Treatment Pulmonary Hypertension

Review
Treatment of pulmonary hypertension

Marius M Hoeper, Vallerie V McLaughlin, Abdullah M Al Dalaan, Toru Satoh, Nazzareno Gali
The most common forms of pulmonary hypertension are pulmonary arterial hypertension, chronic thromboembolic
pulmonary hypertension, and pulmonary hypertension due to left-sided heart and lung disease. The treatment of
pulmonary arterial hypertension has advanced substantially over the past 20 years. Five dierent classes of drugs are
now availableie, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, soluble guanylate cyclase
stimulators, prostacyclin analogues, and prostacyclin receptor agonists. Long-term studies have provided evidence
that various combinations of these compounds improve the progression-free survival of patients with pulmonary
arterial hypertension. For patients with chronic thromboembolic pulmonary hypertension, surgical pulmonary
endarterectomy is the treatment of choice. For patients who are inoperable and have chronic thromboembolic
pulmonary hypertension, riociguat, a stimulator of soluble guanylate cyclase, has proven ecacious. Additionally,
interventional approaches could become a treatment option for these patients. For patients with pulmonary
hypertension due to left-sided heart disease or lung disease, the use of pulmonary vasodilator treatment has not been
proven to be safe and eective.
Introduction
Pulmonary hypertension, dened by a mean pulmonary
artery pressure of 25 mm Hg or more at rest,1 is a
common disorder frequently associated with various
diseases, predominantly left-sided heart disease and lung
disease. The term pulmonary arterial hypertension is
used to describe a rare subtype of pulmonary
hypertension characterised by an angioproliferative
vasculopathy aecting mainly the small pulmonary
arteries, which results in progressive pulmonary vascular
remodelling, increased pulmonary vascular resistance
and, eventually, right-sided heart failure.2,3
Haemodynamically, pulmonary hypertension is
classied as precapillary or postcapillary on the basis of
left-sided cardiac lling pressureie, the pulmonary
artery wedge pressure (PAWP) or, in the absence of
mitral stenosis, the left ventricular end-diastolic pressure.
In precapillary pulmonary hypertension, the left-sided
cardiac lling pressure is normalie, 15 mm Hg or less.
In postcapillary pulmonary hypertension, left-sided
cardiac lling pressures are elevated (>15 mm Hg). Some
patients with postcapillary pulmonary hypertension have
an additional precapillary component as indicated by a
diastolic pressure gradient (the dierence between the
diastolic pulmonary artery pressure and the PAWP) of
7 mm Hg and more or an increased pulmonary vascular
resistance (>3 Wood units or >240 dyn s cm).4
From a pathophysiological, clinical, and therapeutic
perspective, pulmonary hypertension is divided into ve
groups: pulmonary arterial hypertension; pulmonary
hypertension due to left-sided heart disease; pulmonary
hypertension due to lung disease or hypoxia; chronic
thromboembolic
pulmonary
hypertension;
and
pulmonary hypertension with unclear multifactorial
mechanisms.57 The epidemiology of these pulmonary
hypertension groups is reviewed in another Review.8
Over the past 20 years, substantial therapeutic progress
has been made for pulmonary arterial hypertension and
chronic thromboembolic pulmonary hypertension,
although no established treatments are available for most
www.thelancet.com/respiratory Vol 4 April 2016
of the other forms of pulmonary hypertension.912 This

Review summarises the present knowledge on the
management of the most common forms of pulmonary
hypertension with a particular focus on long-term trials
in the eld of pulmonary arterial hypertension and the
recent guidelines for the diagnosis and treatment of
pulmonary hypertension, published jointly by the
European Society of Cardiology (ESC) and the European
Respiratory Society (ERS).6,7
Group 1pulmonary arterial hypertension

Pulmonary arterial hypertension consists of idiopathic,
drug-associated, and heritable forms, and pulmonary
arterial hypertension associated with connective tissue
Lancet Respir Med 2016;

4: 32336
Published Online
March 11, 2016
http://dx.doi.org/10.1016/
S2213-2600(15)00542-1
See Editorial page 241
See Review page 306
See Online for podcast interview
with Marius Hoeper
Department of Respiratory
Medicine, Hannover Medical
School and German Centre for
Lung Research, Hannover,
Germany (Prof M M Hoeper MD);
Department of Internal
Medicine, University of
Michigan Health System,
Ann Arbor, MI, USA
(Prof V V McLaughlin MD);
Section of Pulmonary Medicine,
King Faisal Specialist Hospital
and Research Center, Riyadh,
Saudi Arabia (A M Al Dalaan MD);
Division of Cardiology,
Department of Medicine, Kyorin
University School of Medicine,
Tokyo, Japan (Prof T Satoh MD);
Department of Experimental,
Diagnostic and Specialty
Medicine (DIMES), University of
Bologna, Bologna, Italy
(Prof N Gali MD)
Key messages
The most common forms of pulmonary hypertension are pulmonary arterial
hypertension, chronic thromboembolic pulmonary hypertension, and pulmonary
hypertension due to left-sided heart disease and lung disease.
Five dierent classes of drugs are available to treat pulmonary arterial hypertension
ie, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, soluble guanylate
cyclase stimulators, prostacyclin analogues, and prostacyclin receptor agonists.
The SERAPHIN trial has shown improved progression-free survival with the
endothelin receptor antagonist, macitentan, in patients with pulmonary arterial
hypertension, irrespective of whether they were treatment naive or pretreated with a
phosphodiesterase-5 inhibitor.
The AMBITION study has shown improved progression-free survival in patients with
pulmonary arterial hypertension receiving initial combination therapy with
ambrisentan, an endothelin receptor antagonist, and tadalal, a phosphodiesterase-5
inhibitor, compared with monotherapy with these compounds.
For patients with chronic thromboembolic pulmonary hypertension, surgical
pulmonary endarterectomy is the preferred treatment.
For patients with chronic thromboembolic pulmonary hypertension who are
inoperable, new treatment options include balloon pulmonary angioplasty and
treatment with riociguat, a stimulator of the soluble guanylate cyclase.
Existing evidence is not sucient to establish whether pulmonary vasodilators are
safe and eective in patients (or subsets of patients) with pulmonary hypertension
due to left-sided heart disease or lung disease.
323
Review
Correspondence to:
Prof Marius M Hoeper,
Department of Respiratory
Medicine, Hannover Medical
School, 30623 Hannover,
Germany
hoeper.marius@mh-hannover.
de
324
disease, HIV infection, portal hypertension, congenital

heart disease, and schistosomiasis.5 All of these entities
share common haemodynamic features with precapillary
pulmonary hypertension, often accompanied by a low
cardiac output, and a high pulmonary vascular resistance.
The histological hallmark of pulmonary arterial
hypertension is obliteration of small pulmonary arteries
caused by proliferating endothelial cells and pulmonary
vascular smooth muscle cells.2 As a consequence, the
pulmonary vascular resistance rises, putting incremental
strain on the right ventricle.3 Left untreated, pulmonary
arterial hypertension is a progressive disease and rightsided heart failure is the most frequent cause of death in
these patients. In the US National Institutes of Health
registry, which enrolled patients between 1981 and 1985
before eective treatments became available, the median
survival was 28 years after diagnosis.13 This registry
included patients with what at that time was called
primary pulmonary hypertension, which today would be
classied predominantly as idiopathic pulmonary arterial
hypertension. In patients with pulmonary arterial
hypertension associated with connective tissue disease
and pulmonary arterial hypertension associated with
portal hypertension, survival is even worse, whereas
patients with pulmonary arterial hypertension associated
with congenital heart disease tend to have a better longterm survival.14,15
Treatment is similar for all forms of pulmonary arterial
hypertension, albeit almost all randomised controlled
trials have included predominantly patients with
idiopathic pulmonary arterial hypertension or pulmonary
disease. Generally, the main results of these trials have
been conrmed by smaller trials and case series of
patients with other forms of pulmonary arterial
hypertension.16,17
thrombosis in the aected pulmonary vessels and

