2018 科隆共识会议建议：慢性血栓栓塞性肺动脉高压（CTEPH）

a b s t r a c t

Article history: Received 9 August 2018 Accepted 24 August 2018 Available online xxxx

Keywords: Chronic thromboembolic pulmonary hyper tension Chronic thromboembolic disease Pulmonary endarterectomy Balloon pulmonary angioplasty Medical therapy

Chronic thromboembolic pulmonary hypertension (CTEPH) is a subgroup of pulmonary hypertension that differs from all other forms of PH in terms of its pathophysiology, patient characteristics and treatment. For implementation of the European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension in Germany, the Cologne Consensus Conference 2016 was held and last updated in spring of 2018. One of the working groups was dedicated to CTEPH, practical and controversial issues were commented and updated. In every patient with suspected PH, CTEPH or chronic thromboembolic disease (CTED, i.e. symptomatic residual vasculopathy without pulmonary hypertension) should be excluded. Primary treatment is surgical pulmonary endarterectomy (PEA) in a multidisciplinary CTEPH centre. Inoperable patients or patients with persistent or recurrent CTEPH after PEA are candidates for targeted drug therapy. There is increasing experience with balloon pulmonary angioplasty (BPA) for inoperable patients; this option, like PEA, is reserved for specialised centres with expertise in this treatment method.

$\copyright$ 2018 Published by Elsevier B.V.

1. Introduction

Chronic thromboembolic pulmonary hypertension (CTEPH) is a speci fi c type of pulmonary hypertension (PH) [ 1 , 2 ] that is characterised by

obstruction or occlusion of subsegmental, segmental or larger pulmonary arteries by postembolic fi brotic material. Typical pathoanatomical fi ndings are intimal irregularity, stenoses with ring-, web- or slit-like forms and pouch defects, tapered vascular stenosis or complete occlusion caused by fi brotic intraluminal material, occasionally with an overlying thrombus. Anastomoses between bronchial arteries and precapillary pulmonary arterioles and between bronchial arteries and pulmonary veins with hypertrophic remodelling of the pulmonary veins are also found [ 3 ].

Please cite this article as: H. Wilkens, et al., Chronic thromboembolic pulmonary hypertension (CTEPH): Updated Recommendations from the Cologne Consensus Conference 2018, Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.08.079

Table 1 Group 4 in the clinical classi fi cation of PH.

|Chronic thromboembolic pulmonary hypertension (CTEPH) and other pulmonary| |---| |artery obstructions| |4.1 CTEPH| |4.2 Other pulmonary artery obstructions| |4.2.1 Angiosarcoma| |4.2.2 Other intravascular tumours| |4.2.3 Arteritis| |4.2.4 Congenital pulmonary artery stenosis| |4.2.5.Parasites (echinococcus-related hydatidosis)|

2. De fi nitions

CTEPH is categorised as Group 4 in the classi fi cation of PH [ 1 ] ( Table 1 ), and the diagnosis is based on the following criteria:

• PH con fi rmed by right heart catheterisation (mean pulmonary arterial pressure ${\geq}25\,\mathrm{mm}\,\mathrm{Hg}$ and pulmonary arterial wedge pressure (PAWP) ${\leq}15\;\mathrm{mm\,Hg}$ at rest) and • Mismatch on ventilation/perfusion (V/Q) scintigraphy (usually V/Q single-photon emission computed tomography [SPECT]) with at least one large perfusion defect in one segment or in two subsegments, or evidence of pulmonary vascular lesions on computed tomography (CT) and/or magnetic resonance imaging (MRI) or pulmonary angiography. • These fi ndings should be obtained after at least 3 months of effective anticoagulation

Chronic thromboembolic pulmonary vascular disease without PH (CTED) has the same criteria as listed above except for the evidence of PH at rest. With similar symptoms and reduction in quality of life, these patients are offered the same surgical or interventional treatment as patients with CTEPH ( Table 2 ) [ 4 ].

Table 2 Recommendations for CTEPH.

|Recommendation| Level of recommendation evidence ||| |---|---|---|---| ||ia||C| | In PE survivors with exercise dyspnoea, CTEPH should be considered. |||| | Life-long anticoagulation is recommended for all patients with CTEPH. |||C| | It is recommended that for all patients with CTEPH the assessment of operability and decisions |||| ||||| | regarding other treatment strategies should be made by a multidisciplinary team of experts. |||| ||||C| | Surgical PEA in deep hypothermia and circulatory arrest is recommended for CTEPH patients at |||C| | an experienced PEA centre (>30-50 operations per year). |||| ||||| | Riociguat is recommended for symptomatic patients I who have been classified as having |||B| |persistent/recurrent CTEPH after PEA or|||B| |inoperable CTEPH by a multidisciplinary CTEPH|||B| |team including at least one surgeon.|||| | Off-label use of targeted PAH drugs may be considered in symptomatic patients with ||Ib|B| |persistent/recurrent CTEPH after surgical|||B| |treatment or with inoperable CTEPH.|||| |Interventional BPA may be considered in patients||IIb|C| ||||C| | who are technically inoperable or have an unfavourablerisk/benefit ratiofor PEA as assessedunfavourablerisk/benefit ratiofor PEA as assessed by a CTEPH team. |||| | Screening for CTEPH in asymptomatic survivors of PE is currently not recommended. |||C| ||||C|

BPA = balloon pulmonary angioplasty; CTEPH $=$ chronic thromboembolic pulmonary hypertension; PAH = pulmonary arterial hypertension; $\mathrm{PE}=$ pulmonary embolism; PEA $=$ pulmonary endarterectomy.

Comments: Despite the clear criteria, CTEPH can be dif fi cult to diagnose and appropriate evaluation is often delayed. Especially in patients with comorbidities, diagnosis may be challenging, therefore all patients should be referred to a PH expert centre promptly [ 1 , 2 ] .

The main differential diagnoses besides PAH are heart failure with preserved ejection fraction (HFpEF) or rare diseases such as mediastinal fi brosis, tumours of the pulmonary arteries, pulmonary vasculitis, and congenital or acquired pulmonary artery stenoses.

3. Epidemiology and risk factors

The incidence of CTEPH is thought to be 4 per 1 million adults [ 5 ]. It is dif fi cult to obtain exact numbers for the incidence of CTEPH due to the lack of speci fi c symptoms, misdiagnoses due to the diagnostic complexity of CTEPH and a large number of suspected cases where CTEPH remains undiagnosed. Information on the incidence of CTEPH after acute pulmonary embolism is also variable and ranges between 0.4 and $9.1\%$ [ 6 – 9 ]. The reasons for the range of values are the dif fi culty in distinguishing between an acute pulmonary embolism and a recurrent embolism in pre-existing CTEPH and heterogeneous inclusion criteria, observation periods, and methods of con fi rming the diagnosis (echocardiography versus invasive measurements).

In most cases, CTEPH is associated with a prior venous thromboembolism. For example, in an international prospective CTEPH database, $74.8\%$ of CTEPH patients had a history of acute pulmonary embolism and $56.1\%$ had a history of deep vein thrombosis [ 10 ].

