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Chronic thromboembolic pulmonary hypertension is a complication of pulmonary embolism and a treatable cause of pulmonary hypertension. The pathology is a unique combination of mechanical obstruction due to failure of clot resolution, and a variable degree of microvascular disease, that both contribute to pulmonary vascular resistance. Accordingly, multiple treatments have been developed to target the disease components. However, accurate diagnosis is often delayed. Evaluation includes high-quality imaging modalities, necessary for disease confirmation and for appropriate treatment planning. All patients with chronic thromboembolic pulmonary disease, and especially those with pulmonary hypertension, should be referred to expert centres for multidisciplinary team decision on treatment. The first decision remains assessment of operability, and the best improvement in symptoms and survival is achieved by the mechanical therapies, pulmonary endarterectomy and balloon pulmonary angioplasty. With the advances in multimodal therapies, excellent outcomes can be achieved with 3-year survival of >90%., Competing Interests: Conflict of interest: N.H. Kim reports consultancy fees from Bayer, Janssen, Merck, United Therapeutics and Pulnovo, payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer, Janssen and Merck, participation on a data safety monitoring board or advisory board with Bayer, Janssen, Merck and United Therapeutics, and leadership roles with International CTEPH Association and CTEPH.com. A.M. D'Armini reports payment or honoraria for lectures, presentations, manuscript writing or educational events from AOP Health and MSD, and participation on a data safety monitoring board or advisory board with AOP Health. M. Delcroix reports consultancy fees from Actelion/Janssen/J&J, Acceleron/MSD, Gossamer and Ferrer, and payment or honoraria for lectures, presentations, manuscript writing or educational events from Actelion/Janssen/J&J, Acceleron/MSD and Ferrer. X. Jaïs reports grants from Acceleron, Janssen, MSD and Bayer HealthCare, and consultancy fees and payment or honoraria for lectures, presentations, manuscript writing or educational events from MSD. M. Jevnikar reports payment or honoraria for lectures, presentations, manuscript writing or educational events and support for attending meetings from Janssen and MSD. M.M. Madani reports royalties or licences from Wexler Surgical, consultancy fees from Bayer/MSD and Actelion/Janssen/J&J, and participation on a data safety monitoring board or advisory board with International CTEPH Association. H. Matsubara reports grants from Nippon Shinyaku, payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer, Janssen, Kaneka Medix, Mochida, MSD, Nippon Shinyaku, Nipro and AOP Orphan, payment for expert testimony from MSD, participation on a data safety monitoring board or advisory board with Bayer, Janssen, Mochida and MSD, and a leadership role with International CTEPH Association. M. Palazzini reports consultancy fees, payment or honoraria for lectures, presentations, manuscript writing or educational events, and support for attending meetings from Janssen. C.B. Wiedenroth reports consultancy fees from J&J, OrphaCare and MSD, payment or honoraria for lectures, presentations, manuscript writing or educational events from J&J, AOP-Health, Bayer, Inari, MSD and Pfizer, and a leadership role with International CTEPH Association. G. Simonneau has no potential conflicts of interest to disclose. D.P. Jenkins reports consultancy fees and payment or honoraria for lectures, presentations, manuscript writing or educational events from Janssen, and and a leadership role with International CTEPH Association., (Copyright ©The authors 2024.)

Background: Pulmonary endarterectomy (PEA), pulmonary arterial hypertension (PAH) therapy and balloon pulmonary angioplasty (BPA) are currently accepted therapies for chronic thromboembolic pulmonary hypertension (CTEPH). This international CTEPH Registry identifies clinical characteristics of patients, diagnostic algorithms and treatment decisions in a global context., Methods: 1010 newly diagnosed consecutive patients were included in the registry between February 2015 and September 2016. Diagnosis was confirmed by right heart catheterisation, ventilation-perfusion lung scan, computerised pulmonary angiography and/or invasive pulmonary angiography after at least 3 months on anticoagulation., Results: Overall, 649 patients (64.3%) were considered for PEA, 193 (19.1%) for BPA, 20 (2.0%) for both PEA and BPA, and 148 (14.7%) for PAH therapy only. Reasons for PEA inoperability were technical inaccessibility (n=235), comorbidities (n=63) and patient refusal (n=44). In Europe and America and other countries (AAO), 72% of patients were deemed suitable for PEA, whereas in Japan, 70% of patients were offered BPA as first choice. Sex was evenly balanced, except in Japan where 75% of patients were female. A history of acute pulmonary embolism was reported for 65.6% of patients. At least one PAH therapy was initiated in 35.8% of patients (26.2% of PEA candidates, 54.5% of BPA candidates and 54.1% of those not eligible for either PEA or BPA). At the time of analysis, 39 patients (3.9%) had died of pulmonary hypertension-related causes (3.5% after PEA and 1.8% after BPA)., Conclusions: The registry revealed noticeable differences in patient