Multicenter Prospective Study of Low-Flow Low-Gradient Aortic Stenosis (TOPAS Study)

Study Overview
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Brief Summary
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Low-flow, low-gradient (LF-LG) aortic stenosis (AS) may occur with depressed (i.e. Classical LF; CLF) or preserved (i.e. Paradoxical LF; PLF) LV ejection fraction (LVEF) and both situations are amongst the most challenging encountered in patients with valvular heart disease. Although, CLF-LG AS is recognized has an important clinical entity, current ACC/AHA-ESC guidelines however do not provide precise recommendations for clinical management of these patients . PLF-LG AS is a new entity recently described by our group, which is characterized by more pronounced LV concentric remodeling with smaller LV cavity size and a restrictive physiology leading to impaired LV filling, altered myocardial function, and a low-flow state. Up to recently, this entity was often misdiagnosed, leading to underestimation of AS severity and inappropriate delays for aortic valve replacement surgery (SAVR). The two main challenges in patients with CLF- or PLF- LG AS are to distinguish between a true-severe (TS) versus a pseudo-severe (PS) stenosis and to accurately quantify the extent of myocardial impairment. Unfortunately, the traditional resting and stress echocardiographic parameters currently used to assess the severity of valvular and myocardial dysfunction in patients with LF-LG AS are far from being optimal, and as a consequence, quantification of disease severity and therapeutic management may not be appropriate in a substantial proportion of these patients. THE GENERAL OBJECTIVES of the TOPAS study are to develop and validate new parameters and biomarkers to improve the assessment of stenosis severity and myocardial impairment, the risk-stratification, and the clinical decision making in patients with LF-LG AS and to assess the impact of the different therapeutic strategies on patient outcomes.

Detailed Description
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Low-flow, low-gradient (LF-LG) aortic stenosis (AS) may occur with depressed (i.e. Classical LF; CLF) or preserved (i.e. Paradoxical LF; PLF) LV ejection fraction (LVEF) and both situations are amongst the most challenging encountered in patients with valvular heart disease. Although, CLF-LG AS is recognized has an important clinical entity, current ACC/AHA-ESC guidelines however do not provide precise recommendations for clinical management of these patients because there is an important lack of data on this condition. PLF-LG AS is a new entity recently described by our group, which is characterized by more pronounced LV concentric remodeling with smaller LV cavity size and a restrictive physiology leading to impaired LV filling, altered myocardial function, and a low-flow state. Up to recently, this entity was often misdiagnosed, leading to underestimation of AS severity and inappropriate delays for aortic valve replacement surgery (SAVR). The two main challenges in patients with CLF- or PLF- LG AS are to distinguish between a true-severe (TS) versus a pseudo-severe (PS) stenosis and to accurately quantify the extent of myocardial impairment. Unfortunately, the traditional resting and stress echocardiographic parameters currently used to assess the severity of valvular and myocardial dysfunction in patients with LF-LG AS are far from being optimal, and as a consequence, quantification of disease severity and therapeutic management may not be appropriate in a substantial proportion of these patients. Furthermore, it remains uncertain which is the optimal timing and mode of treatment (SAVR vs. Transcatheter Aortic Valve Implantation [TAVI] vs. Medical) for the different subsets of patients with LF-LG AS patients (CLF- vs. PLF- LG AS; TS vs. PS AS; absence vs. presence of myocardial contractile reserve etc.) THE GENERAL OBJECTIVES of the TOPAS study are to develop and validate new parameters and biomarkers to improve the assessment of stenosis severity and myocardial impairment, the risk-stratification, and the clinical decision making in patients with LF-LG AS and to assess the impact of the different therapeutic strategies on patient outcomes. THE SPECIFIC AIMS of the phase III of the TOPAS study are: (1) To obtain and analyze the parameters of stenosis severity and LV functional impairment measured by stress echocardiography (SE), the degree of valvular calcification measured by multidetector computed tomography (CT), the extent of myocardial fibrosis measured by magnetic resonance imaging (MRI), the blood levels of natriuretic peptides and markers of extracellular matrix (ECM) turn-over, and the occurrence of clinical events in a series of 310 patients with CLF-LG AS (210 in TOPAS- I and II + 100 in TOPAS-III) and in a series of 380 patients with PLF-LG AS (80 in TOPAS II + 300 in TOPAS-III). (2) To measure the weight and calcification of the valves explanted from the patients who will undergo SAVR during follow-up in order to corroborate the actual severity of the stenosis. (3) To assess the usefulness of: i) the projected aortic valve area measured by SE to separate TS from PS AS and predict outcomes in PLF-LG AS; ii) the amount of valvular calcium measured by CT to separate TS from PS AS and predict outcomes in CLF- and PLF- LG AS; iii) the myocardial contractile reserve measured by SE, the extent of myocardial fibrosis measured by MRI, and the plasma levels of BNP and ECM biomarkers to predict operative (SAVR) / procedural (TAVI) risk as well as hemodynamic (LV function), functional (DASI and 6-min walk test distance), and clinical (morbidity-mortality) outcomes in CLF- and PLF- LG AS. (4) To compare the different modes of treatment (SAVR, TAVI, Medical), with respect to hemodynamic, functional, and clinical outcomes. RELEVANCE OF THE STUDY: There have been very few prospective studies performed until now in patients with LF-LG AS and these studies have included a relatively small number of patients, have often used only one imaging modality (Doppler-echo) and a limited number of biomarkers, and they have generally not included the patients with PLF-LG AS. Our prospective study is the first of its kind, as it will use a complementary multimodality imaging approach and it will measure prospectively conventional parameters of disease severity as well as new emerging parameters and biomarkers developed by our team in large prospective series of patients with CLF- and PLF- LG AS. This study shall contribute to improve the diagnostic evaluation and clinical conduct in patients with LF-LG AS. This new knowledge will lead to the establishment of clinical guidelines for the management of these high-risk patients.

