Assessment of Paravalvular Leak After TAVI by Hemodynamic Measurements and Cardiac MRI
Assessment of Paravalvular Leak After TAVI by Hemodynamic Measurements and Cardiac MRI
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.
1. 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.

 2. 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

 3. 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.

 4. 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.
Inclusion Criteria:

 1. Patients must be >18 years old.

 2. Written informed consent is obtained from all patients.

 3. 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.

 4. 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).

 5. 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.

 6. The aortic annulus diameter as measured by ECG-triggered CT-scanning < 6months prior
 to inclusion meets the ranges indicated in the instructions for use.

 7. 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.

 8. 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:

 1. Patient is unwilling or unable to comply with study-required follow-up evaluations.

 2. There is evidence of a myocardial infarction within 30 days to index procedure.

 3. The presence of severe mitral regurgitation or stenosis.

 4. The presence of pre-existing prosthetic cardiac device, valve or prosthetic ring in
 any position.

 5. Left ventricular ejection fraction (LVEF) less than 30%.

 6. Untreated significant coronary artery disease requiring revascularization.

 7. Echocardiographic evidence of intra-cardiac mass, thrombus or vegetation suggesting
 active endocarditis.

 8. The patient is hemodynamically unstable, requiring inotropic or vasopressive and / or
 mechanical support.

 9. The presence of pulmonary edema or intra venous diuretics to stabilize heart failure
 at index procedure.

 10. Renal insufficiency, defined as a serum creatinin greater than 250umol/l or end-stage
 renal disease requiring dialysis.

 11. Morbid obesity, defined as a BMI ≥40.

 12. A life expectancy of less than one year.