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Heterotaxy Is Not a Risk Factor for Adverse Long-Term Outcomes After Fontan Completion
Journal Pre-proof Heterotaxy is not a risk factor for adverse long-term outcomes following Fontan completion Supreet P. Marathe, MCh, Diana Zannino, MSc, Jacob Y. Cao, MBBS, Karin du Plessis, PhD, Shilpa S. Marathe, MD, Julian Ayer, FRACP, David S. Celermajer, FRACP, Thomas L. Gentles, FRACP, Gary F. Sholler, FRACP, Robert N. Justo, FRACP, Nelson Alphonso, FRACS, Yves d’Udekem, MD, David S. Winlaw, FRACS PII:
S0003-4975(19)31974-5
DOI:
https://doi.org/10.1016/j.athoracsur.2019.11.015
Reference:
ATS 33350
To appear in:
The Annals of Thoracic Surgery
Received Date: 9 September 2019 Revised Date:
31 October 2019
Accepted Date: 4 November 2019
Please cite this article as: Marathe SP, Zannino D, Cao JY, du Plessis K, Marathe SS, Ayer J, Celermajer DS, Gentles TL, Sholler GF, Justo RN, Alphonso N, d’Udekem Y, Winlaw DS, Heterotaxy is not a risk factor for adverse long-term outcomes following Fontan completion, The Annals of Thoracic Surgery (2020), doi: https://doi.org/10.1016/j.athoracsur.2019.11.015. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 by The Society of Thoracic Surgeons
Heterotaxy is not a risk factor for adverse long-term outcomes following Fontan completion Running Head: Heterotaxy outcomes after Fontan Supreet P. Marathe, MCh1,2, Diana Zannino, MSc3, Jacob Y. Cao, MBBS 4,5, Karin du Plessis, PhD3,6, Shilpa S. Marathe, MD1, Julian Ayer, FRACP7,8,9, David S. Celermajer, FRACP4,5, Thomas L. Gentles, FRACP10, Gary F. Sholler, FRACP7,8,9, Robert N. Justo, FRACP1,2, Nelson Alphonso, FRACS1,2, Yves d’Udekem, MD 3,6,11, David S. Winlaw, FRACS 7,8,9 1
Queensland Children’s Hospital, Brisbane, Australia
2
University of Queensland, Brisbane, Australia
3
Murdoch Children’s Research Institute, Melbourne, Australia
4
Sydney Medical School, University of Sydney, Sydney, Australia
5
Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia
6
Department of Pediatrics, Faculty of Medicine, University of Melbourne, Melbourne, Australia
7
Heart Centre for Children, The Children’s Hospital at Westmead, Sydney, Australia
8
Faculty of Health and Medicine, Sydney Medical School, Discipline of Child and Adolescent Health, University of Sydney, Sydney, Australia
9
Sydney Children’s Hospital Network Cardiac Services, Sydney, Australia
10
Starship Green Lane Pediatric and Congenital Cardiac Service, Starship Children’s
Hospital, Auckland, New Zealand 11
Royal Children’s Hospital, Melbourne, Australia
Keywords: Single ventricle, Fontan, heterotaxy, isomerism 1
Word count: 4542 Corresponding author: Prof. David S. Winlaw Pediatric Cardiothoracic Surgeon Heart Centre for Children, The Children’s Hospital at Westmead, WESTMEAD NSW 2145, AUSTRALIA [email protected]
2
Abstract Background: Heterotaxy is considered to be a risk factor for poor outcomes after the Fontan operation. However, long-term data to support this notion are lacking. The aim of our study was to ascertain the long-term outcomes of patients with heterotaxy following hospital discharge after Fontan completion and compare them with a contemporary non-heterotaxy cohort. Methods: A bi-national Fontan Registry (n =1,540) was analysed to identify heterotaxy patients and compare with non-heterotaxy patients. The primary composite end point was ‘Fontan failure’ encompassing death, heart transplantation, Fontan takedown or conversion, protein-losing enteropathy, plastic bronchitis, or New York Heart Association functional class III or IV. Results: One hundred and nine heterotaxy patients were identified which were compared with 1,431 non-heterotaxy Fontans following Fontan completion. There was no difference in unadjusted 15-year freedom from Fontan failure (heterotaxy: 78% vs non-heterotaxy: 85%, p=0.2). Patients in the heterotaxy group had a significantly higher cumulative incidence of post-Fontan arrhythmias (p<0.001). Propensity-score matching for confounders yielded 73 heterotaxy patients matched with 439 non-heterotaxy patients, in which 15-year freedom from Fontan failure was also not different (heterotaxy: 76% vs non-heterotaxy: 81%, p=0.2). There was no difference in 15-year freedom from Fontan failure in patients with right vs left isomerism (right isomerism: 80% vs left isomerism: 76%, p=0.7). Conclusions: Whilst heterotaxy may complicate the pre-Fontan course, once the Fontan is successfully completed it does not appear to be an important risk factor for Fontan failure. Heterotaxy patients are at a higher risk of post Fontan arrhythmias compared to nonheterotaxy patients. 3
Patients with heterotaxy present a challenging surgical substrate due to a multitude of problems occurring in tandem (1,2). Many of these patients are destined for the single ventricle (Fontan) pathway as biventricular repair is not possible. Traditionally, heterotaxy is considered to be a risk factor for poor outcomes after the Fontan operation (3). However, the interpretation of these studies is hampered by discrepancies in centre-specific practices, duration of follow-up, and the lack of a matched non-heterotaxy Fontan comparison group (1). It is unclear whether the presence of heterotaxy remains a risk factor impacting mortality and increasing the risks of failure of the Fontan circulation in the decades following this operation. In order to clarify this association, we decided to study these outcomes in the patients of the Australia-New Zealand Fontan Registry which collects health data for periods extending to 42 years. Patients and Methods The Australia-New Zealand Fontan Registry includes patients who have undergone the Fontan operation in either country or have undergone their procedure elsewhere and are being followed-up in the region. The details of the Registry have been described elsewhere (4). Ethics approval was granted nationally in Australia and New Zealand and by the institutional review board of participating institutions. All Fontan patients coded as heterotaxy/isomerism were identified from the Registry which included patients over a period of 42 years (1975 to 2017). Patients who died prior to discharge after the Fontan procedure and those who underwent Fontan takedown during the same admission were excluded from the study. End-points
4
