95th Annual Meeting: American Association for Thoracic Surgery Late survival and RV performance in matched children after Norwood: Norwood-BT vs Norwood-Sano Travis Wilder Brian McCrindle Alistair Phillips Eugene Blackstone Rajeswaran Jeevanantham William Williams William DeCampli Jeffery Jacobs Marshall Jacobs Tara Karamlou Paul Kirshbom Gary Lofland Gerhard Ziemer Edward Hickey Good morning, Dr. Ohye, members and guests 95th Annual Meeting: American Association for Thoracic Surgery 2015, Seattle, WA

No disclosures

Congenital Heart Surgeons’ Society N = 692 Neonates Critical Left Ventricular Outflow Tract Obstruction 2005 – 2014: 21 Institutions Aortic atresia/critical AS Ductal-dependent The Congenital heart surgeons society has enrolled 692 neonates with critical Left ventricular outflow tract obstruction into a research database since 2005…

Congenital Heart Surgeons’ Society N = 692 Neonates Critical Left Ventricular Outflow Tract Obstruction 2005 – 2014: 21 Institutions Aortic atresia/critical AS Ductal-dependent Aortic Valvotomy n = 107 Ross-Konno/ Yasui n = 8 Transplant n = 5 Norwood n = 454 Hybrid n = 110 and because this is an all-inclusive inception cohort, covering a broad spectrum of disease, neonates were managed with a variety of initial procedures; however, the majority – 454 – underwent a stage-1 Norwood operation…

Stage-1 Norwood n = 454 BT (51%) n = 232 SANO (49%) n = 222 Ohye RG, et al. NEJM, 362;21 May, 2010 Ohye RG, et al. NEJM, 362;21 May, 2010 …which included 232 Norwood-BT shunt operations and 222 Norwood operations with Sano modifications … and recently the Sano operation has been shown to have improved early survival However, the enthusiasm for the Sano operation has somewhat diminished because of concerns surrounding long-term ventricular dysfunction

BT vs SANO Difference in survival Difference in RV dysfunction Difference in tricuspid regurgitation So we set out to determine the difference is long-term survival, RV dysfunction and TR

Overall survival for all children SANO 71% 59% % Survival P < 0.001 BT Among all children, the overall, unadjusted survival was superior after a Sano; however, comparing survival among all children from each group doesn’t adjusted for potential baseline differences between the groups… so in order to try and compare apples to apples our analysis focused on a subset of propensity-matched children… Years after Norwood

Propensity-Matching 100% BT vs SANO 100% And to briefly conceptualize this strategy, consider the red boxes represent all children who had a BT, blue boxes are children who had a SANO and the shapes are variations in baseline characteristics … Using a propensity-score, generated from these baseline characteristics we identified, as close as possible similar children in each group...

Matched Children BT (75%) n = 169 SANO (74%) n = 169 n = 338 which subsequently resulted in 169 matched-pairs, or about three-quarters of all children who underwent a Norwood…

Age at operation (days) 6.5 ± 5 6.3 ± 5 .14 Birth weight (kg)   BT (169) SANO (169) Variable Value P Age at operation (days) 6.5 ± 5 6.3 ± 5 .14 Birth weight (kg) 3.2 ± 0.4 3.2 ± 0.5 .92 Birth weight < 2.5 kg 9 (5%) 11 (7%) .61 BSA at operation (m2) 0.21 ± 0.02 .71 Aortic valve annulus (cm) 0.15 ± 0.2 0.14 ± 0.2 .82 Aortic valve atresia 90 (55%) 89 (57%) .74 TV annulus (cm) 1.3 ± .2 .77 MV annulus (cm) .24 ± .3 .22 ± .4 .44 Mitral valve atresia 70 (45%) 75 (48%) AI 22 (15%) 19 (13%) Transverse arch coarctation 52 (32%) 50 (30%) .81 Small/restrictive ASD 54 (44%) 49 (41%) .67 Important RV dysfunction 2 (1%) .97 Important TR 10 (6%) 14 (9%) .42 Renal insufficiency 1 (1%) 2 ( 1%) .56 Metabolic acidosis 20 (12%) 1 …and this list of baseline characteristics…

