[ Recent Advances in Chest Medicine ]

Pulmonary Hypertension in Parenchymal

Lung Diseases
Any Future for New Therapies?
Sergio Harari, MD; Davide Elia, MD; and Marc Humbert, MD, PhD

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

Precapillary pulmonary hypertension (PH) COPD and idiopathic pulmonary fibrosis

is defined by a mean pulmonary artery
pressure (mPAP) $ 25 mm Hg at rest with
a normal pulmonary capillary wedge
pressure (ie, # 15 mm Hg). A normal
mPAP (T standard deviation) is equal to
14 T 3 mm Hg. Thus, an mPAP of 21
to 24 mm Hg at rest is above the upper
limit of normal but does not qualify for
the diagnosis of PH.1 PH due to
parenchymal lung diseases, such as
(IPF), is a relatively frequent condition that
has a negative impact on the prognosis of
affected patients, regardless of their
underlying respiratory condition (Table 1,
group 3).2 Indeed, mPAP > 20 mm Hg
and up to 35 mm Hg has been commonly
observed in patients with severe COPD,
and in some selected series, 1% to 5% of
patients with COPD have shown severe
PH defined by mPAP > 35 mm Hg

ABBREVIATIONS: 6MWD = 6-min walk distance; DLCO = diffusing
capacity of the lung for carbon monoxide; IPF = idiopathic pulmonary
fibrosis; mPAP = mean pulmonary artery pressure; PAH = pulmonary
arterial hypertension; PH = pulmonary hypertension; PVR = pulmo-
nary vascular resistance
AFFILIATIONS: From the Unità di Pneumologia e Terapia Semi-
Intensiva Respiratoria (Drs Harari and Elia), Servizio di Fisiopatologia
Respiratoria ed Emodinamica Polmonare, Ospedale San Giuseppe,
Milan, Italy; and the Université Paris-Sud, Faculté de Médecine (Dr
Humbert), Université Paris-Saclay, AP-HP, Service de Pneumologie
(Dr Humbert), Hôpital de Bicêtre, and INSERM UMR_S 999 (Dr
Humbert), Le Kremlin Bicêtre, France.
CORRESPONDENCE TO: Sergio Harari, MD, Unità di Pneumologia e
Terapia Semi-Intensiva Respiratoria, Servizio di Fisiopatologia
Respiratoria ed Emodinamica Polmonare, Ospedale San Giuseppe,
Milan 20123, Italy; e-mail: sharari@hotmail.it
Copyright © 2017 American College of Chest Physicians. Published by
Elsevier Inc. All rights reserved.
DOI: http://dx.doi.org/10.1016/j.chest.2017.06.008

chestjournal.org 217
TABLE 1 ] Classification of PH According to European
Society of Cardiology/European Respiratory
Society Guidelines
1. Pulmonary arterial hypertension
10. Pulmonary venoocclusive disease and/or pulmonary
capillary hemangiomatosis
100 . Persistent PH of the newborn
2. PH due to left heart disease
3. PH due to lung diseases and/or hypoxia
3.1. COPD
3.2. Interstitial lung disease
3.3. Other pulmonary diseases with mixed restrictive
and obstructive pattern
3.4. Sleep-disordered breathing
3.5. Alveolar hypoventilation disorders
3.6. Chronic exposure to high altitude
3.7. Developmental lung diseases
4. Chronic thromboembolic PH and other pulmonary
artery obstructions
5. PH with unclear and/or multifactorial mechanisms
Adapted from Galiè et al.2 PH ¼ pulmonary hypertension.
or mPAP $ 25 mm Hg with a cardiac index (CI) < 2.5
L/min/m2.3
PH is a well-known complication of IPF. Its prevalence
varies greatly according to the severity of the disease
and the diagnostic tools used for PH detection.4 PH
has been found in 30% to 50% of patients affected by
moderate-to-severe IPF and in more than 60% of those
with end-stage IPF.5,6 The severity of PH, in most of
these patients, was mild to moderate, but a subgroup
of patients presented with severe PH. In the most
recent European guidelines, a hemodynamic
classification of PH due to lung diseases was suggested
and is shown in Table 2.2 Both in COPD and IPF the
presence of PH is associated with increased morbidity
and mortality.6,7
The only possible therapeutic approach to this condition
remains hypoxia correction. This confers a prognostic
advantage only in COPD, as randomized controlled
trials have not studied the use of long-term oxygen
therapy in other conditions. Since long-term oxygen
therapy does not result in either normalization of
increased PAP or reversal of pulmonary vascular
remodeling, drugs approved for group 1 PH have been
tested in patients with severe PH due to parenchymal
lung diseases.3 In this review we discuss new insights
about the treatment of PH associated with COPD
and IPF.
