Clinical trial NCT04162444: Results of the Aortic Valve Reconstruction in Children
Official title: Short-term and Midterm Results of the Aortic Valve Reconstruction With Autopericardium in Children
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Aortic Valve Insufficiency
Keywords: Aortic Valve Insufficiency/surgery
Aortic Valve/surgery
Child
Reconstructive Surgical Procedures/methods
Cardiac Surgical Procedures
Hemodynamics
Pericardium/transplantation
Transplantation, Autologous
Treatment Outcome
Heart Valve Prosthesis Implantation
Lead sponsor: National Medical Research Center for Children's Health, Russian Federation
Sponsor class: OTHER_GOV
First posted: 2019-11-14
Enrollment: 40
Sex: ALL
Minimum age (years): 29
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: The study will enroll the participants from the patients of the the Department of Cardiac Surgery 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.

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Death Rate
timeFrame: From baseline till 1 month after the surgery
Secondary outcomes:
measure: Number of Participants with Repeat Aortic Valve Surgery
timeFrame: During the 5-6 years of the follow-up period since the surgery
measure: Number of Participants with Aortic Valve Mean Gradient over 40 mmHg
timeFrame: During the 5-6 years of the follow-up period since the surgery
measure: Number of Participants with Aortic Insufficiency Stage 2-4
timeFrame: During the 5-6 years of the follow-up period since the surgery
measure: Neo-aortic valve effective area less than 1.0 cm2/m2
timeFrame: During the 5-6 years of the follow-up period since the surgery
measure: Number of Participants with Hemorrhage requiring surgery
timeFrame: During the 5-6 years of the follow-up period since the surgery
measure: Number of Participants with Acute Disorders of Cerebral Circulation
timeFrame: During the first 30 days after the surgery
measure: Number of Participants with Acute Kidney Injury Stages 2 or 3
timeFrame: During the 5-6 years of the follow-up period since the surgery
measure: Number of Participants withAcute Coronary Syndrome
timeFrame: During the 5-6 years of the follow-up period since the surgery
measure: Number of Participants with Dysfunction of the Neo-valve Requiring Repeat Intervention
timeFrame: During the 5-6 years of the follow-up period since the surgery
Other outcomes:
Locations:
city: Moscow
country: Russian Federation
facility: National Medical Research Center of Children's Health
Study officials:
affiliation: National Research Center of Children's Health
name: Dmitry V. Ryabtsev, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Salomon NW, Stinson EB, Oyer P, Copeland JG, Shumway NE. Operative treatment of congenital aortic stenosis. Ann Thorac Surg. 1978 Nov;26(5):452-60. doi: 10.1016/s0003-4975(10)62925-6.
citation: Brown JW, Ruzmetov M, Vijay P, Rodefeld MD, Turrentine MW. Surgery for aortic stenosis in children: a 40-year experience. Ann Thorac Surg. 2003 Nov;76(5):1398-411. doi: 10.1016/s0003-4975(03)01027-0.
citation: Karamlou T, Jang K, Williams WG, Caldarone CA, Van Arsdell G, Coles JG, McCrindle BW. Outcomes and associated risk factors for aortic valve replacement in 160 children: a competing-risks analysis. Circulation. 2005 Nov 29;112(22):3462-9. doi: 10.1161/CIRCULATIONAHA.105.541649.
citation: Alsoufi B. Aortic valve replacement in children: Options and outcomes. J Saudi Heart Assoc. 2014 Jan;26(1):33-41. doi: 10.1016/j.jsha.2013.11.003. Epub 2013 Nov 13.
citation: Alsoufi B, Al-Halees Z, Manlhiot C, McCrindle BW, Al-Ahmadi M, Sallehuddin A, Canver CC, Bulbul Z, Joufan M, Fadel B. Mechanical valves versus the Ross procedure for aortic valve replacement in children: propensity-adjusted comparison of long-term outcomes. J Thorac Cardiovasc Surg. 2009 Feb;137(2):362-370.e9. doi: 10.1016/j.jtcvs.2008.10.010.
citation: Ruzmetov M, Vijay P, Rodefeld MD, Turrentine MW, Brown JW. Evolution of aortic valve replacement in children: a single center experience. Int J Cardiol. 2006 Nov 10;113(2):194-200. doi: 10.1016/j.ijcard.2005.11.011. Epub 2006 Jan 10.
citation: Alsoufi B, Manlhiot C, McCrindle BW, Canver CC, Sallehuddin A, Al-Oufi S, Joufan M, Al-Halees Z. Aortic and mitral valve replacement in children: is there any role for biologic and bioprosthetic substitutes? Eur J Cardiothorac Surg. 2009 Jul;36(1):84-90; discussion 90. doi: 10.1016/j.ejcts.2009.02.048. Epub 2009 Apr 14.
citation: Polimenakos AC, Sathanandam S, Elzein C, Barth MJ, Higgins RS, Ilbawi MN. Aortic cusp extension valvuloplasty with or without tricuspidization in children and adolescents: long-term results and freedom from aortic valve replacement. J Thorac Cardiovasc Surg. 2010 Apr;139(4):933-41; discussion 941. doi: 10.1016/j.jtcvs.2009.12.015.
