Chronic Thromboembolic Pulmonary Hypertension (CTEPH) PDF 2023 - Lancet Respiratory Medicine

Series Pulmonary Hypertension 3 Chronic thromboembolic pulmonary hypertension: realising the potential of multimodal management Mar...

Series Pulmonary Hypertension 3 Chronic thromboembolic pulmonary hypertension: realising the potential of multimodal management Marion Delcroix, Marc de Perrot, Xavier Jaïs, David P Jenkins, Irene M Lang, Hiromi Matsubara, Lilian J Meijboom, Rozenn Quarck, Gérald Simonneau, Christoph B Wiedenroth, Nick H Kim Lancet Respir Med 2023; Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism. 11: 836–50 Important advances have enabled better understanding, characterisation, and treatment of this condition. Guidelines Published Online recommending systematic follow-up after acute pulmonary embolism, and the insight that CTEPH can mimic acute August 14, 2023 pulmonary embolism on initial presentation, have led to the definition of CTEPH imaging characteristics, the https://doi.org/10.1016/ S2213-2600(23)00292-8 introduction of artificial intelligence diagnosis pathways, and thus the prospect of easier and earlier CTEPH diagnosis. See Comment page 760 In this Series paper, we show how the understanding of CTEPH as a sequela of inflammatory thrombosis has driven This is the third in a Series of successful multidisciplinary management that integrates surgical, interventional, and medical treatments. We three papers about pulmonary provide imaging examples of classical major vessel targets, describe microvascular targets, define available tools, and hypertension. All papers in the depict an algorithm facilitating the initial treatment strategy in people with newly diagnosed CTEPH based on a Series are available at www. multidisciplinary team discussion at a CTEPH centre. Further work is needed to optimise the use and combination of thelancet.com/series/ pulmonary-hypertension-2023 multimodal therapeutic options in CTEPH to improve long-term outcomes for patients. Clinical Department of Respiratory Diseases, Introduction showing very high systolic pulmonary arterial pressure University Hospitals of Leuven With advances in multimodal therapeutic management, (sPAP; ie, >60 mm Hg) or features of right ventricular and Laboratory of Respiratory the 3-year survival for people with chronic thrombo­ dysfunction and hypertrophy, or both, should further Diseases and Thoracic Surgery (BREATHE), Department of embolic pulmonary hypertension (CTEPH) has improved raise suspicion of underlying CTEPH.5,6,14 In addition, Chronic Diseases and to more than 90% for both operable1 and inoperable some conditions have been associated with CTEPH, such Metabolism (CHROMETA), KU patients.2–4 In this Series paper, we show how all as antiphospholipid syndrome, malignancies, splen­ Leuven–University of Leuven, components of the disease can be targeted by a specific ectomy, implanted devices (eg, port catheters, Leuven, Belgium (Prof M Delcroix MD, therapeutic approach. Because we are aware of some ventriculo-atrial shunts, or pacemaker leads), inflam­ R Quarck PhD); Division of resistance to the referral of patients to multidisciplinary matory bowel disease, and thyroid hormone replacement Thoracic Surgery, Toronto CTEPH centres due to the invasiveness of surgery, therapy;8,15–17 these conditions might also raise the General Hospital, Toronto, ON, patient refusal, or travel distances, we felt it timely to suspicion of CTEPH in the affected individuals. Canada (Prof M de Perrot MD); Assistance Publique-Hôpitaux summarise the excellent results of the therapeutic In this Series paper, we aim to describe the underlying de Paris (AP-HP), Service de approaches, both separately and in combination. mechanisms of disease; the involvement of different Pneumologie, Hôpital Bicêtre, CTEPH is part of group 4 of the pulmonary vascular components—ie, the large proximal (lobar-to- Université Paris-Saclay, Le hypertension classification5,6 and generally seems to segmental) and small distal (subsegmental) pulmonary Kremlin-Bicêtre, France (X Jaïs MD, affect more than a third of the patients referred to arteries, the pulmonary microvasculature, and the Emeritus Prof G Simonneau MD); pulmonary hypertension centres. It is considered a rare systemic and bronchial circulation; the imaging of typical Department of Cardiothoracic complication of pulmonary embolism, with an incidence lesions; the specific therapeutic approach to the different Surgery, Royal Papworth of around 3% in pulmonary embolism survivors.7 lesions; and the multimodal approach in individual Hospital, Cambridge, UK (Prof D P Jenkins MD); Division However, a previous venous thromboembolic episode is patients. of Cardiology, Department of not always documented.8 The observed incidence of Internal Medicine II, Vienna CTEPH in the general population is around six cases Disease mechanisms in CTEPH General Hospital, Centre for per million but could in reality