The Year in Review: I have no financial relationships with a - - PowerPoint PPT Presentation

3/9/2019 1

The Year in Review: Clinical Science

Mary P. Mullen, M.D., Ph.D. Boston Children’s Hospital Harvard Medical School Conflict of Interest Disclosure

Mary P. Mullen

• I have no financial relationships with a
• I have no financial relationships with a commercial

entity producing healthcare-related products or services

• Site investigator for GSK, Bayer, Actelion and United

Therapeutics sponsored PH studies

• Talk will include discussion of drugs which have not

been FDA approved in pediatric age range

Road map

• WSHPH - lessons from Nice
• Precision Medicine

– New genes – Individualized monitoring

• Predicting complications and mortality
• Therapeutics
• Burden of disease

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Overview

• WSHPH - lessons from Nice
• Precision Medicine

– New genes – Individualized monitoring of disease course and progression

• Predicting complications and mortality
• Therapeutics
• Burden of disease

6th World Symposium on Pulmonary Hypertension – Nice, France

• Pediatric Task force – January, 2018
• Consensus opinions – Feb 27-March 1, 2018
• Manuscript, Eur Resp J. 2019:53

Key Takeaways

• Adopted adult hemodynamic definition of PAH

as > 20 mmHg with PVR > 3 WU as new definition for pediatric PAH

• Standardization of AVT testing for children

– Sitbon criteria for vasodilator testing advised for use in acute vasodilator testing for determining response

–  mPAP by at least 10 mmHg to < 40 mmHg with

sustained cardiac output

Rosenzweig EB et al. Eur Respir J 2018

WSPH General Guidance for

• perability in CHD-PAH

PVR index WU m2 PVR WU Correctability / favourable long-term

• utcome

< 4 < 2.3 Yes 4 – 8 2.3 – 4.6 Individualize > 8 > 4.6 No

Rosenzweig EB et al. Eur Respir J 2018 The long term impact of defect closure in the presence of PAH with increased PVR is unknown.

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Updates in pediatric classification

• Group 1.5 PAH Long term responders to CCBs
• Group 1.3 Drug and toxin induced PAH

– Diazoxide

• Group 1.7 Persistent PH of the newborn

syndrome

– Multiple associated conditions

Rosenzweig et al Eur Respir J 2019; 53:1-18.

PPHN: Associated Disorders

Classification Updates continued

• Group 2.4 Congenital post-capillary
• bstructive lesions

– Pulmonary vein stenosis – Cor triatriatum – Obstructed total anomalous pulmonary venous return – Mitral/aortic stenosis – Coarctation of the aorta

• Group 3.5 Developmental lung disorders

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Classification continued

• Group 5.4 Complex CHD
• PH in this setting is difficult to define or

classify

– Segmental pulmonary hypertension – Single ventricle – Scimitar syndrome

• Down syndrome

– Phenotype of DS related PH variable – Classified as Group 3 in the absence of CHD

WSPH Summary

• Highlighted differences between children and

adults

• New findings in pediatric PH
• Noted need for pediatric specific clinical trials

and clinical endpoints for children with PH

• Need to understand how new definitions and

classifications affect diagnosis, clinical trials and our interpretation of previous data

PAH AS A GENETIC DISORDER 2018- genetic causes of PAH

• Novel genetic mutations reveal new heritable

causes of idiopathic PAH

• Sox 17 transcription factor involved in vascular

development and remodeling

– Identified in cohorts of adults and children with heritable, idiopathic and congenital heart disease associated PAH

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Rare SOX17 variants associated with PAH and congenital heart disease

PAH-CDH with: ASDs, VSDs, PDAs, ASD/VSD/AV canal defect

Zhu N, et al. Genome Medicine 2018:10:56

GWAS suggests SOX17 enhancer region associated with PAH risk

Rhodes CJ, et al. Lancet Respir Med 2019;7:227-238

Loss-of-Function ABCC8 Mutations in Pulmonary Arterial Hypertension, Volume: 11, Issue: 10, DOI: (10.1161/CIRCGEN.118.002087)