characteristics (rates of pulmonary embolism and sex) and therapeutic approaches in Japan compared with Europe and AAO., Competing Interests: Conflict of interest: S. Guth reports personal fees from Actelion, Bayer, GSK, MSD and Pfizer outside the submitted work. Conflict of interest: A.M. D'Armini reports personal fees from Actelion, Bayer and MSD outside the submitted work. Conflict of interest: M. Delcroix reports grants and personal fees from Actelion, and personal fees from Bayer, MSD, Reata and Bellarophon, outside the submitted work. Conflict of interest: K. Nakayama has nothing to disclose. Conflict of interest: E. Fadel has nothing to disclose. Conflict of interest: S.P. Hoole has nothing to disclose. Conflict of interest: D.P. Jenkins reports personal fees from Actelion, and grants and personal fees from Bayer, outside the submitted work. Conflict of interest: D.G. Kiely reports grants, personal fees and nonfinancial support from Actelion, Bayer and GSK, and personal fees and nonfinancial support from MSD, outside the submitted work. Conflict of interest: N.H. Kim reports personal fees from Actelion, Bayer and Merck, and grants from United Therapeutics and SoniVie, outside the submitted work. Conflict of interest: I.M. Lang reports grants and personal fees from Actelion and AOPOrphan Pharma, personal fees from MSD, and nonfinancial support from Medtronic, during the conduct of the study; and grants and personal fees from Actelion and AOPOrphan, and personal fees from MSD and Ferrer, outside the submitted work. Conflict of interest: M.M. Madani is a consultant for Actelion. Conflict of interest: H. Matsubara reports personal fees from Actelion, AOP orphan Pharmaceuticals AG, Bayer, GlaxoSmithKline, Pfizer Japan, Inc., United Therapeutics, Nippon Shinyaku, Co., Ltd, and Kaneka Medix Corporation, outside the submitted work. Conflict of interest: A. Ogawa reports personal fees from Nippon Shinyaku Co., Ltd., outside the submitted work. Conflict of interest: J. Ota-Arakaki has nothing to disclose. Conflict of interest: R. Quarck has nothing to disclose. Conflict of interest: R. Sadushi-Kolici has nothing to disclose. Conflict of interest: G. Simonneau has nothing to disclose. Conflict of interest: C.B. Wiedenroth reports personal fees from Actelion, AOP, Bayer, MSD and Pfizer outside the submitted work. Conflict of interest: B. Yildizeli has nothing to disclose. Conflict of interest: E. Mayer reports personal fees from Actelion, Bayer, MSD and BMS outside the submitted work. Conflict of interest: J. Pepke-Zaba reports personal fees and nonfinancial support from Actelion and Merck, and nonfinancial support from GSK, outside the submitted work., (Copyright ©The authors 2021.)

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism, either symptomatic or not. The occlusion of proximal pulmonary arteries by fibrotic intravascular material, in combination with a secondary microvasculopathy of vessels <500 µm, leads to increased pulmonary vascular resistance and progressive right heart failure. The mechanism responsible for the transformation of red clots into fibrotic material remnants has not yet been elucidated. In patients with pulmonary hypertension, the diagnosis is suspected when a ventilation/perfusion lung scan shows mismatched perfusion defects, and confirmed by right heart catheterisation and vascular imaging. Today, in addition to lifelong anticoagulation, treatment modalities include surgery, angioplasty and medical treatment according to the localisation and characteristics of the lesions.This statement outlines a review of the literature and current practice concerning diagnosis and management of CTEPH. It covers the definitions, diagnosis, epidemiology, follow-up after acute pulmonary embolism, pathophysiology, treatment by pulmonary endarterectomy, balloon pulmonary angioplasty, drugs and their combination, rehabilitation and new lines of research in CTEPH.It represents the first collaboration of the European Respiratory Society, the International CTEPH Association and the European Reference Network-Lung in the pulmonary hypertension domain. The statement summarises current knowledge, but does not make formal recommendations for clinical practice., Competing Interests: Conflict of interest: M. Delcroix reports grants and other (investigator, speaker and consultant fees received by the institution) from Actelion/J&J, other (investigator, speaker and consultant fees received by the institution) from Bayer, other (speaker and consultant fees received by the institution) from MSD, other (investigator fees received by the institution) from Reata, other (investigator and consultant fees received by the institution) from Bellarophon, other (consultant fees received by the institution) from Acceleron, outside the submitted work. Conflict of interest: A. Torbicki reports grants and personal fees for lectures and consultancy from Actelion/Janssen, Bayer and MSD, personal fees for lectures from AOP, personal fees for lectures and consultancy from Pfizer, outside the submitted work. Conflict of interest: D. Gopalan reports other (speaker fees) from Actelion/J&J, other (consultancy work and speaker fees) from Bayer, outside the submitted work. Conflict of interest: O. Sitbon reports grants, personal fees and non-financial support from Actelion Pharmaceuticals and MSD, grants from GlaxoSmithKline, personal fees from Bayer, Acceleron