Impact of Beta Blockers on TAVI (BETA-TAVI)

Study Overview
=================
Brief Summary
-----------------
This is a prospective, multicentre, investigator-initiated, randomized clinical trial clinical trial investigating the impact of beta-blockers administration among patients undergoing TAVI for severe aortic valve stenosis. Adults already receiving beta-blockers be assigned randomly in 1:1 ratio to either continue or withdraw the beta-blockers medication at least 72 hours before and at least 7 days after TAVI. The primary endpoint is permanent pacemaker implantation rates in 7 days after the procedure. Secondary endpoints include death, cardiogenic shock and arrhythmias/conduction abmormalities with time frame 12 months.

Detailed Description
-----------------
INTRODUCTION AND RATIONALE Aortic Stenosis is the most common valvulopathy in the developed world. Approximately, 5% of people over 65 years old, in the general population, suffer from aortic stenosis, and the percentage increases with ageing. The natural progress of the disease consists of a long-term asymptomatic period with low morbidity and mortality, followed by the symptomatic period. However, the symptoms manifestation (such as syncope, angina, dyspnea and heart failure) is accompanied with a serious increase in morbidity and mortality. The standard diagnostic technique is the transthoracic cardiac ultrasound. Transcatheter aortic valve implantation (TAVI) is an established and valuable treatment option for patients with both severe symptomatic aortic stenosis and increased risk for surgical aortic valve replacement (SAVR). The use of TAVI is rapidly expanding worldwide and the indications are widening into lower risk populations in view of favorable outcomes among high and intermediate risk patients. Treatment with beta blockers is a cornerstone for patients belonging in the wide range of heart failure, especially in those with heart failure with reduced ejection fraction. They are also widely used for the management of various arrhythmias and sudden cardiac death prevention as well as the coronary artery disease. Severe valvulopathy is a major cause of heart failure and arrhythmogenesis but the role of beta blockers in the valvulopathies per se is not clarified. Increased left ventricular intracavital gradient leading to mid-ventricular or outflow tract obstruction with potentially severe hemodynamic compromise has been described in patients with left ventricular hypertrophy undergoing SAVR. The term suicide left ventricle has been adopted for this clinical setting and is possible to be revealed after TAVI as well. Beta blocker administration is a recognized way to alleviate left ventricular outflow tract (LVOT) obstruction in patients with obstructive hypertrophic cardiomyopathy and may also prevent or decrease intracavital gradients after TAVI. However, as a way to avoid conduction abnormalities and permanent pacemaker implantation (PPI) after TAVI, it is common that operators withdraw beta blockers before TAVI. A large observational trial from the OCEAN-TAVI registry comparing with propensity matching patients undergoing TAVI with or without beta blocker exhibited no significant differences in PPI between the two group. Another observational trial investigating arrhythmic risk in TAVI patients regarding beta blocker administration concluded that beta blocker withdrawal was associated with increased arrhythmic burden and more PPIs. The latter paradoxical outcome was attributed by the authors to sick sinus syndrome revelation secondary to increased atrial fibrillation (AF) development in patients that discontinued beta blockers. Clinical data concerning this topic are scarce and safety and efficiency of beta blockers during and post-TAVI are not well-documented. The aim of this clinical trial is to investigate the impact of beta blocker administration among patients undergoing TAVI. DESCRIPTION OF THE PROTOCOL 2.1 Study design. This a prospective, multicentre, investigator-initiated, randomized clinical trial investigating the impact of beta blockers administration among patients undergoing TAVI. 2.2 Study population. Eligible patients are adults that TAVI is indicated as therapy to severe aortic valve stenosis and will be assigned randomly in 1:1 ratio to either continue or withdraw the beta-blockers medication. Furthermore, they should satisfy eligibility criteria (inclusion and exclusion). 2.3 Study centers. Hospitals with operators experienced in TAVI operations will be selected. 