DGPK Guideline Pulmonary Arterial Hypertension (PAH) in Infancy and Adolescence Siegrun Mebus (DHM, TU München) Christian Apitz (UKGM, Giessen) Gerhard-Paul Diller (UKM, Münster; RBH London, GB) Marius M. Hoeper (MHH, Hannover) Oliver Miera (DHZB, Berlin) Matthias Gorenflo (Universitätsklinikum Heidelberg)

Conflicts of Interests Leitlinienkoordinator: Prof. Dr. med. Jochen Weil Leitlinie: Pulmonary arterial hypertension (PAH) in infancy and adolescence S. Mebus C. Apitz G.-P. Diller M.M. Hoeper O. Miera M. Gorenflo 1 Berater- bzw. Gutachtertätigkeit oder bezahlte Mitarbeit in einem wissenschaftlichen Beirat eines Unternehmens der Gesundheitswirtschaft (z.B. Arzneimittelindustrie, Medizinproduktindustrie), eines kommerziell orientierten Auftragsinstituts oder einer Versicherung Actelion Actelion Actelion Actelion, Bayer, Gilead, GSK, Lilly, Pfizer, Novartis Actelion Pfizer Actelion Bayer Schering Ø DGPK DGK DGKJ GNPI AEPC UK Heidelberg ZU Leuven 2 Honorare für Vortrags- und Schulungstätigkeiten oder bezahlte Autoren- oder Co-Autorenschaften im Auftrag eines Unternehmens der Gesundheitswirtschaft, eines kommerziell orientierten Auftragsinstituts oder einer Versicherung Actelion Pfizer GSK Actelion Pfizer Actelion GB Actelion, Bayer, Gilead, GSK, Lilly, Pfizer, Novartis Actelion Pfizer 3 Finanzielle Zuwendungen (Drittmittel) für Forschungsvorhaben oder direkte Finanzierung von Mitarbeitern der Einrichtung von Seiten eines Unternehmens der Gesundheitswirtschaft, eines kommerziell orientierten Auftragsinstituts oder einer Versicherung Pfizer Ø Actelion GB Pfizer GB Actelion Bayer Pfizer Novartis Ø 4 Eigentümerinteresse an Arzneimitteln/Medizinprodukten (z. B. Patent, Urheberrecht, Verkaufslizenz) Ø Ø Ø Ø Ø 5 Besitz von Geschäftsanteilen, Aktien, Fonds mit Beteiligung von Unternehmen der Gesundheitswirtschaft Ø Ø Ø Ø Ø 6 Persönliche Beziehungen zu einem Vertretungsberechtigten eines Unternehmens Gesundheitswirtschaft Ø Ø Ø Ø Ø 7 Mitglied von in Zusammenhang mit der Leitlinienentwicklung relevanten Fachgesellschaften/Berufsverbänden, Mandatsträger im Rahmen der Leitlinienentwicklung DGPK DGKJ AEPC KN-AHF DGPK DGKJ AEPC keine relevanten DGK ERS ESC Ø 8 Politische, akademische (z.B. Zugehörigkeit zu bestimmten „Schulen“), wissenschaftliche oder persönliche Interessen, die mögliche Konflikte begründen könnten Ø Ø keine relevanten Ø Ø 9 Gegenwärtiger Arbeitgeber, relevante frühere Arbeitgeber der letzten 3 Jahre DHM, TUM UKGM Giessen RBP, London UKM MHH DHZB

Definition PAH Dana Point (2008) resting mean pulmonary arterial pressure mPAP ≥ 25 mmHg pulmonary arterial wedge pressure ≤ 15 mmHg PH has been defined as a resting mean pulmonary arterial pressure (mPAP) 25 mm Hg, or an mPAP with exercise 30 mm Hg. The subgroup of PH known as pulmonary arterial hypertension (PAH) adds the criterion that the pulmonary arterial wedge pressure must be 15 mm Hg. Some definitions have also included pulmonary vascular resistance (PVR), requiring that it be 2 or 3 Wood units.