The primary composite endpoint was ‘Fontan failure’. Fontan failure was defined as any of the following events: death, heart transplantation, Fontan takedown or conversion, protein-losing enteropathy, plastic bronchitis, or New York Heart Association (NYHA) functional class III or IV at follow-up. Secondary endpoints were prolonged effusions, time to first (new onset) arrhythmia episode and time to first thromboembolic event post Fontan. Re-interventions were either surgical or trans-catheter. Prolonged effusions were defined as effusions lasting for >30 days or requiring reoperation. Arrhythmia events included tachyarrhythmias or bradyarrhythmias. Tachyarrhythmias were defined as a sustained (requiring ongoing treatment) episode of supraventricular tachycardia (SVT) including atrial fibrillation or flutter and junctional tachycardia. Bradyarrhythmias included sick sinus syndrome, bradycardia and complete heart block. Thromboembolic events were defined as thrombus within the Fontan circuit, pulmonary embolism, transient ischemic attack/reversible neurological deficit (lasting 1–72 hours) or persistent stroke (lasting >72 hours). Statistical analysis Statistical analyses were performed using R software (Version 3.5.1, htpp://www.Rproject.org). Categorical data were summarised as counts and percentages and compared using Fisher’s exact test. Continuous data were summarised as mean (standard deviation [SD]) or median (interquartile range [IQR]) depending on normality of distribution and compared using the t-test or Wilcoxon rank sum test. Survival was assessed by the Kaplan–Meier method and the cumulative incidence function was estimated for time to first arrhythmia and thromboembolic events with death and heart transplantation as a competing risk. Multivariable Cox regression models for these endpoints (cause-specific Cox regression for endpoints subjected to competing risks) were 5
adjusted for: ventricular morphology, cardiac position, total anomalous pulmonary venous drainage (TAPVD), bilateral superior vena cava (SVC), interrupted inferior vena cava (IVC), pulmonary artery (PA) banding, systemic-pulmonary shunt, PA reconstruction, common atrio-ventricular (AV) valve repair or replacement, age at Fontan, Fontan type and year of Fontan procedure. Time-varying covariate Cox regression analysis was used to analyse the rate of Fontan failure in patients who experienced arrhythmia events during follow-up. Propensity-score analysis was performed to account for the baseline differences between the heterotaxy and non-heterotaxy groups. Matching was performed with the Rpackage ‘MatchIt’ using the ‘nearest’ method with a fixed caliper width of 0.1. Due to the large number of single ventricle patients available, a matching ratio of 13:1 was used with balance being adequate if the standardised mean difference (SMD) across all variables being less than 0.1. Variables (pre-Fontan or at time of Fontan) included in the propensity score matching are the same as those listed for the multivariable Cox regression analysis. Results Over the study period of 42 years (1975-2017), 1,540 Fontan patients were available for analysis. Seven percent (n=109) of patients were identified to have heterotaxy leaving 1,431 patients in the non-heterotaxy group. The baseline characteristics (pre-Fontan) of both groups are presented in Table 1. Details of the Fontan procedure for the two groups are presented in Table 2. The median age at Fontan was 5.4 years [IQR 4.2-7.9] in the heterotaxy group compared to 4.6 years [IQR 3.6-6.0] in the non-heterotaxy group (p=0.001). The extracardiac conduit was the most common type of Fontan operation in both groups. Fontan failure 6
Median follow-up for the entire study population (n=1540) was 11.9 years (IQR, 4.819.5 years). The median follow-up between the two groups was comparable (heterotaxy 12.0 years, non-heterotaxy 11.9 years, log rank p=0.3). There was no difference in 15-year freedom from Fontan failure between the two groups (heterotaxy: 78% (95% confidence interval [CI], 69% to 88%] vs non-heterotaxy: 85% [95% CI, 83% to 88%], Wald p=0.2) (Figure 1). On multivariable Cox regression, there was no association between heterotaxy and late Fontan failure (hazard ratio, 1.35 [95% CI, 0.73-2.48], p=0.3). The individual components of Fontan failure are presented in Supplementary Table 1. Secondary end-points Patients with heterotaxy had a significantly higher cumulative incidence of post-Fontan arrhythmias as compared to the non-heterotaxy group (at 15 years, heterotaxy 33.6% vs nonheterotaxy 18.1%, Wald p = 0.007) (Gray’s test p<0.001) (Figure 2). When analysed by the type of arrhythmia, patients in the heterotaxy group had a significantly higher cumulative incidence of post-Fontan tachyarrhythmias (p<0.001), but not bradyarrhythmias (p=0.96) as compared to the non-heterotaxy group (Supplementary Figure 1 A, B). There was no difference between the two groups with respect to prolonged pleural effusions, thromboembolic events (supplementary figure 2). Re-interventions apart from components of Fontan failure are depicted in supplementary table 2. Propensity score matched analysis (Heterotaxy vs Non-Heterotaxy Fontans) The propensity score model performed well with 73 heterotaxy patients matched with 439 non-heterotaxy patients (supplementary table 3). We were unable to include 'diagnosis' in the propensity model due to profound differences between the two groups with respect to primary diagnosis. However, we included 'common AV valve repair/replacement' which can be considered a surrogate marker to depict the high proportion of AVSDs in the heterotaxy 7
group. In the matched cohort, there was no difference in 15-year freedom from Fontan failure (heterotaxy: 76% (95% CI, 64% to 89%] vs non-heterotaxy: 81% [95% CI, 77% to 86%], Wald p=0.4) (Figure 3). Univariable Cox regression analysis of the propensity matched groups did not demonstrate any association between presence of heterotaxy and late Fontan failure (hazard ratio, 1.31 [95% CI, 0.76 to 2.26], p=0.3). Subgroup analysis of Heterotaxy patients A detailed comparison of right vs left isomerism with respect to baseline and Fontan characteristics is presented in supplementary table 4 and 5. Freedom from Fontan failure in heterotaxy patients was 98% (95% CI 96-100%) at 1 year, 92% (95% CI 87-98%) at 5 years, 84% (95% CI 76-92%) at 10 years, 78% (95% CI 69-89%) at 15 years and 71% (95% CI 6085%) at 20 years. On univariable analysis, the presence of TAPVD increased the risk of Fontan failure by 4 times (hazard ratio, 3.99 [95% CI, 1.58 to 10.0], p=0.003) (Supplementary Table 6). Interestingly, the age at Fontan, type of Fontan and era of Fontan were not associated with an increase in the risk of Fontan failure. New onset tachyarrhythmias were a predictor of Fontan failure (hazard ratio, 2.83 [95% CI, 1.13 to 7.07], p=0.03). There was no difference in 15-year freedom from Fontan failure in patients with right vs left isomerism (right isomerism: 80% (95% CI, 69% to 92%] vs left isomerism: 76% [95% CI, 61% to 94%], Wald p=0.7) (Figure 4). There was no difference between the two groups with respect to overall arrhythmias (p=0.5), tachyarrhythmias (p=0.4), bradyarrhythmias (p=0.5) (supplementary figure 3 A, B, C respectively) or thromboembolic events (p=0.2) (supplementary Figure 4). Comment
