Clinical trial NCT04557345: Evaluation of the Inflammatory Response in Post-operated Aortic Valve Replacement Patients.
Official title: Evaluation of the Inflammatory Response and Long-term Calcification in Post-operated Aortic Valve Replacement Patients.
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Aortic Valve Disease
Aortic Valve Stenosis
Aortic Valve Calcification
Prosthetic Valve Malfunction
Lead sponsor: Instituto Nacional de Cardiologia Ignacio Chavez
Sponsor class: OTHER
First posted: 2020-09-21
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: OTHER
Sampling method: PROBABILITY_SAMPLE
Study population: Patients who have had a biological prosthetic valve implanted in aortic position manufactured at the National Institute of Cardiology "Ignacio Chávez" with an anti-calcifying system, imported biological prosthetic aortic valve or mechanical aortic valve from January 1990 to May 2020.

Brief summary: Background

Calcification of the aortic valve affects more than 26% of adult patients over 65 years of age and is the main indication for valve replacement in the United States of America. Previous evidence shows that aortic valve calcification is an active biological process associated with inflammation. The only actual treatment for severe aortic stenosis is surgical aortic valve replacement (AVR). The materials with which the different types of prostheses are manufactured could induce inflammation per se. Biological prostheses, an incomplete cell removal process and therefore, the presence of residual proteins of animal origin, could induce the immune system's response. In the manufacturing bioprosthesis at the "Ignacio Chávez" National Institute of Cardiology (INC), an evaluation was carried out in the early, and late post-surgical period, it was shown that the inflammatory response after six months is similar to that produced by mechanical prosthesis.

This study's main objective is to evaluate the inflammatory response in patients with post-operated AVR due to biological or mechanical prosthetic valve through different plasma biomarkers in long-term follow-up.

Research question

What is the inflammatory response and calcification in patients who undergo aortic valve replacement for a manufactured prosthesis at the "Ignacio Chávez" National Institute of Cardiology in the long-term follow-up?

Hypothesis

Manufactured bioprostheses at the "Ignacio Chávez" National Institute of Cardiology show a similar or lower inflammatory response to imported bioprostheses or mechanical prostheses associated with less valve dysfunction and more outstanding durability.

Detailed description: Evaluation of the inflammatory response and long-term calcification in post-operated aortic valve replacement patients.

Background

Calcification of the aortic valve affects more than 26% of adult patients over 65 years of age and is the main indication for valve replacement in the United States of America. In Mexico, there is no exact figure for the prevalence and incidence of aortic stenosis. Previous evidence shows that aortic valve calcification is an active biological process, associated with inflammation and increased levels of intracellular adhesion molecule 1 (ICAM-1), pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), interleukin 1 (IL-1), interleukin 17 (IL-17), interleukin 18 (IL-18), extracellular matrix proteins (MMP-1), tenascin-C7, osteopontin and bone sialoprotein followed by osteogenic differentiation.

Osteoprotegerin (OPG) / RANK / RANK ligand also plays a regulatory role in bone metabolism; however, in bioprostheses, the role they play in dysfunction does not seem to be clear. They have been found in patients with early coronary atherosclerosis, and a significant increase in endothelial progenitor cells with osteoblasts, osteocalcin (OCN) and phenotype (EPN-OCN) and it has been shown that it is an important prognostic marker in valvular calcification. In the final stage of the disease, expression of TGFβ1 and VAP-1 has been found; both genes are triggers of the calcification process without any association with osteogenic transformation, which is not influenced by statins' use; however, first use alters its expression.

The only actual treatment for severe aortic stenosis is surgical aortic valve replacement (AVR). However, even after the procedure, the inflammatory response persists in almost half of the patients. It has been shown that there is no correlation between age, gender, smoking, ventricular geometry, transvalvular aortic gradient, and the persistence of the inflammatory state after valve replacement. Even more, the materials with which the different types of prostheses are manufactured could induce inflammation per se. Biological prostheses, an incomplete cell removal process and therefore the presence of residual proteins of animal origin, could induce a response of the immune system through the xenoantigen Gal-3-Gal- and its corresponding anti-Gal antibodies that have been associated with valve prosthetic damage. The presence of metallic components such as titanium could act as a trigger for the inflammatory response. As regards the hemodynamic profile of the bioprosthesis, it is unknown whether it is correlated with an inflammatory response. In the manufacturing bioprosthesis at the "Ignacio Chávez" National Institute of Cardiology (INC), an evaluation was carried out in the early, and late post-surgical period, it was shown that the inflammatory response after six months is similar to that produced by mechanical prosthesis.

This study's main objective is to evaluate the inflammatory response in patients with post-operated AVR due to biological or mechanical prosthetic valve through different plasma biomarkers in long-term follow-up.

