2021 ISHLT共识文件：慢性血栓栓塞性肺动脉高压的评估和管理

KEYWORDS:

pulmonary emboli; CTEPH; pulmonary thromboendarterectomy; balloon pulmonary angioplasty; pulmonary hypertension; guidelines

ISHLT members have recognized the importance of a consensus statement on the evaluation and management of patients with chronic thromboembolic pulmonary hypertension. The creation of this document required multiple steps, including the engagement of the ISHLT councils, approval by the Standards and Guidelines Committee, identification and selection of experts in the field, and the development of 6 working groups. Each working group provided a separate section based on an extensive literature search. These sections were then coalesced into a single document that was circulated to all members of the working groups. Key points were summarized at the end of each section. Due to the limited number of comparative trials in this field, the document was written as a literature review with expert opinion rather than based on level of evidence.

J Heart Lung Transplant 000;000:1 − 26

2021 International Society for Heart and Lung Transplantation. All rights reserved.

Definition, epidemiology and clinical presentation

Definition

Chronic thromboembolic pulmonary hypertension (CTEPH) is a distinct pulmonary vascular disease classified as group 4 in the classification of pulmonary hypertension. 1 It is characterized by chronic stenosis and occlusion of the pulmonary arteries due to obstructive intraluminal orga2 , 3 nized thromboembolic material.

The diagnosis of CTEPH requires a mean pulmonary artery pressures (PAP) ${\geq}25~\mathrm{mmHg}$ with a pulmonary arterial wedge pressure (PAWP) of $\leq15\;\mathrm{mmHg}$ documented at invasive right heart catheterization with radiographic evidence of organized thrombi involving the pulmonary arter4 ies after 3 months of anticoagulation.

At the 6th World Symposium on Pulmonary Hypertension in Nice, a new definition was presented with a mean PAP ${>}20\:\mathrm{\mmHg}$ combined with a pulmonary vascular resistance $(\mathrm{PVR})\geq3$ WU and P $\mathrm{A W P\leq15\;m m H g.}$ . 5

Incidence

The exact incidence of CTEPH in the general population is not well defined as the disease remains largely underdiagnosed.

CTEPH has been reported with a cumulative incidence ranging between $0.1\%$ and $9.1\%$ within the first 2 years 6 , 7 after an acute PE event. The large range in incidence is due to referral bias, variability in diagnostic criteria, paucity of early symptoms, and the difficulty in differentiating acute PE from CTEPH.

A meta-analysis revealed a $2.8\%$ incident rate of CTEPH 7 in survivors of acute PE.

Epidemiological studies estimate an annual incidence in the United States and Europe as high as 3-5 cases per 100,000 8 population, with a lower rate of 1.9 case per 100,000 in Japan.

As disease awareness increases in the medical community, the incidence and prevalence of CTEPH in the general population should progressively become more accurate.

Genetics

Although known contributors to pathways of coagulation and fibrinolysis dominate the genetic risk factors for venous

9-12 thromboembolic (VTE) disease, their contribution to the development of CTEPH is currently considered to be lim13-19 ited.

Non-blood group 0, lupus anticoagulant, antiphospholipid antibodies, fibrinogen polymorphism, and possibly factor V Leyden can be associated with a higher risk of 7 , 17-23 24-26 CTEPH. BMPR2 is not mutated in CTEPH.

Recent studies have shown that CTEPH is associated with elevated plasma concentrations of factor VIII and increased level of von Willebrand factor (VWF) that are persistent after PEA, suggesting that they play a role in the 19 , 27 , 28 pathogenesis of CTEPH.

Pathophysiology

CTEPH has a complex pathophysiology due to vascular derangement in both the elastic and the resistive pulmonary 29-45 arteries. Unlike acute PE, there is no linear correlation between the extent of mechanical obstruction on imaging and 30 the severity of PVR. CTEPH is characterized by a progressive pulmonary vascular remodeling that develops in both occluded and non-occluded small pulmonary arteries. In its most severe form, CTEPH can also present with focal capillary haemangiomatosis and post-capillary venous remodeling 46 as a consequence of the bronchial-to-pulmonary shunting. Experimental investigations have shown that staphylococcal infection, endothelial dysfunction, unbalanced fibrinolysis, dysfunctional angiogenesis and inflammatory or immunolog37-44 ical mechanisms can be associated with CTEPH. One of the major limitations in CTEPH studies is the difficulty to 47-66 reproduce the disease in animal models.

## Clinical presentation

The clinical presentation of CTEPH always involves dys67-71 pnea at rest or with exertion. Other symptoms can include fatigue, chest pain, syncope, dizziness, and 68 , 69 hemoptysis.

Symptoms are not specific and consequently the median time between the beginning of symptoms and diagnosis of 27 , 68 CTEPH is about 14 months. Therefore, it is essential to keep a high index of suspicion for CTEPH particularly in the context of an acute PE, a new diagnosis of PH, or in the presence of unexplained dyspnea.

de Perrot et al.

Evaluation and management of patients with chronic thromboembolic pulmonary hype

Delayed diagnosis of CTEPH results in unnecessary suf72-83 fering and monetary waste on inappropriate treatments. Progression of disease can also lead to worsening of the small vessel vasculopathy and the development of right heart failure, which can be associated with worse surgical 84 , 85 outcomes in terms of operative risks and PH resolution.

The initial investigations in suspected CTEPH should include an echocardiogram and a ventilation-perfusion (VQ) scan. These tests are easy to perform and interpret, widely available, non-invasive, and acceptable to 70 , 81 patients. Echocardiogram is generally the first choice since it will provide an estimation of the PH, and information on other parameters of cardiac function, which may 82-90 contribute to dyspnea. A VQ scan is important in the presence of residual symptoms after acute PE and in patients with newly diagnosed PH to demonstrate the presence of perfusion defects. Additional testing with cardiopulmonary exercise testing and/or right heart catheterization with exercise may be helpful to investigate the possibility of CTEPH, particularly in the absence of PH on echocardiogram despite 3 , 91-94 persistent VQ mismatches. Of importance, CTEPH often coexists with other comorbidities such as COPD or left heart failure with preserved ejection fraction and therefore these comorbidities should not prevent further investigations 27 , 68 , 95-102 for CTEPH.

CTEPH in the context of acute PE

80 CTEPH can mimic acute PE at presentation. Thus, CTEPH can be mislabeled as acute PE, which is one of the reasons for delayed diagnosis. It is therefore essential to keep a high index of suspicion for CTEPH in the context of acute PE. Although there is currently no indication to routinely screen for CTEPH after an acute PE, follow-up imaging with echocardiogram and VQ scan is indicated in some specific situations. These include evidence of PH on echocardiogram, CT scan findings suggestive of CTEPH, large clot burden, recurrent PE, and persistent dyspnea despite anticoagulation. Other factors that can increase the risk of CTEPH include history of splenectomy, infected pacemaker leads, ventriculo-atrial shunts, chronic inflammatory disease, antiphospholipid 19 , 33 , 34 , 71 syndrome, and hypothyroidism.

The initiation of anticoagulation is frequently associated with clinical improvement as the acute component of the clot burden resolves. However, CTEPH does persists and it is prudent to pursue further investigations in the presence of persistent symptoms despite clinical improvement. The optimal moment for investigating the presence of CTEPH is after 3 months of anticoagulation, but earlier work-up may be necessary in highly symptomatic or deteriorating 72-79 81 , 82 , patients. A CTEPH risk score has been developed

102 to help stratify the risk of CTEPH and guide the need for further investigations ( Table 1 ). A strategy using this score accurately excluded CTEPH without the need for echocardiography in the overall majority of PE patients. Moreover, CTEPH was identified early after acute PE, resulting in a substantially shorter diagnostic delay than in

|Points Denotes a 'high risk'|| |---|---| |Points for score|| |Unprovoked PE|| |Known hypothyroidism| +16 +T3 | |Symptom onset greater than 2 weeks before PE diagnosis|+13| ||| |Right ventricular dysfunction on CT or echocardiogram|+T:2| ||1③| |Thrombolytic therapy or embolectomy|1③| |A Score greater than 6 points denotes a "high risk" for CTEPH||

CT, computed tomography; PE, pulmonary embolism; VTE, venous thromboembolism.

current practice. Table 2 provides an overview of initial diagnostic tests that are relevant for patients with functional impairment in the clinical follow-up of acute PE and unexplained dyspnea.

Thrombolysis and CTEPH

Currently, there is no indication to administer thrombolytic therapy to prevent CTEPH. Thrombolytic therapy should remain an indication for the management of patients with 103-106 acute PE only.

The impact of early thrombolytic treatment to decrease the risk of CTEPH in the long term was prospectively addressed in the international PEITHO (Pulmonary Embolism Thrombolysis) trial, which compared a single intravenous bolus of the thrombolytic agent tenecteplase to placebo 105 in the context of submassive PE. A total of 290 patients from the PEITHO trial had long-term echocardiographic fol106 low-up with a median follow-up exceeding 3 years. There was no difference in the incidence of CTEPH between the two groups in the long-term. The diagnosis of CTEPH was confirmed in $2.1\%$ and $3.2\%$ of the patients randomized to tenecteplase and placebo, respectively.