Pharmaceuticals, Gossamer Bio and Ferrer, outside the submitted work. Conflict of interest: F.A. Klok reports research grants from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi-Sankyo, MSD and Actelion, the Dutch Heart Foundation and the Dutch Thrombosis association, outside the submitted work. Conflict of interest: I. Lang reports grants and personal fees from Actelion-Janssen and AOP Orphan Pharma, personal fees from Medtronic, Ferrer and United Therapeutics, outside the submitted work. Conflict of interest: D. Jenkins reports grants from Bayer, personal fees for advisory board work from Actelion, outside the submitted work. Conflict of interest: N.H. Kim reports personal fees for consultancy from Actelion, Bayer and Merck, outside the submitted work. Conflict of interest: M. Humbert reports grants and personal fees from Actelion and Bayer, personal fees from Acceleron, GSK, Merck, Novartis, AstraZeneca and Sanofi, outside the submitted work. Conflict of interest: X. Jais reports personal fees and non-financial support from Actelion and MSD, grants from Bayer, outside the submitted work. Conflict of interest: A. Vonk Noordegraaf is supported by the Netherlands CardioVascular Research Initiative (CVON-2012-08 PHAEDRA, CVON-2017-10 DOLPHIN-GENESIS) and the Netherlands Organization for Scientific Research (NWO-VICI: 918.16.610), has received speakers’ money from Johnson & Johnson and Ferrer in the past 3 years, and served as a member of the scientific advisory board of Morphogen-XI. Conflict of interest: J. Pepke-Zaba has received speaker fees and honoraria for consultations from Actelion, Merck and Bayer, and her institution received research and educational grants from Actelion and Merck. Conflict of interest: P. Brénot has nothing to disclose. Conflict of interest: P. Dorfmuller has nothing to disclose. Conflict of interest: E. Fadel has nothing to disclose. Conflict of interest: H-A. Ghofrani reports personal fees and other (consultancy fees) from Actelion, Bayer AG, GlaxoSmithKline, Novartis and Pfizer, other (consultancy fees) from Bellerophon Pulse Technologies and MSD, grants from Deutsche Forschungsgemeinschaft (DFG), during the conduct of the study. Conflict of interest: M.M. Hoeper reports personal fees for consultancy and lectures from Bayer AG, MSD, Actelion, Jansen, Acceleron and Pfizer, during the conduct of the study. Conflict of interest: P. Jansa reports other (investigator) from Actelion, personal fees and other (investigator) from Bayer Pharma AG and Reata Pharmaceuticals, personal fees from AOP and MSD, outside the submitted work. Conflict of interest: M. Madani reports personal fees for consultancy from Actelion and Wexler Surgical, outside the submitted work. Conflict of interest: H. Matsubara reports personal fees from Actelion Pharmaceuticals Japan, Ltd, AOP Orphan Pharmaceuticals AG, Bayer Yakuhin, Ltd, Pfizer Japan, Inc., Nippon Shinyaku, Co., Ltd, Kaneka Medix Corporation, GlaxoSmithKline Pharmaceuticals, Ltd and United Therapeutics Corporation, outside the submitted work. Conflict of interest: T. Ogo has nothing to disclose. Conflict of interest: E. Grünig reports fees for lectures and/or consultations from Actelion, Bayer AG, GSK, MSD, United Therapeutics and Pfizer, outside the submitted work. Conflict of interest: A. D'Armini reports personal fees from Actelion Phamaceuticals, Bayer AG and Merck Sharp & Dohme, outside the submitted work. Conflict of interest: N. Galie reports grants and personal fees from Actelion and Janssen, personal fees from Pfizer and Ferrer, outside the submitted work. Conflict of interest: B. Meyer reports personal fees for lectures from Bayer AG, outside the submitted work. Conflict of interest: P. Corkery has nothing to disclose. Conflict of interest: G. Meszaros reports personal fees from Actelion Pharmaceuticals, outside the submitted work. Conflict of interest: E. Mayer reports personal fees for lectures and consultancy from Actelion, Bayer and MSD, during the conduct of the study. Conflict of interest: G. Simonneau reports personal fees and non-financial support from Actelion, Bayer and MSD, outside the submitted work., (Copyright ©ERS 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Chronic thromboembolic pulmonary hypertension (CTEPH) is a type of pulmonary hypertension, resulting from fibrotic transformation of pulmonary artery clots causing chronic obstruction in macroscopic pulmonary arteries and associated vascular remodelling in the microvasculature.Pulmonary endarterectomy (PEA) offers the best chance of symptomatic and prognostic improvement in eligible patients; in expert centres, it has excellent results. Current in-hospital mortality rates are <5% and survival is >90% at 1 year and >70% at 10 years. However, PEA, is a complex procedure and relies on a multidisciplinary CTEPH team led by an experienced surgeon to decide on an individual's operability, which is determined primarily by lesion location and the haemodynamic parameters. Therefore, treatment of patients with CTEPH depends largely on subjective judgements of eligibility for surgery by the CTEPH team.Other controversies discussed in this article include eligibility for PEA versus balloon pulmonary angioplasty, the new treatment algorithm in the European Society of Cardiology/European Respiratory Society guidelines and the definition of an "expert centre" for the management of this condition., (Copyright ©ERS 2017.)

