3/8/2019 TOPP-1 TOPP-1: GLOBAL REGISTRY 31 Sites in 19 Countries - PowerPoint PPT Presentation

3/8/2019 The TOPP Registry The Board of Association of Ped PH • Epidemiologic research on PH in children and adolescents • To generate real-world data • To draw conclusions on the every-day clinical practice in these patients • Sponsored by Actelion 1 TOPP-1 TOPP-1 Patient Population Registry Design • Age at diagnosis: >= 3 months and <= 18 years • Diagnosed with PH on/after 1 January 01 • Multicenter, prospective, observational, non-interventional (prevalent and incident patients) • Present with PH belonging to one of the following categories: • Patients included are treated as determined by their physician • WHO group 1, • No therapy protocol, no predetermined visit schedule incl. CHD with residual PH following surgery, with no residual left side obstruction ( PCWP mean <= 12mmHg) • WHO Group 3 • WHO Group 4 • WHO Group 5 3 4

3/8/2019 TOPP-1 TOPP-1: GLOBAL REGISTRY 31 Sites in 19 Countries Timelines & Sample Size • Incident and prevalent cases (ratio ~ 1/3 to 2/3)TOPP-1 closure in 2015 • Inclusion of prevalent cases stopped in 2009 • In July 2015, the TOPP-1 registry closed after including 699 patients, of which over 50% were newly diagnosed patients numbers refer to number of patients enrolled geographically at time 5 of first TOPP-data cut Feb 2010 TOPP: Clinical Features Pediatric PAH, Epidemiology Results • Enrolled: 456 patients (≥ 3 mos and ≤ 18 yrs at Dx); Data cut Feb 2010 PH with increased PVR confirmed in 362 † patients TOPP 1 Reveal-Adults 2 21% had to be excluded Patients, n 362 2525 • All of the following analyses are for PH confirmed patients only Age at Dx (yrs), median 7.5 53 Female, % 59 80 • 59% female Group 1: PAH 317 (88) 2525 (100) IPAH/HPAH 212 (53) 1166 (46) • Median age at diagnosis 7 yrs CHD 160 (40) 215 (10) CTD 9 (3) 639 (25) • At enrollment, 102 (28%) newly diagnosed* Portopulmonary 2 (1) 136 (5) 260 (72%) previously diagnosed** Other 14 (4) 255 (10) Group 3: Lung disease 42 (12) NE Date of diagnosis: date of confirmatory RHC Other 3 (1) NE † Reasons for exclusion: PVRI < 3 units  m 2 n=6; PCWP > 12 mm Hg n=5; lack of data to calculate PVRI n=86; Values given are n (%) unless otherwise indicated 1. Berger et al. Lancet 2012. *Confirmatory RHC ≤ 3 mos of enrollment; **Confirmatory RHC > 3 mos prior to enrollment 2. Badesch et al. Chest 2010.

3/8/2019 Pediatric PAH, Symptoms: Pediatric PAH, Comorbidities TOPP-1 TOPP 2 Patients, n 362 Patients, n 362 Age (yrs), median 7.5 Dyspnea at exertion, % 235 (65) Age (yrs), median 8.9 Syncope 73 (20) Comorbidities 86 (24) Idiopathic PAH 57 (31) CHD (shunt) 0 (0) Trisomy 21 42 (12) WHO functional class (%) Other 44 (12) I 12 chromosomal, II 51 non-chromosomal, III 30 syndromes IV 7 PPHN 8 (2*) mPAP (mmHg) 58 ≥ 10 times normal; PVRi (WU.m2) 16 ≥ 2.5 times higher controlling for trisomy 21 CI (L/min/m2) 3.7 Berger et al. Lancet 2012; TOPP-1 Hemodynamics HC data sets of ALL patients underwent blinded review for validation and confirmation of hemodynamic measurements and calculations . 11 12

3/8/2019 Hemodynamics Hemodynamics Background Results • Pulmonary hypertension in children is associated with high morbidity and mortality • 568 patients enrolled in registry; Data cut February 2012 • Hemodynamic evaluation by cardiac catheterization remains “gold-standard” • 480 PH-confirmed 18% had to be excluded • Confirmation of diagnosis • Assessment of disease severity • Review during follow-up • Invasive procedure with potential complications 13 14 Hemodynamics Hemodynamics Pediatric PH, hemodynamic profile Hemodynamic profile, relation with etiology All patients • mPAP: 58 ± 19 mmHg • PVRI 17 ± 12 WU.m2 • CI 3.7 ± 3.7 L/min/m2; 24% presented with CI < 2.5 L/min/m2 • mRAP 7 ± 4 mmHg 8% had a mRAP > 12 mmHg 4% had both CI < 2.5 L/min/m2 and mRAP > 12 mmHg. 15 16

3/8/2019 Hemodynamics Hemodynamics Hemodynamic profile, relation with age at Dx Hemodynamic profile, relation with WHO-FC 100 100 Hemodynamic profile: severity Hemodynamic profile: severity 80 80 60 60   40 40 20 20 0 0 18 0 Age  I II III IV WHO-FC  17 18 Heart catheterization in Pediatric PH Heart catheterization in pediatric PH Complications Complications • n=908 cardiac catheterizations (555 patients) • n=554 at diagnosis (554 patients) • n=354 in follow up (235 patients) • Conscious sedation: n=257 (46%) • General anesthesia: n=291 (54%) 19 20

