Ross for Valve Replacement in AduLts Trial

Study Overview
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Brief Summary
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This study evaluates two methods of aortic heart valve replacement in adults aged 18-60, the Ross procedure versus conventional aortic valve replacement using a biologic or mechanical heart valve. The Ross procedure replaces a patient's diseased aortic valve with his/her own pulmonary valve and uses a donor valve in the pulmonary position which receives less stress than the aortic valve. Mechanical valves tend to form blood clots so they need long-term blood thinners that increase risk of bleeding and lower quality of life. Animal tissue valves reduce clotting and bleeding risks but wear out sooner and shorten patient life-span.

Detailed Description
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Heart valves help control blood flow through the heart and, if diseased, may need to be replaced. After having a heart valve replaced, patients have a higher risk of death than people who have not had a valve replaced. In young adult patients, replacing the aortic heart valve with a mechanical valve halves their life-span compared to other people their age. Mechanical valves tend to form blood clots so they need long-term blood thinners that increase risk of bleeding and lower quality of life. Animal tissue valves reduce clotting and bleeding risks but wear out sooner and shorten patient life-span. An operation, called the Ross procedure, replaces a patient's diseased aortic valve with his/her own pulmonary valve and uses a donor valve in the pulmonary position which receives less stress than the aortic valve. The Ross procedure aims to improve valve durability with less clotting, avoiding use of blood thinners. Patients and physicians need a large, high-quality study comparing the Ross procedure and standard valve replacement to know if either approach is better. The investigators will perform a 3-year feasibility study in seven sites, in Canada and abroad, to test the study design and ability to do a larger, conclusive study comparing the impact of the Ross procedure to standard valve replacement on survival without valve-related life-threatening complications. Patients will be randomized, like flipping a coin, to receive the Ross or standard valve surgery. The goals are 1) to evaluate if the investigators can recruit 6 patients per site per year, 2) to test if the assigned procedure is performed in over 90% of study patients, and 3) to see how many mechanical vs. tissue valves are used in the standard valve group. Patients eligible but not enrolled in the trial will be asked if the investigators can collect some data on how they do after their surgery. If the investigators show the study is feasible, they will proceed to the full study and will include the feasibility patients in the full study.

Official Title
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Ross for Valve Replacement in AduLts Trial

Conditions
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Aortic Valve Disease

Intervention / Treatment
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* Procedure: Ross procedure
* Procedure: Conventional aortic valve replacement


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-60 years Undergoing clinically indicated aortic valve replacement Provided written informed consent Exclusion Criteria: Previous valve replacement not in the aortic position Patients undergoing concomitant CABG or other valve procedure during aortic valve replacement Known connective tissue disease Severe (grade 3 or 4) right or left ventricular dysfunction Pulmonary valve dysfunction or anomaly not compatible with the Ross procedure (as determined by the consulting cardiac surgeon) Life expectancy less than 5 years (as determined by the consulting cardiac surgeon) Documented severe aortic insufficiency not solely due to leaflet issue Previous intervention on the pulmonary valve