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There is no doubt that the presence of heterotaxy is a risk factor for early mortality in single ventricle palliation (1,5). The fact that there are only 109 (7%) such patients out of 1540 Fontans in our region over 42 years is indicative of the pre-Fontan attrition. There are numerous reasons for this fact. A large proportion of these patients have an abnormal pulmonary venous drainage necessitating surgery with a concomitant shunting procedure and it is known that the association of these two procedures is a risk factor for mortality (6). A large proportion of them have a common AV valve and the propensity for these valves to fail has been identified to be risk factor for poor outcomes (7). We also know that patients with heterotaxy are more prone to arrhythmias and our study confirms this fact (8). Though there are several studies in the literature which report outcomes of heterotaxy patients after a Fontan, drawing definite conclusions has been difficult due to the small numbers of patients in individual studies, limited follow-up and potential selection bias (9– 15). Consequently, the evidence to determine whether heterotaxy Fontans have different outcomes as compared to non-heterotaxy Fontans has been conflicting. Several studies report heterotaxy to be a risk factor for poor long term outcomes after Fontan (9–11). However, other studies report that heterotaxy is not a risk factor (12,13). This divergence in results may, in part relate to the wide variation in baseline characteristics of heterotaxy and nonheterotaxy groups, necessitating a propensity matched comparison which has not been done before. A few studies report improving outcomes of the Fontan operation for heterotaxy patients (14,15). However, these studies had a limited follow-up and lack direct comparison with a contemporary non-heterotaxy Fontan group. Stamm et al from Boston reported the outcomes of 135 heterotaxy patients after Fontan completion in 2002 (14). The 10-year survival for patients operated after 1990 was 93%. The mean follow-up was limited to 5.8 years and there was no comparison group. The largest series to date has been reported by Bartz et al from the Mayo clinic in 2006 (16). They 9
reported 142 heterotaxy Fontan patients followed for a median period of 4 years and again, did not compare with a non-heterotaxy group. The fifteen-year survival was 53%. Kim et al reported a comparison of 62 heterotaxy Fontans with 123 non-heterotaxy Fontans (12). They found no difference in survival between the two groups. The follow up was limited to 8 years and the comparison was not propensity matched. The main finding of our study is that patients with heterotaxy who have survived the Fontan procedure seem to have similar survival and similar rate of failure than those who do not share the same characteristics. Our results suggest that after the Fontan procedure, most of the pre-Fontan characteristics may be irrelevant and the outcomes determined only by the inherent imperfections of the Fontan circulation. We have previously demonstrated that arrhythmias after Fontan can manifest either as tachyarrhythmias or bradyarrhythmias (17). Heterotaxy patients are inherently prone to develop arrhythmias (8). A combination of heterotaxy with Fontan creates a highly arrhythmogenic substrate due to a self-perpetuating cycle of atrial stretch, arrhythmias, ventricular dilation and valvular regurgitation. Interestingly, the arrhythmia burden related to the presence of heterotaxy seem to be tachyarrhythmias only as there was no difference in the rate of bradyarrhythmias observed between survivors with and without heterotaxy. Since these patients have a higher rate of tachyarrhythmias, one can suspect that they will be subjected to an earlier demise of their circulation. But at least in the first 15 years following the Fontan, that does not seem to be the case and this finding cannot justify the pessimistic views shed on this patient population. Overall, right isomerism is considered to be an unfavourable heterotaxy subset as compared to left isomerism. This is due to a combination of cardiac anomalies such as TAPVD, AV valve regurgitation and non-cardiac anomalies such as asplenia (18). This has been demonstrated in several reports (19,20). However, this risk appears to be mitigated post 10
Fontan. The studies by Stamm et al and Kim et al report no difference in post-Fontan survival comparing patients having right and left isomerism (12,14). Our findings were similar – we found no difference in freedom from Fontan failure in patients with right or left isomerism. This is another reassuring fact on the quality of these hearts and their potential to maintain long-term survival. Due to small numbers and limited follow-up duration, predictors of adverse postFontan outcomes have not been consistently reported in the literature. Stamm et al identified anomalous pulmonary venous drainage as a predictor of death (14). Similarly, Bartz et al identified AV valve replacement to be a predictor of death (16). Thus, the focus of most studies has only been on ‘mortality’ as an endpoint without considering ‘Fontan failure’. In our study, by analysing a composite endpoint of Fontan failure, we have been able to provide a more comprehensive picture of long-term post-Fontan outcomes. In patients with heterotaxy, we have identified presence of TAPVD and new onset tachyarrhythmias postFontan to be predictors of long-term Fontan failure. Limitations The results of our study should be interpreted with caution. Firstly, it needs to be emphasized that the outcomes of patients with heterotaxy are comparable to the nonheterotaxy group only after Fontan survival. These results are not indicative of the overall heterotaxy subset and does not take into account the pre-Fontan deaths which are known to be substantial (5). Secondly, heterotaxy patients who reach a Fontan may be a favourable and selected subset. Thirdly, the study period spans several decades, and an era effect cannot be excluded though we have used propensity matching to minimize its impact. Our study is limited by a retrospective database which is restricted to pre-recorded variables. We have been unable to ascertain the impact of non-cardiac anomalies on the outcomes. Due to the 11
design of the database which follows patients after successful Fontan completion, we are unable to report in-hospital mortality which is known to be improving but still high (12,16). We have been unable to present and analyse hemodynamic data. It is possible that differences between the heterotaxy/non-heterotaxy groups as well as right/left isomerism groups may be evident over a longer follow-up period. Conclusion Heterotaxy is not a risk factor for long term Fontan failure. If heterotaxy patients are successfully staged to a Fontan and discharged from hospital, the outcomes are comparable to non-heterotaxy Fontans. Heterotaxy patients are at a higher risk of post-Fontan tachyarrhythmias compared to non-heterotaxy patients. There is no difference in post-Fontan outcomes of patients with right or left isomerism.
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Jonas RA. Surgical Management of the Neonate With Heterotaxy and Long-Term
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Outcomes of multistage palliation of infants with functional single ventricle and heterotaxy syndrome. J Thorac Cardiovasc Surg 2016;151(5):1369-1377e2. 6.
Nakata T, Fujimoto Y, Hirose K, Osaki M, Tosaka Y, Ide Y, et al. Functional single
ventricle with extracardiac total anomalous pulmonary venous connection. Eur J Cardiothoracic Surg 2009;36(1):49–56. 7.
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Patient With Heterotaxy Syndrome and a Functional Single Ventricle. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2012;15(1):88–95. 8.