Definition PAH Dana Point (2008) resting mean pulmonary arterial pressure mPAP ≥ 25 mmHg pulmonary arterial wedge pressure ≤ 15 mmHg no threshold value for pulmonary vascular resistance (PVR) even though: PVRI > 3 Wood units (U*m2) pathological increased PH has been defined as a resting mean pulmonary arterial pressure (mPAP) 25 mm Hg, or an mPAP with exercise 30 mm Hg. The subgroup of PH known as pulmonary arterial hypertension (PAH) adds the criterion that the pulmonary arterial wedge pressure must be 15 mm Hg. Some definitions have also included pulmonary vascular resistance (PVR), requiring that it be 2 or 3 Wood units.

Classification PAH Idiopathic PAH (IPAH) Heritable PAH (HPAH) APAH-CHD Simonneau JACC 2009

Classification PAH Idiopathic PAH (IPAH) Heritable PAH (HPAH) APAH-CHD Simonneau JACC 2009

General Issues

General Issues Epidemiology incidence: 0,48/1 M children/year prevalence: IPAH/HPAH 2,07/1 M children f:m = 1,7:1

General Issues Epidemiology Survival Period incidence: 0,48/1 M children/year prevalence: IPAH/HPAH 2,07/1 M children f:m = 1,7:1 Survival Period

General Issues Epidemiology Survival Period Pathophysiology incidence: 0,48/1 M children/year prevalence: IPAH/HPAH 2,07/1 M children f:m = 1,7:1 Survival Period Pathophysiology Histopathology Rabinovitch 1996 Rabinovitch 1997 Rabinovitch 2008

General Issues Epidemiology Survival Period Pathophysiology incidence: 0,48/1 M children/year prevalence: IPAH/HPAH 2,07/1 M children f:m = 1,7:1 Survival Period Pathophysiology Histopathology Genetic Aspects BMPR2 50-70% HPAH 10-40% sporadic IPAH Rabinovitch 1996 Rabinovitch 1997 Rabinovitch 2008

Symptoms UNSPECIFIC ! Varying Clinical Findings cor: cardiac murmur lungs: obstructive pulmonary disease advanced stages: signs of right heart insufficiency symptoms at rest APAH-CHD: Eisenmenger´s Syndrome signs of chronical cyanosis

Diagnostic Investigation Aims To confirm the diagnosis evaluate severity of PAH identify right ventricular function find out causation of PAH evaluate pulmonary vasoreagibility

Useful Diagnostics in individual cases Diagnostic Tools Diagnostic Tools Useful Diagnostics in individual cases echocardiography ECG pulse oximetry chest-X-ray pulmonary function test CPX 6-MWT laboratory assessment cardiac catheterisation incl. acute pulmonary vasodilator testing spiral CT scan MRI angiography V/Q-Scan sleep laboratory/ polysomnography genetic analysis Procedures: pediatric cardiologist experienced pediatric cardiologic center

ECG normal ECG doesn´t exclude PAH! right heart strain? rhythm disturbances? Eisenmenger patients: cardiac arrhythmia (Holter-ECG) is associated with a poor prognosis

Echocardiography most significant non-invasive screening method detection/ exclusion of characteristic morphological and functional signs of PAH useful for follow-up (e.g. therapeutic effects?) estimation of intracardiac and pulmonary pressure levels exclusion of structural cardiac disease postcapillary PAH

Echocardiography

Laboratory assessment Diagnostic and prognostic marker

Cardiac catheterisation incl. acute pulmonary vasodilator testing gold standard (accurate differential diagnosis) quantitation of pulmonary arterial pressures pulmonary vasoreactivity

Cardiac catheterisation incl. acute pulmonary vasodilator testing spontaneous breathing (anesthetic risk) baseline hemodynamics testing of acute pulmonary vascular reactivity with iNO, O2, inh. Iloprost, combinations thereof http://www.kompetenznetz-ahf.de/ forschung/klinische-studien/leitlinien

Cardiac catheterisation present pulmonary vascular reactivity decrease of Rp/Rs ≥ 20% IPAH/HPAH: response to medical treatment with CCB likely CAVE: follow-up early invasive re-evaluation  to detect decrease in pulmonary vascular reactivity