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ross procedure<br>The patient will undergo the Ross procedure where the surgeon will replace the aortic valve using a pulmonary autograft (Ross procedure) with pulmonary homograft replacement of the pulmonary root. | Procedure: Ross procedure<br>* The patient will undergo the Ross procedure where the surgeon will replace the aortic valve using a pulmonary autograft (Ross procedure) with pulmonary homograft replacement of the pulmonary root. Identified Ross experts will perform all Ross procedures.<br>|
| Active Comparator: Conventional aortic valve replacement<br>The patient will undergo Conventional aortic valve replacement where the surgeon will replace the aortic valve with another prosthesis which can include a mechanical prosthesis, a stented biological prosthesis, a stentless biological valve or root, or a catheter valve. | Procedure: Conventional aortic valve replacement<br>* The patient will undergo Conventional aortic valve replacement where the surgeon will replace the aortic valve with another prosthesis which can include a mechanical prosthesis, a stented biological prosthesis, a stentless biological valve or root, or a catheter valve.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Full trial primary outcome - The rate of survival free of a composite of life-threatening valve-related complications (major bleeding, stroke or systemic thromboembolism, valve thrombosis, and operated-on valve reintervention) | The primary outcome is the rate of survival free of life-threatening valve-related complications (major bleeding, stroke or systemic thromboembolism, valve thrombosis, and operated-on valve reintervention) over duration of follow-up. Assessment of this composite over time is particularly important, as the Ross procedure may show initial benefit secondary to thromboembolic and bleeding reduction, however should the technique show high late rates of reoperation as suggested in some observational literature, the effect magnitude may change significantly over time. | Through trial completion, estimated to be 10 years | 
| Measure the pilot trial capacity to enrol a mean of 6 patients per centre per year to determine the feasibility of a full trial | The outcome measures of the pilot trial, in order of importance, are: To evaluate the capacity to enroll a mean of 6 patients per centre per year. | Through completion of the pilot trial, estimated to be 3 years | 
| The rate of compliance with allocation in the pilot trial to determine the feasibility of a full trial | To determine the rate of compliance with randomization allocation. | Through completion of the pilot trial, estimated to be 3 years | 
| Measure the proportions of type of conventional valve used in the pilot trial | To validate the proportion of mechanical (at least 65%) versus biological (at most 35%) valves in the conventional arm. | Through completion of the pilot trial, estimated to be 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The rate of perioperative and non-perioperative major bleeding over the duration of patient follow-up | Perioperative (index surgery only) Intraoperative: After administration of protamine, delay of chest closure for bleeding > 500 mL/hr requiring packing and transfusion of more than 3 units red blood cells /whole blood. Upon leaving OR to 48hrs postop (modified BARC type 4) Intracranial bleeding within 48hrs Reoperation after sternum closure for purpose of controlling bleeding or relief of tamponade Transfusion of ≥ 5 units packed red blood cells /whole blood in the 48hr period Chest tube output ≥ 2L in the first 24hr Non-perioperative Per the International Society of Thrombosis and Hemostasis (ISTH) major bleeding definition. | Through trial completion, estimated to be 10 years | 
| The rate of stroke or systemic thromboembolism over the duration of patient follow-up | Stroke is acute focal brain dysfunction due to a vascular cause lasting ≥ 24 hrs in the absence of brain imaging or requires evidence of acute stroke on brain imaging (if there is a stroke documented by CT or MRI or at autopsy, the duration of symptoms/signs may be < 24 hours). Stroke is divided into 3 types: ischemic stroke, hemorrhagic stroke, and undetermined stroke. If death occurs within 24 hours, the neurological deficit must persist up to the time of death. Systemic arterial embolism is an abrupt vascular insufficiency associated with evidence of arterial occlusion in the absence of other likely mechanisms. Clinical signs/symptoms must be consistent with embolic arterial occlusion, there must be clear evidence of abrupt occlusion of a systemic artery, with at least one type of supporting evidence (surgical report indicating evidence of arterial embolism, pathological specimens related to embolism removal, imaging evidence consistent with arterial embolism, or autopsy report). | Through trial completion, estimated to be 10 years | 
| The rate of valve thrombosis per VARC criteria over the duration of patient follow-up | Valve thrombosis is defined as any thrombus not caused by infection attached to or near an operated valve that occludes part of the blood flow path, interferes with valve function, or is large enough to warrant treatment. Valve thrombus found at autopsy in a patient whose cause of death was not valve related or found at operation for and unrelated indication is to be counted as valve thrombosis. | Through trial completion, estimated to be 10 years | 
| The rate of operated-on valve reintervention over the duration of patient follow-up | Rate of valve reintervention Any surgical or percutaneous procedure that repairs, or otherwise alters or adjusts, or replaces a previously implanted prosthesis or valve. | Through trial completion, estimated to be 10 years | 
| Rate of mortality within 30 days post-operatively | Rate of mortality within 30 days post-operatively | 30 days | 
| Measure health related quality of life using the 36-Item Short Form Survey (SF-36) questionnaire over the duration of patient follow-up | The SF-36 is a health related quality of life questionnaire that measure eight health domains and each survey provides psychometrically-based physical component summary (PCS) and mental component summary (MCS) scores. The domains are physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. The questionnaire is calibrated such that scored values of 50 represent the norm and higher scored values according to the scoring key represent a more favourable health state. A baseline score will be obtained prior to the patient's surgery and the SF-36 will be administered annually thereafter over the duration of patient follow-up. | Annually through trial completion, estimated to be 10 years | 
| The rate of operated-valve endocarditis over the duration of patient follow-up | Defined as any infection involving a valve on which an operation has been performed. The diagnosis is based on one or more of the following: 1) reoperation with evidence of abscess, paravalvular leak, pus, or vegetation confirmed as secondary to infection by histologic or bacteriologic studies; 2) autopsy findings of abscess, pus, or vegetation involving an operated-on valve; or 3) the meeting of Duke criteria for endocarditis. | Through trial completion, estimated to be 10 years | 
| The rate of aortic valve re-intervention over the duration of patient follow-up | Any surgical or percutaneous procedure that repairs, or otherwise alters or adjusts, or replaces a previously implanted prosthesis or valve in the aortic position. | Through trial completion, estimated to be 10 years | 
| The rate of pulmonary valve re-intervention over the duration of patient follow-up | Any surgical or percutaneous procedure that repairs, or otherwise alters or adjusts, or replaces a previously implanted prosthesis or valve in the pulmonary position. | Through trial completion, estimated to be 10 years | 
| Mean aortic valve gradient | Measured through echocardiography | Through trial completion, estimated to be 10 years | 
| Mean pulmonic valve gradient | Measured through echocardiography | Through trial completion, estimated to be 10 years | 
| Severity of aortic valve regurgitation | Measured through echocardiography, categorized as mild, moderate, or severe | Through trial completion, estimated to be 10 years | 
| Severity of pulmonic valve regurgitation | Measured through echocardiography, categorized as mild, moderate, or severe | Through trial completion, estimated to be 10 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardiac surgery, Aortic valve replacement, Ross procedure