2.4 Informed consent. Enrolment can be started when signed informed consent has been obtained. The investigator will explain the nature of the inventory, potential risks and benefits of participation, and answer questions for the patient. All patients must provide informed consent in accordance with the local Institutional Review Board (IRB), using an IRB- approved informed consent form. Any of the patients, who already provided informed consent to this trial, can withdraw their consent from the study anytime. STUDY PROCEDURES 3.1 Pre-procedure (Baseline). Patient preparation will occur in accordance with standard hospital policy for the care of patients undergoing TAVI. A complete blood test panel (Appendix 2) will be obtained and analysed. Electrocardiogram (ECG) and transthoracic cardiac ultrasound (TTE) will be performed as well. Patients assigned in the beta blockers continuation arm will be receiving per os beta blocker medication for at least 72 hours before TAVI without interruption after it. Patients assigned to interrupt the beta blockers treatment will abstain from beta blockers for at least 72 hours before TAVI. 3.2 Medication Patients will receive appropriate antithrombotic and antibiotic medication according to standard hospital and operators' practice. 3.3 TAVI procedure Qualifying subjects will undergo TAVI procedure. The access site and the prosthetic valve type and size will be selected from the operators. The necessity of balloon pre and/or post dilatation will be in the discretion of each operator. Whenever feasible, the temporary pacing cable will be initially inserted in the right atrium in order to measure the effective refractory period of the atrioventricular node as well as the cycle length of antegrade Wenckebach atrioventricular block detection. The type of anaesthesia (local, general, sedation) will be selected by the operators as well. Every step and complication that occurred and materials and techniques that were used will be catalogued. 3.4 Post-procedural care Following the procedure, the patient will be treated in accordance with hospital standard of care. ECG and laboratory blood tests will be obtained post-TAVI and during hospitalization as necessary. A Post-TAVI TTE will be performed as well. Any possible complication or adverse event will be managed based on the nature of the event according to local policy. In the interruption arm, beta-blockers could be reinitiated the sooner 7 days after TAVI. Patients belonging in the continuation arm should continue treatment for at least 7 days after TAVI. In case of adverse event or endpoint that requires immediate initiation or interruption of beta-blockers, the steering committee may terminate a subject's participation in the trial for safety reasons. 3.5 Follow-up Follow-up will examination will be performed in 7 days, 30 days and 12 months. At the visits, any adverse event or endpoint will be catalogued. ECG, TTE and laboratory tests will be part of the visit and in selected patients, further arrhythmic risk stratification will be made. ENDPOINT MEASURES 4.1 Primary endpoint The trial's primary endpoint is PPI rates (time frame: 7 days). The indications of PPI are mentioned in the 2021 European Society of Cardiology Guidelines on cardiac pacing and cardiac resynchronization therapy. 4. SUBJECT SAFETY This trial is intending to clarify the role and impact of beta blockers in TAVI procedures. This single intervention could provide hemodynamic benefit to the patient, whereas from the available clinical data no increased risk of PPI is documented(16, 17). The procedural screening and preparation, the procedure itself and the post-procedural management of the patients will not be affected by this study. The standard TAVI (in patients without implanted permanent pacemaker) is being performed with a temporary pacemaker electrode in the right ventricle to enable rapid ventricular pacing and as a back-up in case of high degree conduction abnormalities and bradycardia. This step ensures the patient's safety in the case of beta blocker contribution to the conduction abnormalities or bradycardia. The thorough monitoring of the patients during TAVI and hospitalisation furtherly increases safety. Beta-blockers will be only received by patients in whom there is an indication according to international guidelines. Heart failure with reduced or mildly reduced ejection fraction, atrial fibrillation, atrial or ventricular arrhythmogenesis, symptomatic stable coronary artery disease, prior myocardial infarction are the most frequently encountered diseases that beta blockers are indicated. 5. STATISTICAL CONSIDERATIONS 5.1 Sample size. The incidence of PPI (primary endpoint) was calculated at 12.4% for patients under beta blockers and 11.3% for patients in a primary observational trial by Saito et al. As 11.3% was the point estimate, the steering committee of the BETA-TAVI trial considered that beta blocker administration for TAVI could be regarded as non-inferior to no beta blocker in the lower margin of the confidence interval does not lie above the rate of 11.3% by more than 8% (i.e., if it is not >19.3%). Based on these assumptions, we expect that a sample size of 312 patients is required to achieve 80% power to demonstrate the safety of beta blockers administration, when type I error rate is set at 0.05. To eliminate possible impact of a small dropout rate, we aimed to recruit a total of 347 patients. 