Disclosures Discussion of targeted PAH therapies in children is off - PowerPoint PPT Presentation

4/21/2018 Disclosures • Discussion of targeted PAH therapies in children is off label aside from bosentan. • Investigator – clinical trials (Actelion, Bayer, Gilead, Lung Rx, United Therapeutics) Methods • pubmed search 2017-2018 • Diagnostics • pulmonary hypertension • Genetics – children • Drugs – pediatrics • Collaborative clinical guidance – Dunbar Ivy • And some other things.... 1

4/21/2018 • Aim: To determine the effect of prostacyclin analogues on RV function assessed by echocardiography in children with PH. • Retrospective cohort study of children with PH treated with a prostacyclin analogue (epoprostenol or treprostinil) between January 2001 and August 2015 at CHOP. • Data were collected before initiation of treatment (baseline) and at 1–3 and 6–12 months after. Pulm Circ. 2018 RV Function and Clinical Improvement in Kids with PAH on Prostanoids RV Function and Clinical improvment in kids with PAH on Prostanoids • Echocardiogram measurements including TAPSE and RV global longitudinal strain were made with blinding to clinical information. • 49 individuals (65% female), aged 0–29 years at the time of prostacyclin initiation were included. • Disease types included pulmonary arterial hypertension (idiopathic [35%], heritable [2%], and congenital heart disease-associated [18%]), developmental lung disease (43%), and chronic thromboembolic PH (2%). • Participants received intravenous (IV) epoprostenol (14%) and IV/subcutaneous (SQ) (67%) or inhaled (18%) treprostinil. Prostacyclin analogues were associated with improvement in TAPSE (P. 0.007), RV strain (P< 0.001), and qualitative RV function (P. 0.037) by echocardiogram, and BNP (P< 0.001), functional class (P. 0.047) and Hopper RK, et al. Pulm Circ. 2018 6MW distance (P. 0.001). Hopper RK, et al. Pulm Circ. 2018 2

4/21/2018 RV Function and Clinical improvment in kids with PAH on Prostanoids Circ Cardiovasc Imaging, 2017 • 42 children with PAH and 26 age- and • TAPSE and strain improved at early follow up (P. 0.05 and P. 0.002, respectively) size-matched controls underwent despite minimal RV pressure change. comprehensive CMR evaluation. • Pediatric PAH patients have a focal • In children with PH, prostacyclin analogues are associated with an early and increase in the apparent ascending sustained improvement in RV function measured as TAPSE and strain as well as aortic stiffness as assessed by cardiac clinical markers of PH severity. magnetic resonance studies. • The apparent aortic stiffness is strongly • RV strain may be a sensitive marker of RV function in this population associated with the degree of distension of the MPA. Hopper RK, et al. Pulm Circ. 2018 • Associations between MPA/Ascending aorta size ratio and LV ejection fraction (left) and LV ventricular-vascular coupling ratio (right). • Both trends are suggestive of negative MPA expansion effect on the ascending aorta resulting in increased LV afterload. Schafer M., Circ Cardiovasc Imaging, 2017 Schafer M., Circ Cardiovasc Imaging, 2017 3

4/21/2018 “We speculate that distension of the MPA contributes to aortic stiffness due to its role in limiting full aortic expansion during systole within a restricted space of the thoracic cavity. We propose that in addition to ventricular interdependency, vascular interdependency of the MPA and aorta can potentially have negative effects on LV performance in pediatric PAH, which is primarily due to the mechanical effects of MPA distension.” European Heart J – CV Imaging, 2017 Schafer M., Circ Cardiovasc Imaging, 2017 RV function and strain: prognosis • Retrospective review of all infants and children <2 years of age with PH from January 2011 to August 2016. Differences in characteristics between survivors and nonsurvivors were analyzed • 56 patients – most extremely premature; and had BPD. Patients who died were more likely to have underlying CHD; have a higher increase in the concentration of CO2 in the blood with a corresponding greater mean percentage decrease in pH and percentage rise in NTpro BNP during PH exacerbations; more likely to have been on medications for pulmonary hypertension; and have a higher RVSP/SBP (%) ratio and S/D ratio. • Positive correlations between percentage rise in NT-pro BNP and pCO2; NT-pro BNP and RVSP/SBP (%) ratio; and RVSP/SBP (%) ratio and S/D ratio. Pei-Ni J. et al., Eur Heart J –CV imaging, 2017 4

