Guida alla terapia dell’Ipertensione Arteriosa Polmonare Carlo D’Agostino Cardiologia Ospedaliera Policlinico Bari Ca

DISCLOSURE INFORMATION Carlo D’Agostino negli ultimi due anni non ho avuto rapporti anche di finanziamento con soggetti portatori di interessi commerciali in campo sanitario

5th World Symposium on PH: Modified classification of PH 3. PH due to lung diseases and/or hypoxia 3.1 COPD 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental lung diseases 4. CTEPH 5. PH with unclear multifactorial mechanisms 5.1 Haematological disorders: chronic haemolytic anaemia, myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: tumoural obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH 1. Pulmonary arterial hypertension 1.1 Idiopathic PAH 1.2 Heritable PAH 1.2.1 BMPR2 1.2.2 ALK1, ENG, SMAD9, CAV1, KCNK3 1.2.3 Unknown 1.3 Drug- and toxin-induced 1.4 Associated with 1.4.1 Connective tissue diseases 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart disease 1.4.5 Schistosomiasis 1’ Pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis 1’’ Persistent PH of the newborn (PPHN) 2. PH due to LHD 2.1 LV systolic dysfunction 2.2 LV diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired left heart inflow/outflow obstruction 10% 5% 1,5% 5% 78% Simonneau G, et al. J Am Coll Cardiol 2013; 62:D34-41.

Ipertensione Arteriosa Polmonare - Gruppo 1 OMS Idiopatica Ereditaria BMPR2 ALK1 SCONOSCIUTA Da farmaci e tossine Associata con (APAH) Connettivopatia HIV Ipertensione portale Cardiopatia congenita Schistosomiasi 1.1 IAP veno occlusiva e capillari 1.2 IAP persistente del neonato Circa il 5% delle PH Prevalenza = 5,9-15 casi/milione Incidenza = 2,4 casi/milione/anno 39,2% IPAH 3,9% FPAH 15,3% Connettivopatia (prevalentemente sclerodermia) 11,3% Cardiopatia congenita 10,4% Ipertensione Portale 9,5% Anoressizzanti 6,2% HIV

Prognosi dei pazienti con Ipertensione Arteriosa Polmonare Classe NYHA alla presentazione Distanza percorsa al 6MWT alla presentazione Humbert M, et al . Circulation 2010;122:158-63

Strategia Il ricorso motivato e ragionato a mezzi idonei al raggiungimento di uno scopo. Devoto-Oli Vocabolario della lingua italiana La descrizione di un piano d'azione di lungo termine usato per impostare e successivamente coordinare le azioni tese a raggiungere uno scopo predeterminato. Wikipedia

#1 Counselling #2 Terapia di supporto #3 Vasoreattività #1 Counselling #2 Terapia di supporto #3 Vasoreattività? > Ca antagonisti #4 Inizio terapia specifica #5 Rivalutazione periodica frequente #6 Implementazione/modifica della terapia (rivalutazione e cateterismo cardiaco) #7 Terapia interventistica (settostomia/Trapianto….)

Exercise training improves peak oxygen consumption and haemodynamics in patients with severe pulmonary arterial hypertension and inoperable chronic thrombo-embolic pulmonary hypertension: a prospective, randomized, controlled trial Ehlken E et al. Eur Heart J. 2016 Jan 1;37(1):35-44.

Exercise training improves peak oxygen consumption and haemodynamics in patients with severe pulmonary arterial hypertension and inoperable chronic thrombo-embolic pulmonary hypertension: a prospective, randomized, controlled trial Ehlken E et al. Eur Heart J. 2016 Jan 1;37(1):35-44. Primary endpoint: change in peak oxygen uptake. Left graph: The abscissa shows peak VO 2 /kg at baseline, and the ordinate shows change of peak VO 2 /kg from baseline after 15 weeks for each patient. The solid points represent patients of the training group, and the circles represent patients of the control group. This graph shows equal distribution of baseline peak VO 2 in both groups as well as changes after 15 weeks of exercise training. Change in peak VO 2 did not correlate with baseline peak VO 2 . Right graph: the boxplots at the right side show median change of VO 2 max in the control vs. training group after 15 weeks. A significant increase can be shown in the training group ( P < 0.001), whereas the control group shows a small reduction in peak VO 2 after 15 weeks. Multiple imputations showed the same P -value.

Exercise training improves peak oxygen consumption and haemodynamics in patients with severe pulmonary arterial hypertension and inoperable chronic thrombo-embolic pulmonary hypertension: a prospective, randomized, controlled trial Ehlken E et al. Eur Heart J. 2016 Jan 1;37(1):35-44.

Exercise training improves peak oxygen consumption and haemodynamics in patients with severe pulmonary arterial hypertension and inoperable chronic thrombo-embolic pulmonary hypertension: a prospective, randomized, controlled trial Ehlken E et al. Eur Heart J. 2016 Jan 1;37(1):35-44. QoL. Mean changes of QoL+2 standard errors of the mean and sample sizes below each bar. The bars of the control group are shown on the left side of each category. Exercise and respiratory training significantly improved the subscale score for vitality (P . 0.036), compared with the control group, in which this parameter slightly worsened. The subscales role limitations due to physical restrictions (P . 0.099), role limitations due to emotional restrictions (P . 0.09), and general health perception (0.091) were significant in trend in the original data, but showed inconsistent findings in multiple imputation.