be 3-times higher than After an acute episode of pulmonary embolism, a CardioVascular Medicine, Medical University of Vienna, this, as estimated from pulmonary embolism multifactorial process of reorganisation and Vienna, Austria incidence.9,10 recanalisation resolves thrombi within 3 months in the (Prof I M Lang MD); National CTEPH is characterised by persistent fibrothrombotic vast majority of patients.18 Venous thrombi undergo a Hospital Organization vascular obstruction of the pulmonary arteries. Patients change in structural composition, from erythrocyte-rich Okayama Medical Center, Okayama, Japan often present with non-specific symptoms of exertional to fibrin-rich and collagen-rich clots,19 which involves (Prof H Matsubara MD); dyspnoea and fatigue, but can also present with signs sequential recruitment of leukocytes to the thrombus Department of Radiology and of right heart failure and, rarely, haemoptysis.8,11 formation site. Neutrophils are the first cell type to be Nuclear Medicine, Amsterdam 2019 guidelines recommending a systematic follow-up recruited, followed by monocyte-derived macrophages; Cardiovascular Sciences, Amsterdam UMC, Vrije assessing residual symptoms after acute pulmonary intra-thrombus collagen deposition is enhanced and Universiteit Amsterdam, embolism and providing awareness on imaging endothelial-lined channels become apparent within the Amsterdam, Netherlands characteristics of chronic thromboembolism have thrombus to potentially restore blood flow, a process (L J Meijboom MD); Department supported the diagnosis of CTEPH.12,13 Echocardiograms often referred to as neovascularisation.20 836 www.thelancet.com/respiratory Vol 11 September 2023 Descargado para Anonymous User (n/a) en University of Guadalajara de ClinicalKey.es por Elsevier en enero 19, 2024. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.  Series CTEPH pathogenesis involves a cascade of events that of Thoracic Surgery, Kerckhoff starts with the incomplete resolution and organisation of Key messages Clinic, Bad Nauheim, Germany (C B Wiedenroth MD); Division the thrombus, followed by a defect in thrombus Chronic thromboembolic pulmonary hypertension of Pulmonary, Critical Care and angiogenesis, which results in the obstruction of large (CTEPH) is a three-compartment disease involving Sleep Medicine, University of pulmonary arteries by fibrothrombotic lesions and (1) proximal (ie, lobar-to-segmental) and (2) distal California San Diego, La Jolla, adaptive remodelling of pulmonary pre-capillary vessels. CA, USA (Prof N H Kim MD) (ie, subsegmental) pulmonary arteries that are obstructed The chronology and regulation of the cellular and by persistent fibrothrombotic material, and Correspondence to: Prof Marion Delcroix, Clinical molecular mechanisms that result in the persistence of (3) pre-capillary pulmonary arteries that can be affected as Department of Respiratory obstructing fibrothrombotic material remain incompletely in pulmonary arterial hypertension Diseases, University Hospitals of understood. However, different hypotheses have been Advanced imaging with CT pulmonary angiography, Leuven and Laboratory of explored. Patients with CTEPH display an elevated Respiratory Diseases and digital subtraction angiography, and selective Thoracic Surgery (BREATHE), prevalence of abnormalities in fibrinogen structure and angiography helps to distinguish proximal from distal Department of Chronic Diseases function, such as the Thr312Ala mutation in the obstructive disease, but cannot establish the degree of and Metabolism (CHROMETA), fibrinogen Aα-chain21 or polymorphisms within its pre-capillary microvasculopathy, which is estimated by KU Leuven–University of Leuven, α-chains and β-chains,22 resulting in impaired Leuven 3000, Belgium considering the discrepancy between obstructive disease [email protected] fibrinolysis.23,24 Pulmonary arterial smooth muscle and seen on imaging and haemodynamic severity, most endothelial cells from patients with CTEPH display altered notably pulmonary vascular resistance properties25–28 and, by potentially interacting with the The therapeutic strategy relies on a stepwise approach, thrombus, might contribute to the progression of CTEPH. starting with an operability assessment for pulmonary The presence of progenitor cells in endarterectomised endarterectomy from both technical and medical tissues from patients with CTEPH supports their standpoints; for inoperable patients, balloon pulmonary involvement in the formation of fibrothrombotic tissue.29,30 angioplasty (BPA) feasibility is then evaluated and, in The concept of inflammatory thrombosis24—based on an parallel, medical treatment with pulmonary hypertension elevated prevalence of inflammatory diseases,15 the drugs is considered presence of inflammatory cells within the fibrothrombotic Physiological re-evaluations, including exercise capacity material obstructing proximal pulmonary arteries,27,31–34 the and