218 Recent Advances in Chest Medicine
TABLE 2 ] Hemodynamic Classification of PH Due to
Lung Disease
Terminology Hemodynamics (Right Heart Catheterization)
COPD/IPF/CPFE mPAP < 25 mm Hg
without PH
COPD/IPF/CPFE mPAP $ 25 mm Hg
with PH
COPD/IPF/CPFE mPAP > 35 mm Hg, or mPAP
with severe PH $ 25 mm Hg in the presence
of low cardiac output (CI < 2.5
L/min/m2, not explained by other
causes)
Adapted from Galiè et al.2 CI
¼ cardiac index; CPFE¼combined pul-
monary fibrosis and emphysema; IPF¼idiopathic pulmonary fibrosis;
mPAP ¼mean pulmonary arterial pressure. See Table 1 legend for
expansion of other abbreviation.
Studies on IPF and Other Fibrotic Lung
Diseases With PH
The various clinical trials carried out so far with
pulmonary arterial hypertension (PAH) therapies (eg,
endothelin receptor antagonists, phosphodiesterase type
5 inhibitors, guanylate cyclase stimulators, and
prostacyclin analogues) have yielded only discouraging
results in IPF.4
Endothelin Receptor Antagonists
The clinical use of endothelin receptor antagonists for
the treatment of IPF has been studied in various groups
of patients.8 However, this approach has raised some
skepticism due to the negative results obtained in a
clinical trial on IPF with no PH9 and in a double-blind
randomized controlled trial comparing the dual
endothelin receptor antagonist bosentan with placebo
in patients with fibrosing interstitial lung diseases and
PH.10 The latter study lasted for 16 weeks and assessed
the therapeutic response of pulmonary vascular
resistance (PVR) vs baseline in 60 patients, of whom
only 39 were available for hemodynamic monitoring;
the results did not reveal any benefits. Raghu et al11
reported the negative results of using ambrisentan,
an endothelin receptor type-A selective antagonist,
for the treatment of IPF. More recently, the authors5
issued a detailed analysis of the patients with PH
randomized in this trial. Patients received either 5 mg
of ambrisentan daily for the first 2 weeks (after which
the dose was increased to 10 mg if the drug was
tolerated) or placebo, at a 1:2 ratio. Of the initial 488
subjects randomized in the global trial, PH was found
in 68 individuals (mPAP > 22 mm Hg and pulmonary
artery wedge pressure # 15 mm Hg). Follow-up
hemodynamic data were available for only 19 patients
[ 1 5 3 #1 C H E S T J A N U A R Y 2 0 1 8 ]
(12 in the ambrisentan arm and 7 in the placebo arm)
and did not reveal any major differences. Lack of
efficacy in the entire study group and the higher
incidence of disease progression in the ambrisentan
arm led the authors to advise against the use of
ambrisentan in patients with IPF. It should also be
noted that 9% of the entire sample showed an increase
in left ventricular filling pressure, suggesting subclinical
left ventricular disease, and that 5% showed a similar
increase due to PH. Early termination of the trial
because of lack of efficacy in the actively treated group
restricted exposure to the experimental drug to only
34 weeks on average.
Guanylate Cyclase Stimulators
A small nonrandomized 12-week pilot study, which
evaluated the use of riociguat in 15 patients affected by
various forms of interstitial lung disorders, showed
that the drug was able to improve the cardiac index,
PVR, and 6-min walk distance (6MWD) by 26 m. In
addition, the arterial oxygen saturation decreased
while the mixed venous oxygen saturation slightly
increased. However, clinical improvement was unclear
and the authors concluded that further studies were
necessary to evaluate the safety and efficacy of
riociguat in these diseases.12 Riociguat was later tested
in a randomized controlled trial vs placebo in patients
with PH due to idiopathic interstitial lung disease.
