195

Review

Chronic thromboembolic pulmonary

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hypertension a diagnostic and

therapeutic update
Hans Stricker

Angiology, Ospedale La Carit, Locarno, Switzerland

Summary: Chronic thromboembolic pulmonary hypertension (CTEPH), an important cause of severe pulmonary hypertension, is still underdia-
gnosed, mainly due to the insufcient use of V/Q scannning in patients with pulmonary hypertension. This article reviews the current diagnostic
approach and discusses the therapeutic options in this particular form of pulmonary hypertension. Every patient with CTEPH should undergo
an evaluation in a specialised centre with experience in pulmonary arterial endarteriectomy (PEA) as the potentially curative surgical tech-
nique. Partly unresolved questions regard the status of the recently described percutaneous transluminal pulmonary angioplasty and the best
medical treatment in patients with inoperable or recurrent/persistent pulmonary hypertension after PEA.

Key words: Chronic thromboembolic pulmonary hypertension, diagnosis, therapy, pulmonary thrombarteriectomy, riociguat

Introduction
Chronic thromboembolic pulmonary hypertension (CTEPH)
has been classified as a separate entity (group 4) within the
realm of pulmonary hypertension, although it shares some
important similarities with pulmonary artery hyperten-
sion (PAH) at the level of small vessel changes. The main
reasons for this are the potential curability which is unique
for patients suffering from pulmonary hypertension, and
an apparently evident pathophysiological mechanism with
its history of venous thromboembolism. Several reviews
on this topic were recently published [13], which include
the findings discussed at the last World Symposium on
Pulmonary Hypertension in Nice 2013. The aim of this ar-
ticle is to review the pathophysiological characteristics, the
diagnostic work-up and the current therapeutic options of
the disease.
Denition
CTEPH is defined as precapillary pulmonary hyperten-
sion by invasive right heart catheterisation with a mean
pulmonary artery pressure at rest 25 mm Hg and a
mean pulmonary arterial wedge pressure 15 mm Hg
and documented chronic/organised flow-limiting
thromboemboli in the elastic pulmonary arteries (main,
lobar, segmental, subsegmental) after at least 3 months
of effective anticoagulation [1]. Risk factors for the de-
velopment of CTEPH are inadequate anticoagulation,
recurrent thromboembolism and occlusion of proximal
pulmonary arteries. The condition is associated with lu-
pus anticoagulants and/or antiphospholipid antibodies,
and with elevated FVIII in blood plasma [5]. Other risk
factors include splenectomy, ventriculoatrial shunts, in-
fected pacemakers, chronic inflammatory conditions,
non-O blood groups, thyroid replacement, and malig-
nancy [6].

Epidemiology
The incidence of CTEPH after a documented venous
thromboembolism varies by a factor of 20 among the stud-
ies (from 0.4 to 9.1, (1)) but seems to be <1% if only the
cases after a documented pulmonary embolism are con-
sidered. The difference in data may be due to referral bias,
the difficulty distinguishing between acute PE and CTEPH
on imaging, and a specific patient history of the acute
event. In a large European registry, only 3 out of 4 patients
with CTEPH reported a history of PE [4].
Pathogenic mechanisms
After an episode of acute pulmonary embolism, complete
resolution may be achieved in 708 5% of all patients 6 to
12 months after initial PE diagnosis with partial resolution
in the vast majority of the remaining patients [rev. in 7].
From V/Q scintigraphic studies, we know that the resolu-
tion of thrombi appears to reach a plateau after 3 months
of adequate treatment [rev. in 7]. The exact mechanisms

