Dr G. Galgano UOC Cardiologia Acquaviva delle Fonti Ambulatorio Multidisciplinare Ipertensione Polmonare

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1 Dr G. Galgano UOC Cardiologia Acquaviva delle Fonti Ambulatorio Multidisciplinare Ipertensione Polmonare

2 I Farmaci Via endotelina Via NO Via prostacicline ERA: Bosentan Ambrisentan Macitentan Con NO: Riociguat Sildenafil Tadalafil SENZA NO: Riociguat PC: Iloprost Epoprostenolo Treprostinil Selexipag

3 Early Diagnosis Early Treatment

4 Esperienza Singolo Centro n=165 pz GRUPPO 1 Media :60 aa >70 aa: 21%

5 n pazienti Classe NYHA Alla Diagnosi III 71% I II IV 0 I II III IV

6 Treatment Algorithm Task-Force -Endpoints Clinici negli Studi- * Test del Cammino non è più considerato un valido surrogato clinico nella PAH * Efficacia clinica ESPRESSA in termini di riduzione morbi-morbilità per tutte le cause * Durata maggiore del trattamento sperimentale

7 End-Point Time To Clinical Failure is a composite endpoint and is defined as the first occurrence of any of the following events: 1 Death (all-cause) 2 Hospitalization for worsening PAH (adjudicated), which comprised any of the following: Any hospitalization for worsening PAH Lung or heart/lung transplant Atrial septostomy Initiation of parenteral prostanoid therapy 3 Disease progression (adjudicated), defined as follows: > 15% decrease from baseline in the 6MWD combined with WHO class III or IV symptoms (at 2 consecutive post baseline clinic visits separated by 14 days) 4 Unsatisfactory long-term clinical response (adjudicated), which comprised all 3 of the following criteria: Receiving 1 dose of randomized treatment and in the study for 6 months

8 Nuovi Studi AMBITION:AMBRI-TADAL. SERAPHIN:MACITENTAN PATENT:RIOCIGUAT GRIPHON:SELEXIPAG

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10 no CW Cumulative Prop Monoterapia ed Eventi 1,0 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,0 Breath-1 NEJM 2002 Patent-2- Mc Laughlin ERJ 2005 Provencher Thorax 2005 Aries 1-2 Seraphin Time, days

11 La mono-terapia orale non è la cura piu giusta della IAP >40% dei pz a 3 aa peggiorano!

12 Un cambiamento di strategia! Non dobbiamo aspettare il peggioramento, Ma iniziare una terapia di combinazione se il pz è grave

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14 Efficacy of initial combination therapy (up-front) for PAH AMBITION SITBON BREATH-2 Kemp

15 Terapeutic Goals Analisi multiparametrica: Classe Funzionale NYHA * Segni Clinici di Scompenso e Progressione * Ecocardiografia/RMN * Emodinamica: (IC, AD, SVo2) * 6MWT * Peak V02 * NT-Pro-BNP

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17 Moderno Algoritmo Terapeutico Pz Naïve

18 Algoritmo Terapeutico Pz in trattamento

19 Treatment Goals Task-Force OBIETTIVI: * Classe Funzionale NYHA (I-II) * Ecocardiografia/RMN (normalizzazione VD) * Emodinamica: (normalizzazione VD: RAP<8 mmhg; IC> l/min/m2) * 6MWT (> m') * Peak V02>15 ml/min/kg * BNP (normalizzato)

20 terapie per la Ipertensione polmonare cronica tromboembolica (CTEPH)

21 Ipertensione Polmonare Cronica Tromboembolica (IPCTE or CTEPH) Prossimale Distale Am Resp Crit Care Med 2000

22 Nostra Esperienza n=21( ) Time sintomi/diagnosi 20,7 mesi TVP pregressa: 37% EP manifesta: 74% Trombofilia: 34%

23 Capacità D esercizio Pre e Post PEA

24 Classe NYHA

25 Dati Emodinamici n=12 sottoposti a PEA

26 CTHEP : TRATTAMENTO CHIRURGICO P.A. 76 aa F., Classe NYHA IV Ottobre 2014 A. D Armini Policlinico S. Matteo Pavia

27 BASELINE Pre PEA FOLLOW-UP Post-PEA 6 MESI IC : 1.72 l/min/m l/min/m2 Resistenze Vascolari 11 WU 1.73 WU

28 Terapia: Real Life

29 Conclusioni-1- I farmaci specifici per il trattamento dell ipertensione Arteriosa Polmonare consentono un miglioramento delle condizioni cliniche e della mortalità (10-15% annua)

30 Conclusioni-2- Terapia di associazione iniziale nei pz «naive» II-III Protocollo AMBITION III-IV Prostanoidi+ERA/PDE-5i

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32 Conclusioni-3- Le Strategie Terapeutiche, nel rispetto delle indicazioni, sono affidate alla sensibilità ed esperienza clinica di tutti noi

33 Emodinamica Classe Funzionale Drug Interaction costi Scelta del pz Clinico Comorbilità Effetti collaterali

34 SELEXIPAG MEETS PRIMARY ENDPOINT IN PIVOTAL PHASE III GRIPHON OUTCOME STUDY IN PATIENTS PAH Giuseppe GALGANO U.O.C. Cardiologia e U.T.I.C.

35 ABOUT SELEXIPAG Selexipag, is a potent, orally available, selective prostacyclin IP receptor agonist. Selexipag selectively targets the prostacyclin receptor (also called IP-receptor). The IP receptor is one of 5 types of prostanoid receptor. Prostacyclin activates the IP receptor inducing vasodilation and inhibiting proliferation of vascular smooth muscle cells via cyclic adenosine monophosfate. Kuwano et al. J Pharmacol Exp Ther 2007;322: Kuwano et al. J Pharmacol Exp Ther 2008;326: GRIPHON OUTCOME STUDY IN PATIENTS PAH

36 ABOUT GRIPHON The drug selexipag significantly reduced the risk of a morbidity/mortality event by 40% versus placebo (p<0.0001) in patients with pulmonary arterial hypertension (PAH). The reduction in risk of a morbidity/mortality event was consistent across key subgroups; age, gender, PAH etiology, baseline WHO Functional Class and irrespective of background therapy, including patients receiving selexipag on top of a combination of both an ERA and a PDE-5i. VV. McLaughlin (presenter) Oral presentation. American College of Cardiology (ACC) Congress in San Diego, March 2015, USA GRIPHON OUTCOME STUDY IN PATIENTS PAH

37 CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION: SURGICAL TREATMENT P.A. 66 yrs M Jun 2001 PEA #60 Before PEA 3 months mpap CI PVR A. D Armini Policlinico S. Matteo Pavia

38 Pulmonary endarterectomy (PEA) is the treatment of choice for CTEPH Operable Surgically accessible thrombi Acceptable operative risk Inoperable Small vessel disease Unacceptable operative risk Mismatch between haemodynamics and extent of occlusions Recurrent PH

39 CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION: SURGICAL TREATMENT TYPE OF OPERATION Median sternotomy Cardio Pulmonary Bypass Deep hypotermia (16-18ºC) Circulatory arrest ( 25 min) Reperfusion period ( 10 min) Bilateral J Thorac Cardiovasc Surg 1993;106: A. D Armini Policlinico S. Matteo Pavia

40 Bosentan in CTEPH: studio BENEFiT Patients enrolled n = 157 Randomized and treated Premature discontinuations n = 5 (4 due to AE, 1 due to death) Placebo n = 80 n = 3 (2 due to AE, 1 due to death) Bosentan n = 77 Completed week 16 n = 75 n = 74 Entered OLE n = 74 n = 74 AE=adverse event, PVR=pulmonary vascular resistance, 6MWD=6-minute walk distance, OLE=open-label extension 40

41 BENEFiT Summary of results Clinically relevant improvement in cardiac hemodynamics: PVR decreased (p < ) Cardiac index increased NT-pro-BNP decreased No effect on exercise capacity (p = ns) Improvement in Borg dyspnea index Positive trends on other endpoints: Fewer bosentan-treated patients worsened WHO functional class Time to clinical worsening trends in favor of bosentan Safety and tolerability: Consistent with previous controlled trials with bosentan in PAH

42 Riociguat in CTEPH Primary end-point - 6MWD 46 meters (p<0.0001) after 16 weeks compared with placebo. Secondary endpoints - Pulmonary vascular resistance (PVR) (p<0.0001), - N-terminal prohormone brain natriuretic peptide (NT-pro BNP) (p<0.0001), - WHO functional class (FC) (p=0.0026), - Borg dyspnea score (p=0.0035) - A trend in Time to clinical worsening (TTCW) (p=0.17)

43 Algoritmo terapeutico Digitale? Diuretici Anticoagulanti O2 terapia Test acuto - CalcioAnt II o III NYHA + IC >2,5 l/min/m2 Macitentan/ Ambrisentan/riociguat Sildenafil/Tadalafil III + IC < 2,5 - IV NYHA Treprostinil Epoprostenolo Iloprost + Oral Up-Front Combo Oral Settostomia Atriale Trapianto Polmonare

44 Conclusioni 3 Terapia chirurgica elettiva (endoarterectomia polmonare) per la forma cronica tromboembolica Studi per verificare l efficacia nelle altre forme di IP