Key points

1. The exact incidence of CTEPH in the general population is not well defined as the disease remains largely underdiagnosed. 2. The clinical presentation is not specific and can mimic acute PE diagnosis. As a consequence, the diagnosis is frequently delayed. 3. It is essential to keep a high index of suspicion for CTEPH: (1) In patients with risk factors for CTEPH in the context of an acute PE, (2) In patients with a new diagnosis of PH, and (3) In patients with unexplained dyspnea. 4. Risk factors for CTEPH in the context of acute PE include CT findings suggestive of CTEPH, evidence of PH on echocardiogram, large clot burden, recurrent PE, unprovoked PE, history of splenectomy, infected pacemaker leads, chronic inflammatory disease,

Table 2 Overview of Initial Diagnostic Tests That May Point to CTEPH and are Relevant for Patients With Functional Impairment in the Clinical Follow-up of Acute PE or With Unexplained Dyspnea in General

||Indication|Limitation| |---|---|---| |ECG| Evaluation of heart rhythm and function, may be used in combination with NT-proBNP to rule out CTEPH | Not sufficiently sensitive to be used as single test to rule out CTEPH; signs of PH include P pulmonale, right axis deviation, RV hyper- trophy, RV | ||| strain, right bundle branch block and QTc prolongation. | |NT-proBNP| Evaluation of heart failure, may be used in combination with ECG to rule out CTEPH |Non-specific test in general, not sufficiently| |Spirometry|| sensitive to be used as single test to rule out CTEPH. | || Evaluation of pulmonary function to explain symptoms | Not sensitive for CTEPH; many patients with PAH have mild to moderate reduction of lung volumes and decreased lung diffusion capac-volumes and decreased lung diffusion capac- ity for carbon monoxide. | |Cardiopulmonary exercise testing| Assessment of the exercise responses of the pulmonary and cardiovascular system to explain symptoms | Not sensitive for CTEPH; signs of PH include a typical pattern with a low end-tidal partial pressure of carbon dioxide, high ventilatory equivalents for carbon dioxide, low oxygen pulse and low peak oxygen uptake. | |Chest X-ray| General screening for cardiopulmonary condi- tions to explain symptoms | pressure of carbon dioxide, high ventilatory equivalents for carbon dioxide, low oxygen pulse and low peak oxygen uptake. Not sensitive or specific for CTEPH; Signs of PH include central pulmonary arterial dilatation and RA and/or | |Ventilation perfusion scintigraphy |y Rule out CTEPH with high certainty.| pulmonary arterial dilatation and RA and/or RV enlargement and RV hypertrophy Radiation exposure. Not specific for CTEPH. Will not demonstrate alternative diagnoses; Mismatched perfusion defect is indicative of | ||| Will not demonstrate alternative diagnoses; Mismatched perfusion defect is indicative of thromboembolic disease until proven otherwise. | |Echocardiography| Suspected CTEPH, screening for other cardiac comorbidities to explain symptoms | Less sensitive for CTEPH than ventilation per- fusion scintigraphy. Can miss the diagnosis in patients with mild PH or with exercise |

CTEPH, chronic thromboembolic pulmonary hypertension; ECG, Electrocardiography; PAP, pulmonary artery pressure; PH, pulmonary hypertension; RA, right atrial; RV, right ventricular.

antiphospholipid syndrome, hypothyroidism, ventriculo-atrial shunt, and persistent symptoms despite anticoagulation.

5. There is no indication to administer thrombolytic therapy to prevent CTEPH.

6. If CTEPH is suspected, screening investigations should be performed after 3 months of anticoagulation with echocardiogram and VQ scan. Earlier assessment can be performed in the presence of worrisome signs or symptoms of heart failure.

Diagnostic approach to CTEPH

Blood markers

Several inflammatory biomarkers can be elevated in 107-124 CTEPH. However, none of them are validated for routine clinical use. Brain natriuretic peptide (BNP) and NT-pro-BNP are most frequently used for prognosis of 100 , 102 , 116-118 , 124 CTEPH.

Inflammatory biomarkers can correlate with the severity of disease. For instance, IP-10 negatively correlated with cardiac index, 6-min walk distance and carbon monoxide diffusion capacity, while IL-6 positively correlated with 116 PVR, right atrial pressure and NT-proBNP. These correlations were observed in CTEPH, but not in idiopathic PAH, suggesting that persistent inflammation may be more 116 important in the pathophysiology of CTEPH than PAH. One major limitation in biomarkers evaluation for CTEPH is that most studies are single center series with small cohorts of patients.

Echocardiography

Echocardiogram is generally the first step in evaluating patients with suspected PH. The potential signs of PH based 89 on established guidelines are summarized in Table 3 .

Echocardiogram can miss CTEPH diagnosis in patients 83 , 91 with mild PH or with exercise induced PH. Therefore, patients with persistent symptoms after an acute PE should undergo further investigations despite a normal echocardiogram.

de Perrot et al. Evaluation and management of patients with chronic thromboembolic pulmonary hype

Table 3 Echocardiographic Signs Suggesting Pulmonary 89 Hypertension (based on Reference )

Ventricles:

' Peak tricuspid regurgitation velocity ${>}2.8\;\mathsf{m}/\mathsf{s}$ ' Right ventricle/left ventricle basal ratio ${>}1.0$ ' Flattening of the interventricular septum (left ventricular eccentricity index ${>}1.1$ in systole and/or diastole) Pulmonary artery: ' Right ventricular outflow acceleration time ${<}105$ msec and/or midsystolic notching ' Early diastolic pulmonary regurgitation velocity ${>}2.2~\mathsf{m}/$ sec Inferior vena cava and right atrium: ' Inferior vena cava diameter ${>}21$ mm with decreased inspi ratory collapse ( $\cdot{<}50\%$ with a sniff or ${<}20\%$ with quiet inspiration) ' Right atrial area (end-systole) ${>}18\,\mathsf{c m}^{2}$

Echocardiogram is also an important test to determine right ventricular function in patients with PH. Recent work has shown that the peak velocity combined with RV end systolic area index (RVESAi) could be a good surrogate of RV-PA coupling and thus potentially be a valuable clinical parameter to predict PH outcome by 125 echocardiography.

Echocardiographic parameters to predict outcome may be different in PAH than CTEPH. Parameters of RV pressure overload such peak tricuspid regurgitation, right ventricular acceleration time and LV systolic eccentricity index are better to risk stratify CTEPH patients, while parameters of RV systolic function such as global right ventricular longitudinal strain, free-wall right ventricular longitudinal strain, RV FAC, and TAPSE are better to risk 126 stratify PAH patients.

Further work will be required to determine the importance of echocardiographic parameters on the surgical risks before PEA.

Cardio-pulmonary exercise testing

Cardio-pulmonary exercise testing (CPET) provides important insights into the pulmonary vascular reserve and imparts additional understanding into the cause of patient limitations. CTEPH has specific features on CPET characterized by a dramatic reduction in ventilatory efficiency, which can be helpful to assess patients after acute PE as 127 , 128-133 well as before and after PEA. Ventilatory effi- ciency is quantified by an increase in ventilation relative to CO2 production (VE/VCO2) and higher physiologic dead127 space fraction (VD/VT). The degree of dead space ventilation and ventilatory efficiency have been associated with 134 , 135 exercise impairment and survival in CTEPH. In comparison to other forms of PH, patients with CTEPH appear to have a lower heart rate response, which may account for some of the differences observed during exercise, even after 134 PEA. The degree to which abnormalities in exercise

response during CPET can inform treatment choice for patients with CTEPH remains to be studied.

SPECT VQ

VQ scintigraphy remains the imaging technique of choice 1 for CTEPH screening. In CTEPH, VQ SPECT has been demonstrated to be significantly more sensitive than planar imaging for detecting regional lung mismatched perfusion 136 defects. Evolving dual modality techniques ( Figure 1 ) with varying combinations of hybrid SPECT/CT pulmonary imaging can improve VQ SPECT specificity by promoting the identification of lung diseases other than PE in patients 137 , 138 with perfusion abnormalities. In-spite of the many obvious advantages, VQ SPECT and hybrid pulmonary imaging are not necessarily available in every department and hence there will be geographical variation in its usage.

CT pulmonary angiogram

Computed tomography pulmonary angiography (CTPA) is commonly used in CTEPH evaluation because of its ability to visualize chronic thromboembolic disease. In a metaanalysis, CTPA was shown to be sensitive and specific for the identification of chronic PE, with pooled high-quality studies demonstrating a sensitivity of $99\%$ and specificity $97\%$ 139 of . All studies required optimal imaging quality and expert radiology readers. These direct signs of chronic PE include slits/webs, eccentric thrombus, and occlusions/ 140 pouch defects. The CT appearances are analogous to 141 findings at conventional angiography. Other CT signs of CTEPH include enlarged bronchial arteries with vascularized adhesions from the mammary and intercostal arteries, under-perfused lung with a mosaic lung attenuation pattern, cylindrical bronchial dilatation and chronic infarcts. CTPA is also useful for evaluation of generic features of PH ( Figure 2 ).

Recognition of CTEPH signs requires a high quality diagnostic CTPA, particularly for disease located at the segmental level. We recommend reviewing multiplanar images in mediastinal windows using a slice thickness of $\leq$ 1 mm. Webs and wall thickening can measure $<1~\mathrm{mm}$ in thickness and may not be visible using thick slice reconstructions. A lung algorithm is useful for identification of mosaic lung attenuation. Occasionally, the protocol will 142 need to be modified to account for artifacts.