5.2 General statistical analysis All safety and efficacy outcomes will be summarized using descriptive statistics. Continuous variables will be expressed as mean ± standard deviation or median and interquartile range ([IQR]; 25th, 75th percentile) depending on normality of distribution. Categorical values will be presented as frequencies and percentages. Baseline characteristics will by compared using analysis of variance (ANOVA), chi square, or Fisher's exact tests where appropriate. All primary and secondary endpoints will be analyzed according to the intention-to-treat principle, i.e., according to the assigned treatment, without reference to treatment compliance or changes. Additional sensitivity analyses will be performed per-protocol, i.e., resembling the ideal scenario in which all the participants comply to the assigned treatment and protocol rules. No statistical adjustment will be made for the multiple secondary endpoints in their analysis but the reporting of all secondary endpoint analyses will make clear whether the primary endpoint was statistically significant and will state the number of secondary endpoints proposed a priori in the study protocol. 6. ETHICAL AND REGULATORY STANDARDS This study complies with the principles laid down by the 18th World Medical Assembly (Helsinki, 1964) and all applicable amendments laid down by the World Medical Assemblies, and the ICH, GCP guidelines. The local IRB has approved the realization of this trial (General hospital of Athens Hippokration IRB decision No19 of 26th/13Dec2022 meeting with protocol number 22271-27/12/2022). 6.1 Privacy protection. Subjects participating in this study will be given a specific code. There will be no patients' information, which can be utilized to identify patient, stored in the e-CRF. Data that are being stored such as year of birth, date of examination, age /sex of the subject amongst other things, but none of which will identify the specific subject. Although Ethical Committee may examine adverse event form, case report form and so on during or after clinical trial, no identifiable data will be provided even in this case. In case identification of a specific subject is needed, one needs to obtain access to the hospital records which are already protected. This study does not involve the obtaining or inclusion of body material. In case during the study an unexpected finding is obtained concerning the health of the involved subject. The subject involved will be informed at the time of test. If the subject does not wish to be informed then he/she will not be able to participate in this study. Subjects are allowed to withdraw from this study at any time. Information gathered, however, will be used where applicable for the results of the study. 6.2 Conflict of interest. No conflict of interest is present. 6.3 Informed consent. The investigator, or a person designated by the investigator, should fully inform the subject of all pertinent aspects of the clinical study including the written information given approval / favourable opinion by the Ethics Committee or the institution's appropriate scientific board (IRB). Prior to a subject's participation in the clinical study, the Informed Consent Form should be signed and personally dated by the subject and by the person who conducted the informed consent discussion. 7. STUDY MONITORING 7.1 Responsibility of the investigators. The investigators undertake to perform the study in accordance with this protocol and Good Clinical Practice. For the trial duration, the investigator(s) will maintain complete and accurate documentation including - but not limited to - medical records, trial progress records, laboratory reports, case report forms, signed informed consent forms, device accountability records, correspondence with the IRB, adverse event reports, and information regarding patient discontinuation or completion of the trial. 7.2 Case report forms. It is the responsibility of the investigator to maintain an accurate e-CRF to record all observations and other data pertinent to the clinical and laboratory investigations. All e-CRF should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of data. The data may be recorded either on hard copies (case report forms) or electronic data capture. This data will be monitored by and forwarded to the PI in an expedited fashion. 8. ADVERSE EVENTS All events will be registered in the e-CRF. Adverse events will be actively checked during follow-up. Patient folder will provide contact information for patients in case of questions and when complications occur. 9. PUBLIC DISCLOSURE AND PUBLICATION POLICY Regardless of the results of this study maximum effort for publication will be made. 10. RECORD RETENTION The investigator(s) will maintain all records pertaining to this study for fifteen years after the study is discontinued.

