4/21/2018 Disclaimer Pediatric Risk Stratification Models in Children No conflicts of interest with Pulmonary Arterial Hypertension Marlies Haarman, MD Network Pediatric Pulmonary Hypertension University Medical Center Groningen - Center for Congenital Heart diseases University Medical Center Groningen Center for Congenital Heart diseases Background Risk assessment in adult PAH Transplant-free survival % 100 80 • Poor prognosis of patients with 60 pulmonary arterial hypertension (PAH) 40 • A high need for improvement of 20 prognosis and refinement of treatment strategies 0 • Risk stratification as a crucial 0 1 2 3 4 5 cornerstone in the standard care Time years of patients with PAH Galié et al., Eur Heart J, 2015. University Medical Center Groningen Center for Congenital Heart diseases University Medical Center Groningen Center for Congenital Heart diseases 1
4/21/2018 Survival in adult PAH based on risk stratification Survival in adult PAH based on risk stratification Boucly et al., Eur Respir J, 2017. Boucly et al., Eur Respir J, 2017. University Medical Center Groningen Center for Congenital Heart diseases University Medical Center Groningen Center for Congenital Heart diseases Survival in adult PAH based on risk stratification Pediatric determinants of risk 5 th WSPH, Pediatric Task Force, JACC, 2013. Boucly et al., Eur Respir J, 2017. University Medical Center Groningen Center for Congenital Heart diseases University Medical Center Groningen Center for Congenital Heart diseases 2
4/21/2018 Pediatric determinants of risk Pediatric determinants of risk Low-risk criteria Determinants of risk Low-risk criterion WHO functional class I+II Syncope N0 Growth - Z-score BMI >-2 - Z-score height >-2 NT-proBNP ≤1200 ng/L • TAPSE: ≥12mm Echocardiography • RA area: <18cm² • Acute vasoreactivity Hemodynamics • Systemic CI ≥2.5 l/min/m 2 • mPAP/mSAP ≤0.75 • RAP ≤10 mmHg • PVRi ≤20 WU*m 2 • SvO 2 > 65% 6MWD ≥7years >352 m 5 th WSPH, Pediatric Task Force, JACC, 2013. Galié et al., Eur Heart J, 2015. 5 th WSPH, Pediatric Task Force, JACC, 2013. University Medical Center Groningen Center for Congenital Heart diseases University Medical Center Groningen Center for Congenital Heart diseases Pediatric determinants of risk Study design Low-risk criteria • Determinants of risk Low-risk criterion Dutch national registry WHO functional class I+II • Syncope N0 Children ≤ 18 years with IPAH/HPAH Growth - Z-score BMI >-2 • Pediatric WSPH risk model - Z-score height >-2 NT-proBNP ≤1200 ng/L • Risk stratification: • TAPSE: ≥12mm Echocardiography • RA area: <18cm² – At diagnosis • Acute vasoreactivity Hemodynamics – At one-year follow-up • Systemic CI ≥2.5 l/min/m 2 • • mPAP/mSAP ≤0.75 Outcome defined as transplant-free survival • RAP ≤10 mmHg • Aim: to investigate the prognostic value of the pediatric WSPH risk model • PVRi ≤20 WU*m 2 • SvO 2 > 65% at diagnosis and one-year follow-up 6MWD ≥7years >352 m Galié et al., Eur Heart J, 2015. 5 th WSPH, Pediatric Task Force, JACC, 2013. University Medical Center Groningen Center for Congenital Heart diseases University Medical Center Groningen Center for Congenital Heart diseases 3
4/21/2018 Models Patient characteristics Characteristics n(%), Median (IQR) • 3 Models Female 31 (53) – Model A: The full model Age at diagnosis, y 6.8 (2.2-13.4) – Model B: The model with non-invasive low-risk criteria • At diagnosis Follow-up, y 3.1 (0.7-8.4) • At one-year follow-up – Model C: The model with only those variables that were significantly associated with Mortality 24 (41) outcome in univariable Cox regression analysis WHO-FC • At diagnosis • I+II 19 (33) • At one-year follow-up • III 23 (40) • IV 16 (27) NT-proBNP, ng/L 1391 (221-5911) 6MWD, m 382 (296-448) University Medical Center Groningen Center for Congenital Heart diseases University Medical Center Groningen Center for Congenital Heart diseases Model A ‘The full model’ Model A ‘The full model’ No. of Transplant-free survival (%) low-risk criteria 100 12 80 11 10 60 9 8 40 7 6 20 p=0.041 5 0 4 0 1 2 3 4 5 3 2 Time (years) HR (95%CI) 0.78 (0.68-0.89) (p<0.001) University Medical Center Groningen Center for Congenital Heart diseases University Medical Center Groningen Center for Congenital Heart diseases 4
