Treatment of Severe Aortic Stenosis with Transfemoral TAVI with or Without Coronary Angiogram During Diagnostic Work-up (PURE TAVI)

The study will be conducted in patients with Severe aortic stenosis referred to transcatheter aortic valve implantation (TAVI). The recommended treatment for severe aortic stenosis is a procedure called transcatheter aortic valve implantation (TAVI). Currently, before TAVI, doctors usually perform a coronary angiography to check if the blood vessels supplying the heart (the coronary arteries) are clear and free of blockages and to determine the right size of valve. If blockages are found, they are treated before or during TAVI. However, many patients who need TAVI are older and may have cardiovascular comorbidities, which means that they have other conditions that coexist with their cardiovascular disease, such as high blood pressure, diabetes, or obesity. This increases the risk of complications due to coronary angiography. These risks include kidney problems from the contrast dye used in the test, bleeding, or complications at the access site where the procedure is done.

This study aims to evaluate whether a TAVI pathway procedure without prior coronary angiography is non-inferior to a standard TAVI pathway procedure in which routine coronary angiography with or without revascularization is included, in patients with significant aortic stenosis who do not experience typical chest pain or discomfort that occurs when a part of your heart doesn't get enough blood and oxygen, classified as CCS 3 or higher. "Non-inferior" means that the aim of the study is to demonstrate that the TAVI pathway procedure without prior coronary angiography is at least as effective as the standard TAVI pathway procedure with routine coronary angiography with or without revascularization. In both groups, the CE-certified Myval™ transcatheter heart valve series will be used. The Myval™ transcatheter heart valve series device is commercially available. This valve is designed to expand with a balloon and allows for a precise fit and good performance.

This clinical study will be conducted at multiple sites; a total of approximately 620 patients are expected to participate. The study is an Investigator initiated study organized by Rede Optimus (RO), Alte Steinhauserstrasse 1, 6330 Cham, Switzerland. RO functions as the sponsor of this study and aims to answer unanswered questions in vascular medicine with investigator-led studies. The study is financed by the medical device manufacturer Meril Life Sciences Pvt Ltd, Bilakhia House, Survey No. 135/139, Muktanand Marg, Chala, Vapi - 396 191, Gujarat, India.

A total number of 620 patients will be enrolled across 20 centres in 6 countries in Europe. A duration of 42 months is anticipated with an inclusion period of 18 months and a follow up period of 24 months.

This study aims to evaluate whether a TAVI pathway without prior coronary angiography is non-inferior to a conventional TAVI pathway, in which routine coronary angiography with or without revascularization is included, in patients with significant aortic stenosis who do not experience typical angina pectoris classified as CCS 3 or higher.

Hypothesis: For patients with significant aortic stenosis who do not experience typical angina pectoris classified as CCS 3 or higher, omitting a coronary angiography prior to or during transfemoral TAVI is non-inferior to a traditional diagnostic work-up, including coronary angiography and, if deemed necessary based on angiography results, revascularization, for the composite endpoint of all-cause death, spontaneous or periprocedural myocardial infarction, urgent revascularization during unplanned hospitalization, readmission for heart failure, acute renal injury, major, life-threatening or disabling bleeding, major vascular complication, or any stroke at 12 months follow-up.

Primary endpoints

Primary Safety Endpoint:

* Composite of all-cause death, spontaneous or periprocedural myocardial infarction, urgent revascularization during unplanned hospitalization, readmission for heart failure, acute renal injury, major or life-threatening or disabling bleeding, major vascular complication, or any stroke at 12-months follow-up
* Spontaneous myocardial infarction, defined as occurring before or \>72 h after the invasive cardiac procedure. It is defined in accordance with current guideline recommendations:
* Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least 1 value above the 99th percentile URL, together with the evidence of myocardial ischemia with at least 1 of the following: (i) Symptoms of ischemia, (ii) ECG changes indicative of new ischemia (new ST-T changes or new left bundle branch block), (iii) new pathological Q-waves in at least 2 contiguous leads, (iv) imaging evidence of a new loss of viable myocardium or new wall motion abnormality, (v) Identification of an intracoronary thrombus by angiography or autopsy
* Sudden, unexpected cardiac death or aborted cardiac death, involving cardiac arrest, often with symptoms suggestive of myocardial ischaemia, but death occurring before blood samples could be obtained, or at a time before the appearance of cardiac biomarkers in the blood and accompanied by at least 1 of the following: i) Presumably new ST elevation, ii) New LBBB, iii) Evidence of fresh thrombus by coronary angiography and/or at autopsy
* Pathological findings of a MI20
* Periprocedural myocardial infarction during TAVI procedure, defined in accordance with VARC-3 definitions. CK-MB is the preferred biomarker in accordance with VARC-3, with an increase of ≥10 times the 99th percentile URL or ≥5 times the 99th percentile URL along with ancillary criteria (i.e.new acute electrocardiographic signs, evidence of loss of viable myocardium or regional wall motion abnormalities at echocardiogram, angiographic evidence suggestive of ischaemia) to define PMI after TAVI. In cases where CK-MB measurements are not available, cTn cut-off thresholds are considered suggestive of TAVI-related PMI when there is an increase is ≥70 times the 99th percentile URL or ≥35 times the 99th percentile URL, along with ancillary criteria.21
* Urgent revascularization during unplanned hospitalization, defined as revascularization during admission for acute coronary syndrome, which covers patients with STEMI, NSTEMI and unstable angina.22
* Heart failure event, defined as any unplanned hospitalization or unplanned physician contact due to new or worsening heart failure on the basis of symptoms and signs of heart failure with confirmation by diagnostic tests and necessitating treatment using intravenous or mechanical heart failure therapies.21
* Acute renal injury, defined as increase in serum creatinine to 150%\< (1.5x or more increase compared with baseline) OR increase of ≥0.3mg/dl (≥26.4 mmol/l) OR Urine output \<0.5 ml/kg/h for \>6 hrs OR necessity of hemodialysis21
* Major or life-threatening or disabling bleeding, defined in accordance with Bleeding Academic Research Consortium (BARC) criteria, classified as

  1. Life-threatening or disabling bleeding:

     1. Fatal bleeding (BARC type 5) OR
     2. Bleeding in a critical organ, such as intracranial, intraspinal, intraocular, or pericardial necessitating pericardiocentesis, or intramuscular with compartment syndrome (BARC type 3b and 3c) OR
     3. Bleeding causing hypovolaemic shock or severe hypotension requiring vasopressors or surgery (BARC type 3b) OR
     4. Overt source of bleeding with drop in haemoglobin \>5 g/dL or whole blood or packed red blood cells (RBCs) transfusion \>4 units (BARC type 3b)
  2. Major bleeding (BARC type 3a):

     1. Overt bleeding either associated with a drop in the hemoglobin level of at least 3.0 g/dl or requiring transfusion of two or three units of whole blood/RBC, or requiring surgery AND
     2. Does not meet criteria of life-threatening or disabling bleeding
* Major vascular complication, defined as one of the following:21
* Aortic dissection or aortic rupture
* Vascular (arterial or venous) injury (perforation, rupture, dissection, stenosis, ischaemia, arterial or venous thrombosis including pulmonary embolism, arteriovenous fistula, pseudoaneurysm, haematoma, retroperitoneal haematoma, infection) or compartment syndrome resulting in death, VARC type 2 or higher grade bleeding, limb or visceral ischaemia, or irreversible neurologic impairment
* Distal embolization (non-cerebral) from a vascular source resulting in death, amputation, limb or visceral ischaemia, or irreversible end-organ damage n Unplanned endovascular or surgical intervention resulting in death, VARC type 2 or higher grade bleeding, limb or visceral ischaemia, or irreversible neurologic impairment
* Closure device failure resulting in death, VARC type 2 or higher grade bleeding, limb or visceral ischaemia, or irreversible neurologic impairment.
* Ischaemic stroke