Although CTEPH is a thromboembolic disease, patients generally do not have a de fi ned disturbance in coagulation and/or fi brinolysis. However, elevated levels of Factor VIII [ 8 ] and phospholipid antibodies/lupus anticoagulans are signi fi cantly more common in CTEPH than in PAH [ 8 , 11 ]. CTEPH patients have higher percentages of blood types A, B and AB compared with the general population [ 12 – 14 ], which is linked to elevated plasma Factor VIII levels [ 11 ].

4. Pathological mechanisms

The consequence of elevated pulmonary artery pressures is right ventricular strain resulting in right ventricular hypertrophy and dilatation, which can lead to death due to right-sided heart failure, if left untreated. The underlying cause of the vascular disease in CTEPH is vascular wall remodelling due to thromboembolism, with subsequent remodelling of the peripheral resistance vasculature of the lungs. This cannot be distinguished from the remodelling observed in PAH. It is thought that a pulmonary embolism is transformed into a fi brotic vascular occlusion via the interplay of several factors including in fl ammation [ 12 ], infection [ 15 ], inhibition of vascular regeneration [ 16 , 17 ], circulating microparticles [ 18 ], abnormal fi brinogen [ 19 ], splenectomy [ 14 , 18 ], and abnormal circulating phospholipids with reduced thrombus resolution [ 18 ].

5. Diagnostics

5.1. Screening

Based on current evidence routine screening for CTEPH is not recommended for survivors of an acute pulmonary embolism [ 1 ]. A signi fi cant number of patients with CTEPH develop the disease without a history of a clinically apparent pulmonary embolism.

Comments: While there is no scienti fi c justi fi cation for screening asymptomatic patients, it has been shown that examination of persistently symptomatic patients after acute PE results in a diagnosis of CTEPH/CTED in $8.5\%$ of cases [ 20 ]. Furthermore, it has been reported that there is not always a “ honeymoon period ” between the occurrence of an acute pulmonary embolism and the development of CTEPH, but rather that a number of patients never become symptom-free again after an acute pulmonary embolism [ 20 , 21 ]. Therefore, steps should be

Please cite this article as: H. Wilkens, et al., Chronic thromboembolic pulmonary hypertension (CTEPH): Updated Recommendations from the Cologne Consensus Conference 2018, Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.08.079

taken to rule out CTEPH in persistently symptomatic patients after acute pulmonary embolism and at least 3 months of effective anticoagulation.

5.2. Clinical presentation

The median age of patients at diagnosis is 63 years with both sexes being affected equally [ 10 ], whereas paediatric patients are rare [ 22 ]. The predominant symptom of CTEPH is exercise-induced dyspnoea; other symptoms are non-speci fi c or absent in early CTEPH. Signs of chronic right-sided heart failure only become evident in advanced disease. Early diagnosis remains a challenge and should be pursued for reasons of prognosis [ 23 ]. There is a median latency period of 14 months between the onset of symptoms and diagnosis at expert centres. The diagnostic algorithm is shown in Fig. 1 .

Comments: The ESC/ERS guidelines do not distinguish between functional and imaging-based diagnostic tests and, if there is evidence of CTEPH, recommend echocardiography. If this suggests an intermediate or high probability of PH, V/Q lung scan is recommended. Because echocardiography can miss both CTEPH and CTED [ 24 ], it seems, at least in cases of patients with pronounced symptoms, inappropriate to stop the diagnostic process if echocardiography results in a determination of low probability of PH, or to simply carry out a follow-up echocardiogram after 3 – 6 months. Because both CTEPH and CTED may have signs of pulmonary perfusion anomalies that are detectable by cardiopulmonary exercise testing (CPET) ( Fig. 2 ) [ 24 , 25 ], this test should be performed if there is a clinical suspicion of CTED/CTEPH and a low echocardiographic probability of PH. As the degree of vascular obstruction and the haemodynamics of CTEPH correlate poorly, and because there

are patients who have symptoms but only minor functional limitations, and patients with pathological scintigraphy fi ndings but no objective limitations, functional diagnostic testing can prove helpful in determining the signi fi cance of the pathological fi ndings observed in the imaging tests.

If there is a strong clinical suspicion of PH after echocardiography and, where appropriate, CPET, imaging techniques should be used, and an invasive haemodynamic assessment conducted via right heart catheterisation (see Fig. 1 ).

5.3. Radiological/nuclear medicine diagnostics

While multi-detector CT pulmonary angiography (CTPA) is the investigation of choice to diagnose acute pulmonary embolism, V/Q scintigraphy (preferably with single photon emission computed tomography; SPECT) remains the initial imaging modality of choice for CTEPH [ 1 ], as it has a $96.97\%$ sensitivity and a $90–95\%$ speci fi city for the diagnosis [ 26 ]. In idiopathic PAH and pulmonary veno-occlusive disease (PVOD), V/Q SPECT scans are typically normal or show non-segmental defects [ 27 ]. Recent work suggests that both V/Q SPECT and modern CTPA may be accurate methods for detecting CTEPH, with excellent diagnostic accuracy at expert centres [ 28 , 29 ].

Comments: A V/Q SPECT without perfusion defects largely rules out CTEPH. In patients with PH, a V/Q mismatch in at least one segment, or in two subsegments, indicates the possible presence of CTEPH. V/Q SPECT involves low radiation exposure and can also be used in patients with advanced renal failure. In the current era it should be performed as a SPECT investigation [ 30 , 31 ], as in comparative studies V/Q SPECT is

 Fig. 1. Diagnostic algorithm for CTEPH \* see Table 7A and Table 7B in pocket guide “ Diagnostik und Therapie der pulmonalen Hypertonie ” by the German Society for Cardiology and Cardiovascular Research (Deutsche Gesellschaft für Kardiologie – Herz-und Kreislaufforschung). \*\* Signs of CTEPH/CTED on cardiopulmonary exercise testing include limited exercise capacity and evidence of a pulmonary perfusion disorder (reduced $\mathrm{PETCO}_{2}$ , elevated $\operatorname{P}(\mathsf{a}\mathrm{-}\mathsf{E}\mathrm{T})C O_{2}$ , $\operatorname{EQ}0_{2}$ , EQ ${\mathsf{C}}{\mathsf{O}}_{2}$ , $\mathsf{V E/V C O}_{2}$ slope or P(A-a) $^{0_{2,}}$ . \*\*\* or evidence of pulmonary artery clots/obstructions using other imaging techniques such as computed tomography, magnetic resonance imaging or conventional pulmonary angiography \*\*\*\* if necessary, coronary angiography ${\mathsf{C}}{\mathsf{O}}_{2}=$ carbon dioxide; CTED $=$ chronic thromboembolic pulmonary vascular disease without pulmonary hypertension; CTEPH $=$ chronic thromboembolic pulmonary hypertension; $\mathrm{EQ}=$ respiratory equivalent; $0_{2}=$ oxygen; $\begin{array}{r l}{\mathrm{P(a-A)C O_{2}=}}\end{array}$ partial pressure of arterial/alveolar carbon dioxide; $\begin{array}{r l}{\lefteqn{\mathrm{P}(\mathsf{a}\mathrm{-}\mathrm{ET})\mathsf{C O}_{2}=}}\end{array}$ partial pressure of arterial end-tidal carbon dioxide; $\mathrm{PETCO_{2}=}$ partial pressure of end-tidal carbon dioxide; $\mathrm{RH}=$ pulmonary hypertension; $\mathsf{V E/V C}0_{2}=$ minute ventilation/carbon dioxide output.