Dual energy CT (DECT) and lung subtraction iodine mapping (LSIM) have yielded promising results for the concomitant visualisation of the morphological changes in the pulmonary vasculature as well as lung perfusion abnormalities.( Figure 3 ) In CTEPH, segmental perfusion defects on pulmonary arterial phase demonstrate delayed parenchymal enhancement as a consequence of the systemic collat143 eral supply. Perfusion alterations are more frequent and 144 heterogeneous in CTEPH compared to PAH. DECT has been shown to be accurate at the segmental level and identi98 , 145 fies more peripheral emboli than CTPA. The pulmonary perfused blood volume (PBV) score on DECT can be a useful and non-invasive measure of CTEPH severity with 146 , 147 inverse correlation to mean PAP and PVR. It has also been used to demonstrate improvement in perfusion post148 BPA. Whilst the information obtained from DECT is no

 Figure 1 VQ-SPECT CT in a 38 year old male with CTEPH. Coronal perfusion views from the SPECT series (Top) demonstrates multiple segmental perfusion defects in both lungs (black arrows). Coronal, sagittal and axial reconstructions (Bottom) delineates the perfusion component overlaid on the axial low dose CT. The addition of CT to SPECT improves the specificity of the VQ by promoting the identification of lung diseases. CTEPH, Chronic thromboembolic pulmonary hypertension. VQ, ventilation-perfusion.

doubt useful, its utility in the diagnosis and prognosis of CTEPH must further be investigated in larger patient groups before it can be properly integrated into routine clinical practice.

 Figure 2 Signs of CTEPH on CTPA. (A) Eccentric calcific thrombus (arrow) in distal right main pulmonary artery. (B) Magnified view of the right lower lobe demonstrates a slit (arrow) in the segmental artery. Multiple slits are termed a web. (C) Stenosis (arrow) in left upper lobe artery (D) Dilated and tortuous bronchial artery collaterals (arrow) & occlusive thrombus (chevron) in the left interlobar artery. (E) Dilatation of the main pulmonary artery measuring 37 mm, larger than the accompanying ascending aorta (AA). (F) Dilated right ventricle (long double-ended arrow) relative to the left ventricle (short double-ended arrow). Also note hypertrophy of the right ventricular wall (white arrow). (G) Mosaic attenuation. The hypodense lung (\*) corresponds to areas of decreased perfusion. (H) Curvilinear subpleural band opacities (arrow) corresponding to chronic pulmonary infarct. CTEPH, Chronic thromboembolic pulmonary hypertension; CTPA, Computed tomography pulmonary angiography.

de Perrot et al.

 Figure 3 Coronal views of a dual Energy CTPA in a 55 year old with CTEPH. There is a large perfusion defect (\*) in the anterior segment of the right upper lobe (Left) with corresponding occlusion (arrow) of the anterior right upper lobe pulmonary artery (Right). CTEPH, Chronic thromboembolic pulmonary hypertension; CTPA, Computed tomography pulmonary angiography.

Magnetic Resonance Imaging (MRI)

Cardiac MRI is the reference standard for the non-invasive assessment of RV function with high observer variability 149 and interstudy reproducibility, but its role in the CTEPH diagnostic algorithm is profoundly influenced by the availability of local expertise resulting in wide institutional variation in its usage. The evaluation of the pulmonary circulation involves a two-step approach for the lung parenchyma and the pulmonary vasculature ( Figure 4 ). Three-dimensional contrast enhanced lung perfusion MR has been demonstrated to have a high sensitivity equivalent to perfusion scintigraphy 150 in diagnosing CTEPH. High resolution contrastenhanced angiography (CE-MRA) is the most effective MR technique for delineation of the pulmonary macrocirculation. The sensitivity and specificity of CE-MRA is $98\%$ and $94\% $ respectively in diagnosing proximal and distal 151 CTEPH. Whilst post-processing techniques such as rotating maximum intensity projections provide a comprehensive overview, it is also necessary to interrogate the source data and review multiplanar reformations to elicit all the morphological findings. Emerging applications for tissue characterisation such as 152 153 late gadolinium enhancement, myomaps, myocardial 154 155 tissue tagging, and 3-D strain imaging have the potential to enhance the value of MRI in CTEPH by providing better evaluation of the RV performance. The paramagnetic properties of molecular oxygen as contrast medium is another promising tool for assessing ventilation on

 Figure 4 MR of the pulmonary circulation in CTEPH. Coronal perfusion (left panel) dataset reveals lobar perfusion defect in the right upper and segmental perfusion defects in the right middle and left lower lobes (white star). On the angiography volume rendered technique (right panel), note the corresponding lobar occlusion in right upper and segmental disease in the right middle and left lower lobes (white arrow). CTEPH, Chronic thromboembolic pulmonary hypertension.

156 , 157 MRI but its use in CTEPH is yet to be established. Parameters such as flow vortices in the main PA as well as metrics such as wall shear stress and kinetic energy losses measured by 4-D flow MR technique are not available from routine right heart catheterization and therefore have great potential for early recognition of PH and longitudinal fol158 , 159 low-up. A case report of a patient with CTEPH showed substantial late-systole vortex flow in the main PA with complete normalization of the flow patterns after suc160 cessful BPA. As the utility of these novel MR parameters in CTEPH continues to evolve, multicentre prospective clinical trials are needed to determine their clinical usefulness.

Right heart catheterization

Formal hemodynamic assessment is critical to establish the 1 diagnosis of PH. In CTEPH, it is also useful to inform on the severity of the PVR and facilitate triage of these patients for PEA.

Current recommendations for the diagnosis of CTEPH require a mean $\mathrm{AP}\geq25~\mathrm{mmHg}$ at rest without the hemodynamic influence of left sided cardiac disease inferenced by a PAWP $<\,15\,\mathrm{\mmHg}$ . 1 A mean PAP ${>}20\ \mathrm{mmHg}$ in combination with PVR > 3WU and PAWP ${<}15~\mathrm{mmHg}$ can be accepted for CTEPH diagnosis based on the 6th World 5 Symposium on PH. The impact of this new definition on CTEPH management is unknown, but possibly limited considering that some of these patients were already considered 3 for PEA. Of note, the PAWP is not always reliable in CTEPH due to the occlusion of pulmonary artery branches, and left sided heart disease may need to be ruled out by left ventricular end diastolic pressure (LVEDP) during left heart catheterization or with echocardiogram.

The mean PAP and PVR in CTEPH tend to be lower 68 , 161 , 162 than in PAH. This has been generally attributed to the hemodynamic influence of more proximal pulmonary vascular obstruction that may impart an additional load by altering the propagation of the pressure wave during RV ejection into the PA resulting in an increase in pulse pressure and can be quantified by measuring pulmonary vascu163 , 164 lar compliance. In health and disease (unlike the systemic circuit) there appears to be a predictable relationship between PVR and pulmonary arterial compliance, expressed as the RC time constant; this has been shown to 165 , 166 be higher in PAH compared to CTEPH.

The degree of recovery after PEA appears to be dependent on improvement in both PVR and pulmonary vascular compliance. Patients who do not have a sufficient improvement in pulmonary vascular compliance (in the face of 135 improved PVR) tend to have worse functional outcomes. Additionally, pulmonary vascular compliance during exercise after PEA is inversely correlated with the degree of 134 exercise impairment. These observations suggests that the elasticity of the pulmonary artery can remain abnormal after PEA despite normalization of the pulmonary pressures.

Pulmonary angiogram

Catheter based pulmonary angiography is still the gold standard for CTEPH diagnosis as well as BPA treatment planning. Whilst a high quality CTPA is adequate for the diagnosis of chronic thromboembolic disease, in the context of a negative CTPA and high index of clinical suspicion for CTEPH, pulmonary angiography remains complementary.

A typical pulmonary angiography procedure includes a right heart catheterization (if not yet performed) followed by individual right and left pulmonary arterial injection in frontal and lateral or oblique views ( Figure 5 ). Selective lobar injections can be performed to better identify treatable lesions. The pulmonary angiogram should be performed in the institution where therapy is planned.

Historical data on diagnostic pulmonary angiography has suggested a major complication rate of ${<}1\%$ and minor complication rate of ${\tt<}5\%$ . 167 Unlike conventional arterial angiography where stenotic lesions are readily identified, CTEPH lesions can be more challenging to recognize. Kawakami and colleagues have described a novel angiographic classification of lesions in CTEPH that includes: (1) ring-like stenosis lesion, (2) web lesion, (3) subtotal occlusion lesion, (4) total occlusion lesion and (5) tortuous 168 lesion. Complementary techniques such as optical coherence tomography (OCT) can be hepful to characterize these lesions, but are yet to be validated in large scale clinical 169 trials.

Artificial intelligence

Technological advances in cardiac imaging coupled with exceptional computing power and innovative analytical

 Figure 5 Catheter pulmonary angiography in a 57 year old female with CTEPH. Frontal (left) and Oblique (right) views demonstrates constellation of signs including intimal thrombus (chevron) in right lower lobe pulmonary artery, segmental stenosis with post-stenotic dilatation (thin arrow), proximal web (block arrow) that is only appreciable on the oblique view, abruptly truncated vasculature with loss of perfusion $(^{*})$ in the parenchymal phase. CTEPH, Chronic thromboembolic pulmonary hypertension.

de Perrot et al.