Loss of function mutations in ABCC8 encoding a regulatory subunit of the ATP sensitive potassium channel are associated with PAH

Frequency of Genetic Mutations in Pediatric and Adult PAH

Enrichment of variants in TBX4 but not other risk genes in pediatric

• nset

Zhu N, et al. Circulation. Genomics and Precision Medicine 2018; April; 11 Total: 21.5%

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Frequency of heritable PAH mutations in adult and pediatric patients

• Next Gen Sequencing on 268 PAH and PVOD/PCH

patients

• Pathogenic mutations in 19.4% of sporadic PAH,

and 54.5% of familial PAH

• BMPR-2, TBX4 most common
• BMP9 in 1.2%
• BMP10 in two cases

Eyries M, et al. Eur Respir J 2018 (December)

Karolak JA, et al. Am J Hum Gen 2019;104:213-228

Association of Lethal Lung Developmental Disorders with disruption of the TBX-FGF Pathway

Acinar dysplasia, ACD, pulmonary hypoplasia

TBX4

Genetic Data Transforms Disease

Genetics: Implications

• Guidelines for genetic testing in patients and

families with PAH are needed

• Classification schemes should evolve to reflect

understanding of genetic causes of PAH

• Outcomes and prospective clinical trials need

to be defined for heritable / non-heritable cases

• Underscores need for targeted therapeutics

addressing molecular basis of disease

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PH in Children with DS

• Association well recognized
• Congenital heart disease/left to right shunt

– Increases risk

• Incidence of PPHN higher
• Underlying disease burden, role of specific co-

morbidities, exacerbating factors

– Not completely understood

PH in Children with Down Syndrome (Colorado)

• Cohort of 1242 children with Down syndrome
• Incidence of PH was 28%
• Comorbid contributors:

– OSA – Intermittent hypoxia – GERD – Chronic lung disease – Chronic aspiration

Bush Doug, et al. J Pediatric 2018:202:212-9

PH in Children with Down Syndrome

Bush D, et al. J Pediatric 2018:202:212-9 86% first year of life

Focused approach to genetic syndromes associated with PAH

• Illustrates variability of PH in children with DS
• CHD major risk factor
• Multiple respiratory co-morbidities
• Major disease burden in first year of life
• Ongoing need for respiratory evaluation after

initial pulmonary hypertension management

• Demonstrates challenges of diagnosis,

therapies and compliance in this population

Bush D, et al. J Pediatric 2018:202:212-9

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Individualized approach to monitoring progression of disease

• Novel MRI biomarkers

– Flow dynamics – RV performance

• Specific predictors of outcome

– RV ejection fraction, LV stroke volume index, RV volume

• New research measures include assessment of

ventricular-vascular coupling and RV stroke work

Right Ventricular Stroke Work /EF Predicts Clinical Worsening in a Cohort of PAH patients (Stanford)

Weiguang Yang; Alison L. Marsden; Michelle T. Ogawa; Charlotte Sakarovitch; Keeley K. Hall; Marlene Rabinovitch; Jeffrey A. Feinstein; Pulm Circ 2018; 8, 2045894018780534. D

Clinically Stable Clinically Worsening

Precision therapeutics in Pediatric PH

• Targeted approach to disease
• Careful diagnosis and classification of each

patient

• Taking into account susceptibility to develop

particular disease and disease recurrence

• Focused treatment strategy
• Individualized monitoring of disease progress

PREDICTING COMPLICATIONS AND MORTALITY IN PEDIATRIC PAH

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Impact Registry: Pediatric PAH (0-21 yrs)

• 88 hospitals
• 8111 procedures in 7729 patients
• Composite outcome of catheterization complications:

death in 1-2 days, cardiac arrest, initiation of ECMO

• Rate of catastrophic adverse event: 1.4%

– Rate of death before discharge: 5.2% – Risk of major non-death AE: 5%

• Predictors of adverse events:

