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

• ClinicalTrials.gov Identifier: NCT04666454
• Recruitment Status: Recruiting
• First Posted: December 14, 2020
• Last Update Posted: January 3, 2024
• Sponsor: Vastra Gotaland Region
• Collaborator: Göteborg University
• Information provided by (Responsible Party): Vastra Gotaland Region

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Takotsubo Syndrome	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	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 1000 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Intervention Model Description: Multinational, Multicentre, registry-based, open-label, randomized controlled trial with 2 × 2 factorial design
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: BROKEN-SWEDEHEART- Optimized Pharmacological Treatment for Broken Heart (Takotsubo) Syndrome. A Multinational, Multicentre, Registry-based, Open-label, Randomized Controlled Trial.
• Actual Study Start Date: December 14, 2020
• Estimated Primary Completion Date: December 2028
• Estimated Study Completion Date: December 2028

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Randomisation 1: Adenosine and Dipyridamole; 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; Adenosine infusion 70 µg/kg/min for 3 hours.; Drug: Dipyridamole 200 mg; 200 mg b.i.d
Randomisation 1: Control; 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; This treatment will vary depending on local routines and the degree of adherence to the recommendations.
Active Comparator: Randomisation 2: Apixaban; 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; 5mg b.i.d
No Intervention: Randomisation 2: No anticoagulant therapy

Outcome Measures

Primary Outcome Measures :

1. Randomization 1: First co-primary endpoint: Wall motion score index (defined as the semi-quantitative score according to the American Society of Echocardiography) [ Time Frame: 48-96 hours ]
2. 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% [ Time Frame: up until day 30 day respectively at 48-96 hours ]
3. 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 [ Time Frame: up until day 30 respectively 48-96 hours ]

Secondary Outcome Measures :

1. 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% [ Time Frame: all time to the first occurrence up until day 30 respectively at 48-96 hours (binary) ]
2. Randomization 1: Ejection fraction [ Time Frame: at 48-96 hours (continuous) ]
3. Randomization 1: Any sustained ventricular tachycardia or fibrillation [ Time Frame: within 48-96 hours (binary) ]
4. Randomization 1: Any high-grade atrioventricular block or sinus arrest [ Time Frame: within 48-96 hours (binary) ]
5. Randomization 1: Need for cardiac assist device [ Time Frame: up until day 30 day (binary) ]
6. Randomization 1: Death [ Time Frame: up until day 30 (binary) ]
7. Randomization 1: Stroke [ Time Frame: up until day 30 (binary) ]
8. 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) [ Time Frame: up until day 30 ]
9. Randomization 2: Presence of cardiac thrombus [ Time Frame: at 48-96 hours ]
10. Randomization 2: Thrombolysis in Myocardial Infarction (TIMI) bleeding criteria minor or major [ Time Frame: up until day 30 (binary) ]
11. Randomization 2: Bleeding Academic Research Consortium (BARC) grade 2-5 [ Time Frame: up until day 30 (binary) ]
12. Randomization 2: BARC grade 3-5 [ Time Frame: up until day 30 (binary) ]
13. Randomization 2: Any blood transfusion [ Time Frame: up until day 30 (binary) ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Age ≥ 18 years.
2. A clinical diagnosis of TS (see definition 2.1), including an ejection fraction (EF) ˂ 50 % at baseline
3. Written informed consent obtained

Exclusion Criteria:

1. Previous randomization in the trial
2. Any concomitant condition resulting in a life expectancy of less than one month
3. Previously diagnosed left ventricular ejection fraction <50%
4. Known cardiomyopathy (except previous Takotsubo syndrome)
5. Known hemodynamically significant valve disease (moderate or severe aortic/mitral regurgitation) or stenosis
6. Heart transplant or left ventricular assist device recipient
7. Most recent (within the most recent 3 months) haemoglobin ˂10 g/dL
8. Systolic blood pressure <80 mm Hg at screening
9. Estimated glomerular filtration rate <30 mL/min/1.73m2
10. Current dialysis
11. Pregnancy or of childbearing potential who is not sterilized or is not using a medically accepted form of contraception

