BROKEN-SWEDEHEART-Optimized Pharmacological Treatment for Broken Heart (Takotsubo) Syndrome

Study Overview
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Brief Summary
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The aim of this study is to document an optimized pharmacologic treatment for patients with Takotsubo Syndrome. There is currently no published documentation in a large number of patients. The study is a Randomized Registry Clinical Trial and in total 1000 patients registered in SWEDEHEART will be included.

Official Title
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Optimized Pharmacological Treatment for Broken Heart (Takotsubo) Syndrome

Conditions
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Takotsubo Syndrome

Intervention / Treatment
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* Drug: Adenosine
* Drug: Dipyridamole 200 mg
* Drug: Apixaban 5 mg Oral Tablet
* Other: Care as recommended by the Taskforce on Takotsubo Syndrome of the Heart Failure Association of the European Society of Cardiology for takotsubo syndrome


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years. A clinical diagnosis of Takotsubo syndrome (TS) Written informed consent obtained Exclusion Criteria: Previous randomization in the study Any contra-indication for treatment with adenosine or dipyridamole (including AV-block II and III, sick sinus syndrome in patients who do not have a functioning pacemaker, unstable angina, ongoing treatment with dipyridamole) Any concomitant condition resulting in a life expectancy of less than one month Previous myocardial infarction Previously diagnosed left ventricular ejection fraction <50% Known cardiomyopathy Known hemodynamically significant valve disease (moderate or severe aortic/mitral regurgitation or stenosis) Heart transplant or left ventricular assist device recipient Most recent (within the most recent 3 months) haemoglobin <100 g/L Systolic blood pressure <80 mm Hg at screening Estimated glomerular filtration rate <30 mL/min/1.73m2 Current dialysis Pregnancy or of childbearing potential who is not sterilized or is not using a medically accepted form of contraception Not suitable in the opinion of the investigator due to severe or terminal comorbidity with poor prognosis, or characteristics that may interfere with adherence to the study-protocol Specific subject exclusion criteria (Randomization 2) Any contra-indication for anticoagulant treatment. Current indication for treatment with, anticoagulant or dual antiplatelet therapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: Multicentre, registry-based, open-label, randomized controlled trial with 2 × 2 factorial design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Randomisation 1: Adenosine and Dipyridamole<br>Adenosine infusion 70 µg/kg/min for 3 hours, followed (first dose 60 minutes apart from the end of the adenosine infusion) by daily oral treatment with the adenosine reuptake inhibitor dipyridamole (200 mg b.i.d.) until normalization of Left Ventricular (LV) function (EF≥50%) is documented on the study-specific echocardiographic assessment at 48-96 hours or at any subsequent echocardiographic examination, or for 30+7 Days. | Drug: Adenosine<br>* Adenosine infusion 70 µg/kg/min for 3 hours.<br>Drug: Dipyridamole 200 mg<br>* 200 mg b.i.d<br>|
| Other: Randomisation 1: Control<br>Care as recommended by the Taskforce on Takotsubo Syndrome of the Heart Failure Association of the European Society of Cardiology. | Other: Care as recommended by the Taskforce on Takotsubo Syndrome of the Heart Failure Association of the European Society of Cardiology for takotsubo syndrome<br>* This treatment will vary depending on local routines and the degree of adherence to the recommendations.<br>|
| Active Comparator: Randomisation 2: Apixaban<br>Apixaban 5mg b.i.d. per oral until normalization of LV function (EF≥50%) is documented on the study-specific echocardiographic assessment at 48-96 hours or any subsequent echocardiographic examination, or for 30+7 Days. | Drug: Apixaban 5 mg Oral Tablet<br>* 5mg b.i.d<br>|
| No Intervention: Randomisation 2: No anticoagulant therapy<br> | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Randomization 1: First co-primary endpoint: Wall motion score index (defined as the semi-quantitative score according to the American Society of Echocardiography) |  | 48-96 hours | 
| Randomization 1: Second co-primary endpoint: The occurrence of the composite of death, cardiac arrest, or the need for cardiac mechanical assist device, or re-hospitalization for heart failure or ejection fraction <50% |  | up until day 30 day respectively at 48-96 hours | 
| Randomization 2: The occurrence of any thromboembolic event (defined as ischemic stroke, peripheral arterial embolization or myocardial infarction) or death, or the presence of a cardiac thrombus, as assessed by echocardiography |  | up until day 30 respectively 48-96 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Randomization 1: The hierarchical occurrence (in descending order of importance) of time to death, time to cardiac assist device, time to cardiac arrest and ejection fraction <50% |  | all time to the first occurrence up until day 30 respectively at 48-96 hours (binary) | 
| Randomization 1: Ejection fraction |  | at 48-96 hours (continuous) | 
| Randomization 1: Any sustained ventricular tachycardia or fibrillation |  | within 48-96 hours (binary) | 
| Randomization 1: Any high-grade atrioventricular block or sinus arrest |  | within 48-96 hours (binary) | 
| Randomization 1: Need for cardiac assist device |  | up until day 30 day (binary) | 
| Randomization 1: Death |  | up until day 30 (binary) | 
| Randomization 1: Stroke |  | up until day 30 (binary) | 
| Randomization 1: Worsening heart failure in hospital (defined as worsening signs or symptoms of heart failure, necessitating intensification of intravenous pharmacologic heart failure therapy or mechanical ventilation) |  | up until day 30 | 
| Randomization 2: Presence of cardiac thrombus |  | at 48-96 hours | 
| Randomization 2: Thrombolysis in Myocardial Infarction (TIMI) bleeding criteria minor or major |  | up until day 30 (binary) | 
| Randomization 2: Bleeding Academic Research Consortium (BARC) grade 2-5 |  | up until day 30 (binary) | 
| Randomization 2: BARC grade 3-5 |  | up until day 30 (binary) | 
| Randomization 2: Any blood transfusion |  | up until day 30 (binary) |