Evaluation and management of patients with chronic thromboembolic pulmonary hype

modelling offer an unprecedented amount of biological data that can contribute to the search for novel imaging biomarkers. Deep learning algorithms have been used in the automatic detection and segmentation of the ventricular chambers and can provide accurate quantitative measure170 , 171 ments of RV volumes and ejection fraction. A machine-learning based survival model that includes complex motion phenotypes has been shown to have incremental prognostic power when compared with conventional parameters and was able to more accurately predict patient 172 outcomes in different PH groups including CTEPH. Such computational simulations can help in understanding pathophysiological mechanisms of RV failure, risk stratifi- cation and identification of imaging end-points following therapeutic interventions.

Key points

1. Echocardiogram can be negative in patients with mild PH or exercise induced PH and it is necessary to consider downstream investigations if there is a high index of suspicion for CTEPH. 2. Cardiopulmonary exercise test is a useful tool for detection of pulmonary vascular disease in patients with suspected PH and normal echocardiography. 3. VQ scan is the screening test of choice to exclude CTEPH. SPECT VQ is superior to planar VQ for the delineation of perfusion defects. 4. High quality CTPA is sufficient for confirming CTEPH diagnosis but a negative CTPA cannot exclude CTEPH. 5. Pulmonary angiography is the gold standard for depicting the pulmonary vasculature. It is best performed in the institution where therapy is planned and often can be done at the same setting as the right heart catheterization. 6. Right heart catheterization is mandated to confirm the diagnosis, determine the severity of the hemodynamic impairment and establish prognosis, thereby informing clinical decision-making in the management of CTEPH. 7. The pulmonary artery wedge pressure is not always reliable in CTEPH due to the occlusion of pulmonary artery branches, and left sided heart disease may need to be ruled out by left ventricular end diastolic pressure (LVEDP) during left heart catheterization or with echocardiogram.

Pulmonary endarterectomy

PEA in segmental and subsegmental CTEPH

PEA using deep hypothermic circulatory arrest is the standard-of-care for CTEPH. The technique has been adopted by the vast majority of the surgical centers performing PEA and progressively refined with increasing 85 , 173-178 experience. Currently, patients with disease located in the segmental and subsegmental pulmonary artery on imaging are candi dates for PEA with excellent early and long-term outcome 85 , 178 in expert centers. A key factor of success in segmental

176 and subsegmental disease is excellent quality imaging. These patients can frequently be misdiagnosed if the imaging is not optimal or mislabeled as inoperable in centers with less experience.

Although the subjective correlation between the extent of chronic thromboembolic disease on preoperative pulmonary angiogram and the severity PVR is a reassuring parameter, the imaging tends to underestimate the amount of disease. Therefore, the subjective correlation between the extent of disease on imaging and the severity of the PVR is not a reliable parameter to determine surgical candidacy in segmental and subsegmental disease. Patients can have a dramatic benefit after PEA with normalization of their hemodynamic postoperatively despite limited amount of disease. Imaging tends to underestimate the disease as the chronic thromboembolic material retracts the lumen of the artery and branches of small calibers enlarge after PEA ( Figure 6 ).

Up to $90\%$ of the patients are surgical candidates in expert centers despite potentially higher risks at the time of surgery due to medical comorbidities or severe right heart 177 , 178 failure. Considering the long-term impact of PEA on functional capacity and quality of life, a second opinion from an expert center is recommended for patients who are 90 deemed not eligible for surgery. The value of the second opinion was demonstrated in the CHEST-1 study where local and central adjudication committees reviewed imag177 ing from inoperable patients. They observed that among the 312 patients considered inoperable, $16\%$ were surgical candidates after local review of the imaging and $25\%$ were surgical candidates after central review of the imaging.

Misdiagnosis and misconception in surgical candidacy

There are a number of conditions that mimic CTEPH and may constitute a diagnostic dilemma ( Table 4 ). The importance of making the distinction between CTEPH and these other conditions is important since PEA is not indicated in these other conditions with the exception of pulmonary 179-189 artery sarcoma.

There are a number of misconceptions related to surgical decision making that are important to clarify. First, there is no evidence that the deep hypothermic circulatory arrest causes 174 cognitive dysfunction in CTEPH patients. The PEACOG trial, which randomized 74 patients between antegrade cerebral perfusion and intermittent periods of DHCA demonstrated that periods of circulatory arrest were necessary to achieve complete clearance of the thromboembolic material 174 with adequate visualization of the distal PA branches. The trial also demonstrated that on average the cognitive function improved at 3 months and 12 months after PEA compared to before the surgery, possibly as a result of better cardiac output and brain perfusion following PEA. Despite deep hypothermic circulatory arrest, a majority of patients do not require any 85 , 175 blood transfusion during and after PEA.

Second, there is no upper limit of PVR beyond which PEA is contraindicated. The operative risk is higher when

 Figure 6 Coronal oblique CTPA MIP reformat of the left pulmonary arteries in a 56 year old man with CTEPH. A. Preoperative CTPA demonstrates a stenosis of the left lower lobe basal trunk (long arrow) due to webs and a complete occlusion of the lingular PA (short arrow). Note the paucity of vessels at the subsegmental level in the lung periphery (asterisk). B. Postoperative CTPA in the same patient demonstrates improved patency of the left lower lobe basal trunk (long arrow), reconstitution of the lingular pulmonary artery (short arrow) and a marked increase in vasculature at the subsegmental level (asterisk). MIP − Maximum intensity projection; CTPA − Computed tomography pulmonary angiogram.

Table 4 Conditions That may be Misdiagnosed as CTEPH

179 Pulmonary artery sarcoma 180 Fibrosing mediastinitis 181 Sarcoidosis 182 , 183 Large vessel vasculitis, including Takayasu 184 Peripheral pulmonary artery stenosis 185 Congenital pulmonary artery anomalies 186 In situ pulmonary artery thrombosis 187 Pulmonary veno-occlusive disease 188 Moyamoya disease

− 5 the PVR is greater than 1,000 dynes.s.cm (12.5 Wood 85 Units). However, even with PVR greater than 1,000 − 5 dynes.s.cm (12.5 Wood Units), PEA is not contraindicated and in fact, these patients often have the most to gain, particularly in the presence of right heart failure. These patients can present with difficulty to wean CPB, but venoarterial extracorporeal membrane oxygenation (VAECMO) has become an important and successful option to bridge these patients to recovery.

Third, evidence demonstrates that patients over the age of 70 years derive as much benefit from PEA as those less 190 , 191 than 70 years. Although age may not be a contraindication to PEA by itself, the presence of other comorbidities 192 in older patients must be kept in mind.

ECMO is required in about $5\%$ of the patients in large surgical series. Currently, over $70\%$ of patients requiring ECMO after PEA are decannulated and up to $79\%$ are discharged home ( Table 5 ). Occasionally, VA ECMO can be used preoperatively to stabilize patients with decompensated right heart failure to transfer them from other institutions for their surgery or to optimize their clinical status 200-202 before proceeding with PEA.

The type of ECMO required is determined by the primary cause of failure. VA ECMO is indicated at the end of PEA in the presence of difficulty weaning CPB or postoperatively in the presence of worsening right heart failure. Central ECMO can be performed by using the sites of cannulation from CPB through the sternotomy. Alternatively, the femoral vessels can be cannulated.

VV ECMO is indicated for respiratory failure due to reperfusion pulmonary edema or severe intrapulmonary shunting with a steal phenomenon leading to severe hypoxemia. VV ECMO can be performed with two single stage venous cannula in the jugular vein and the femoral vein or with a dual lumen catheter (Avalon Elite, Avalon Laboratories, Rancho Dominguez, CA, USA) inserted into the right jugular vein.

The success of ECMO support is determined by the indications so that those with a reversible insult such as airway hemorrhage or reperfusion injury have a higher chance of successful weaning than those with persistent PH and RV failure.

Role of ECMO in CTEPH

ECMO can be used after PEA as a bridge to recovery in case of persistent PH with difficulty weaning CPB, severe airway hemorrhage, and reperfusion pulmonary edema.

Short and long-term outcome data after PEA

The early results of PEA are well established and described in many case series and registries. In expert centers, this operation is well tolerated and the hospital mortality is 84 , 85 , 178 , 191 , 203-205 almost equivalent to other cardiac surgeries.

de Perrot et al. Evaluation and management of patients with chronic thromboembolic pulmonary hype

Table 5 Outcome of ECMO After PEA

| First author (Reference)|Years|Number of PEA|Number of ECMO|Wean from ECMO| Discharged home| |---|---|---|---|---|---| |Donahoe, L., et al.193|2005-2019|¥39:0|19 (4.9%)|17 (89%)|15(79%)| |Sugiyama, K., et al.194|2012-2015|¥35|4(11%)|4(100%)|3(75%)| |Kelava, M., et a.195|1997-2015|¥15:0|14 (9.3%)|NA|6(43%)| |Nierlich, et al.196|2001-2013|161|31 (19.3%)|28(90%)|20(65%)| |Boulate, D., et al.197|2005-2013|¥829|31 (3.7%)|NA|15(48%)| |Berman, M., et a.193|2005-2007|１２７|7(5.5%)|5(73%)|4(57%)| |Thistlethwaite, P.A., etal99|1990-2006|1,790|20 (1.1%)|8(40%)|6(30%)|

Improved hemodynamic parameters is the most important variable that has been shown to change immediately after 89 PEA. Improvement in functional status and exercise capacity take longer than hemodynamic changes as the right heart remodels over 3 to 12 months after PEA. The International 27 , 84 CTEPH Registry demonstrated that bridging therapy with PH-targeted therapy before PEA, NYHA class IV, history of cancer, and dialysis-dependent renal failure were independent risk factors for death after PEA. The most important predictor of mortality was functional class IV at registry entry.

