Adenosin to Rapidly Reverse Left Ventricle Impairment in Takotsubo Syndrome (TITAN)
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|ClinicalTrials.gov Identifier: NCT02867878|
Recruitment Status : Terminated (inability to recruiti a sufficient number of patients)
First Posted : August 16, 2016
Last Update Posted : October 23, 2018
|First Submitted Date ICMJE||August 10, 2016|
|First Posted Date ICMJE||August 16, 2016|
|Last Update Posted Date||October 23, 2018|
|Actual Study Start Date ICMJE||August 2016|
|Actual Primary Completion Date||October 2018 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||left ventricle ejection fraction (%) [ Time Frame: 48 hours ]
an indipendent corelab will review all images from 48-hour ecocardiography to establish LVEF value (%)
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT02867878 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||Adenosin to Rapidly Reverse Left Ventricle Impairment in Takotsubo Syndrome|
|Official Title ICMJE||Rapid Recovery of Left Ventricular Function in Patients With Takotsubo Syndrome Undergoing Systemic Infusion of Adenosine: a Randomized Controlled Trial (TITAN Study)|
|Brief Summary||The investigators will randomize patients admitted to hospital with Takotsubo diagnosis to systematic high-dose adenosine infusion for 3 minutes (in addition to standard of care) vs. standard of care. The primary aim of the study is to demonstrate that adenosine infusion is associated with a larger and more rapid recovery of left ventricle function.|
Takotsubo syndrome is a heart condition that is characterized by the rapid onset of left ventricular dysfunction, usually reversible, and meeting the following diagnostic criteria:
Epidemiology Since the Takotsubo syndrome has been described for the first time in 1991, its incidence, with the passing of years has been increasing, thanks to the possibility with networks for the treatment of acute myocardial infarction, to have a early access to coronary angiography study. Currently this syndrome accounts for 2% of all acute coronary syndromes who are undergoing coronary angiography.
Pathophysiology The pathophysiology of Takotsubo syndrome is complex, and not fully clarified. There are several causes have been suggested over the years to explain the occurrence of this syndrome (vascular and / or myocardial). One of the mechanisms suggested is that there is a systemic response, by the body, to a severe stress which causes a sudden increase of catecholamines endogenous and exogenous; this increase has an effect on the cardiovascular system leading to acute heart failure.
Stress is one of the most common causes behind the onset of this syndrome, and emotional stress (eg. Mourning,quarrel, etc.) and physical (eg. Surgical emergencies, obstetric or psychiatric), but it is not always a present condition.
Recent case reports and clinical studies have shown that patients with this syndrome may experience a reversible damage of the coronary microcirculation, which could be the basis of the important ventricular dysfunction that is observed in these patients. This characteristic may play a significant role in the management of these patients. In fact any targeted therapies to the rapid recovery of the coronary microcirculation function with subsequent improvement in left ventricular function could reduce or prevent the complications related to this case.
Complications During the acute phase of Takotsubo Syndrome the incidence of complications is frequent (18-34% involvement of the right ventricle; obstruction of left ventricular outflow 12-54%; mitral regurgitation 14-25%, 9-20% cardiogenic shock, ventricular thrombus 2-8%, 5-15% atrial fibrillation, ventricular arrhythmias 4-9%, 2-5% bradycardia-asystole) and these complications are often the consequence of left ventricular dysfunction. In fact, the presence of major depression of the ejection fraction (EF) is the main cause of complications in patients with Takotsubo and that the slow pace of recovery of normal EF is closely connected to this risk of complications.
Diagnosis Takotsubo syndrome diagnosis requires, as basic examinations, coronary angiography (allows us to exclude the coronary artery diseases and to highlight the presence of the typical pattern "apical balloon" to the ventriculography) and the echocardiogram ( allow us to highlight the regional alterations of left ventricular kinetics).
Risk Stratification Patients in whom the diagnosis of Takotsubo syndrome is made, they have to be stratified according to their risk profile in patients at high and low risk
Therapy Recently the European Society of Cardiology has prepared a document in which it is suggested therapy to be performed in patients with Takotsubo syndrome according to risk stratification and clinical and echocardiographic data, based on a consensus among the authors in the absence of current randomized clinical studies in support of this strategy.
Mortality The data available report an in-hospital (1-4.5%) and 5 years (3-17%) mortality non-negligible.