Official Title
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Multicenter Prospective Study of Low-Flow Low-Gradient Aortic Stenosis (TOPAS Study Phase III)

Conditions
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Aortic Valve Stenosis

Intervention / Treatment
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* Other: Echocardiography
* Other: Computed tomography
* Other: Magnetic resonance imaging
* Other: Blood biomarkers
* Other: Stress echocardiography


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: LVEF≤ 40% Indexed aortic valve area (AVA) ≤ 0.6 cm²/m² Mean transvalvular gradient < 40 mmHg Exclusion criteria: Pregnant or lactating women advanced renal failure tumor with metastasis

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 90 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Classical Low-Flow, Low-Gradient AS<br>Observational study in patients with Classical Low-Flow, Low-Gradient Aortic Stenosis and Low LV Ejection Fraction undergoing surgical aortic valve replacement, transcatheter aortic valve replacement, or conservative management: I- Baseline visit: Medical history, physical / functional evaluation, blood biomarkers, resting echocardiography, stress echocardiography, aortic valve calcium scoring by computed tomography, myocardial fibrosis by magnetic resonance imaging II- Follow-up: clinical outcomes, physical / functional evaluation, echocardiography, blood biomarkers | Other: Echocardiography<br>* Observational Study using Imaging and Biomarkers<br>Other: Computed tomography<br>* Observational Study using Imaging and Biomarkers<br>Other: Magnetic resonance imaging<br>* Observational Study using Imaging and Biomarkers<br>Other: Blood biomarkers<br>* Observational Study using Imaging and Biomarkers<br>Other: Stress echocardiography<br>* Observational Study using Imaging and Biomarkers<br>|
| Paradoxical Low-Flow, Low-Gradient AS<br>Observational study in patients with Paradoxical Low-Flow, Low-Gradient Aortic Stenosis and Preserved LV Ejection Fraction undergoing surgical aortic valve replacement, transcatheter aortic valve replacement, or conservative management: I- Baseline visit: Medical history, physical / functional evaluation, blood biomarkers, resting echocardiography, stress echocardiography, aortic valve calcium scoring by computed tomography, myocardial fibrosis by magnetic resonance imaging II- Follow-up: clinical outcomes, physical / functional evaluation, echocardiography, blood biomarkers | Other: Echocardiography<br>* Observational Study using Imaging and Biomarkers<br>Other: Computed tomography<br>* Observational Study using Imaging and Biomarkers<br>Other: Magnetic resonance imaging<br>* Observational Study using Imaging and Biomarkers<br>Other: Blood biomarkers<br>* Observational Study using Imaging and Biomarkers<br>Other: Stress echocardiography<br>* Observational Study using Imaging and Biomarkers<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| all-cause mortality |  | Patients will be followed for 5 years, with an average of 3.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 30-day mortality (for patients treated by SAVR or TAVR) |  | Patients will be followed for 5 years, with an average of 3.5 years | 
| cardiovascular mortality |  | Patients will be followed for 5 years, with an average of 3.5 years | 
| new major cardiovascular events as defined by VARC: myocardial infarction, stroke, vascular complications, and re-hospitalization for heart failure composite end-point of cardiovascular mortality and hospitalization for heart failure |  | Patients will be followed for 5 years, with an average of 3.5 years | 
| composite end-point of cardiovascular mortality and hospitalization for heart failure |  | Patients will be followed for 5 years, with an average of 3.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aortic Stenosis, Low Flow, Low Gradient, Left Ventricle, Echocardiography, Doppler