citation: Lupinetti FM, Duncan BW, Lewin M, Dyamenahalli U, Rosenthal GL. Comparison of autograft and allograft aortic valve replacement in children. J Thorac Cardiovasc Surg. 2003 Jul;126(1):240-6. doi: 10.1016/s0022-5223(03)00041-2.
citation: Solowiejczyk DE, Bourlon F, Apfel HD, Hordof AJ, Hsu DT, Crabtree G, Galantowicz M, Gersony WM, Quaegebeur JM. Serial echocardiographic measurements of the pulmonary autograft in the aortic valve position after the Ross operation in a pediatric population using normal pulmonary artery dimensions as the reference standard. Am J Cardiol. 2000 May 1;85(9):1119-23. doi: 10.1016/s0002-9149(00)00707-4.
citation: Elkins RC, Knott-Craig CJ, Ward KE, McCue C, Lane MM. Pulmonary autograft in children: realized growth potential. Ann Thorac Surg. 1994 Jun;57(6):1387-93; discussion 1393-4. doi: 10.1016/0003-4975(94)90089-2.
citation: Solymar L, Sudow G, Holmgren D. Increase in size of the pulmonary autograft after the Ross operation in children: growth or dilation? J Thorac Cardiovasc Surg. 2000 Jan;119(1):4-9. doi: 10.1016/s0022-5223(00)70211-x.
citation: Simon P, Aschauer C, Moidl R, Marx M, Keznickl FP, Eigenbauer E, Wolner E, Wollenek G. Growth of the pulmonary autograft after the Ross operation in childhood. Eur J Cardiothorac Surg. 2001 Feb;19(2):118-21. doi: 10.1016/s1010-7940(00)00638-2.
citation: Hraska V, Krajci M, Haun Ch, Ntalakoura K, Razek V, Lacour-Gayet F, Weil J, Reichenspurner H. Ross and Ross-Konno procedure in children and adolescents: mid-term results. Eur J Cardiothorac Surg. 2004 May;25(5):742-7. doi: 10.1016/j.ejcts.2004.01.009.
citation: Elkins RC, Thompson DM, Lane MM, Elkins CC, Peyton MD. Ross operation: 16-year experience. J Thorac Cardiovasc Surg. 2008 Sep;136(3):623-30, 630.e1-5. doi: 10.1016/j.jtcvs.2008.02.080.
citation: Alsoufi B, Al-Halees Z, Manlhiot C, McCrindle BW, Kandeel M, Al-Joufan M, Kalloghlian A, Fadel B, Canver CC. Superior results following the Ross procedure in patients with congenital heart disease. J Heart Valve Dis. 2010 May;19(3):269-77; discussion 278.
citation: Hazekamp MG, Grotenhuis HB, Schoof PH, Rijlaarsdam ME, Ottenkamp J, Dion RA. Results of the Ross operation in a pediatric population. Eur J Cardiothorac Surg. 2005 Jun;27(6):975-9. doi: 10.1016/j.ejcts.2005.01.018.
citation: Takkenberg JJ, Klieverik LM, Schoof PH, van Suylen RJ, van Herwerden LA, Zondervan PE, Roos-Hesselink JW, Eijkemans MJ, Yacoub MH, Bogers AJ. The Ross procedure: a systematic review and meta-analysis. Circulation. 2009 Jan 20;119(2):222-8. doi: 10.1161/CIRCULATIONAHA.107.726349. Epub 2008 Dec 31.
citation: Alsoufi B, Manlhiot C, Fadel B, Al-Ahmadi M, Tamim M, McCrindle BW, Canver CC, Al-Halees Z. The Ross procedure in children: preoperative haemodynamic manifestation has significant effect on late autograft re-operation. Eur J Cardiothorac Surg. 2010 Nov;38(5):547-55. doi: 10.1016/j.ejcts.2010.03.025. Epub 2010 Apr 21.
citation: Woods RK, Pasquali SK, Jacobs ML, Austin EH, Jacobs JP, Krolikowski M, Mitchell ME, Pizarro C, Tweddell JS. Aortic valve replacement in neonates and infants: an analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database. J Thorac Cardiovasc Surg. 2012 Nov;144(5):1084-89. doi: 10.1016/j.jtcvs.2012.07.060. Epub 2012 Aug 24.
citation: Shinkawa T, Bove EL, Hirsch JC, Devaney EJ, Ohye RG. Intermediate-term results of the Ross procedure in neonates and infants. Ann Thorac Surg. 2010 Jun;89(6):1827-32; discussion 1832. doi: 10.1016/j.athoracsur.2010.02.107.
citation: Hickey EJ, Yeh T Jr, Jacobs JP, Caldarone CA, Tchervenkov CI, McCrindle BW, Lacour-Gayet F, Pizarro C. Ross and Yasui operations for complex biventricular repair in infants with critical left ventricular outflow tract obstruction. Eur J Cardiothorac Surg. 2010 Feb;37(2):279-88. doi: 10.1016/j.ejcts.2009.06.060. Epub 2009 Sep 17.