There are now increasing reports describing the long25 , 36 , 206-214 term outcome after PEA. Normal quality of life, sustained improvement in hemodynamics, good functional class and excellent survival rates are the most important results of these studies. The long-term national cohort study from the UK, which included 880 consecutive patients, demonstrated that the cumulative 30-day mortality decreased from $13.2\%$ for the earliest fraction of the cohort to $2.4\%$ for the most recent cohort with an overall survival of $72\%$ at 10 years for the whole cohort. 214

Residual PH following PEA

Despite significant improvement in all haemodynamic 84 , 197 , 198 , 214- parameters, residual PH is frequent after PEA.

219 However, there is no clear definition of what constitutes residual PH after PEA and thus the actual incidence of residual PH has been difficult to quantify.

The data from the UK cohort demonstrated that a mean $\mathrm{PAP}\!>\!38\;\mathrm{mmHg}$ and $\mathrm{PVR}>425$ dynes.sec.cm − 5 /5.3 Units were associated with an increased risk of death due to right 214 heart failure. This data thus suggests that in patients surviving PEA, moderate residual PH is well tolerated and clinically meaningful residual PH after PEA mainly occur when the mean PAP is greater than ${30}{\cdot}{35}\;\mathrm{mmHg}$ .

The lack of data on PH after PEA in the literature is leading to variability in practice between centers in terms of monitoring and reinvestigations after PEA as well as implementation of medical therapy or initiation of BPA. The risk of recurrent PH in the long-term underlines the importance of formally re-evaluating patients after PEA and to follow them in the long term.

Currently, it is recommended to proceed with repeat investigations including exercise testing (6 minute walk test and/or cardiopulmonary exercise testing), right heart

catheterization and imaging such as VQ scan and CTPA within the first year after PEA. Patients should then be monitored on a yearly basis, or more frequently depending on their clinical condition. Long-term follow-up is also important due to the risk of progression of PH.

Surgery in patients without PH at rest

Major improvement in early outcome after PEA have led several centres to extend the indication of PEA to patients without evidence of PH at rest.

This group of patients currently represent 6 to $7\%$ of all 3 , 91 , 220 patients undergoing PEA in large programs. Patient selection for PEA in the absence of PH at rest can be challenging and an extensive work-up to rule out other causes of shortness of breath is important. Several reports have shown that adequately selected patients without PH at rest can have significant improvement in their quality of life 3 , 221 , 222 and exercise performance after PEA.

CPET and right heart catheterization on exercise are helpful to select surgical candidates in the absence of PH at rest. CPET can document the reduction in ventilatory effi- 92 , 130 ciency (VE/VC02) on exercise. CPET also helps to evaluate the degree of deconditioning, which is a frequent cause of dyspnea after acute PE and may warrant referral to 132 a rehabilitation program.

Right heart catheterization during exercise provides an excellent means to evaluate the physiological impact of the 93 pulmonary vascular disease. The mean PAP can rise rapidly during exercise in relation to the cardiac output (CO) with a ratio mean PAP-CO slope ${>}3.0\ \mathrm{mmHg/min}/1$ , suggestive of exercise induced PH.

The final decision about whether to proceed with PEA or not in these patients must be done after careful discussion with the patient on the risks and benefit of the surgery. The surgery is predominantly performed for quality of life and 221 must be balanced against the risks of PEA. Although cases of progression to CTEPH have been described, the 91 risk is extremely low.

What constitutes standard-of-care in PEA

Early and long-term outcomes after PEA are excellent when performed in expert CTEPH centers.

The hospital mortality is currently 2 to $3\%$ and the 5- year survival greater than $70\%$ in surgical centers perform84 , 85 , 214 , 220 , 223-225 ing more than 50 PEAs per year. The risks of PEA depends on the location of the disease in the pulmonary artery, the severity of right heart failure and the degree of comorbidities.

224 Jenkins et al on behalf of the International CTEPH Association proposed criteria to determine centers with surgical expertise based on the annual number of PTEs performed ${\left({>}50\prime\right.}$ year), outcomes (in-hospital mortality ${<}5\%$ ) and availability of specialists for medical and interventional therapies for CTEPH, recognizing that international networks is important for improving education in smaller centres to limit the learning curve of this demanding operation.

Key points

1. PEA under deep hypothermic circulatory arrest is the standard-of-care for CTEPH. 2. Excellent quality imaging is a key factor for surgical evaluation. 3. Segmental and subsegmental disease is accessible to PEA in experienced centers with excellent short and long-term outcome. These patients can be misdiagnosed if the imaging is not optimal or mislabeled as inoperable in centers with less experience. Second opinion should be sought from expert centers if necessary. 4. Imaging tends to underestimate the amount of disease. Therefore, the subjective correlation between the extent of disease on imaging and the severity of the pulmonary vascular resistance is not a reliable parameter to determine surgical candidacy, particularly in segmental and subsegmental disease. 5. ECMO provides an important back-up strategy for patients with postoperative complications. 6. PEA leads to excellent functional results and quality of life. However, residual PH is common and therefore patients should be reassessed with exercise testing (6 minute walk test and/or cardiopulmonary exercise testing), imaging and right heart catheterization within the first year after PEA. Long-term follow-up is also important due to the risk of progression of PH. 7. Chronic thromboembolic disease in the absence of PH at rest can be an indication for PEA in expert centers after careful patient selection.

Medical therapy for patients with CTEPH

Indications for targeted PH therapy

The histopathological remodeling of the precapillary pulmonary arteries in CTEPH are similar to those observed in idiopathic PAH. Hence, PH-targeted therapies have been studied in CTEPH patients, particularly in those who are 218 , 226-237 deemed inoperable.

Randomized controlled trials with targeted PH therapy in non-surgical CTEPH

A total of 5 randomized clinical trials have been completed and one is in progress in patients with CTEPH who were not candidates for PEA or presented with residual PH after PEA ( Table 6 ).

A double-blind, placebo-controlled pilot study randomized 19 patients with inoperable CTEPH to sildenafil vs pla228 cebo for 12 weeks. The overall severity of CTEPH at baseline was lower in the placebo arm than in the sildenafil arm. Although the study showed no significant improvement in 6MWD $\mathit{\check{p}}=0.38\$ , primary endpoint), significant improvement was seen in the secondary endpoints of WHO-FC $(p=0.02)$ and PVR $(p=0.04)$ . When transitioned to open label sildenafil for 12 months, significant improvement was noted in 6MWD and PVR.

The BENEFiT study evaluated the safety and efficacy of dual endothelin receptor antagonist bosentan in 157 patients with inoperable CTEPH or persistent/ recurrent PH post 229 PEA. This 16-week randomized placebo-controlled trial demonstrated advantages with bosentan in terms of PVR ( $24\%$ reduction, $p~<~0.0001$ ) and NT-pro BNP levels $(p=0.003)$ , but the primary combined end point of a reduction in PVR and an increment in 6MWD was not met. There was no statistically significant decrease in time to clinical worsening with bosentan versus placebo (hazard ratio 0.63, $95\%$ CI 0.15-2.64).

In the double-blind CHEST-1 trial, oral soluble guanylate cyclase stimulator, riociguat, was randomly assigned to 173 of 261 enrolled patients with inoperable CTEPH or per218 sistent/ recurrent PH post PEA for 16 weeks. There was a mean increase of 39 meters in the 6MWD $(p<0.001\$ , pri5 mary endpoint) and a drop in PVR of 246 dynes/cm/sec ( p $<\,0.001$ , secondary endpoint). Riociguat was also associated with significant improvements in NT-pro BNP level ( p $<0.001)$ and WHO FC $(p=0.003)$ , although the time to clinical worsening remained unchanged. Following CHEST-1, 237 of these patients entered the open label 230 extension arm of the study (CHEST-2). Improvements in 6MWD and WHO FC observed in CHEST-1 persisted up to 1 year. Riociguat is currently the only approved medical therapy in many countries for inoperable CTEPH and for residual PH after PEA.

MERIT-1 is a phase 2, double-blind, randomized, placebo controlled trial assessing macitentan in CTEPH 231 patients adjudicated as inoperable. Of importance, this trial allowed treatment with phosphodiesterase-5 inhibitors and oral or inhaled prostanoids for WHO functional class III/IV patients, thus supporting combina212 tion therapy in CTEPH. There was a mean PVR reduction to $73\%$ of baseline in the macitentan group and to $87\%$ in the placebo group $(p~=~0.041)$ ), and improvement in 6MWD $(p\,=\,0.033)$ and NT-pro BNP $(p\,=\,0.040)$ . The open label extension arm (MERIT-2) to assess the long-term safety, efficacy and tolerability of macitentan in inoperable CTEPH is ongoing.

