L’ipertensione polmonare nelle malattie polmonari
Tiberio OggionniSC PneumologiaFondazione IRCCS Policlinico S. Matteo - Pavia
Pavia 21/05/2011
Updated clinical classification of pulmonaryhypertension (Dana Point, 2008)
Updated clinical classification of pulmonaryhypertension (Dana Point, 2008)
Updated clinical classification of pulmonaryhypertension (Dana Point, 2008)
Pulmonary vascular remodelling in COPD
Serial sections of a pulmonary muscular artery with prominent intimal hyperplasia and luminal narrowing
Pathobiology of PH in COPD
Factors Leading to an Increased PulmonaryVascular Resistance in COPD
Structural factorsReduction–destruction (emphysema)
Mechanical factorsCompression of alveolar vessels (lung hyperinflation)
Functional factorsHypercapnia, acidosisHyperviscosity (polycythemia)Hypervolemia (polycythemia)
Factors Leading to an Increased PulmonaryVascular Resistance in COPD
Patients with PH had significantly higher frequencies of the 5HTT-L-allele (52%) compared to individuals without PH (36%)
Out-of-proportion PH: the L-allelic frequency was even 75%
mPAP (mm Hg) by 5HTT allelic variants
S Ulrich. Respiration 2010;79:288–295
Prevalence of PH in COPD
It has not been screened systematicallyusing right-heart catheterization
The criteria used to define PH in COPDvary among different studies
The majority of haemodynamic studies inCOPD have been performed in patients withadvanced disease (stage III or IV of the GlobalInitiative on Obstructive Lung Disease [GOLD]classification)
Prevalence of PH in COPD
120 patients with severe emphysema (mean FEV1 27%) screened LVRS
The incidence of PH (PAP >20 mmHg) was very high (91%)
In the majority of patients (86%) it was in the mild to moderate (range 20–35 mmHg)
Only 5% of patients showed PAP >35 mmHg
The correlation between PAP and lung function was very weak.
Scharf SM, et al. Am J Respir Crit Care Med 2002; 166 (3): 314-22
Prevalence of PH in COPD
Haemodynamic studies of 998 COPD patients
27 patients (2.7%) with severe PH (PAP > 40mmHg)
16 of them had another disease capable of causing PHIn 11 (1.1%) COPD was the only cause
The patients had moderate airway obstruction (FEV1 50% predicted), severe hypoxaemia, hypocapnia, very low carbon monoxide diffusing capacity (DLCO)
Chaouat A, et al. Am J Respir Crit Care Med 2005; 172 (2): 189-94
Prevalence of PH in COPD
215 patients with severe COPD (FEV1 24% predicted), candidates for LVRS or lung transplantation
PH (PAP>25mmHg) was present in 50% of the patients
In 36.5% it was mild (26–35 mmHg)
In 9.8% it was moderate (36–45 mmHg)
In 3.7% it was severe (>45 mmHg)
Thabut G, et al. Chest 2005; 127 (5): 1531-6
Registro Italiano di Trapianto PolmonareRegistro Italiano di Trapianto Polmonare
Prevalenza PH all’inserimento in lista d’attesa per Tx
PAPm Pz %≥ 25 mmHg – 35 mmHg 38.7%
36 mmHg – 45 mmHg 8.6%
> 45 mmHg 6.7%
Dal 1991 al 2007 inseriti in lista d’attesa per Tx 256 pz con COPD
Prevalenza PH (PAPm al cateterismo cardiaco ≥ 25 mmHg):
53.9% (138 pz)
Impact of PH on survival in patients with advanced COPD
Oswald-Mammosser M , et al . Chest . 1995 ; 107 ( 5 ): 1193 –1198
Patients with COPD with a mPAP of ≥ 25 mm Hg at the beginning of longterm oxygen therapy had a significantly ( P < .001) shorter life expectancy than patients with an mPAP of < 25 mm Hg
< 25 mm Hg
≥ 25 mm Hg
Registro Italiano di Trapianto PolmonareRegistro Italiano di Trapianto Polmonare
22
26
30
34
38
42
46
50
54
IN LISTA DEC < 1 Y IN LISTA VIVI > 1 Y
41.5
27.6
± Std. Err.