– Increased PA pressure – Increased PVRI – Decreased cardiac index – Fewer PAH cardiac catheterizations at center

O’Byrne ML, et al. JAHA: J Am Heart Assoc 2018 Risk Factors for Major Early Adverse Events Related to Cardiac Catheterization in Children and Young Adults With Pulmonary Hypertension: An Analysis of Data From the IMPACT (Improving Adult and Congenital Treatment) Registry. O’Byrne ML, et al. JAHA: J Am Heart Assoc 2018

Perioperative events in children with PH undergoing non-cardiac procedures

• Single center retrospective cohort (JH)
• 77 children with PH undergoing cardiac cath
• r non-cardiac procedures
• BPD (46.7%), CHD (29.9%), CDH (14.3%)
• Major events – failed extubation (5.6%),

postop arrest (4.7%), intraop arrest (2%), postop death (1.4%)

Bernier et al, Pulmonary Circulation 2017

Perioperative events in children with PAH undergoing non-cardiac procedures (Johns Hopkins)

Bernier ML, et al. Pulmonary Circulation 2017 Major events - more frequent in severe PH Incidence associated with procedure type

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Mortality and morbidity associated with PAH in PICU (UCSF)

• Retrospective multicenter cohort study
• 153 centers in Virtual PICU Systems database

– 2009-2015

Mortality and morbidity associated with PAH in PICU (UCSF)

Balkin EM, et al. Pulmonary Circulation 2017 Younger Longer LOS Higher illness severity score More likely to receive

• mechanical ventilation
• CPR
• ECMO

Mortality by admission type

Balkin EM, et al. Pulmonary Circulation 2017

Multivariate predictors of mortality in children with pulmonary hypertension

Balkin EM, et al. Pulmonary Circulation 2017

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Predictors of Outcomes for Procedures and PICU

• Cardiac catheterization

– Adverse hemodynamics – Center experience – Prematurity – Inotropes

• Non-cardiac surgery

– PH severity – Surgical procedure

• PICU

– ”Primary” PH – Age –younger+older – Mechanical ventilation

Opportunities for improvement going forward

• Careful pre-procedure/preoperative screening
• Multidisciplinary care with input from PH

specialists

• Understand PH patients at highest risks
• Utilize postoperative monitoring strategies
• Determine optimal anesthetic techniques for

children with PH

THERAPEUTICS

Therapeutics in Pediatric PH 2018

• Prostanoids

– RV function – Safety/efficacy

• Sildenafil

– Experience – NICU

• Prostaglandin E1 in CDH
• Potts Shunt

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Effect of prostacyclin analogues on RV function in children (CHOP)

• Retrospective cohort analysis
• 2001-2015
• 49 patients age 0-29 years at drug initiation
• Treated with epoprostenol (IV)or treprostinil
• (IV/SQ/inhaled)
• RV function assessed by echocardiography

Hopper RK, et al. Pulmonary Circulation 2018:8:1-8 Hopper RK, et al. Pulmonary Circulation 2018:8:1-8

RV function mirrors clinical improvement

Subcutaneous treprostinil infusion in severe pediatric PH (multicenter)

• 56 pediatric patients with PAH (1-200 months)
• 83% improved WHO functional class, 6 minute

walk distance, NT-proBNP and PVR

• 12 minor site infections
• No episodes of sepsis
• Site pain in 21%, 9/12 manageable

Levy M, et al. Int J Cardiol 2018;264:153-157

Outcome of 56 patients treated with SC treprostinil

Levy M, et al. Int J Cardiol 2018;264:153-157

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Survival for patients treated with SC treprostinil

Levy M, et al. Int J Cardiol 2018;264:153-157 Survival: FC III-IV Event-free Survival: FC III-IV Event-free Survival incl Potts: FC III-IV Event-free Survival incl Potts, incident pts Survival 6months, 1,3, 5 yrs = 94%, 88%, 85%, 85%