Please cite this article as: H. Wilkens, et al., Chronic thromboembolic pulmonary hypertension (CTEPH): Updated Recommendations from the Cologne Consensus Conference 2018, Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.08.079

 Fig. 2. Cardiopulmonary exercise test of a patient with severe CTEPH with A) increased slope of minute ventilation/CO2 exhalation(VE/VCO2, low and decreasing end-tidal carbon dioxide tension (PETCO2) and C) elevated and increasing ventilatory equivalents for oxygen $({\mathrm{E}}Q0_{2}$ ) and carbon dioxide ( $\langle\mathrm{EQCO}_{2}\rangle$ as signs of pulmonary perfusion defects with ineffective ventilation.

superior to planar V/Q scintigraphy [ 32 ] (see Fig. 3 ). Despite the recommendations in the guidelines in favour of V/Q, this technique is still not performed consistently as part of a PH diagnostic work-up; for example, being only performed in approximately one in two patients in a North American PH cohort of nearly 800 patients [ 33 ].

5.4. CT of the chest

Multidetector CTPA is an established imaging modality for con fi rming CTEPH [ 28 ]. However, it cannot de fi nitively rule out CTEPH [ 1 , 26 ]. CTPA can detect typical fi ndings, comorbidities and complications of the disease, such pulmonary artery dilatation with subsequent compression of the left main coronary artery or bleeding from bronchial artery collaterals. A high resolution CT scan of the chest produces images of the lung parenchyma and identi fi es structural lung changes and bronchial disease, as well as lung infarcts, vascular and pericardial malformations and

thoracic wall deformities. Perfusion inequalities manifest as a mosaic perfusion pattern, with hypertransparent areas corresponding to decreased perfusion. Although a mosaic perfusion pattern is common in CTEPH, it can also be observed in up to $12\%$ of patients with PAH [ 34 ].

Comments: Current work on CTPA using collimators with spatial resolution in the sub-millimetre range is promising in terms of characterising segmental manifestations of CTEPH, with a resolution similar to selective digital subtraction angiography (DSA) [ 28 , 35 ]. Direct changes such as vessel wall thickening and irregularities, occlusions, fi lling defects and mosaic patterns are important in evaluating and planning surgical therapy [ 36 – 38 ], post-stenotic vascular dilatations, and intravascular rings and webs can be displayed. A new development in CT imaging is the dual energy CT (DECT), which can measure the contrast agent uptake in the parenchyma as an expression of perfusion ( Fig. 4 ). Initial results suggest that this modality has a high sensitivity for perfusion de fi cits [ 39 ].

 Fig. 3. Ventilation-perfusion scintigraphy in a patient with CTED. A) planar views in 6 projections showing perfusion defects with mismatch to ventilation. Ventilation scans can be recognized by the tracer signal of the trachea (arrow), which is absent in the perfusion scans. B) Single photon emission computed tomography (SPECT) showing multiple segmental perfusion defects.

Please cite this article as: H. Wilkens, et al., Chronic thromboembolic pulmonary hypertension (CTEPH): Updated Recommendations from the Cologne Consensus Conference 2018, Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.08.079

 Fig. 4. Dual-energy computed tomography derived iodine map depicting multiple perfusion defects.

5.5. Magnetic resonance pulmonary angiography (MRA) and other imaging techniques

MRA is currently considered inferior to CT [ 36 ], but this modality, as well as cone beam CT [ 40 , 41 ], dual-energy CT (see Fig. 4 ), angioscopy [ 42 ], intravascular ultrasound and optical coherence tomography (OCT), are increasingly used as complementary investigations providing additional information, depending on local experience.

Comments: The spatial resolution of MRA for contrast-enhanced imaging of the pulmonary vasculature is limited for technological reasons and to date remains insuf fi cient for depicting subtle intravascular fi ndings. The results of investigations conducted at specialised centres on perfusion imaging and changes in segmental post-operative perfusion are available [ 43 ].

5.6. Pulmonary angiography

The fi nal step in con fi rming the diagnosis of CTEPH and assessing technical suitability for surgery is selective pulmonary angiography in at least two planes (anterior – posterior and lateral projections). Typical signs of CTEPH are webs, ring-like stenoses, pouches, tortuous lesions and complete vascular obstructions [ 44 ] (see Fig. 5 ).

Comments: Pulmonary angiography should be performed sideselective in an anterior-posterior and lateral projection at a CTEPH

centre that has the relevant experience and works closely with an experienced surgical team. Angiography plays a key role in determining whether surgical or interventional therapies are feasible. In addition to visualising the exact vascular morphology, angiography also can help to assess central and subpleural-capillary fi lling (see Fig. 5 ). Poor subpleural perfusion in the context of PH is thought to be associated with distal vessel angiopathy or other primary lung diseases. This is also associated with a higher surgical risk [ 45 ]. Angiographic imaging of subsegmental stenoses and obstructions is becoming increasingly signi fi cant, especially with the advances in balloon angioplasty of the pulmonary arteries (BPA). Cone-beam CT is recently used in combination with pulmonary angiography for an improved depiction especially of peripheral lesions in the pulmonary arteries [ 41 ].

5.7. Right heart catheterisation

A right heart catheterisation which records pressure measurements in the right atrium, right ventricle, and the pulmonary artery (systolic, diastolic and mean pulmonary arterial pressures [PAP] and PAWP) as well as determining cardiac output volume and oxygen saturation (pulmonary arterial, vena cava) and the calculation of pulmonary vascular resistance is obligatory. Determining the correct PAWP in patients with CTEPH can be dif fi cult, therefore measurement of the LVEDP may be necessary. Pre-operative and post-operative PVR are long-term predictors of prognosis [ 46 ].

Please cite this article as: H. Wilkens, et al., Chronic thromboembolic pulmonary hypertension (CTEPH): Updated Recommendations from the Cologne Consensus Conference 2018, Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.08.079

ARTICLEN PRESS

 Fig. 5. Pulmonary angiography of the right lung in a patient with CTEPH with ring-like stenosis [ 1 ], wall irregularities [ 2 ], abrupt narrowing [ 3 ], webs [ 4 ], perfusion defects [ 5 ], complete vascular obstructions [ 6 ] and decreased subpleural-capillary fi lling [ 7 ].

6. Treatment of CTEPH

6.1. Pulmonary endarterectomy (PEA)

PEA is the treatment of choice for CTEPH provided there are no serious contraindications (such as comorbidities) [ 1 ] (see Fig. 6 ). The intra-hospital fatality rate depends on the surgical experience, which corresponds with the annual number of PEAs. In Europe, specialised centres ${\sim}50$ PEAs/year) have a case fatality of ${\le}3.5\%$ [ 47 ], in centres that perform 11 – 50 PEAs per year the case fatality is $4.7\%$ [ 6 ] and in centres who perform fewer than 11 PEAs/year it is $7.4\%$ [ 6 ]. In centres with a smaller number of cases, the proportion of patients who are deemed inoperable is higher than in centres with higher numbers of PEA cases. The surgery should therefore take place in a CTEPH centre with an adequate number of operations and a low case fatality [ 48 ]. In addition to having ample experience in diagnosing and treating CTEPH, a CTEPH centre should have an multidisciplinary team composed of specialists in respiratory medicine, cardiology, radiology, nuclear medicine, intensive care and anaesthesiology as well as an experienced PEA surgeon [ 48 ].

