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As outlined in chapter 1 the birth prevalence of congenital heart disease is increasing (van der Linde et al., 2011), and combined with advances in the prenatal diagnosis and surgical management of children with congenital heart disease of there has been a dramatic improvement in overall survival to adulthood. However, beyond this point, the prognosis for adults with congenital heart disease is uncertain. Life expectancy is poorly defined, furthermore as outlined in the previous chapter corrective surgery is often palliative rather than curative, and this results in extensive

morbidity. There are a host of recognised long term sequelae following surgical repair, some of these may be generic, for example endocarditis and arrhythmia, whilst others relate to the specific surgical technique involved, for example severe pulmonary regurgitation in the case of transannular patch repair of Tetralogy of Fallot. Some of these complications have been recognised only recently, e.g. aortic root dilatation in Tetralogy of Fallot (Mongeon et al., 2013), raising the possibility of more as yet under-

recognised complications in later adult life. Furthermore, as patients age so they are at risk of developing acquired cardiovascular disease, and it is unclear whether or not they are at greater risk of this than their contemporaries (Tutarel, 2014).

In this chapter I characterise what is already known about the long term mortality and morbidity in the two cohorts of ACHD patients relevant to my thesis; those with a systemic right ventricle and those with surgically repaired Tetralogy of Fallot. These conditions are rare - birth prevalence per 1000 live births has been reported at 0.34 for TOF and 0.31 for TGA (van der Linde et al., 2011), and at less than 0.07 for CCTGA (McCombe et al., 2016), but they are among the more common of the congenital cardiac conditions of at least moderate complexity, and for the reasons outlined in chapter 1 comprise a well defined population with regular follow-up.

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3.2 Methods

I undertook a literature search of Ovid MEDLINE and Embase (1980 to November 2016 week 3) to identify papers relating to long term prognosis in systemic right ventricle and repaired Tetralogy of Fallot. Eligibility criteria included:

1. Must refer to outcomes in:

a. Transposition of the Great Arteries post atrial switch surgery

b. Congenitally Corrected Transposition of the Great Arteries c. Surgically repaired Tetralogy of Fallot

2. Must provide longitudinal data on mortality and morbidity into adulthood, i.e. papers were excluded if they related exclusively to outcomes in neonatal or paediatric patients

3. Include at least 50 patients 4. English language publication

Three search queries were run: a subheading search specific to each

of Medline and Embase, and a textword search run simultaneously for both Medline and Embase. Terms used included "congenital heart disease", "survival", "mortality", "morbidity", "transposition of the great arteries", "congenitally corrected transposition of the great arteries", "systemic right ventricle", "D-TGA", "L-TGA", "Mustard", Senning", "atrial inversion",

"tetralogy", and "Fallot". I screened titles and abstracts, and if an article was deemed to be relevant then the full text was reviewed to see if the paper met the eligibility criteria outlined above.

It became apparent in the course of the project that some centres published outcomes from the same cohort of patients on more than one occasion, and if the dates of follow-up overlapped then there was of course the risk of duplicating the same data. In these cases generally the most up

62 to date paper was used, an important exception being if it had fewer years of patient follow-up owing to the subject of interest being a specific subgroup of that cohort. Additionally in the TGA-atrial switch and CCTGA groups care had to be taken that the cohort included patients with a systemic right ventricle; therefore papers were excluded if they related exclusively to patients undergoing surgical correction of TGA or CCTGA that resulted in the left ventricle being placed in the systemic or subaortic position. Examples of such procedures include the Arterial Switch (Jatene) procedure for TGA, the Rastelli, REV (Réparation a l'Étage Ventriculaire) and Nikaidoh procedures for TGA complicated by the presence of a VSD and pulmonary stenosis, and combinations of these procedures with an atrial switch operation for complex CCTGA - a "double switch" or "anatomical" repair. Papers were also excluded if they related to patients with the most severe form of TGA and CCTGA who were palliated by means of a

univentricular repair, with the end result being the formation of a Fontan circuit. These patients, even though the right ventricle is in the systemic position, have a very different physiology to those patients with a

functionally biventricular heart, and so outcomes and prognosis are not readily comparable to their contemporaries. If a paper related to patients with TGA or CCTGA who underwent various types of repair then an attempt was made to exclude any data relating to those patients who did not have a systemic right ventricle. In the case of TGA this was often straightforward as the results were typically presented separately, unfortunately for the

papers relating to CCTGA data was often presented for the cohort as a whole, and therefore was much more difficult to disentangle. In this case I made the decision to include these papers and present them as published, as in general the number of patients undergoing an anatomic repair or Fontan was small, and if I instead excluded these papers outright there would have been no papers relating exclusively to adult patients with CCTGA whatsoever.

63 The following data were extracted according to diagnosis: centre name, number of cases, anatomical subtype or type of surgical repair, ratio of male/female patients, age at surgical repair (where applicable), surgical era (earliest and latest year of initial surgery), baseline for the purposes of follow-up, mean/median follow-up duration, number of deaths, cumulative survival at 1-5 year intervals, incidence of morbidity, and risk factors associated with mortality. Centres differed in their reporting of

perioperative or early postoperative mortality (generally defined as a death occurring within 30 days of surgery). Where possible this was highlighted in the results tables, furthermore if early mortality was not included in the survival analysis the number of patients in the cohort as baseline was adjusted to ensure it accurately reflected this.

Morbidity outcomes were lesion specific but where relevant included incidence of reoperation, device implantation, arrhythmia, and heart failure. Morbidity information was expressed as a percentage of the whole cohort, unless follow-up was incomplete and some patients had missing data. If this was evident then the denominator was adjusted to reflect the number of patients for whom follow-up was available. Risk factors for mortality were included if they were statistically significant (defined as p less than or equal to 0.05) on a multivariate analysis.

Some papers summarised data regarding more than one congenital cardiac diagnosis. Where this occurred the data was stratified according to diagnosis. The diagnosis-specific data had to include more than 50 patients, relate to adult patients, and also correlate with one of the diagnostic groups outlined in the data collection (so data was excluded if for example the study reported outcomes for a group of patients with TGA but did not distinguish between patients with an atrial or arterial switch).

64 Data were tabulated; no meta-analysis was attempted as the studies were sufficiently heterogeneous that it would not have been possible to adjust for crucial underlying differences between each study population.

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