricular arrhythmia, cardiac arrest with successful resuscitation due to cardiac cause or heart failure. Sample Size: A total of approximately 3570 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. 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 6 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. Assessment of primary study and safety end points: 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 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 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: Intention-to-treat analysis will be carried out. Additionally, a secondary per-protocol analysis will be performed, where compliant BB-users patients are considered exposed during follow-up. Outcome analysis will be assessed by using cumulative incidence and 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. 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.

Acute Myocardial Infarction, Non-ST Elevation Myocardial Infarction (nSTEMI), ST Elevation Myocardial Infarction

Treatment with beta blockers plus standard of care. Type and dosage according to treating cardiologist choice 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

The composite endpoint of all-cause mortality, recurrent non-fatal MI, revascularisation with PCI or CABG, stroke, ventricular arrhythmia, cardiac arrest with successful resuscitation due to cardiac cause or heart failure.

Time to the composite of all-cause mortality, recurrent non-fatal MI, revascularisation with PCI or CABG, stroke, ventricular arrhythmia, cardiac arrest with successful resuscitation due to cardiac cause or heart failure on an intention to treat analysis. The composite outcome will be assessed through nationwide registries.

Data on exercise capacity (VO2peak) will measured before and after rehabilitation and recorded in the Danish Cardiac Rehabilitation database after 24 months and at study end. This data is only available for patients participating in cardiac rehabilitation.

Data on blood pressure (systolic and diastolic ) will measured before and after rehabilitation and recorded in the Danish Cardiac Rehabilitation database after 24 months and at study end. This data is only available for patients participating in cardiac rehabilitation.

Data on diabetes (new diagnosis and dysregulation) will measured through hba1c before and after rehabilitation and recorded in the Danish Cardiac Rehabilitation database after 24 months and at study end. This data is only available for patients participating in cardiac rehabilitation.

EQ5D (a measure of health-related quality of life that can be used in a wide range of health conditions and treatments)

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

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.