Niu MC, Dickerson HA, Moore JA, de la Uz C, Valdés SO, Kim JJ, et al. Heterotaxy
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Driscoll DJ, Offord KP, Feldt RH, Schaff H V, Puga FJ, Danielson GK. Five- to
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Downing TE, Allen KY, Glatz AC, Rogers LS, Ravishankar C, Rychik J, et al. Long-
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Table 1: Baseline characteristics and pre-Fontan data Variable
Statistic/Level
Heterotaxy
No heterotaxy
P value
Total
Female
46 (42%)
612 (43%)
0.9
658 (43%)
Male
63 (58%)
819 (57%)
Left
28 (26%)
863 (61%)
Right
57 (53%)
449 (32%)
506 (33%)
Biventricular
12 (11%)
83 (6%)
95 (6%)
Indeterminate
11 (10%)
28 (2%)
39 (3%)
Missing
1
8
9
Normal
72 (66%)
1330 (93%)
37 (34%)
101 (7%)
0 (0%)
341 (24%)
7 (6%)
252 (18%)
259 (17%)
16 (15%)
193 (14%)
209 (14%)
AVSD
60 (55%)
61 (4%)
121 (8%)
Pulmonary Atresia
3 (3%)
157 (11%)
160 (10%)
HLHS
2 (2%)
197 (14%)
199 (13%)
ccTGA
2 (2%)
93 (7%)
95 (6%)
Other
19 (17%)
134 (9%)
153 (10%)
Missing
0
3
3
No
74 (68%)
1412 (99%)
Yes
35 (32%)
19 (1%)
No
77 (71%)
1327 (93%)
Yes
32 (29%)
104 (7%)
No
83 (76%)
1406 (98%)
Yes
26 (24%)
25 (2%)
TGA
24 (22%)
345 (24%)
0.7
369 (24%)
Hypoplastic aortic arch
3 (3%)
81 (6%)
0.3
84 (5%)
Interrupted aortic arch
1 (1%)
20 (1%)
>0.99
21 (1%)
Coarctation
9 (8%)
118 (8%)
>0.99
127 (8%)
57 (55%)
133 (10%)
<0.001
190 (13%)
BAS
2 (2%)
85 (6%)
0.08
87 (6%)
Atrial Septectomy
5 (5%)
417 (29%)
<0.001
422 (28%)
PA Band
19 (18%)
348 (25%)
0.1
367 (24%)
Systemic to pulmonary artery shunt
44 (41%)
560 (39%)
0.8
604 (40%)
Gender 882 (57%) <0.001
891 (58%)
Ventricular morphology
Cardiac position
<0.001
1402 (91%)
Dextrocardia/ 138 (9%)
Mesocardia Tricuspid Atresia
<0.001
341 (22%)
Double Inlet Left Ventricle Double
Outlet
Right Ventricle Primary diagnosis
<0.001
1486 (96%)
TAPVD 54 (4%) <0.001
1404 (91%)
Bilateral SVC 136 (9%) <0.001
1489 (97%)
Interrupted IVC 51 (3%)
Syndrome/NonYes cardiac anomaly
16
Norwood
1 (1%)
233 (16%)
<0.001
234 (15%)
ASO
1 (1%)
11 (1%)
0.6
12 (1%)
DKS
5 (5%)
142 (10%)
0.1
147 (10%)
20 (19%)
4 (0%)
Yes
24 (2%) <0.001
TAPVD repair No
87 (81%)
1416 (100%)
Aortic arch/Coarctation repair
4 (4%)
145 (10%)
0.027
149 (10%)
PA reconstruction
39 (36%)
822 (58%)
0.014
103 (7%)
BCPS
39 (36%)
822 (58%)
<0.001
861 (56%)
BCPS with forward flow
72 (67%)
931 (66%)
0.8
1003 (66%)
21 (20%)
8 (1%)
Yes
1503 (98%)
29 (2%) <0.001
Kawashima No
86 (80%)
1412 (99%)
1498 (98%)
Hemi Fontan
1 (1%)
35 (2%)
0.5
36 (2%)
LVOTO resection/enlargement of BVF
0 (0%)
9 (1%)
>0.99
9 (1%)
Tricuspid repair/replacement
3 (3%)
38 (3%)
0.8
41 (3%)
Mitral repair/replacement
1 (1%)
17 (1%)
>0.99
18 (1%)
Common AV valve repair/replacement
11 (10%)
8 (1%)
<0.001
19 (1%)
Pre-Fontan
Mean (SD)
81.4 (7.6)
82.2 (6.7)
0.3
82.2 (6.8)
Missing
31
361
Mean (SD)
11.5 (2.8)
11.5 (3.6)
Missing
30
334
Yes
21 (27%)
324 (30%)
Missing
30
337
Yes
15 (19%)
83 (8%)
Missing
31
349
Yes
2 (2%)
13 (1%)
oxygen saturation (%) Pre-Fontan mean
392 0.96
11.5 (3.5)
PA pressure (mm hg) Pre-Fontan
364 0.6
345 (29%)
systemicpulmonary
367
collaterals Pre-Fontan
0.002
98 (8%)
arterio-venous malformations
380
Pre-Fontan 0.3
15 (1%)
arrhythmia
Abbreviations: ASO = Arterial switch operation; AV = atrio-ventricular; AVSD = Atrioventricular septal defect; BAS = Balloon atrial septostomy; BCPS = Bidirectional cavopulmonary shunt; BVF = Bulboventricular foramen; ccTGA = congenitally corrected transposition of the great arteries; DKS = Damus-Kaye-Stansel procedure; HLHS = Hypoplastic left heart syndrome; IVC = inferior vena cava; LVOTO = Left ventricular 17
outflow tract obstruction; PA = Pulmonary artery, SVC = superior vena cava; TAPVD = Total anomalous pulmonary venous drainage; TGA = transposition of the great arteries; VA = ventriculo-arterial. P values in bold indicate statistically significant.
18
Table 2: Fontan characteristics No Variable
Statistic/Level
Heterotaxy
P value
Total
0.001
4.6 [3.6-6.1]
heterotaxy Age at Fontan Median [IQR]
5.4 [4.2 - 7.9]
4.6 [3.6 - 6]
(0-3]
10 (9%)
179 (13%)
39 (36%)
677 (47%)
(years)
Age at Fontan (3-5]
189 (12%) 716 (46%) 0.01
groups (years)
Adult Fontan
(5-7]
27 (25%)
323 (23%)
350 (23%)
(7-41]
33 (30%)
252 (18%)
285 (19%)
>18 years
4 (4%)
23 (2%)
AP
10 (9%)
216 (15%)
LT
19 (17%)
266 (19%)
ECC
80 (73%)
941 (66%)
1021 (67%)
Missing
0
8
8
5 (5%)
106 (7%)
1975-1989
10 (9%)
179 (13%)
1990-1999
21 (19%)
340 (24%)
0.12
27 (2%) 226 (15%)
0.2
285 (19%)
Type of Fontan
Single stage Fontan
Era of Fontan
hospital (days)
111 (7%) 189 (12%) 361 (23%)
0.4
Fenestration*
Length
0.3
2000-2009
44 (40%)
474 (33%)
518 (34%)
2010-2017
34 (31%)
438 (31%)
472 (31%)
No
73 (67%)
883 (63%)
956 (63%)
Yes
36 (33%)
527 (37%)
Missing
0
21
18 [13 - 28]
14 [11 - 21]
23
378
of Median [IQR]
0.4
563 (37%) 21
0.001
14 [11 - 22]
stay Missing
401
Abbreviations: ACC = Aortic cross clamp; AP = Atrio-pulmonary; CPB = Cardiopulmonary bypass; ECC = Extra cardiac conduit; LT = Lateral tunnel. *
Fenestration practices differ among the participating centres.