More recently, the randomized double-blind controlled CTREPH (ClinicalTrials.gov, NCT01416636) trial

de Perrot et al. Evaluation and management of patients with chronic thromboembolic pulmonary hype

Table 6 Summary of Randomized Trials Looking at Medical Treatment for CTEPH

||Sildenafil|BENEFiT|Chest 1|MERIT 1|CTREPH| |---|---|---|---|---|---| |Drug| Sildenafil|Bosentan|Riociguat|Macitentan|Treprostinil| |Trial design| Randomized, placebo| Randomized, multi-cen-| Randomized, multi-cen-| Randomized, multi-cen- ter, placebo controlled, | Randomized, double| || controlled, double blind | ter, placebo controlled, double blind | ter, placebo controlled, double blind | ter, placebo controlled, double blind | blind, randomized to high versus low dose | |Author (Year) (Ref)| Suntharalingam et al. (2008)228 |(2008)229|Ghofrani et al. (2013)218|Ghofrani et al. (2017)231| Sadushi-Kolici et al. (2018)232 | | Number of patients ran- domized to active |9/19|77/157|173/261|40/80|53/52 (high/low dose)| | domized to active drug/ enrolled |||||| | CTEPH patients included| Inoperable| Inoperable, persistent/ recurrent PH post PEA || Inoperable| Inoperable, persistent/ recurrent PH post PEA | |Goal drug dose|40 mg TID|| recurrent PH post PEA 2.5 mg TID |10 mg daily|| | Study duration|3 months|||| Low dose - 3ng/kg/min High dose - 30 ng/kg/ | | Primary endpoint||| 16 weeks 6MWD | 16 weeks PVR | 24 weeks 6MWD | || 6MWD WHO FC, NT-pro BNP, hemodynamics, QOL | WHO FC, hemodynamics, Borg index, QOL scores, | 6MWD WHO FC, PVR, NT-pro BNP, time to clinical worsening, Borg index, |WHO FC, 6MWD|| | Secondary endpoints| hemodynamics, QOL scores |||| WHO FC, Borg index, QoL, clinical worsening, HR | | Change in endpoints |||QOL, safety||| | noted -6MWD |+17.9 m (0.38)|+2.9 m (p = 0.54)||+35 m (p = 0.03)|| ||-5.8 (p = 0.052) -179|-2.5 (p = 0.06)||-17% (p = 0.04)|| |- PAP mean|(p=0.044)|-24.1% (p ||||

demonstrated safety and efficacy of high dose subcutaneous treprostinil compared to low dose in inoperable CTEPH or recurrent PH after PEA. At week 24, the mean 6-minutes walk distance improved by $44.98\,\mathrm{~m~}$ ( $95\%$ CI 27.52 − 62.45) in the high-dose group, and by $4.29\,\mathrm{~m~}$ $95\%$ CI -13.34 − 21.92) in the low-dose group (treatment effect $40.69\:\mathrm{m}$ $95\% $ $p=0.0016\$ 232 , CI 15.86 to 65.53, ).

The SELECT study (ClinicalTrials.gov NCT03689244 ) assessing the efficacy and safety of selexipag in subjects with inoperable or persistent/recurrent CTEPH is ongoing.

Bridging therapy for PEA with targeted PH therapy

There have been two small randomized, prospective studies 233 , 234 of bridging therapy before PEA, both using bosentan, although only one of them reported post-PEA results ( Table 7 ). Thirteen of 25 patients received bosentan for 16 214 weeks prior to PEA. Hemodynamics and exercise capacity were significantly improved in the bosentan group compared to baseline and to the placebo group. However, hemodynamic improvement following PEA was similar between the 2 groups with no additional benefit related to the use of bosentan.

Two retrospective studies analyzed the outcome after bridging therapy for PEA using epoprostenol. These studies included 21 patients in total, the majority with PVR > 12 Wood Units and reported improvement in hemodynamics prior to PEA following treatment with IV

235 , 236 epoprostenol. Post-operatively, there was significant hemodynamic improvement from PEA with similar results between patients treated or not with epoprostenol.

A large retrospective single center study found minimal pre-operative hemodynamic benefit in 111 patients who received targeted PH therapies before PEA compared to 244 patients who did not. Both groups had similar hemody227 namic benefit and outcome following PEA. However, those treated with medical therapy had a significant delay 227 in the time to referral for PEA.

The International CTEPH Registry reported that bridging therapy was associated with higher mortality after PEA (HR 2.62, $95\%\mathrm{CI}$ , 1.30-5.28, $p\,=\,0.007)$ ). 27 Although this observation could be due to the use of targeted PH therapies predominantly in higher risk patients before PEA, it also point out to a possible deleterious effect from delayed PEA.

An ongoing randomized trials (ClinicalTrials.gov NCT03273257 ) with bridging therapy before PEA was initiated, but closed early due to the lack of 237 accrual.

Overall, currently there is no indication for targeted PH therapy before PEA in surgical candidates.

Targeted PH therapy in BPA candidates

BPA candidates with mean PAP greater than $35~\mathrm{mmHg}$ are treated with targeted PH therapy before BPA to reduce the risk of reperfusion injury during BPA ( Table 8 ). This approach is supported by 2 recent studies demonstrating

Table 7 Studies of Bridging Therapy Prior to PEA

|Author|Year|Study|Patients (n)| Medical treatment before PEA (%) | |---|---|---|---|---| |Nagaya, N., et al.,235|2003|Prospective|33|36| |Bresser, P.,et al.236|2004|Retrospective|246|| ||2009|Retrospective||| |Reesink, H.J., et al.233|2010|Randomized| 355 | 31 52 | |Surie, S., et al.234|2013|Randomized|15|53| |Delcroix, M., et al.27|201６|Prospective|404|| |||||20|

that high mean PAP predicts the occurrence of lung injury 251 , 252 as a complication of BPA. In addition, since multiple sessions of BPA are usually necessary, PH medications can improve symptoms while the sessions of BPA are being completed. The soluble guanylate cyclase inhibitor riociguat is most commonly utilized,

The RACE study (ClinicalTrials.gov NCT02634203 ) randomized CTEPH patients who are not eligible for PEA to riociguat or BPA with a cross over. The results from this trial will provide important information on the role of targeted PH therapy in patients who are candidates for BPA. Preliminary results found that PVR is reduced by $68\%$ with BPA and by $41\%$ with riociguat.

IVC filters in the management of CTEPH

Routine use of vena-cava filters in CTEPH is not justified by available evidence. Initially recommended for patients undergoing PEA, this practice has been abandoned by most expert centers. The International CTEPH Registry showed that $40\%$ of patients had IVC filters, but there was no evi27 dent benefit in long-term outcome.

Use of anti-coagulants in CTEPH

Vitamin K antagonists are the standard of care for patients with CTEPH targeting an INR between 2 and 3 to prevent

both recurrent venous thromboembolism and in situ pulmo89 nary artery thrombosis.

Although DOACs are increasingly used in CTEPH, there is limited data published in this patient population. DOACs presently are indicated only in the treatment of acute PE and deep vein thrombosis, atrial fibrillation, and acute coro253 , 254 nary syndromes. They have been shown to be inferior to vitamin K antagonists for anticoagulation in patients 253 , 254 with mechanical valves. A recent retrospective multicenter study comparing 794 patients treated with vitamin K antagonists to 206 patients with DOACs demonstrated a small but significant increase in the rate of VTE recurrence 255 with DOACs. The rate of major bleeding was otherwise equivalent between the 2 groups.

No recommendation can be made at this time regarding the use of DOACs in CTEPH before or after PEA. The full dose of DOACs should be used. There is no data to support the use of low dose DOACs in CTEPH. These observations provide a strong rational for prospective registry data to evaluate the safety of DOACs in CTEPH compared to vitamin K antagonist.

Multidisciplinary management of CTEPH patients

It has been well established that patients with CTEPH 113 , require multidisciplinary care at expert CTEPH centers.

204 CTEPH coordinators are helpful to provide comprehensive patient care and coordination between PEA centers and

Table 8 Studies of Bridging Therapy Prior to BPA

|||||Medical treatment | |---|---|---|---|---| |Author|Year|Study|Patients (n)|before BPA (%)| |Sugimura, K., et al.238|201２| Prospective|¥1２|¥10:0| ||201２|Retrospective|68|| |Andreassen, A.K, et al.240|2013| Retrospective|20| ¥10:0 HO | |Inami, T., et al.241|2014|Retrospective|¥6:8|| |Taniguchi, Y., et al.242|2014|Retrospective|¥20|¥１0:0| |Fukui, S., et al.243|2014| Retrospective|¥20|| |Tsugu, T., et al,244|2015|Prospective|25|10:0| |Roik, M., et al.245|201６|Prospective||55| |Inami, T., et al.246|20１６|Retrospective|170|9１| |Kurzyna, M., et al.247|201７| Retrospective|56|¥8:0| |Ogo, T., et al.248|201７|Retrospective|¥8:0|¥61| |Aoki, T., et al.249|201７|Prospective|84|| |Olsson, K.M., et al.250|201７|Prospective|¥56|95|

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Evaluation and management of patients with chronic thromboembolic pulmonary hype

256 community-based referring practitioners. These coordinators are typically registered nurses who provide smooth transition for the patients and their families in the CTEPH journey. The CTEPH team should also have accessed to extended multidisciplinary teams including social worker, psychiatrist, physiotherapist and occupational therapist to address unique patient needs or situations.