#1 Counselling #2 Terapia di supporto #3 Vasoreattività #1 Counselling #2 Terapia di supporto #3 Vasoreattività? > Ca antagonisti #4 Inizio terapia specifica #5 Rivalutazione periodica frequente #6 Implementazione/modifica della terapia (rivalutazione e cateterismo cardiaco) #7 Terapia interventistica (settostomia/Trapianto….)

#1 Counselling #2 Terapia di supporto #3 Vasoreattività #1 Counselling #2 Terapia di supporto #3 Vasoreattività? > Ca antagonisti #4 Inizio terapia specifica #5 Rivalutazione periodica frequente #6 Implementazione/modifica della terapia (rivalutazione e cateterismo cardiaco) #7 Terapia interventistica (settostomia/Trapianto….)

TEST DI VASOREATTIVITA’ Risposta positiva = Riduzione PAPm ≥10 mmHg per raggiungere un valora assoluto di PAPm ≤40 mmHg con CO incrementata o immodificata.

#1 Counselling #2 Terapia di supporto #3 Vasoreattività #1 Counselling #2 Terapia di supporto #3 Vasoreattività? > Ca antagonisti #4 Inizio terapia specifica #5 Rivalutazione periodica frequente #6 Implementazione/modifica della terapia (rivalutazione e cateterismo cardiaco) #7 Terapia interventistica (settostomia/Trapianto….)

Meccanismi coinvolti Humbert M, Sitbon O, Simonneau G: NEJM 2004;351:1425 Disunzone endoteiale che porta ad una ridotta produzione di fattori vasodilatatori ed antiproliferativi come l’ossido nitrico e le prostacicline ed una sovraespressione di fattori vasocostrittori e proliferativi come il trombssano A2 e l’endotelina 1

Farmaci approvati per il trattamento della IAP

Approval of PAH therapies Iloprost inhaled 2004 – US 2003 – Europe Iloprost i.v. Only approved in New Zealand Beraprost† 1999 Room-temperature stable epoprostenol i.v. 2012 – US, Switzerland & Canada 2013 – Japan & Europe* Bosentan 2001 – US 2002 – Europe Sildenafil 2005 Beraprost‡† 2007 2010 2015 2005 1995 2000 Epoprostenol i.v. 1995 – US 2001 – Europe Treprostinil i.v. or s.c. 2002 – US 2005 – Europe Ambrisentan 2007 – US 2008 – Europe 2013 Macitentan† Treprostinil oral† US Riociguat† 2013 – US 2014 – Europe 2009 Treprostinil inhaled† Tadalafil 2008 – Europe 2009 – US *End of decentralised procedure in EU; local approvals ongoing †Approval of these therapies varies by country, and thus they might not be approved in the indications mentioned in your country. Please refer to your local full SmPC before prescribing. ‡Prolonged release derivative

Sebbene ci sia stato un miglioramento dell’outcome negli ultimi 15 anni, la prognosi a lungo termine rimane insiddisfacente Benza RL et al Chest 2012; 142:448-56

Significato prognostico della variazione al follow up WHO I I WHO III-IV I-II WHO I-II III-IV WHO III-IV III-IV CI ≥2,5 L/min/m2 = CI <2,5 L/min/m2 ≥2,5 CI ≥2,5 L/min/m2 <2,5 CI <2,5 L/min/m2 = SvO2 ≥ 65% = SvO2 <65% ≥ 65% SvO2 ≥ 65%  <65% SvO2 <65% = NT-proBNP <1800 = NT-proBNP ≥1800<1800 NT-proBNP <1800 >1800 NT-proBNP ≥1800≥1800 Nickel N, et al . Eur Respir J 2012;39:589-596

Scelta della strategia terapeutica Monoterapia iniziale Con quale farmaco? Come proseguire? Terapia di combinazione iniziale Con quali farmaci

Possibili terapie di associazione Antagonisti Recettoriali della ET-1 Prostanoidi (e.v., s.c., os, inal) Inibitori della Fosfodiesterasi 5 o GCS

Time to 1st morbidity or mortality event A decrease in 6MWD of at least 15%, confirmed by 2 tests on different days Worsening of PAH symptoms, which must include either: An increase in FC, or Appearance or worsening of symptoms of right heart failure Need for new PAH treatment(s): Oral or inhaled prostanoids Oral PDE-5 inhibitors ERA after discontinuation of study drug Intravenous diuretics AND All-cause death Atrial septostomy Lung transplantation Initiation of i.v. or s.c. prostanoids OR Other worsening of PAH

SERAPHIN: Macitentan improved long-term outcomes in PAH-CTD patients Subgroup Macitentan 10 mg Placebo No. of patients / no. of events Overall 242/76 250/116 Hazard ratio (95% CI) PAH aetiology (interaction p-value = 0.84) CTD 73/20 82/31 Congenital shunts 21/4 26/10 Idiopathic/Other* 147/52 140/75 0.1 0.2 0.5 1 2 5 10 *Other aetiology consists of idiopathic or familial PAH, or PAH related to HIV infection or drugs and toxins. Macitentan better Placebo better CI: Confidence interval; CTD: Connective tissue disease; HIV: Human deficiency disorder Pulido T, et al. N Engl J Med 2013; 369:809-18.