P values in bold indicate statistically significant 19
Figure Legends: Figure 1: Freedom from Fontan failure (heterotaxy vs non-heterotaxy) Kaplan-Meier analysis showing freedom from Fontan failure between heterotaxy and nonheterotaxy Fontan groups. (Overall log rank p=0.2; at 15 years, Wald p=0.2)
Figure 2: Cumulative incidence of arrhythmias (heterotaxy vs non-heterotaxy) Cumulative incidence curves comparing arrhythmias between heterotaxy and non-heterotaxy Fontan groups. (Incidence at 15 years: heterotaxy 33.6%, non-heterotaxy 18.1%, Wald p = 0.007; Gray’s test p<0.001)
Figure 3: Freedom from Fontan failure (Propensity matched) Kaplan-Meier analysis showing freedom from Fontan failure between propensity matched heterotaxy and non-heterotaxy Fontan groups. (Overall log rank p=0.2; at 15 years, Wald p=0.4)
Figure 4: Freedom from Fontan failure (right vs left isomerism) Kaplan-Meier analysis showing freedom from Fontan failure between right isomerism and left isomerism heterotaxy Fontan groups. (Overall log rank p=0.7; at 15 years, Wald p=0.7)
20
S0003-4975(19)31974-5
DOI:
https://doi.org/10.1016/j.athoracsur.2019.11.015
Reference:
ATS 33350
To appear in:
The Annals of Thoracic Surgery
Received Date: 9 September 2019 Revised Date:
31 October 2019
Accepted Date: 4 November 2019
Please cite this article as: Marathe SP, Zannino D, Cao JY, du Plessis K, Marathe SS, Ayer J, Celermajer DS, Gentles TL, Sholler GF, Justo RN, Alphonso N, d’Udekem Y, Winlaw DS, Heterotaxy is not a risk factor for adverse long-term outcomes following Fontan completion, The Annals of Thoracic Surgery (2020), doi: https://doi.org/10.1016/j.athoracsur.2019.11.015. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 by The Society of Thoracic Surgeons
Heterotaxy is not a risk factor for adverse long-term outcomes following Fontan completion Running Head: Heterotaxy outcomes after Fontan Supreet P. Marathe, MCh1,2, Diana Zannino, MSc3, Jacob Y. Cao, MBBS 4,5, Karin du Plessis, PhD3,6, Shilpa S. Marathe, MD1, Julian Ayer, FRACP7,8,9, David S. Celermajer, FRACP4,5, Thomas L. Gentles, FRACP10, Gary F. Sholler, FRACP7,8,9, Robert N. Justo, FRACP1,2, Nelson Alphonso, FRACS1,2, Yves d’Udekem, MD 3,6,11, David S. Winlaw, FRACS 7,8,9 1
Queensland Children’s Hospital, Brisbane, Australia
2
University of Queensland, Brisbane, Australia
3
Murdoch Children’s Research Institute, Melbourne, Australia
4
Sydney Medical School, University of Sydney, Sydney, Australia
5
Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia
6
Department of Pediatrics, Faculty of Medicine, University of Melbourne, Melbourne, Australia
7
Heart Centre for Children, The Children’s Hospital at Westmead, Sydney, Australia
8
Faculty of Health and Medicine, Sydney Medical School, Discipline of Child and Adolescent Health, University of Sydney, Sydney, Australia
9
Sydney Children’s Hospital Network Cardiac Services, Sydney, Australia
10
Starship Green Lane Pediatric and Congenital Cardiac Service, Starship Children’s
Hospital, Auckland, New Zealand 11
Royal Children’s Hospital, Melbourne, Australia
Keywords: Single ventricle, Fontan, heterotaxy, isomerism 1
Word count: 4542 Corresponding author: Prof. David S. Winlaw Pediatric Cardiothoracic Surgeon Heart Centre for Children, The Children’s Hospital at Westmead, WESTMEAD NSW 2145, AUSTRALIA [email protected]
2
Abstract Background: Heterotaxy is considered to be a risk factor for poor outcomes after the Fontan operation. However, long-term data to support this notion are lacking. The aim of our study was to ascertain the long-term outcomes of patients with heterotaxy following hospital discharge after Fontan completion and compare them with a contemporary non-heterotaxy cohort. Methods: A bi-national Fontan Registry (n =1,540) was analysed to identify heterotaxy patients and compare with non-heterotaxy patients. The primary composite end point was ‘Fontan failure’ encompassing death, heart transplantation, Fontan takedown or conversion, protein-losing enteropathy, plastic bronchitis, or New York Heart Association functional class III or IV. Results: One hundred and nine heterotaxy patients were identified which were compared with 1,431 non-heterotaxy Fontans following Fontan completion. There was no difference in unadjusted 15-year freedom from Fontan failure (heterotaxy: 78% vs non-heterotaxy: 85%, p=0.2). Patients in the heterotaxy group had a significantly higher cumulative incidence of post-Fontan arrhythmias (p<0.001). Propensity-score matching for confounders yielded 73 heterotaxy patients matched with 439 non-heterotaxy patients, in which 15-year freedom from Fontan failure was also not different (heterotaxy: 76% vs non-heterotaxy: 81%, p=0.2). There was no difference in 15-year freedom from Fontan failure in patients with right vs left isomerism (right isomerism: 80% vs left isomerism: 76%, p=0.7). Conclusions: Whilst heterotaxy may complicate the pre-Fontan course, once the Fontan is successfully completed it does not appear to be an important risk factor for Fontan failure. Heterotaxy patients are at a higher risk of post Fontan arrhythmias compared to nonheterotaxy patients. 3
Patients with heterotaxy present a challenging surgical substrate due to a multitude of problems occurring in tandem (1,2). Many of these patients are destined for the single ventricle (Fontan) pathway as biventricular repair is not possible. Traditionally, heterotaxy is considered to be a risk factor for poor outcomes after the Fontan operation (3). However, the interpretation of these studies is hampered by discrepancies in centre-specific practices, duration of follow-up, and the lack of a matched non-heterotaxy Fontan comparison group (1). It is unclear whether the presence of heterotaxy remains a risk factor impacting mortality and increasing the risks of failure of the Fontan circulation in the decades following this operation. In order to clarify this association, we decided to study these outcomes in the patients of the Australia-New Zealand Fontan Registry which collects health data for periods extending to 42 years. Patients and Methods The Australia-New Zealand Fontan Registry includes patients who have undergone the Fontan operation in either country or have undergone their procedure elsewhere and are being followed-up in the region. The details of the Registry have been described elsewhere (4). Ethics approval was granted nationally in Australia and New Zealand and by the institutional review board of participating institutions. All Fontan patients coded as heterotaxy/isomerism were identified from the Registry which included patients over a period of 42 years (1975 to 2017). Patients who died prior to discharge after the Fontan procedure and those who underwent Fontan takedown during the same admission were excluded from the study. End-points
4
The primary composite endpoint was ‘Fontan failure’. Fontan failure was defined as any of the following events: death, heart transplantation, Fontan takedown or conversion, protein-losing enteropathy, plastic bronchitis, or New York Heart Association (NYHA) functional class III or IV at follow-up. Secondary endpoints were prolonged effusions, time to first (new onset) arrhythmia episode and time to first thromboembolic event post Fontan. Re-interventions were either surgical or trans-catheter. Prolonged effusions were defined as effusions lasting for >30 days or requiring reoperation. Arrhythmia events included tachyarrhythmias or bradyarrhythmias. Tachyarrhythmias were defined as a sustained (requiring ongoing treatment) episode of supraventricular tachycardia (SVT) including atrial fibrillation or flutter and junctional tachycardia. Bradyarrhythmias included sick sinus syndrome, bradycardia and complete heart block. Thromboembolic events were defined as thrombus within the Fontan circuit, pulmonary embolism, transient ischemic attack/reversible neurological deficit (lasting 1–72 hours) or persistent stroke (lasting >72 hours). Statistical analysis Statistical analyses were performed using R software (Version 3.5.1, htpp://www.Rproject.org). Categorical data were summarised as counts and percentages and compared using Fisher’s exact test. Continuous data were summarised as mean (standard deviation [SD]) or median (interquartile range [IQR]) depending on normality of distribution and compared using the t-test or Wilcoxon rank sum test. Survival was assessed by the Kaplan–Meier method and the cumulative incidence function was estimated for time to first arrhythmia and thromboembolic events with death and heart transplantation as a competing risk. Multivariable Cox regression models for these endpoints (cause-specific Cox regression for endpoints subjected to competing risks) were 5