Exercise training and physical rehabilitation of CTEPH patients is an evolving topic. All exercise programs for patients with CTEPH should be supervised by a physiotherapist and/or CTEPH specialist due to the possibility of adverse effects such as presyncope, syncope, cardiac arrhythmias, or chest pain secondary to PH. Initially, post PEA patients with no residual PH should engage in cardiopulmonary exercises and slowly increase the intensity until sternal healing takes place. Thereafter, weight based training can be added gradually while monitoring symptoms of fatigue, dyspnea, and chest pain. Pulmonary and cardiac rehabilitation programmes in patients after BPA treatment or after PEA surgery demonstrated improved 6-minute walk distance, peak oxygen consumption, exercise capacity 257-260 and quality of life. Although studies have shown that obesity did not increase the surgical risks in patients undergoing PEA and similar functional outcome can be achieved in obese and non-obese patients after PEA, CTEPH patients should nevertheless still be encouraged to follow adequate 261 , 262 nutrition to keep healthy body weight.

Key points

1. Pharmacotherapy targeting PH is an option for CTEPH patients who are not candidates for PEA and those with residual PH after PEA. 2. There is currently no evidence to support using targeted PH therapy before PEA in patients with operable CTEPH. 3. Life-long anticoagulation is recommended for patients with CTEPH. 4. Direct oral anti-coagulants (DOACs) are increasingly used in CTEPH, but limited data is available in this specific patient population. 5. There is no data to support the routine use of IVC filter in CTEPH patients.

5. Balloon pulmonary angioplasty

History and current results

The first series of balloon pulmonary angioplasty (BPA) 263 was reported by Feinstein et al in 2001 in 18 patients with inoperable CTEPH. They showed that BPA could improve functional parameters. 263 However, $61\% $ of patients developed reperfusion pulmonary edema including one third requiring mechanical ventilation.

Since then, staged approaches to avoid opening too many segments in one session, use of softer wires to avoid guide wire injury, and careful selection of balloon size in relation to hemodynamic severity have significantly

reduced the rate of complications and enhanced the role of BPA as an excellent treatment option for inoperable patients with CTEPH and patients with persistent PH after 238 , 239 , 249 , 264 surgery.

The largest BPA cohort published to date is the Japanese multicenter registry of 308 patients who underwent 1,408 265 BPA procedures from 2004 to 2013. Twelve patients $(3.9\%)$ died during follow-up, including 8 within 30 days after BPA $(2.6\%)$ . The main causes of death were similar to those post-PEA: right heart failure, multiorgan failure and sepsis. Complications occurred in $36.3\%$ and included predominantly pulmonary injury $(17.8\%)$ , hemoptysis $(14.0\%)$ , and pulmonary artery perforation $(2.9\%)$ . Oneyear survival was $96.8\%$ ( $95\%$ CI, $93.7\%–98.4\%)$ ) and 3- year survival $94.5\%$ ( $95\%$ CI, $89.3\%–97.3\%$ ). The decrease in PVR after BPA was maintained during follow-up, with a reduction of concomitant use of PH-targeted therapy and 265 need of oxygen supplementation. Information on longterm outcome after BPA was limited.

The French group assessed the evolution of their activity following the initiation of the BPA program in their institu266 tion in 2014. The BPA program did not reduce the number of patients who underwent PEA. Patients undergoing PEA in the BPA era, however, appeared to have lower early mortality (although non-significant) at 30- and 90-days despite more distal lesions (type III of the Jamieson’s classification), suggesting that PEA and BPA can be complementary therapeutic options.

Since 2017, a large number of centers have reported their results with BPA around the world ( Table 9 ). Around $12\%$ of BPAs were performed for residual PH after PEA. The proportion of women undergoing BPA is higher than men, $80\% $ 265 reaching up to in the Japanese registry. This may be related to the fact that women are at increased risk of residual 267 PH after PEA and have more segmental disease than men.

Mean PA pressures have consistently improved after BPA to an average ranging between 31 and $33\;\mathrm{mmHg}$ in all series of patients published in the English literature since 2017 ( Table 9 ). The only notable exception is the Japanese experience with an average dropped in mean PA pressure to 24 mmHg ( Table 9 ). Whether this difference is related to the larger Japanese experience or to different patient’s characteristics is unknown. Brenot et al demonstrated that outcome 252 and complication rates improve with growing experience.

In addition to hemodynamic improvements in right atrial pressure, pulmonary artery pressure, cardiac index and PVR, other parameters that have been shown to improve after BPA including 6MWD, functional class, NT-proBNP, and right heart imaging parameters including tricuspid 245 , 250 , 269-281 annular plane systolic excursion. In addition, cardiopulmonary exercise testing has proven enlightening, with clear improvement in ventilatory efficiency (VE/ VC02) that likely accounts for a significant component of the improvement in dyspnea and physical functioning that 272 have become the hallmark of successful BPA treatment.

This improvement in ventilatory efficiency and its bene fits for patient perception of dyspnea provides a strong rationale for preferring BPA over medical therapy for these 278 patients, particularly in the absence of PH at rest. A

The Journal of Heart and Lung Transplantation, Vol 00, No 00, Month 2021

Summary of Published BPA Experience Around the World Since 2017 Table 9

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recent meta-analysis of published reports of BPA and medical therapy for CTEPH is consistent with greater improvement in hemodynamics and 6-minute walk distance with BPA. The report also showed marked heterogeneity in the 280 incidence of reperfusion injury. The frequency of serious complications from BPA appears to be declining with increasing center experience, so it is anticipated that the role of BPA in management of CTEPH will continue to expand.

Patient selection for BPA

Patients diagnosed with CTEPH should be assessed by expert centers to determine operability for PEA and BPA in a multidisciplinary meeting that includes PEA surgeons, interventional radiologists/ cardiologists experienced in pulmonary vascular imaging and cardiologists/pulmonologists with 89 expertise in PH. Eligibility for BPA is decided on the basis of a consensus among the multidisciplinary team.

Currently, the selection for PEA and BPA is in part dependent on the center expertise. In high volume PEA centers, material that is located in the first subsegmental generation of the pulmonary vasculature can be accessible surgically. Therefore, optimized imaging $0.5{\mathrm{-}}1~\mathrm{mm}$ slices CTPA and selective pulmonary angiography) is crucial for treatment decision making. Furthermore, in highly selected patients, severe comorbidities in technically operable CTEPH may be reasons to decide for BPA.

In very rare situations, patients with upper lobe predominant COPD and lower lobe predominant CTEPH may present with significant problems of hypoxemia resulting from very adverse VQ mismatch (poor perfusion in the lower segments that are reasonably ventilated, and poor ventilation in the upper segments that are reasonably perfused). This can be accompanied by the hemodynamic compromise of pulmonary hypertension (mixed Group III and IV) with impaired cardiac output and right ventricular function at rest and with activity. BPA can be particularly effective in these patients in reducing oxygen requirements, improving dyspnea, and improving hemodynamics and activity tolerance.

Target lesions for BPA

The most common target lesions for BPA are sub-segmentally located stenoses such as “webs” and “slits” ( Figure 7 ). Subtotal obstructions can also be targeted, with careful wire technique and a sense of when to back off. Pouch lesions in more proximal segments are generally avoided since accessing the distal lumen of the vessel is very challenging, with increased risk of vascular perforation.

Selective right and left pulmonary angiography with rotational Dyna CT imaging can be very useful in visualizing the pulmonary vascular tree prior to initiating a series of BPA sessions (272). Visualization of extent of perfusion defects can also be improved with SPECT scan, which provides more volumetric and easily visualized assessment of the perfusion defects. This can also be fused with the CT 281 angiographic images to define the target arears for BPA.

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17

 Figure 7 Two patients (A and B) post endarterectomy with residual left lower lobe distal segmental severe stenosis (arrows). Challenging area to reach surgically. Balloon pulmonary angioplasty to 3mm with improvement in angiographic result.

BPA is performed as a staged procedure with a limited number of pulmonary segments per session, depending on disease severity. Factors to be considered with regard to number of segments to dilate at a given session include contrast load which can be significant, presence of renal insuffi- ciency that will impact amount of contrast that can be safely utilized per session, and extent of baseline elevation in PA pressure since that impacts the risk of reperfusion injury.

Dilatation strategies to reduce risk of reperfusion injury include only partially opening segments, utilizing a pressure wire to assess baseline and residual pressure gradient, and then returning on a different occasion to more fully 275 open the segments. An alternative approach is to fully open the segments that are being treated in a particular session, but to limit the number of vessels and size of distribution of the segments so that if reperfusion edema does occur, the extent of lung involved is tolerable.

Because vascular injury causes most complications, including the majority of those that are labeled as reperfusion edema, cautious handling and avoiding advancement of the wire or balloon too far peripherally is useful in preventing complications

Longitudinal assessment

BPA generally aims to treat all target lesions. If patients have been pretreated with riociguat or other pulmonary

vasodilators, it can be possible to withdraw the medication following successful completion of the BPA sessions. Reassessment with 6MWD, CPET, echocardiography, NTproBNP, and right heart catheterization is helpful in confirming extent of improvement and assurance that there is no need for additional BPA sessions or other therapy. Restenosis does not appear to be a problem with BPA, so there does not appear to be need for repeat dilation of previously effectively treated segments.

