The Optimal Timing of Stage-2-Palliation after the Norwood Operation: A Multi-Institutional Analysis from the CHSS CHSS Fall Work Weekend November 19, 2016 James M. Meza, MD and Jake Jaquiss, MD (Study PI), for the Optimal Timing of Stage 2 Working Group

Overview Background, Rationale, Hypothesis Study Population and Characteristics Outcomes and Risk Factors Determinants of Timing of Stage-2-Palliation Optimal Timing – Methods and Results Effect of interval procedures – Methods and Results Interpretation and Clinical Implications

Mortality during Staged Palliation Survival through single ventricle palliation = 50-70% Mortality after Norwood and before Stage-2-Palliation (S2P) remains high Timing of S2P is physician modifiable Effect of timing not well understood

Timing of S2P is a Complex Decision Earlier S2P Reduce volume load on systemic ventricle Eliminate shunt-associated risks Normalize coronary blood flow in those with BT shunt Normalize pulmonary vascular flow and pressure Underdevelopment of pulmonary vasculature Failure of PVR to decrease Later S2P Growth of infant and pulmonary vasculature Potentially decreased resource utilization Increased exposure to risks of Norwood-associated physiology

Hypothesis An optimal timing exists Norwood S2P Fontan ? An optimal timing exists Is based on patient-specific characteristics

Study Population & Characteristics

Patient Data Source Data Source = CHSS Critical Left Ventricular Outflow Tract Obstruction Registry Neonate ≤ age 30 days at admission to a CHSS institution 2005 onward AV & VA concordance Precludes an adequate systemic cardiac output through the aortic valve Study inclusion criteria Initial Norwood operation

Study Population 924 with an initial procedure, 72 excluded CHSS LVOTO N=924 Eligible N=852 Initial procedure N=702 Norwood N=534 924 with an initial procedure, 72 excluded 852 included, 702 had an initial operation, 83 had an initial catheter procedure, 13 died before initial procedure , 54 alive without surgical information 534 Norwoods of the 702

Demographic Characteristics   Overall Cohort (N=534) Sex, male 66% (346) Prenatal diagnosis 73% (383) Prenatal intervention 1% (4) Gestational age (weeks) 39.0 (38-39) Birth weight (kg) 3.2 (1.6-3.8) Low birth weight (< 2.5 kg) 16% (87) Genetic abnormality 7% (41) White race 84% (363)

Institutional Diagnoses   Overall Cohort (N=534) Hypoplastic left heart syndrome 92% (493) Critical aortic stenosis 2% (13) Aortic valve atresia 0.6% (4) Mitral stenosis 0.2% (2) Mitral atresia Coarctation of the aorta 1% (3) Interrupted aortic arch 2% (11) Hypoplastic aortic arch

Echocardiographic Data   Overall Cohort (N=534) Aortic atresia/mitral atresia 28% (151) Aortic atresia/mitral stenosis 18% (96) Aortic stenosis/mitral atresia 1% (5) Aortic stenosis/mitral stenosis 16% (84) Isolated aortic atresia 2% (13) Isolated aortic stenosis 7% (38) Isolated mitral atresia 2% (11) Isolated mitral stenosis 2% (8) Other 3% (16) Bilateral SVC 5% (19)

Outcomes and Risk Factors

Outcomes after Norwood

Norwood Operative Characteristics   Overall Cohort (N=534) Age at Norwood (days) 6.0 (0-48) Shunt type MBTS 49% (263) RVPA conduit 50% (268) Central shunt 1% (3) Weight at Norwood (kg) 3.2 (2.9-3.5) Elapsed time on CPB (min) 149.9 ± 45.9 Modified cerebral perfusion 91% (349) Duration of circulatory arrest (min) 8.0 (4.0-34.0)

Hazard Model for Death after Norwood Probability of Survival Red line is parametric model, circles are KM estimates, dashed lines are 70% CL Months since Norwood

Multivariable Model Candidate covariates = baseline, demographic, clinical through end of Norwood

Death after Norwood

Outcomes after S2P

Age at S2P Median = 5.1 (4.3–6.2) months Range = 1.7-17.2 months 154 days (129-188) Range = 1.7-17.2 months 51-523 days Not normally distributed

Hazard Model for Death after S2P Probability of Survival Red line is parametric model, circles are KM estimates, dashed lines are 70% CL Months since S2P