invasive haemodynamics, and long-term follow-up role of neutrophil extracellular traps in promoting fibrous are needed after mechanical interventions (eg, pulmonary occlusions in chronic thrombosis,35 elevated circulating endarterectomy or BPA), and regular follow-up is required inflammatory mediators,34,36–39 elevated factor VIII,40 and in patients treated medically to evaluate the need for the identification of epigenetic modification of von additional interventions Willebrand factor promoter driving platelet aggregation on All treatment decisions should be made in the context of the pulmonary endothelium in CTEPH41—has been a multidisciplinary CTEPH team that includes a pulmonary extensively explored. Inhibition of angiogenesis as a driver endarterectomy surgeon, a BPA expert, a pulmonary of misguided thrombus resolution,42–47 and the finding that hypertension specialist, and a thoracic radiologist the degree of neovascularisation of the fibrothrombotic Advances in multimodal therapeutic management mean material obstructing large pulmonary arteries is associated that both operable and inoperable patients with CTEPH with the outcome in patients with CTEPH,34,48 suggest that now have excellent survival rates, averaging 90% at 3 years deficient angiogenesis is also a key event in CTEPH progression. Chronic thromboembolic pulmonary disease (CTEPD) In the absence of pulmonary hypertension at rest and if has been proposed as an overarching term to characterise other causes of exercise limitation have been excluded symptomatic patients with mismatched perfusion (ie, ventilatory limitation due to lung diseases or cardiac defects on ventilation–perfusion lung scan and specific limitation due to left heart diseases), mechanical signs of chronic clots on CT pulmonary angiography interventions (ie, pulmonary endarterectomy and balloon (CTPA) or digital subtraction angiography (DSA) pulmonary angioplasty [BPA]) can be considered. This imaging. This disease term can be applied to those with approach is particularly justified in younger patients with or without pulmonary hypertension at rest.5,6,49 In patients high expectations regarding their exercise capacity. without pulmonary hypertension at rest, exercise limitation can be explained either by exercise-induced Types of lesion in CTEPH pulmonary hypertension, defined by a mean pulmonary Vascular components artery pressure (mPAP)–cardiac output slope of more Anatomically, two different types of pulmonary vascular than 3 mm Hg,5,6 or by a low ventilatory efficiency due to lesion contribute to an increase in pulmonary vascular dead space ventilation. The reason why patients with resistance (PVR) in patients with CTEPH (figure 1): (1) an similar lesion severity on imaging can present with or intravascular obstruction of pulmonary arteries by without pulmonary hypertension at rest is still poorly organised fibrotic clots, proximally at the lobar-to- understood. Additionally, CTEPD without pulmonary segmental level, or distally at the subsegmental level; and hypertension is not necessarily an early stage of CTEPH.50 (2) a secondary microvasculopathy characterised by a www.thelancet.com/respiratory Vol 11 September 2023 837 Descargado para Anonymous User (n/a) en University of Guadalajara de ClinicalKey.es por Elsevier en enero 19, 2024. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.  Series A B C D E Lobar Subsegmental F I H G Microvascular Figure 1: Types of lesion in CTEPH (A) Histological section through an obstructed lobar artery. (B) Histological section through an obstructed subsegmental artery. (C) Optical coherence tomography of a subsegmental artery. (D) Intravascular ultrasound of a subsegmental artery. (E, F) Histological sections showing microvascular changes. (G) Angioscopy showing webs in subsegmental arteries. (H) Surgical specimen of right lower lobar obstruction. (I) Surgical specimen with lobar, segmental, and subsegmental obstructions. CTEPH=chronic thromboembolic pulmonary hypertension. Created with BioRender.com. non-thrombotic obstructive remodelling, involving high-flow correction,56 and post-obstructive micro­ pulmonary arterioles and capillaries.51 In the non- vasculopathy as well as systemic vascularisation of the obstructed territories, the microvasculopathy is explained lung regressed after pulmonary artery reperfusion.57,58 by diversion of flow from the obstructed territories and shear stress induced by high flow and pressure. In the Assessment of microvasculopathy obstructed territories, the arteriopathy is attributed to Although current imaging is indispensable for the high flow from the systemic collateral circulation, arising diagnosis of CTEPH, no direct imaging of microvascular from bronchial, intercostal, or coronary arteries feeding changes is possible today. Several techniques have been into large vascular obstructions, and connecting to described to assess microvasculopathy in patients with pulmonary