An Update on the Management of Chronic Thromboembolic Pulmonary Hypertension

Author’s Accepted Manuscript An Update on the Management of Chronic Thromboembolic Pulmonary HypertensionCTEPH Justin A. Edward, Stacy Mandras

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To appear in: Current Problems in Cardiology Cite this article as: Justin A. Edward and Stacy Mandras, An Update on the Management of Chronic Thromboembolic Pulmonary HypertensionCTEPH, Current Problems in Cardiology, http://dx.doi.org/10.1016/j.cpcardiol.2016.11.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

An Update on the Management of Chronic Thromboembolic Pulmonary Hypertension Justin A Edward, MS1 and Stacy Mandras, MD2 1

Tulane University Health Sciences Center, New Orleans, LA 70112, USA.

2

Department of Cardiovascular Diseases, John Ochsner Heart and Vascular Institute, New Orleans, LA 70121, USA.

Running Title: CTEPH

Corresponding Author: [email protected]

Keywords: chronic thromboembolic pulmonary hypertension

Footnote: The online version of this article contains supplemental material.

Author disclosure: Dr. Mandras reports serving as a consultant or paid advisory board member for Actelion Pharmaceuticals US, Inc, and Bayer Pharmaceuticals. Dr. Mandras also reports receipt of lecture fees on behalf of Actelion Pharmaceuticals US, Inc, and Gilead Pharmaceuticals.

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Abstract Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but life-threatening form of pulmonary artery hypertension (PAH) that is defined as a mean arterial pulmonary pressure greater than 25 mmHg that persists for more than 6 months of anticoagulation therapy in the setting of pulmonary emboli (PE). CTEPH is categorized by the World Health Organization (WHO) as group IV pulmonary hypertension and is thought to be due to unresolved thromboemboli in the pulmonary artery circulation. Among the five classes of pulmonary hypertension, CTEPH is unique in that it is potentially curable with the use of pulmonary thromboendarterectomy (PTE) surgery. Despite an increasing array of medical and surgical treatment options for patients with CTEPH over the past two decades, patients commonly present with advanced disease and carry a poor prognosis, thus, the need for early diagnosis and appropriate referral to an expert center. This review article will first highlight the epidemiology, pathophysiology, and clinical presentation of CTEPH. The article will then provide diagnostic and therapeutic algorithms for the management of the patient with suspected CTEPH.

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Introduction Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening form of pulmonary artery hypertension (PAH) that is defined as a mean arterial pulmonary pressure (mPAP) greater than 25 mmHg that persists for more than 6 months following anticoagulation therapy in the setting of pulmonary emboli (PE). According to the World Health Organization (WHO), which classifies pulmonary hypertension into five groups, CTEPH is currently categorized as group IV pulmonary hypertension and is thought to be due to unresolved thromboemboli in the pulmonary artery circulation [1]. Among the five classes of pulmonary hypertension, CTEPH is categorized as a separate entity in part due to its unique etiology and that it is potentially curable solely with the use of pulmonary thromboendarterectomy (PTE) surgery [2]. One of the first descriptions of CTEPH was made at autopsy in the 1950s [3]. During this time, the finding of organized thrombi in the pulmonary circulation and development of cor pulmonale was simply an autopsy observation [4]. Cardiothoracic surgical advancements in the subsequent decade eventually led to the first successful PTE in 1963 [5]. This landmark procedure removed the obstructing thromboembolic material, allowing for restoration of blood flow in the pulmonary vasculature and successfully relieving both right heart strain and pulmonary hypertension in CTEPH patients. With initial mortality rates of approximately 22% between the 1960s and 1980s [6], advances in surgical techniques and improved patient diagnosis lowered operative mortality rate of patients with CTEPH undergoing PTE to 12% in the 1990s [7]. Over the past 30 years, the number of PTEs performed has steadily increased, perhaps reflecting improvements in this surgical procedure and a better understanding of both PAH and CTEPH [8]. Today, PTE remains the mainstay of treatment for patients with CTEPH and is the only cause of severe PAH that is treatable without the need for lung transplantation. With recent advances in the field of PAH over the past decade, there is an increase in

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the availability of medical therapy targeting PAH and select CTEPH patients not amenable to surgery. Studies are ongoing to determine the role of medical therapy in this population. Novel therapeutic agents and the development of balloon pulmonary angioplasty have also provided an increasing array of treatment options for patients; thus, the need for early diagnosis and appropriate referral has become more important. The aim of this review article is to highlight recent advances in our understanding of CTEPH and determine the role for medical therapy in clinical practice.