adjusted for: ventricular morphology, cardiac position, total anomalous pulmonary venous drainage (TAPVD), bilateral superior vena cava (SVC), interrupted inferior vena cava (IVC), pulmonary artery (PA) banding, systemic-pulmonary shunt, PA reconstruction, common atrio-ventricular (AV) valve repair or replacement, age at Fontan, Fontan type and year of Fontan procedure. Time-varying covariate Cox regression analysis was used to analyse the rate of Fontan failure in patients who experienced arrhythmia events during follow-up. Propensity-score analysis was performed to account for the baseline differences between the heterotaxy and non-heterotaxy groups. Matching was performed with the Rpackage ‘MatchIt’ using the ‘nearest’ method with a fixed caliper width of 0.1. Due to the large number of single ventricle patients available, a matching ratio of 13:1 was used with balance being adequate if the standardised mean difference (SMD) across all variables being less than 0.1. Variables (pre-Fontan or at time of Fontan) included in the propensity score matching are the same as those listed for the multivariable Cox regression analysis. Results Over the study period of 42 years (1975-2017), 1,540 Fontan patients were available for analysis. Seven percent (n=109) of patients were identified to have heterotaxy leaving 1,431 patients in the non-heterotaxy group. The baseline characteristics (pre-Fontan) of both groups are presented in Table 1. Details of the Fontan procedure for the two groups are presented in Table 2. The median age at Fontan was 5.4 years [IQR 4.2-7.9] in the heterotaxy group compared to 4.6 years [IQR 3.6-6.0] in the non-heterotaxy group (p=0.001). The extracardiac conduit was the most common type of Fontan operation in both groups. Fontan failure 6
Median follow-up for the entire study population (n=1540) was 11.9 years (IQR, 4.819.5 years). The median follow-up between the two groups was comparable (heterotaxy 12.0 years, non-heterotaxy 11.9 years, log rank p=0.3). There was no difference in 15-year freedom from Fontan failure between the two groups (heterotaxy: 78% (95% confidence interval [CI], 69% to 88%] vs non-heterotaxy: 85% [95% CI, 83% to 88%], Wald p=0.2) (Figure 1). On multivariable Cox regression, there was no association between heterotaxy and late Fontan failure (hazard ratio, 1.35 [95% CI, 0.73-2.48], p=0.3). The individual components of Fontan failure are presented in Supplementary Table 1. Secondary end-points Patients with heterotaxy had a significantly higher cumulative incidence of post-Fontan arrhythmias as compared to the non-heterotaxy group (at 15 years, heterotaxy 33.6% vs nonheterotaxy 18.1%, Wald p = 0.007) (Gray’s test p<0.001) (Figure 2). When analysed by the type of arrhythmia, patients in the heterotaxy group had a significantly higher cumulative incidence of post-Fontan tachyarrhythmias (p<0.001), but not bradyarrhythmias (p=0.96) as compared to the non-heterotaxy group (Supplementary Figure 1 A, B). There was no difference between the two groups with respect to prolonged pleural effusions, thromboembolic events (supplementary figure 2). Re-interventions apart from components of Fontan failure are depicted in supplementary table 2. Propensity score matched analysis (Heterotaxy vs Non-Heterotaxy Fontans) The propensity score model performed well with 73 heterotaxy patients matched with 439 non-heterotaxy patients (supplementary table 3). We were unable to include 'diagnosis' in the propensity model due to profound differences between the two groups with respect to primary diagnosis. However, we included 'common AV valve repair/replacement' which can be considered a surrogate marker to depict the high proportion of AVSDs in the heterotaxy 7
group. In the matched cohort, there was no difference in 15-year freedom from Fontan failure (heterotaxy: 76% (95% CI, 64% to 89%] vs non-heterotaxy: 81% [95% CI, 77% to 86%], Wald p=0.4) (Figure 3). Univariable Cox regression analysis of the propensity matched groups did not demonstrate any association between presence of heterotaxy and late Fontan failure (hazard ratio, 1.31 [95% CI, 0.76 to 2.26], p=0.3). Subgroup analysis of Heterotaxy patients A detailed comparison of right vs left isomerism with respect to baseline and Fontan characteristics is presented in supplementary table 4 and 5. Freedom from Fontan failure in heterotaxy patients was 98% (95% CI 96-100%) at 1 year, 92% (95% CI 87-98%) at 5 years, 84% (95% CI 76-92%) at 10 years, 78% (95% CI 69-89%) at 15 years and 71% (95% CI 6085%) at 20 years. On univariable analysis, the presence of TAPVD increased the risk of Fontan failure by 4 times (hazard ratio, 3.99 [95% CI, 1.58 to 10.0], p=0.003) (Supplementary Table 6). Interestingly, the age at Fontan, type of Fontan and era of Fontan were not associated with an increase in the risk of Fontan failure. New onset tachyarrhythmias were a predictor of Fontan failure (hazard ratio, 2.83 [95% CI, 1.13 to 7.07], p=0.03). There was no difference in 15-year freedom from Fontan failure in patients with right vs left isomerism (right isomerism: 80% (95% CI, 69% to 92%] vs left isomerism: 76% [95% CI, 61% to 94%], Wald p=0.7) (Figure 4). There was no difference between the two groups with respect to overall arrhythmias (p=0.5), tachyarrhythmias (p=0.4), bradyarrhythmias (p=0.5) (supplementary figure 3 A, B, C respectively) or thromboembolic events (p=0.2) (supplementary Figure 4). Comment
8
There is no doubt that the presence of heterotaxy is a risk factor for early mortality in single ventricle palliation (1,5). The fact that there are only 109 (7%) such patients out of 1540 Fontans in our region over 42 years is indicative of the pre-Fontan attrition. There are numerous reasons for this fact. A large proportion of these patients have an abnormal pulmonary venous drainage necessitating surgery with a concomitant shunting procedure and it is known that the association of these two procedures is a risk factor for mortality (6). A large proportion of them have a common AV valve and the propensity for these valves to fail has been identified to be risk factor for poor outcomes (7). We also know that patients with heterotaxy are more prone to arrhythmias and our study confirms this fact (8). Though there are several studies in the literature which report outcomes of heterotaxy patients after a Fontan, drawing definite conclusions has been difficult due to the small numbers of patients in individual studies, limited follow-up and potential selection bias (9– 15). Consequently, the evidence to determine whether heterotaxy Fontans have different outcomes as compared to non-heterotaxy Fontans has been conflicting. Several studies report heterotaxy to be a risk factor for poor long term outcomes after Fontan (9–11). However, other studies report that heterotaxy is not a risk factor (12,13). This divergence in results may, in part relate to the wide variation in baseline characteristics of heterotaxy and nonheterotaxy groups, necessitating a propensity matched comparison which has not been done before. A few studies report improving outcomes of the Fontan operation for heterotaxy patients (14,15). However, these studies had a limited follow-up and lack direct comparison with a contemporary non-heterotaxy Fontan group. Stamm et al from Boston reported the outcomes of 135 heterotaxy patients after Fontan completion in 2002 (14). The 10-year survival for patients operated after 1990 was 93%. The mean follow-up was limited to 5.8 years and there was no comparison group. The largest series to date has been reported by Bartz et al from the Mayo clinic in 2006 (16). They 9