Official Title
-----------------
Impact of Beta-blockers Among Patients Undergoing TAVI: a Randomized Multicenter Trial

Conditions
-----------------
Aortic Valve Stenosis

Intervention / Treatment
-----------------
* Drug: Beta blocker


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adults ≥18 years old. Patient with severe symptomatic aortic stenosis defined by mean aortic gradient > 40 mmHg or/and peak jet velocity > 4.0 m/s or/and aortic valve area (AVA) < 1cm2 or/and AVA indexed to body surface area (BSA) of <0.6 cm2/m2 Patient is symptomatic (heart failure with New York Heart Association (NYHA) Functional Class ≥II. Patients are considered at high risk for mortality with conventional surgical aortic valve replacement as assessed by a Heart Team consisting of at least a cardiologist and surgeon. Patients with anatomic characteristics suitable for TAVI. Patients receiving beta-blockers as a part of the indicated treatment plan for the valvulopathy itself or co-morbidities. Patient understands the purpose, the potential risks as well as benefits of the trial and is willing to participate in all parts of the follow-up. Patient has given written consent to participate in the trial. Exclusion Criteria: A known hypersensitivity or contraindication to any of the following which cannot be adequately pre-medicated: aspirin, heparin, bivalirudin, clopidogrel, titanium, nickel, cobaltium, chromium, contrast media. Patients with permanent pacemaker or defibrillator. Ongoing infection, including active endocarditis. Patients with prosthetic aortic valve. Echocardiographic evidence of LV or LA thrombus. The patient that has any contraindication for antithrombotic treatment. Patient that denies blood transfusion. Estimated life expectancy of less than 12 months. Pregnancy. 2nd and 3rd degree atrioventricular (AV) block. Bradycardia (<55 beats per minute). Any other condition witch, in the opinion of the investigator or operator, may pose a significant hazard to the subject if he/she is enrolled in the study. Co-morbidity that excludes follow-up. Enrolment in another study that competes or interferes with this study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Eligible patients will be assigned randomly in 1:1 ratio to either continue or withdraw the already receiving beta-blockers medication
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Beta-blockers continuation<br>Patients assigned in the beta-blockers continuation arm will be receiving per os beta blocker medication for at least 72 hours before TAVI without interruption after it. | Drug: Beta blocker<br>* Investigation on beta-blockers in TAVI and brief post-TAVI period.<br>|
| Active Comparator: Beta-blockers interruption<br>Patients assigned to interrupt the beta-blockers treatment will abstain from beta blockers for at least 7 days after TAVI. | Drug: Beta blocker<br>* Investigation on beta-blockers in TAVI and brief post-TAVI period.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Permanent pacemaker implantation | Permanent pacemaker implantation | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality | All-cause mortality | 12 months | 
| Cardiovascular mortality | Cardiovascular mortality | 12 months | 
| Shock | Shock necessitating use of inotropic or vasoconstrictive medication | 12 months | 
| Atrial fibrillation | New documented atrial fibrillation | 12 months | 
| Ventricular tachycardia/fibrillation | New documented ventricular tachycardia/fibrillation | 12 months | 
| New conduction abnormalities | complete left bundle branch block, complete right bundle branch block, alternating bundle branch block, 1st grade AV block, 2nd degree AV block, 3rd degree AV block | 12 months | 
| New severe bradycardia | <50 beats per minute | 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
TAVR, Pacemaker implantation, Beta blocker, TAVI, Aortic valve stenosis