• Retrospective cohort of 164 infants with CDH
• 17 treated with treprostinil
• 2011-2016
• Severity of PH assessed by BNP and echo
• Compared with concurrent CDH population,

those receiving treprostinil had longer hospital stays, longer need for mechanical ventilation, more likely to require ECMO

Treprostinil in Severe PH associated with CDH (CHOP)

Lawrence KM, et al. J Pediatrics 2018;200:44-9

Treprostinil in PH associated with CDH

Decrease in BNP after drug initiation

Lawrence KM, et al. J Pediatrics 2018;200:44-9

Treprostinil in PH associated with CDH

Lawrence KM, et al. J Pediatrics 2018;200:44-9 Improvement in Echocardiographic Assessment of PH Severity at Serial Time Points

• n Treprostinil

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FDA approved Medtronic Implantable System for Treprostinil 2018

Impact for adolescents and transition patient with PH

System and Indications

• Synchromed II implantable drug infusion pump

and intravascular catheter

– adult patients with New York Heart Association (NYHA) Class I, II and III pulmonary arterial hypertension who have previously been receiving treprostinil intravenously through an external catheter – DelIVery for PAH trial

• Prospective, single arm, non-randomized open label study -

10 sites/64 patients

• Low late catheter complications
• High rate of patient satisfaction

Sildenafil

• Extensively used off- label for pediatric PH since 2005
• STARTS-1 Trial – improvement in peak VO2 and

hemodynamics in medium/high dose

• STARTS -2 Long term extension – increased mortality in

high dose in IPAH

• FDA/European Medication Agency – contradictory

recommendations – eventually

– EMA approved –warning on high dose – FDA warning revised – consider risks/benefits individual patients

• Important to continue to review data on use of

sildenafil in infants and children with PH

Sildenafil in Children with PH (Columbia)

• Retrospective cohort design
• 269 children

– 47 idiopathic (older; tended to require additional meds) – 53 congenital heart disease – 135 BPD – 24 CDH

• Median follow up 3.1 years
• 1 mg/kg q8
• 84% monotherapy, 14% add on, 1 % initial combination

Cohen JL, et al. J Pediatrics 2019;205:29-34

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Survival curve in children treated with sildenafil

Cohen JL, et al. J Pediatrics 2019;205:29-34 Survival worse in group 3 vs 1 1, 3, 5 yr 90%, 86%, 84%

Sildenafil in Children with PH Outcomes in trisomy 21

PH type N Remains on sildenafil or tadalafil Stopped

• wing to PH

improvement Died / Lost to follow up

iPAH 4 2 2 BPD 7 2 2 3 CHD 18 10 5 3

Cohen JL, et al. J Pediatrics 2019;205:29-34 Outcomes not significantly different from patients without T21

Sildenafil in the Neonatal ICU (Duke)

• Retrospective chart review of infants

discharged from 349 community and tertiary care center NICUs from 2001-2016

• Identified infants > 23 weeks gestational age

exposed to sildenafil in the first 180 postnatal days

Sildenafil exposure in NICU

Thompson EJ, et al. Amer J Perinatol 2019; 36(03): 262-267 1 million discharged Sildenafil -1336

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Sildenafil exposure in NICU

Thompson EJ, et al. Amer J Perinatol 2019; 36(03): 262-267 Length of treatment Further studies of dosing, safety, efficacy needed.

