Ipertensione polmonareIpertensione polmonare

Roberto CassandroU.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 PH/PAH should be suspected in any patient with otherwiseotherwise unexplained dyspnea on exertion, unexplained dyspnea on exertion,

syncope, and/or signs of right ventricular syncope, and/or signs of right ventricular dysfunction. Transthoracic echocardiography dysfunction. Transthoracic echocardiography

continues to be the most important noninvasive continues to be the most important noninvasive screening tool to assess the possibility of PH, but screening tool to assess the possibility of PH, but

RHC remains mandatory to establish the diagnosis”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:D34-41.

New gene mutations

addedNew 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:D34-41.

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

100

90

80

70

60

50

40

30

20

10

0

Su

rviv

al (%

)

1 year 3 years 5 years 8 years

Years of follow-up

100%

75%

31%

25%

17%

81% 73%

64%

Routine practice PAH-SSc

Detected PAH-SSc

p = 0.0037

HR = 4.15 (95% CI 1.47 - 11.71)

Humbert M, et al. Arthritis Rheum 2011;.

.

SCREENING DEI PAZIENTI AFFETTI DA SScSCREENING DEI PAZIENTI AFFETTI DA SSc

With this method only 4 With this method only 4 % of patients are missed.% of patients are missed.

By echocardiography By echocardiography

alone 29% of patients are alone 29% of patients are missedmissed

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 2014

22 USA SSc centers

The Pharos registry

Inclusion criteria: sPAP > 40 mmHg at TTE

FVC >70% and DLco < 55%

FVC:%DLco ratio >1.6

434 patients enrolled and submitted to RHC

Lorinda Chung et al. Arthritis Care and Research 2014

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; 26:131-137

SSC

IPFIPF Sarcoidosis

Simonneau G, Simonneau G, et al. J Am Coll et al. J Am Coll Cardiol Cardiol 2013; 62:D34-41.2013; 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 IPFPrevalence of PH in IPF

Author Year Pati N Diagn Definition of PH Preval, %

Leutche et al. 2004 IPF 28 RHCRHC mPAP>35 mmHg 21.4

Nadrous et al. 2005 IPF 88 EchoEcho sPAP>35 mmHgsPAP>50 mmHg

84

31

Hamada et al. 2007 IPF 70 RHCRHC mPAP>25 mmHg 8.1

Zisman et al. 2007 IPF 65 RHCRHC mPAP>25 mmHg 41.5

Patel et al. 2007 IPF 41 RHCRHCmPAP>25 mmHg +PCWP

≤15 mmHg 20

Shorr et al. 2007 IPF 2.5 RHCRHC mPAP>25 mmHg 46.1

Nathan et al. 2008 IPF 118 RHCRHC mPAP>25 mmHg 40.7

Song et al. 2009 IPF 131 EchoEcho sPAP>40 mmHg 25

Minai et al. 2009 IPF 148 RHCRHC mPAP>25mmHgmPAP>40mmHg

45.914.2

Kimura et al. 2012 IPF 101 RHCRHC mPAP > 20 mmHg 34,6

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: 288-94

Type of lung

disease

Investigator/year

Type of study

N Therapy Outcome

Lung fibrosis

Ghofrani et al, 2002 OL-RCT 16

(IPF=7)

Sildenafil, Sildenafil, iNO, iNO,

epoprostenepoprostenolol

Sildenafil improved

pulmonary hemodynamics

and gas exchange

IPFKrowka et al,

2007(multicenter)

DB-RCT 51Inhaled Inhaled iloprostiloprost

No improvement in

6MWT, NYHA/WHO

Class

IPFCollard et al,

2007 OL trial 14SildenafilSildenafil 57% 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: 641 -649

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: NCT00768300)

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: 641 - 649

Treatment of idiopathic pulmonary fibrosis with ambrisentan A parallel, randomized trial

Raghu G. et al. Ann Inter Med 2013;158: 641 - 649

Bosentan in Pulmonary Hypertension Associated withFibrotic Idiopathic Interstitial PneumoniaCorte 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 withFibrotic Idiopathic Interstitial PneumoniaCorte 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 thebosentan and placebo groups over 16 weeks. Our data do not support the use of the dual endothelin-1 receptor antagonist, bosentan, inpatients with PH and fibrotic IIP.

SSC

IPF

SarcoidosisSarcoidosis

PULMONARY HYPERTENSIONDIAGNOSTIC 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:

Extrinsic compression of large pulmonary arteries by mediastinal or hilar

adenopathies or fibrosis

Specific vasculitis, with infiltration of the walls of pulmonary arteries and/or

veins by granulomas (steroid sensitive ?)

Destruction of the distal capillary bed by fibrotic process and resulting

hypoxia (stage IV)

PULMONARY VASCULAR INVOLVEMENT IN SARCOIDOSIS

Nunes et al. Thorax 2006

Pulmonary hypertension in sarcoidois occurs in two very different settings

In the absence of pulmonary fibrosis, PH appears to be related to a specific vasculopathy and may be steroid-sensitive

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

PULMONARY VASCULAR INVOLVEMENT IN PULMONARY VASCULAR INVOLVEMENT IN SARCOIDOSISSARCOIDOSIS

No correlation between mPAP, FEV1 and TLC

Pulmonary hypertension was out of proportion with alterations in lung function

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 > 35-40 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 Bosentan for Sarcoidosis-Associated Pulmonary HypertensionHypertensionA Double-Blind Placebo Controlled Randomized A Double-Blind Placebo Controlled Randomized TrialTrial

Baughman RP, et al. Chest 2014; 145; S10Baughman RP, et al. Chest 2014; 145; S1039 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 Bosentan for Sarcoidosis-Associated Pulmonary HypertensionHypertension

A Double-Blind Placebo Controlled Randomized A Double-Blind Placebo Controlled Randomized TrialTrial

Baughman RP, et al. Chest 2014; 145; S10Baughman 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 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 with bosentan. The treatment was well tolerated. The effect of treatment over longer

periods will require further investigationperiods will require further investigation.

CONCLUSIONSCONCLUSIONS

GRIPHON study(phase III) ProstaGlandin I2 Receptor agonist In Pulmonary arterial HypertensiON

Ambrisentan + tadalafil

AMBITION STUDY

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