Epidemiology and Risk Factors Of the nearly 600,000 cases of acute PE that occur annually in the United States, only 150,000 patients with PE are diagnosed, suggesting that thousands of PEs go undetected each year [9, 10]. Over the past decade, CTEPH has become one of the leading causes of precapillary PAH [11]. The prevalence rate of CTEPH in the United States has been estimated at 63 per million among individuals under 65, and 1007 per million among individuals 65 and over [12]. Prevalence studies have also shown that the rates of CTEPH increase with age and are higher among women [12, 13]. It is estimated that there are about 2,500 new cases of CTEPH in the United States annually, and of these patients, approximately 60-75% have no inciting thromboembolic event [14]. This discrepancy has caused some to suggest that either PE might not be an inciting event or that underdiagnosis is more prevalent than previously expected. Once considered a rare condition, CTEPH is currently estimated to occur in up to 4.8% of survivors of acute PE and greater than 10% of patients with recurrent PEs [15-17]. In a series of 834 patients with suspected PE, approximately 1% of patients developed CTEPH [18], while two prospective studies reported that between 3.8-4.8% of patients developed CTEPH within 2 years following a diagnosis of PE [15, 19]. A screening program designed to detect new cases

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of CTEPH found that in 866 patients with acute PE, the overall incidence of CTEPH was 0.57% (95% CI= 0.02-1.2) [20]. Specifically, in patients with unprovoked PE, the incidence was 1.5% (95% CI= 0.08-3.1). Among patients with pulmonary hypertension, the incidence of CTEPH remains unknown. Limited epidemiological studies have been conducted in part due to the difficulty in accurately diagnosing CTEPH. Patients with CTEPH do not present with the classical risk factors associated with venous thromboembolism (VTE), though the majority of CTEPH cases originate from asymptomatic VTE [21]. Patients commonly present with symptoms of dyspnea, occasional chest discomfort, syncope, and lower extremity edema. As these symptoms are nonspecific and are similar to those of asthma and chronic obstructive pulmonary disease, CTEPH often remains underdiagnosed and misdiagnosed [22]. The risk of developing CTEPH is increased in patients with prothrombotic states (lupus anticoagulant, increased levels of factor VIII, history of malignancy), those with risk factors for PE (previous PE, large perfusion defects, pulmonary artery systolic pressure >50 mmHg, persistent pulmonary hypertension >6 months), patients with genetic predisposition (ABO blood groups except for O, HLA polymorphisms), and those with chronic medical conditions (infected surgical cardiac shunts or pacemaker or defibrillator leads, splenectomy, thyroid disease) [23]. In a study of 687 patients, the greatest risk for CTEPH was identified in those with infected pacemakers and cardiac shunts (OR= 76.40, 95% CI= 7.67-10,351) and in post-splenectomy patients (OR= 17.87, 95% CI= 1.56-2,438) [24]. Thyroid disease is a risk factor for both WHO Class I pulmonary hypertension and CTEPH [24, 25]. A retrospective review of 370 patients diagnosed with CTEPH, a lower free triiodothyronine (fT3) is associated with greater mortality (HR= 1.79, 95% CI= 1.14-4.20), likely due to the fact that the major cardiac effects of thyroid hormone are mediated by T3 [26]. In the past, a diagnosis of CTEPH with a mPAP> 50 mmHg indicated a grave prognosis, with a 2-year mortality rate greater than 80% and a 3-year mortality rate of 90% in patients on anticoagulation with a mPAP> 30 mmHg [27, 28]. With the advent of PTE, however, 1-year -5-

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mortality rates from European CTEPH registry studies have been reported to be below 20% [22], while overall operative in-hospital mortality risk is 2.2% following PTE [29]. Given the existence of effective treatments, screening of both symptomatic and asymptomatic patients with acute PE using transthoracic echocardiography (TTE) should be considered to determine the presence of elevated PA pressures and possible CTEPH [30]. Some physicians have limited screening to those with central thrombus in the pulmonary vasculature, evidence of severe right heart strain, and those with documented thrombophilia [16]. Though there are no guidelines for serial TTE monitoring, following patients for 2 years is reasonable considering that there are no documented cases of CTEPH after acute PE after 2 years of follow-up [15].

