Results of the Aortic Valve Reconstruction in Children

Aortic Valve Insufficiency Clinical Trial

Official title:

Short-term and Midterm Results of the Aortic Valve Reconstruction With Autopericardium in Children

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04162444
• Other study ID #: 16072019
• Status: Recruiting
• Start date: February 18, 2020
• Est. completion date: October 2027

Study information

• Verified date: March 2021
• Source: National Medical Research Center for Children's Health, Russian Federation
• Contact: Vladimir P. Miroshnichenko, PhD
• Phone: +7 499 134-04-70
• Email: miroshnichenko[@]nczd.ru
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Aortic valve disease counts up to 5% of cases of congenital heart disease being one of the most common congenital malformations of the cardiovascular system. This disease requires replacement of the damaged valve which in itself is not a trivial task to complete in children as there is still no available best practice for valve replacement. Today, the following alternative variants are performed in children: mechanical aortic prosthesis, xenografts, allografts, and pulmonary autograft (Ross procedure) and each has its potential advantages and disadvantages.

Mechanical aortic prostheses require lifelong anticoagulation therapy and repeated surgeries to replace mechanical valves during child growth. Available xenografts in children also has suboptimal results not only because of absence of growth potential, but also due to development of degenerative changes in biological tissue of the graft leaflets. Allograft tissues are exposed to rapid biodegradation in the recipient body and thus requiring repeated surgeries associated with higher difficulty, high risk of hemorrhages, and injury of the coronary injuries. Ross procedure was proposed as theoretically the most evidence-based reconstruction of the aortic valve in children. Even successfully performed Ross operation transforms one-valve disorder into two-valve disease.

The accumulation of knowledge on the anatomy of the aortic root and improvement of surgical techniques led to the development of new methods for reconstruction of the valve function. The technique is widely applied in adult cardiac surgery, uses glutaraldehyde-treated autopericardium for augmentation of the leaflets. Absence of foreign material provides no need for anticoagulation therapy. Potentially, reconstruction of the aortic valve with autopericardium can be widely used in children.

Aim is to study safety, clinical and hemodynamic efficacy of the method of the aortic valve reconstruction with autopericardium in children with aortic valve disease. Patients aged 29 days to 12 years will be included into the study. The data according to the protocol of the study will be assessed at the stage of inclusion, during the surgery, in 30 days after the surgery, and in 1, 2, and 3 years after the surgery. Data about all the patients included into the research will be analyzed in order to study the endpoints and achieve the research aim.

Description:

Aortic valve disease amounts to approximately 5% of the total number of cases of congenital heart disease, thus being one of the most common congenital malformations of the cardiovascular system. This disease requires replacement of the damaged valve, which in itself is not a trivial task to complete in children as there is still no available perfect option for valve replacement. Today, the following alternative variants for the aortic valve reconstruction in children are known: mechanical aortic prosthesis, xenografts, allografts and pulmonary autograft (Ross procedure); each of the above-mentioned variants has its potential advantages and disadvantages.

Mechanical aortic prostheses are widely available, including in small sizes (16 and 18 mm) appropriate for young children. However, the available sizes still do not allow to perform the surgical reconstruction in children of the first year of life. Besides these patients need lifelong anticoagulation therapy and necessity for repeated surgeries in order to replace mechanical valves with a child's growth.

Available xenografts have various types but usually, their sizes begin from 19 mm which does not fit for the majority of young children. Aortic xenografts are characterized by low risk of thromboembolism complications and do not require lifelong antithrombotic therapy. However, application of these grafts in children also has suboptimal results not only because of the absence of growth potential but also due to the development of degenerative changes in biological tissue of the graft leaflets.

Allografts are characterized by perfect hemodynamic parameters which are similar to the native healthy aortic valve. Risk of thromboembolic complications in implantation of allografts is very low, so there is no need for anticoagulation therapy. As in xenografts, allograft tissues are exposed to rapid biodegradation in the recipient body with the following development of obstruction or insufficiency and thus requiring a repeat operation. Implantation of allografts is associated with higher difficulty and high risk of hemorrhages and injury of the coronary injuries.

Ross procedure was proposed as theoretically the most justified choice for reconstruction of the aortic valve in children. As a conduit for reconstruction of the aortic valve the host's intact native pulmonary valve - autograft - is used; and the pulmonary valve is usually replaced by xenograft. Even successfully performed Ross operation, according to some authors, resolves the problem of the aortic valve only for a while; moreover, it causes another problem with the pulmonary valve, thus transforming one-valve disorder into two-valve disease.