because of observational data suggesting improved
survival in patients with idiopathic pulmonary arterial
hypertension receiving anticoagulation.1921 However,
clear evidence is missing and the 2015 ESC/ERS
pulmonary hypertension guidelines state that
anticoagulation might be considered in patients with
idiopathic pulmonary arterial hypertension but not in
other forms of pulmonary arterial hypertension, in which
the riskbenet ratio seems to be unfavourable.6,7,22
Vasoreactivity testing and high-dose calcium channel

blocker treatment
Most patients with pulmonary arterial hypertension
exhibit little acute haemodynamic response to pulmonary
vasodilators, such as inhaled nitric oxide. However, about
510% of these patients show distinct pulmonary
vasoreactivity with normalisation or near normalisation
of their pulmonary haemodynamics during acute
vasodilator challenge.23 These so-called responders can
have a remarkable response to high-dose calcium
channel blocker treatment with sustained improvement
or even normalisation of haemodynamics and an
excellent long-term outcome.23 Such long-term
responders are reported almost exclusively in patients
with idiopathic pulmonary arterial hypertension and
predominantly in young females. Patients with other
forms of pulmonary arterial hypertension almost never
experience long-term improvement with calcium
channel blocker treatment, even if these patients seem to
be responders during acute vasoreactivity testing.24
Hence, the present ESC/ERS guidelines recommend
pulmonary vasoreactivity testing only in patients with
idiopathic pulmonary arterial hypertension (including
heritable and drug-associated forms) but not in other
forms of pulmonary arterial hypertension, or pulmonary
hypertension.6,7
General measures and supportive treatments for

patients with pulmonary arterial hypertension
Targeted therapies
General measures such as immunisation against

inuenza and pneumococcal infection, psychosocial
support, and supervised exercise training are
recommended for patients with pulmonary arterial
hypertension.6,7 Supportive measures include home
oxygen treatment when the partial pressure of oxygen in
the arterial blood is consistently less than 60 mm Hg or
when oxygen saturation deteriorates substantially during
exercise or sleep. Iron deciency or anaemia, if present,
should be corrected.18 Diuretics are administered as
needed. The choice of agents is empirical because no
studies have compared the use of various diuretic
strategies in patients with pulmonary arterial
hypertension. The same is true for the use of
mineralocorticoid receptor antagonists, such as
spironolactone or eplerenone. Anticoagulation has been
advocated for pulmonary arterial hypertension, mainly
because of histological ndings showing in situ
Several drugs are currently approved for the treatment

of pulmonary arterial hypertension: the endothelin
receptor antagonists ambrisentan, bosentan, and
macitentan; the phosphodiesterase-5 inhibitors
sildenal and tadalal; the soluble guanylate cyclase
stimulator riociguat; the prostacyclin analogues
beraprost (in Japan and South Korea only), epoprostenol,
iloprost, and treprostinil; and the prostacyclin receptor
agonist selexipag. With the exception of macitentan and
selexipag, all available drugs for treatment of pulmonary
arterial hypertension have been approved on the basis
of short-term trials of 1224 weeks duration, which have
focused mainly on exercise capacity as assessed by
change in 6 min walk distance. The main characteristics
and key ndings of these trials are listed in table 1.
Some, but not all, of these studies showed a delay in the
time to clinical worsening, a composite endpoint that
included dierent variables (such as a decline in exercise
Review
Functional
class
improved
TTCW
improved
Main adverse events
Number of
participants
Study
duration
Primary endpoint(s)*
BREATHE-1 (bosentan vs placebo; all patients

treatment naive)25
213
12 weeks
6MWD +35 m with 125 mg of bosentan

twice daily (p<001)
Elevated liver
aminotransferases in 4%
EARLY (bosentan vs placebo; patients in functional

class II, 84% treatment naive, 16% pretreated with
sildenal)26
185
24 weeks
Improvement in PVR (p=00001), but not

in 6MWD (p=008)
Elevated liver
aminotransferases in 8%
ARIES-1 (ambrisentan vs placebo; all patients were

treatment naive)27
202
12 weeks
6MWD +51 m with 10 mg of ambrisentan

(p<0001)
Peripheral oedema and nasal

congestion
ARIES-2 (ambrisentan vs placebo; all patients were

treatment naive)27
192
12 weeks
6MWD +59 m with 5 mg of ambrisentan

(p<0001)
Nasal congestion
SUPER (sildenal vs placebo; all patients were

treatment naive)28
278
12 weeks
6MWD +45 m with 20 mg of sildenal

three times a day (p<0001)
Flushing, dyspepsia, and

diarrhoea
PACES (addition of sildenal vs placebo to

epoprostenol)29
267
16 weeks
6MWD +29 m with 80 mg of sildenal

Headache, dyspepsia, leg pain,

and nausea
PHIRST (tadalal vs placebo; 47% of the patients

were treatment naive, 53% on background
treatment with bosentan)30
405
16 weeks
6MWD +33 m with 40 mg of tadalal

daily (p<001)
Headache, myalgia, and

ushing
PATENT (riociguat vs placebo; 50% treatment naive,

44% pretreated with ERA, 6% pretreated with PCA)31
443
12 weeks
6MWD +36 m with 25 mg of riociguat

Headache, dyspepsia, and

hypotension
PATENT-PLUS (riociguat or placebo added to

sildenal)32
18
12 weeks
Maximum change in supine blood

pressure not dierent between groups
Hypotension and adverse

events, especially in the longterm extension of the study
Barst and colleagues (epoprostenol vs standard care;

all patients treatment naive)33
81
12 weeks
6MWD +47 m with 92 ng (08) per Kg of

epoprostenol (p<0003)
Jaw pain, headache, diarrhoea,

and catheter-related sepsis
AIR (inhaled iloprost vs placebo; all patients

treatment naive)34
203
12 weeks
Improvement in both functional class and

6MWD by at least 10% from baseline in
17% of patients in the iloprost group vs
5% in the placebo group (p=0007)
Flushing and jaw pain
STEP (inhaled iloprost vs placebo added to

bosentan)35
67
12 weeks
Change in 6MWD +26 m (p=0051)
Headache, coughing, jaw pain,

and ushing
COMBI (open label, addition of inhaled iloprost to

bosentan vs bosentan alone)36
40
12 weeks
Study terminated early after futility

analysis, no improvement in 6MWD
Headache, coughing, and

ushing
Simonneau and colleagues (subcutaneous

treprostinil vs placebo; all patients were treatment
naive)29
470
12 weeks
Infusion site pain, diarrhoea,

jaw pain, and ushing
FREEDOM-C1 (oral treprostinil vs placebo; patients

on background therapy with ERA,
phosphodiesterase-5 Inhibitors, or both)37
350
16 weeks
Primary endpoint of placebo-corrected

change in 6MWD at week 16 was not
met; change in 6MWD +11 m (p=007)
Headache, nausea, vomiting,