Pathophysiology The pathophysiology of CTEPH is complex. In CTEPH, the pulmonary vasculature becomes blocked and narrowed due to recurrent blood clots, eventually leading to the release of vasoconstrictive peptides and worsening of pulmonary hypertension. The development of secondary vasculopathy occurs from the formation of pro-inflammatory compounds as well as increased resistance due to mechanical obstruction from persistent thromboembolic material in the pulmonary circuit. Despite the use of anticoagulation, the disease typically worsens due to secondary vasculopathy. In some patients, however, collateral vessels from the systemic circulation (ie, coronary, bronchial, costal arteries) are formed in an effort to perfuse regions distal to areas of complete obstruction [31]. Hypercoagulation, hyperviscosity, and thrombocytosis all contribute to major vessel obliteration in CTEPH. As the majority of CTEPH cases occur following an initial episode of acute PE, current research efforts are focused on identifying the transition process from isolated thromboembolism to chronic thromboembolic events. Current hypotheses include increases in localized inflammation in the pulmonary vasculature, endothelial dysfunction, and disrupted

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angiogenesis [32]. Venous thrombi are removed by complex degradation and adaptive recanalization of the vessel lumen, processes similar to the formation of granulation tissue in wound healing. Thrombus resolution involves both leukocyte recruitment and angiogenesis, and inflammatory changes in the vessel microenvironment may contribute in failure to resolve the thrombus. In CTEPH patients, pro-inflammatory cytokine markers such as tumor necrosis factor-α (TNF-α) and monocyte chemotactic protein (MCP)-1 have been found to be elevated in both plasma and thrombus tissues [33, 34]. Under normal circumstances, endothelial cells lining vessels affected by thrombus are activated and penetrate the thrombus. Eventually, vascular channels are formed via the release of vascular endothelial growth factor and fibroblastic growth factor. The result is angiogenesis of the thrombus. In CTEPH, this process is disrupted. Additional studies on pulmonary thrombi from CTEPH patients have found a deficiency in angiogenetic gene expression by both differential display analysis and RT-PCR, suggesting that thrombus resolution failure may be linked to a deficiency in angiogenesis [32]. Patients with CTEPH were also found to have dysfunctional endothelial cells due to collagen-secreting cells; the result of which is ineffective angiogenesis [35]. The presence of abnormal fibrinogen and failure to cleave fibrinogen are other explanations for deficient clot resolution. Abnormal fibrinogen y-chain variants and dysfunctional fibrinogen fragmentation have both been implicated as mechanisms for ineffective fibrinolysis [36, 37]. Genetic studies have also identified abnormal variants of fibrinogen in CTEPH patients. In particular, a fibrinogen (Fg)-Aα Thr312Ala polymorphism was identified in CTEPH subjects compared to controls, while no difference in genotype and allele frequencies were found between PE patients and controls [38]. The fibrinogen (Fg)-Aα Thr312Ala polymorphism could be used as a potential biomarker in differentiating CTEPH from PE. In CTEPH, organized thrombi are formed in the normal vessel lumen and are attached to the pulmonary arterial medial layer. Reductions in the cross-sectional area of the pulmonary -7-

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vasculature and small vessel arteriopathy can worsen disease prognosis and lead to further abnormal vascular remodeling. Eventually, however, increased vasoconstriction and resultant secondary vasculopathy leads to the development of CTEPH. Isolated cell studies from thrombus tissues in CTEPH patients found that there is increased differentiation of progenitor cells into smooth muscle cells as well as increased migration of adventitial fibroblasts [39]. These studies have characterized the remodeling process observed in the pulmonary vasculature of CTEPH patients. Endothelin-1, a potent vasoconstrictive peptide produced in pulmonary vascular endothelial cells, was found to closely correlate with disease severity and hemodynamic stability in CTEPH patients, and it has been posited that obtaining preoperative endothelin-1 levels might serve as a tool to identify patients at risk of persistent pulmonary hypertension after PTE surgery [40]. Furthermore, there is an increase in type B endothelin receptor expression in patients with CTEPH [41]. Changes in endothelin signaling promote chronic vasoconstriction and similar observations have been made in patients with PAH. The development of CTEPH is a result of persistent macrovascular obstruction, vascular remodeling, and vasoconstriction that causes increases in PA systolic pressures and right heart strain. With the right ventricle (RV) working against a higher resistance and a compromised pulmonary vasculature, there is progressive RV dilatation, RV dysfunction, and eventually RV failure. The resulting pressure overload is exceedingly higher in CTEPH patients than in those with only acute PE, and presents a unique challenge for the cardiologist.