SERAPHIN primary endpoint: Morbidity/mortality (composite endpoint) up to end of treatment Macitentan reduced the risk of a morbidity/mortality event (composite endpoint) by 45% (hazard ratio 0.55; p < 0.001) 20 40 80 100 60 12 18 24 30 36 6 Patients without an event (%) Macitentan 10 mg Placebo Time from treatment start (months) Patients at risk 242 208 187 171 155 91 41 Macitentan 10 mg 250 188 160 135 122 64 23 Placebo Pulido T, et al. N Engl J Med 2013; 369:809-18. Confidential

Raccomandazioni per la monoterapia nella IAP Galiè N. et al Eur Heart J 2015, Eur Respir J, 2015

2015; 379(9):834–44.

Combination vs pooled monotherapy AMBITION Combination vs pooled monotherapy Galie N et al, et al. New Engl J Med 2015; 379(9):834–844.

BONSAI: Six-month results: % change comparison Mono (11) Upfront Combo (19) p RAP (%) +11 ± 67 -17 ± 50 0.205 mPAP (%) -19 ± 16 -33 ± 13 0.017 CI (%) +23 ± 19 +56 ± 31 0.003 PVR (%) -40 ± 10 -61 ± 12 < 0.001 PA-SO2 (%) +6 ± 9 +17 ± 11 0.007 6MWD (%) +10 ± 21 +25 ± 16 0.038 When we compare the short term efficacy of the 2 treatment, espressed as percentage change of median, we find a clear absence of significant differences both in haemodynamics and functional parameters. Bachetti C. et al. J Respir Crit Care Med 2015.

4/6-month results: % change comparison AMBITION - BONSAI Ambrisentan + Tadalafil (19) Joint - INTENTION Bosentan + Sildenafil (23) RAP (%) -17 - 36 mPAP (%) -33 - 21 CI (%) +56 +63 PVR (%) -61 -60 PA-SO2 (%) +17 +25 6MWD (%) + 42 When we compare the short term efficacy of the 2 treatment, espressed as percentage change of median, we find a clear absence of significant differences both in haemodynamics and functional parameters. M. Palazzini et al, ATS 2016.

Raccomandazioni per la terapia di combinazione iniziale nella IAP 38 Raccomandazioni per la terapia di combinazione iniziale nella IAP Galiè N. et al Eur Heart J 2015, Eur Respir J, 2015

#1 Counselling #2 Terapia di supporto #3 Vasoreattività #1 Counselling #2 Terapia di supporto #3 Vasoreattività? > Ca antagonisti #4 Inizio terapia specifica #5 Rivalutazione periodica frequente #6 Implementazione/modifica della terapia (rivalutazione e cateterismo cardiaco) #7 Terapia interventistica (settostomia/Trapianto….)

#1 Counselling #2 Terapia di supporto #3 Vasoreattività #1 Counselling #2 Terapia di supporto #3 Vasoreattività? > Ca antagonisti #4 Inizio terapia specifica #5 Rivalutazione periodica frequente #6 Implementazione/modifica della terapia (rivalutazione e cateterismo cardiaco) #7 Terapia interventistica (settostomia/Trapianto….)

Raccomandazioni per la terapia sequenziale nella IAP Galiè N. et al Eur Heart J 2015, Eur Respir J, 2015

#1 Counselling #2 Terapia di supporto #3 Vasoreattività #1 Counselling #2 Terapia di supporto #3 Vasoreattività? > Ca antagonisti #4 Inizio terapia specifica #5 Rivalutazione periodica frequente #6 Implementazione/modifica della terapia (rivalutazione e cateterismo cardiaco) #7 Terapia interventistica (settostomia/Trapianto….)

5th World Symposium on PH: Evidence-based treatment algorithm Combination therapy and interventional procedures Inadequate clinical response Sequential combination therapy (I-A) ERAs Prostanoids PDE-5i or sGCS + Initial therapy with PAH approved drugs Referral for LUNG TRANSPLANTATION (I-C) Consider eligibility for lung transplantation BAS (IIa-C) Inadequate clinical response on maximal therapy Galiè N, et al. J Am Coll Cardiol 2013; 62:D60-72.

Galiè N. et al Eur Heart J 2015, Eur Respir J, 2015 46 Recommendations for evaluation of severity of pulmonary arterial hypertension and clinical response to therapy Galiè N. et al Eur Heart J 2015, Eur Respir J, 2015

Definizione della prognosi nella IAP 2015 ESC/ERS Guidelines

REGISTRO ITALIANO IPERTENSIONE POLMONARE REAL IP REGISTRO ITALIANO IPERTENSIONE POLMONARE