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Pulmonary hypertension (PH) due to chronic lung disease is associated with a poor prognosis,
regardless of the underlying respiratory condition. Updated PH guidelines recommend optimal
treatment of the underlying lung disease, including long-term oxygen therapy, in patients with
chronic hypoxemia despite the lack of randomized controlled clinical trials supporting this
statement. So far, randomized controlled trials of drugs approved for pulmonary arterial
hypertension have yielded discouraging results in both interstitial lung diseases and COPD with
PH. In some cases, the trials were terminated because of an increase in death and other major
adverse events in the active treatment arm vs placebo. In cases of PH due to idiopathic
pulmonary fibrosis, new therapies under investigation use a combination of novel antifibrotic
treatments and other treatments approved for pulmonary arterial hypertension. The choice of
robust end points as well as a target group of patients with specific hemodynamic criteria
may help in the selection of innovative therapeutic strategies. The aim of this review is to
discuss recent studies and clinical trials for the treatment of PH due to the main chronic res-
piratory diseases and to discuss possible future scenarios for the evaluation of new therapeutic
strategies. CHEST 2018; 153(1):217-223
ABBREVIATIONS: 6MWD = 6-min walk distance; DLCO = diffusing (Dr Humbert), Hôpital de Bicêtre, and INSERM UMR_S 999 (Dr
capacity of the lung for carbon monoxide; IPF = idiopathic pulmonary Humbert), Le Kremlin Bicêtre, France.
fibrosis; mPAP = mean pulmonary artery pressure; PAH = pulmonary CORRESPONDENCE TO: Sergio Harari, MD, Unità di Pneumologia e
arterial hypertension; PH = pulmonary hypertension; PVR = pulmo- Terapia Semi-Intensiva Respiratoria, Servizio di Fisiopatologia
nary vascular resistance Respiratoria ed Emodinamica Polmonare, Ospedale San Giuseppe,
AFFILIATIONS: From the Unità di Pneumologia e Terapia Semi- Milan 20123, Italy; e-mail: sharari@hotmail.it
Intensiva Respiratoria (Drs Harari and Elia), Servizio di Fisiopatologia Copyright © 2017 American College of Chest Physicians. Published by
Respiratoria ed Emodinamica Polmonare, Ospedale San Giuseppe, Elsevier Inc. All rights reserved.
Milan, Italy; and the Université Paris-Sud, Faculté de Médecine (Dr DOI: http://dx.doi.org/10.1016/j.chest.2017.06.008
Humbert), Université Paris-Saclay, AP-HP, Service de Pneumologie
chestjournal.org 217
TABLE 1 ] Classification of PH According to European TABLE 2 ] Hemodynamic Classification of PH Due to
Society of Cardiology/European Respiratory Lung Disease
Society Guidelines
Terminology Hemodynamics (Right Heart Catheterization)
1. Pulmonary arterial hypertension
COPD/IPF/CPFE mPAP < 25 mm Hg
10. Pulmonary venoocclusive disease and/or pulmonary without PH
capillary hemangiomatosis
COPD/IPF/CPFE mPAP $ 25 mm Hg
100 . Persistent PH of the newborn with PH
2. PH due to left heart disease COPD/IPF/CPFE mPAP > 35 mm Hg, or mPAP
3. PH due to lung diseases and/or hypoxia with severe PH $ 25 mm Hg in the presence
of low cardiac output (CI < 2.5
3.1. COPD L/min/m2, not explained by other
3.2. Interstitial lung disease causes)
3.3. Other pulmonary diseases with mixed restrictive Adapted from Galiè et al.2 CI
¼ cardiac index; CPFE¼combined pul-
and obstructive pattern monary fibrosis and emphysema; IPF¼idiopathic pulmonary fibrosis;
3.4. Sleep-disordered breathing mPAP ¼mean pulmonary arterial pressure. See Table 1 legend for
expansion of other abbreviation.