Cardiac catheterisation APAH-CHD Rp/Rs < 0,2  OP Rp/Rs 0,2-0,3  increased OP-risk Rp/Rs > 0,3  individual treatment plan special surgical methods necessary e.g. fenestration

PAH = fatal, not-curable disease Therapy PAH = fatal, not-curable disease

PAH = fatal, not-curable disease Therapy PAH = fatal, not-curable disease general therapeutic goals delay of disease progression improvement of symptoms improvement of quality of life

PAH = fatal, not-curable disease Therapy & Indication PAH = fatal, not-curable disease general therapeutic goals delay of disease progression improvement of symptoms improvement of quality of life IPAH/HPAH APAH-CHD no causal therapeutic options related to rapid progression  early treatment OP in time post-OP persistent high Rp  pulmonary vasodilatators Eisenmenger NYHA II/III  pulmonary vasodilatators

PAH = fatal, not-curable disease Therapeutic Options PAH = fatal, not-curable disease general therapeutic goals delay of disease progression improvement of symptoms improvement of quality of life General Measures Interventional Procedures Drug Therapy Surgical Aspects

General Measures general measures/ specific treatment strategies physical training, school sport avoid situation, which aggravate PH (pyrexia, situations which increase intrathoracic pressure –obstipation, diving, trumped–) minimize risk of infections –complete vaccination status? surgical procedures  high risk  experienced centers Drug Therapy Interventional Procedures Surgical Aspects

General Measures general measures/ specific treatment strategies physical training, school sport avoid situation, which aggravate PH (pyrexia, situations which increase intrathoracic pressure –obstipation, diving, trumped–) minimize risk of infections –complete vaccination status? surgical procedures  high risk  experienced centers travel at high altitude/ flying quality of life! right heart failure: height of 1200-1400 m above sea level uncomplicated air pressure in plane cabins corresponds to air pressure at a height of 1800-2400 m above sea level  individual discussions Drug Therapy Interventional Procedures Surgical Aspects

General Measures phlebotomy only in symptomatic erythocytoses with hyperviscosity symptoms iron deficiency iron replacement? close laboratory controls defiency of folic acid, vitamin-B12? Drug Therapy Interventional Procedures Surgical Aspects

General Measures phlebotomy contraception only in symptomatic erythocytoses with hyperviscosity symptoms iron deficiency iron replacement? close laboratory controls defiency of folic acid, vitamin-B12? contraception adequate contracaption in time consulting service with pediatric cardiologist and experienced gynecologist CAVE: interactions with some drugs (e.g. ERA) Drug Therapy Interventional Procedures Surgical Aspects

General Measures oxygen APAH-CHD: controversial, at the discretion of physician others: SpO2 < 90%, PaO2 < 60 mmHg, subjective benefit Drug Therapy Interventional Procedures Surgical Aspects

General Measures oxygen oral anticoagulation APAH-CHD: controversial, at the discretion of physician others: SpO2 < 90%, PaO2 < 60 mmHg, subjective benefit oral anticoagulation IPAH/HPAH, thromboembolic PH: Ø hempotysis  OAK (class of recommendation IIa; INR 2,0-3,0) APAH-CHD: only in particular cases (e.g. rhythm disturbances, thromboembolie) Drug Therapy Interventional Procedures Surgical Aspects

Drug Therapy General Measures according to rareness of disease  sparse literature available for medical treatment in children children: case reports, small case series drug application in children  adults approved drugs for children: Bosentan & Sildenafil Drug Therapy Interventional Procedures Surgical Aspects

Calcium Channel Blockers IPAH/HPAH responder positive experiences in adults NOT in APAH-CHD General Measures In children off label-use. Approved fields of application: Primary arterial hypertension. Symptomatic coronary heart disease. Chronic stable, instable and vasospastic angina pectoris.   Amlodipin children: 0,2-0,5 mg/kg/d in 1-2 doses p.o. adults: max. 10 mg/d in 1 dose p.o. Diltiazem children: 1,5-3,5 mg/kg/d in 3-4 doses p.o. adults: max. 360 mg/d in 1-3 doses p.o. Nifedipin children: 1-2 mg/kg/d in 1 dose p.o. adults: 40-max. 120 mg in 1-2 doses p.o. Drug Therapy Interventional Procedures Surgical Aspects