citation: Alsoufi B, Al-Halees Z, Manlhiot C, Awan A, Al-Ahmadi M, McCrindle BW, Al-Joufan M, Canver CC. Intermediate results following complex biventricular repair of left ventricular outflow tract obstruction in neonates and infants. Eur J Cardiothorac Surg. 2010 Oct;38(4):431-8. doi: 10.1016/j.ejcts.2010.02.035. Epub 2010 Apr 10.
citation: David TE. Aortic Valve Replacement in Children and Young Adults. J Am Coll Cardiol. 2016 Jun 21;67(24):2871-3. doi: 10.1016/j.jacc.2016.04.023. No abstract available.
citation: Duran CM, Gometza B, Kumar N, Gallo R, Martin-Duran R. Aortic valve replacement with freehand autologous pericardium. J Thorac Cardiovasc Surg. 1995 Aug;110(2):511-6. doi: 10.1016/S0022-5223(95)70248-2.
citation: Duran CM, Gallo R, Kumar N. Aortic valve replacement with autologous pericardium: surgical technique. J Card Surg. 1995 Jan;10(1):1-9. doi: 10.1111/j.1540-8191.1995.tb00582.x.
citation: Ozaki S, Kawase I, Yamashita H, Uchida S, Nozawa Y, Matsuyama T, Takatoh M, Hagiwara S. Aortic valve reconstruction using self-developed aortic valve plasty system in aortic valve disease. Interact Cardiovasc Thorac Surg. 2011 Apr;12(4):550-3. doi: 10.1510/icvts.2010.253682. Epub 2011 Jan 27.
citation: Ozaki S, Kawase I, Yamashita H, Uchida S, Nozawa Y, Takatoh M, Hagiwara S. A total of 404 cases of aortic valve reconstruction with glutaraldehyde-treated autologous pericardium. J Thorac Cardiovasc Surg. 2014 Jan;147(1):301-6. doi: 10.1016/j.jtcvs.2012.11.012. Epub 2012 Dec 8.
citation: Zhang HF, Ye M, Yan XG, Chen G, Tao QL, Jia B. Application of a Simplified Hand-Sewn Trileaflet Valved Conduit in Right Ventricular Outflow Tract Reconstruction as an Alternative for Bovine Jugular Vein Graft: Single-Center Experience. Artif Organs. 2018 Jan;42(1):41-48. doi: 10.1111/aor.12968. Epub 2017 Oct 2.
citation: Hosseinpour AR, Gonzalez-Calle A, Adsuar-Gomez A, Santos-deSoto J. A simple method of aortic valve reconstruction with fixed pericardium in children. Interact Cardiovasc Thorac Surg. 2013 May;16(5):695-7. doi: 10.1093/icvts/ivs547. Epub 2013 Jan 23.
citation: Hammer PE, Roberts EG, Emani SM, Del Nido PJ. Surgical reconstruction of semilunar valves in the growing child: Should we mimic the venous valve? A simulation study. J Thorac Cardiovasc Surg. 2017 Feb;153(2):389-396. doi: 10.1016/j.jtcvs.2016.08.019. Epub 2016 Aug 31.
citation: Dashkevich A, Blanke P, Siepe M, Pache G, Langer M, Schlensak C, Beyersdorf F. Preoperative assessment of aortic annulus dimensions: comparison of noninvasive and intraoperative measurement. Ann Thorac Surg. 2011 Mar;91(3):709-14. doi: 10.1016/j.athoracsur.2010.09.038.
citation: Ross RD. The Ross classification for heart failure in children after 25 years: a review and an age-stratified revision. Pediatr Cardiol. 2012 Dec;33(8):1295-300. doi: 10.1007/s00246-012-0306-8. Epub 2012 Apr 5.
citation: Lacour-Gayet F, Clarke D, Jacobs J, Comas J, Daebritz S, Daenen W, Gaynor W, Hamilton L, Jacobs M, Maruszsewski B, Pozzi M, Spray T, Stellin G, Tchervenkov C, Mavroudis And C; Aristotle Committee. The Aristotle score: a complexity-adjusted method to evaluate surgical results. Eur J Cardiothorac Surg. 2004 Jun;25(6):911-24. doi: 10.1016/j.ejcts.2004.03.027.
citation: Bigi S, Fischer U, Wehrli E, Mattle HP, Boltshauser E, Burki S, Jeannet PY, Fluss J, Weber P, Nedeltchev K, El-Koussy M, Steinlin M, Arnold M. Acute ischemic stroke in children versus young adults. Ann Neurol. 2011 Aug;70(2):245-54. doi: 10.1002/ana.22427.
citation: RANKIN J. Cerebral vascular accidents in patients over the age of 60. II. Prognosis. Scott Med J. 1957 May;2(5):200-15. doi: 10.1177/003693305700200504. No abstract available.