However, this study included broadly different
pathological conditions such as cryptogenic organizing
pneumonia together with IPF and acute interstitial
pneumonia. Moreover, the primary end point
(6MWD) is a surrogate end point, which has never
been validated for the specific indication of
parenchymal diseases with PH and has been associated
with different results in different trials. The trial was
prematurely terminated because of an increased risk of
death and other serious adverse events in the active
treatment arm.13
Phosphodiesterase Type 5 Inhibitors
Hemodynamic results obtained after right heart
catheterization have been recorded in a small series
of patients with severe PH due to hypersensitivity
pneumonitis and IPF treated with phosphodiesterase
type 5 inhibitors (sildenafil or tadalafil). Follow-up
analysis at 6.9 T 5.8 months showed an increase in
cardiac index (P ¼ .04) and a decrease in PVR (P ¼ .03)
while 6MWD and brain natriuretic peptide did not
change significantly.14
chestjournal.org
STEP-IPF (Sildenafil Trial of Exercise Performance in
Idiopathic Pulmonary Fibrosis) was a randomized
controlled trial on the use of sildenafil vs placebo in
patients with advanced IPF (ie, patients characterized by
a diffusing capacity of the lung for carbon monoxide
[DLCO] < 35% of the predicted value). The study design
included a first 12-week period of double-blind
evaluation vs placebo (patients at a 1:1 ratio) and a
second open 12-week phase during which all 180
patients enrolled received sildenafil (20 mg, three times
daily). The primary end point, which was a
20% improvement of 6MWD vs baseline, was not
met although small but noticeable differences in arterial
oxygenation, DLCO, degree of dyspnea, and quality of life
were registered among patients treated with sildenafil
during the double blind phase.15
A subsequent analysis of a subset of 119 patients for
whom baseline echocardiographic data were available
showed an improvement in 6MWD ( þ 99 m) at the end
of the observation period in sildenafil-treated patients
with right ventricular dysfunction at time zero (18.6% of
the patients, ie, 11 per each treatment arm) and a higher
score in the quality of life assessment questionnaires.
The same positive outcome was not observed in patients
with right ventricular hypertrophy, as shown by baseline
echocardiography, in or those with increased pulmonary
systolic pressure of any type.16
Hoeper et al17 have analyzed COMPERA (Comparative,
Prospective Registry of Newly Initiated Therapies for
PH) data for 151 patients with PH with idiopathic
interstitial pneumonia. Among these patients, those who
responded to PAH therapies (phosphodiesterase type 5
inhibitors in 80% of the patients) saw an improvement
in 6MWD of at least 20 m or an improvement in
functional class and tended to have better survival.
While these data should be considered as “hypothesis
generating,” there is currently no evidence that
phosphodiesterase type 5 inhibitors has a positive effect
on short-term or long-term outcome in PH due to
interstitial lung diseases.
Prostacyclin Analogues
The effect of the prostacyclin analogue treprostinil
was tested in 15 patients with IPF and severe PH
(mPAP $ 35 mm Hg) who were on a waiting list for
lung transplantation. Pulmonary hemodynamics, right
ventricular function, and 6MWD all improved during
therapy.14 However, the study was strongly criticized in
a letter to the editor because the article did not clearly
state that 9 of the 15 patients were already receiving
219
off-label PAH therapies (phosphodiesterase type 5
inhibitors in 7 cases) before the start of the study. The
results recorded for the majority of patients had thus
been obtained in patients receiving combination
therapy. This is questionable in IPF as there are no data
available about the use of a combination of two or more
PAH drugs in that setting.18
New Perspectives for PH Due to IPF in the Era
of Antifibrotic Therapies
The role of the new antifibrotic agents pirfenidone and
nintedanib in patients with IPF and PH requires
separate consideration. Although no data on these
agents are currently available the possible beneficial role
of nintedanib in patients with IPF with PH needs to be
evaluated. Imatinib, another tyrosine kinase inhibitor,
improved exercise capacity and hemodynamics in
patients with advanced PAH. However, serious adverse
events ensued, which led to a high rate of study
discontinuation in the active treatment arm vs placebo.19
Other tyrosine kinase inhibitors such as dasatinib,20
ponatinib,21 and bosutinib22 have been reported to
induce PAH. The effect of nintedanib on PH due to IPF
therefore remains an open area of investigation.