Acute onset of focal neurological signs or symptoms conforming to a focal or multifocal vascular territory within the brain, spinal cord, or retina (NeuroARC Type 1a or 1aH) and fulfilling one of the following criteria:

* Signs or symptoms lasting ≥24 h or until death, with pathology or neuroimaging evidence of CNS infarction, or absence of other apparent causes
* Symptoms lasting \<24 h, with pathology or neuroimaging confirmation of CNS infarction in the corresponding vascular territory‡

  * Haemorrhagic stroke Acute onset of neurological signs or symptoms due to intracranial bleeding from intracerebral or subarachnoid haemorrhage not due to trauma (NeuroARC Types 1b or 1c)
  * Stroke, not otherwise specified Acute onset of neurological signs or symptoms persisting ≥24 h or until death but without sufficient neuroimaging or pathology evidence to be classified (NeuroARC Type 1d)

Secondary and explorative Endpoint

* Composite of all-cause death, spontaneous or periprocedural myocardial infarction, urgent revascularization during unplanned hospitalization, readmission for heart failure, acute renal injury, major or life-threatening or disabling bleeding, major vascular complication, or stroke at 24-months follow-up
* Individual components of the primary endpoint at 6-months follow-up
* Change in angina class by CCS angina between baseline and 6 months follow-up.
* Change in New York Heart Association functional class (I, II, III, or IV) between baseline and 6 months follow-up.
* EQ-5D-5L change between baseline and 6 months follow-up.
* Kansas City Cardiomyopathy Questionnaire (KCCQ) change between baseline and 6 months follow-up.
* Any revascularization at 12-months follow-up
* Individual components of the primary endpoint at 12-months follow-up.
* Change in angina class by CCS angina between baseline and 12 months follow-up.
* Change in New York Heart Association functional class (I, II, III, or IV) between baseline and 12 months follow-up.
* EQ-5D-5L change between baseline and 12 months follow-up.
* KCCQ change between baseline and 12 months follow-up
* Individual components of the primary endpoint at 24-months follow-up.
* Any revascularization at 24-months follow-up
* Change in angina class by CCS angina between baseline and 24 months follow-up.
* Change in New York Heart Association functional class (I, II, III, or IV) between baseline and 24 months follow-up.
* EQ-5D-5L change between baseline and 24 months follow-up.
* KCCQ change between baseline and 24 months follow-up.

Inclusion Criteria

* Patient is older than 18 years with severe AS considered for TAVI by a multidisciplinary heart team.
* Patient is candidate for transfemoral TAVI as per local standards and current guidelines.

Patient is willing and capable to give written consent to participate to the trial and confirmed to be able to attend the expected follow up visits.

Exclusion Criteria -Patient had a coronary angiogram with or without PCI and/or coronary CT and/or CABG within last 5 years.

* Left main PCI in the medical history
* Patient has CCS of 3 or more.
* Patient has left ventricular ejection fraction \<30%.
* Patients in whom TAVI through femoral access is ad priori not possible based on clinical assessment or medical history
* Patient has been treated for acute myocardial infarction within 30 days before randomization.
* Patient has a planned open-heart surgery.
* Patient has a life expectancy less than 1 year due to other severe non-cardiac disease.
* Patient is participating in another clinical study with an investigational product that has not yet completed the follow up period.
* Patient has received previous treatment for aortic valve implantation or replacement.
* Female patient who is pregnant at the time of inclusion.

QUALITY ASSURANCE AND DATA MANAGEMENT Data collection will be conducted via an electronic case report form (eCRF). The investigator or an authorized member of the research team will electronically sign all completed eCRFs using an electronic signature, with a password provided by the data management center at the study's onset. All patient data will be pseudonymized to ensure confidentiality, meaning only the enrolling center will have access to personal information. Each subject will be identified by a code that contains no elements leading to direct patient identification. In the event of a data security breach, the data protection officer will be immediately informed, and relevant authorities will be notified based on the breach's severity. Additionally, the breach will be documented internally, and preventive measures will be implemented. Clinical data management will follow established data cleaning procedures, applying to both eCRF data and data from other sources (e.g., ICA, ECGs). Appropriate computer programs will be run to verify the database's accuracy, and the investigator will be queried regarding any incomplete, inconsistent, or missing data. GDPR regulations will be followed.

