Justus-Liebig-University Hybrid Therapy for Hypoplastic Left Heart Syndrome – Myth, Alternative or Standard? Can Yerebakan, Klaus Valeske, Hatem Elmontaser, Matthias Mueller, Juergen Bauer, Josef Thul, Dietmar Schranz, Hakan Akintuerk Justus-Liebig-University Giessen, Germany Dear chairmen, dear collegues, ladies and gentlemen, I would like to thank the scientific committee for the privilege to present our work here. This talk is going to be about operative outcome in our hybrid experience in HLHS in an attempt to find the answer to the provocating question which is stated in the title of the presentation. AATS 95th Annual Meeting 25.-29. April, 2015, Seattle, WA, USA

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Hybrid Therapy for HLHS Background Norwood palliation vs. Hybrid palliation Since we are going to talk about patients with HLHS nowadays two therapeutic options are available. Generally these patients are directed towards a neonatal performance of Norwood palliation, which follows a well established algorithm worldwide. However, the hybrid therapy for all types of HLHS and variants is accepted in only a few institutions as the primary therapy. More importantly in several reports there are substantial differences in patient selection, operative techniques and follow-up management. We are still seeking an answer to the question whether the hybrid strategy can stand the continuing improvement in the results of the classical Norwood operation.

Hybrid Therapy for HLHS The Giessen hybrid strategy Neonatal period Giessen hybrid stage I At 4 months Comprehensive Stage II Our experience with the hybrid treatment began in Giessen quite early in 1998. Based on the idea of Gibbs et al. we have developed an individual strategy for the hybrid stage I involving surgical BPAB and subsequent ductal stenting or continuous prostaglandine therapy in the neonatal period and the followed this principle by combining the first two steps of the Norwood procedure in the comprehensive stage II operation. This is our first patient Brandon in his first day of primary school.

Hybrid Therapy for HLHS Objectives Single institutional retrospective analysis of 118 patients with HLHS Mortality - Early and late survival (including subgroups) Pulmonary artery development (stage II – Fontan) Morbidity - Re-interventions on the pulmonary arteries - Outcome of the aortic arch reconstruction Cardiac MRI Cardiac cath

Biventricular correction Hybrid Therapy for HLHS Patients Giessen hybrid stage I n=182 HLHC n=41 HLHS (and variants) n=141 awaiting BVC n=2 (n=7) Htx n=8 Since 1998 182 patients with HLHS, HLHC and variants underwent hybrid stage I in our center during a 17-year period. Among this group 41 patients have been categorized having HLHC. From the remaining patients 8 patients received heart transplantation and 8 patients were handled with comfort care. 7 Patients from the HLHS group allowed a cross over to the BVC group. A total of 46 BVC have been performed. These patients are excluded from this study since the results of 40 have already been published las year. Comfort care n=8 Biventricular correction n=46

Giessen hybrid stage I with HLHS n=118 Hybrid Therapy for HLHS Patients Giessen hybrid stage I with HLHS n=118 65% As a consequence in this study 118 patients are distributed to HLHS subgroups similar to other study cohorts in the literature with a proportion of patients having AA in 65 % of cases.

Hybrid Therapy for HLHS Methods – Hybrid palliation HLHS Giessen hybrid stage I procedure (n=118) Median age 6 d (0-237) - Median weight 3.2 kg (1.2-7) Hybrid stage I is performed at the median age of 6 d and weight of 3.2 kg. Pulmonary arteries were banded bilaterally with 3.5 mm PTFE if over 3.0 kg otherwise with 3.0 PTFE. Ductal stenting followed 24-48 later in the cath lab using self-expandable sinus superflex stents with CE mark for ductal stenting. 1. Surgical BPAB with 3.0/3.5 mm PTFE 2. Ductal stenting in the cath lab 24-48 h later

Hybrid Therapy for HLHS Methods – Hybrid palliation HLHS Giessen comprehensive stage II procedure 1. Bilateral debanding with L/RPA dilation/reconstruction 2. Stent removal and aortic arch reconstruction 3. Bidirectional Glenn anastomosis 4. Atrioseptectomy Median age 4.5 mo (2.9-39.5) - Median weight 5 kg (4.4-9.4) Comprehensive stage II operation was performed at the median age of 4.5 months by bilateral debanding and LRPA reconstruction or simple intraoperative ballon dilation, aortic arch reconstruction with a curved xenopericardial patch, BDG anastomosis as well as atrioseptectomy. SCP was used in 90% of the cases and selective myocardial perfusion in 20%.

Hybrid Therapy for HLHS Methods – Hybrid palliation HLHS Fontan completion On beating heart at 34°C 1. 19 mm ring enforced PTFE extracardiac conduit 2. No standard fenestration 3. (PA reconstruction) 4. (AV-Valve repair) Median age 33.7 mo (21-108) - Median weight 13 kg (8.5-19.7) For the last step we used the extracardiac Fontan modification followed at a median age of 34 months with a mostly 19 mm ring enforced PTFE conduit on a beating heart in 92 %. A 4 mm fenestration was created in 50 % of the cases.