diarrhoea, ushing, and jaw
pain
FREEDOM-C2 (oral treprostinil versus placebo;

patients on background treatment with ERA,
phosphodiesterase-5 inhibitors, or both)38
310
16 weeks
Primary endpoint of placebo-corrected

change in 6MWD at week 16 was not
met; change in 6MWD +10 m (p=0089)

pain
FREEDOM-M (oral treprostinil vs placebo; all patients

were treatment naive)39
349
12 weeks

pain
TRIUMPH (inhaled treprostinil vs placebo; patients

on background therapy with ERA or
phosphodiesterase-5 inhibitors)40
235
12 weeks
Coughing, headache, and

ushing
TTCW=time to clinical worsening. 6MWD=6 min walking distance. PVR=pulmonary vascular resistance. ERA=endothelin receptor antagonists. PCA=prostacyclin receptor agonist. *Changes in 6MWD are placebo
corrected.
Table 1: Key data from randomised, controlled trials of 1224 weeks duration with drugs approved for the treatment of pulmonary arterial hypertension
capacity, admission to hospital for pulmonary arterial

hypertension, the need for additional pulmonary arterial
hypertension treatment, or a combination of outcomes).
Long-term trials
Long-term, event-driven trials entered the specialty of
pulmonary arterial hypertension only recently. In the last
3 years two such trials, COMPASS-241 and AMBITION,42

explored treatment strategies with already approved
drugs and another two, SERAPHIN43 and GRIPHON,44
assessed new compounds (table 2).
COMPASS-2 investigated the hypothesis that bosentan
added to sildenal in stable patients with pulmonary
arterial hypertension would improve long-term outcome.41
325
Review
The primary endpoint was the time to the rst morbidity

or mortality event (dened as all-cause mortality,
admission to hospital for worsening of pulmonary arterial
hypertension, initiation of intravenous prostacyclin
treatment, atrial septostomy, lung transplantation, or
clinical worsening). Secondary endpoints included
change in 6 min walk distance and change in functional
class of the disease at week 16, change in N-terminal
fragment of probrain natriuretic peptide (NT-proBNP)
over time, and all-cause mortality.
Over 6 years, the study enrolled 334 patients,
predominantly with idiopathic pulmonary arterial
hypertension (64%) or pulmonary arterial hypertension
associated with connective tissue disease (26%), who were
randomised to placebo (n=175) or bosentan (n=159). The
study did not meet its primary endpoint. A clinical
worsening event occurred in 90 (51%) patients randomised
to placebo and in 68 (43%) of the patients randomised to
bosentan (hazard ratio [HR] 083; 95% CI 058119;
p=0251). The 6 min walk distance at week 16 improved by
218 m in the bosentan group compared with the placebo
group (p=0011). NT-proBNP concentrations improved as
well. However, no improvement was noted in functional
class (HR 098; 95% CI 060161; p=100) and in allcause mortality at the end of the study (HR 0855; 95% CI
05441344, p=0497). Potential reasons for the negative
results of COMPASS-2 include insucient power
and a high number of premature discontinuations.41
Additionally, bosentan decreases sildenal plasma
concentrations by 60% to 70%,45,46 which might render
sildenal less ecacious.
Number of
participants
Mean study
duration
(treatment
group)
COMPASS-2 (bosentan added to

background treatment with
sildenal)41
334
38 months
SERAPHIN (macitentan as
monotherapy or added to
background therapy with
phosphodiesterase-5 inhibitors
or PCA)43
742
104 weeks
(macitentan
10 mg)
AMBITION (ambrisentan and

tadalal as initial combination
treatment vs monotherapy with
these compounds)42
500
73 weeks
GRIPHON (selexipag as
monotherapy or added to ERA
or phosphodiesterase-5
inhibitors, or both background
treatment)44
1156
71 weeks
(selexipag
group)
The AMBITION study explored a new treatment

strategy: initial combination treatment with the
endothelin receptor antagonist ambrisentan and the
phosphodiesterase-5 inhibitor tadalal versus monotherapy with these compounds.42 The primary endpoint
was the time from randomisation to the rst clinical
failure event, which was a composite of death; admission
to hospital for worsening of pulmonary arterial
hypertension; disease progression; or unsatisfactory longterm response, indicating that the patient was in
functional class III or IV after at least 6 months of
treatment. Secondary endpoints included the change
from baseline to week 24 in 6 min walk distance,
functional class, and NT-proBNP concentrations.
The primary analysis set comprised 500 patients with
treatment naive pulmonary arterial hypertension who
were randomly assigned to combination treatment
(n=253), or monotherapy with either ambrisentan (n=126)
or tadalal (n=121). The primary endpoint was signicantly
reduced in the combination treatment group versus the
pooled monotherapy groups (HR 050; 95% CI 035072;
p<0001) as well as both individual monotherapy groups.42
This eect was achieved mainly by a reduction in hospital
admissions (HR 037; 95% CI 022064; p<0001).
Additionally, signicant improvements were reported
with initial combination treatment at week 24 in 6 min
walk distance and NT-proBNP (both p<0001), but not in
functional class (p=024). All-cause mortality at the end of
the study was not signicantly dierent among the
treatment groups. The adverse events that were more
common with combination treatment included headache,
Primary endpoint
Key secondary endpoints
Main adverse events
Primary endpoint not met;

time to rst morbidity or
mortality event not
signicantly reduced
(HR 0831; p=025)
Improvement in 6MWD by
22 m at 16 weeks, no
improvement in functional
class, no reduction in
PAH-related admissions to
hospital
Elevated liver
aminotransferases
Macitentan reduced morbidity Reduction in PAH-related

admissions to hospital;
or mortality events (HR 055,
improvements in 6MWD and
95% CI, 039076; p<0001)
functional class
Headache,
nasopharyngitis, and
anaemia
Time to clinical failure

signicantly reduced with
initial combination treatment
(HR 05; 95% CI 035072;
p<0001)
Improvement in 6MWD
Peripheral oedema,
headache, and nasal
congestion
Delay in rst morbidity or

mortality event; HR 060
(99% CI 046078; p<0001)
Improvement in 6MWD by
12 m at 26 weeks, no
improvement in functional
class
Headache, diarrhoea,
nausea, and jaw pain
HR=hazard ratio. 6MWD=6 min walking distance. PAH=pulmonary arterial hypertension. PCA=prostacyclin receptor agonist. ERA=endothelin receptor antagonists.
Table 2: Key data from randomised, controlled, event-driven trials in pulmonary arterial hypertension
326
Review
nasal congestion, peripheral oedema, and anaemia.

