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

3/8/2019

The TOPP Registry

• 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

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The Board of Association of Ped PH TOPP-1 Registry Design

• Multicenter, prospective, observational, non-interventional
• Patients included are treated as determined by their physician
• No therapy protocol, no predetermined visit schedule

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TOPP-1 Patient Population

• Age at diagnosis: >= 3 months and <= 18 years
• Diagnosed with PH on/after 1 January 01

(prevalent and incident patients)

• Present with PH belonging to one of the following categories:
• WHO group 1,
• 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

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TOPP-1 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

TOPP-1: GLOBAL REGISTRY 31 Sites in 19 Countries

numbers refer to number of patients enrolled geographically at time

• f first TOPP-data cut Feb 2010

TOPP: Clinical Features

Results

• Enrolled: 456 patients (≥ 3 mos and ≤ 18 yrs at Dx); Data cut Feb 2010

PH with increased PVR confirmed in 362† patients

• All of the following analyses are for PH confirmed patients only
• 59% female
• Median age at diagnosis 7 yrs
• At enrollment,

102 (28%) newly diagnosed* 260 (72%) previously diagnosed**

Date of diagnosis: date of confirmatory RHC

† Reasons for exclusion: PVRI < 3 units  m2 n=6; PCWP > 12 mm Hg n=5; lack of data to

calculate PVRI n=86; *Confirmatory RHC ≤ 3 mos of enrollment; **Confirmatory RHC > 3 mos prior to enrollment

21% had to be excluded

Pediatric PAH, Epidemiology

Reveal-Adults2 2525 53 80 2525 (100) 1166 (46) 215 (10) 639 (25) 136 (5) 255 (10) NE NE

• 1. Berger et al. Lancet 2012.
• 2. Badesch et al. Chest 2010.

Values given are n (%) unless otherwise indicated

TOPP 1 Patients, n 362 Age at Dx (yrs), median 7.5 Female, % 59 Group 1: PAH 317 (88) IPAH/HPAH 212 (53) CHD 160 (40) CTD 9 (3) Portopulmonary 2 (1) Other 14 (4) Group 3: Lung disease 42 (12) Other 3 (1)

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Pediatric PAH, Symptoms:

TOPP-1 Patients, n 362 Age (yrs), median 7.5 Dyspnea at exertion, % 235 (65) Syncope 73 (20)

Idiopathic PAH 57 (31) CHD (shunt) 0 (0)

WHO functional class (%) I 12 II 51 III 30 IV 7 mPAP (mmHg) 58 PVRi (WU.m2) 16 CI (L/min/m2) 3.7

Berger et al. Lancet 2012;

Pediatric PAH, Comorbidities

TOPP 2 Patients, n 362 Age (yrs), median 8.9 Comorbidities 86 (24) Trisomy 21 42 (12) Other 44 (12)

chromosomal, non-chromosomal, syndromes

PPHN 8 (2*) ≥ 10 times normal; ≥ 2.5 times higher controlling for trisomy 21

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TOPP-1 Hemodynamics HC data sets of ALL patients underwent blinded review

for

validation and confirmation

• f

hemodynamic measurements and calculations.

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Hemodynamics

Background

• Pulmonary hypertension in children is associated with high

morbidity and mortality

• Hemodynamic evaluation by cardiac catheterization remains

“gold-standard”

• Confirmation of diagnosis
• Assessment of disease severity
• Review during follow-up
• Invasive procedure with potential complications

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Hemodynamics

Results

• 568 patients enrolled in registry; Data cut February 2012
• 480 PH-confirmed

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18% had to be excluded

Hemodynamics

Pediatric PH, hemodynamic profile 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.

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Hemodynamics

Hemodynamic profile, relation with etiology

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Hemodynamics

Hemodynamic profile, relation with age at Dx

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20 40 60 80 100 18 Hemodynamic profile: severity  Age 

Hemodynamics

Hemodynamic profile, relation with WHO-FC

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20 40 60 80 100 I II III IV Hemodynamic profile: severity  WHO-FC 

Heart catheterization in pediatric PH

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%)

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Heart catheterization in Pediatric PH

Complications

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Heart catheterization in Pediatric PH

reasons for death

• Cardiac arrest post-HC
• Complications of extracorporealmembrane oxygenation (ECMO)
• At induction of anaesthesia,
• Severe bleeding during HC procedure,
• Progressive heart failure after HC
• Brain lesions following cardiac arrest during HC.