Variables – post-Norwood Weights (z-score) Norwood, echo, cath, clinic, S2P Echo AVVR RV Function Cath PVR QpQS PA stenosis PA hypoplasia Chromosomal abnormality/genetic syndrome Shunt type and size Geographic region of S2P Season of S2P Bilateral SVC Post-Norwood Course Hospital LOS after Norwood Length of mechanical ventilation after Norwood Failed extubation after Norwood Home oxygen Tracheostomy Respiratory illness Unplanned readmission pre-S2P and LOS Delayed S2P? Diagnosis of NEC Diagnosis of GERD Interval cath and operative procedures Inpatient vs. outpatient status at time of Stage 2 Limits of documentation Mechanical ventilation at time of Stage 2 Pre-S2P clinic visit O2 sats at pre-op clinic

Post-Norwood Course Overall Cohort (N=534)   Overall Cohort (N=534) Length of Norwood hospitalization (days) 25 (16-40) Length of mechanical ventilation 7 (5-11) Required re-intubation after Norwood 7% (37) Required readmission for respiratory infection 5% (25) Required home oxygen 5% (27) Required tracheostomy 1% (3) Diagnosis of necrotizing enterocolitis 12% (64) Diagnosis of gastro-esophageal reflux 30% (158)

Pre-S2P Cardiac Catheterization   Overall Cohort (N=534) Age at pre-S2P catheterization (days)  118 (84-154) Interval from catheterization to S2P (days) 28 (12-58) Weight (kg) 5.5 (4.5-6.3) Weight-for-age z-score -1.1 (-2.0 - -0.3) Pulmonary vascular resistance (Wood units) 1.9 (1.5-2.5) QpQs 1.0 (0.74-1.32) Coarctation 15% (79/534) Moderate-severe RPA stenosis 15% (80) Moderate-severe RPA hypoplasia 10% (54) Moderate-severe LPA stenosis 17% (89) Moderate-severe LPA hypoplasia 13% (67)

Pre-S2P Echocardiogram   Overall Cohort (N=534) Age at echocardiogram (days) 96 (28 – 139) Interval from echocardiogram to S2P (days) 40 (11-107) Weight (kg) 4.6 (3.5-5.9) Weight-for-age z-score -1.2 (-2.0 - -0.5) Moderate-severe RV dysfunction 10% (51/534) Moderate-severe AVV regurgitation 22% (117/534)

Pre-S2P Clinic Visit Overall Cohort (N=534) Age at clinic visit (days)   Overall Cohort (N=534) Age at clinic visit (days) 121 (93-157) Interval from clinic visit to S2P(days) 28 (12-58) Weight (kg) 5.4 (4.8-6.2) Weight-for-age z-score -1.1 (-2.2 – 0.1) Oxygen saturation (%) 80 (76-83)

Model for Death after S2P

Determinants of Timing of S2P

Determinants of Timing Linear regression Outcome = age at S2P Candidate covariables – all from 1st two models

Determinants of Age at S2P

Determinants of Age at S2P

Analyzing Staged Procedures and Optimal Timing

Staged Procedures Conditional survival analysis [ CS = S(t|s) ] Norwood S2P 4-Years Model 1 Model 2 Conditional survival analysis [ CS = S(t|s) ] Use both models Predict survival to day of S2P, then 2nd model for S2P for four years Accounts for all patients!

Survival After Norwood %

Survival after Norwood, through S2P %

Survival through S2P Probability of Survival Months since Norwood Survival at 4 years = 71±5% Probability of Survival COHORT AVERAGE Months since Norwood

Analyzing Timing Age at S2P identified as risk factor Parametric model = mathematical equation Nomogram of survival vs. Age at S2P

post-Norwood Survival Optimal Timing, by Age Risk-adjusted, 4-Year, post-Norwood Survival Age at S2P (months) “Cohort average”

Timing, by Age, with RV Dysfunction No RV Dysfunction Risk-adjusted, 4-Year, post-Norwood Survival RV Dysfunction Age at S2P (months)

Timing, by Age, by Shunt Type RVPA Conduit Risk-adjusted, 4-Year, post-Norwood Survival MBTS Age at S2P (months)

Optimal Timing, by Age Across various risk profiles Low risk Average-risk Risk-adjusted, 4-Year, post-Norwood Survival High risk Age at S2P (months)

post-Norwood Survival Optimal Timing, by WAZ -5 -4 -3 -2 -1 0 1 2 3 4 5 Risk-adjusted, 4-Year, post-Norwood Survival Weight-for-Age Z-score at the pre-S2P cath “Cohort average”

Timing, by WAZ, with RV Dysfunction No RV Dysfunction RV Dysfunction Risk-adjusted, 4-Year, post-Norwood Survival -5 -4 -3 -2 -1 0 1 2 3 4 5 Weight-for-Age Z-score at the pre-S2P cath

Timing, by WAZ, by Shunt Type -5 -4 -3 -2 -1 0 1 2 3 4 5 Risk-adjusted, 4-Year, post-Norwood Survival Weight-for-Age Z-score at the pre-S2P cath RVPA MBTS

