Clinical trial NCT02968264: Tetralogy of Fallot for Life
Official title: Tetralogy of Fallot for Life
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Tetralogy of Fallot
Congenital Heart Disease
Congenital Heart Defect
Lead sponsor: Population Health Research Institute
Sponsor class: OTHER
Collaborators: name: The Hospital for Sick Children
First posted: 2016-11-18
Enrollment: 1108
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: TOF patients of any age undergoing their first cardiac intervention. Please refer to the eligibility criteria for more details.

Brief summary: The aim is to conduct a prospective multi-centre international inception cohort study with an enrollment goal of 3,000 TOF patients and 2 year follow-up post-repair. The proposed sample size and methodology will result in statistically powerful results to allow for evidence-based change to current TOF surgical practices.

Detailed description: Background: Tetralogy of Fallot (TOF) is the most common cyanotic heart defect consisting of 7-10% of all congenital heart disease with an estimated annual global incidence rate of 38,000. It is fatal if untreated; only 50% of patients are alive at 1 year of age. Surgery has dramatically improved the survival so that \>95% of repaired TOF children are alive by one year. The initial justified enthusiasm for the benefit of surgical therapy are now tempered by the findings of late sudden cardiac death secondary to right ventricular (RV) dysfunction. The original trans-ventricular/trans-annular patching repair results in significant pulmonary insufficiency which leads to RV dilation, subsequent functional tricuspid regurgitation, atrial arrhythmias, and eventual RV failure and ventricular arrhythmias. In attempt to break this cycle, an increasing number of patients are undergoing late pulmonary valve implantation.

Recognizing that the RV adapts to stress signals has led to the idea that leaving mixed residual stenosis and regurgitation may yield to an adaptive change that limits RV dilation while still allowing for adequate cardiac output. Early attempts to limit pulmonary insufficiency and RV damage involve minimal trans-annular patching or complete annulus preservation (AP). Emerging data suggest that patients with a mixed lesion have improved survival, so that 96.6% are alive at 25-years in comparison to 85-90% survival for the conventional technique.

Preliminary Data: A review of data comparing AP to TAP repair at our institution (n=185, AP repair=124, TAP=61) demonstrated that at 10-15 year follow-up those who received an AP repair had smaller RV volumes and pulmonary regurgitant jet width. They were also seen to have improved exercise capacity as measure by VO2 max tests. The AP technique also has been seen to significantly decrease the risk of reoperation in comparison to TAP, 11% and 29% respectively.

Current Problem: Although trans-ventricular VSD closure along with a TAP is known to result in increased risk of long-term morbidity and mortality, it continues to be the predominant repair strategy implemented globally according to STS/EACTS databases. Reasons for this are:

* Trans-ventricular/TAP approach is technically easier than annulus preservation, which often requires multiple pump runs
* There is a fear of leaving too much obstruction
* High quality evidence supporting one approach over the other is lacking.

Gaps in Literature

1. Most data on the impact of surgical strategy emerge from single centre experiences that are retrospective and based on small patient population. This makes the results difficult to standardize to the general TOF population.
2. Retrospective registry data published by STS and EACTS omit many crucial surgical and clinical variables that can potentially impact outcomes.
3. None of the current evidence are based on anatomically matched/adjusted patients

Eligibility criteria: Inclusion Criteria:

* TOF with RVOT stenosis. TOF is defined as anterio-cephalad deviation of the ventricular outlet septum with no more than 50% aortic override and a single outflow VSD.
* TOF with pulmonary atresia and confluent pulmonary arteries.
* Admitted with intent to treat (i.e. patient planned to undergo a primary or staged repair).
* Patients with coronary artery anomalies, right aortic arch, and 22q11 deletion may be included

Exclusion Criteria:

* TOF with absent pulmonary valve
* Other major cardiac anomalies such as AVSD, multiple VSDs, right atrial isomerism, and MAPCAs. In this instance, the definition of MAPCAs does not include dilated bronchial collateral arteries.
* Unbalanced ventricles precluding biventricular repair
* Major genetic abnormalities/syndromes e.g. trisomy 13,18, and 21
* Major extra cardiac anomalies e.g. diaphragmatic hernia, omphalocele, absent sternum, cerebral palsy
* Infective endocarditis as an indication for intra-cardiac repair
* Stroke in the last 30 days prior to palliation or intra-cardiac repair
* Known diagnosis of HIV or hepatitis B
* Any previous cardiac procedures
* Patient's circumstance that precludes completion of follow-up telephone call and/or obtaining information from the 2-year cardiology follow-up