arteries and veins.52,53 These anastomoses are CTEPH, one of them being the measurement of mPAP, essential to keep the capillary bed open, precluding lung PVR, or a diastolic pulmonary vascular gradient that is out ischaemia and infarction in these areas.52 They can be of proportion to the degree of mechanical major vessel responsible for significant haemoptysis. Increased left obstruction. Acute haemodynamic testing with inhaled ventricular filling pressures in about a third of patients nitric oxide has been proposed but not systematically might contribute to the addition of a post-capillary implemented.59 Furthermore, the pulmonary artery pulmonary hypertension component.54 occlusion technique has been developed to assess the Remodelling of pre-capillary arteries in the non- presence of pre-capillary arterial and capillary–venous obstructed lung areas partially explains the discordance disease. In CTEPH, it allows the partitioning of PVR into between perfusion defects and PVR observed in CTEPH— larger arterial and small arterial plus venous in contrast to acute pulmonary embolism55—and might be components,60–62 but it has not been established generally responsible for the progression of CTEPH despite optimal as part of invasive haemodynamic assessment. Therefore, anticoagulation and no signs of recurrent pulmonary microvasculopathy is still empirically evaluated by embolism. Microvasculopathy in both obstructed and comparing imaging of vessel obstruction with pulmonary non-obstructed lung areas can explain persistent haemodynamics, which is subjective and lacks accuracy. pulmonary hypertension after successful mechanical treatment of obstructive lesions. Some data suggest that Imaging of CTEPH these microvascular lesions are potentially reversible if the Recent guidelines12,13 for the diagnosis and management cause is removed. In several animal models, pulmonary of acute pulmonary embolism, which recommended a microvasculopathy induced by high flow regressed after systematic follow-up after acute pulmonary embolism 838 www.thelancet.com/respiratory Vol 11 September 2023 Descargado para Anonymous User (n/a) en University of Guadalajara de ClinicalKey.es por Elsevier en enero 19, 2024. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.  Series and provided awareness of imaging characteristics of thromboembolic lesions and detect perfusion defects in chronic thromboembolism, have supported the diagnosis one investigation. of CTEPH. Studies have shown that the following signs Chronic thromboembolic lesions can have similar or are of utmost importance in recognising CTEPH on a different appearances on CTPA and DSA images. The CTPA performed for acute pulmonary embolism: proximal, laminated mural thrombus encroaching on intravascular bands or webs, arterial narrowing or the vessel lumen is seen as a filling defect on CTPA and retraction, dilated bronchial arteries, and right ventricular DSA images. Proximal, complete arterial occlusions are hypertrophy.63,64 seen as pouch defects on DSA and as acute stop or Advancements in CT techniques have led to improved missing vessels on CTPA. The fibrotic intravascular visualisation of the detailed morphology of chronic webs are seen as intraluminal strands on CTPA, but thromboembolic lesions in segmental and subsegmental when they are small and more distal, they can easily be pulmonary arteries.65–67 Mural thrombus, complete missed on DSA images. Segmental or subsegmental arterial occlusions, intravascular webs or bands, and artery retraction is seen as a missing part of a vessel on artery narrowing or retraction are all signs of CTEPD CTPA and as perfusion defects on DSA. It has been and can accurately be visualised on CTPA (figure 2). suggested that microvascular disease is seen as a distal Very peripheral chronic thromboembolic disease is peripheral rim of absent perfusion.70 To differentiate difficult to recognise on CTPA because of the small vascular pruning that might be observed in patients calibre of the vessels, but its proper visualisation is very with severe emphysema or fibrotic lung disease from important, not only for the diagnosis, but also for vascular retraction in people with CTEPH, it is optimal treatment planning.68 In this respect, perfusion important to simultaneously look at the lung images have additional value. Dual-energy CT is a parenchyma of the supplying artery.71 Lung cavities can relatively new CT technique, which can provide excellent be seen in patients with CTEPH (figure 2), which might morphological images of the pulmonary arteries with be solely related to lung infarction or the consequence perfusion images of the lungs based on iodine maps.69 of chronic infectious conditions;72 their prevalence is DSA can also be used to assess the morphology of the unknown. A B C D E i i i i i ii ii ii ii ii iii iii iii iii iv Figure 2: Imaging of target lesions in CTEPH (Ai) Ventilation–perfusion scan showing multiple perfusion