The majority of patients experience substantial post-operative relief of symptoms and a signi fi cant improvement of haemodynamics [ 47 , 48 ]. In contrast to surgical embolectomy for acute pulmonary embolism, the treatment of CTEPH necessitates a true bilateral endarterectomy through the medial layer of the pulmonary arteries. To do this, phases of circulatory arrest in deep hypothermia are necessary [ 47 ] in order to keep the surgical fi eld free of blood via the bronchopulmonary collaterals and at the same time reliably protect neurocognitive function [ 49 ].

Cologne Consensus Conference 2018, Int J Cardiol (2018),

Comments: Whether a patient with CTEPH can be successfully treated by PEA is determined by multiple factors that cannot easily be standardised; principally, these include the technical operability and the risk bene fi t ratio for PEA (accessibility of the obstructions, preoperative haemodynamics, comorbidities), the expertise of the surgical team and the available resources. Advanced age in itself does not constitute a contraindication to surgery, nor is there a PVR threshold or a limit to the extent of RV dysfunction that would rule out PEA.

The expertise of both the surgeon and the CTEPH team is essential in determining which changes are deemed too “ distal ” or too “ peripheral ” , and thus which patients are classi fi ed as inoperable. The same applies to the correlation between accessible obstructions and the extent of pathologically altered haemodynamics. The combination of primarily “ distal ” obstructions and a high PVR constitutes a risk factor, but is not a contraindication for PEA.

In cases of CTEPH with a very high PVR but only a moderate proximal obstruction pattern, is relevant microvasculopathy is suspected. Nonetheless, PEA may be useful in such cases to signi fi cantly reduce the PVR and thus the RV stress. The presence of microvasculopathy may be the reason for residual post-surgical PH in approximately $50\%$ of patients who have had PEA surgery, however this does not mean that the operation was not successful [ 50 ].

The option of intra- and post-operative ECMO therapy is part of the recommended standard of care at CTEPH centres [ 1 ], especially for severe cases (e.g. PVR N 15 Wood units) [ 51 – 53 ]. Acute respiratory distress due to early post-operative reperfusion oedema may be bridged with veno-venous ECMO. In contrast, veno-arterial ECMO support is indicated for right ventricular pump failure in persistent severe PH or as bridging to lung transplantation.

Patients who do not undergo PEA or suffer from persistent or recurrent PH after PEA face a poor prognosis without additional therapy [ 10 ].

Comments on the treatment algorithm:

1. A CTEPH centre should have experience in diagnosing and treating patients with CTEPH and PAH. At CTEPH centres, patient care is managed by a multidisciplinary team: specialists in respiratory medicine, cardiology, radiology, and nuclear medicine working in close collaboration with a PEA surgeon whose team performs ${>}20$ PEAs annually. The recommendation to get a second opinion has been removed from the current ESC/ERS treatment algorithm for CTEPH. However, in cases of doubt it is necessary to request a second opinion at another experienced CTEPH centre [ 54 ].

2. The algorithm now differentiates between technically operable and technically inoperable patients. In addition, for technically operable patients there is mention of a “ non-acceptable ” risk/bene fi t ratio in the presence of comorbidities, although there is no de fi nition for this ratio. Because the assessment of both technically operable and inoperable patients and those with an “ unacceptable risk/bene fi t ratio ” hinges crucially on the experience and expertise of the surgeon and the corresponding team, obtaining a second opinion at another experienced CTEPH centre is recommended in cases where there is doubt. The cases of patients who refuse surgery should be discussed with a PEA surgeon and, where applicable, these patients should meet with a PEA surgeon for an informative discussion, before long-term medical therapy is initiated.

6.2. Medical therapy

Supportive medical treatment for CTEPH consists of anticoagulants and diuretics, and long-term oxygen therapy in cases of hypoxaemia [ 1 ]. Lifelong anticoagulation is recommended even after PEA, and no data exist on the ef fi cacy and safety of new oral anticoagulants for CTEPH [ 1 , 2 ]. Further supportive measures are recommended, in keeping with the recommendations for treating patients with PAH [ 55 ].

Comments: The recommendations for anticoagulation in CTEPH are derived primarily from the recommendations for anticoagulation after

ARTICLEINPRESS

 balloon pulmonary angioplasty; CTED $=$ chronic thromboembolic pulmonary vascular disease without pulmonary hypertension; CTEPH $\mathrm{RH}=$ pulmonary hypertension

Fig. 6. Therapeutic algorithm for CTEPH [ 1 ] BPA

recurrent pulmonary embolisms, as there is a lack of reliable evidence from randomised controlled clinical trials (RCT) on the effect of anticoagulation in CTEPH patients [ 2 ]. Both “ classical ” oral anticoagulants (coumarin derivatives) and non-vitamin-K-dependent oral anticoagulants (NOACs), which inhibit Factor Xa or prothrombin, are currently available as therapy in the post-acute phase of a pulmonary embolism. Owing to decades of clinical experience with vitamin K antagonists, they are still considered the standard treatment for CTEPH according to the current guidelines [ 1 ]. On the basis of the individual risk/bene fi t assessment or in patients whose CTEPH cannot be well controlled with vitamin K-antagonists, a switch can be made to a NOAC, although there is less evidence on the treatment of CTEPH with NOACs [ 2 ]. Routine vena cava fi lter placement is not justi fi ed based on the available evidence [ 1 ].

The positive effects of controlled, “ low-dose ” exercise training have also been demonstrated for CTEPH [ 56 ].

6.3. Therapy with PH medications

Pulmonary microvascular disease in CTEPH has provided the rationale for the use of drugs approved for PH [ 10 ]. Currently only the oral soluble guanylate cyclase (sGC) stimulator, riociguat, has been approved for the treatment of inoperable or persistent/recurrent CTEPH after PEA, however it can be expected that combination therapies will also be available for administration in future, fi rst results have been published.

Targeted medical treatment of CTEPH may be considered in patients with an unacceptable risk/bene fi t ratio for PEA [ 1 ]. Patients with persistent or recurrent PH after PEA are also candidates for targeted medical treatment [ 1 ].

The pre-operative use of PH therapy in patients with an indication for PEA and severe haemodynamic compromise has not yet been supported by scienti fi c evidence. The effects were relatively small [ 57 ] in

Cologne Consensus Conference 2018, Int J Cardiol (2018),

one RCT and one retrospective study indicated no difference in postoperative outcomes, but there was a signi fi cant delay in performing surgery in patients treated with medical therapies [ 58 ]. Prospective RCTs are needed in patients who may bene fi t from medical treatment [ 1 ], for example, patients with a high PVR and technically challenging anatomy. After PEA, patients should continue to be managed at a CTEPH centre, with at least one haemodynamic re-assessment by means of right heart catheterisation at 6 – 12 months postintervention [ 1 ]. Repeat imaging is only necessary if there is evidence of persistent PH.