Comprehensive Stage II Hybrid Therapy for HLHS Results - Mortality Follow-up is complete - median 4.6 years (0-17) Hybrid stage I n=118 3 deaths (2.5%) Stage I 2 Htx 8 deaths (6.9%) 4 awaiting stage II c Comprehensive Stage II n=101 5 deaths (4.9%) Stage II 3 Htx Let me move on to our first operative results as of February 2015. Giessen hybrid stage I led to only 3 deaths so far, this 2.5%. With 8 deaths in the interstage and 4 patients still waiting for stage II 101 patients reached CSII that led to 5 operative and 5 interstage deaths. 26 patients are still waiting fora Fontan completion whereas no operative deaths at the Fontan operation but 4 late deaths were seen, 2 following and one on the waiting list for HTX. 5 deaths (5.3%) 26 awaiting stage III c Fontan operation n=62 Stage III 0 deaths 2 late deaths (one on Htx list) 2 late Htx (both died)

Hybrid Therapy for HLHS Results – Survival all Survival time (years) 0.8 0.0 0.4 0.6 0.2 1.0 5 10 15 All patients (n=182) after Giessen hybrid palliation at 1 year = 80 % at 10 years = 79.1% Probability of survival 182 114 85 61 32 17 7 Patients at risk Kaplan Meier estimated survival of all patients the number is as mentioned 182 79% at 10 years.

Hybrid Therapy for HLHS Results – Survival HLHS 0.8 0.0 0.4 0.6 0.2 1.0 5 10 15 HLHS (n=141) (including comfort care, Htx and BVC) at 1 year = 79.9% at 10 years = 74.5% Patients at risk Probability of survival Survival time (years) 141 88 66 48 26 14 Similar survival estimates can be reported when we focus on patients with HLHS including cc, HTx and patients who crossed over to biventricular correction. At 10 years the number is 74.5%

Hybrid Therapy for HLHS Results – Survival HLHS 0.8 0.0 0.4 0.6 0.2 1.0 5 10 15 HLHS (n=118) (excluding comfort care, Htx and BVC) at 1 year = 83.7% at 10 years = 78.2% Survival time (years) Probability of survival 118 76 54 37 18 4 Patients at risk Excluding the subgroups with cc, Htx and BVC 78 % estimated survival can be acvieved in the HLHS group.

Hybrid Therapy for HLHS Results – Survival HLHS AA/MA 0.8 0.0 0.4 0.6 0.2 1.0 10 15 HLHS AA/MA only (n=36) at 1 year = 10 years = 77.4% Probability of survival Survival time (years) Patients at risk 36 24 4 5 14 8 2 1 Even in the high risk subgroup of aortic atresia we have unchanged survival of 77% at 10 years.

Hybrid Therapy for HLHS Results – Survival < 2.5 kg 0.8 0.0 0.4 0.6 0.2 1.0 10 BW < 2.5kg (n=33) vs. BW > 2.5kg (n=149) Similar probability of survival p=0.75 Probability of survival Survival time (years) 5 15 Even in high risk groups with a extremely high mortality after classical Norwood type palliation survival chance of the patients below 2.5kg, o total of 33 patients, did not differ from patient over 2.5 kg.

Hybrid Therapy for HLHS Results – PA growth in cMRI (n=33) LPA diameter (mm) Stage II Fontan p=0.012 * RPA diameter (mm) Stage II Fontan p<0.001 * McGoon ratio Stage II Fontan p=0.991 Prior to Fontan operation Growth and reintervention of the pulmonary arteries is a highly debated issue by the goal of a sufficient pulmonary artery bed for the Fontan circulation. We have analysed PAG in 33 patients between CS II operation and the Fontan operation. The number is low due to a later avaibility and usage of the MRI after 2008 for these patients. Absolute meddian diameters of both the Pas show a significant growth which revealed an unchanged McGoon ratio between CS Ii and Fontan operation.

Hybrid Therapy for HLHS Results – Freedom from PA intervention 1.0 Freedom from PA re-intervention after comprehensive stage II at 1 year = 53.8% at 10 years = 32.2% 0.8 0.6 Probability of freedom from intervention 0.4 Freedom from intervention on the pulmonary arteries at 10 years is 32.2%. A total of 152 interventions were performed in 62 patients within 17 years. Most of the interventions took place on the LPA with 84 stent implantations. Not shown here but the intervention rate did not show a significant difference between the early era of our experience and the later period in which mor intraoperative dilations rather than reconstructions were performed. 0.2 0.0 2 4 6 8 10 12 14 Time after stage II (years)