defects. (Aii) SPECT perfusion defects in the lower lobes. (Aiii) Dual-energy CTPA peripheral perfusion defects on iodine map. (Bi) CTPA mural thrombus. (Bii) CTPA intravascular web. (Biii) CTPA pulmonary artery retraction and tapering (on angiogram subtotal occlusion). (Ci) CTPA mosaic perfusion (hypoperfused region; purple arrow). (Cii) CTPA lung cavity. (Ciii) CTPA peripheral wedge-shaped consolidation, classical for lung infarction. (Di) DSA perfusion defects (purple arrow) and subtotal occlusion (green arrow). (Dii) DSA peripheral perfusion defects. (Ei) Selective pulmonary angiography ring-like stenosis (purple arrow) and complex web (green arrow). (Eii) Selective pulmonary angiography subtotal occlusion. (Eiii) Selective pulmonary angiography total occlusion hump. (Eiv) Selective pulmonary angiography tortuous lesion, with two components: the occlusion (purple arrow) and the capillary network (green arrow). CTEPH=chronic thromboembolic pulmonary hypertension. CTPA=CT pulmonary angiography. DSA=digital subtraction angiography. SPECT=single-photon emission CT. www.thelancet.com/respiratory Vol 11 September 2023 839 Descargado para Anonymous User (n/a) en University of Guadalajara de ClinicalKey.es por Elsevier en enero 19, 2024. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.  Series Typical vascular lesions can be better seen by selective repair of the tricuspid valve is unnecessary as pulmonary angiography and have been classified by regurgitation is reduced by the drop in pressure and Kawakami and colleagues.73 Even more granular volume overload immediately following surgery. information has been obtained by angioscopy,74 optical Pulmonary endarterectomy can nearly normalise coherence tomography,75 or intravascular ultrasound pulmonary haemodynamics in 70–75% of operated (figure 1).76 These latter techniques are not used patients.80,81 The overall operative mortality is currently in routinely for treatment assessment. the range of 2–3% in specialised centres (table 1). The surgical risks depend on the preoperative PVR, but even Available therapeutic approaches in patients with the most severe forms of disease, In view of the pathophysiology of CTEPH, two mechanical characterised by a preoperative PVR of more treatment modalities targeting major vessel obstructions than 1000 dyn·s·cm–⁵ (12·5 Wood units), the operative are available: pulmonary endarterectomy and BPA. The mortality has decreased to less than 5%.78,87 Most patients theoretical target of pulmonary hypertension drugs is the undergoing pulmonary endarterectomy do not require secondary microvasculopathy. any allogeneic blood product transfusion.88 Despite the circulatory arrest, cognitive function improves, on Pulmonary endarterectomy average, after pulmonary endarterectomy as a Pulmonary endarterectomy is the guideline- consequence of better haemodynamics and improved recommended treatment of choice for operable patients brain perfusion.89 Reperfusion lung injury, a localised with CTEPH5,6 because of its ability to treat the widest high-permeability pulmonary oedema, usually develops variety of thromboembolic lesions over the largest in the first 72 h after pulmonary endarterectomy; it might anatomical distribution, from the pulmonary valve to be clinically or radiologically apparent to some degree in subsegmental branches.77 This is important because the up to 40% of patients. Management is generally pathology of CTEPH involves the whole pulmonary supportive, with oxygen therapy to correct hypoxaemia, circulation from the pulmonary valve to the micro­ positive-pressure ventilation, and promotion of diuresis. circulation. Most patients improve within a few days. Trials of steroid The aim of the operation is to remove all macroscopic therapy and specific low tidal volume ventilation obstructive material within the pulmonary arteries to strategies have not shown benefit. When reperfusion reduce PVR and improve ventilation–perfusion injury is severe and conventional ventilation inadequate, matching. The operation necessitates general anaesthesia venovenous extracorporeal membrane oxygenation can and a midline sternotomy incision to expose the heart. be life-saving. Cardiopulmonary bypass is required to divert most of the Quality of life, activity, and symptoms improve blood from the heart and lungs and provide perfusion of significantly in patients who have undergone pulmonary oxygenated blood to the body. However, this alone does endarterectomy compared with non-operated patients not provide enough of a bloodless field within the (table 1), and the improvement is sustained in patients pulmonary arteries to facilitate dissection, as the without clinically significant residual pulmonary bronchial circulation from the thoracic aorta delivers hypertension.90 In the long term, 5-year overall survival retrograde collateral blood flow in the surgical field. reaches 87% and 10-year overall survival reaches 