Primary outcomes:
measure: RV physiology and morphology
timeFrame: 2 years post-repair
Secondary outcomes:
measure: Number of patients undergoing various palliation procedures and surgical repair strategies
timeFrame: 2 years
measure: Cardiovascular mortality rate
timeFrame: 30 days and 2 years after repair
measure: Rate of palliation failure
timeFrame: 2 years
measure: Effect of palliation procedures on cardiac morphology
timeFrame: 2 years
measure: Post-operative restrictive physiology
timeFrame: 2 years
measure: Cardiac re-interventions
timeFrame: 2 years
measure: RV physiology and morphology following TOF pulmonary atresia repair
timeFrame: 2 years
Other outcomes:
Locations:
city: Orlando
country: United States
facility: Nemours Children's Hospital
state: Florida
city: New York
country: United States
facility: Morgan Stanley Children's Hospital
state: New York
city: Parkville
country: Australia
facility: Royal Children's Hospital
state: Victoria
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Chengdu
country: China
facility: West China Hospital
state: Sichuan
city: Beijing
country: China
facility: Beijing Fuwai Hospital
city: Guangdong
country: China
facility: Guangzhou Women and Children's Medical Center
city: Guangdong
country: China
facility: Guangdong Cardiovascular Institute
city: Shanghai
country: China
facility: Shanghai Children's Medical Centre
city: Shanghai
country: China
facility: Shanghai Xinhua Hospital
city: New Delhi
country: India
facility: Fortis Escorts Heart Institute
state: Delhi
city: Mumbai
country: India
facility: Kokilaben Dhirubhai Ambani Hospital & Medical Research Institutev
city: Jakarta
country: Indonesia
facility: National Cardiovascular Center Harapan Kita
city: Okayama
country: Japan
facility: Okayama University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Kathmandu
country: Nepal
facility: Manmohan Cardiothoracic Vascular and Transplant Center
city: Novosibirsk
country: Russian Federation
facility: Academician E.N. Meshalkin Research
city: Jeddah
country: Saudi Arabia
facility: King Abdulaziz University Hospital
state: Makkah
city: Jeddah
country: Saudi Arabia
facility: King Faisal Specialist Hospital and Research Centre - Jeddah
city: Kyiv
country: Ukraine
facility: Children's Cardiac Center - Ukraine
Study officials:
affiliation: University of California, Los Angeles
name: Glen Van Arsdell, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Population Health Research Institute
name: Richard Whitlock, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sarris GE, Comas JV, Tobota Z, Maruszewski B. Results of reparative surgery for tetralogy of Fallot: data from the European Association for Cardio-Thoracic Surgery Congenital Database. Eur J Cardiothorac Surg. 2012 Nov;42(5):766-74; discussion 774. doi: 10.1093/ejcts/ezs478.
citation: Al Habib HF, Jacobs JP, Mavroudis C, Tchervenkov CI, O'Brien SM, Mohammadi S, Jacobs ML. Contemporary patterns of management of tetralogy of Fallot: data from the Society of Thoracic Surgeons Database. Ann Thorac Surg. 2010 Sep;90(3):813-9; discussion 819-20. doi: 10.1016/j.athoracsur.2010.03.110.
citation: Gatzoulis MA, Balaji S, Webber SA, Siu SC, Hokanson JS, Poile C, Rosenthal M, Nakazawa M, Moller JH, Gillette PC, Webb GD, Redington AN. Risk factors for arrhythmia and sudden cardiac death late after repair of tetralogy of Fallot: a multicentre study. Lancet. 2000 Sep 16;356(9234):975-81. doi: 10.1016/S0140-6736(00)02714-8.
citation: d'Udekem Y, Galati JC, Rolley GJ, Konstantinov IE, Weintraub RG, Grigg L, Ramsay JM, Wheaton GR, Hope S, Cheung MH, Brizard CP. Low risk of pulmonary valve implantation after a policy of transatrial repair of tetralogy of Fallot delayed beyond the neonatal period: the Melbourne experience over 25 years. J Am Coll Cardiol. 2014 Feb 18;63(6):563-8. doi: 10.1016/j.jacc.2013.10.011. Epub 2013 Oct 30.
citation: Pondorfer P YT, Cheung M, Ashburn D, Manlhiot C, McCrindle B, Mertens L, Grosse-Wortmann L, Redington A, Van Arsdell G. Abstract 18833: Annulus Preservation Strategy Improves Late Outcomes in Tetralogy of Fallot: An Anatomical Equivalency Study. Circulation. 2014;130:A18833.