The antifibrotic mechanism of action of pirfenidone has
not been elucidated, but it is known that this agent
combines an antiproliferative with an antiinflammatory
activity. Interestingly, inflammation is the underlying
phenomenon in many forms of PH, for example, in
patients with idiopathic PAH or PAH associated with
HIV infection, portal hypertension, and connective
tissue diseases.23 The antiinflammatory effect of
pirfenidone could be of importance in the treatment of
PH, although no data currently support this hypothesis.
A recently launched phase IIb randomized controlled
trial aims at studying the efficacy, safety, and tolerability
of pirfenidone in combination with sildenafil in patients
with advanced IPF and in patients with group 3 PH
with intermediate- or high-probability IPF (https://
clinicaltrials.gov/ct2/show/NCT02951429).
Studies on COPD With PH
The use of PAH therapies in patients with COPD with
group 3 PH has also provided unclear results. From a
prospective database, Girard et al24 analyzed 26
consecutive patients with COPD with severe PH
(mPAP $ 35 mm Hg) who received specific PAH
therapy (mostly endothelin receptor antagonists and
phosphodiesterase type 5 inhibitors) and who
220 Recent Advances in Chest Medicine
underwent right heart catheterization at baseline and
after 3 to 12 months of treatment. Pulmonary
hemodynamics improved in treated patients while there
was no significant difference in 6MWD.
Endothelin Receptor Antagonists
Because PH is common during exercise in severe COPD,
Stolz et al25 hypothesized that the use of the endothelin
receptor antagonist bosentan can improve
cardiopulmonary hemodynamics during exercise and
thus increase exercise tolerance in patients with severe
COPD. In this double-blind placebo-controlled study, 30
patients with severe COPD received either bosentan or
placebo for 12 weeks. Compared with patients in the
placebo group, the patients treated with bosentan
showed no significant improvement of the primary end
point (6MWD). Bosentan not only failed to improve
exercise capacity but also worsened hypoxemia and the
functional status of patients with severe COPD without
PH at rest. As demonstrated by Barberà et al,26 the use of
pulmonary vasodilators such as nitric oxide in patients
with COPD whose hypoxemia is caused mainly by
ventilation/perfusion imbalance may lead to an increased
mismatch by an increase in perfusion distribution in
poorly ventilated alveolar units. In a small open study
bosentan was administered to 16 patients for a period of
18 months. This therapy improved both pulmonary
hemodynamics and 6MWD.27
Phosphodiesterase Type 5 Inhibitors
The efficacy of sildenafil in improving exercise tolerance
in patients with COPD and moderately increased PAP
was tested in a double-blind randomized controlled trial
of 60 patients. Of these patients, 29 received sildenafil
(20 mg, three times daily) and 31 received placebo, while
all underwent pulmonary rehabilitation for 3 months.
The primary end point was the gain in cycle endurance
time at a constant work rate. Secondary end points
included performance in the incremental exercise test,
6MWD, and quality of life. None of the end points was
reached. The authors concluded that in patients with
severe COPD and moderately increased PAP
concomitant treatment with sildenafil does not improve
the results of pulmonary rehabilitation on exercise
tolerance.28 Similar disappointing results were obtained
in a study involving 120 patients with COPD and mild
PH randomized to tadalafil (10 mg/d) or placebo for
12 weeks, with exercise tolerance and stress test within a
respiratory rehabilitation program as the primary end
points.29 A 16-week multicenter double-blind
[ 1 5 3 #1 C H E S T J A N U A R Y 2 0 1 8 ]
randomized controlled trial evaluated sildenafil (20 mg,
three times daily) in patients with severe PH and COPD
(SPHERIC-1: Sildenafil and PH in COPD). Change in
pulmonary vascular resistance was the primary end
point. Secondary end points included BODE index
(body mass index, airflow obstruction, dyspnea, and
exercise capacity), 6MWD, and quality of life. Changes
in the PaO2 were also evaluated as a safety parameter.
Twenty-eight patients (18 in the sildenafil group and
10 in the placebo group) were randomized in this trial.
At 16 weeks patients treated with sildenafil had a
significant decrease in PVR, while BODE index, D LCO,
and quality of life improved without relevant
deterioration of PaO2.30
The efficacy of endothelin receptor antagonists, and in
particular, phosphodiesterase type 5 inhibitors, for the
treatment of PAH in patients affected by interstitial lung
diseases and COPD is still unclear. The data currently
available are conflicting and it is not clear whether there
is a relationship between hemodynamic changes,
functional parameters, and significant improvement.