79%, Hence, complete arrest of the circulation is required, with a disease-specific survival of 91% and 85%, which necessitates hypothermia to reduce the metabolic respectively.86 The cumulative incidence of additional rate and protect vital organs during the absence of pulmonary hypertension therapy after pulmonary perfusion. Clinical experience has shown that core endarterectomy is about 30% at 10 years, emphasising cooling to 20°C is sufficient to allow safe arrest periods of the importance of a multidisciplinary approach and long- up to 20 min, usually enough to complete clearance of term follow-up, particularly for patients with segmental disease on one side.78,79 and subsegmental disease.86 Relative contraindications to The pulmonary arteries are opened within the peri­ pulmonary endarterectomy surgery include major cardium and an endarterectomy plane created within the parenchymal lung disease such that improving perfusion pulmonary artery wall. This plane is extended from might not be of benefit, another condition such as cancer proximal to distal to remove the inner lining of the that significantly limits the lifespan, and a contra­ pulmonary artery, including all obstructive material. All indication to or refusal of anticoagulation. CTEPH lesions can be removed, including proximal laminated thrombus within the main and lobar vessels, Balloon pulmonary angioplasty blind-ending vessel occlusions, fibrotic webs and With the 2022 European Society of Cardiology–European stenoses at the lobar and segmental bifurcations and Respiratory Society Guidelines for the diagnosis and trifurcations, distal fine webs in subsegmental branches, treatment of pulmonary hypertension, BPA has been and occlusive distal tails of less than 1 mm in diameter upgraded and is recommended in patients with that shear off beyond the reach of the forceps with inoperable CTEPH or residual pulmonary hypertension appropriate gentle traction. In the majority of cases, after pulmonary endarterectomy with appropriate target 840 www.thelancet.com/respiratory Vol 11 September 2023 Descargado para Anonymous User (n/a) en University of Guadalajara de ClinicalKey.es por Elsevier en enero 19, 2024. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.  Year of Total mPAP (mm Hg) PVR (dyn·s·cm–⁵) 30-day Functional class I–II 6MWD (m) 3-year 5-year 10-year PH therapy BPA publication number of mortality survival survival survival at 5 years after patients PEA Pre-PEA Post-PEA Pre-PEA Post-PEA Pre-PEA Post-PEA Pre-PEA Post-PEA 79 UCSD (USA) Last 500 patients 2003 1500 46 (11) 28 (10) 893 (444) 285 (215) 4·4% ·· ·· ·· ·· ·· ·· ·· ·· ·· Type 1* 2003 1500 47 (10) 28 (9) 873 (444) 275 (201) 2·1% ·· ·· ·· ·· ·· ·· ·· ·· ·· Type 2 2003 1500 46 (12) 28 (10) 809 (419) 273 (219) 5·3% ·· ·· ·· ·· ·· ·· ·· ·· ·· Type 3 2003 1500 47 (12) 32 (11) 973 (488) 344 (194) 5·0% ·· ·· ·· ·· ·· ·· ·· ·· ·· Type 4 2003 1500 55 (10) 55 (13) 1163 (491) 868 (422) 25·0% ·· ·· ·· ·· ·· ·· ·· ·· ·· UCSD (USA)78 Last 500 patients 2012 2700 46 (12) 26 (8) 719 (383) 253 (149) 2·2% ·· ·· ·· ·· ·· ·· ·· ·· ·· Previous 1000 patients 2012 2700 46 (11) 29 (10) 861 (446) 295 (204) 5·2% ·· ·· ·· ·· ·· ·· ·· ·· ·· www.thelancet.com/respiratory Vol 11 September 2023 International CTEPH Registry (ICA)8† Overall 2011 386 ·· ·· 736 248 25% 90% 362 459 ·· ·· ·· ·· ·· (702–827) (230–263) (340–399) (440–473) International CTEPH Registry (ICA)1‡ Surgical patients 2016 679 48 ·· 728 ·· ·· 19% ·· 340 ·· 89% ·· ·· ·· ·· (17–80) (97–2880) (20–700) Non-surgical patients 2016 679 45 ·· 676 ·· ·· 18% ·· 315 ·· 70% ·· ·· ·· ·· (14–81) (165–2800) (11–677) Royal Papworth Hospital (UK)82 Overall 2016 880 47 (11) 27 (10) 830 (382) 317 (239) 13·2% 9% 85% 260 (126) 353 (118) 84% 79% 72% 30% ·· Last 440 patients 2016 880 ·· ·· ·· ·· 2·4% ·· ·· ·· ·· 90% ·· ·· ·· ·· ASPIRE Registry (Sheffield, UK)83 Surgical patients 2018 550 ·· ·· ·· ·· ·· ·· ·· ·· ·· 87% 83% ·· ·· ·· Non-surgical patients 2018 550 ·· ·· ·· ·· ·· ·· ·· ·· ·· 68% 55% ·· ·· ·· US CTEPH Registry (USA)84,85§ Surgical patients 2021 750 44 24 552 208 3·9% 22% 83% ·· ·· 90% ·· ·· 20%¶ 1% (36–52) (20–30) (378–823) (154–294) Non-surgical patients 2021 750 45 ·· 506 ·· ·· ·· ·· ·· ·· 80% ·· ·· ·· ·· (34–50) (358–729) Toronto (Canada)86 Type 1–2* 2022 401 44 (13) 22 (8) 957 (478) 372 (172) 2·3% 21% 92% 370 (151) 490 (129) 93% 91% ·· 20% 1% Type 3 2022 401 42 (13) 25 (10) 928 (541) 420 (180) 2·8% 28% 77% 367 (139) 424 (124) 82% 80% ·· 38% 8% Data are mean (SD), unless otherwise stated. 6MWD=6-min walk distance. BPA=balloon pulmonary angioplasty. CTEPH=chronic thromboembolic pulmonary hypertension. ICA=International CTEPH Association. mPAP=mean pulmonary artery pressure. PEA=pulmonary endarterectomy. PH=pulmonary hypertension. PVR=pulmonary vascular resistance. UCSD=University of California San Diego. *Type assigned on the basis of the location and morphology of thromboembolic and vascular wall disease. †Data are median (95% CI). ‡Data are median (min–max). §Data are median (IQR). ¶At 1 year. Table 1: Outcomes of pulmonary endarterectomy in large series, by subgroup analysis Descargado para Anonymous User (n/a) en University of Guadalajara de ClinicalKey.es por Elsevier en enero 19, 2024. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados. aspire-registry/ see https://www. cteph-registry.html usctephregistry.com respiratory-medicine/ about/our-directorates/ Series Registry see http://www. For more on the US CTEPH CTEPH Registry see https:// www.cteph-association.org/ sheffieldclinicalresearch.org/ pulmonary-vascular-disease- For more on the International and-pulmonary-hypertension/ 841 For more on the ASPIRE Registry  Series lesions.5,6 The intervention is performed in conscious the rate of severe complications and might therefore be patients without the need for general anaesthesia. administered in patients with a PVR of more Venous access is gained to reach the targeted pulmonary than 320 dyn·s·cm–⁵ (4 Wood units).5,6,93 artery branches with some guiding catheters. Obstructing The most commonly experienced complication of BPA lesions are crossed with guidewires and slightly is pulmonary haemorrhage, usually accompanied by undersized balloons are used for dilatation. A staged haemoptysis, caused by vessel injury during the concept, with a limited number of pulmonary segments intervention. The severity of haemoptysis can range from treated per session, depending on disease severity, is one or two bloody sputum expectorations to the preferred to reduce the risk of reperfusion injury.5,6,91 development of severe lung injury with radiographic Angioplasty of all reasonably accessible lesions is a opacity and significant hypoxaemia. Even with extensive widely accepted treatment goal for BPA.92 experience, vascular injury and haemoptysis cannot Over the past 10 years, considerable improvements in always be avoided. However, it is important to apply pulmonary haemodynamics, right heart function, and haemostatic measures before these complications functional capacity have been described after BPA become serious.105 In addition, the incidence of serious (table 2).4,91,98–100 Although long-term data remain scarce, life-threatening lung injury, which occurred in 60% of existing studies show promising haemodynamic cases in early reports,91,98 has become almost non-existent results,101 as well as 3-year survival rates of 92–95%3,4,96 in recent years in expert centres, as BPA techniques have and 5-year survival rates of 88–90%.2,95 improved and early treatment of vascular injuries has The aim of the intervention is similar to that of become common.93,94 pulmonary endarterectomy: by treating endoluminal In this context, a steep learning curve has been lesions, right ventricular afterload will decrease and described,4 with more experience leading to a significant perfusion of lung parenchyma will improve. However, reduction in the rate of adverse events.4,91,103 For this desobliteration is not possible by catheter technique, but reason, as for the surgical therapy of CTEPH, treatment balloon inflation leads to a rupture of fibrotic tissue, in an experienced centre is recommended.5,6 resulting in an increase in antegrade flow. The indication Only severe iodine allergy that cannot be controlled by for BPA is based on excellent imaging: visualisation of medical measures is an absolute contraindication to pulmonary arterial lesions up to the fourth subsegmental BPA. Renal dysfunction might limit the use of contrast generation is needed as this still belongs to the target media during the intervention, but is not a area. Different types of lesion have been described and contraindication because renal function generally correlated with success rates as well as complications: improves with BPA.106–108 Because of excessive ring-like stenoses (type A), web lesions (type B), subtotal complication rates, lesion-based relative contraindications occlusions (type C), total occlusions (type D), and to BPA would be tortuous lesions.73 tortuous lesions (type E; figure 2).73 In addition, haemodynamic parameters are also associated with the Medical therapy risk of complications;4,62,102–104 in particular, a mPAP of Lifelong therapeutic anticoagulation is recommended for more than 45 mm Hg indicates an increased risk of patients with CTEPH.5,6 Although data from randomised serious adverse events.93 Medical pre-treatment decreases controlled trials (RCTs) are lacking, the goals of Year of Number of mPAP (mm Hg) PVR (Wood units) 30-day 6MWD (m) 3-year publication patients mortality survival Pre-BPA Post-BPA Pre-BPA Post-BPA Pre-BPA Post-BPA Prospective RCTs France93 2022 52 46·5 (8·4) 27·8 9·6 (3·1) 3·9 (1·6) 0% 380 (103) 430 ·· Japan94 2022 31 38·1 (7·9) 21·4 (4·7) 8·1 (3·3) 3·3 (0·8) 0% 364 (105) 427 (117) ·· Multicentre registries Japan3 2017 308 43·2 (11·0) 22·5 (5·4) 10·7 (5·6) 3·6 (2·4) 3% 318 (122) 430 (109) 95% Poland95 2022 236 46·1 (10·6) 32·7 (10·9) 7·9 (5·5) 4·3 (2·2) 2% 346 (135) 402 (137) 92% Single-centre reports France4 2019 184 43·9 (9·5) 31·6 (9·0) 7·6 (2·8) 4·1 (2·2) 3% 396 (120) 441 (104) 95% Austria96 2021 120 38·8 (10·7) 25·5 (5·2) 6·2 (2·9) 3·5 (1·7) 3% ·· ·· 92% Germany2 2023 142 39·7 (11·2) 28 (23–35)* 6·6 (4·1–8·7)* 3·6 (2·6–5·0)* 1% 396 (109) 441 (112) 93% USA97 2022 153 37 (10·9) 31·4 (9·2) 5·0 (2·8) 3·8 (2·2) 0% 416 (135) 453 (132) ·· Data are mean (SD), unless otherwise stated. 