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Heart catheterisation in pediatric PH

risk factors for complications

• Younger Age
• Higher WHO-FC
• General Anesthesia

(mostly used in children < 2 yrs)

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Risk of cath-related adverse events:

• Ped. Cath. Intervention > Ped PH > Adult PH

10-20% ± 6% ± 1%

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2016

To “cath” or not in pediatric pulmonary hypertension, letter. J Am Coll Cardiol 2016

Diagnostic Evaluation

Background

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• Diagnosis/Confirmation of PH
• Exclusion/Identification
• f associated conditions
• Assessment of severity

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Diagnostic Evaluation

All patients (N=456) All (n=456) Incident (n=135) Prevalent (n=321) ECG, n (%) 430 (94) 131 (97) 299 (93) Abnormal, n (%) 385 (90) 116 (89) 269 (90) Chest X-ray, n (%) 406 (89) 126 (93) 280 (87) Abnormal, n (%) 325 (80) 103 (82) 222 (80) Echocardiogram, n (%) 439 (96) 132 (98) 307 (96) Abnormal, n (%) 436 (99) 132 (100) 304 (99) All 3 tests normal 2 tests normal 15 (3) 6 (4) 9 (3) 1 test normal 81 (18) 23 (17) 58 (18)

Data cut Feb 2010

ECG, CXR and Echo are abnormal in most children with PH and seem suitable for screening

Diagnostic Evaluation

Conclusions Exclusion/Diagnosis of associated conditions:

• Not all patients underwent a complete work-up

Often no pulmonary evaluation (CT, polygraphy, LFT) in PH group 3 Also not in iPAH, although a diagnosis per exclusionem This seems only partly due to age limitations

• No differences between incident and prevalent patients
• No differences based on date of diagnosis (2001-2010)

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

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Acute Vasodilator Testing (AVT)

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AVT in pediatric PAH

• To describe current clinical

practice of AVT and

• subsequent treatment

decisions and outcome

• Data cut May 2013

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15% excluded

28%

TOPP-2 investigator meeting – 5 Nov 2016 – Chicago, USA 31 TOPP-2 investigator meeting – 5 Nov 2016 – Chicago, USA

AVT-responders

stratified for CCB treatment

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Only Sitbon Responders tended to survive longer over time when on CCB therapy

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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
• f 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.

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Growth in Pediatric PAH Collaboration of four prospective registries

• 1. Tracking Outcomes and Practice in Paediatric Pulmonary Hypertension (TOPP)

A global, multicentre registry;

• 2. The Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL)

A US-based multicentre registry

• 3. The Dutch National Network for Paediatric Pulmonary Hypertension,

A national registry of The Netherands

• 4. ItinerAIR-Pediatrie,

A French, multicentere registry These registries together represent 53 centres for pediatric pulmonary hypertension in 19 countries.

Ploegstra et al Lancet RM 2016

Growth in Pediatric PAH

• 4 registries: period 2008 -2013
• Children with PAH (IPAH/HPAH; APAH-CHD; APAH-Other)
• ≥ 2 measurements of height and BMI
• N=601 patients were included

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• Age
• Etiology
• Comorbidities:
• Trisomy 21
• “Concomittant conditions”

(genetic traits, syndromes)

• Ex-prematurity
• WHO functional class
• Duration of the disease

Determinants of growth in pediatric PAH

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

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Treatment initiation

Pediatric Pulmonary Hypertension

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Incident patients (n=244) Data cut Feb 2012 Treatment naïve for PH targeted medication (n=217) No treatment (n=28) Supportive therapy only (n=19) PH targeted medication (n=170) PH targeted medication before cardiac catheterization (n=26) Changes in treatment (n=11) No changes in treatment (n=15) No data (n=1)

PAH targeted Rx

mono duo triple

Treatment initiation in Pediatric Pulmonary Hypertension – insights from a multinational registry

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Tilman Humpl, Rolf MF Berger, Eric D Austin, Margrit S Fasnacht Boillat, Damien Bonnet, Dunbar D Ivy, Malgorzata Zuk, Maurice Beghetti, Ingram Schulze-Neick for the TOPP Investigators Cardiol Young 2016, accepted

• To describe the paediatric PAH population
• To describe the occurrence of individual and composite disease progression
• utcomes:

*Increased right heart failure, haemoptysis; †Increase ≥1 WHO FC i.v., intravenous; PAH, pulmonary arterial hypertension; s.c., subcutaneous; WHO FC, World Health Organization Functional Class