Treatment discontinuations due to adverse events
occurred in 12% of the patients receiving combination
treatment, which was similar to ambrisentan (11%) and
tadalal monotherapy (12%).
SERAPHIN assessed the long-term safety and ecacy
of macitentan, a new endothelin receptor antagonist, in
patients with pulmonary arterial hypertension.43 The
primary endpoint was the time to the rst morbidity or
mortality event, which included all-cause mortality, atrial
septostomy, lung transplantation, initiation of parenteral
prostacyclin treatment, or pulmonary arterial
hypertension worsening as dened by a reduction in
6 min walk distance of at least 15% from baseline,
worsening in functional class, and need for additional
pulmonary arterial hypertension treatments. Secondary
outcome measurements included the change in 6 min
walk distance and the proportion of patients with an
improved functional class, both at 6 months of treatment.
The study enrolled 742 patients who were randomly
assigned to placebo (n=250), macitentan at 3 mg once
daily (n=250), and macitentan at 10 mg once daily
(n=242). At inclusion, 36% of the patients were treatment
naive, whereas 64% were receiving background treatment
with other pulmonary arterial hypertension drugs, most
(61%) with a phosphodiesterase-5 inhibitor. Both doses
of macitentan were reported to be eective, but
macitentan at a daily dose of 10 mg had more pronounced
eects on the primary endpoint than macitentan had at a
daily dose of 3 mg, particularly in patients receiving
background treatment. This nding was the main reason
why only the 10 mg dose has been approved for the
treatment of pulmonary arterial hypertension. The
hazard ratio for the 10 mg dose compared with placebo
was 055 (98% CI 039076, p<0001).
Worsening of pulmonary arterial hypertension was the
most frequent primary endpoint event. Risk reduction
was noted in patients who were treatment naive
(HR 045; 95% CI 028072; p<0001) as well as in
patients who were pretreated (HR 062; 95% CI
043089; p=0009), and independently of whether the
patients were presenting in functional class II or III at
inclusion. Additionally, macitentan at 10 mg per day
reduced the composite endpoint of death or admission to
hospital due to pulmonary arterial hypertension by 50%
(HR 05, 975% CI 034075; p<0001). The median
placebo-corrected improvement in 6 min walk distance
after 6 months of treatment was 22 m (p=0008) in the
10 mg macitentan group. 22% of the patients in the
macitentan group improved functional class compared
with 13% in the placebo group (p=0006). The most
frequent adverse events associated with macitentan were
headache, nasopharyngitis, and anaemia. Liver function
test abnormalities and treatment discontinuations due to
adverse events were not more frequent with macitentan
than with placebo. The number of patients who
discontinued the study drug because of adverse events
was 12% in the placebo group and 11% in the macitentan

10 mg group.
The GRIPHON study assessed the safety and ecacy
of selexipag, an oral prostacyclin receptor agonist that
was individually titrated to the highest tolerated dose.44
The primary outcome measure was the time to the rst
clinical worsening event, a composite endpoint that
included all-cause mortality or disease progression
needing atrial septostomy, lung transplantation,
intravenous prostacyclin treatment, chronic oxygen
treatment, or hospital admission. Secondary outcome
measures included the change in 6 min walk distance
after 26 weeks of treatment, the absence of worsening in
functional class after 26 weeks of treatment, and allcause mortality at the end of the study.
GRIPHON enrolled 1156 patients, most having idiopathic
pulmonary arterial hypertension (56%) or pulmonary
disease (29%). 204% of patients were treatment naive at
inclusion whereas the remaining patients were pretreated
with endothelin receptor antagonists (147%), phosphodiesterase-5 inhibitors (324%), or both (325%). The study
met its primary endpoint. The hazard ratio for selexipag
versus placebo was 060 (99% CI 046078, p<0001) and
the risk reduction was similar in patients with no
pulmonary arterial hypertension treatment at baseline as
well as in patients receiving pulmonary arterial
hypertension treatment as monotherapy or as combination
treatment. Disease progression and admission to hospital
accounted for 816% of the events. The placebo-corrected
change in 6 min walk distance was increased by 12 m
(p=0003) in the selexipag group. No signicant dierence
was reported in the proportion of patients with worsened
functional class. All-cause mortality at the end of the study
was not dierent between treatment groups (HR 097;
p=042).
Selexipag was associated with prostacyclin-type sideeects, especially headache, diarrhoea, nausea, and jaw
pain.44 During the course of the study, 143% of patients
treated with selexipag discontinued treatment because of
adverse events compared with 71% patients given the
placebo (p<0001).
Approach to pulmonary arterial hypertension therapy

The long-term trials discussed are changing the
therapeutic approach to patients with pulmonary arterial
hypertension. Previous guidelines recommended initial
monotherapy with an approved drug, followed by regular
reassessments and initiation of combination treatments
when treatment goals were not met.9,47,48 These treatment
goals varied among patients but were aimed at reaching
and maintaining functional class I or II and a
well-preserved right ventricular function.49,50
According to the 2015 ESC/ERS pulmonary hypertension guidelines,6,7 treatment decisions should be
based on risk assessments, which take place at the time
of diagnosis as well as during each follow-up visit.
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Review
Patients are classied as low, intermediate, or high risk

based on several variables (table 3).6,7 The main treatment
objective is reaching and maintaining a low risk prole.
For patients presenting at low or intermediate risk, initial
monotherapy is still deemed to be an option, and
endothelin receptor antagonists and phosphodiesterase5-inhibitors seem to have similar short-term and longterm ecacy.42,51 Initial combination therapy, in particular
with an endothelin receptor antagonist and a
phosphodiesterase-5 inhibitor, is a viable alternative.
Based on the results of AMBITION, initial combination
treatment with ambrisentan and tadalal received a
higher level of evidence and a higher grade of
recommendation than other possible combinations of
endothelin receptor antagonists and phosphodiesterase-5
inhibitors.6,7 SERAPHIN and GRIPHON suggested that
patients with pulmonary arterial hypertension who were
at low or intermediate risk had a better long-term
outcome when macitentan or selexipag, respectively,
were added to background treatments.43,44 Taken together,
AMBITION, SERAPHIN, and GRIPHON provide a
strong rationale for using initial or early combination
regimens in these patients. The evidence is particularly
robust for the combination of endothelin receptor
antagonists and phosphodiesterase-5 inhibitors.
The therapeutic role for riociguat in pulmonary arterial
hypertension is less clear. Long-term data from controlled
trials are not available, and riociguat must not be
combined with phosphodiesterase-5 inhibitors because
of the risk of hypotension and adverse events.32 The
RESPITE study (NCT02007629) is evaluating whether
patients with pulmonary arterial hypertension with an
insucient clinical response to phosphodiesterase-5
inhibitors benet from switching to riociguat. Results

are expected in mid-2016.
Inhaled and oral prostacyclin analogues have not
shown consistent improvements in exercise capacity and
clinical outcomes, especially when added to other
background treatments (table 1), so these analogues have
an ancillary role in the management of pulmonary
arterial hypertension.52,53
For high-risk patients, monotherapy is no longer
deemed to be appropriate and the present guidelines6,7
strongly recommend the use of initial double or triple
combination treatment including an intravenous
prostacyclin analogue, although the evidence for this
approach is based on uncontrolled case series.5456 The use
of intravenous prostacyclin analogues is deemed to be
mandatory in high-risk patients, as this is the only
treatment that has been shown to improve survival in
patients with severe disease.33 For patients who are
deteriorating despite optimised medical treatment, lung
transplantation is a viable treatment option and potentially
eligible patients should be referred early to a transplant
centre.57 The gure shows the present treatment algorithm
for patients with pulmonary arterial hypertension.
Group 2pulmonary hypertension due to

left-sided heart disease
Pulmonary hypertension due to left-sided heart disease is
arguably the most common type of pulmonary
hypertension and consists of three main groups
pulmonary hypertension due to left ventricular systolic
dysfunction, pulmonary hypertension due to left
ventricular diastolic dysfunction, and pulmonary
hypertension due to valvular disease.4 Pulmonary
Low risk (<5%)
Intermediate risk (510%)
High risk (>10%)
Clinical signs of right-sided heart failure
Absent
Absent
Present
Progression of symptoms
No
Slow
Rapid
Syncope
No
Occasional syncope*
Repeated syncope
WHO functional class
I and II
III
IV
6MWD
>440 m
165440 m
<165 m
Cardiopulmonary exercise testing
Peak VO2 <11 mL/min/kg