Enrolment Procedure Prior to enrolment into the clinical investigation, all patients will be evaluated by their physician for achieving the general inclusion criteria. This includes review of the CT imaging to confirm eligibility for the TAVI procedure. Informed consent for the collection of personal medical data must be obtained from the patient prior to enrolment. A patient is considered enrolled in the study if there is full compliance with the in- and exclusion criteria and has provided written consent.

Concomitant Medications The concomitant medication during hospital stay and follow-ups are at the discretion of the investigator and will be applied according to the standard-of-care.

Pre-procedure At each participating treatment center, all patients showing up during the recruitment phase who meet the general inclusion criteria will be documented with the aid of a screening form. Inclusion/exclusion criteria will be in this form resulting in a decision about study participation.

A signed written informed consent must be obtained for all patients who are potential trial candidates prior to provisional enrollment. Additionally, the following evaluations must be completed for all enrolled subjects prior to the procedure. If one of the following evaluations are considered standard of care (SOC), it is allowed to have them performed before the enrolment:

* Medical history
* Demographics
* Medication registration
* Health questionnaires

  o EQ-5D-5L

  o KCCQ

  o NIHSS

  o mRS
* Laboratory tests (troponins or CK, CK-MB)
* ECG and echocardiography
* Randomization Only patients will be included and randomized, who are clinically deemed eligible for TAVI through transfemoral access based on clinical considerations.

Randomization : The randomization process will be integrated into the eCRF system. Once the investigator confirms eligibility criteria and informed consent, randomization is triggered, assigning participants to either the experimental group (omission of coronary angiography prior to or during TAVI, unless suspicion of potentially revascularization-indicating stenosis of the left main stem based on the TAVI-CT); or the control group (coronary angiography with or without PCI prior to TAVI). The randomization will be performed using blocked randomization with randomly varied block sizes, and stratified by age (≤80 vs. \>80 years), diabetes status, and region.

Procedure and diagnostic method A visits schedule describing the data collected from screening until completion of the 24-month follow-up visit unless subject withdraws consent. In the clinical investigation, the investigational procedure for treatment of severe aortic stenosis will consists of transfemoral TAVI with or without coronary angiography prior to procedure. PCI is recommended, according to current guidelines, for significant lesions located in the proximal-to-middle segments of major coronary arteries. Details of PCI should follow local practices also in terms of access site, staged or ad hoc procedures, timing, hospitalization, lesion assessment, lesion preparation, antiplatelet therapies, etc. Transfemoral TAVI will be done in both groups in accordance with local practice. Details of the procedure should follow local practice in terms of secondary access site, puncture guidance, pacing, hospitalization, etc.

Discharge visit Post procedure, subjects will be monitored in-hospital as per standard of care until discharge. Prior to discharge, the medication currently in use will be documented. Any adverse events and device deficiencies occurring from the procedure through hospital discharge will be recorded.

Follow up visits In-hospital follow-up visits will occur at 6 months (183±30 days), 12 months (365±30 days), and 24 months (730±30 days), with all timeframes referenced from the procedure date.

At each follow up visit, patients will complete four health questionnaires: the EuroQol 5 Dimension 5 Level (EQ-5D-5L), the Kansas City Cardiomyopathy Questionnaire (KCCQ), the NIH Stroke Scale (NIHSS), and the modified Rankin Scale (mRS). The medication in use at the time of the follow up visit will be documented. Finally, any adverse events and device deficiencies occurring during the post-procedure follow up will be reported. An ECG and echocardiography can be performed at the operators discretion.

Unscheduled follow-up visits The study will document all subject visits until study exit. Unscheduled visits may occur at any point during the investigation, either as required per site practices, or for instance, to assess possible adverse events and/or changes in medication. These unscheduled visits should be recorded in the EDC and the following assessments/procedures should be documented: physical examination, medication change, adverse event, device deficiency, and protocol deviation.