reported 142 heterotaxy Fontan patients followed for a median period of 4 years and again, did not compare with a non-heterotaxy group. The fifteen-year survival was 53%. Kim et al reported a comparison of 62 heterotaxy Fontans with 123 non-heterotaxy Fontans (12). They found no difference in survival between the two groups. The follow up was limited to 8 years and the comparison was not propensity matched. The main finding of our study is that patients with heterotaxy who have survived the Fontan procedure seem to have similar survival and similar rate of failure than those who do not share the same characteristics. Our results suggest that after the Fontan procedure, most of the pre-Fontan characteristics may be irrelevant and the outcomes determined only by the inherent imperfections of the Fontan circulation. We have previously demonstrated that arrhythmias after Fontan can manifest either as tachyarrhythmias or bradyarrhythmias (17). Heterotaxy patients are inherently prone to develop arrhythmias (8). A combination of heterotaxy with Fontan creates a highly arrhythmogenic substrate due to a self-perpetuating cycle of atrial stretch, arrhythmias, ventricular dilation and valvular regurgitation. Interestingly, the arrhythmia burden related to the presence of heterotaxy seem to be tachyarrhythmias only as there was no difference in the rate of bradyarrhythmias observed between survivors with and without heterotaxy. Since these patients have a higher rate of tachyarrhythmias, one can suspect that they will be subjected to an earlier demise of their circulation. But at least in the first 15 years following the Fontan, that does not seem to be the case and this finding cannot justify the pessimistic views shed on this patient population. Overall, right isomerism is considered to be an unfavourable heterotaxy subset as compared to left isomerism. This is due to a combination of cardiac anomalies such as TAPVD, AV valve regurgitation and non-cardiac anomalies such as asplenia (18). This has been demonstrated in several reports (19,20). However, this risk appears to be mitigated post 10
Fontan. The studies by Stamm et al and Kim et al report no difference in post-Fontan survival comparing patients having right and left isomerism (12,14). Our findings were similar – we found no difference in freedom from Fontan failure in patients with right or left isomerism. This is another reassuring fact on the quality of these hearts and their potential to maintain long-term survival. Due to small numbers and limited follow-up duration, predictors of adverse postFontan outcomes have not been consistently reported in the literature. Stamm et al identified anomalous pulmonary venous drainage as a predictor of death (14). Similarly, Bartz et al identified AV valve replacement to be a predictor of death (16). Thus, the focus of most studies has only been on ‘mortality’ as an endpoint without considering ‘Fontan failure’. In our study, by analysing a composite endpoint of Fontan failure, we have been able to provide a more comprehensive picture of long-term post-Fontan outcomes. In patients with heterotaxy, we have identified presence of TAPVD and new onset tachyarrhythmias postFontan to be predictors of long-term Fontan failure. Limitations The results of our study should be interpreted with caution. Firstly, it needs to be emphasized that the outcomes of patients with heterotaxy are comparable to the nonheterotaxy group only after Fontan survival. These results are not indicative of the overall heterotaxy subset and does not take into account the pre-Fontan deaths which are known to be substantial (5). Secondly, heterotaxy patients who reach a Fontan may be a favourable and selected subset. Thirdly, the study period spans several decades, and an era effect cannot be excluded though we have used propensity matching to minimize its impact. Our study is limited by a retrospective database which is restricted to pre-recorded variables. We have been unable to ascertain the impact of non-cardiac anomalies on the outcomes. Due to the 11
design of the database which follows patients after successful Fontan completion, we are unable to report in-hospital mortality which is known to be improving but still high (12,16). We have been unable to present and analyse hemodynamic data. It is possible that differences between the heterotaxy/non-heterotaxy groups as well as right/left isomerism groups may be evident over a longer follow-up period. Conclusion Heterotaxy is not a risk factor for long term Fontan failure. If heterotaxy patients are successfully staged to a Fontan and discharged from hospital, the outcomes are comparable to non-heterotaxy Fontans. Heterotaxy patients are at a higher risk of post-Fontan tachyarrhythmias compared to non-heterotaxy patients. There is no difference in post-Fontan outcomes of patients with right or left isomerism.
12
References: 1.
Jonas RA. Surgical Management of the Neonate With Heterotaxy and Long-Term
Outcomes of Heterotaxy. World J Pediatr Congenit Hear Surg 2011;2(2):264–74. 2.
Kothari S. Non-cardiac issues in patients with heterotaxy syndrome. Ann Pediatr
Cardiol 2014;7(3):187. 3.
Kouchoukos NT, Blackstone EH, Hanley FL, Kirklin JK. No Title. In:
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Iyengar AJ, Winlaw DS, Galati JC, Gentles TL, Weintraub RG, Justo RN, et al. The
Australia and New Zealand fontan registry: Description and initial results from the first population-based fontan registry. Intern Med J 2014;44(2):148–55. 5.
Alsoufi B, McCracken C, Schlosser B, Sachdeva R, Well A, Kogon B, et al.
Outcomes of multistage palliation of infants with functional single ventricle and heterotaxy syndrome. J Thorac Cardiovasc Surg 2016;151(5):1369-1377e2. 6.
Nakata T, Fujimoto Y, Hirose K, Osaki M, Tosaka Y, Ide Y, et al. Functional single
ventricle with extracardiac total anomalous pulmonary venous connection. Eur J Cardiothoracic Surg 2009;36(1):49–56. 7.
Kasahara S, Arai S, Tateishi A, Sano S, Fujii Y. Atrioventricular Valve Repair for
Patient With Heterotaxy Syndrome and a Functional Single Ventricle. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2012;15(1):88–95. 8.
Niu MC, Dickerson HA, Moore JA, de la Uz C, Valdés SO, Kim JJ, et al. Heterotaxy
syndrome and associated arrhythmias in pediatric patients. Hear Rhythm 2018;15(4):548–54. 9.
Driscoll DJ, Offord KP, Feldt RH, Schaff H V, Puga FJ, Danielson GK. Five- to
fifteen-year follow-up after Fontan operation. Circulation 1992;85(2):469–96.
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D’Udekem Y, Xu MY, Galati JC, Lu S, Iyengar AJ, Konstantinov IE, et al. Predictors
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Follow-Up after the Fontan Operation Long-Term Outcomes of 1,052 Patients. J Am Coll Cardiol 2015;66(15):1700–10. 12.
Kim SJ, Kim WH, Lim HG, Lee CH, Lee JY. Improving Results of the Fontan
Procedure in Patients With Heterotaxy Syndrome. Ann Thorac Surg 2006;82(4):1245–51. 13.
Downing TE, Allen KY, Glatz AC, Rogers LS, Ravishankar C, Rychik J, et al. Long-
term survival after the Fontan operation: Twenty years of experience at a single center. J Thorac Cardiovasc Surg 2017;154(1):243-253.e2. 14.
