Clinical trial NCT01835028: Multicenter Prospective Study of Low-Flow Low-Gradient Aortic Stenosis (TOPAS Study)
Official title: Multicenter Prospective Study of Low-Flow Low-Gradient Aortic Stenosis (TOPAS Study Phase III)
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Aortic Valve Stenosis
Keywords: Aortic Stenosis
Low Flow
Low Gradient
Left Ventricle
Echocardiography, Doppler
Lead sponsor: Laval University
Sponsor class: OTHER
Collaborators: name: University Hospital, Brest
First posted: 2013-04-18
Enrollment: 320
Sex: ALL
Minimum age (years): 21
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: patients with moderate to severe aortic stenosis and Low Fow Low Gradiwnt , with Low and preserved Ejection Fraction wil be selected at primary care clinic

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: all-cause mortality
timeFrame: Patients will be followed for 5 years, with an average of 3.5 years
Secondary outcomes:
measure: 30-day mortality (for patients treated by SAVR or TAVR)
timeFrame: Patients will be followed for 5 years, with an average of 3.5 years
measure: cardiovascular mortality
timeFrame: Patients will be followed for 5 years, with an average of 3.5 years
measure: 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
timeFrame: Patients will be followed for 5 years, with an average of 3.5 years
measure: composite end-point of cardiovascular mortality and hospitalization for heart failure
timeFrame: Patients will be followed for 5 years, with an average of 3.5 years
Other outcomes:
measure: (1) Stenosis severity: We will use the weight and calcification of the valve explanted at the time of SAVR as a flow-independent marker of stenosis severity
timeFrame: Patients will be followed for 5 years, with an average of 3.5 years
measure: Hemodynamic (LV function) outcome: The outcome variables will be the changes during follow-up in resting and peak stress values of stroke volume, LVEF, longitudinal strain and plasma levels of BNP; LV flow reserve; LV contractile reserve
timeFrame: Patients will be followed for 5 years, with an average of 3.5 years
measure: Functional outcome: Another important objective of treatment is to improve the patient's functional status and quality of life. The outcome variables will be the changes in Duke Activity Score Index and the 6-min walk test distance during follow-up
timeFrame: Patients will be followed for 5 years, with an average of 3.5 years
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Pittsburgh
country: United States
facility: Pittsburgh Medical Center
state: Pennsylvania
city: Vienna
country: Austria
facility: Viena General Hospital
city: Liège
country: Belgium
facility: CHU Start Tilman
city: Ottawa
country: Canada
facility: Ottawa Heart Institute University
state: Ontario
city: Québec
country: Canada
facility: Institut Universitaire de Cardiologie et de Pneumologie de Québec
city: Vancouver
country: Canada
facility: St Paul's Hospital, Vancouver
city: Marseille
country: France
facility: Hôpital La Timone
city: Paris
country: France
facility: Hôpital Bichat
city: Rennes
country: France
facility: CHU, Rennes
city: Munster
country: Germany
facility: University Hospital
Study officials:
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