Optimized pharmacological treatment for broken heart (takotsubo) syndrome

The primary objective of this study is to evaluate the efficacy of treatment with **adenosine** and the adenosine reuptake inhibitor **dipyridamole** in improving clinical outcomes for patients diagnosed with **Takotsubo syndrome**. This is compared to the standard of care as per the current recommendations from the European Society of Cardiology (ESC) taskforce for Takotsubo Syndrome. Additionally, the study aims to assess whether treatment with **apixaban** can reduce the risk of thromboembolic events compared to no treatment with antithrombotic drugs. These objectives are clinically relevant as they aim to enhance therapeutic strategies for Takotsubo syndrome, potentially improving patient outcomes and reducing complications associated with the condition.

The clinical trial focuses on patients diagnosed with **Takotsubo syndrome**, a condition characterized by a temporary weakening of the heart muscle. The study population includes both male and female participants aged 18 years and older. Participants are required to have a clinical diagnosis of Takotsubo Syndrome, with an ejection fraction (EF) of less than 50% at baseline. The trial does not specifically target a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria include obtaining written informed consent from all participants. Lifestyle factors such as diet, physical activity, or habits are not specified as part of the study's considerations. The trial aims to evaluate the efficacy of adenosine and dipyridamole, as well as apixaban, in improving clinical outcomes and reducing thromboembolic events in this patient population.

The clinical trial is designed to evaluate the efficacy of pharmacological treatments in patients diagnosed with **Takotsubo syndrome**. This study is a randomized, double-blind, controlled trial with two primary randomizations. The first randomization assesses the impact of **adenosine** and the adenosine reuptake inhibitor **dipyridamole** on clinical outcomes compared to standard care. The second randomization evaluates whether **apixaban** reduces the risk of thromboembolic events compared to no antithrombotic treatment. The trial is expected to run from March 2021 to March 2028, with participant involvement lasting up to 30 days.

Participants will undergo a series of study visits, beginning with an inclusion visit to confirm eligibility based on criteria such as age (18 years or older) and a clinical diagnosis of Takotsubo syndrome with an ejection fraction below 50%. Written informed consent is required. Follow-up visits will occur at 48-96 hours and up to 30 days post-randomization to monitor primary endpoints, including wall motion score index and the occurrence of thromboembolic events or cardiac complications. The end-of-study visit will assess long-term outcomes, including rehospitalization and mortality rates at 6 months and up to 10 years.

Participants may be withdrawn from the study if they experience adverse events that compromise safety or if they withdraw consent. The trial's primary endpoints include the wall motion score index at 48-96 hours and the occurrence of death, cardiac arrest, or the need for cardiac mechanical assist devices. Secondary endpoints involve time to death, cardiac events, and rehospitalization rates. The study aims to enhance understanding of the efficacy of medical treatments in managing Takotsubo syndrome, contributing to improved clinical guidelines and patient outcomes.

The clinical trial involves the administration of **Dipyridamole**, marketed as Dipyridamol Alternova 200 mg, in the form of **prolonged-release capsules, hard**. The active substance, dipyridamole, is of chemical origin. The medication is administered orally with a maximum daily dose of 400 mg, and the treatment period extends up to 30 days. The purpose of this treatment is to evaluate its efficacy in improving clinical outcomes in patients with Takotsubo Syndrome when used in conjunction with adenosine.

**Apixaban**, marketed as Eliquis 5 mg, is provided in the form of **film-coated tablets**. This chemical-origin medication is also administered orally, with a maximum daily dose of 10 mg over a treatment period of 30 days. The trial aims to assess whether apixaban reduces the risk of thromboembolic events in patients with Takotsubo Syndrome compared to no antithrombotic treatment.

**Adenosine**, marketed as Adenosin Life Medical 5 mg/ml, is available as a **solution for injection/infusion**. The active substance, adenosine, is of chemical origin and is administered via infusion. The maximum dose is 70 µg/kg, with a treatment period limited to a single day. This treatment is evaluated for its potential to improve clinical outcomes in patients with Takotsubo Syndrome when used alongside dipyridamole.

In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. Participant compliance with the dosing schedules is monitored to ensure adherence to the treatment protocols. The trial's objective is to optimize pharmacological treatment for Takotsubo Syndrome by evaluating the efficacy of these medications.

Efficacy in the clinical trial investigating treatments for Takotsubo Syndrome will be assessed using several primary and secondary endpoints. The primary endpoints for Randomization 1 include the **Wall motion score index** measured at 48-96 hours and the occurrence of a composite of death, cardiac arrest, or the need for a cardiac mechanical assist device up until day 30. Additionally, an ejection fraction less than 50% at 48-96 hours or rehospitalization for heart failure up until day 30 will be evaluated. For Randomization 2, the primary endpoint is the occurrence of any thromboembolic event, such as ischemic stroke, peripheral arterial embolization, or myocardial infarction, or death up until day 30, as well as the presence of a cardiac thrombus at 48-96 hours assessed by echocardiography.

Secondary endpoints include a hierarchical assessment of time to death, time to cardiac assist device, and time to cardiac arrest, all measured up until day 30. Other secondary measures include ejection fraction at 48-96 hours, any sustained ventricular tachycardia or fibrillation within 48-96 hours, and any high-grade atrioventricular block or sinus arrest within the same timeframe. Additional endpoints involve the need for a cardiac assist device, death, stroke, and rehospitalization for Takotsubo Syndrome at various time points, including 6 months and 1-10 years. Specific to Randomization 2, endpoints include cardiac thrombus at 48-96 hours, thrombolysis in Myocardial Infarction (TIMI) bleeding criteria, ejection fraction less than 50% at 48-96 hours, Bleeding Academic Research Consortium (BARC) grade 2-5, and any blood transfusion, all assessed up until 30 days.