3/8/2019 Heart catheterization in Pediatric PH Heart catheterisation in pediatric PH reasons for death risk factors for complications • Cardiac arrest post-HC • Younger Age • Complications of extracorporealmembrane oxygenation (ECMO) • Higher WHO-FC • At induction of anaesthesia, • General Anesthesia • Severe bleeding during HC procedure, (mostly used in children < 2 yrs) • Progressive heart failure after HC • Brain lesions following cardiac arrest during HC. Risk of cath-related adverse events: Ped. Cath. Intervention > Ped PH > Adult PH 10-20% ± 6% ± 1% 21 22 Diagnostic Evaluation Background 2016 - Diagnosis/Confirmation of PH - Exclusion/Identification of associated conditions - Assessment of severity To “cath” or not in pediatric pulmonary hypertension, letter. J Am Coll Cardiol 2016 23 24

3/8/2019 Diagnostic Evaluation Diagnostic Evaluation Conclusions All patients (N=456) Data cut Feb 2010 Exclusion/Diagnosis of associated conditions : All (n=456) Incident (n=135) Prevalent (n=321) ECG, n (%) 430 (94) 131 (97) 299 (93) • Not all patients underwent a complete work-up Abnormal, n (%) 385 (90) 116 (89) 269 (90) Often no pulmonary evaluation (CT, polygraphy, LFT) in PH group 3 Chest X-ray, n (%) 406 (89) 126 (93) 280 (87) ECG, CXR and Echo Also not in iPAH, although a diagnosis per exclusionem Abnormal, n (%) 325 (80) 103 (82) 222 (80) are abnormal in most children with PH This seems only partly due to age limitations Echocardiogram, n (%) 439 (96) 132 (98) 307 (96) and seem suitable for screening • No differences between incident and prevalent patients Abnormal, n (%) 436 (99) 132 (100) 304 (99) • No differences based on date of diagnosis (2001-2010) All 3 tests normal 0 0 0 2 tests normal 15 (3) 6 (4) 9 (3) 1 test normal 81 (18) 23 (17) 58 (18) Diagnostic Evaluation Conclusions Evaluation of severity and follow up: • Exercise testing is done mostly after the age of 7 years; CPET is still rarely performed • 6 Minute Walk Test is only performed in 71% of the patients over 12 years • Serum biomarkers (e.g. BNP) are followed only in a minority of centers 27 28

3/8/2019 Acute Vasodilator Testing (AVT) AVT in pediatric PAH - To describe current clinical 15% excluded practice of AVT and - subsequent treatment decisions and outcome - Data cut May 2013 28% 29 30 AVT-responders stratified for CCB treatment Only Sitbon Responders tended to survive longer over time when on CCB therapy TOPP-2 investigator meeting – 5 Nov 2016 – Chicago, USA 31 TOPP-2 investigator meeting – 5 Nov 2016 – Chicago, USA 32

3/8/2019 AVT in pediatric PAH Conclusions • The proportion of acute pulmonary vasodilator responders in children with IPAH/FPAH, using the Sitbon criteria for acute response, was similar to that reported in adults with IPAH/FPAH and appeared unrelated to age. • From a registry evaluating AVT in children with IPAH/FPAH from 2001 to 2013, the practice of identifying acute responders to AVT in children with IPAH/FPAH was widely variant and inconsistent with current internationally recommended diagnostic algorithms for both adult and pediatric patients. • the majority of children with IPAH/FPAH, classified as acute responders, were not treated with CCB therapy. • This study suggests that, as in adult IPAH/FPAH, the Sitbon criteria are the criteria of choice in pediatric IPAH/FPAH to identify children who will show sustained benefit from CCB therapy. 33 34 Growth in Pediatric PAH Growth in Pediatric PAH Collaboration of four prospective registries 1. Tracking Outcomes and Practice in Paediatric Pulmonary Hypertension (TOPP) • 4 registries: period 2008 -2013 A global, multicentre registry; 2. The Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) • Children with PAH (IPAH/HPAH; APAH-CHD; APAH-Other) A US-based multicentre registry 3. The Dutch National Network for Paediatric Pulmonary Hypertension, • ≥ 2 measurements of height and BMI A national registry of The Netherands 4. ItinerAIR-Pediatrie , • N=601 patients were included A French, multicentere registry These registries together represent 53 centres for pediatric pulmonary hypertension in 19 countries . Ploegstra et al Lancet RM 2016 36

3/8/2019 Determinants of growth in pediatric PAH • Age • Etiology • Comorbidities: • Trisomy 21 • “Concomittant conditions” (genetic traits, syndromes) • Ex-prematurity • WHO functional class • Duration of the disease 37 38 Ploegstra et al Lancet RM 2016 Growth in pediatric PAH • PAH is associated with impaired growth, especially in younger children and those with PAH-CHD • The degree of impairment is independently associated with cause of PAH and comorbidities, but also with disease severity and duration • A “favourable clinical course” was associated with catch-up growth. • Therefore, height for age could serve as an additional and globally available clinical parameter to monitor patients’ clinical condition 39 40