Peak VO2 >15 mL/min/kg (>65% Peak VO2 1115 mL/min/kg
predicted); VE/VCO2 slope <360 (3565% predicted); VE/VCO2 slope (<35% predicted);
VE/VCO2 slope 450
360449
NT-proBNP plasma levels
BNP <50 ng/L;

NT-proBNP <300 ng/L
BNP 50300 ng/L; NT-proBNP

3001400 ng/L
Imaging (echocardiography and CMR imaging)
Right atrium area <18 cm; no

pericardial eusion
Right atrium area 1826 cm; no or Right atrium area >26 cm;
minimal pericardial eusion
pericardial eusion
Haemodynamics
Right atrial pressure <8 mm Hg; Right atrial pressure 814 mm Hg;
cardiac index 2024 L/min/m;
cardiac index 25 L/min/m;
SvO2 6065%
SvO2 >65%
BNP >300 ng/L;

NT-proBNP >1400 ng/L
Right atrial pressure

>14 mm Hg; cardiac index
<20 L/min/m; SvO2 <60%
Most of the proposed variables and cuto values are based on expert opinion. Values might provide prognostic information and might be used to guide therapeutic decisions
but application to individual patients must be done carefully. Most of these variables have been validated mainly for idiopathic pulmonary arterial hypertension and the
cuto levels used might not necessarily apply to other forms of pulmonary arterial hypertension. 6MWD=6 min walk distance. VO2=oxygen consumption.
VE/VCO2= ventilatory ecacy for carbon dioxide. BNP=brain natriuretic peptide. NT-proBNP=N-terminal pro-brain natriuretic peptide. CMR=cardiac magnetic resonance.
SvO2=mixed venous oxygen saturation. *Occasional syncope during brisk or heavy exercise or occasional orthostatic syncope in an otherwise stable patient. Repeated
episodes of syncope, even with little or regular physical activity.
Table 3: Risk assessment in patients with pulmonary arterial hypertension by determinants of prognosis, estimated 1 year mortality6,7
328
Review
hypertension is common in all of these disorders, and is

associated with aggravated clinical symptoms and a poor
outcome. In patients with left-sided heart disease,
pulmonary hypertension presents either as isolated
postcapillary pulmonary hypertension or as postcapillary
pulmonary hypertension with a precapillary component.
Postcapillary pulmonary hypertension with a precapillary
component has been associated with particularly poor
survival and might be an important treatment target.58,59
However, there is little evidence to suggest that the drugs
used for pulmonary arterial hypertension are safe and
eective in patients with left-sided heart disease, with or
without pulmonary hypertension.
The FIRST study60 investigated the eects of intravenous
epoprostenol compared with standard treatment in
471 patients with severe congestive heart failure and a left
ventricular ejection fraction of less than 25%, a cardiac
index of 22 L/min/m2 or less, and a pulmonary artery
wedge pressure of 15 mm Hg or more. Dose titration of
epoprostenol in the catheter room resulted in a signicant
increase in cardiac index from 18 to 26 L/min/m and a
decrease in the wedge pressure from 25 mm Hg to 20 mm
Hg. Still, no improvement was noted in walk distance and
the trial was terminated early because of a trend towards
decreased survival in patients treated with epoprostenol.
Several endothelin receptor antagonists have been
investigated as treatments for left-sided heart failure but
none of them were reported to be ecacious.6164 Sideeects were common, in particular uid retention. So
far, only one randomised controlled trial specically
addressed the safety and ecacy of an endothelin
receptor antagonist, bosentan, in patients with heart
failure (left ventricular ejection fraction <35%) and
presumed pulmonary hypertension as assessed by
echocardiography (systolic pulmonary artery pressure
>40 mm Hg).65 The primary endpoint was the change in
the systolic pulmonary artery pressure after 20 weeks of
treatment. The study enrolled 94 patients who were
randomly assigned to bosentan (n=60) or placebo (n=34).
At the end of the study, no dierences were reported
between both treatment groups in systolic pulmonary
artery pressure (p=024) or in other echocardiographic
variables. More patients in the bosentan group had
serious adverse events, mainly weight gain and oedema,
and 20 patients prematurely discontinued the study drug
compared with three patients in the placebo group.
Phosphodiesterase-5 inhibitors, especially sildenal,
have also been assessed in patients with left-sided heart
disease, with and without pulmonary hypertension. To
many researchers, these drugs are of particular interest
in these patients because the drugs not only reduce the
pulmonary vascular resistance but might also improve
left ventricular systolic and diastolic function.6671
However, data from randomised controlled trials7274 are
sparse and have yielded conicting results.
In a double-blind, single centre study, Guazzi and coworkers72 randomly assigned 44 patients with heart
General measures*
Pulmonary arterial hypertension
confirmed by expert centre
Treatment-naive
patient
Supportive treatment
Calcium channel
blocker therapy
Acute vasoreactivity test

Vasoreactive
Non-vasoreactive
Low or intermediate risk
Initial monotherapy with

pulmonary arterial
hypertension approved drugs
Patient already
on treatment
Initial oral combination

of pulmonary arterial
hypertension approved drugs
High risk
Initial combination treatment

including intravenous
prostacyclin analogue
Inadequate clinical response
Consider referral for

lung transplantation
Double or triple sequential combination treatment

with pulmonary arterial hypertension approved drugs
Inadequate clinical response
Consider listing for lung transplantation
Figure: Treatment algorithm showing the therapeutic approach to patients with pulmonary arterial
hypertension
Modied from Gali and colleagues6,7 with permission by Oxford University. *General measures include
immunisations, psychosocial support, supervised exercise training, and avoidance of pregnancy. Supportive
measures include the use of diuretics and oxygen and iron supplementation as needed. Initial combination with
ambrisentan plus tadalal has proven to be superior to initial monotherapy with ambrisentan or tadalal in delaying
clinical failure, dened as time to the rst occurrence of a composite of death, admission to hospital for worsening
of pulmonary arterial hypertension, disease progression, or unsatisfactory long-term clinical response, but other
combinations of endothelin receptor antagonists and phosphodiesterase-5 inhibitors should be considered as well.
Intravenous epoprostenol should be prioritised because it has reduced 3 month mortality in patients with
high-risk pulmonary arterial hypertension. Intermediate or high risk according to the criteria depicted in table 3.
failure with preserved ejection fraction and pulmonary

hypertension, most of them postcapillary with a
precapillary component, to sildenal at a dose of 50 mg
given three times daily (n=22) or placebo (n=22). After
12 months of treatment, haemodynamics were
unchanged in the placebo group. In the sildenal group,
mean pulmonary artery pressure decreased from
39 mm Hg to 21 mm Hg, right atrial pressure decreased
from 23 mm Hg to 9 mm Hg, PAWP decreased from
22 mm Hg to 18 mm Hg, and pulmonary vascular
resistance decreased from 39 Wood units to 10 Wood
units (all p<001 vs baseline and vs placebo). Data for
drug safety and tolerability were not reported other than
that none of the patients receiving sildenal
discontinued treatment prematurely. Additionally, the
elevated baseline right atrial pressure (23 mm Hg)
raises doubts about the appropriate dose of diuretics at
inclusion.
329
Review
In the RELAX trial,73 216 patients with heart failure and