2016 Hogrefe Vasa (2016), 45 (3), 195 199

DOI 10.1024/0301-1526/a000525
 196
why thromboemboli will eventually be transformed in fi-
brotic tissue that encroaches the lumen of the pumonary
vessels in up to 30% of patients is not known. Among the
factors for poor thrombus clearance, abnormal genetic
variants of fibrinogen, predisposing pulmonary endotheli-
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al cell abnormalities, impairments in the angiogenesis pro-
cess, and bacterial infection of fresh thrombi have been
suggested to play a role [7]. Classic thrombophilia includ-
ing antithrombin deficiency, protein C deficiency, protein
S deficiency, factor V Leiden, and plasminogen deficiency
is not found more frequently in patients with CTEPH than
in patients with pulmonary embolism who do not develop
CTEPH, and anomalies in circulating plasmatic fibrinolyt-
ic factors are not involved [8, 9]. Besides the territories
with unresolved thromboemboli, the development of
CTEPH is characterised by involvement of the small pul-
monary arteries though a remodelling, which includes in-
timal thickening, medial hypertrophy, and plexiform le-
sions, not only in areas that are affected but also in those
that are spared by thromboembolic occlusion. It is by this
type of pulmonary arteriopathy that CTEPH closely re-
sembles the histopathology of patients with idiopathic
PAH with the occurrence of in situ thrombosis caused by a
dysfunctional endothelium that loses the anticoagulant
properties which usually prevent the intravascular clotting
of blood material. Due to this distal pulmonary vascular
remodelling specific for CTEPH, pulmonary artery pres-
sure rises disproportionally to what could have been ex-
pected by the amount of areas with unresolved thrombi.
Support for this hypothesis is provided by the lack of cor-
relation between pulmonary artery pressure and the de-
gree of angiographic pulmonary vascular bed obstruction,
by the progress of pulmonary hypertension without recur-
rent embolism, and by the higher pulmonary vascular re-
sistance in CTEPH patients compared to those with acute
PE and a similar obstruction index [7]. A large burden of
small vessel arteriopathy constitutes the main limit in
haemodynamic improvement after pulmonary thromben-
darterectomy and offers the rationale for pulmonary vaso-
dilator therapy in some CTEPH patients with prevalent
distal disease [6].
Figure 1. Pulmonary ventilation/perfusion scintigraphy. The perfusion
of the patient shows patchy central and wedge-shaped peripheral de-
fects of both lungs.
Vasa (2016), 45 (3), 195 199
H. Stricker: CTEPH update
In summary, the mechanisms depicted above in patients
after acute pulmonary embolism could represent a continu-
um of events that may, in rare instances, result in the clinical
entity of CTEPH, which would then be the final stage of that
which Klok et al. called a post-PE syndrome [7].
Symptoms
The median age of patients with CTEPH is 63 years [4];
although patients with CTEPH can present at any age, it is
rare in childhood. Both sexes are equally affected. CTEPH
is less frequent than pulmonary artery hypertension
(PAH). In a recently published report from the Swiss Regis-
try, CTEPH was diagnosed roughly half as frequently as
PAH (in 249 vs. 549 patients or 45%); interestingly, the
quote increased when comparing the diagnoses in the
years from 2000 to 2004 with those from 2009 to 2012
(from 35% to 58%, p=0.01), which could be the result of a
qualitatively improved diagnostic work-up by better ad-
herence to guidelines recommending V/Q scanning [10].
Symptoms of dyspnoea, fatigue, chest pain, syncope, pe-
ripheral oedema, and palpitations are unspecific, and di-
agnosis is often delayed. After a documented episode of
pulmonary embolism, a period of honeymoon with ab-
sence of symptoms is typically seen, after which dyspnoea
reappears. Haemoptysis occurs more frequently in CTEPH
compared with idiopathic PAH (4.8% versus 0.6%) [11].
Diagnosis
Given the unspecific nature of the symptoms, more common
pathologic conditions are frequently diagnosed. Conse-
quently, if simple diagnostic techniques such as chest radi-
ography or pulmonary function tests do not support clinical
settings such as COPD, asthma or deconditioning, pulmo-
nary hypertension should be considered. The subsequent
diagnostic work-up includes echocardiography and meas-
urement of BNP levels as a biomarker for right heart dys-
function. In fact, normal N-terminal proBNP together with
non-suspect ECG have been proposed as a means to exclude
CTEPH 6 months after a pulmonary embolism [12]. If echo-
cardiography suggests pulmonary hypertension, the subse-
quent diagnostic measures will follow in a step-wise fashion
[13]. Ventilation/perfusion scanning (V/Q scanning, Fig. 1)
with a negative predictive value of 98%, a sensitivity rate
of 96% and specificity rate of 90% for the detection of
CTEPH, is essential in distinguishing pulmonary hyperten-
sion from CTEPH. Ensuing right-heart catheterisation, ide-
ally combined with pulmonary angiography which is needed
to evaluate operability, will confirm pulmonary hyperten-
sion and assess its gravity. Computed tomographic pulmo-
nary angiography (Fig. 2) is widely used to provide confirma-
tory information, but this technique cannot be used to
exclude CTEPH (contrarily to V/Q scanning) or to be a sub-
2016 Hogrefe
 H. Stricker: CTEPH update 197

