Transcript Ipertensione polmonare

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 precapillary 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
Updated classification is
now the same for adult
and pediatric patients
PPHN moved from
Group 1 (PAH) as has
more differences
than
New gene
similarities to other
mutations added
PAH subgroups
Added for consistency
with pediatric
classification
* Main modifications to the
previous WSPH proceedings
(Dana point) are indicated by
green boxes
New gene mutations
added
Chronic hemolytic anemia
moved from Group 1 (PAH)
given the differences to PAH
in pathological findings,
hemodynamics and
response to therapy
Simonneau G, et al. J Am Coll Cardiol 2013; 62:D34-41.
Updated classification for drug- and
toxin-induced PAH
New addition
(included as a risk
factor in ESC/ERS
Guidelines)
New additions
Moved from ‘possible’
to ‘definite’ risk factor
New
New addition
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.
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
Screening for PAH-SSc
ESC/ERS guidelines 2009
Symptomatic patients
(breathlessness, fatigue,
weakness, angina, syncope…)
Yearly ECHO
is recommended
Asymptomatic
patients
Yearly ECHO
may be considered
RHC is indicated in all suspected PAH-SSc
Prognosis of “routine practice” and
“detected” PAH-SSc patients
100%
100
p = 0.0037
81%
73%
HR = 4.15
(95% CI 1.47 - 11.71)
90
80
64%
Survival (%)
70
60
75%
Detected
PAH-SSc
50
40
31%
25%
30
20
17%
10
0
1 year
3 years
5 years
Years of follow-up
Humbert M, et al. Arthritis Rheum 2011;.
8 years
Routine
practice
PAH-SSc
SCREENING DEI PAZIENTI AFFETTI DA SSc
.
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.
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
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
 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
Prevalence of PH in IPF
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
Author
Year
Pati
N
Diagn
Definition of PH
Preval, %
Leutche et al.
2004
IPF
28
RHC
mPAP>35 mmHg
21.4
Nadrous et al.
2005
IPF
88
Echo
sPAP>35 mmHg
sPAP>50 mmHg
84
31
Hamada et al.
2007
IPF
70
RHC
mPAP>25 mmHg
8.1
Zisman et al.
2007
IPF
65
RHC
mPAP>25 mmHg
41.5
Patel et al.
2007
IPF
41
RHC
mPAP>25 mmHg +PCWP
≤15 mmHg
20
Shorr et al.
2007
IPF
2.5
RHC
mPAP>25 mmHg
46.1
Nathan et al.
2008
IPF
118
RHC
mPAP>25 mmHg
40.7
Song et al.
2009
IPF
131
Echo
sPAP>40 mmHg
25
Minai et al.
2009
IPF
148
RHC
mPAP>25mmHg
mPAP>40mmHg
45.9
14.2
Kimura et al.
2012
IPF
101
RHC
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
Trials of therapy for PH in IPF
Type of
lung
disease
Lung
fibrosis
IPF
IPF
Investigator/
year
Ghofrani et
al, 2002
Type of
study
OL-RCT
N
16
(IPF=7)
Krowka et al,
2007
DB-RCT
(multicenter)
Collard et al,
2007
OL trial
51
14
Therapy
Outcome
Sildenafil,
iNO,
epoprosten
ol
Sildenafil
improved
pulmonary
hemodynamics
and gas
exchange
Inhaled
iloprost
No
improvement in
6MWT,
NYHA/WHO
Class
Sildenafil
57% had
significant
increase in
6MWT
Sildenafil in IPF with
Right-sided Ventricular Dysfunction
A substudy of STEP-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
Treatment of idiopathic pulmonary fibrosis with ambrisentan
A parallel, randomized trial
Raghu
G. et
et al.
al. Ann
Ann Inter
Inter Med
Med 2013;158:
2013;158: 641
641 -649
- 649
Ragu G.
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
Measurements: Time to disease progression, defined as death, respiratory
hospitalization, or a categorical decrease in lung function.
Conclusion: Ambrisentan was not effective in treating IPF and may be
associated with an increased risk for disease progression and respiratory
hospitalizations
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 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)
5. PH with unclear or
multifactorial mechanisms
• Sarcoidosis
PULMONARY VASCULAR INVOLVEMENT IN
SARCOIDOSIS
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)
Nunes et al. Thorax 2006
PULMONARY VASCULAR INVOLVEMENT IN
SARCOIDOSIS



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 steroidsensitive
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
 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
Hypertension
A Double-Blind Placebo Controlled Randomized Trial
Baughman RP, et al. Chest 2014; 145; S10
39 pts in NYHA IIIII in stable therapy
for sarcoidosis
Double blind
randomized
placebo controlled
trial of 16 weeks
(2:1)
Bosentan
for
Hypertension
Sarcoidosis-Associated
Pulmonary
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
.
CONCLUSIONS
GRIPHON study(phase III)
ProstaGlandin I2 Receptor agonist
In Pulmonary arterial HypertensiON
Ambrisentan + tadalafil
AMBITION STUDY
Thank You