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

September 20, 2021 updated by: Philippe Pibarot, Laval University

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Observational

Enrollment (Anticipated)

320

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

21 years to 90 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

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

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Classical Low-Flow, Low-Gradient AS

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
Observational Study using Imaging and Biomarkers
Other: Computed tomography
Observational Study using Imaging and Biomarkers
Other: Magnetic resonance imaging
Observational Study using Imaging and Biomarkers
Other: Blood biomarkers
Observational Study using Imaging and Biomarkers
Other: Stress echocardiography
Observational Study using Imaging and Biomarkers
Paradoxical Low-Flow, Low-Gradient AS

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
Observational Study using Imaging and Biomarkers
Other: Computed tomography
Observational Study using Imaging and Biomarkers
Other: Magnetic resonance imaging
Observational Study using Imaging and Biomarkers
Other: Blood biomarkers
Observational Study using Imaging and Biomarkers
Other: Stress echocardiography
Observational Study using Imaging and Biomarkers

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure
Time Frame
30-day mortality (for patients treated by SAVR or TAVR)
Time Frame: Patients will be followed for 5 years, with an average of 3.5 years
Patients will be followed for 5 years, with an average of 3.5 years
cardiovascular mortality
Time Frame: Patients will be followed for 5 years, with an average of 3.5 years
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
Time Frame: Patients will be followed for 5 years, with an average of 3.5 years
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
Time Frame: Patients will be followed for 5 years, with an average of 3.5 years
Patients will be followed for 5 years, with an average of 3.5 years

Other Outcome Measures

Outcome Measure
Time Frame
(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
Time Frame: Patients will be followed for 5 years, with an average of 3.5 years
Patients will be followed for 5 years, with an average of 3.5 years
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
Time Frame: Patients will be followed for 5 years, with an average of 3.5 years
Patients will be followed for 5 years, with an average of 3.5 years
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
Time Frame: Patients will be followed for 5 years, with an average of 3.5 years
Patients will be followed for 5 years, with an average of 3.5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Laval University

Collaborators

University Hospital, Brest

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2002

Primary Completion (ANTICIPATED)

January 1, 2024

Study Completion (ANTICIPATED)

January 1, 2024

Study Registration Dates

First Submitted

April 16, 2013

First Submitted That Met QC Criteria

April 16, 2013

First Posted (ESTIMATE)

April 18, 2013

Study Record Updates

Last Update Posted (ACTUAL)

September 21, 2021

Last Update Submitted That Met QC Criteria

September 20, 2021

Last Verified

September 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MOP-57745

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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