Hybrid Therapy for HLHS Results – Freedom from aortic arch re-intervention 1.0 0.8 0.6 (n=46) 9 re-interventions no re-operation Freedom from re-intervention at 10 years = 74% Probability of Freedom from Re-intervention after AAR 0.4 Aortic arch reconstruction during CSII operation was analysed in 46 patients who were operated using a single type of patch by a single surgeon after 2004. Freedom from reintervention at 10 years is 74%. 9 catheter interventions as expected mostly in the distal aortic arch had to be performed with 5 ballon dilations and 4 stent implantations. No patient had to be reoperated. 0.2 0.0 Survival Time (days)

Hybrid Therapy for HLHS Limitations Single institution, retrospective Still short median follow-up Measurement of distal pulmonary arteries in the cMRI Limited number of cMRI data Availability LPA-stenting Aortic arch reconstruction during CSII operation was analysed in 46 patients who were operated using a single type of patch by a single surgeon after 2004. Freedom from reintervention at 10 years is 74%. 9 catheter interventions as expected mostly in the distal aortic arch had to be performed with 5 ballon dilations and 4 stent implantations. No patient had to be reoperated.

Conclusions The hybrid approach emerges for all patients with HLHS as a reasonable alternative to the conventional strategy by the neonatal performance of the Norwood procedure. Successful rehabilitation of the pulmonary arteries after BPAB can be accomplished shown with the outcome of the Fontan operation. Strict interstage follow-up and inter-departmental collaboration is needed. Neurological outcome will probably determine the future role of the hybrid approach in the treatment of HLHS and variants.

Thank you for your attention! 22

Hybrid Therapy for HLHS Background The outcome of the classical Norwood palliation in its two variations is meanwhile well-known. Transplant-free survival after 12 months is 65 % for the BT-shunt group and 74% for the Sano group.

Hybrid Therapy for HLHS Biventricular repair With an overall mortality of 10 % after a median follow-up of 8 years.

Hybrid Therapy for HLHS History in Giessen 1988 first HLHS-TX in University Clinic Giessen (Patient is alive and 26 years old today) Prof.Dr. H.H. Scheld 1988-2013 191 HTX / 56 HLHS-HTX (29%) Ladies and gentlemen, in general for patients with small left-sided structures the correct treatment strategy with regard to uni- versus biventricular pathway or heart transplantation should optimally be determined in the newborn period to achieve a favourable outcome. Well-known long-term challenges of a univentricular circulation following a multistage palliative approach makes a biventricular circulation preferable. However, a biventricular approach in this patient group may indeed be complicated with multiple interventions and operations in the follow-up or even with high mortality in unsuitable candidates. A switch from each therapy to another is theoretically possible but may also unfavorable. 1988-2001 93 HTX / 45 HLHS-HTX (48%) 2002-2013 98 HTX / 11 HLHS-HTX (11%)

Gelehrter et al., Pediatr Cardiol 2011 HLHS Outcome < 2500 g HLHS < 2500 g, Ann Arbor Gelehrter et al., Pediatr Cardiol 2011

15 North American Centers Comparison of Shunt Types in the Norwood Procedure for Single-Ventricle Lesions Richard G. Ohye et al. N Engl J Med 2010;362:1980-92 MBT shunt n=257 pat. RVPA shunt n=274 pat. 15 North American Centers TX free survival at 12 months 64% 74% (p=0,01) (p=0,003) (p=0,002) Interventions and complications Similar in two group RV size and function at 14 months Follow-up 32+/- 11 months (TX free survival) Nonsignificant difference (p=0,06)

Newborn (3.5 kg, 50 cm), LVEDV= 22ml/m2 AV= 0.49 cm, [0.73 cm (0.60-0.86)] => z-score = -3.1

4 mo after Stage I, (6.5 kg, 83 cm), LVEDV= 40 ml/m2 AV= 9 mm, [0.96 cm (0.81-1.11)] => z-score= -0.64

3 years after Comprehensive stage II prior to TCPC LPA

LPA stent due to acute thrombosis or stenosis

Giessen Hydrid Norwood Procedure Patient over 3kg ; 3,5 mm PTFE prosthesis Patient under 3kg; 3,0 mm PTFE prosthesis

Bilateral Pulmonary Arterial Banding 3.5mm graft tube or 3.0mm graft tube Newborn > 3kg or Newborn < 3kg RPA LPA

Giessen Hybrid Norwood Procedure After BPAB transfemoral ductal stent implantation Local anesthesia “Meaverin” Vygon 2F arterial cath. 4F + 6F Terumo sheath 4F right Judkins 4F multipurpose Cath. 4F wedge cath. + guidewire: 0.014inch floppy wire 0.035inch wire Vygon needle, Colombus Giessen

Neurological Outcome Mental Development Index MDI MW 100, 1 SD 15 Punkte Psychomotoric Development Index PDI MW 100, 1 SD 15 Punkte

50% PDI < 70

Motorik PDI MW = 90, n=19, 5% <70

Kognition MDI, n=19, MW= 91, 5% <70