Combined approach with PEA and BPA

BPA and PEA can be complementary and combined in different sequences. This includes elective BPA in patients with residual PH after PEA ( Figure 7 ). Urgent BPA after PEA does carry high risks of complications due to hemody217 namic instability and is generally avoided. BPA before PEA allegedly entails difficulties for surgery as the plane of endarterectomy is fractured by the balloon angioplasty, which may make PEA impossible in segments that have been dilated. Hybrid options are also feasible, either with preoperative BPA for left lower lobe segmental disease that may be more difficult to reach at surgery or with concomitant procedures in the operating room, using BPA during the rewarming period after PEA in an hybrid operating 279 room. Concomitant procedures in the operating room,

however, has generally not been recommended due to the complexity and risks.

Limitations and futures studies

The three treatment modalities (PEA, targeted PH therapy, BPA) lead to various possible combinations. Hence, individualized long-term multimodality concepts do play an important role in the treatment of CTEPH patients. Longterm data of BPA treated patients remains limited, so that the ultimate role of BPA in management of CTEH needs to continue to be refined and understood.

Key Points

1. Balloon pulmonary angioplasty should be performed at centers with multidisciplinary expertise in management of CTEPH. 2. Pretreatment with targeted PH therapy in patients with mean PA pressure greater than $35~\mathrm{mmHg}$ may reduce risk of reperfusion pulmonary edema and facilitate earlier symptomatic improvement in CTEPH. 3 Balloon pulmonary angioplasty can result in clinically important improvement in dyspnea, activity tolerance, hemodynamics, right ventricular function, and ventilatory efficiency in appropriately selected patients. 4. Optimal role of BPA and long term outcome requires additional study.

Conclusions

The field of CTEPH is rapidly evolving with regards to diagnosis, therapy and monitoring. Future studies will continue to refine an integrated multidisciplinary approach, analyze the application of new diagnostic options, and evaluate the implementation of new therapies in the management of CTEPH such as for instance pulmonary artery 282 denervation.

Summary of key points

Definition, epidemiology and clinical presentation

1. The exact incidence of CTEPH in the general population is not well defined as the disease remains largely underdiagnosed. 2. The clinical presentation is not specific and can mimic acute PE diagnosis. As a consequence, the diagnosis is frequently delayed. 3. It is essential to keep a high index of suspicion for CTEPH: (1) In patients with risk factors for CTEPH in the context of an acute PE, (2) In patients with a new diagnosis of PH, and (3) In patients with unexplained dyspnea. 4. Risk factors for CTEPH in the context of acute PE include CT findings suggestive of CTEPH, evidence of PH on echocardiogram, large clot burden, recurrent PE, unprovoked PE, history of splenectomy, infected pacemaker leads, chronic inflammatory disease, antiphospholipid syndrome, hypothyroidism, ventriculo-atrial shunt, and persistent symptoms despite anticoagulation. 5. There is no indication to administer thrombolytic therapy to prevent CTEPH. 6. If CTEPH is suspected, screening investigations should be performed after 3 months of anticoagulation with echocardiogram and VQ scan. Earlier assessment can be performed in the presence of worrisome signs or symptoms of heart failure.

Diagnostic approach to CTEPH

1. Echocardiogram can be negative in patients with mild PH or exercise induced PH and so it is necessary to consider downstream investigations if there is a high index of suspicion. 2. Cardiopulmonary exercise testing is a useful tool for detection of pulmonary vascular disease in patients with suspected PH and normal echocardiography. 3. VQ scan is the screening test of choice to exclude CTEPH. SPECT VQ is superior to planar VQ for the delineation of perfusion defects. 4. High quality CTPA is sufficient for confirming CTEPH diagnosis but a negative CTPA cannot exclude CTEPH. 5 Pulmonary angiography is the gold standard for depicting the pulmonary vasculature. It is best performed in the institution where therapy is planned and often can be done at the same setting as the right heart catheterization. 6. Right heart catheterization is mandated to confirm the diagnosis, determine the severity of the hemodynamic impairment and establish prognosis, thereby informing clinical decision-making in the management of CTEPH. 7. The pulmonary artery wedge pressure is not always reliable in CTEPH due to the occlusion of pulmonary artery branches, and left sided heart disease may need to be ruled out by left ventricular end diastolic pressure (LVEDP) during left heart catheterization or with echocardiogram.

Pulmonary endarterectomy

1. PEA under deep hypothermic circulatory arrest is the standard-of-care for CTEPH. 2. Excellent quality imaging is a key factor for surgical evaluation. 3. Segmental and subsegmental disease is accessible to PEA in experienced centers with excellent short and long-term outcome. These patients can be misdiagnosed if the imaging is not optimal or mislabeled as inoperable in centers with less experience. A second opinion should be sought from expert centers if necessary. 4. Imaging tends to underestimate the amount of disease. Therefore, the subjective correlation between the extent of disease on imaging and the severity of the pulmonary vascular resistance is not a reliable parameter to

de Perrot et al.

determine surgical candidacy, particularly in segmental and subsegmental disease. 5. ECMO provides an important back-up strategy for patients with postoperative complications. 6. PEA leads to excellent functional results and quality of life. However, residual PH is common and therefore patients should be reassessed with exercise testing (6 minute walk test and/or cardiopulmonary exercise testing), imaging and right heart catheterization within the first year after PEA. Long-term follow-up is also important due to the risk of progression of PH. 7. Chronic thromboembolic disease in the absence of PH at rest can be an indication for PEA in expert centers after careful patient selection.

Medical therapy for patients with CTEPH

1. Pharmacotherapy targeting PH is an option for CTEPH patients who are not candidates for PEA and those with residual PH after PEA. 2. There is currently no evidence to support using targeted PH therapy before PEA in patients with operable CTEPH. 3. Life-long anticoagulation is recommended for patients with CTEPH. 4. Direct oral anti-coagulants (DOACs) are increasingly used in CTEPH, but limited data is available in this specific patient population. 5. There is no data to support the routine use of IVC filter in CTEPH patients.

Balloon pulmonary angioplasty

1. Balloon pulmonary angioplasty should be performed at centers with multidisciplinary expertise in management of CTEPH. 2. Pre-treatment with targeted PH therapy in patients with mean PA pressure greater than $35~\mathrm{mmHg}$ may reduce risk of reperfusion pulmonary edema and facilitate earlier symptomatic improvement in CTEPH. 3. Balloon pulmonary angioplasty can result in clinically important improvement in dyspnea, activity tolerance, hemodynamics, right ventricular function, and ventilatory efficiency in appropriately selected patients. 4. The optimal role of BPA and long-term outcome requires additional study.

D’Armini received personal fees from MSD outside the submitted work. Marion Delcroix reports grants from Actelion and other support from Actelion, Bayer, MSD, Acceleron outside the submitted work. Marc de Perrot received personal fees from Actelion, AstraZeneca, Bayer, Merck, Roche and unrestricted financial support provided to his institution from Bayer outside the submitted work,. Robert P Frantz received personal fees from Janssen, Liquidia, Shouti, and Up-To-Date, institutional grant from Bayer, and institutional payment from United Therapeutics and Gossamer Bio. John T Granton received unrestricted financial support provided to his institution from Bayer and Janssen Pharmaceuticals outside the submitted work. Gustavo A Heresi received personal fees from Bayer, and Janssen outside the submitted work. David Jenkins received personal fees from Actelion and grant from Bayer outside the submitted work. Manreet Kanwar received personal fess from Amiomed, Bayer and CareDx (Advisory Board) outside of the submitted work. Kim M Kerr receives personal fees from Actelion and grants from Bayer outside the submitted work. Erik A Klok received research grants from Bayer, Bristol-Myers Squibb, Boehringer-Ingelheim, MSD, Daiichi-Sankyo, Actelion, the Dutch thrombosis association, The Netherlands Organisation for Health Research and Development and the Dutch Heart foundation, all outside the submitted work. Irene M Lang received personal fees from Janssen, AOP Orphan Pharma, United Therapeutics, and grants from Janssen, AOP Orphan Pharma, Neutrolis, and non-financial support from AOP Orphan Pharma, outside of the submitted work. Michael M Madani received personal fees as a consultant for Wexler Surgical outside the submitted work. Micheal McInnis received personal fees from Bayer outside of the submitted work. Olaf Mercier received personal fees from MSD outside the submitted work. Isabelle Opitz received personal fees from AstraZeneca, MSD, Roche, and AstraZeneca, and grants from Roche, and Medtronic, outside the submitted work. Joanna Pepke-Zaba received personal fess from Actelion, Merck and Bayer. Ivan M Robbins received personal fees from Bayer and Acceleron. His institution received payment for participating in multicenter registry studies and studies evaluating treatment of patients with pulmonary arterial hypertension. Mark Toshner received personal fees from Bayer, MSD, GSK as well as grants and personal fees from Actelion/J&J outside the submitted work. Christoph B Wiedenroth received personal fees Actelion, Bayer, Pfizer, MSD, AOP Orphan Pharmaceuticals, BTG outside the submitted work.

Disclosures

Anastasia Bykova , Elie Fadel, Deepa Gopalan, Sebastian Mafeld , David McGiffin and Patricia A Uber has nothing to disclose.

William R Auger received personal fees from Bayer, Actelion, Cereno Scientific and non-financial support from Bayer outside the submitted work. Raymond Benza received personal fees and institution grants from Bayer and Janssen outside the submitted work. Andrea M

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