Assessment of Paravalvular Leak After TAVI by Hemodynamic Measurements and Cardiac MRI

Study Overview
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Brief Summary
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Rationale: Transcatheter aortic valve implantation (TAVI) has become the standard therapy for elderly patients with high surgical risks. Paravalvular leakage after TAVI is relatively common and there is conflicting evidence regarding the clinical impact of mild paravalvular leakage in self-expanding devices. Prospective data for self-expanding devices are required to compare the extent of paravalvular leakage as a result of device design. Grading paravalvular leakage after TAVI is difficult. Echocardiography and angiography systematically underestimate paravalvular leakage (PVL) as compared to cardiac MRI. Hemodynamic measurements are used to aid decision making directly after TAVI implantation. Prospective data comparing hemodynamic measurements with cardiac MRI are needed to design an optimal strategy to grade paravalvular leakage peri-operatively in order to optimize TAVI outcomes. Objective: To assess procedural hemodynamic measurements in patients with paravalvular regurgitation quantified by means of cardiac MRI (CMR) and to analyse its association with impaired clinical outcome during 5-year follow-up. Study design: This is a prospective, single center clinical trial. Patients will receive a TAVI. After implantation different hemodynamic indices of paravalvular leakage will be assessed. At 1 month a cardiac MRI will be performed to quantify the amount of paravalvular leakage. Standardized clinical follow-up will take place at discharge, 30 days, 3 months and yearly up to 5 years. Study population: Approximately 80 patients with severe symptomatic aortic valve stenosis with an indication for TAVI will be included. Intervention: Patients will undergo cardiac MRI on top of standard clinical care within 30 days after TAVI. Main study parameters/endpoints: The primary endpoint is defined as paravalvular leakage regurgitation fraction as measured by cardiac MRI. The secondary endpoint will comprise a composite of device success, early safety and clinical efficacy as defined by the Valve Academic Research Consortium-2 (VARC-2)(1) and will comprise death, vascular complications, stroke/ Transient Ischemic Attack (TIA), life threatening bleeding requiring transfusion, and acute kidney injury requiring dialysis.

Detailed Description
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INTRODUCTION AND RATIONALE Transcatheter aortic valve implantation (TAVI) has become the standard of care in elderly patients with severe symptomatic aortic valve stenosis and increased surgical risks due to advanced age and multiple comorbidity(2-4). However, in contrast to surgical aortic valve replacement (SAVR), paravalvular leakage after TAVI is fairly common. More than moderate paravalvular leakage is associated with intermediate and long-term morbidity and mortality(5). Since the introduction of TAVI, implantation- and device technology have improved significantly. Nevertheless, mild paravalvular leakage remains a common finding after implantation of new generation devices. Conflicting evidence exists regarding the impact of mild versus none to trivial paravalvular leakage on mortality and morbidity. Several factors might be of influence on these conflicting results. Patients with left ventricular hypertrophy and no previous aortic regurgitation might experience rapidly rising end-diastolic pressures resulting in heart failure even at small regurgitant volumes as seen with mild paravalvular leakage (6-9). Moreover, paravalvular leakage might have greater impact on survival in patients with impaired left ventricular function as compared to patients with preserved left ventricular ejection fraction(10). Furthermore, studies have used different definitions of paravalvular leakage, assessed paravalvular leakage at different time intervals and used different prostheses. Since paravalvular leakage might decrease over time in self- expandable TAVI devices, this potentially influenced outcomes(11). The widely used VARC-2 criteria for paravalvular leakage grading comprise echocardiographic measurements only(1). Especially quantitative assessment of paravalvular leakage in the intermediate strata (mild-moderate) using echocardiography (TTE) remains difficult. TAVI under conscious sedation or local anesthesia more or less preclude the use of peri-operative trans esophageal echocardiography (TEE). TTE analysis and grading of paravalvular leakage is limited by patient factors such as pulmonary disease, patient habitus and prior cardio-thoracic surgery. Moreover, TTE has been shown to underestimate paravalvular leakage as compared to cardiac MRI(12-14). However,the presence of clinical relevant paravalvular leakage necessitates post-dilatation; therefore grading of paravalvular leakage preferably should be done intra-operatively. Hemodynamic parameters have been shown to be of great value in grading paravalvular leakage post implantation(15-18). These objective parameters are easily obtained during TAVI and have been shown to have prognostic relevance. All of these parameters are a function of left ventricular end-diastolic pressure (LVEDP). For instance, diastolic delta (DD), defined as the gradient between diastolic aortic pressure and LVEDP, ≤18 millimetres of mercury (mmHg) was associated with adverse prognosis(15). Heart rate adjusted diastolic delta (HR-DD) (HR-DD= [DD/heartrate] *80) <25 mmHg/beats per minute (BPM) was associated with mortality at 1 year in a retrospective study(16). Combined with angiography and (transesophageal) echocardiography, it was associated with impaired clinical outcome in balloon-expandable bioprostheses (16, 17). Furthermore, the aortic regurgitation index (ARI), defined as the ratio of the diastolic delta to systolic aortic pressure (Aortic regurgitation index = (DD/Aortic pressure systolic)*100) >25 combined with angiographic or echocardiographic assessment of paravalvular leakage had a negative predictive value of 95%-100% for the occurrence of more than mild paravalvular leakage. ARI <25 was associated with 1 year mortality, even after adjustment for paravalvular leakage severity(18-20). However, interpretation of ARI is challenging; bradycardia might lead to an ARI <25 without the presence of relevant paravalvular leakage. Determination of ARI should therefore be performed at a heart rate between 60-80 BPM and preferably over several cycles, especially when measured during atrial fibrillation or extrasystoles. Both echocardiographic and hemodynamic measures provide an estimation of the amount of paravalvular leak. In contrast to echocardiography, MRI provides accurate quantification of paravalvular leakage volume. In this study the investigators want to assess the contributive value of hemodynamic indices of paravalvular leakage based on paravalvular leakage volume measured by means of cardiac MRI and to assess its association with impaired clinical outcomes during 5 year follow-up. OBJECTIVES 2.1 Primary Objective To assess per-procedural hemodynamic indices of paravalvular leakage and to relate these to paravalvular leakage as quantified by cardiac MRI. 2.2 Secondary Objectives To exploratory assess short- and long-term outcomes in patients with different severity of paravalvular leakage STUDY DESIGN The study is designed as a single center, investigator-initiated, clinical trial. In case patients want to participate there is no change of standard clinical care. After TAVI, study participants will receive additional cardiac MRI within 1 month. Subsequent 3-month and 1-year out-patient clinical follow-up will be performed. Telephone follow-up will be performed after 2,3,4 and 5 years. The end of the study is defined as the day when the last patient completes her/his last visit planned in the protocol. STUDY POPULATION 4.1 Population (base) Patients with severe symptomatic aortic valve stenosis allocated to TAVI by a dedicated heart team will be screened for potential participation. The definition of severe symptomatic aortic valve stenosis is defined in the inclusion criteria.