Disease progression 1 Disease progression 2 Disease progression 3

Death (all-cause) Death (all-cause) Death (all-cause) PAH-related hospitalisation* PAH-related hospitalisation* PAH-related hospitalisation* Lung transplantation Lung transplantation Lung transplantation Atrial septostomy Atrial septostomy Atrial septostomy WHO FC deterioration† WHO FC deterioration† Initiation of i.v./s.c. prostanoids (only first event) Initiation of i.v./s.c. prostanoids (only first event) Syncope Syncope PAH worsening (symptoms)

Composite disease progression endpoint in paediatric PAH clinically meaningful and feasible for clinical research

Beghetti, AEPC 2016

Patient characteristics

Characteristic Incident patients N=255 Female, n (%) 153 (60.0) Median age at diagnosis (Q1, Q3), years 6.5 (2.6, 12.6) Aetiology, n (%) IPAH/FPAH APAH-CHD 159 (62.4%) 96 (37.6%) WHO FC, %* I/II III/IV 13/43 34/9 Median observation period (Q1, Q3), months 33.0 (12.0, 55.0)

*Data missing for two patients APAH-CHD, pulmonary arterial hypertension associated with congenital heart disease; FPAH, familial pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; Q, quartile; WHO FC, World Health Organization Functional Class

Beghetti M, AEPC 2016

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Association for Pediatric Pulmonary Hypertension (PePH)

Events occurring first within the composite disease progression outcomes

Beghetti, AEPC 2016

13 7 78 1 1 8 5 41 1 1 38 2 5 8 5 35 1 1 33 2 4 12 10 20 30 40 50 60 70 80 90 All-cause death PAH-related death PAH-related hospitalisation Transplantation Atrial septostomy Deterioration in WHO FC Initiation of i.v./s.c. prostanoid Syncope PAH worsening

Proportion of events, % Disease progression 1 (n = 121) Disease progression 2 (n = 173) Disease progression 3 (n = 175)

Association for Pediatric Pulmonary Hypertension (PePH)

First events predictive of long-term outcomes death and lung transplantation (multivariate)

HRs and 95% CIs from multivariate analysis including variables from univariate analysis with p<0.15. *p<0.01; †p<0.05 CI, confidence interval; HR, hazard ratio; PAH, pulmonary arterial hypertension; WHO FC, World Health Organization Functional Class

3.49 1.47 8.29 2.62

1.32 5.20

2.13

1.02 4.45 1 2 3 4 5 6 7 8 9 WHO FC deterioration PAH-related hospitalisation PAH worsening

* *

†

Increased risk of death or transplantation Independent risk factors for long-term outcomes: WHO FC deterioration PAH-related hospitalisation and PAH worsening Independent risk factors for long-term outcomes: WHO FC deterioration PAH-related hospitalisation and PAH worsening Beghetti, AEPC 2016

TOPP-2 investigator meeting – 5 Nov 2016 – Chicago, USA

Goals of the TOPP-2 registry

Validate and assess treatment goals

• Goal 1: Validate the observed changes in the variables proposed in Nice as

treatment goals in PePH and identify new treatment goals

• Key variables collected by the TOPP-2 registry suggested as treatment goals1

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Death Elevated brain natriuretic peptide levels (BNP) Transplantation PVR index Hospitalization for PAH Ratio of pulmonary artery pressure (mPAP) to systemic artery pressure (mSAP) Clinical evidence of right ventricular failure 6-minute walking distance Progression of symptoms Vasoreactivity WHO functional class III/IV Echocardiographic parameters, e.g. systolic to diastolic duration ratio Syncope

1 D Ivy et al. JACC (2013).

TOPP-2 investigator meeting – 5 Nov 2016 – Chicago, USA

Goals of the TOPP-2 registry

Clinical worsening

• Typical components of clinical worsening (CW) encompass
• Goal 2: Describe the frequency of CW components
• Goal 3: Evaluate the predictive value of these components and their contribution

to CW

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All-cause death Deterioration of WHO FC PAH-related hospitalization Initiation of i.v. / s.c. prostanoids Lung transplantation Syncope Atrial septostomy

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TOPP-2 investigator meeting – 5 Nov 2016 – Chicago, USA

Goals of the TOPP-2 registry

Disease characteristics

• Goal 7: Characterize pulmonary arterial hypertension with congenital heart disease

(PAH-CHD) with regard to presentation, clinical course and treatment strategy, according to the proposed ABCD system1

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ABCD system for PAH-CHD patients A: Eisenmenger Syndrome B: Left to right Shunt, considered inoperable C: PAH with co-incidental CHD D: Post-operative PAH Unclassifiable

1 G Simonneau et al. JACC (2013).