The accumulation of knowledge on the anatomy of the aortic root and improvement of surgical techniques has led to the development of new methods for reconstruction of the valve function. The experience of various options for interventions on the aortic valve leaflet gained in adult cardiac surgery allowed to consider such interventions as an alternative method to valve reconstruction in children. About ten years ago, Professor Shigeyuki Ozaki brought the reconstruction of the aortic valve with the patient's own tissues to a completely new technological level. This technique includes the use of glutaraldehyde-treated autopericardium for augmentation of the leaflets; the reproducibility of the method was significantly increased due to usage of the template sets and special tools for the measurement of the native valve. Since no foreign material is used, there is no need for anticoagulation therapy after such intervention, which the authors of the method referred to as the valve reconstruction, not implantation of the graft. Potentially, reconstruction of the aortic valve with autopericardium can be widely used in children. In this population of patients, the various variants of the leaflets dysmorphogenesis are much more common, a wide range of morphological diversity of structure with inadequate hemodynamics can be found: monocuspid, bicuspid and pseudobicuspid valves; which does not allow to perform the valve reconstruction by restoring the original anatomy.

The normal anatomy of the aortic valve assumes three-valve structure, and most augmentation techniques suppose formation of tricuspid anatomy. At the same time, there is an alternative variant of hemodynamically adequate valve structure in the human body - bicuspid anatomy of the venous valves in the vena cava inferior system. Theoretical calculations obtained through computer simulation show that the neo-valve formed by three artificial leaflets will retain its locking function with increasing the diameter of the fibrous ring only by 8%. At the same time, the bicuspid valve with an increased height of the leaflets is able to maintain the shut-off function with an increase in the diameter of the fibrous ring by 67%.

The aim is to study safety, clinical and hemodynamic efficacy of the method of the aortic valve reconstruction with autopericardium in children with aortic valve disease. Primary endpoints: patient's death due to various causes during the first 30 days after the surgery. Secondary endpoints for efficacy assessment: аreedom from repeated surgeries on the aortic valve; mean gradient at the aortic valve over 40 mmHg; аortic insufficiency over 2 degree; effective area of the neo-aortic valve less than 1.0 cm2/m2 Secondary endpoint for safety assessment: acute disorders of cerebral circulation within the first 30 days after the surgery; hemorrhage needing revision surgery; acute kidney injury, stages 2 or 3, including the necessity for renal replacement therapy; acute coronary syndrome; dysfunction of the neo-valve requiring repeated surgery.

Patients aged from 29 days to 12 years old with dysfunction of the native aortic valve with and without manifestations, with indications for the aortic valve reconstruction, and without concomitant supravalvular and subvalvular aortic stenosis and major congenital heart diseases, will be included into the study. The study design is planned to be prospective, cohort, single-center, observational. In total 40 patients will be included into the study. The data according to the protocol of the study will be assessed at the stage of inclusion, during the surgery, in 30 days after the surgery, and in 1, 2, and 3 years after the surgery. Data about all the patients included in the research will be analyzed in order to study the endpoints and achieve the research aim.

The first report on safety of the operation will be published when all the patients included in the study are carried out the procedure of augmentation of the aortic valve with autopericardium and all of them are examined within 30 days after the surgery. A report about the efficacy of the operation within the first year after the performed surgery of augmentation of the aortic valve with autopericardium; it will be published after all the patients included in the study are examined at the control visit in one year after the surgery. Report about clinical and hemodynamic efficacy of the operation within three years after the performed reconstruction of the aortic valve with autopericarduim; it will be published after all the patients included in the study are examined in three years after the surgery. Final report on the study will be published when for all patients included in the study all the follow-up periods are completed, or patients are excluded from the study due to other causes.

For compensation for the lost quantitative or qualitative data, statistical methods will not be applied. If there is a lack in patient's data due to any causes, such a patient will be excluded from this block of analysis. A number of patients included in each analysis will be represented in the report, so readers could themselves assess the influence of the lost data on the published result.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. completion date: October 2027
• Est. primary completion date: October 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 12 Years

Eligibility

Inclusion Criteria:

• Age from 29 days to 12 years

• Patient's official caregivers have to sign the informed consent after they are thoroughly explained the meaning of the study, its protocol and timelines.

• Patients with manifestations, with mean gradient at the aortic valve >40 mmHg with normal left ventricular ejection fraction (LVEF), or patients with manifestations with the mean gradient < 40 mmHg with decreased LVEF, or patients with manifestations with severe aortic insufficiency, or patients without manifestations, but with decreased LVEF with aortic insufficiency, or patients with concomitant moderate aortic insufficiency and moderate aortic stenosis with manifestations.

• Aortic Z-score over -1,5

• Absence of subvalvular and supravalvular aortic stenosis

• Absence of intracardiac malformations requiring correction, except for septal defects

Non-inclusion criteria:

• Known hypersensitivity to aspirin, heparin, nitinol, intravenous contrast or contradictions to their administration due to other causes.

• Previous replacement of the aortic valve with mechanical or xenografts.

• Confirmed active sepsis or endocarditis.

• Hypoplasia of the fibrous ring of the aortic valve with Z score under -1,5.

• Life expectancy less than 3 years due to concomitant diseases.

• Participation in another clinical research.

• Indications for urgent surgery.

• Intracardiac malformations requiring momentary surgical correction.

• Geographical instability of a patient and his/her official caregivers, complicating significantly the constant contact during the study

Exclusion Criteria:

• Refusal of patient's caregivers to participate further in the study.