3.5. Alveolar hypoventilation disorders
3.6. Chronic exposure to high altitude
3.7. Developmental lung diseases Studies on IPF and Other Fibrotic Lung
4. Chronic thromboembolic PH and other pulmonary Diseases With PH
artery obstructions The various clinical trials carried out so far with
5. PH with unclear and/or multifactorial mechanisms pulmonary arterial hypertension (PAH) therapies (eg,
Adapted from Galiè et al.2 PH ¼ pulmonary hypertension.
endothelin receptor antagonists, phosphodiesterase type
5 inhibitors, guanylate cyclase stimulators, and
prostacyclin analogues) have yielded only discouraging
or mPAP $ 25 mm Hg with a cardiac index (CI) < 2.5 results in IPF.4
L/min/m2.3
Endothelin Receptor Antagonists
PH is a well-known complication of IPF. Its prevalence
The clinical use of endothelin receptor antagonists for
varies greatly according to the severity of the disease
the treatment of IPF has been studied in various groups
and the diagnostic tools used for PH detection.4 PH of patients.8 However, this approach has raised some
has been found in 30% to 50% of patients affected by skepticism due to the negative results obtained in a
moderate-to-severe IPF and in more than 60% of those
clinical trial on IPF with no PH9 and in a double-blind
with end-stage IPF.5,6 The severity of PH, in most of
randomized controlled trial comparing the dual
these patients, was mild to moderate, but a subgroup
endothelin receptor antagonist bosentan with placebo
of patients presented with severe PH. In the most in patients with fibrosing interstitial lung diseases and
recent European guidelines, a hemodynamic PH.10 The latter study lasted for 16 weeks and assessed
classification of PH due to lung diseases was suggested
the therapeutic response of pulmonary vascular
and is shown in Table 2.2 Both in COPD and IPF the
resistance (PVR) vs baseline in 60 patients, of whom
presence of PH is associated with increased morbidity
only 39 were available for hemodynamic monitoring;
and mortality.6,7 the results did not reveal any benefits. Raghu et al11
The only possible therapeutic approach to this condition reported the negative results of using ambrisentan,
remains hypoxia correction. This confers a prognostic an endothelin receptor type-A selective antagonist,
advantage only in COPD, as randomized controlled for the treatment of IPF. More recently, the authors5
trials have not studied the use of long-term oxygen issued a detailed analysis of the patients with PH
therapy in other conditions. Since long-term oxygen randomized in this trial. Patients received either 5 mg
therapy does not result in either normalization of of ambrisentan daily for the first 2 weeks (after which
increased PAP or reversal of pulmonary vascular the dose was increased to 10 mg if the drug was
remodeling, drugs approved for group 1 PH have been tolerated) or placebo, at a 1:2 ratio. Of the initial 488
tested in patients with severe PH due to parenchymal subjects randomized in the global trial, PH was found
lung diseases.3 In this review we discuss new insights in 68 individuals (mPAP > 22 mm Hg and pulmonary
about the treatment of PH associated with COPD artery wedge pressure # 15 mm Hg). Follow-up
and IPF. hemodynamic data were available for only 19 patients
chestjournal.org 219
off-label PAH therapies (phosphodiesterase type 5 underwent right heart catheterization at baseline and
inhibitors in 7 cases) before the start of the study. The after 3 to 12 months of treatment. Pulmonary
results recorded for the majority of patients had thus hemodynamics improved in treated patients while there
been obtained in patients receiving combination was no significant difference in 6MWD.