Age at operation (days) 6.5 ± 5 6.3 ± 5 .14 Birth weight (kg)   BT (169) SANO (169) Variable Value P Age at operation (days) 6.5 ± 5 6.3 ± 5 .14 Birth weight (kg) 3.2 ± 0.4 3.2 ± 0.5 .92 Birth weight < 2.5 kg 9 (5%) 11 (7%) .61 BSA at operation (m2) 0.21 ± 0.02 .71 Aortic valve annulus (cm) 0.15 ± 0.2 0.14 ± 0.2 .82 Aortic valve atresia 90 (55%) 89 (57%) .74 TV annulus (cm) 1.3 ± .2 .77 MV annulus (cm) .24 ± .3 .22 ± .4 .44 Mitral valve atresia 70 (45%) 75 (48%) AI 22 (15%) 19 (13%) Transverse arch coarctation 52 (32%) 50 (30%) .81 Small/restrictive ASD 54 (44%) 49 (41%) .67 Important RV dysfunction 2 (1%) .97 Important TR 10 (6%) 14 (9%) .42 Renal insufficiency 1 (1%) 2 ( 1%) .56 Metabolic acidosis 20 (12%) 1 …shows a similar baseline profile between groups…

Age at operation (days) 6.5 ± 5 6.3 ± 5 .14 Birth weight (kg)   BT (169) SANO (169) Variable Value P Age at operation (days) 6.5 ± 5 6.3 ± 5 .14 Birth weight (kg) 3.2 ± 0.4 3.2 ± 0.5 .92 Birth weight < 2.5 kg 9 (5%) 11 (7%) .61 BSA at operation (m2) 0.21 ± 0.02 .71 Aortic valve annulus (cm) 0.15 ± 0.2 0.14 ± 0.2 .82 Aortic valve atresia 90 (55%) 89 (57%) .74 TV annulus (cm) 1.3 ± .2 .77 MV annulus (cm) .24 ± .3 .22 ± .4 .44 Mitral valve atresia 70 (45%) 75 (48%) AI 22 (15%) 19 (13%) Transverse arch coarctation 52 (32%) 50 (30%) .81 Small/restrictive ASD 54 (44%) 49 (41%) .67 Important RV dysfunction 2 (1%) .97 Important TR 10 (6%) 14 (9%) .42 Renal insufficiency 1 (1%) 2 ( 1%) .56 Metabolic acidosis 20 (12%) 1 Including key variables such as birth weight

Age at operation (days) 6.5 ± 5 6.3 ± 5 .14 Birth weight (kg)   BT (169) SANO (169) Variable Value P Age at operation (days) 6.5 ± 5 6.3 ± 5 .14 Birth weight (kg) 3.2 ± 0.4 3.2 ± 0.5 .92 Birth weight < 2.5 kg 9 (5%) 11 (7%) .61 BSA at operation (m2) 0.21 ± 0.02 .71 Aortic valve annulus (cm) 0.15 ± 0.2 0.14 ± 0.2 .82 Aortic valve atresia 90 (55%) 89 (57%) .74 TV annulus (cm) 1.3 ± .2 .77 MV annulus (cm) .24 ± .3 .22 ± .4 .44 Mitral valve atresia 70 (45%) 75 (48%) AI 22 (15%) 19 (13%) Transverse arch coarctation 52 (32%) 50 (30%) .81 Small/restrictive ASD 54 (44%) 49 (41%) .67 Important RV dysfunction 2 (1%) .97 Important TR 10 (6%) 14 (9%) .42 Renal insufficiency 1 (1%) 2 ( 1%) .56 Metabolic acidosis 20 (12%) 1 Aortic valve atresia

Age at operation (days) 6.5 ± 5 6.3 ± 5 .14 Birth weight (kg)   BT (169) SANO (169) Variable Value P Age at operation (days) 6.5 ± 5 6.3 ± 5 .14 Birth weight (kg) 3.2 ± 0.4 3.2 ± 0.5 .92 Birth weight < 2.5 kg 9 (5%) 11 (7%) .61 BSA at operation (m2) 0.21 ± 0.02 .71 Aortic valve annulus (cm) 0.15 ± 0.2 0.14 ± 0.2 .82 Aortic valve atresia 90 (55%) 89 (57%) .74 TV annulus (cm) 1.3 ± .2 .77 MV annulus (cm) .24 ± .3 .22 ± .4 .44 Mitral valve atresia 70 (45%) 75 (48%) AI 22 (15%) 19 (13%) Transverse arch coarctation 52 (32%) 50 (30%) .81 Small/restrictive ASD 54 (44%) 49 (41%) .67 Important RV dysfunction 2 (1%) .97 Important TR 10 (6%) 14 (9%) .42 Renal insufficiency 1 (1%) 2 ( 1%) .56 Metabolic acidosis 20 (12%) 1 And baseline RV dysfunction and TR… So we are in fact comparing apples to apples.