Comments: Additional data on medical therapy in CTEPH are now available from the open-label, single-arm extension of the CHEST study, which demonstrated a sustained effect of riociguat on physical endurance and clinical disease course [ 59 ]. However, these are not controlled data. For example, improvements in the 6-minute walk distance and NT-proBNP after 3 months persisted over the next 2 years, and, in contrast to studies in PAH patients, there was a signi fi - cant correlation between improvement in 6-minute walk distance and survival. The following conditions apply to the use of riociguat in patients with CTEPH:

• Technical inoperability according to an interdisciplinary CTEPH team including an experienced PEA surgeon; • A poor risk bene fi t ratio for PEA according to the CTEPH team • Relevant post-operative PH after PEA; • Initiation of treatment at a PH centre • Close blood pressure monitoring during the adjustment phase.

First results of a randomised placebo-controlled study with the dual endothelin receptor antagonist macitentan (MERIT study) have been published showing signi fi cant improvement in 6-minute walk distance, haemodynamics and NTproBNP in the treatment group [ 60 , 61 ].

Incompatibility or an insuf fi cient therapeutic response that requires combination therapy may be the reasons for the off-label use of PAH

medications in patients with CTEPH. Such treatments should only be undertaken at PH centres.

In the CTEPH registry, treatment with PAH drugs was a predictor of poor outcome, presumably because of a bias towards more severe patients in this group. Dedicated studies are under way testing the role of medical treatment prior to and following PEA, and BPA. Currently, no recommendations can be based on study data.

There is a risk that the initiation of PAH-speci fi c medication will delay surgery in operable patients resulting in surgery with more advanced disease and a correspondingly poorer prognosis [ 55 ].

Therapy outcomes must be monitored closely; where appropriate, the option of PEA or BPA should be re-evaluated.

6.4. Balloon pulmonary angioplasty (BPA)

BPA is a percutaneous interventional treatment option for patients with inoperable CTEPH. This procedure involves treatment of vascular CTEPH lesions with semi-compliant balloons at relatively low pressures (about 6 – 10 atm), in several sessions. Since its fi rst reported use in a small patient series $.n=18$ ) in 2001 [ 62 ], BPA has been re fi ned considerably, in particular in Japan, a country in which PEA is not widely performed [ 63 – 65 ]. BPA is now also being used increasingly in inoperable patients in Europe [ 66 , 67 ].

Comments: BPA therapy is performed over multiple sessions, each of which is usually limited to working on one lobe and at most one additional segment of the lung. Injuries are largely avoided by the consistent use of dilatation balloons that have a smaller diameter than the lumen of the target vessel. Even so, serious and fatal complications have been reported, primarily bleeding caused by balloon or wire-induced pulmonary artery perforation and reperfusion oedema resulting in variations of lung injury, with desaturation, hemoptysis, in fi ltrations and ARDS, depending on the severity. The initially high rate of complications, with a periprocedural mortality of up to $10\%$ [ 62 ], has been lowered substantially and was recently reported to be between 0 and 1% [ 63 – 65 , 68 ]. At the same time, the short- and medium-term haemodynamics and clinical effects are promising. Re-stenosis and re-obstruction appear to be rare and stenting of the pulmonary vasculature is not necessary. However, there are only rare data on long-term outcomes [ 69 ], and no controlled trials.

In Europe BPA is performed in patients who are inoperable, and have accessible lesions [ 63 , 65 ]. The principal diagnostic imaging technique used is pulmonary angiography, which is occasionally supplemented by CT angiography. Biplane digital subtraction angiography (DSA) is considered the standard, however C-arm CT is superior to conventional DSA for visualising intravascular lesions in the subsegmental pulmonary arteries [ 41 ].

Before BPA is considered, PEA must de fi nitively be de fi nitively ruled out as an appropriate treatment option. Meanwhile, even hybrid approaches combining PEA surgery with intraoperative BPA have been described [ 70 ]. To develop the therapeutic strategy in each individual CTEPH patients, a multidisciplinary conference with experienced PEA surgeons, interventionalists and PH specialists is mandatory. As long as no systematic long-term data for BPA are available from countries in which PEA surgery is well established, this technique should be performed at those centres that also offer PEA. This will ensure that the question of operability will be de fi nitively determined and that the procedure is established to begin with at centres that manage a suf fi cient number of patients. The German CTEPH centres currently collect their BPA data in a shared prospective database in order to evaluate a number of factors including which patients do or do not particularly bene fi t from this procedure [ 67 ].

In the algorithm of the ESC/ERS guidelines, the next step recommended to immediately follow “ technically inoperable ” for PEA is “ BPA ” , but to date there are no data to support this. In Germanspeaking countries there is a consensus that BPA should not be used until other established techniques have been exhausted.

These include drug therapies recommended for inoperable patients. In patients with CTED there is currently insuf fi cient experience to support treatment with BPA.

After all other treatment options have been exhausted, lung transplantation may be considered for eligible patients (no signi fi cant comorbidity, biological age $\mathord{<\!60}$ years). In this situation, the patient should be referred to a transplantation centre in a timely manner.

6.5. Pulmonary artery sarcoma

The primary tumours of the pulmonary artery are the highly malignant and extremely rare sarcomas [ 71 ], which are also listed in Group 4 of the clinical classi fi cation of PH (see Table 1 ). Originating from the pulmonary valve, the intima of the main trunk of the pulmonary artery or the bulbus cordis, the predominantly intraluminal growth results in stenoses of the pulmonary vasculature. Thrombus apposition and embolisation of thrombi or tumour portions in peripheral sections of the pulmonary circulation result in progressive right-sided heart strain. A suspected diagnosis is based on a mosaic of clinical, laboratory and imaging fi ndings. The following observations are indicative of this diagnosis:

• Central space-occupying mass in the pulmonary artery involving the main trunk of the pulmonary artery, the pulmonary valve or the right ventricular out fl ow tract. • Bulging of a central “ thrombus ” in the direction of the main stem or the pulmonary valve (positive eclipse sign) [ 72 ] • “ Thrombus ” increases in size despite adequate anticoagulation [ 73 ] • Pressure gradient observed during right heart catheterisation, with drop in pressure beyond the central “ thrombus ” • No history of pulmonary embolism • Uptake of contrast medium by the “ thrombus ” on MRI or CT diagnostic scans • Increased radionuclide uptake on a positron emission tomography-CT scan [ 74 ] • B symptoms

The prognosis for a pulmonary artery sarcoma is poor. The mean survival after diagnosis is 17 months. The treatment of choice is resection of the tumour. Even from a palliative perspective, this operation is justi fi ed to reduce the tumour mass or remove a high-grade obstruction of the right ventricular out fl ow tract. During the operation, tissue samples for histology are secured fi rst before the peripheral anomalies are resected using a type of tumour endarterectomy, similar to the PEA technique used in CTEPH. Depending on the location and in fi ltration of the central tumour portion, resection and prosthetic replacement of the pulmonary artery, the pulmonary main stem or the pulmonary valve up into the right ventricular outfl ow tract may be necessary from an oncological perspective. Lung metastases are removed by means of atypical resection to the point of pneumonectomy.

The post-operative management corresponds to that for PEA, although anticoagulation is not necessary. Most patients are advised to undergo prolonged thromboembolism prophylaxis with lowmolecular-weight heparin at therapeutic doses for 6 weeks.

Depending on the histological subtyping and the patient's clinical condition, adjuvant doxorubicin/ifosfamide-based chemotherapy is currently recommended in the context of, or analogous to, the IAWS 1-2006 registry analysis. The soft-tissue sarcoma working group offers a number of other open-for-enrolment or planned studies in which patients can be included.