Prostaglandin E1 as treatment for PH in congenital diaphragmatic hernia (CHOP/multi)

• PGE used to maintain ductal patency and unload

the suprasystemic RV in neonates with CDH

• Retrospective chart review
• 170 patients with CDH from 2011-2016
• 41% received PGE

– PGE cohort had more severe pulmonary hypoplasia – PGE cohort more likely to receive additional PH treatments such as iNO, treprostinil, or sildenafil – PGE cohort more likely to require non-primary closure

• f diaphragm defects, ECMO and had longer hospital

stay

Lawrence KM, et al. J Pediatric Surg 2019;54:55-59

Prostaglandin E1 as treatment for PH in congenital diaphragmatic hernia

Lawrence KM, et al. J Pediatric Surg 2019;54:55-59

Improvement in echocardiographic markers of PH severity in congenital diaphragmatic hernia after PGE

Lawrence KM, et al. J Pediatric Surg 2019;54:55-59 Right to left shunting Bowed intraventricular septum Suprasystemic TR jet

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• 12 Consecutive pediatric patients
• Median age 11.2 yrs, wt 32.8 kg
• Potts shunt 2013-2017
• 8 survived median 27 months post shunt
• 2 died, 1 lung transplant
• In survivors: WHO functional class improvement, 5/8 off pulmonary vasodilators

Potts Shunt Improves Right Ventricular Function and Coupling With Pulmonary Circulation in Children With Suprasystemic Pulmonary Arterial Hypertension ( St Louis Children’s Hospital)

Aggarwal Manish et al. Circulation: Cardiovascular Imaging 2018;11: Aggarwal M, et al. Circulation: Cardiovascular Imaging 2018;11:

Echocardiographic measurements of right ventricular function and RV-pulmonary coupling before and after Potts shunt

Therapeutics in Pediatric PH 2018

• Prostanoids

– Improvement in RV function mirrors clinical effect – SC safe, effective

• Sildenafil

– Experience large series of children – NICU

• Prostaglandin E1 in CDH
• Potts Shunt

– Need to understand timing and patient characteristics

BURDEN OF ILLNESS

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Total Admissions and Readmissions of patients with PAH increasing since 2005 (Pediatric Health Information System Database) (Baylor)

Awerbach JD et al. J Pediatrics 2018;195:95-101.

Total Annual Hospital Costs

Awerbach JD et al. J Pediatrics 2018;195:95-101.

Trends in PPH Pharmacotherapy: Hospitalizations 2005-2014

Awerbach JD et al. J Pediatrics 2018;195:95-101. Need better understanding of costs, Resource utilization and clinical outcomes

Quality of Life: patients and parents

• Prospective cohort of children age 2-18 with

PAH

• N = 33
• PedsQL surveys by children and parents
• Compared to historical cohorts assessed on

same survey instruments

Handler SS, et al. Pulmonary Circulation 2018

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PH vs other chronic diseases of children

Varni, et al. 2007

10 20 30 40 50 60 70 80 90

Total Score Physical Health Psychosocial Health Emotional Functioning Social Functioning School Functioning

Cardiac Cancer PHT Diabetes P value < 0.01 for all except emotional functioning

Quality of Life: patients and parents

Handler SS, et al. Pulmonary Circulation 2018

Quality of Life: patients and parents

Handler SS, et al. Pulmonary Circulation 2018

Health related QOL in pediatric PH

• Study demonstrated decreased QOL by both

parents and children with PH

• Both parents and children report impaired QOL
• Markers of disease severity - functional class,

number of medications, mean PAp- associated with lower scores

• Highlights importance of this outcome as survival

improves and chronicity of disease increases.

• We need to increase visibility and resources for

patients with chronic PH

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Summary

• WSPH (Nice) Pediatric Task force provided new

guidelines focusing on differences and understanding of childhood PH

• Genetic diagnosis transforms disease
• Growing insight into complications associated

with procedures and ICU stays

• Increased experience with treatments targeted

for children and infants

• High financial and personal cost of PAH for

patients and families

Future directions

• Interpretation of genetic findings to add to

evolving classification of pediatric PAH

• Studies exploring strategies to improve safety for

PH patients undergoing interventions and procedures

• PH clinical trials in children focusing on well

defined phenotypes and using clinically meaningful endpoints

• Development of target therapies and treatments

aimed at specific mechanisms of disease

• Increased understanding of patient experience of

disease