Problem Statement

The pattern of the inflammatory response and long-term calcification of the prosthetic valve manufactured in the National Institute of Cardiology "Ignacio Chávez" is not known, in the study carried out by Soto López and Cols in which patients undergoing prosthetic valve change were evaluated in a state of early and late post-surgical (6 months) it was observed that there is no difference between biological or mechanical prosthesis. We believe that the inflammatory process associated with the INC bioprosthesis persists over time. However, it could be even less than an imported bioprosthesis or mechanical prosthesis, so it is necessary to evaluate its inflammatory pattern in long-term follow-up.

Justification

Degenerative aortic stenosis is a significant health problem, and its treatment through valve replacement modifies morbidity and mortality. There are currently more than 5000 prostheses implanted in the INC, and the leading cause of dysfunction is calcification. The long-term inflammatory response in INC bioprostheses has not been evaluated to date, identifying, and comparing the inflammatory pattern between these bioprostheses could identify potential therapeutic targets. Demonstrating non-inferiority and a similar or less inflammatory pattern could provide one more reason to start its generalized use in public health institutions in the country.

Research question

What is the inflammatory response and calcification in patients who undergo aortic valve replacement for a manufactured prosthesis at the "Ignacio Chávez" National Institute of Cardiology in the long-term follow-up?

Aims

Primary objectives

• Quantify the long-term inflammatory response of INC bioprostheses implanted in the aortic position.

Secondary objectives

* Compare the long-term inflammatory response of INC bioprostheses implanted in the aortic position to imported bioprostheses and mechanical prostheses.
* The inflammatory response of post-bioprosthesis operated patients will be compared with a control group.

Hypothesis

Null hypothesis

The inflammatory response is more significant in manufactured bioprostheses at the "Ignacio Chávez" National Institute of Cardiology, associated with more significant prosthetic valve dysfunction.

Alternative hypothesis

Manufactured bioprostheses at the "Ignacio Chávez" National Institute of Cardiology show a similar or lower inflammatory response to imported bioprostheses or mechanical prostheses, which is associated with less valve dysfunction and more outstanding durability.

Methodology

Design type

Observational, longitudinal, descriptive ambispective cohort study.

Sample size

The sample size of 56 patients (14 patients per group) was calculated using a test for difference of independent proportions, with a power of 80 %, probability of error of 0.5, based on the RANK concentration from the previous studies.

Statistic analysis.

The normality of continuous variables will be sought with the Shapiro Wilks test. According to the distribution, continuous variables will be expressed as mean ± standard deviation or median and interquartile ranges. The categorical variables will be expressed in number and percentage. Comparisons will be made using the Chi-square test or Fisher's exact test for categorical variables; For dimensional variables, the Student's t-test or Mann-Whitney's U test will be used. The differences will be considered statistically significant when the value of p is less than 0.05.

Schedule of activities.

The preparation of the protocol and review by the ethics committee will be carried out in the months of June to August 2017, the obtaining of the information will take place from August 2017 to February 2018, the obtaining of the inflammatory profile will be carried out in the months of March 2018 to July 2019, the information processing will take place in August and December 2019, the review by the committee will be enhanced in January to July 2020 and the disclosure of results It is carried out during the months of November to December 2020.

Eligibility criteria: Inclusion Criteria:

1. Patients over 18 years of age underwent an aortic valve exchange for an INC bioprosthesis, imported bioprosthesis, or mechanical prosthesis.
2. Patients with follow-up two-dimensional transthoracic echocardiography.
3. Patients who agree to take a blood sample for an inflammatory profile.

Exclusion Criteria:

1. Patients in whom more than one cardiac prosthesis was implanted in any valve position.
2. Inflammatory and connective tissue disease (systemic lupus erythematosus, rheumatoid arthritis, antiphospholipid syndrome).
3. Patients undergoing aortic valve replacement due to prosthetic valve dysfunction.

Primary outcomes:
measure: Quantify the long-term inflammatory response of INC bioprostheses implanted in the aortic position.
timeFrame: An average of 6 years
Secondary outcomes:
measure: Compare the long-term inflammatory response of INC bioprostheses implanted in the aortic position to imported bioprostheses and mechanical prostheses.
timeFrame: An average of 6 months
measure: The inflammatory response of post-bioprosthesis operated patients will be compared with a control group.
timeFrame: Through study completion, an average of 6 years
Other outcomes:
Locations:
city: Ciudad de mexico
country: Mexico
facility: Instituto Nacional Ignacio Chavez
Study officials:
affiliation: Instituto Nacional de Cardiologia Ignacio Chavez
name: Maria Elena Soto Lopez, PhD
role: PRINCIPAL_INVESTIGATOR
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