Mean
PA
Pm
COPD in lista: deceduti < 1 anno vs sopravv > 1 anno
Interval free of hospitalization for exacerbation
Kessler R, Am J Respir Crit Care Med 1999;159:158–164
mPAP ≤ 18 mmHg
mPAP > 18 mmHg
64 patients
%
years
Relative Risk 2(95% CI 1.3–3.1)
p = 0.0013
Long-Term Oxigen Therapy
Medical Research Council (MRC)
PAP remained unaltered in patients receiving LTOT(more than 15 h/day)
In the control group PAP rose by a mean of 2.7 mmHg per yearLancet 1981
Nocturnal Oxygen Therapy Trial (NOTT)
117 patients were evaluated after 6 months of treatment
In pts receiving continuous LTOT (more than 18 h/day) PAP decreased by an average of 3mmHg
PAP did not change in the group receiving nocturnal LTOT (10–12 h/day) Ann Intern Med 1980
Specific Therapy for PAH in COPD
Study Drug Design No. Dose Timepts (mg) (mo)
Alp Sildenafil Uncontrolled 6 50 bid 3
Madden Sildenafil Uncontrolled 7 50 tid 2
Rietema Sildenafil Uncontrolled 14 20 tid 3
Stolz Bosentan Double-blind 30 125 bid 3placebo-controlled
Specific Therapy for PAH in COPD
6MWD (m) PAP (mmHg) PaO2 (mmHg)pre - post pre - post pre – post
Sildenafil 351 – 433 30 – 25 NR – NR
Sildenafil 107 – 145 39 – 35 NR – NR
Sildenafil 385 – 394 20 – NR NR – NR
Bosentan 331 – 329 32 – 30 65 – 61
Specific Therapy for PAH in COPD
20 patients with COPD-associated PH:11 patients 20 mg9 patients 40 mg
I. Blanco. Am J Respir Crit Care Med. 181; 270–278, 2010
PAP decreased -6 mmHg (95%CI,-7 to-4) at rest
-11 mmHg (95% CI,-14 to-8) during exercise
Sildenafil
Specific Therapy for PAH in COPD
20 patients with COPD-associated PH:11 patients 20 mg9 patients 40 mg
PaO2 decreased -6 mmHg (95% CI,-8 to -4) at rest
No change in PaO2 (95% CI, -3 to 0.2 mm Hg) during exercise
Sildenafil
REST EXERCISE
I. Blanco. Am J Respir Crit Care Med. 181; 270–278, 2010
Specific Therapy for PAH in COPD
Inhaled iloprost(2.5 g)
Mean improvement in 6MWT 49.8 m(95% CI 14.8 to 84.7; p = 0.02)
TA. Dernaika. Respiration 2010;79:377–382
Specific Therapy for PAH in COPD
Double-blind parallel design
53 COPD patients with PH were randomly assigned to receive either placebo or PRAVASTATIN (40 mg/day) over a period of 6 months
Echocardiographically derived sPAP decreased significantly from 47 8 to 40 6 mmHg (P <0.05)
Significant improvement in the Borg dyspnoea score (P <0.05)
The exercise time significantly increased 52%from 660352 to 1006 316 s (P<0.0001)
TM Lee. Clinical Science (2009): 116; 497–505
‘Out of proportion’ PH
Characterized by dyspnoea insufficiently explained by lung mechanical disturbancesand mean PAP ≥ 40–45 mmHg at rest
European Heart Journal (2009) 30, 2493–2537
‘Out of proportion’ PH
COPD stabile in ottimale trattamento farmacologico e in O2 terapia a lungo termine se ipossici, con PaO2 a riposo in aria o corretta ≥ 60 mmHg e PaCO2≤ 55 mmHg:
• Gruppo 1COPD GOLD I‐III (post broncodilatatore FEV1 ≥ 30%, TLC ≥ 70%) + PAPm ≥ 30 mmHg
• Gruppo 2COPD GOLD IV (post broncodilatatore FEV1 <30%, TLC ≥ 70%)+ PAPm ≥ 35 mmHg
Specific Therapy for PAH in COPD
RSM, 51 anni
COPD + PH
FEV1 22%PAPs/m/d 96/65/44 mmHg; CO 4.48 l/min, CI 2.41 l/min/m2
NYHA IV
08/2008: Sildenafil (inserito in lista per Tx)
09/2008: + Iloprost inalatorio 2.5 mcg 6 volte/die
12/2008 trapianto bipolmonare(NYHA III)
Updated clinical classification of pulmonaryhypertension (Dana Point, 2008)
Pathogenesis of PH in IPF
Anatomical factors:loss of pulmonary vascular bedcompression of small vessels
Hypoxia:pulmonary vasoconstriction
Pulmonary artery remodelling:profibrogenic leukotrienesprostaglandin E2 endothelin (ET)-1 PDGFTGF-
Histopathology of a patient with IPF and associated PH
Right heart catheterization at initial evaluation in a group of 61 IPF patients:
PH (PAP >25 mm Hg) in only 8.1% of the patients
Prevalence of PH in ILD
Hamada K. Chest 2007;131:650–656
United Network for Organ Sharing and the Organ Procurement and Transplant Network registries for
IPF patients listed for lung transplantation
January 1995 - June 2004
2,525 of the 3,457 patients listed had RHC results available
932 (37.0%) had an mPAP >25 mm Hg
231 (9.1%) had an mPAP >40 mm Hg
Prevalence of PH in ILD
Shorr AF. Eur Respir J 2007;30:715–21.