Patients who receive surgery and adjuvant treatment have the best prognosis. Long-term survival data of ${>}7$ years after the primary procedure have been reported. Systemic metastases are rare. Accordingly, repeat surgery or metastasectomy is indicated [ 75 ].

Please cite this article as: H. Wilkens, et al., Chronic thromboembolic pulmonary hypertension (CTEPH): Updated Recommendations from the Cologne Consensus Conference 2018, Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.08.079

ARTICLEINPRESS

Con fl icts of interest/author disclosures

HW has received fees for consultations and/or lectures from Actelion, Bayer, Boehringer Ingelheim, GSK, Novartis, P fi zer und Roche. SK has received speaker's and/or consultant fees from Actelion, Bayer, Boehringer Ingelheim, Bristol-Myers, Daiichi-Sankyo, GSK, P fi zer. IML has received speaker's and/or consultant fees from Actelion, AOP Orphan, Astra-Zeneca, Bayer-Schering, Cordis, Daiichi-Sankyo, Edwards, GSK, Medtronic, Novartis, P fi zer, Servier, United Therapeutics. ACB has received speaker's and/or consultant fees from Philips, Guerbet, General Electric GE. MG has received speaker's and/or consultant fees from Actelion, AOP Orphan, GlaxoSmithKline. FG has received speaker's fees from Actelion; research grants to institution from Actelion. AG has received fees for consultations and/or lectures from Actelion, Bayer, Bracco Imaging, Hermes Medical Solutions, P fi zer and Siemens Medical Solutions. CG has received speaker's and/or consultant fees from BMS, Novartis, Boehringer, Bayer, MSD and Roche. SG has received speaker's and/or consultant fees from Actelion, Bayer, GSK and P fi zer. MH has received speaker's and/or consultant fees from Actelion, Bayer, Berlin Chemie, Boehringer, GSK, MSD, Novartis, P fi zer, United Therapeutics. JB has nothing to disclose. MMH has received fees for consultations and/or lectures from Actelion, Bayer, Gilead, GSK, MSD and P fi zer. WK has nothing to disclose. TK has received speaker's and/or consultant fees from Actelion, Bayer, GSK, P fi zer. UK has received fees for consultations and/or lectures from Actelion, Bayer Healthcare. ML has received fees for consultations and/or lectures from Actelion, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, MSD and P fi zer. BCM has received fees for consultations and/or lectures from Bayer, MSD and Siemens Healthcare. KMO has received fees for consultations and/or lectures from Actelion, Bayer, GSK, and United Therapeutics. HJS has nothing to disclose. MS has nothing to disclose. HJS has received speaker's and/or consultant fees from Actelion, Bayer, GSK. SU receives grants from the Swiss National Science Foundation and the Zurich Lung. She has received speaker fees and unrestricted grant money from Actelion, Bayer, Orpha-Swiss. CBW has received speaker's fees or consultant honoraria from Bayer AG, BTG, MSD and P fi zer. EM has received speaker's and/or consultant fees from Actelion, Bayer, MSD and P fi zer.

References

[1] N. Galie, M. Humbert, J.L. Vachiery, et al., 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT), Eur. Heart J. 37 (1) (2016) 67 – 119. [2] S.V. Konstantinides, A. Torbicki, G. Agnelli, et al., ESC guidelines on the diagnosis and management of acute pulmonary embolism, Eur. Heart J. 35 (43) (2014) 3033 – 3069 (69a-69k). [3] F.A. Klok, C. Tesche, L. Rappold, et al., External validation of a simple non-invasive algorithm to rule out chronic thromboembolic pulmonary hypertension after acute pulmonary embolism, Thromb. Res. 135 (5) (2015) 796 – 801. [4] D. Taboada, J. Pepke-Zaba, D.P. Jenkins, et al., Outcome of pulmonary endarterectomy in symptomatic chronic thromboembolic disease, Eur. Respir. J. 44 (6) (2014) 1635 – 1645.

[5] M.M. Hoeper, M. Humbert, R. Souza, et al., A global view of pulmonary hypertension,