4/21/2018 Univariable Cox regression analysis of low-risk Univariable Cox regression analysis of low-risk criteria criteria At diagnosis p-value At 1-year follow-up p-value At diagnosis p-value At 1-year follow-up p-value Low-risk criterion Hazard ratio (95% CI) Hazard ratio (95% CI) Low-risk criterion Hazard ratio (95% CI) Hazard ratio (95% CI) WHO-FC I+II 0.21 (0.074-0.61) 0.004 0.29 (0.11-0.81) 0.018 WHO-FC I+II 0.21 (0.074-0.61) 0.004 0.29 (0.11-0.81) 0.018 No syncope 0.72 (0.33-1.55) 0.40 0.42 (0.10-1.68) 0.22 No syncope 0.72 (0.33-1.55) 0.40 0.42 (0.10-1.68) 0.22 Z-score BMI > -2 0.73 (0.333-1.62) 0.44 2.05 (0.27-15.76) 0.49 Z-score BMI > -2 0.73 (0.333-1.62) 0.44 2.05 (0.27-15.76) 0.49 Z-score height > -2 0.63 (0.26-1.53) 0.30 23.45 (0.003-159585) 0.48 Z-score height > -2 0.63 (0.26-1.53) 0.30 23.45 (0.003-159585) 0.48 TAPSE ≥ 12mm 0.57 (0.17-1.89) 0.35 1.00 (0.17-5.79) >0.999 TAPSE ≥ 12mm 0.57 (0.17-1.89) 0.35 1.00 (0.17-5.79) >0.999 RA area <18 cm² 0.78 (0.34-1.78) 0.56 0.66 (0.21-2.07) 0.47 RA area <18 cm² 0.78 (0.34-1.78) 0.56 0.66 (0.21-2.07) 0.47 NT-proBNP ≤1200 ng/L 0.37 (0.14-0.95) 0.038 0.31 (0.087-1.13) 0.075 NT-proBNP ≤1200 ng/L 0.37 (0.14-0.95) 0.038 0.31 (0.087-1.13) 0.075 mPAP/mSAP <0.75 0.51 (0.22-1.20) 0.12 NA - mPAP/mSAP <0.75 0.51 (0.22-1.20) 0.12 NA - CI ≥2.5 l/min/m² 0.60 (0.28-1.31) 0.20 NA - CI ≥2.5 l/min/m² 0.60 (0.28-1.31) 0.20 NA - mRAP ≤ 10 mmHg 0.43 (0.19-0.96) 0.040 NA - mRAP ≤ 10 mmHg 0.43 (0.19-0.96) 0.040 NA - PVRi ≤20 WU∙m² 0.30 (0.13-0.71) 0.006 NA - PVRi ≤20 WU∙m² 0.30 (0.13-0.71) 0.006 NA - SvO 2 , >65% 0.29 (0.12-0.69) 0.005 NA - SvO 2 , >65% 0.29 (0.12-0.69) 0.005 NA - 6MWD, >352 m 0.75 (0.59-0.94) 0.015 0.54 (0.19-1.51) 0.24 6MWD, >352 m 0.75 (0.59-0.94) 0.015 0.54 (0.19-1.51) 0.24 University Medical Center Groningen Center for Congenital Heart diseases University Medical Center Groningen Center for Congenital Heart diseases Model B ‘The non-invasive model’ Model B ‘The non-invasive model’ Transplant-free survival (%) No. of low-risk 100 criteria 80 7 60 6 5 40 4 20 3 p=0.006 2 0 0 1 2 3 4 5 Time (years) At diagnosis: HR (95%CI) 0.63 (0.49-0.82) (p=0.001) University Medical Center Groningen Center for Congenital Heart diseases University Medical Center Groningen Center for Congenital Heart diseases 5
4/21/2018 Model B ‘The non-invasive model’ Model C ‘The model with significant low-risk criteria’ Transplant-free survival (%) No. of Transplant-free survival % No. of low-risk 100 100 low-risk criteria 80 criteria 80 7 7 60 6 60 6 5 40 40 5 4 4 20 3 20 p=0.006 3 2 0 0 0 1 2 3 4 5 0 1 2 3 4 5 Time (years) Time (years) At diagnosis: At one-year follow-up: HR (95%CI) 0.63 (0.49-0.82) (p=0.001) HR (95%CI) 0.61 (0.41-0.92) (p=0.019) University Medical Center Groningen Center for Congenital Heart diseases University Medical Center Groningen Center for Congenital Heart diseases Model C ‘The model with significant low-risk criteria’ Model C ‘The model with significant low-risk criteria’ Transplant-free survival (%) Transplant-free survival (%) Transplant-free survival (%) No. of No. of No. of low-risk low-risk 100 100 100 low-risk criteria criteria 80 80 80 criteria 5 5 60 60 60 2 4 4 3 3 1 40 40 40 2 2 0 20 20 20 1 1 p<0.001 p<0.001 0 0 0 0 0 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5 Time (years) Time (years) Time (years) At diagnosis: At diagnosis: At one-year follow-up: HR (95%CI) 0.64 (0.52-0.80) (p<0.001) HR (95%CI) 0.64 (0.52-0.80) (p<0.001) HR (95%CI) 0.30 (0.15-0.58)(p<0.001) University Medical Center Groningen Center for Congenital Heart diseases University Medical Center Groningen Center for Congenital Heart diseases 6
4/21/2018 Treatment Algorithm Treatment Algorithm 5 th WSPH, Pediatric Task Force, JACC, 2013. 5 th WSPH, Pediatric Task Force, JACC, 2013. University Medical Center Groningen Center for Congenital Heart diseases University Medical Center Groningen Center for Congenital Heart diseases Treatment target Treatment target Transplant-free survival (%) No. of low-risk criteria 100 at diagnosis --> no. of low-risk criteria at 80 one-year follow-up 60 5-7 --> 5-7 40 0-4 --> 5-7 20 5-7 --> 0-4 p=0.004 0-4 --> 0-4 0 0 1 2 3 4 5 Time (years) University Medical Center Groningen Center for Congenital Heart diseases University Medical Center Groningen Center for Congenital Heart diseases 7
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