preserved ejection fraction were randomly assigned to
placebo (n=103) or sildenal (n=113) at a daily dose of
20 mg for 12 weeks followed by 60 mg daily for 12 weeks.
These patients did not undergo right heart catheterisation
and did not necessarily have pulmonary hypertension.
After 24 weeks of treatment, no changes were noted in
peak oxygen consumption, 6 min walk distance, or
quality of life.73 The numbers of patients who had adverse
or serious adverse events were similar in both groups.
Three deaths were noted in the sildenal group as
compared with none in the placebo group.
Hoendermis and co-workers74 published the results of a
single-centre, randomised, double-blind study with
sildenal in 52 patients with pulmonary hypertension
due to heart failure with preserved ejection fraction. Most
of these patients had isolated postcapillary pulmonary
hypertension without a precapillary component. The
sildenal dose was gradually titrated to 60 mg given three
times per day. After 12 weeks of treatment, sildenal had
no benecial eects compared with placebo on mean
pulmonary artery pressure, cardiac output, and peak
oxygen uptake.74
Two randomised controlled trials with riociguat have
been done in patients with left heart disease and
pulmonary hypertension.75,76 The LEPHT study75 enrolled
patients with pulmonary hypertension due to left
ventricular systolic dysfunction. The primary outcome
was the change at week 16 in the mean pulmonary artery
pressure. Overall, 201 patients with a left ventricular
ejection fraction of 40% or less and a mean pulmonary
artery pressure of 25 mm Hg or more were randomly
assigned to various target doses of riociguat (05 mg,
10 mg, or 20 mg three time per day) or placebo. The
primary endpoint was not met, but treatment with
riociguat at a dose of 20 mg three times a day increased
cardiac output and stroke volume and decreased
pulmonary and systemic vascular resistances.75 The
haemodynamic eects achieved with lower dosages of
riociguat did not reach statistical signicance. After
16 weeks of treatment, none of the riociguat doses
studied had led to signicant improvements in 6 min
walking distance, functional class, or NT-proBNP. The
most frequently reported adverse events associated with
riociguat were nausea, diarrhoea, headache, dizziness,
and hypotension. Three deaths were reported in the
riociguat group as compared with none in the placebo
group.
The DILATE-1 study76 assessed the acute haemodynamic
eects of riociguat given as a single dose of 05 mg,
10 mg, or 20 mg compared with placebo in patients
with pulmonary hypertension due to heart failure with
preserved ejection fraction. Measurements took place
over 6 h after study drug administration. In this setting,
riociguat had no signicant eect on the mean
pulmonary artery pressure but improved stroke volume
(p=0.04) and cardiac index (p=0.03).
330
Two randomised controlled, phase 2 studies have been

implemented with vericiguat, another stimulator of the
soluble guanylate cyclase, one in patients with left
ventricular systolic dysfunction (SOKRATES-REDUCED;
NCT01951625)77 and one in patients with left ventricular
diastolic
dysfunction
(SOKRATES-PRESERVED;
NCT01951638). SOKRATES-REDUCED was mainly a
dose-nding study that enrolled 456 patients with heart
failure and reduced ejection fraction. The patients were
randomly assigned to placebo or vericiguat at target
doses of 125 mg, 25 mg, 5 mg, or 10 mg per day.77 The
primary endpoint was the change from baseline to
week 12 in serum NT-proBNP in the pooled three highest
dose vericiguat groups. This endpoint was not met. An
exploratory secondary analysis suggested that higher
doses of vericiguat were associated with greater
reductions in NT-proBNP, improved left ventricular
ejection fraction, and numerically, but not statistically
signicant, lower rates of admission to hospital. A larger,
phase 3 study will be needed to establish whether
vericiguat has benecial long-term eects in patients
with heart failure and reduced ejection fraction. Results
of SOKRATES-PRESERVED are expected by mid-2016.
Existing trials with pulmonary vasodilators in patients
with heart failure with preserved ejection fraction have
yielded conicting results. The main lesson from the
FIRST study was that improved haemodynamics do not
necessarily translate into improved symptoms or
improved outcomes,60 raising the question whether
haemodynamics are appropriate endpoints for proof-ofconcept studies in this patient population. In fact, these
results are reminiscent of the experiences with
phosphodiesterase-3 inhibitors in patients with left heart
failure that also showed short-term improvements in
haemodynamics but detrimental long-term eects on
survival.78
The endothelin receptor antagonists studied so far in
patients with left heart disease have also not yielded
clinical benets, but have been associated with a high rate
of side-eects, especially uid retention.63,65 However,
most of these compounds have been studied in nonselected cohorts of patients with left heart disease and not
explicitly in patients with left heart disease and combined
precapillary and postcapillary pulmonary hypertension
identied by right heart catheterisation. Such patients are
enrolled into the MELODY-1 study, a phase 2 trial
assessing the safety and ecacy of macitentan
(NCT02070991). The results are expected in 2016.
Phosphodiesterase-5 inhibitors and riociguat still hold
promise for the treatment of pulmonary arterial
hypertension, but long-term event-driven trials in well
characterised cohorts are needed to establish if and when
these drugs are benecial in patients with left heart
disease.
At present, the use of drugs approved for pulmonary
arterial hypertension is not recommended for patients
with pulmonary hypertension due to left heart disease.
Review
Patients with combined precapillary and postcapillary

pulmonary hypertension should be referred to expert
centres for individual treatment decisions.6,7
Group 3pulmonary hypertension due to lung

disease
After left heart disease, lung diseases are the second
most common cause of pulmonary hypertension,
particularly chronic obstructive pulmonary disease
(COPD) and interstitial lung disease. Patients with
advanced disease stages are more often aected, but
pulmonary hypertension might also develop in patients
with mild lung function abnormalities and no tight
correlation exists between impairment in lung function
and severity of pulmonary hypertension. In COPD as
well as in Interstitial lung disease, the development of
pulmonary hypertension is associated with worsening
symptoms, impaired gas exchange, and poor survival.7981
Hence, a rationale to use drugs targeting pulmonary
hypertension exists in this patient population but, as in
left-sided heart disease, no compelling evidence is
available that such treatments are safe and eective in
patients with pulmonary hypertension due to lung
disease.
Pulmonary vasodilators in patients with COPD

Stolz and co-workers82 randomly assigned 30 patients
with severe COPD to bosentan or placebo. These patients
did not have pulmonary hypertension at rest, but the
authors reasoned that they were prone to pulmonary
hypertension on exercise, which was the rationale to
study bosentan. After 12 weeks, no improvements were
reported in 6 min walking distance, maximum oxygen
uptake, and systolic pulmonary artery pressure estimated
by echocardiography, while arterial oxygen pressure
dropped and quality of life deteriorated.82 Similar ndings
were reported in a randomised crossover trial with
sildenal in patients with COPD and emphysema, but
without pulmonary hypertension.83 Several short-term
trials with sildenal in patients with COPD showed
improved haemodynamics but worsened oxygenation
and no eects on exercise capacity.8386
A randomised placebo-controlled trial assessed the use
of tadalal in patients with COPD and suspected
pulmonary hypertension based on a systolic pulmonary
artery pressure >30 mm Hg, as estimated by
echocardiography.87 The primary endpoint was the
change in 6 min walk distance after 12 weeks of therapy.
A total of 120 patients were randomised to receive
tadalal at a dose of 10 mg once daily (n=60) or placebo
(n=60). The primary endpoint was not met as the
changes in 6 min walk distance at week 12 were virtually
identical in both groups (placebo-corrected change in
6 min walk distance 05 m; 95% CI 116 to 125,
p=0937). Several echocardiographic variables suggested
improvements in pulmonary artery pressure and right
ventricular function, but changes in NT-proBNP levels
did not dier between the two groups. The most

