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

Tracking Information

• First Submitted Date: December 7, 2020
• First Posted Date: December 14, 2020
• Last Update Posted Date: January 3, 2024
• Actual Study Start Date: December 14, 2020
• Estimated Primary Completion Date: December 2028 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 17, 2022)

• 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 ]
• 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 ]
• 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 ]

Original Primary Outcome Measures (submitted: December 7, 2020)

• Randomisation 1:The occurrence of the composite of death, cardiac arrest (defined as ventricular fibrillation or asystole >30 seconds), or the need for cardiac mechanical assist device [ Time Frame: within 30 days ]
• Randomisation 1:The occurrence of ejection fraction <50% [ Time Frame: at 72 hours ]
• Randomisation 1:The occurrence of re-hospitalization for heart failure [ Time Frame: within 30 days ]
• Randomisation 2: The occurrence of any thromboembolic event (defined as ischemic stroke, peripheral arterial embolization or myocardial infarction) [ Time Frame: within 30 days ]
• Randomisation 2: The occurrence of death [ Time Frame: within 30 days ]
• Randomisation 2: The presence of a cardiac thrombus [ Time Frame: at 72 hours ]
  as assessed by echocardiography

Current Secondary Outcome Measures (submitted: January 17, 2022)

• 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) ]
• Randomization 1: Ejection fraction [ Time Frame: at 48-96 hours (continuous) ]
• Randomization 1: Any sustained ventricular tachycardia or fibrillation [ Time Frame: within 48-96 hours (binary) ]
• Randomization 1: Any high-grade atrioventricular block or sinus arrest [ Time Frame: within 48-96 hours (binary) ]
• Randomization 1: Need for cardiac assist device [ Time Frame: up until day 30 day (binary) ]
• Randomization 1: Death [ Time Frame: up until day 30 (binary) ]
• Randomization 1: Stroke [ Time Frame: 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) [ Time Frame: up until day 30 ]
• Randomization 2: Presence of cardiac thrombus [ Time Frame: at 48-96 hours ]
• Randomization 2: Thrombolysis in Myocardial Infarction (TIMI) bleeding criteria minor or major [ Time Frame: up until day 30 (binary) ]
• Randomization 2: Bleeding Academic Research Consortium (BARC) grade 2-5 [ Time Frame: up until day 30 (binary) ]
• Randomization 2: BARC grade 3-5 [ Time Frame: up until day 30 (binary) ]
• Randomization 2: Any blood transfusion [ Time Frame: up until day 30 (binary) ]

Original Secondary Outcome Measures (submitted: December 7, 2020)

• Randomisation 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 within 30 days respectively 72 hours (binary) ]
• Randomisation 1: Ejection fraction [ Time Frame: at 72 hours (continuous) ]
• Randomisation 1: Any ventricular tachycardia or fibrillation [ Time Frame: within 72 hours (binary) ]
• Randomisation 1: Any high-grade atrioventricular block or sinus arrest [ Time Frame: within 72 hours (binary) ]
• Randomisation 1: Need for cardiac assist device (binary) [ Time Frame: within 30 days ]
• Randomisation 1: Death [ Time Frame: within 30 days ]
• Randomisation 2: Presence of cardiac thrombus [ Time Frame: at 72 hours ]
• Randomisation 2: Thrombolysis in Myocardial Infarction (TIMI) bleeding criteria minor or major [ Time Frame: within 30 days (binary) ]
• Randomisation 2: Bleeding Academic Research Consortium (BARC) grade 2-5 [ Time Frame: within 30 days ]
• Randomisation 2: BARC grade 3-5 [ Time Frame: within 30 days (binary) ]
• Randomisation 2: Any blood transfusion (binary) [ Time Frame: within 30 days ]

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

Descriptive Information

• Brief Title: BROKEN-SWEDEHEART- Optimized Pharmacological Treatment for Broken Heart (Takotsubo) Syndrome.
• Official Title: BROKEN-SWEDEHEART- Optimized Pharmacological Treatment for Broken Heart (Takotsubo) Syndrome. A Multinational, Multicentre, Registry-based, Open-label, Randomized Controlled Trial.
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 4

Study Design

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

• Condition: Takotsubo Syndrome

Intervention

• Drug: Adenosine
  Adenosine infusion 70 µg/kg/min for 3 hours.
• Drug: Dipyridamole 200 mg
  200 mg b.i.d
• Drug: Apixaban 5 mg Oral Tablet
  5mg b.i.d
• 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.

Study Arms

• 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.
  Interventions:

  • Drug: Adenosine
  • Drug: Dipyridamole 200 mg
• Randomisation 1: Control
  Care as recommended by the Taskforce on Takotsubo Syndrome of the Heart Failure Association of the European Society of Cardiology.
  Intervention: Other: Care as recommended by the Taskforce on Takotsubo Syndrome of the Heart Failure Association of the European Society of Cardiology for takotsubo syndrome
• 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.
  Intervention: Drug: Apixaban 5 mg Oral Tablet
• No Intervention: Randomisation 2: No anticoagulant therapy

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 7, 2020): 1000
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2028
• Estimated Primary Completion Date: December 2028 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

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

• Listed Location Countries: Denmark, Norway, Sweden

Administrative Information

• NCT Number: NCT04666454
• Other Study ID Numbers: BROKEN SWEDEHEART
• 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: Yes
• Plan Description: To be decided.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Supporting Materials: Analytic Code
• Time Frame: To be decided
• Access Criteria: To be decided (TBD)

• Current Responsible Party: Vastra Gotaland Region
• Original Responsible Party: Same as current
• Current Study Sponsor: Vastra Gotaland Region
• Original Study Sponsor: Same as current
• Collaborators: Göteborg University

Investigators

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

• PRS Account: Vastra Gotaland Region
• Verification Date: May 2023