stitute for invasive angiography, due to a low 51% sensitivity

in diagnosing CTEPH. V/Q scanning is reportedly under-
used in the diagnostic work-up of pulmonary hypertension
(3), and efforts have to be made to improve adherence to di-
agnostic guidelines.
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Catheter-based selective pulmonary angiography (Fig. 3)

is considered the gold-standard diagnostic tool for confir-
mation of CTEPH. It can be used to assess the extent and
distribution of disease which are essential data that can
provide the patients eligibility for PEA. Typical angio-
graphic defects represent organised and recanalised
thrombi following an acute thromboembolic event. These
include pulmonary artery webs or bands, intimal irregu-
larities, abrupt narrowing of the pulmonary arteries, proxi-
mal obstruction and pouch defects, and are very distinct
from those observed in acute PE.
Among newer diagnostic techniques magnetic reso-
nance pulmonary angiography may have a role in the func-
tional assessment of the right heart and the pulmonary
circulation and could play a role in pre- and post-operative
assessment of right ventricular function in the future, but Figure 2. CT- pulmonary angiography. This 70-year-old patient was di-
more expertise is needed for this technique confined to agnosed with pulmonary hypertension (mean pulmonary artery pres-
sure of 43 mmHg, pulmonary vascular resistance of 363 DS/cm5) as a
only a few centres. consequence of a supposed pulmonary embolism nine months earlier.
The angiographic reconstruction shows abrupt vessel narrowing, int-
raluminal bands, irregular vascular wall thickening and dilated central
pulmonary arteries.

Treatment
CTEPH is associated with a dismal prognosis in the ab- Prior to the intervention, angiography is currently the
sence of specific intervention. Especially in the presence gold standard for the anatomical assessment of pulmonary
of signs and symptoms of right heart failure the average artery obstructions, which together with right-heart cath-
survival is poor, as demonstrated in a study where it was eterisation is essential for distinguishing proximal, opera-
found to be only 1.7 years after diagnostic catheterisation; ble CTEPH from distal disease. Most patients will have
in contrast, without heart failure, patients lived on average
4.7 years. If the mean pulmonary artery pressure meas-
ured >50 mmHg, the 2-year survival was 20% [14].
All patients should receive life-long anticoagulation in
order to prevent recurrent venous thromboembolism.
Formally, the new direct oral anticoagulants have not
been tested, and until more data are available, it may be
prudent for patients to be anticoagulated with vitamin K
antagonists.

Surgical treatment

Pulmonary endarterectomy (PEA) is the treatment of choice

and has the potential to cure some of the patients with
CTEPH. It is a surgically demanding technique and requires
experience for the assessment of operability as well as tech-
nical skills for its performance. There are only a few centres
worldwide with a case load >1000 interventions and its deli-
cate postoperative surveillance necessary to obtain a periop-
erative mortality <5% [15]. An expert centre is by definition
one that performs at least 20 PEA operations per year with a
Figure 3. Pulmonary angiography (Courtesy of Diagnostic Radiology,
mortality rate of <10%. Recent guidelines recommend that
Uniklinik Giessen). The preoperative angiography of the index patient
expert centres should aim at improved mortality rates (<7%) shows constrictive bands and abrupt vessel narrowing in one of the
and early haemodynamic improvements after PEA [16]. examined lobar arteries.