Endothelin-Receptor-Antagonists General Measures Bosentan Approval: age ≥ 2 years Approved fields of application: „Verbesserungen des Krankheitsbildes bei Patienten mit PAH der funktionellen NYHA-Klasse II & III. Wirksamkeit nachgewiesen bei - primärer (idiopathischer und erblicher) PAH - Sek. PAH in Assoziation mit Sklerodermie ohne signifikante interstitielle Lungenerkrankung. - PAH in Assoziation mit kongenitalen Herzfehlern und Eisenmenger-Physiologie Reduzierung der Anzahl neuer digitaler Ulzerationen bei Patienten mit systemischer Sklerose, die an digitalen Ulzerationen leiden.“ children: 4 mg/kg/d in 2 doses p.o. (target dose) adults: 62,5 mg BID p.o. (initial dose for 4 weeks), 125 mg BID p.o. (target dose)   Ambrisentan children: no approval adults: 5 - 10 mg qd p.o. Drug Therapy Interventional Procedures Surgical Aspects side effects: liver toxicity drug interactions

Phosphodiesterase-5-Inhibitors General Measures Sildenafil Approval: age ≥ 1 year Approved fields of application: „PAH der WHO-Funktionsklasse II & III Wirksamkeit nachgewiesen bei primärer PAH und pulmonaler Hypertonie in Verbindung mit einer Bindegewebskrankheit bei Kindern zudem bei pulmonaler Hypertonie in Verbindung mit AHF.“ children: dosing recommendation as EMA approved: BW 8 kg < x ≤ 20 kg, age ≥ 1 year: 10 mg tid p.o. BW > 20 kg: 20 mg tid p.o. pediatric PH-experts: 1-4 mg/kg/d in 3-4 doses p.o. adults: 20 mg tid oral (as per expert information) experts consent (Kölner Konsensus Konferenz): prn increase of doses to max. 80 mg tid p.o. (off-label-use) Tadalafil children: no approval adults: 40 mg qd p.o. Drug Therapy Interventional Procedures Surgical Aspects 10/2011: “Rote-Hand-Brief” STARTS-1: pediatric PAH patients: Sildenafil 10-80 mg tid p.o. 16 weeks: VO2 max improved higher mortality risk in patients with higher doses compared to low-dose treatment

Prostanoids Combination Therapy General Measures Prostanoids In children and adolescense off label-use. small case series application many times daily side effects (bronchial obstruction, cough)  limited compliance in children use on a regular basis  improvement for a period of years Combination therapy Insufficient data  indication only in expert centers Drug Therapy Interventional Procedures Surgical Aspects

Interventional Procedures General Measures Atrial septostomy / Stent in case of failing medical therapy palliation in decompensated pts with RV failure high risk Drug Therapy Interventional Procedures Surgical Aspects

Surgery failing medical/ interventional treatment General Measures failing medical/ interventional treatment thoracic organ transplantation LTX, HLTX CAVE: survival rates children with PAH: bil. LTX - mean survival 45 months (2-123 months) - 5.8 years experimental: Pott´s shunt Drug Therapy Interventional Procedures Surgical Aspects

throughout life ! Follow-up regular, in cooperation with specialized PAH-centers medical history, physical examination, clinical status (BW, .... ) symptoms 6-MWT, pulmonary function test, CPX, pulse oxymetry special functional parameters - echocardiography - blood tests: blood gases, blood cell count, kidney-/ liver-parameters, (NT-pro)BNP progress of PAH  therapeutic escalation catheterization throughout life ! 40

Prevention APAH-CHD OP in time IPAH/HPAH no specific prevention chance: genetic counselling 41

DGPK Guideline Pulmonary Arterial Hypertension (PAH) in Infancy and Adolescence www.kinderkardiologie.org/dgpkLeitlinien.shtml