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