common side-eects related to tadalal were headache
and dyspepsia. Peripheral oxygen saturations did not
change with tadalal treatment.
Pulmonary vasodilators in patients with interstitial

lung disease
At least ve randomised controlled trials have assessed
the eects of endothelin receptor antagonists in patients
with interstitial lung disease, three with bosentan, and
one each with ambrisentan and macitentan.8892 These
studies were targeting pulmonary brosis, not pulmonary
hypertension, but none of them reported positive eects.
The studies using bosentan and macitentan did not show
an eect on outcome, whereas the ARTEMIS-IPF trial
was terminated early because of an increased rate of
disease progression, admissions to hospital for
respiratory reasons, and deaths in patients receiving
ambrisentan.91
A randomised controlled trial specically addressed the
use of bosentan in patients with pulmonary hypertension
due to interstitial lung disease.93 In this study, patients
with interstitial lung disease and a catheter-based
diagnosis of pulmonary hypertension were randomly
assigned 2:1 to bosentan or placebo. The primary
outcome measure was the change in the pulmonary
vascular resistance index after 16 weeks of treatment.
The study enrolled 60 patients (40 to bosentan, and 20 to
placebo) but only 39 were available for a repeat right
heart catheterisation (25 in the bosentan group and 14 in
the placebo group). The study reported no signicant
eects of bosentan on pulmonary haemodynamics,
symptoms, functional class, or deaths.
The STEP-IPF study94 addressed the use of sildenal in
patients with advanced idiopathic pulmonary brosis
and a low diusion capacity (less than 35% of the
predicted value). This cuto value was chosen to enrich
the study with patients having a higher likelihood of
concomitant pulmonary hypertension, but right-sided
heart catheterisations were not part of the protocol.
A total of 180 patients were randomly assigned to
sildenal at a dose of 20 mg administered three times
daily (n=89) or placebo (n=91). The primary endpoint was
the proportion of patients with 20% or greater
improvement in 6 min walk distance after 12 weeks of
treatment. This endpoint was met in 10% of the patients
in the sildenal group and in 7% of the patients in the
placebo group (p=039). Statistically signicant
improvements were modest in arterial oxygen saturation,
diusion capacity, Borg dyspnoea index, and quality-oflife scores. Adverse events and serious adverse events
were similar in both groups.
A small, non-controlled phase 2A study of riociguat in
22 patients with pulmonary hypertension due to
interstitial lung disease has been completed.95 This study
showed an increase in cardiac output along with
decreases in pulmonary and systemic vascular resistance
331
Review
after 12 weeks of treatment. Arterial oxygen tension

deteriorated whereas 6 min walk distance increased by
25 m. During the rst 12 months of therapy, 13 of
22 patients discontinued the study drug, most because of
adverse events. A larger phase 2B trial (RISE-IIP;
NCT02138825) is assessing the eects of riociguat on
6 min walk distance and other outcome measures in
patients with pulmonary hypertension due to interstitial
lung disease. Results are expected in 2017.
None of the trials that have been done so far with
pulmonary vasodilators in patients with lung disease
have shown convincing evidence suggesting ecacy.
However, all of the trials had various limitations
including sample size, duration, selection of endpoints,
and absence of invasive haemodynamics.
During the 5th World Symposium on Pulmonary

Hypertension, held in 2013 in Nice, France, a working
group proposed criteria for severe pulmonary
hypertension in patients with chronic lung disease.
Severe pulmonary hypertension was dened by a mean
pulmonary artery pressure of 35 mm Hg or more, or a
mean pulmonary artery pressure of 25 mm Hg or more,
together with a cardiac index below 20 L/min/m at
rest.79 This denition was not based on any evidence but
on the notion that such severe forms of pulmonary
hypertension are rarely encountered in patients with
lung disease and that this extent of pulmonary
hypertension would be expected to cause circulatory
restriction contributing to impaired exercise capacity. So
far, no randomised controlled trials have assessed the
Phase
Intervention
Comments
ARROW (NCT02234141)
Safety, ecacy, and dose nding of GS-4997, an ASK1 inhibitor; primary

endpoint is change in PVR from baseline to week 24
Estimated completion date is

August, 2016
LARIAT (NCT02036970)
2A
Estimated study completion date is

Dose-nding study with bardoxolone methyl, a compound with antiinammatory and antiproliferative properties, in patients with pulmonary December, 2016
arterial hypertension or group III and V pulmonary hypertension; primary
endpoint is change in 6MWD from baseline to week 16
FK-506, TransformPAH
(NCT01647945)
2A
Dose nding study assessing the safety and ecacy of tacrolimus in

patients with pulmonary arterial hypertension
Results have been published101
RESPITE (NCT02007629)
3B
Open label study addressing safety and ecacy of riociguat in patients

with an insucient clinical response to phosphodiesterase-5 inhibitors;
primary endpoint is change in 6MWD from baseline to week 24
Estimated completion date is June,

2016
TRITON (NCT02558231)
3B
Ecacy and safety of initial triple combination treatment with

macitentan, tadalal, and selexipag vs double combination treatment
with macitentan and tadalal; primary endpoint is change in PVR from
baseline to week 26
Planned study start is January,

2016; planned completion date is
December, 2018
APD811 (NCT02279160)
Safety and ecacy of APD811, an oral prostaglandin I receptor agonist;

primary endpoint is change in PVR from baseline to week 22
Estimated primary completion

date is August, 2016
FREEDOM-ev (NCT01560624)
3B
Safety and ecacy of oral treprostinil in patients receiving background

monotherapy with an ERA or a phosphodiesterase-5 inhibitors; primary
endpoints are change in 6MWD from baseline to week 24 and time to
clinical worsening during long-term follow-up

August, 2016
INOvation (NCT not available)
Safety and ecacy of inhaled nitric oxide; primary endpoint is change in

6MWD from baseline to week 18
Enrolment expected to start in

2016
Pulmonary arterial hypertension
Pulmonary hypertension due to left-sided heart disease

MELODY-1 (NCT02070991)
Safety and ecacy of macitentan in patients with pulmonary

hypertension due to left heart failure with preserved ejection fraction;
primary outcome measure is safetyie, the incidence of uid retention or
worsening in functional class
Completion date is February, 2016

(awaiting completed data)
SOCRATES-PRESERVED
(NCT01951638)
Safety and ecacy of vericiguat in patients with pulmonary hypertension

due to heart failure with preserved ejection fraction; primary outcome
measures are changes in serum NT-proBNP and left atrial volume
Results expected by May, 2016
Pulmonary hypertension due to lung disease

RISE-IIP (NCT02138825)
Estimated primary completion

Safety and ecacy of riociguat in patients with idiopathic interstitial
pneumonias and pulmonary hyperternsion; primary endpoint is change in date is January, 2017
6MWD from baseline to week 26
Chronic thromboembolic pulmonary hypertension

MERIT-1 (NCT02021292)
24 week, placebo-controlled study with macitentan in patients with

inoperable chronic thromboembolic pulmonary hypertension; primary
endpoint is change in PVR at week 16