Lancet Respir. Med. 4 (4) (2016) 306 – 322. [6] D. Poli, E. Grifoni, E. Antonucci, et al., Incidence of recurrent venous thromboembolism and of chronic thromboembolic pulmonary hypertension in patients after a fi rst episode of pulmonary embolism, J. Thromb. Thrombolysis 30 (3) (2010) 294 – 299. [7] D. Marti, V. Gomez, C. Escobar, et al., Incidence of symptomatic and asymptomatic chronic thromboembolic pulmonary hypertension, Arch. Bronconeumol. 46 (12) (2010) 628 – 633. [8] I.M. Lang, M. Madani, Update on chronic thromboembolic pulmonary hypertension, Circulation 130 (6) (2014) 508 – 518. [9] F.A. Klok, O. Dzikowska-Diduch, M. Kostrubiec, et al., Derivation of a clinical prediction score for chronic thromboembolic pulmonary hypertension after acute pulmonary embolism, J. Thromb. Haemost. 14 (1) (2016) 121 – 128. [10] J. Pepke-Zaba, M. Delcroix, I. Lang, et al., Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry, Circulation 124 (18) (2011) 1973 – 1981. [11] D. Bonderman, P.L. Turecek, J. Jakowitsch, et al., High prevalence of elevated clotting factor VIII in chronic thromboembolic pulmonary hypertension, Thromb. Haemost. 90 (3) (2003) 372 – 376. [12] D. Bonderman, J. Jakowitsch, C. Adlbrecht, et al., Medical conditions increasing the risk of chronic thromboembolic pulmonary hypertension, Thromb. Haemost. 93 (3) (2005) 512 – 516. [13] I.M. Lang, G. Simonneau, J.W. Pepke-Zaba, et al., Factors associated with diagnosis and operability of chronic thromboembolic pulmonary hypertension. A casecontrol study, Thromb. Haemost. 110 (1) (2013) 83 – 91. [14] D. Bonderman, H. Wilkens, S. Wakounig, et al., Risk factors for chronic thromboembolic pulmonary hypertension, Eur. Respir. J. 33 (2) (2009) 325 – 331. [15] D. Bonderman, J. Jakowitsch, B. Redwan, et al., Role for staphylococci in misguided thrombus resolution of chronic thromboembolic pulmonary hypertension, Arterioscler. Thromb. Vasc. Biol. 28 (4) (2008) 678 – 684. [16] D. Zabini, C. Nagaraj, E. Stacher, et al., Angiostatic factors in the pulmonary endarterectomy material from chronic thromboembolic pulmonary hypertension patients cause endothelial dysfunction, PLoS One 7 (8) (2012), e43793 [17] S. Alias, B. Redwan, A. Panzenbock, et al., Defective angiogenesis delays thrombus resolution: a potential pathogenetic mechanism underlying chronic thromboembolic pulmonary hypertension, Arterioscler. Thromb. Vasc. Biol. 34 (4) (2014) 810 – 819. [18] M.K. Frey, S. Alias, M.P. Winter, et al., Splenectomy is modifying the vascular remodeling of thrombosis, J. Am. Heart Assoc. 3 (1) (2014), e000772 [19] T.A. Morris, J.J. Marsh, P.G. Chiles, et al., High prevalence of dys fi brinogenemia among patients with chronic thromboembolic pulmonary hypertension, Blood 114 (9) (2009) 1929 – 1936. [20] M. Held, A. Hesse, F. Gott, et al., A symptom-related monitoring program following pulmonary embolism for the early detection of CTEPH: a prospective observational registry study, BMC Pulm. Med. 14 (2014) 141. [21] M. Held, M. Grün, R. Holl, et al., Chronic thromboembolic pulmonary hypertension: time delay from onset of symtoms to diagnosis and clinical condition at diagnosis, Dtsch. Med. Wochenschr. 139 (33) (2014) 1647 – 1652. [22] R.M. Berger, M. Beghetti, T. Humpl, et al., Clinical features of paediatric pulmonary hypertension: a registry study, Lancet 379 (9815) (2012) 537 – 546. [23] D. Tscholl, F. Langer, O. Wendler, H. Wilkens, T. Georg, H.J. Schafers, Pulmonary thromboendarterectomy – risk factors for early survival and hemodynamic improvement, Eur. J. Cardiothorac. Surg. 19 (6) (2001) 771 – 776. [24] M. Held, M. Grün, R. Holl, et al., Cardiopulmonary exercise testing to detect chronic thromboembolic pulmonary hypertension in patients with normal echocardiography, Respiration 87 (5) (2014) 379 – 387. [25] M. Held, P. Kolb, M. Grün, et al., Functional characterization of patients with chronic thromboembolic disease, Respiration 91 (2016) 503 – 509. [26] N. Tunariu, S.J. Gibbs, Z. Win, et al., Ventilation-perfusion scintigraphy is more sensitive than multidetector CTPA in detecting chronic thromboembolic pulmonary disease as a treatable cause of pulmonary hypertension, J. Nucl. Med. 48 (5) (2007) 680 – 684. [27] A. Seferian, B. Helal, X. Jais, et al., Ventilation/perfusion lung scan in pulmonary veno-occlusive disease, Eur. Respir. J. 40 (1) (2012) 75 – 83. [28] J. He, W. Fang, B. Lv, et al., Diagnosis of chronic thromboembolic pulmonary hypertension: comparison of ventilation/perfusion scanning and multidetector computed tomography pulmonary angiography with pulmonary angiography, Nucl. Med. Commun. 33 (5) (2012) 459 – 463. [29] M.M. Hoeper, E. Mayer, G. Simonneau, L.J. Rubin, Chronic thromboembolic pulmonary hypertension, Circulation 113 (16) (2006) 2011 – 2020. [30] M. Bajc, J.B. Neilly, M. Miniati, C. Schuemichen, M. Meignan, B. Jonson, EANM guidelines for ventilation/perfusion scintigraphy: part 2. Algorithms and clinical considerations for diagnosis of pulmonary emboli with V/P(SPECT) and MDCT, Eur. J. Nucl. Med. Mol. Imaging 36 (9) (2009) 1528 – 1538. [31] M. Bajc, J.B. Neilly, M. Miniati, et al., EANM guidelines for ventilation/perfusion scintigraphy: part 1. Pulmonary imaging with ventilation/perfusion single photon emission tomography, Eur. J. Nucl. Med. Mol. Imaging 36 (8) (2009) 1356 – 1370. [32] X. Soler, K.M. Kerr, J.J. Marsh, et al., Pilot study comparing SPECT perfusion scintigraphy with CT pulmonary angiography in chronic thromboembolic pulmonary hypertension, Respirology 17 (1) (2012) 180 – 184. [33] V.V. McLaughlin, A. Langer, M. Tan, et al., Contemporary trends in the diagnosis and management of pulmonary arterial hypertension: an initiative to close the care gap, Chest 143 (2) (2013) 324 – 332. [34] A.D. Sherrick, S.J. Swensen, T.E. Hartman, Mosaic pattern of lung attenuation on CT scans: frequency among patients with pulmonary artery hypertension of different causes, AJR Am. J. Roentgenol. 169 (1) (1997) 79 – 82.

Please cite this article as: H. Wilkens, et al., Chronic thromboembolic pulmonary hypertension (CTEPH): Updated Recommendations from the

Cologne Consensus Conference 2018, Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.08.079