6MWD=6-min walk distance. BPA=balloon pulmonary angioplasty. mPAP=mean pulmonary arterial pressure. PVR=pulmonary vascular resistance. RCT=randomised controlled trial. *Data are median (IQR). Table 2: Outcomes of balloon pulmonary angioplasty 842 www.thelancet.com/respiratory Vol 11 September 2023 Descargado para Anonymous User (n/a) en University of Guadalajara de ClinicalKey.es por Elsevier en enero 19, 2024. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.  Series anticoagulant therapy are to prevent recurrent venous riociguat treatment was associated with a significant thromboembolism and in-situ pulmonary artery improvement in PVR, and the post-hoc analysis of thrombosis. Although vitamin K antagonists remain the haemodynamic data showed that riociguat also improved standard of care for CTEPH, non-vitamin K oral right ventricular function parameters (ie, stroke volume, anticoagulants (NOACs) are increasingly being used.5,6,49 stroke volume index, and cardiac efficiency).119 The Two (retrospective and prospective) studies have shown improvement in 6MWD observed in CHEST-1 was equivalent major bleeding rates for vitamin K antagonists maintained at 2 years in the 98% of patients who entered and NOACs,109,110 although higher rates of venous thrombo­ the long-term extension, CHEST-2.120 Consequently, embolism recurrence were observed with NOACs than riociguat became the first medical therapy approved for with vitamin K antagonists. In addition, patients on inoperable CTEPH and for residual pulmonary NOACs were twice as likely to have associated acute hypertension after pulmonary endarterectomy. The thrombi at surgery.111 Furthermore, NOACs are inferior to MERIT-1 study assessed the dual endothelin receptor vitamin K antagonists in patients with antiphospholipid antagonist macitentan in patients with inoperable syndrome,112,113 a common thrombophilic condition in CTEPH, allowing those in WHO functional class III CTEPH;8,84 consequently, NOACs are not recommended in or IV to receive phosphodiesterase type-5 inhibitors and this context.12,13 oral or inhaled prostanoids before study entry, thereby The pre-capillary microvasculopathy in CTEPH is supporting combination medical therapy in CTEPH. similar to that observed in pulmonary arterial Macitentan improved both PVR and 6MWD, irrespective hypertension, which is the major rationale for the use of of background therapy at baseline.116 In the CTREPH drugs approved for pulmonary arterial hypertension to trial, subcutaneous administration of high-dose treat patients with CTEPH who are deemed to be treprostinil, a stable prostacyclin analogue, showed inoperable or who have residual or recurrent pulmonary beneficial effects on 6MWD in patients with inoperable hypertension after pulmonary endarterectomy. To date, CTEPH or persistent or recurrent pulmonary five notable RCTs have assessed the efficacy and safety of hypertension after pulmonary endarterectomy, with pharmacological treatments in patients with inoperable 30% receiving background therapy.117 Consequently, CTEPH or with residual pulmonary hypertension after treprostinil received marketing authorisation for the pulmonary endarterectomy (table 3). The BENEFiT study CTEPH indication. In a Japanese study that allowed demonstrated beneficial effects of bosentan, a dual concomitant use of riociguat, endothelin receptor endothelin receptor antagonist, on PVR but not on 6-min antagonists, or phosphodiesterase type-5 inhibitors, walk distance (6MWD) in patients with inoperable selexipag, an orally selective prostacyclin receptor CTEPH or persistent or recurrent pulmonary agonist, significantly improved PVR but not 6MWD in hypertension after pulmonary endarterectomy.114 In the patients with inoperable CTEPH or persistent or double-blind CHEST-1 trial, the oral soluble guanylate recurrent pulmonary hypertension after pulmonary cyclase stimulator riociguat significantly improved endarterectomy or BPA.118 6MWD in both inoperable (70%) and persistent or Two additional RCTs were terminated before recurrent CTEPH (30%) subgroups.115 In addition, completion. The AMBER-1 study, which aimed to assess Drug Treatment Number of Study population Primary endpoint Mean treatment effect Treatment effect on PVR, duration patients on 6MWD, m (95% CI) mean (95% CI) BENEFIT114 Bosentan 16 weeks 157 Inoperable CTEPH (n=96) and Change in PVR as percentage of 2·2 –24·1% persistent or recurrent baseline and 6MWD from (–22·5 to 26·8; p=0·54) (–31·5 to –16; p