4/21/2018 Conclusions NT-pro BNP is a useful biomarker for both respiratory exacerbations and mortality, and RVSP/SBP (%) ratio and S/D ratio are echo identifiers for increased mortality. CHD, 2018 J Am Heart Assoc. 2018 • All catheterizations in children and young adults, aged 0 to 21 years, with PH at hospitals submitting data to the IMPACT (Improving Adult and Congenital Observed risk of the composite outcome Treatment) registry between January 1, 2011, and December 31, 2015, were of death, cardiac arrest or MCS during or after studied. catheterization was 1.4%, and the risk of death before discharge was 5.2%. • Using mixed-effects multivariable regression, assessed the association between prespecified subject-, procedure-, and center-level covariates and the risk of death, cardiac arrest, or mechanical circulatory support during or after cardiac catheterization. J Am Heart Assoc. 2018 5

4/21/2018 But, who are these PAH patients? Many interventions at the time of catheterization not typical for diagnostic PAH catheterization O’Byrne ML, Et al, JAHA, 2018 O’Byrne ML, Et al, JAHA, 2018 Risk Factors for Catastrophic Adverse Events Post Risk Factors for Cardiac Cath in PH Catheterization in pediatric PH • Catheterization in premature neonates and non-premature infants was associated with increased risk of catastrophic adverse event, as was pre- catheterization treatment with inotropes and lower systemic arterial saturation . • Increasing PVR and PAP were associated with increased risk ( P< 0.0001 for both) • Increasing volumes of catheterization in patients with PH were associated with reduced risk of composite outcome (odds ratio, 0.8 per 10 procedures; P =0.002) Young patients with PH are a “high-risk” population for diagnostic and interventional cardiac catheterization. Hospital experience with PH is associated with reduced risk , independent of total catheterization case volume. O’Byrne M., J Am Heart Assoc. 2018 J Am Heart Assoc. 2018 6

4/21/2018 Exome Sequencing in Children With Pulmonary Arterial Hypertension Demonstrates Differences Compared With Adults • Overall progress with identification of novel mutations: BMPR2, ALK1, ENG, CAV1, KCNK3, EIF2AK4... BMPR2 mutations underlie ≈70% of adult familial PAH (FPAH) cases, but genetic basis of PAH in children is less understood • Pediatric specific progress: – Genetic analysis of 155 pediatric and 257 adult-onset PAH • TBX4 – potential role in pediatric PAH (small patella syndrome, patients, including both FPAH and sporadic idiopathic PAH (IPAH). Kerstjens-Frederikse WS, et al. J Med Genetics 2013) – After screening for 2 common PAH risk genes, mutation negative • Levy M, ERJ, 2016 noted that ACVRL1 and TBX4 more common FPAH and all IPAH cases were evaluated by exome sequencing. in children than adults TBX4 and Pediatric PH • Significant enrichment of TBX4 mutations in pediatric- compared with adult- onset patients (IPAH: 10/130 pediatric versus 0/178 adult-onset) • TBX4 carriers had younger mean age-of-onset compared with BMPR2 carriers. Zhu N, et al. Circ Genom Precis Med 2018 Zhu N, et al. Circ Genom Precis Med 2018 7

4/21/2018 Exome sequencing: Conclusions • Mutations in known PAH risk genes accounted for ≈70% to 80% of FPAH in both age groups, 21% of pediatric-onset IPAH and 11% of adult-onset IPAH. • Rare, predicted deleterious variants in TBX4 are enriched in pediatric patients and de novo variants in novel genes may explain ≈19% of pediatric-onset IPAH cases. Zhu N, et al. Circ Genom Precis Med 2018 PAH-Specific Treatment Options Approved for Use PAH-Specific Treatment Options Approved for Use in Adults With PAH in Children With PAH in the US Inhaled Parenteral Inhaled Parenteral Oral Therapy Therapy Therapy Oral Therapy Therapy Therapy Prostacyclin Prostacyclin PDE-5 sGC pathway PDE-5 sGC pathway ERAs Inhibitors Stimulator therapy Prostacyclins ERAs Inhibitors Stimulator therapy Prostacyclins Bosentan Bosentan Sildenafil Riociguat Treprostinil Iloprost Epoprostenol Treprostinil Ambrisentan Tadalafil Selexipag Treprostinil (SC or IV) RTS Macitentan Epoprostenol 8