12. 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 trial protocol

    Specific exclusion criteria for Randomization 1

13. Any contra-indication for treatment with adenosine or dipyridamole (including AV-block II and III, sick-sinus syndrome in subjects who don´t have a functioning pacemaker, unstable angina, ongoing treatment with dipyridamole)
14. Severe asthma (defined as asthma requiring medium or high-dose inhaled corticosteroids combined with other long-acting medications) and severe Chronic Obstructive Pulmonary Disease (COPD), (defined as FEV-1 ˂ 50 %)
15. Ongoing treatment with dipyridamole
16. Declined participation in study 1

Specific exclusion criteria for Randomization 2

1. Any contra-indication for anticoagulant treatment.
2. Current indication for treatment with, anticoagulant or dual antiplatelet therapy
3. Declined participation in study 2

Contacts and Locations

Contacts

Contact: Elmir Omerovic, MD PhD; 31 3421000 ext +46; elmir@wlab.gu.se

Contact: Björn Redfors, MD, PhD; 31 3421000 ext +46

Locations

Denmark

Aarhus Universitetshospital; Recruiting

Aarhus, Denmark

Contact: Steen Hvitfeldt Poulsen, MD

Rigshospitalet; Recruiting

Copenhagen, Denmark

Contact: Lia Evi Bang, MD

Norway

Oslo University Hospital; Recruiting

Oslo, Norway

Contact: Njord Nordstrand, MD

Sweden

Region Dalarna; Recruiting

Falun, Sweden

Contact: Per Lundberg, MD

Sahlgrenska University Hospital, Department of Cardiology; Recruiting

Gothenburg, Sweden

Skaraborg Hospital; Recruiting

Gothenburg, Sweden

Contact: Lisa Brandin, MD

Region Skane Helsingborg Hospital; Recruiting

Helsingborg, Sweden

Contact: Sven-Erik Olsson, MD

Region Oestergoetland; Recruiting

Linköping, Sweden

Contact: Joakim Alfredsson, MD

Region Skane - Skanes Universitetssjukhus; Recruiting

Lund, Sweden

Contact: Nazim Isma, MD

Danderyds Hospital, Department of Cardiology; Recruiting

Stockholm, Sweden

Contact: Christina Ekenbäck, MD

Karolinska University Hospital, Huddinge, Department of Cardiology; Recruiting

Stockholm, Sweden

Contact: Loghman Henareh, MD

Umeå University Hospital, Department of Cardiology; Recruiting

Umeå, Sweden

Contact: Henrik Hagström, MD

Region Uppsala; Not yet recruiting

Uppsala, Sweden

Contact: Kasper Andersson, MD

Region Orebro lan; Recruiting

Örebro, Sweden

Contact: Anna Nordenskjöld, MD

Sponsors and Collaborators

Vastra Gotaland Region

Göteborg University

Investigators

• Principal Investigator: Elmir Omerovic, MD PhD; Sahlgrenska University Hospital, Sweden

More Information

• Responsible Party: Vastra Gotaland Region
• ClinicalTrials.gov Identifier: NCT04666454
• Other Study ID Numbers: BROKEN SWEDEHEART
• First Posted: December 14, 2020
• Last Update Posted: January 3, 2024
• Last Verified: May 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: To be decided.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
• Time Frame: To be decided
• Access Criteria: To be decided (TBD)

• 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

Additional relevant MeSH terms:

Takotsubo Cardiomyopathy; Syndrome; Disease; Pathologic Processes; Cardiomyopathies; Heart Diseases; Cardiovascular Diseases; Ventricular Dysfunction, Left; Ventricular Dysfunction; Adenosine; Dipyridamole; Apixaban; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anticoagulants; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Arrhythmia Agents; Vasodilator Agents; Purinergic P1 Receptor Agonists; Purinergic Agonists; Purinergic Agents; Neurotransmitter Agents; Phosphodiesterase Inhibitors