Follow-up A recovery of ventricular function is shown at 3-6 months from acute event
Rationale of the study In patients with symptomatic Takotsubo, therapeutic strategies currently used are designed to address, not the pathophysiological mechanism underlying this event, but the complications faced by patients (ie acute heart failure, arrhythmias and hyperkinetic left ventricular thrombosis). No data are currently available about targeted therapies to the treatment of Takotsubo syndrome.
Adenosine is an extracellular signaling molecule that plays a fundamental role in human physiology. Its main effects are: vascular vasodilation, regulation of the activity of the sympathetic nervous system, antithrombotic and regulating blood pressure and heart rate. One of the main uses of adenosine in the cardiovascular field is the production of vasodilation of the coronary microcirculation to produce hyperemia, as for example in the assessment of intermediate coronary stenoses using fractional flow reserve (FFR). It also finds use even in the course of acute myocardial infarction in reducing the phenomenon of slow-flow in the course of primary angioplasty, even if the results of the studies currently available are not unambiguous interpretation.
Galiuto et al. have demonstrated that, regardless of the underlying etiology, in patients with Takotsubo syndrome, it shows the presence of an acute and reversible vasoconstriction of the coronary microcirculation, which may represent a common pathophysiologic mechanism in these patients. In the study the investigators underline also as the use of a systemic infusion of adenosine at a dose of 140 micrograms / kg / min for 90 seconds determines an initial improvement, statistically significant, of the left ventricular function in these patients. The study was observational, and have not been taken into consideration clinical outcomes.
Numerous studies performed in patients with STEMI (ST-segment elevation myocardial infarction) have shown that the adenosine infusion systems, although at high doses, causes only mild adverse effects (es. dyspnea, chest pain, transient ventricular atrium block, hypotension ) and all quick resolution with the suspension of the infusion.
Objective of the study The objective of this study is to demonstrate that in patients with Takotsubo syndrome diagnosis, the use of adenosine infusion at high doses, immediately after the diagnosis of disease, and the absence of documentation of coronary artery disease, it is able to enhance the EF of these patients to 48 hours after diagnosis, compared with standard therapy.
Study Design It is an multicenter, randomized, single-blind study, phase IIa.
Once coronary angiography demonstrated the absence of coronary artery disease and confirmed the diagnosis of Takotsubo syndrome patients will undergo a baseline echocardiography and then randomized, using a randomization system electronic, 1: 1 to receive:
Randomization will be stratified by the following variables:
All patients will be followed up with clinical follow-up up to one year.
PRESPECIFIED SUBSTUDY As has been shown in previous studies, patients with Takotsubo syndrome have reversible coronary microvascular damage.
The purpose of our study is to assess whether the infusion of high-dose adenosine e.v favors the improvement of left ventricular ejection function quickly.
With this sub-study we want to evaluate, also, if there is also in our series a damage of the coronary microcirculation.
Patients participating in the sub-study, randomized in the Adenosine arm, the evaluation of coronary microcirculation will be performed by calculating the IMR (microcirculatory resistance index) during the infusion of adenosine required by randomization.
The IMR is a validated method for measuring the function of the coronary microcirculation. By using a previously positioned guide pressure on the left anterior descendent (LAD) coronary artery, IMR is evaluated by the thermodilution technique analyzing the transit time of a predetermined quantity (3 ml) of saline at room temperature injected into the coronary artery.
3 consecutive injection of 3 mL of saline solution are performed at baseline, and evaluated the average transit time for resting (Tmn). Later, during maximal hyperemia induced by systemic infusion of Adenosine a140μg / kg / min, 3 new injections of saline at room temperature are performed, and the mean transit temple during hyperemia (Tmnhyp) is measured. Tmnhyp multiplying by the average value of distal coronary pressure (Pd) registered during maximal hyperemia, get the IMR value (IMR: Tmnhyp x Pd) which is considered in the normal range if less than 25. A value above 25 indicates the presence of a damage of the coronary microcirculation.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 2|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
|Study Arms ICMJE||
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Terminated|
|Actual Enrollment ICMJE
|Original Estimated Enrollment ICMJE
|Actual Study Completion Date ICMJE||October 2018|
|Actual Primary Completion Date||October 2018 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||18 Years and older (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Italy|
|Removed Location Countries|
|NCT Number ICMJE||NCT02867878|
|Other Study ID Numbers ICMJE||160596|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement ICMJE||
|Responsible Party||Gianluca Campo, University Hospital of Ferrara|
|Study Sponsor ICMJE||University Hospital of Ferrara|
|Collaborators ICMJE||Not Provided|
|PRS Account||University Hospital of Ferrara|
|Verification Date||October 2018|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP