Ipertensione polmonare Roberto Cassandro U.O. di Pneumologia e UTIR Servizio di Emodinamica e Fisiopatologia Respiratoria Ospedale San Giuseppe - Milano

CONCLUSIONS (2013) New Classification

“PH/PAH should be suspected in any patient with otherwise unexplained dyspnea on exertion, syncope, and/or signs of right ventricular dysfunction. Transthoracic echocardiography continues to be the most important noninvasive screening tool to assess the possibility of PH, but RHC remains mandatory to establish the diagnosis” Hoeper MM, et al. J Am Coll Cardiol 2013; 62:D42-50

Hemodynamic definition of PAH PAH is defined as the presence of pre-capillary PH including an end-expiratory PAWP ≤ 15 mmHg and a PVR > 3 Wood units Patients with mPAP values between 21 and 24 mmHg should be carefully followed, particularly if they are at risk of developing PAH (e.g. CTD patients or family members of IPAH/HPAH patients) –The term “borderline PH” should not be used PVR should be included in the hemodynamic characterization of patients with PAH as follows: patients with PAH are characterized by pre- capillary PH (i.e., mPAP ≥ 25 mmHg, PAWP ≤ 15 mm Hg and elevated PVR [> 3 Wood units]) Hoeper MM, et al. J Am Coll Cardiol 2013; 62:D42-50.

Updated classification of PH Simonneau G, et al. J Am Coll Cardiol 2013; 62:D New gene mutations added PPHN moved from Group 1 (PAH) as has more differences than similarities to other PAH subgroups Added for consistency with pediatric classification Chronic hemolytic anemia moved from Group 1 (PAH) given the differences to PAH in pathological findings, hemodynamics and response to therapy * Main modifications to the previous WSPH proceedings (Dana point) are indicated by green boxes Updated classification is now the same for adult and pediatric patients

Updated classification for drug- and toxin-induced PAH Simonneau G, et al. J Am Coll Cardiol 2013; 62:D New addition New additions New addition (included as a risk factor in ESC/ERS Guidelines) Moved from ‘possible’ to ‘definite’ risk factor New addition * Main modifications to the previous WSPH proceedings (Dana point) are indicated by green boxes

. Simonneau G, et al. J Am Coll Cardiol 2013; 62:D34-41.

Summary The updated clinical classification is now the same for adult and pediatric patients A new hemodynamic definition (including PVR) and new screening recommendations for SSc patients have been proposed Methodology, key insights and prognostic data from disease registries have been reviewed An updated treatment algorithm has been provided. A 4-level hierarchy for RCT endpoints has been proposed and new recommendations on rehabilitation and combination therapy have been added Treatment goals have been updated and the need to analyse multiple goals in order to correlate with long-term outcomes has been highlighted

 SSC  IPF  Sarcoidosis

Yearly ECHO may be considered Asymptomatic patients Screening for PAH-SSc ESC/ERS guidelines 2009 Symptomatic patients (breathlessness, fatigue, weakness, angina, syncope…) Yearly ECHO is recommended RHC is indicated in all suspected PAH-SSc

Prognosis of “routine practice” and “detected” PAH-SSc patients Survival (%) 1 year3 years5 years8 years Years of follow-up 100% 75% 31% 25% 17% 81% 73% 64% Routine practice PAH-SSc Detected PAH-SSc p = HR = 4.15 (95% CI ) Humbert M, et al. Arthritis Rheum 2011;.

. SCREENING DEI PAZIENTI AFFETTI DA SSc With this method only 4 % of patients are missed. With this method only 4 % of patients are missed. By echocardiography alone 29% of patients are missed

Recommendations on screening of high-risk populations for PAH Significant progress has been made in the diagnosis of SSc patients, for whom the DETECT study has provided important data on screening for PAH Screening of patients with the SSc spectrum of diseases without clinical signs and symptoms of PH should include a 2-step approach: 1)Clinical assessment for the presence of telangiectasia, anti-centromere antibodies, PFT and DLCO measurements, electrocardiogram and biomarkers (NT-proBNP and uric acid) 1)Electrocardiography and consideration of RHC in patients with abnormal findings, although there is a lack of data with DLCO > 60% Hoeper MM, et al. J Am Coll Cardiol 2013; 62:D42-50.

Lorinda Chung et al. Arthritis Care and Research USA SSc centers The Pharos registry Inclusion criteria: sPAP > 40 mmHg at TTE FVC >70% and DLco < 55% FVC:%DLco ratio > patients enrolled and submitted to RHC

Lorinda Chung et al. Arthritis Care and Research 2014

101 SSc-PAH patients received >3 continous months of PAH therapy At 1 year, 7 patients who were receiving PAH-specific therapies died

Curr Opin Rheumatol 2014; 26:

 SSC  IPF  Sarcoidosis

Simonneau G, et al. J Am Coll Cardiol 2013; 62:D34-41.

The incidence and prevalence of PH in IPF remain unclear, with widely varying estimates. The differences reflect: varying patient populations varying underlying disease severity differing diagnostic modalities

The prevalence of PH complicating the course of patients with IPF has been reported as occurring in 32 to 85% of patients 9% of patients having a mPAP of greater than 40 mm Hg initial prevalence of 41% increasing to more than 90% at follow-up Prevalence of PH in IPF

AuthorYearPatiNDiagnDefinition of PHPreval, % Leutche et al.2004IPF28RHCmPAP>35 mmHg21.4 Nadrous et al.2005IPF88EchosPAP>35 mmHg sPAP>50 mmHg Hamada et al.2007IPF70RHCmPAP>25 mmHg8.1 Zisman et al.2007IPF65RHCmPAP>25 mmHg41.5 Patel et al.2007IPF41RHC mPAP>25 mmHg +PCWP ≤15 mmHg20 Shorr et al.2007IPF2.5RHCmPAP>25 mmHg46.1 Nathan et al.2008IPF118RHCmPAP>25 mmHg40.7 Song et al.2009IPF131EchosPAP>40 mmHg25 Minai et al.2009IPF148RHCmPAP>25mmHg mPAP>40mmHg Kimura et al.2012IPF101RHCmPAP > 20 mmHg34,6

Patients assessed at the time of transplantation evaluation: PH prevalence of 36% At the time of transplantation, 85% of the same patient cohort had PH Conclusions PH is progressive and the prevalence and severity of PH is temporally related to the progression of IPF Nathan SD et al. Respiration 2008; 76:

Type of lung disease Investigator/ year Type of study NTherapyOutcome Lung fibrosis Ghofrani et al, 2002OL-RCT16 ( IPF=7 ) Sildenafil, iNO, epoprosten ol Sildenafil improved pulmonary hemodynamics and gas exchange IPF Krowka et al, 2007 (multicenter) DB-RCT51 Inhaled iloprost No improvement in 6MWT, NYHA/WHO Class IPF Collard et al, 2007OL trial14Sildenafil57% had significant increase in 6MWT Trials of therapy for PH in IPF

Change in 6MWD at 12 weeks by treatment and presence of RVSD Change in SGRQ total score at 12 weeks by treatment and presence or RVSD Patients with any evidence of RVSD treated with sildenafil demonstrated a 99.3 m greater 6MWD as compared with those treated with placebo. Treatment with sildenafil in subjects with RVSD resulted in a significantly lower SGRQ total score Sildenafil in IPF with Right-sided Ventricular Dysfunction A substudy of STEP-IPF

Treatment of idiopathic pulmonary fibrosis with ambrisentan A parallel, randomized trial Ragu G. et al. Ann Inter Med 2013;158: Objective: To determine whether ambrisentan, an ETA receptor– selective antagonist, reduces the rate of IPF progression Design: Randomized, double-blind, placebo-controlled, event driven trial (ClinicalTrials.gov: NCT ) Participants: Patients with IPF aged 40 to 80 years with minimal or no honeycombing on HRCT Intervention: Ambrisentan, 10 mg/d, or placebo Conclusion: Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations Measurements: Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function. Treatment of idiopathic pulmonary fibrosis with ambrisentan A parallel, randomized trial Raghu G. et al. Ann Inter Med 2013;158:

Treatment of idiopathic pulmonary fibrosis with ambrisentan A parallel, randomized trial Raghu G. et al. Ann Inter Med 2013;158:

Bosentan in Pulmonary Hypertension Associated with Fibrotic Idiopathic Interstitial Pneumonia Corte TJ et al. Am J Respir Crit Care Med. 2014; 190; 206 The primary study endpoint was a fall from baseline pulmonary vascular resistance index (PVRi) of 20% or more over 16 weeks.

Bosentan in Pulmonary Hypertension Associated with Fibrotic Idiopathic Interstitial Pneumonia Corte TJ et al. Am J Respir Crit Care Med. 2014; 190; 206 Conclusions: This study shows no difference in invasive pulmonary hemodynamics, functional capacity, or symptoms between the bosentan and placebo groups over 16 weeks. Our data do not support the use of the dual endothelin-1 receptor antagonist, bosentan, in patients with PH and fibrotic IIP.

 SSC  IPF  Sarcoidosis

PULMONARY HYPERTENSION DIAGNOSTIC CLASSIFICATION (updated 5 th WSPAH- Nice 2013) Sarcoidosis 5. PH with unclear or multifactorial mechanisms

Precapillary pulmonary hypertension in the context of sarcoidosis may be due at least in part to: èExtrinsic compression of large pulmonary arteries by mediastinal or hilar adenopathies or fibrosis èSpecific vasculitis, with infiltration of the walls of pulmonary arteries and/or veins by granulomas (steroid sensitive ?) èDestruction of the distal capillary bed by fibrotic process and resulting hypoxia (stage IV) PULMONARY VASCULAR INVOLVEMENT IN SARCOIDOSIS Nunes et al. Thorax 2006

è Pulmonary hypertension in sarcoidois occurs in two very different settings è In the absence of pulmonary fibrosis, PH appears to be related to a specific vasculopathy and may be steroid- sensitive è In case of pulmonary fibrosis, the mechanism of PH is complex, but certainly involves at least in part a specific vasculopathy as PH is out of proportion with alterations in lung fuction. In these patients, physicians have to consider lung transplantation sooner than they would have solely on the basis of lung function PULMONARY VASCULAR INVOLVEMENT IN SARCOIDOSIS

No correlation between mPAP, FEV1 and TLC Pulmonary hypertension was out of proportion with alterations in lung function è Specific pulmonary vasculopathy? Nunes et al. Thorax 2006

PH complicating sarcoidosis About 6% of unselected sarcoidosis patients suffer from PH. The mechanisms of sarcoidosis-PH are multifactorial Some patients exhibit mPAP > mmHg PH carries a poor prognosis in sarcoidosis patients with a significantly increases morbidity and mortality. Data on the efficacy and safety of PAH agents are scarce and discrepant. Nunes et al. Press Med 2012

Bosentan for Sarcoidosis-Associated Pulmonary Hypertension A Double-Blind Placebo Controlled Randomized Trial Baughman RP, et al. Chest 2014; 145; S10 39 pts in NYHA II- III in stable therapy for sarcoidosis Double blind randomized placebo controlled trial of 16 weeks (2:1)

Bosentan for Sarcoidosis-Associated Pulmonary Hypertension A Double-Blind Placebo Controlled Randomized Trial Baughman RP, et al. Chest 2014; 145; S10 In conclusion, we found that 16 weeks of bosentan therapy in patients with SAPH is associated with a significant improvement in PA mean pressure and PVR. No significant improvements in St. George, 6MWD and oxygen saturation (18 pts had fibrosis and FVC < 60%) No significant improvement in 6MWD in pts with FVC > 50% too The level of improvement was similar to that reported in other WHO groups treated with bosentan. The treatment was well tolerated. The effect of treatment over longer periods will require further investigation The level of improvement was similar to that reported in other WHO groups treated with bosentan. The treatment was well tolerated. The effect of treatment over longer periods will require further investigation.

CONCLUSIONS GRIPHON study(phase III) ProstaGlandin I 2 Receptor agonist In Pulmonary arterial HypertensiON Ambrisentan + tadalafil AMBITION STUDY

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