SAFETY RECORDING AND REPORTING All serious adverse events (SAEs) whether or not related to the index procedure or use of study device, as well as AEs that occur during the course of the study that are related to the index procedure or use of the investigation device, shall be fully recorded and reported from investigator to the Sponsor representative. All reported events should be recorded from the time the patient is enrolled in the study.

STUDY ORGANIZATION

1. Executive committee The role of the executive committee consists of the members who have originated the idea of the study and took leading roles in the design of the protocol. The members of the executive committee are the first advisors to sponsor with regards to study set-up and questions related to medicine.
2. Steering committee

   The steering committee of this trial will be composed of the executive committee, the trial methodologist/statistician, as well as the leading Principal Investigator of every participating country. The steering committee will provide oversight of the conduct of the study and meet regularly. The specific responsibilities of the steering committee are:
   * Periodic review of progress of the study
   * To take steps to reduce deviations from the protocol
   * To review data at regular intervals throughout the study
   * Review feedback from CEC and DMC

     3. Clinical Event Committee An independent Clinical Event Committee (CEC) will be established prior to the start of enrolment of patients in the trial. The CEC will be composed of at least three members, with persistent expertise who are nor participants or directly involved in the conduct of the study. All events will be adjudicated by an independent clinical events committee (CEC). The data about the adverse events that belong to the primary endpoint (MACE) will be given to the CEC timely after occurrence. All reviews will be blinded. Each CEC member reviews the case in a first step on his/her own for a subsequent possible discussion (written, phone, or/and in-person) to seek consensus. Special eCRFs for MACE and (S)AEs were developed to collect detailed information. A first decision, if the event can be adjudicated to CT/ICA is made by the principal investigators at the clinical site. The role of the CEC is thus to confirm or reject the decisions of the principal investigators objectively.

   As a basis for decisions the CEC members will receive a report that includes the following:

   -Summary of all (S)AEs that could be a MACE
   * Details from the MACE eCRF
   * Details to enable adjudication and list for decisions if (S)AE, MACE can be adjudicated to ICA/CT as already pre-decided by the principal investigator.

   To define the exact responsibilities of CEC a charter between sponsor and CEC members will be created and signed by all involved parties.

4. Independent Data monitoring committee (DMC/DSMB) A Data monitoring committee (DMC) will be established prior to the start of subject enrolment. The DMC is composed of at least three members with pertinent expertise who are not participants or directly involved in the conduct of the trial.

The responsibility of the DMC is to evaluate safety data during the course of the trial and to advise the Sponsor about the continuing safety of the trial to ensure the wellbeing of the current participants and those yet to be enrolled as well as the continuing validity and scientific merit of the trial. To do so, the DMC will meet regularly to review accumulated study data, the critical endpoints of the trial. After every meeting DMC might formulate an advice to sponsor and executive committee about the continuation of the trial. To define the exact responsibilities of DMC a charter between sponsor and DMC members will be created and signed by all involved parties.

Eligibility Criteria:
Inclusion Criteria:

* Patient is older than 18 years with severe AS considered for TAVI by a multidisciplinary heart team.
* Patient is candidate for transfemoral TAVI as per local standards and current guidelines.
* Patient is willing and capable to give written consent to participate to the trial and confirmed to be able to attend the expected follow up visits.

Exclusion Criteria:

* Patient had a coronary angiogram with or without PCI and/or coronary CT and/or CABG within last 5 years.
* Left main PCI in the medical history
* Patient has CCS of 3 or more.
* Patient has left ventricular ejection fraction \<30%.
* Patients in whom TAVI through femoral access is ad priori not possible based on clinical assessment or medical history
* Patient has been treated for acute myocardial infarction within 30 days before randomization.
* Patient has a planned open-heart surgery.
* Patient has a life expectancy less than 1 year due to other severe non-cardiac disease.
* Patient is participating in another clinical study with an investigational product that has not yet completed the follow up period.
* Patient has received previous treatment for aortic valve implantation or replacement.
* Female patient who is pregnant at the time of inclusion.