1. Parametric hazard analysis: a. Competing end-states b 1. Parametric hazard analysis: a. Competing end-states b. Overall survival c. Transplant-free survival We used parametric hazard analysis to evaluate transition to various competing end-states, overall survival and transplant-free survival

End-states after Norwood All Matched Children (n=338) % Initially end-states were evaluated for 338 propensity matched children Years after Norwood

End-states after Norwood All Matched Children (n=338) Alive without definitive palliation % Immediately after Norwood all children are alive without further intervention – represented by black curve at time-zero, and thereafter transition into various mutually exclusive end-states. 9% Years after Norwood

End-states after Norwood All Matched Children (n=338) Alive without definitive palliation % By 6-years a small percentage of children underwent biventricular repair transplantation Transplant 2-V 9% 4% 2% Years after Norwood

End-states after Norwood All Matched Children (n=338) Alive without definitive palliation Fontan 52% % Just over half reached a Fontan Transplant 2-V 9% 4% 2% Years after Norwood

End-states after Norwood All Matched Children (n=338) Alive without definitive palliation Fontan 52% % Dead 33% And a third of children died Transplant 2-V 9% 4% 2% Years after Norwood

End-states after Norwood Mortality BT (n=169) Death after BT % 42% When end-states were evaluated independently for each operation type, children who underwent BT had a 42% mortality before a definitive palliation Years after Norwood

End-states after Norwood Mortality SANO (n=169) Death after BT % 42% Death after SANO Compared to children who underwent a SANO who only had a 24% mortality… 24% Years after Norwood

End-states after BT (n=169) Definitive Palliation Fontan % 49% Furthermore, children who underwent a BT were less likely to transition to definitive palliation Transplant/2-V 3% Years after Norwood

End-states after SANO (n=169) Definitive Palliation Fontan Fontan 54% % 49% Transplant/2-V Compared to children who underwent a SANO… and although this wasn’t statistically different, it does imply that these children are more likely to reach a definitive palliation - irrespective of the final strategy. Transplant/2-V 10% 3% Years after Norwood

Overall survival n = 338 SANO BT % Survival Years after Norwood 70% 55% % Survival P < 0.001 BT And that is reflected in this overall, survival cure, now for only propensity matched children, with this survival curve showing that the overall survival was significantly better after Sano – regardless of where they end up Years after Norwood

Transplant-free survival SANO 64% 53% % Survival P = 0.004 BT Similarly, when we compared transplant-free survival – although there was a late convergence between the survival curves, children who underwent a Sano had a better freedom from death or transplant at all points in time during the 6-year follow-up. Years after Norwood

SANO Systemic RV Ventriculotomy Ohye RG, et al. NEJM, 362;21 May, 2010 Systemic RV A primary objection to the Sano, is that an incision (or ventriculotomy) is required to the systemic ventricle, which theoretically compromises late ventricular function – and perhaps tricuspid valve performance Ventriculotomy

2. Prevalence of RV dysfunction and TR: Mixed-model regression analysis of repeated echos Therefore we examined the prevalence of RV dysfunction to and tricuspid valve regurgitation between the 2 surgical options… The next portion of our analysis focused on the prevalence of RV dysfunction and tricuspid regurgitation.

Reports analyzed from every echo on every patient 2. Prevalence of RV dysfunction and TR: Mixed-model regression analysis of repeated echos And did so by using mixed-model regression to analyzing reports from every echo we could acquire for all children, throughout follow-up. Reports analyzed from every echo on every patient N = 2,993 echos

Grades of RV dysfunction and TR From institutional echo reports 1=trivial 2=mild 3=mild-to-moderate 4=moderate 5=moderate-to-severe 6=severe Initially, RV dysfunction and TR were graded from trivial to severe using a 6 point scale, according to the reports…

Grades of RV dysfunction and TR From institutional echo reports 1=trivial 2=mild 3=mild-to-moderate 4=moderate 5=moderate-to-severe 6=severe “Important” RV dysfunction and TR However, we considered “moderate or worse” to be clinically important dysfunction and regurgitation, and this is the threshold we used for our analysis.