Optimal Timing, by WAZ Across various risk profiles Risk-adjusted, 4-Year, post-Norwood Survival Weight-for-Age Z-score at the pre-S2P cath -5 -4 -3 -2 -1 0 1 2 3 4 5 Low risk Average-risk High risk

Elective S2P

Indications for S2P

Operative Status vs. Age at S2P

Risk Factors in Elective Patients   Parameter Estimate ± STD P-value Reliability RV dysfunction on pre-S2P echo, moderate or severe 2.34 ± 0.54 < 0.0001 73% Younger age at S2P (days), natural log transformation 1.74 ± 0.84 0.04 50%

post-Norwood Survival Optimal Timing, by Age Risk-adjusted, 4-Year, post-Norwood Survival Age at S2P (months) “Elective average”

High-Risk Patients

Why does it appear that high-risk appear to do better with later S2P? Regardless of age or WAZ – survival poor Especially with early S2P Cannot advocate non-intervention in the deteriorating “high-risk” infant “Length time bias” Highest risk patients die earlier – push down survival Less high risk – survive longer to undergo later S2P

“High-Risk S2P” vs. Transplantation? 11 patients underwent heart transplantation after Norwood All currently still alive Can’t make a model, can only suggest this from descriptive statistics

Interval Procedures Norwood S2P 4-Years

Prevalence of Interval Procedures   Patients Total procedures # of Procedures Survival after Norwood Interval cardiac catheterization procedure 178 275 0-5 97% Interval operation 68 86 0-3 68%

Methodology First analyzed for development of 2nd model But occur during Norwood – S2P interval Time-varying covariables Modulated Renewal

Time-Varying Analysis   Parameter Estimate ± STD P-value Interval cardiac catheterization procedure 0.10 ± 0.25 0.70 Interval operation 0.69 ± 0.24 0.004

Effect of Interval Operations Probability of Survival Months since Norwood

Discussion, Implications, Conclusions

Low- and Average-Risk Patients After 3-4 months and z-score > -2 for low and average risk patients “Elective” Patients are progressing early/being delayed for no reason Younger age – risk factor Converting some from elective non-elective? Outgrowing shunts? Waiting for shunt complications

High-Risk Patients Survival is substantially reduced A high risk patient at Norwood doesn’t become a better candidate after S2P (survival cost still seen) Very poor survival with “early” S2P or low WAZ No weight-for-age z-score, just like no age “maximizes” survival in these patients Heart transplantation may maximize survival

Interval Procedures Low threshold for catheter-based procedures If facing a non-elective S2P with intervenable pathology (e.g. shunt stenosis), try to bridge to a later, elective S2P Operative procedures confer greater risk Don’t avoid doing Marker of more severe pathology and higher risk

Implications Survival through staged procedures should be considered across all, not as individual discrete intervals Active plan can be developed or modified for planning timing of S2P This info can help with prioritization of rare hearts from transplantation – have an idea of who will fail staged palliation

THANK YOU james.meza@sickkids.ca

Median Age at S2P (months)†   Enrolled (n=534)* Mortality after Norwood (n=115)** Reached S2P (n=377) Median Age at S2P (months)† S2P (n=38)‡ Institution P 95 20% (19) 70 5.1 (4.4-5.8) 10% (7) Institution I 63 30% (19) 40 6.3 (5.5-7.6) 15% (6) Institution Q 52 12% (6) 43 4.8 (4.3-5.7) 9% (4) Institution D 47 38 4.6 (3.9-5.1) 11% (4) Institution T 36 19% (7) 29 6.1 (5.1-7.7) 14% (4) Institution M 34 38% (13) 20 5.2 (4.8-5.8) 15% (3) Institution F 30 20% (6) 22 3.2 (2.9-3.6) 14% (3) Institution N 28% (8) 14 6.1 (5.6-7.1) 7% (1) Institution H 0% (0) 21 4.0 (3.0-4.5) 10% (2) Institution K 5.8 (5.1-7.9) Institution A 19 42% (8) 11 6.3 (5.1-7.8) 9% (1) Institution G 18 22% (4) 5.5 (4.4-6.7) Institution S 35% (5) 7 4.0 (3.3-5.6) 14% (1) Institution E 13 38% (5) 6 5.3 (4.9-6.2) Institution B 36% (4) 4.8 (4.0-4.9) 17% (1) Institution O 10 10% (1) 9 3.8 (3.2-4.4) Institution L 11% (1) 8 5.6 (5.4-5.9) Institution C 43% (3) 4 7.6 (6.5-8.3) Institution J 2 6.8 (5.6-8.1) Institution R 1 5.1 (5.1-5.1) Institution U 3.2 (3.2-3.2)