ARTICLEIN PRESS

[35] T. Sugiura, N. Tanabe, Y. Matsuura, et al., Role of 320-slice CT imaging in the diagnostic workup of patients with chronic thromboembolic pulmonary hypertension, Chest 143 (4) (2013) 1070 – 1077. [36] S. Ley, J. Ley-Zaporozhan, M.B. Pitton, et al., Diagnostic performance of state-of-theart imaging techniques for morphological assessment of vascular abnormalities in patients with chronic thromboembolic pulmonary hypertension (CTEPH), Eur. Radiol. 22 (3) (2012) 607 – 616. [37] M. Heinrich, M. Uder, D. Tscholl, A. Grgic, B. Kramann, H.J. Schafers, CT scan fi ndings in chronic thromboembolic pulmonary hypertension: predictors of hemodynamic improvement after pulmonary thromboendarterectomy, Chest 127 (5) (2005) 1606 – 1613. [38] A. Grgic, F. Miodek, H.J. Schafers, et al., Assessment of operability by means of CTPA and perfusion SPECT in patients with chronic thromboembolic pulmonary hypertension, Acta Radiol. 57 (1) (2016) 33 – 40. [39] G. Dournes, D. Verdier, M. Montaudon, et al., Dual-energy CT perfusion and angiography in chronic thromboembolic pulmonary hypertension: diagnostic accuracy and concordance with radionuclide scintigraphy, Eur. Radiol. 24 (1) (2014) 42 – 51. [40] M. Sugiyama, T. Fukuda, Y. Sanda, et al., Organized thrombus in pulmonary arteries in patients with chronic thromboembolic pulmonary hypertension; imaging with cone beam computed tomography, Jpn. J. Radiol. (2014) https://doi.org/10.1007/ s11604-014-0319-8 . [41] J.B. Hinrichs, S. Marquardt, C. von Falck, et al., Comparison of C-arm computed tomography and digital subtraction angiography in patients with chronic thromboembolic pulmonary hypertension, Cardiovasc. Intervent. Radiol. 39 (1) (2016) 53 – 63. [42] D. Shure, G. Gregoratos, K.M. Moser, Fiberoptic angioscopy: role in the diagnosis of chronic pulmonary arterial obstruction, Ann. Intern. Med. 103 (6 (Pt 1)) (1985) 844 – 850. [43] S. Rajaram, A.J. Swift, A. Telfer, et al., 3D contrast-enhanced lung perfusion MRI is an effective screening tool for chronic thromboembolic pulmonary hypertension: results from the ASPIRE registry, Thorax 68 (7) (2013) 677 – 678. [44] T. Kawakami, A. Ogawa, K. Miyaji, et al., Novel angiographic classi fi cation of each vascular lesion in chronic thromboembolic pulmonary hypertension based on selective angiogram and results of balloon pulmonary angioplasty, Circ. Cardiovasc. Interv. 9 (10) (2016). [45] N. Tanabe, T. Sugiura, T. Jujo, et al., Subpleural perfusion as a predictor for a poor surgical outcome in chronic thromboembolic pulmonary hypertension, Chest 141 (4) (2012) 929 – 934. [46] N. Skoro-Sajer, G. Marta, C. Gerges, et al., Surgical specimens, haemodynamics and long-term outcomes after pulmonary endarterectomy, Thorax 69 (2) (2014) 116 – 122. [47] M.M. Madani, W.R. Auger, V. Pretorius, et al., Pulmonary endarterectomy: recent changes in a single institution's experience of more than 2,700 patients, Ann. Thorac. Surg. 94 (1) (2012) 97 – 103. [48] E. Mayer, D. Jenkins, J. Lindner, et al., Surgical management and outcome of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry, J. Thorac. Cardiovasc. Surg. 141 (3) (2011) 702 – 710. [49] A. Vuylsteke, L. Sharples, G. Charman, et al., Circulatory arrest versus cerebral perfusion during pulmonary endarterectomy surgery (PEACOG): a randomised controlled trial, Lancet 378 (9800) (2011) 1379 – 1387. [50] J.E. Cannon, L. Su, D.G. Kiely, et al., Dynamic risk strati fi cation of patient long-term outcome after pulmonary endarterectomy: results from the United Kingdom National Cohort, Circulation 133 (18) (2016) 1761 – 1771. [51] M. Berman, S. Tsui, A. Vuylsteke, et al., Successful extracorporeal membrane oxygenation support after pulmonary thromboendarterectomy, Ann. Thorac. Surg. 86 (4) (2008) 1261 – 1267. [52] M. Mydin, M. Berman, A. Klein, et al., Extracorporeal membrane oxygenation as a bridge to pulmonary endarterectomy, Ann. Thorac. Surg. 92 (5) (2011) e101 – e103. [53] P.A. Thistlethwaite, M.M. Madani, A.D. Kemp, M. Hartley, W.R. Auger, S.W. Jamieson, Venovenous extracorporeal life support after pulmonary endarterectomy: indications, techniques, and outcomes, Ann. Thorac. Surg. 82 (6) (2006) 2139 – 2145. [54] N.H. Kim, M. Delcroix, D.P. Jenkins, et al., Chronic thromboembolic pulmonary hypertension, J. Am. Coll. Cardiol. 62 (25 Suppl) (2013) D92 – D99. [55] H. Wilkens, I. Lang, T. Blankenburg, et al., Chronic thromboembolic pulmonary hypertension – a position paper, Dtsch. Med. Wochenschr. 139 (43) (2014) 2204 – 2206. [56] E. Gruenig, M. Lichtblau, N. Ehlken, et al., Safety and ef fi cacy of exercise training in various forms of pulmonary hypertension, Eur. Respir. J. 40 (1) (2012) 84 – 92. [57] H.J. Reesink, S. Surie, J.J. Kloek, et al., Bosentan as a bridge to pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension, J. Thorac. Cardiovasc. Surg. 139 (1) (2010) 85 – 91. [58] K.W. Jensen, K.M. Kerr, P.F. Fedullo, et al., Pulmonary hypertensive medical therapy in chronic thromboembolic pulmonary hypertension before pulmonary thromboendarterectomy, Circulation 120 (13) (2009) 1248 – 1254. [59] G. Simonneau, A.M. D'Armini, H.A. Ghofrani, et al., Predictors of long-term outcomes in patients treated with riociguat for chronic thromboembolic pulmonary hypertension: data from the CHEST-2 open-label, randomised, long-term extension trial, Lancet Respir. Med. 4 (5) (2016) 372 – 380. [60] X. Jais, A.M. D'Armini, P. Jansa, et al., Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension: BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension), a randomized, placebo-controlled trial, J. Am. Coll. Cardiol. 52 (25) (2008) 2127 – 2134. [61] H. Ghofrani, G. Simonneau, A. D'Armini, et al., Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study, Lancet Respir. Med. 10 (2017) 785 – 794. [62] J.A. Feinstein, S.Z. Goldhaber, J.E. Lock, S.M. Ferndandes, M.J. Landzberg, Balloon pulmonary angioplasty for treatment of chronic thromboembolic pulmonary hypertension, Circulation 103 (1) (2001) 10 – 13. [63] M. Kataoka, T. Inami, K. Hayashida, et al., Percutaneous transluminal pulmonary angioplasty for the treatment of chronic thromboembolic pulmonary hypertension, Circ. Cardiovasc. Interv. 5 (6) (2012) 756 – 762. [64] S. Fukui, T. Ogo, Y. Morita, et al., Right ventricular reverse remodelling after balloon pulmonary angioplasty, Eur. Respir. J. 43 (5) (2014) 1394 – 1402. [65] H. Mizoguchi, A. Ogawa, M. Munemasa, H. Mikouchi, H. Ito, H. Matsubara, Re fi ned balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension, Circ. Cardiovasc. Interv. 5 (6) (2012) 748 – 755. [66] S.K. Maschke, J. Renne, T. Werncke, et al., Chronic thromboembolic pulmonary hypertension: evaluation of 2D-perfusion angiography in patients who undergo balloon pulmonary angioplasty, Eur. Radiol. 27 (2017) 4264 – 4270. [67] K.M. Olsson, C.B. Wiedenroth, J.C. Kamp, et al., Balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension: the initial German experience, Eur. Respir. J. 49 (6) (2017). [68] A.K. Andreassen, A. Ragnarsson, E. Gude, O. Geiran, R. Andersen, Balloon pulmonary angioplasty in patients with inoperable chronic thromboembolic pulmonary hypertension, Heart 99 (19) (2013) 1415 – 1420. [69] T. Inami, M. Kataoka, R. Yanagisawa, et al., Long-term outcomes after percutaneous transluminal pulmonary angioplasty for chronic thromboembolic pulmonary hypertension, Circulation 134 (24) (2016) 2030 – 2032. [70] C.B. Wiedenroth, C. Liebetrau, A. Breithecker, et al., Combined pulmonary endarterectomy and balloon pulmonary angioplasty in patients with chronic thromboembolic pulmonary hypertension, J Heart Lung Transplant 35 (5) (2016) 591 – 596. [71] H.H. Wong, I. Gounaris, A. McCormack, et al., Presentation and management of pulmonary artery sarcoma, Clin. Sarcoma Res. 5 (1) (2015) 3. [72] H.L. Gan, J.Q. Zhang, X.Y. Huang, W. Yu, The wall eclipsing sign on pulmonary artery computed tomography angiography is pathognomonic for pulmonary artery sarcoma, PLoS One 8 (12) (2013), e83200. [73] C.K. Choong, J.S. Lawton, M.R. Moon, R.J. Damiano Jr., Failure of medical therapy for pulmonary “ thromboembolic ” disease: beware the unsuspected primary sarcoma of the pulmonary artery, J. Thorac. Cardiovasc. Surg. 128 (5) (2004) 763 – 765. [74] E.J. Lee, S.H. Moon, J.Y. Choi, et al., Usefulness of fl uorodeoxyglucose positron emission tomography in malignancy of pulmonary artery mimicking pulmonary embolism, ANZ J. Surg. 83 (5) (2013) 342 – 347. [75] S.M. Said, T.M. Sundt 3rd, Y.I. Garces, D.A. Wigle, 5-year survival after multiple repeat metastasectomy for pulmonary artery angiosarcoma, Ann. Thorac. Surg. 91 (4) (2011) e49 – e51.