RV dysfunction after Norwood 2474 echos for 292 children ≥ Moderate RV dysfunction (%) We first determined prevalence of important RV dysfunction for all propensity matched children after Norwood… which is represented by the blue curve which demonstrating the change in prevalence of important RV dysfunction on the vertical axis over time after Norwood operation – on the horizontal axis; and for all survivors, important RV dysfunction peaks to nearly 12% within the initial 6 months, after which there is a decline to low, stable, late levels… Years after Norwood

RV dysfunction after Norwood BT vs SANO Early ,P = 0.019 BT ≥ Moderate RV dysfunction (%) SANO We then stratified the prevalence of RV dysfunction by the type of Norwood, and children who underwent BT had a significant increase in the early prevalence of RV dysfunction, nearly 3 times that of the Sano operation despite similar preoperative RV dysfunction between both groups - Thereafter, however, both groups experienced a declining prevalence, resulting in a non-significant difference in late RV dysfunction. Late, P = 0.36 Years after Norwood

Transplant-free survival and RV dysfunction BT vs SANO Transplant-free survival: BT vs SANO 64% 53% % To get a better idea of the relationship between survival and RV dysfunction we plotted transplant-free survival over the same time… Years after Norwood

Transplant-free survival and RV dysfunction BT vs SANO Transplant-free survival: BT vs SANO 64% 53% % RV dysfunction: BT vs SANO …as the prevalence of RV dysfunction Years after Norwood

Transplant-free survival and RV dysfunction BT vs SANO Transplant-free survival: BT vs SANO 64% 53% % Early hazard RV dysfunction: BT vs SANO And not surprisingly, the early hazard for death, coincided temporally with the peak prevalence of RV dysfunction… and although this is rather intuitive, is suggestive of a causal link between RV dysfunction and survival… and furthermore it suggests the morbidity and mortality of a Norwood occur early… Peak prevalence Years after Norwood

Transplant-free survival after stage-2 BT (n=108) vs SANO (n=125) 81% 80% SANO BT P = 0.68 % Survival Which is emphasized by comparing transplant-free after transition to a stage-2 cavopulmonary shunt operation… and survival conditional on achieving stage-2 – which is now time-zero on this figure – was not different between BT or SANO… Years after Stage-2

RV dysfunction after stage-2 BT vs SANO SANO ≥ Moderate RV dysfunction (%) Similarly, there wasn’t a difference in RV dysfunction after stage-2, and this emphasizes that the cost of Norwood - and specifically a BT - occurs early; However, after transition to a staged ventricular unloading operation, survival and RV dysfunction are stable for both groups. P = 0.675 BT Years after Stage-2

Tricuspid regurgitation after Norwood 2423 echos for 288 children ≥ Moderate TR (%) Finally, switching our attention to trends in tricuspid regurgitation… Notice that clinically important TR generally affects a higher proportion of children - about 10-15% - throughout follow-up, and that the time-related variations are less pronounced than that of RV dysfunction… Years after Norwood

Tricuspid regurgitation after Norwood BT vs SANO Early ,P = 0.003 BT ≥ Moderate TR (%) Late, P = 0.68 SANO And when TR was stratified by type of Norwood, BT operations were associated with a significant early increase in TR, however late TR was similar between groups. Years after Norwood

Summary For comparable neonates with critical LVOTO undergoing stage-1 Norwood: Overall and transplant-free survival are better after SANO

Summary For comparable neonates with critical LVOTO undergoing stage-1 Norwood: Overall and transplant-free survival are better after SANO Early RV dysfunction and TR are worse after BT

Summary For comparable neonates with critical LVOTO undergoing stage-1 Norwood: Overall and transplant-free survival are better after SANO Early RV dysfunction and TR are worse after BT Late RV dysfunction and TR are similar between groups

Implication Children undergoing SANO are more likely to be alive at 6 years – irrespective of final physiology Suggesting that SANO is preferable to BT for stage-1 palliation