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Bartz PJ, Driscoll DJ, Dearani JA, Puga FJ, Danielson GK, O’Leary PW, et al. Early
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15
Table 1: Baseline characteristics and pre-Fontan data Variable
Statistic/Level
Heterotaxy
No heterotaxy
P value
Total
Female
46 (42%)
612 (43%)
0.9
658 (43%)
Male
63 (58%)
819 (57%)
Left
28 (26%)
863 (61%)
Right
57 (53%)
449 (32%)
506 (33%)
Biventricular
12 (11%)
83 (6%)
95 (6%)
Indeterminate
11 (10%)
28 (2%)
39 (3%)
Missing
1
8
9
Normal
72 (66%)
1330 (93%)
37 (34%)
101 (7%)
0 (0%)
341 (24%)
7 (6%)
252 (18%)
259 (17%)
16 (15%)
193 (14%)
209 (14%)
AVSD
60 (55%)
61 (4%)
121 (8%)
Pulmonary Atresia
3 (3%)
157 (11%)
160 (10%)
HLHS
2 (2%)
197 (14%)
199 (13%)
ccTGA
2 (2%)
93 (7%)
95 (6%)
Other
19 (17%)
134 (9%)
153 (10%)
Missing
0
3
3
No
74 (68%)
1412 (99%)
Yes
35 (32%)
19 (1%)
No
77 (71%)
1327 (93%)
Yes
32 (29%)
104 (7%)
No
83 (76%)
1406 (98%)
Yes
26 (24%)
25 (2%)
TGA
24 (22%)
345 (24%)
0.7
369 (24%)
Hypoplastic aortic arch
3 (3%)
81 (6%)
0.3
84 (5%)
Interrupted aortic arch
1 (1%)
20 (1%)
>0.99
21 (1%)
Coarctation
9 (8%)
118 (8%)
>0.99
127 (8%)
57 (55%)
133 (10%)
<0.001
190 (13%)
BAS
2 (2%)
85 (6%)
0.08
87 (6%)
Atrial Septectomy
5 (5%)
417 (29%)
<0.001
422 (28%)
PA Band
19 (18%)
348 (25%)
0.1
367 (24%)
Systemic to pulmonary artery shunt
44 (41%)
560 (39%)
0.8
604 (40%)
Gender 882 (57%) <0.001
891 (58%)
Ventricular morphology
Cardiac position
<0.001
1402 (91%)
Dextrocardia/ 138 (9%)
Mesocardia Tricuspid Atresia
<0.001
341 (22%)
Double Inlet Left Ventricle Double
Outlet
Right Ventricle Primary diagnosis
<0.001
1486 (96%)
TAPVD 54 (4%) <0.001
1404 (91%)
Bilateral SVC 136 (9%) <0.001
1489 (97%)
Interrupted IVC 51 (3%)
Syndrome/NonYes cardiac anomaly
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Norwood
1 (1%)
233 (16%)
<0.001
234 (15%)
ASO
1 (1%)
11 (1%)
0.6
12 (1%)
DKS
5 (5%)
142 (10%)
0.1
147 (10%)
20 (19%)
4 (0%)
Yes
24 (2%) <0.001
TAPVD repair No
87 (81%)
1416 (100%)
Aortic arch/Coarctation repair
4 (4%)
145 (10%)
0.027
149 (10%)
PA reconstruction
39 (36%)
822 (58%)
0.014
103 (7%)
BCPS
39 (36%)
822 (58%)
<0.001
861 (56%)
BCPS with forward flow
72 (67%)
931 (66%)
0.8
1003 (66%)
21 (20%)
8 (1%)
Yes
1503 (98%)
29 (2%) <0.001
Kawashima No
86 (80%)
1412 (99%)
1498 (98%)
Hemi Fontan
1 (1%)
35 (2%)
0.5
36 (2%)
LVOTO resection/enlargement of BVF
0 (0%)
9 (1%)
>0.99
9 (1%)
Tricuspid repair/replacement
3 (3%)
38 (3%)
0.8
41 (3%)
Mitral repair/replacement
1 (1%)
17 (1%)
>0.99
18 (1%)
Common AV valve repair/replacement
11 (10%)
8 (1%)
<0.001
19 (1%)
Pre-Fontan
Mean (SD)
81.4 (7.6)
82.2 (6.7)
0.3
82.2 (6.8)
Missing
31
361
Mean (SD)
11.5 (2.8)
11.5 (3.6)
Missing
30
334
Yes
21 (27%)
324 (30%)
Missing
30
337
Yes
15 (19%)
83 (8%)
Missing
31
349
Yes
2 (2%)
13 (1%)
oxygen saturation (%) Pre-Fontan mean
392 0.96
11.5 (3.5)
PA pressure (mm hg) Pre-Fontan
364 0.6
345 (29%)
systemicpulmonary
367
collaterals Pre-Fontan
0.002
98 (8%)
arterio-venous malformations
380
Pre-Fontan 0.3
15 (1%)
arrhythmia
Abbreviations: ASO = Arterial switch operation; AV = atrio-ventricular; AVSD = Atrioventricular septal defect; BAS = Balloon atrial septostomy; BCPS = Bidirectional cavopulmonary shunt; BVF = Bulboventricular foramen; ccTGA = congenitally corrected transposition of the great arteries; DKS = Damus-Kaye-Stansel procedure; HLHS = Hypoplastic left heart syndrome; IVC = inferior vena cava; LVOTO = Left ventricular 17
outflow tract obstruction; PA = Pulmonary artery, SVC = superior vena cava; TAPVD = Total anomalous pulmonary venous drainage; TGA = transposition of the great arteries; VA = ventriculo-arterial. P values in bold indicate statistically significant.
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Table 2: Fontan characteristics No Variable
Statistic/Level
Heterotaxy
P value
Total
0.001
4.6 [3.6-6.1]
heterotaxy Age at Fontan Median [IQR]
5.4 [4.2 - 7.9]
4.6 [3.6 - 6]
(0-3]
10 (9%)
179 (13%)
39 (36%)
677 (47%)
(years)
Age at Fontan (3-5]
189 (12%) 716 (46%) 0.01
groups (years)
Adult Fontan
(5-7]
27 (25%)
323 (23%)
350 (23%)
(7-41]
33 (30%)
252 (18%)
285 (19%)
>18 years
4 (4%)
23 (2%)
AP
10 (9%)
216 (15%)
LT
19 (17%)
266 (19%)
ECC
80 (73%)
941 (66%)
1021 (67%)
Missing
0
8
8
5 (5%)
106 (7%)
1975-1989
10 (9%)
179 (13%)
1990-1999
21 (19%)
340 (24%)
0.12
27 (2%) 226 (15%)
0.2
285 (19%)
Type of Fontan
Single stage Fontan
Era of Fontan
hospital (days)
111 (7%) 189 (12%) 361 (23%)
0.4
Fenestration*
Length
0.3
2000-2009
44 (40%)
474 (33%)
518 (34%)
2010-2017
34 (31%)
438 (31%)
472 (31%)
No
73 (67%)
883 (63%)
956 (63%)
Yes
36 (33%)
527 (37%)
Missing
0
21
18 [13 - 28]
14 [11 - 21]
23
378
of Median [IQR]
0.4
563 (37%) 21
0.001
14 [11 - 22]
stay Missing
401
Abbreviations: ACC = Aortic cross clamp; AP = Atrio-pulmonary; CPB = Cardiopulmonary bypass; ECC = Extra cardiac conduit; LT = Lateral tunnel. *
Fenestration practices differ among the participating centres.
P values in bold indicate statistically significant 19
Figure Legends: Figure 1: Freedom from Fontan failure (heterotaxy vs non-heterotaxy) Kaplan-Meier analysis showing freedom from Fontan failure between heterotaxy and nonheterotaxy Fontan groups. (Overall log rank p=0.2; at 15 years, Wald p=0.2)
Figure 2: Cumulative incidence of arrhythmias (heterotaxy vs non-heterotaxy) Cumulative incidence curves comparing arrhythmias between heterotaxy and non-heterotaxy Fontan groups. (Incidence at 15 years: heterotaxy 33.6%, non-heterotaxy 18.1%, Wald p = 0.007; Gray’s test p<0.001)
Figure 3: Freedom from Fontan failure (Propensity matched) Kaplan-Meier analysis showing freedom from Fontan failure between propensity matched heterotaxy and non-heterotaxy Fontan groups. (Overall log rank p=0.2; at 15 years, Wald p=0.4)
Figure 4: Freedom from Fontan failure (right vs left isomerism) Kaplan-Meier analysis showing freedom from Fontan failure between right isomerism and left isomerism heterotaxy Fontan groups. (Overall log rank p=0.7; at 15 years, Wald p=0.7)
20