Other Lung Diseases Causing PH Due to
Multifactorial or Unclear Causes (Group 5 of
the PH Classification)
There are few data concerning pathological conditions
in which PH has multifactorial or unknown causes
(group 5 of the Nice PH classification). Many of these
diseases, such as sarcoidosis, pulmonary Langerhans
cells histiocytosis, and lymphangioleiomyomatosis, can
be responsible for varying degrees of PH. Case series
suggest that severe forms of PH due to pulmonary
Langerhans cells histiocytosis31,32 respond to PAH
therapies such as endothelin receptor antagonists and
phosphodiesterase type 5 inhibitors.33,34 A 16-week
double-blind placebo-controlled randomized trial
involving 35 patients with PH due to sarcoidosis (23
patients received bosentan and the remaining 12
received placebo) showed that bosentan improved
pulmonary hemodynamics without modifying
6MWD.35
The Problem With End Points
Finding an adequate end point for PAH and for lung
disease-related PH in clinical trials is still a widely
debated issue. A strong end point is a direct measure of a
clinical benefit for the patient. 6MWD has been largely
used as a primary end point in several short-term PAH
clinical trials. It is indeed an easy test, which does not
chestjournal.org
require any specific tools and which is well known to
physicians. Unfortunately, a meta-analysis of 22 trials on
PAH did not reveal any significant relationship between
the improvement of 6MWD and long-term outcome.36
However, a weak correlation was found between changes
in 6MWD at 3 months and long-term outcome.37
The use of composite end points has been adopted in a
number of PAH trials. Indeed, the combination of
various end points can maximize the results and
facilitate the detection of therapeutic effects without
having to increase the sample size.38
The composite end point time to clinical worsening has
been used in some major PAH trials. Although its
definition varies from trial to trial, it usually represents
the interval of time between the randomization and
mortality, hospitalization, any interventional procedures
(including transplantation), progression of the disease,
symptoms of right heart failure, and/or escalation of
medical treatment. Criteria for disease progression are a
10% to 20% decrease in the 6MWT distance compared
with baseline and an increase in the New York Heart
Association/World Health Organization functional class.
In a phase IIb, randomized, placebo-controlled,
multicenter, international study (ClinicalTrials.gov
identifier, NCT02951429; www.clinicaltrials.gov), a
combined end point will be used to evaluate the primary
efficacy of adding sildenafil to pirfenidone as a treatment
in patients affected by PH associated with IPF.
Conclusions
The European Society of Cardiology/European
Respiratory Society (ESC/ERS) guidelines for the
diagnosis and treatment of PH clearly indicate that
patients with lung disease, PH, and hypoxemia should
receive long-term oxygen treatment and that
management of the underlying lung disease should be
optimized.
Most of the clinical trials carried out on PH caused by
COPD and IPF and treated with PAH therapies have
given disappointing results. In addition, the use of drugs
approved for the treatment of PAH is not recommended
in patients with PH caused by parenchymal lung
diseases.
However, patients with severe PH not explained by the
severity of the underlying lung disease and characterized
by mild lung parenchymal abnormalities, symptoms
insufficiently explained by lung mechanical disturbances
and a hemodynamic presentation of severe PH with high
221
PVR and low cardiac index, as stated in the ESC/ERS
guidelines, may be treated according to the PAH
recommendations. In these cases, it is important to keep
in mind that the coexisting lung diseases can have
implications both for the symptoms and the response to
therapy.2
At the moment, the efficacy of antifibrotic treatments on
PH due to idiopathic interstitial pneumonia has not
been demonstrated. Future results of currently ongoing
clinical trials will provide more extensive information on
the efficacy of these drugs in combination with PAH
medications.
Acknowledgments
Financial/nonfinancial disclosures: The authors have reported to
CHEST the following: S. H. has relationships with Actelion, Roche,
Boehringer Ingelheim, and Intermune. In addition to being an
investigator in trials involving these companies, S. H. is involved in
lectures and is a member of scientific advisory boards. M. H. reports
personal fees from Actelion, Bayer, GSK, Pfizer, and Roche. None
declared (D. E.).
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