June, 2016
ASK1=apoptosis signal-regulating kinase-1. ERA=endothelin receptor antagonist. PVR=pulmonary vascular resistance.
Table 4: Selected recently published or ongoing clinical trials in pulmonary hypertension
332
Review
eects of pulmonary vasodilators in patients with lung

disease fullling these criteria.
Group 4chronic thromboembolic pulmonary

hypertension
Chronic thromboembolic pulmonary hypertension has
been reviewed recently in this journal.96 Hence, the
treatment of chronic thromboembolic pulmonary
hypertension is summarised only briey here and readers
are referred to the previous article for detailed information.
Surgical pulmonary endarterectomy is the preferred
treatment option for patients with chronic thromboembolic
pulmonary hypertension.10,97 For patients who are not
candidates for surgery, interventional balloon pulmonary
angioplasty is an emerging treatment option.98,99 Riociguat
is the only drug approved for patients with inoperable
chronic thromboembolic pulmonary hypertension or
residual postoperative disease.100 Other classes of drugs
might be used with a lower grade of recommendation.6,7
Group 5pulmonary hypertension with unclear

multifactorial mechanisms
Group 5 contains various and heterogeneous forms of
pulmonary hypertension, most of which have not been
studied in randomised controlled trials. Hence, specic
treatment recommendations cannot be made and these
patients should be referred to expert centres for
individual treatment decisions.
Future developments
Most of the present clinical studies in groups 25 use
compounds that have already been shown to be eective in
the treatment of pulmonary arterial hypertension,
although clinical trials in pulmonary arterial hypertension
focus on combination treatments and on drugs that
reverse pulmonary vascular remodelling (table 4). One
such approach has already been tested with imatinib, an
inhibitor of various receptor tyrosine kinases. In patients
with pulmonary arterial hypertension, imatinib improved
haemodynamics, NT-proBNP, and 6 min walking distance,
but not disease progression and survival.102,103 This nding,
together with safety concerns, which included an increased
risk of subdural haematoma, led to a stop of the clinical
development programme.104 Nevertheless, ecacy was
suggested in some patients, and case reports have shown
that disease remission might be possible with long-term
imatinib treatment.105 Hence, tyrosine kinase inhibitors
remain targets of future research.
In addition to medical treatments, an interventional
approach involving pulmonary artery denervation is
being researched for various forms of pulmonary
hypertension.106,107 The available data do not yet allow
prediction of the future role of this strategy.
Conclusions
In pulmonary arterial hypertension, substantial
therapeutic progress has been made over the past
Search strategy and selection criteria

We identied references for this Review through searches of
PubMed from 1970 to September, 2015, by using the terms
pulmonary hypertension, pulmonary arterial hypertension,
and treatment. MMH reviewed all abstracts of the identied
publications and selected articles of interest for this Review.
These articles and relevant references cited in those articles were
reviewed. Particular attention was given to randomised
controlled trials. Studies on paediatric patient populations were
not considered. Only articles published in English were included.
20 years. Five classes of drugs (ie, endothelin receptor

antagonists, phosphodiesterase-5 inhibitors, soluble
guanylate cyclase stimulators, prostacyclin analogues
and prostacyclin receptor agonists) have been approved
to treat this condition. All of these compounds are
eective as monotherapies, but recent studies have
provided compelling evidence that initial or early
combination regimens improve the progression-free
survival of patients with pulmonary arterial hypertension.
Various treatment options are also available for
chronic thromboembolic pulmonary hypertension, with
pulmonary endarterectomy remaining the preferred
treatment. For inoperable patients, riociguat was the rst
drug to be approved for patients with inoperable chronic
thromboembolic pulmonary hypertension or persistent
or recurrent pulmonary hypertension after pulmonary
endarterectomy, and balloon pulmonary angioplasty
might become a new treatment option.
Whether patients or some subgroups of patients with
pulmonary hypertension due to left heart disease or lung
disease benet from pulmonary vasodilator treatment is
still unclear. The clinical trials completed so far have not
yielded conclusive results. Randomised controlled, longterm studies in patients presenting with clinically
signicant pulmonary hypertension are needed to dene
the role of pulmonary vasodilators in these patient
populations.
Contributors
MMH conceived the idea of this Review and was responsible for its
overall content. VVM, AMA, TS, and NG assisted with writing, editing,
and created part of the tables.
Declaration of interests
AMA reports funding for a pulmonary hypertension registry at King
Faisal Specialist Hospital from Actelion, outside of this Review. NG and
MMH received personal fees from Actelion, Bayer, GSK, and Pzer.
VVM received grants and personal fees from Actelion, Bayer, Gilead,
Ikaria, and United Therapeutics, and grants from Novartis. TS received
personal fees from Actelion. This Review is independent of any
inuence from pharmaceutical companies and has been written by the
authors without any third-party support.
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Treatment Pulmonary Hypertension

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Treatment Pulmonary Hypertension

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Review

Treatment of pulmonary hypertension

of the other forms of pulmonary hypertension.912 This

Group 1pulmonary arterial hypertension

Lancet Respir Med 2016;

disease, HIV infection, portal hypertension, congenital

thrombosis in the aected pulmonary vessels and

Vasoreactivity testing and high-dose calcium channel

General measures and supportive treatments for

General measures such as immunisation against

Several drugs are currently approved for the treatment

Main adverse events

BREATHE-1 (bosentan vs placebo; all patients

6MWD +35 m with 125 mg of bosentan

EARLY (bosentan vs placebo; patients in functional

Improvement in PVR (p=00001), but not

ARIES-1 (ambrisentan vs placebo; all patients were

6MWD +51 m with 10 mg of ambrisentan

Peripheral oedema and nasal

ARIES-2 (ambrisentan vs placebo; all patients were

6MWD +59 m with 5 mg of ambrisentan

SUPER (sildenal vs placebo; all patients were

6MWD +45 m with 20 mg of sildenal

Flushing, dyspepsia, and

PACES (addition of sildenal vs placebo to

6MWD +29 m with 80 mg of sildenal

Headache, dyspepsia, leg pain,

PHIRST (tadalal vs placebo; 47% of the patients

6MWD +33 m with 40 mg of tadalal

Headache, myalgia, and

PATENT (riociguat vs placebo; 50% treatment naive,

6MWD +36 m with 25 mg of riociguat

Headache, dyspepsia, and

PATENT-PLUS (riociguat or placebo added to

Maximum change in supine blood

Hypotension and adverse

Barst and colleagues (epoprostenol vs standard care;

6MWD +47 m with 92 ng (08) per Kg of

Jaw pain, headache, diarrhoea,

AIR (inhaled iloprost vs placebo; all patients

Improvement in both functional class and

Flushing and jaw pain

STEP (inhaled iloprost vs placebo added to

Change in 6MWD +26 m (p=0051)

Headache, coughing, jaw pain,

COMBI (open label, addition of inhaled iloprost to

Study terminated early after futility

Headache, coughing, and

Simonneau and colleagues (subcutaneous

Change in 6MWD +16 m (p=0006)

Infusion site pain, diarrhoea,

FREEDOM-C1 (oral treprostinil vs placebo; patients

Primary endpoint of placebo-corrected

Headache, nausea, vomiting,

FREEDOM-C2 (oral treprostinil versus placebo;

Primary endpoint of placebo-corrected

Headache, nausea, vomiting,

FREEDOM-M (oral treprostinil vs placebo; all patients

Change in 6MWD +26 m (p=00001)

Headache, nausea, vomiting,

TRIUMPH (inhaled treprostinil vs placebo; patients

Change in 6MWD +20 m (p=00004)

Coughing, headache, and