Official Title
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Assessment of Paravalvular Leak After Transcatheter Aortic Valve Implantation by Hemodynamic Measurements and Cardiac MRI

Conditions
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Transcatheter Aortic Valve Replacement, Hemodynamic Monitoring, Aortic Valve Insufficiency, Aortic Valve Stenosis

Intervention / Treatment
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* Procedure: cardiac MRI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be >18 years old. Written informed consent is obtained from all patients. Severe aortic valve stenosis is defined as: jet velocity greater than 4.0m/s or Doppler Velocity index <0.25 or an initial aortic valve area (AVA) of ≤ 1.0cm² (indexed EOA≤06 cm²/m²) as measured by trans thoracic echocardiography <6months prior to inclusion. Patients have symptomatic aortic stenosis, as demonstrated by New York Heart Association (NYHA) functional class 2 or greater or other symptoms of aortic stenosis (e.g. syncope or angina in the absence of coronary artery disease). Surgical risk is deemed high or intermediate by Society of Thoracic Surgery (STS) risk score or by documented Heart-team agreement due to frailty or co-morbidities. The aortic annulus diameter as measured by ECG-triggered CT-scanning < 6months prior to inclusion meets the ranges indicated in the instructions for use. The access artery diameters (femoral or subclavian) as measured by CT-scanning < 6 months prior to inclusion meet the ranges indicated in the instruction for use. There are no contra-indications (e.g.: severe claustrophobia, metal implants, severe renal failure) for and patient is willing to undergo cardiac MRI at discharge to 30 days after TAVI. Exclusion Criteria: Patient is unwilling or unable to comply with study-required follow-up evaluations. There is evidence of a myocardial infarction within 30 days to index procedure. The presence of severe mitral regurgitation or stenosis. The presence of pre-existing prosthetic cardiac device, valve or prosthetic ring in any position. Left ventricular ejection fraction (LVEF) less than 30%. Untreated significant coronary artery disease requiring revascularization. Echocardiographic evidence of intra-cardiac mass, thrombus or vegetation suggesting active endocarditis. The patient is hemodynamically unstable, requiring inotropic or vasopressive and / or mechanical support. The presence of pulmonary edema or intra venous diuretics to stabilize heart failure at index procedure. Renal insufficiency, defined as a serum creatinin greater than 250umol/l or end-stage renal disease requiring dialysis. Morbid obesity, defined as a BMI ≥40. A life expectancy of less than one year.

Ages Eligible for Study
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Minimum Age: 18 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: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients who undergo cardiac MRI<br>Patients undergo cardiac within 30 days after TAVI to assess the amount of paravalvular leakage. | Procedure: cardiac MRI<br>* Patients are studied on a clinical 1.5 Tesla scanner with cardiac radiofrequency receiver coil centered over the heart, and ECG monitoring. The following parameters are assessed: Functional imaging: ECG-gated cine Steady-state free precession (SSFP) MRI images are obtained during repeated breath holds in long axis and short axis orientations covering the entire left ventricle. Global systolic and diastolic function are assessed, and left ventricular mass is calculated. Flow imaging: ECG-gated 2D flow measurements are assessed above the prosthetic valve, and at the level of the pulmonary trunk.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The PVL regurgitation fraction | as measured by cardiac MRI | within 30 days after TAVI | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemodynamic measurement diastolic delta | the gradient between diastolic aortic pressure and LVEDP | During TAVI | 
| Hemodynamic measurement Aortic regurgitation index | ratio of the diastolic delta to systolic aortic pressure | During TAVI | 
| Device succes | VARC-2 definition | Up to 1 year | 
| Vascular complications | VARC-2 definition | Up to 1 year | 
| Bleeding | VARC-2 definition | Up to 1 year | 
| Stroke/ TIA | VARC-2 definition | Up to 1 year | 
| Permanent pacemaker implantation | VARC-2 definition | Up to 1 year | 
| Kidney injury | VARC-2 definition | Up to 1 year | 
| Death | VARC-2 definition | Up to 5 year |