2016 Hogrefe Vasa (2016), 45 (3), 195 199

 198
haemodynamic abnormalities at rest, but in selected cas-
es, patients with markedly increased pulmonary vascular
resistance upon exercise have shown to benefit from surgi-
cal intervention [15]. It must be underscored that patients
should be evaluated only by an expert team in PEA before
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operations may be withheld. Temporal delay to evaluation
of operability can result in a negative outcome, and medi-
cal bridging while postponing a specific assessment is not
recommended [15].
The operation is performed in deep hypothermic circu-
latory arrest. Dissection of pulmonary arteries of both
lungs are performed as distally as possible to minimise
postoperative residual pulmonary hypertension. Perioper-
ative complications include lung reperfusion injury in
<10% of patients, characterised by pulmonary oedema
and treated by ECMO, and neurocognitive impairment
due to prolonged circulatory arrest. Operative mortality
correlates with preoperative pulmonary vascular resist-
ance (PVR) but there are no upper limits of PVR, pulmo-
nary artery pressure or parameters of right heart insuffi-
ciency that preclude surgery. Up to 30% of the patients
may present with postoperative residual/persistent pul-
monary hypertension, which negatively influences prog-
nostic outcomes. Those patients may be candidates for
medical treatment [15].
Percutaneous transluminal pulmonary
angioplasty (BPA)
The feasibility of balloon dilatation of obstructed pulmo-
nary arteries was first demonstrated in 2001, and the safe-
ty and efficacy have been shown in a Japanese study which
included 70 mostly elderly patients; however, critical rep-
erfusion pulmonary oedema and vessel injuries may be an
issue [17]. Further studies including the results of long-
term outcomes are needed in order to resolve uncertain-
ties in the approach of CTEPH by this technique.
Medical treatment
Recently published data from a registry revealed that more
than one third of patients are treated with specific drugs for
pulmonary hypertension, irrespective of their operability
[4]. They include endothelin antagonists (Bosentan), pros-
tanoids (epoprostenol, treprostinil), and PDE5-inhibitors
(sildenafil, tadalafil, vardenafil). The results from various
studies with bosentan were analysed in a meta-analysis
with an improvement of haemodynamics and probably of
exercise parameters [18]. The data for prostanoids have also
shown an improvement of haemodynamics, exercise capac-
ity (epoprostenol, treprostinil), and survival (treprostinil),
whereas PDE5-inhibitors, although well tolerated and with
positive influence on certain paraclinical parameters, lack
well-designed studies with respect to survival [2].
Riociguat is a novel drug, which stimulates soluble gua-
nylate cyclase (sGC). The CHEST study included 261 pa-
Vasa (2016), 45 (3), 195 199
H. Stricker: CTEPH update
tients with inoperable CTEPH or with persistent/recurrent
pulmonary hypertension after PEA, treated with Riociguat
or placebo for 16 weeks (CHEST-1), followed by an open
trial (CHEST-2). After 16 weeks, the 6 minute walking test
significantly increased by 46 meters (primary endpoint),
and also the secondary endpoints NT-proBNP, PVR and
WHO-class improved significantly [19]. This agent subse-
quently to the positive results of the trial has been licensed
as the first specific medical treatment for non-operable
CTEPH and for persistent pulmonary hypertension after
PEA. Importantly, riociguat cannot be combined with
PDE5-inhibitors [20], whereas a combination with en-
dothelin antagonists or prostanoids is possible.
Conclusions
CTEPH, an important cause of severe pulmonary hyperten-
sion, is still underdiagnosed, and the use of V/Q scanning as
part of the diagnostic approach in patients with pulmonary
hypertension is essential. Every patient with CTEPH should
undergo evaluation in a specialised centre with a large expe-
rience in PEA. Partly unresolved questions regard the status
of BPA and the best medical treatment in patients with inop-
erable or recurrent/persistent PH after PEA.
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There are no conicts of interest existing.
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2016 Hogrefe Vasa (2016), 45 (3), 195 199

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