Related Conditions & MeSH terms

• Aortic Valve Insufficiency

Intervention

Diagnostic Test:
• Physical examination
A physical examination is a routine screening procedure used to investigate a patient's symptoms or complaints. It consists of a series of questions regarding patient medical history followed by an examination of the symptoms to determine the correct diagnosis and treatment plan.
• The Ross Classification for Heart Failure in Children
The assessment is performed by pediatric cardiologist according to the classic Ross scale. One of the 4 classes of chronic heart failure is registered.
• The Aristotle score
Surgical risks will be assessed by the ARISTOTLE score developed specially for the task. The calculation will be performed online, available from http://www.aristotleinstitute.org.

Other:
• Assessment of administered specific therapy
The data will be registered as groups of administered medicines: Antiplatelet agents Loop diuretics Potassium-sparing diuretics Angiotensin-converting enzyme inhibitors

Diagnostic Test:
• Multispiral computed tomography/3D echocardiography
All patients enrolled in the study should be routinely examined with multispiral computed tomography (MS-CT) or 3D-echo before surgery and 3 years later. As a result, a 3D aortic root reconstruction will be made to assess its size and anatomy and subsequently build a 3D soft model for surgery imitation. At the study onset, we plan to perform MS-CT, then 3D-echo. If the correlation resulting from 3D-echo and the actual sizes will be high, the isolated 3D-echo will be preferred in the future. If none of the methods is available, the patients will not be enrolled in the study. The following data will be registered for further analysis: Perimeter of the aortic valve Diameter of the aortic valve at sinuses level Height of the aortic sinuses Morphology of the aortic valve
• Transthoracic and transesophageal echocardiography
Transthoracic echocardiography is carried out at baseline, at discharge and then annually. It is performed in order to assess the contractile function of the heart and hemodynamic characteristics of the aortic valve and its autopericardium graft. Transesophageal echocardiography is carried out directly after the withdrawal of the artificial circulation when performing augmentation of the aortic valve with autopericardium in order to asses hemodynamic characteristics of the aortic neo-valve.
• 12-lead electrocardiogram
Registering 12-lead electrocardiogram (ECG) is used as a tool for assessment of the regularity of the heart rhythm as well as screening and predictive tool for assessment of fibrosis and hypertrophy processes in the myocardium. The following data will be registered: Heart rate Sinus rhythm (yes/no) Positive R wave in leads V5-6 Angle a less than 0 Presence/absence of abnormal Q wave Presence/absence of ST-segment depression in precordial leads

Locations

Country	Name	City	State
Russian Federation	National Medical Research Center of Children's Health	Moscow

Sponsors (1)

Lead Sponsor	Collaborator
National Medical Research Center for Children's Health, Russian Federation

Country where clinical trial is conducted

Russian Federation, 

References & Publications (36)

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* Note: There are 36 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Death Rate	Patient's death due to various causes during the first 30 days after the surgery.	From baseline till 1 month after the surgery
Secondary	Number of Participants with Repeat Aortic Valve Surgery	We will observe if a patient had an emergency for the repeat surgery on the aortic valve	During the 5-6 years of the follow-up period since the surgery
Secondary	Number of Participants with Aortic Valve Mean Gradient over 40 mmHg	We will register the cases when the mean gradient at the aortic valve will exceed 40 mmHg	During the 5-6 years of the follow-up period since the surgery
Secondary	Number of Participants with Aortic Insufficiency Stage 2-4	We will register the cases when the patients will be diagnosed with aortic insufficiency Stage 2-4	During the 5-6 years of the follow-up period since the surgery
Secondary	Neo-aortic valve effective area less than 1.0 cm2/m2	We will register the cases when the effective area of the neo-aortic valve will be less than 1.0 cm2/m2	During the 5-6 years of the follow-up period since the surgery
Secondary	Number of Participants with Hemorrhage requiring surgery	We will register the patients diagnosed with a hemorrhage requiring surgery	During the 5-6 years of the follow-up period since the surgery
Secondary	Number of Participants with Acute Disorders of Cerebral Circulation	We will register the patients with acute disorders of cerebral circulation after the surgery	During the first 30 days after the surgery
Secondary	Number of Participants with Acute Kidney Injury Stages 2 or 3	We will register the patients with acute kidney injury Stages 2 or 3, including those requiring renal replacement therapy	During the 5-6 years of the follow-up period since the surgery
Secondary	Number of Participants withAcute Coronary Syndrome	We will register the patients diagnosed with acute coronary syndrome	During the 5-6 years of the follow-up period since the surgery
Secondary	Number of Participants with Dysfunction of the Neo-valve Requiring Repeat Intervention	We will register the cases when patients are diagnosed with dysfunction of the neo-valve after the surgery and require repeated operation	During the 5-6 years of the follow-up period since the surgery

External Links

•   Dhand NK, Khatkar MS. (2014). Statulator: an online statistical calculator. Sample Size Calculator for Estimating a Single Proportion. Accessed 15 March 2019