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterised by the presence of thromboembolic material in the pulmonary circulation, and patients have a poor prognosis without treatment. Patients present with nonspecific symptoms, such as breathlessness and syncope, which means that other more common conditions are sometimes suspected before CTEPH, leading to delayed diagnosis and treatment. This is problematic because CTEPH is potentially curable with surgical pulmonary endarterectomy (PEA); indeed, CTEPH should always be considered in any patient with unexplained pulmonary hypertension (PH). Several key evaluations are necessary and complementary to confirm a diagnosis of CTEPH and assess operability. Echocardiography is initially used to confirm a general diagnosis of PH. Ventilation/perfusion scanning is then essential in the first stage of CTEPH diagnosis, with a wedge-shaped perfusion deficit indicative of CTEPH. This should be followed by right heart catheterisation (RHC) which is mandatory in confirming the diagnosis and providing haemodynamic parameters that are key predictors of the risk associated with PEA and subsequent prognosis. RHC is ideally coupled with conventional pulmonary angiography, the gold-standard technique for confirming the location and extent of disease, and thus whether the obstruction is surgically accessible. Computed tomographic pulmonary angiography is also now routinely used as a complementary technique to aid diagnosis and operability assessment. Recent improvements in the resolution of other noninvasive techniques, such as cardiac magnetic resonance imaging, allow for detailed reconstructions of the vascular tree and imaging of vessel defects, and interest in their use is increasing., (Copyright ©ERS 2015.)

Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of inoperable and persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH). In the 16-week CHEST-1 study, riociguat showed a favourable benefit-risk profile and improved several clinically relevant end-points in patients with CTEPH. The CHEST-2 open-label extension evaluated the long-term safety and efficacy of riociguat. Eligible patients from CHEST-1 received riociguat individually adjusted up to a maximum dose of 2.5 mg three times daily. The primary objective was the safety and tolerability of riociguat; exploratory efficacy end-points included 6-min walking distance (6MWD) and World Health Organization (WHO) functional class (FC). Overall, 237 patients entered CHEST-2 and 211 (89%) were ongoing at this interim analysis (March 2013). The safety profile of riociguat in CHEST-2 was similar to CHEST-1, with no new safety signals. Improvements in 6MWD and WHO FC observed in CHEST-1 persisted for up to 1 year in CHEST-2. In the observed population at 1 year, mean±sd 6MWD had changed by +51±62 m (n=172) versus CHEST-1 baseline (n=237), and WHO FC had improved/stabilised/worsened in 47/50/3% of patients (n=176) versus CHEST-1 baseline (n=236). Long-term riociguat had a favourable benefit-risk profile and apparently showed sustained benefits in exercise and functional capacity for up to 1 year., (Copyright ©ERS 2015.)

Patients with chronic thromboembolic pulmonary hypertension (CTEPH), despite successful pulmonary endarterectomy (PEA), can continue to suffer from a limitation in exercise capacity. The objective of this study was to assess whether pulmonary arterial compliance is a predictor of exercise capacity after PEA. Right heart haemodynamics, treadmill incremental exercise test, spirometry, carbon monoxide transfer factor, arterial blood gas and echocardiographic examinations were retrospectively analysed in a population of CTEPH patients who underwent PEA at a single centre. Baseline and 3-month haemodynamic data were available in 296 patients; 5-year follow-up data were available in 68 patients. In a multivariable model the following parameters were found to be independent predictors of exercise capacity after surgery: age, sex, pulmonary arterial compliance, tricuspid annular plane excursion, arterial oxygen tension and carbon monoxide transfer factor (p<0.0001); the model showed good discrimination (Harrell's c=0.84) and calibration (shrinkage coefficient=0.91). Poor exercise capacity at 3 months was loosely associated with higher death rate during subsequent survival (Harrell's c=0.61). In conclusion, after successful PEA, reduced pulmonary arterial compliance is an important determinant of exercise capacity in association with the age and sex of the patients, and the extent of recovery of both cardiac and respiratory function. However, exercise capacity does not explain a large proportion of the effect of surgery on subsequent survival.