Registro Italiano di Trapianto PolmonareRegistro Italiano di Trapianto Polmonare
Prevalenza PH all’inserimento in lista d’attesa per Tx
PAPm Pz %≥ 25 mmHg – 35 mmHg 28.2%
36 mmHg – 45 mmHg 10.7%
> 45 mmHg 7.6%
Dal 1991 al 2007 inseriti in lista d’attesa per Tx 422 pz con ILD
Prevalenza PH (PAPm al cateterismo cardiaco ≥ 25 mmHg):
46.4% (196 pz)
PH in ILD
N.W. Todd.J Heart Lung Transplant. 2010 ; 29(2): 188
Impact of PH on survival in patients with IPF
mPAP < 17 mm Hg (n 37)
mPAP ≥ 17 mm Hg (n 24)
p < 0.001
Hamada K. Chest 2007;131:650–656
In contrast to COPD there is no evidence that LTOT improves survivaland pulmonary hemodynamics in ILD patients with chronic hypoxemia and PH
Long-Term Oxigen Therapy
Specific Therapy for PAH in ILD
HA Ghofrani. Lancet 2002; 360: 895–900
Intravenous epoprostenol (mean 8·0 ng/kg per min; n=8 patients)or oral sildenafil (50 mg; n=8 patients)
Specific Therapy for PAH in ILD
Double-blind, randomized, placebo-controlled trial of sildenafil
12 weeks of a double-blind comparison between sildenafil and a placebo control.
The primary outcome:the proportion of patients with an increase in the 6-minute walk distance ≥ 20%
The secondary outcomes:changes in oxygenation, degree of dyspnea, and quality of life
12-week open-label evaluation involving all patients receiving sildenafil
N Engl J Med 2010;363:620-8
Specific Therapy for PAH in ILD
180 patients
The difference in the primary outcome was not significant (P = 0.39)
6-minute walk distance
9 of 89 patients (10%) in the sildenafil group and 6 of 91 (7%) in the placebo group having an improvement ≥ 20%
N Engl J Med 2010;363:620-8
Specific Therapy for PAH in ILD
Sildenafil Placebo P Value
Shortness 0.22 (−3.10 to 3.54) 6.81 (3.53 to 10.08) 0.006of Breath
St. George’s −1.64 (−3.91 to 0.64) 2.45 (0.17 to 4.72) 0.01RespiratoryQuestionnaire
SF-36 −1.04 (−2.52 to 0.44) −3.89 (−5.37 to −2.42) 0.008 General HealthScore
DLCO (% of pv) −0.33 (−1.36 to 0.71) −1.87 (−2.91 to −0.83) 0.04
PaO2 (mm Hg) −0.63 (−2.41 to 1.16) −3.64 (−5.41 to −1.87) 0.02
N Engl J Med 2010;363:620-8
BUILD-3: A Randomized, Controlled Trial of Bosentan inIdiopathic Pulmonary Fibrosis
AJRCCM Article in Press. Published on April 7, 2011
Prospective, randomized (2:1), double-blind, placebo-controlled, eventdriven, parallel-group, morbidity–mortality trialin adults with IPF of <3 years duration
616 patients were randomized to bosentan (n=407) or placebo (n=209)
Primary endpoint: time to IPF worsening (decrease in FVC ≥10% and DLCO ≥15% or acute exacerbation of IPF) or death
Secondary endpoint: health-related quality of life and dyspnea
No significant difference between treatment groups was observed in the primary endpoint analysis (hazard ratio, 0.85; 95% CI, 0.66 to 1.10; p=0.2110)
No effects were observed on healthrelated quality of life or dyspnea.
Specific Therapy for PAH in ILD
LOF, 59 anniIPF + PH
FVC 72%PAPs/d/m 50/30/41 mmHg, CI 2.4 l/min/m2
6MWT: percorsi 360 m
09/2010: sildenafil (lista d’attesa per Tx)
01/2011:PAPs/d/m 42/25/33 mmHg, CI 2.9 l/min/m2
6MWT: percorsi 390 m
CONCLUSIONI
Importanza della PH nella COPD e nelle ILD nella prognosi dei pz
Al momento, oltre all’O2 terapia per la COPD, non evidenze per altra terapia della PH
Inserimento di tali pz in studi clinici
Eventuale utilizzo della terapia vasodilatatrice polmonare come “bridge” al trapianto polmonare
Identificazione dei pz con PH “out of proportion” rispetto alla patologia parenchimale
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