therapy. This is questionable in IPF as there are no data
available about the use of a combination of two or more Endothelin Receptor Antagonists
PAH drugs in that setting.18 Because PH is common during exercise in severe COPD,
Stolz et al25 hypothesized that the use of the endothelin
New Perspectives for PH Due to IPF in the Era receptor antagonist bosentan can improve
of Antifibrotic Therapies cardiopulmonary hemodynamics during exercise and
The role of the new antifibrotic agents pirfenidone and thus increase exercise tolerance in patients with severe
nintedanib in patients with IPF and PH requires COPD. In this double-blind placebo-controlled study, 30
separate consideration. Although no data on these patients with severe COPD received either bosentan or
agents are currently available the possible beneficial role placebo for 12 weeks. Compared with patients in the
of nintedanib in patients with IPF with PH needs to be placebo group, the patients treated with bosentan
evaluated. Imatinib, another tyrosine kinase inhibitor, showed no significant improvement of the primary end
improved exercise capacity and hemodynamics in point (6MWD). Bosentan not only failed to improve
patients with advanced PAH. However, serious adverse exercise capacity but also worsened hypoxemia and the
events ensued, which led to a high rate of study functional status of patients with severe COPD without
discontinuation in the active treatment arm vs placebo.19 PH at rest. As demonstrated by Barberà et al,26 the use of
Other tyrosine kinase inhibitors such as dasatinib,20 pulmonary vasodilators such as nitric oxide in patients
ponatinib,21 and bosutinib22 have been reported to with COPD whose hypoxemia is caused mainly by
induce PAH. The effect of nintedanib on PH due to IPF ventilation/perfusion imbalance may lead to an increased
therefore remains an open area of investigation. mismatch by an increase in perfusion distribution in
poorly ventilated alveolar units. In a small open study
The antifibrotic mechanism of action of pirfenidone has bosentan was administered to 16 patients for a period of
not been elucidated, but it is known that this agent 18 months. This therapy improved both pulmonary
combines an antiproliferative with an antiinflammatory hemodynamics and 6MWD.27
activity. Interestingly, inflammation is the underlying
phenomenon in many forms of PH, for example, in Phosphodiesterase Type 5 Inhibitors
patients with idiopathic PAH or PAH associated with The efficacy of sildenafil in improving exercise tolerance
HIV infection, portal hypertension, and connective in patients with COPD and moderately increased PAP
tissue diseases.23 The antiinflammatory effect of was tested in a double-blind randomized controlled trial
pirfenidone could be of importance in the treatment of of 60 patients. Of these patients, 29 received sildenafil
PH, although no data currently support this hypothesis. (20 mg, three times daily) and 31 received placebo, while
A recently launched phase IIb randomized controlled all underwent pulmonary rehabilitation for 3 months.
trial aims at studying the efficacy, safety, and tolerability The primary end point was the gain in cycle endurance
of pirfenidone in combination with sildenafil in patients time at a constant work rate. Secondary end points
with advanced IPF and in patients with group 3 PH included performance in the incremental exercise test,
with intermediate- or high-probability IPF (https:// 6MWD, and quality of life. None of the end points was
clinicaltrials.gov/ct2/show/NCT02951429). reached. The authors concluded that in patients with
severe COPD and moderately increased PAP
Studies on COPD With PH concomitant treatment with sildenafil does not improve
The use of PAH therapies in patients with COPD with the results of pulmonary rehabilitation on exercise
group 3 PH has also provided unclear results. From a tolerance.28 Similar disappointing results were obtained
prospective database, Girard et al24 analyzed 26 in a study involving 120 patients with COPD and mild
consecutive patients with COPD with severe PH PH randomized to tadalafil (10 mg/d) or placebo for
(mPAP $ 35 mm Hg) who received specific PAH 12 weeks, with exercise tolerance and stress test within a
therapy (mostly endothelin receptor antagonists and respiratory rehabilitation program as the primary end
phosphodiesterase type 5 inhibitors) and who points.29 A 16-week multicenter double-blind
chestjournal.org 221
PVR and low cardiac index, as stated in the ESC/ERS interstitial pneumonias. http://www.prnewswire.com/news-releases/
bayer-terminates-phase-ii-study-with-riociguat-in-patients-with-
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Haemodynamic changes in pulmonary hypertension in patients with
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15. Idiopathic Pulmonary Fibrosis Clinical Research Network.
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16. Han MK, Bach DS, Hagan PG, et al. Sildenafil preserves exercise
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Financial/nonfinancial disclosures: The authors have reported to
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Boehringer Ingelheim, and Intermune. In addition to being an therapy for pulmonary arterial hypertension. Circulation. 2013;127:
investigator in trials involving these companies, S. H. is involved in 1128-1138.
lectures and is a member of scientific advisory boards. M. H. reports 20. Montani D, Bergot E, Günther S, et al. Pulmonary arterial
personal fees from Actelion, Bayer, GSK, Pfizer, and Roche. None hypertension in patients treated by dasatinib. Circulation.
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