DGPK Guideline Pulmonary Arterial Hypertension PAH in Infancy

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

Definition PAH Dana Point (2008) • resting mean pulmonary arterial pressure m. PAP ≥ 25 mm. Hg • pulmonary arterial wedge pressure ≤ 15 mm. Hg

Definition PAH Dana Point (2008) • resting mean pulmonary arterial pressure m. PAP ≥ 25 mm. Hg • pulmonary arterial wedge pressure ≤ 15 mm. Hg • no threshold value for pulmonary vascular resistance (PVR) even though: PVRI > 3 Wood units (U*m 2) pathological increased

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 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 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 1997 Rabinovitch 1996 Rabinovitch 2008

General Issues • Epidemiology 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 1997 Rabinovitch 1996 • Genetic Aspects BMPR 2 50 -70% HPAH 10 -40% sporadic IPAH 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

Diagnostic Tools Useful Diagnostics in individual cases Diagnostic Tools • • • 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 i. NO, O 2, inh. Iloprost, combinations thereof http: //www. kompetenznetz-ahf. de/forschung/klinischestudien/leitlinien 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

Therapy 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

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

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 Drug Therapy Interventional Procedures Surgical Aspects • 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

General Measures • phlebotomy – – only in symptomatic erythocytoses with hyperviscosity symptoms iron deficiency iron replacement? close laboratory controls defiency of folic acid, vitamin-B 12? 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-B 12? Drug Therapy Interventional Procedures Surgical Aspects • contraception – adequate contracaption in time – consulting service with pediatric cardiologist and experienced gynecologist – CAVE: interactions with some drugs (e. g. ERA)

General Measures • oxygen – APAH-CHD: controversial, at the discretion of physician – others: Sp. O 2 < 90%, Pa. O 2 < 60 mm. Hg, subjective benefit Drug Therapy Interventional Procedures Surgical Aspects

General Measures • oxygen – APAH-CHD: controversial, at the discretion of physician – others: Sp. O 2 < 90%, Pa. O 2 < 60 mm. Hg, 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 Drug Therapy Interventional Procedures Surgical Aspects • children: case reports, small case series • drug application in children adults • approved drugs for children: Bosentan & Sildenafil

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

Endothelin-Receptor-Antagonists General Measures Bosentan Approval: age ≥ 2 years Drug Therapy 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. “ Interventional Procedures Surgical Aspects 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: adults: no approval 5 - 10 mg qd p. o. side effects: liver toxicity drug interactions

Phosphodiesterase-5 -Inhibitors Sildenafil General Measures 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: Drug Therapy Interventional Procedures Surgical Aspects 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. 10/2011: “Rote-Hand-Brief”

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 General Measures • failing medical/ interventional treatment • thoracic organ transplantation Drug Therapy Interventional Procedures Surgical Aspects LTX, HLTX • CAVE: survival rates children with PAH: bil. LTX - mean survival 45 months (2 -123 months) - 5. 8 years • experimental: Pott´s shunt

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 throughout life ! • special functional parameters - echocardiography - blood tests: blood gases, blood cell count, kidney-/ liver-parameters, (NT-pro)BNP progress of PAH therapeutic escalation • catheterization

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

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