Clinical Presentation CTEPH affects both sexes and almost all age groups, with the median age of diagnosis at 63 years [31]. In early CTEPH, common presenting symptoms include exertional dyspnea, exercise intolerance, and fatigue, but physical signs are rare. Furthermore, atypical chest pain, cough, and palpitations are uncommon in early stages of disease. Disease progression includes

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nonspecific signs of right ventricular heart failure. As the right side of the heart fails, patients develop lower extremity edema, ascites, and syncope. In some patients, fatigue and dyspnea begins at the onset of the first pulmonary thromboembolic event and symptoms worsen over time despite anticoagulation therapy. In other patients, however, dyspnea occurs without a known triggering event, and in these patients, proper diagnosis is often delayed. This insidious onset of dyspnea is similar to patients with idiopathic PAH (WHO Group I). In addition, edema and hemoptysis occurs more in CTEPH patients, while syncope is more common in those with idiopathic PAH. Hemoptysis is likely related to lung infarction in the setting of acute pulmonary embolism and in chronic pulmonary thromboembolic obstruction, bleeding is likely from ruptured bronchial arterial collaterals [22]. Few physical exam findings are present early on in the disease course. With disease progression, cardiac examination is notable for a loud, split second heart sound (S2) with accentuation of the pulmonic component due to increased pulmonary pressures, a palpable right ventricular heave, and a tricuspid regurgitation murmur heard best at the left sternal border. Subsequent findings corresponding to disease progression include jugular venous distension, a right-sided third heart sound (S3), hepatomegaly, ascites, peripheral edema, and the presence of a right-sided fourth heart sound (S4) in severe disease. Pulmonary flow bruits can also be appreciated in 30% of CTEPH patients due to turbulent flow across partially occluded pulmonary arteries [42]. Nonspecific findings in both PAH and CTEPH include cardiomegaly and the loss of retrosternal airspace on lateral view due to right heart chamber enlargement [43].

Diagnosis Diagnostic evaluation of CTEPH includes measurement of the extent of obstructive thromboembolic disease, an evaluation of the hemodynamic benefits of surgical resection,

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surgical accessibility of the thrombus or thrombi, and an assessment of perioperative and postoperative risk from surgery. Two particular patient populations should be screened for CTEPH; those with unexplained pulmonary hypertension and patients with acute PE and evidence of ongoing RV dysfunction after 6 months of anticoagulation. In patients with unexplained pulmonary hypertension, proper evaluation of CTEPH is paramount because prompt surgical treatment is potentially curable, unlike other forms of pulmonary hypertension. Patients with acute PE and RV strain should receive a follow-up echocardiogram after 6-12 weeks of anticoagulation to determine whether the elevation in mPAP has resolved [44]. RV dysfunction, however, is not always present in the post-thrombotic state. Thus, it is imperative that other diagnostic modalities are utilized. Distinguishing CTEPH from recurrent PE is challenging because patient risk factors are similar. In differentiating these two separate disease entities, it is important to note that CTEPH patients are not responsive to anticoagulation therapy after 6 months and exhibit a gradual progression of symptoms of RV dysfunction and pulmonary hypertension. Patients with recurrent PE often present with acute dyspnea, chest pain, and fatigue. A thorough evaluation of both clinical symptoms and patient risk factors can determine which tools are most effective for proper diagnosis of CTEPH. A suggested algorithm for the diagnosis of CTEPH is shown in Figure 1.

Echocardiography TTE is one of the first tests that should be utilized to detect RV wall motion abnormalities and the presence of elevated pulmonary pressures in patients suspected of CTEPH. Routine echocardiographic testing within the first 6 months after acute PE has been shown to identify patients at increased risk for CTEPH [45]. Though further studies are warranted, echocardiographic evaluation may lead to earlier diagnosis of CTEPH and help improve patient outcomes. - 10 -

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While TTE with Doppler flow imaging is sensitive for the detection of RV wall motion abnormalities and pulmonary hypertension, it is not specific for the diagnosis of CTEPH. Common findings on echocardiogram in CTEPH patients include RV hypertrophy, both right atrial and RV enlargement, decreased systolic function, tricuspid regurgitation, and septal deviation into the left ventricle due to RV volume overload [46]. Limitations of echocardiogram in assessing disease severity in CTEPH patients include the accurate assessment of RV workload, RV ejection fraction, and overall RV function, particularly in patients with poor acoustic windows. The following echocardiographic parameters are useful to more accurately assess RV function: the tricuspid annular plane systolic velocity, RV myocardial performance index (Tei index), and tricuspid annular place systolic excursion (TAPSE). The Tei index can be used to further assess RV dysfunction by incorporating both systolic and diastolic time intervals to assess both systolic and diastolic ventricular function. In a study of CTEPH patients before and after PTE, the RV Tei index decreased from 0.52 (+/- 0.19) before surgery to 0.33 (+/- 0.10) following surgery compared to controls (0.27 +/- 0.09) [47]. In addition, the study suggests that the RV Tei index might be a valuable diagnostic tool to monitor disease severity in CTEPH patients and outcomes after PTE. While measurements like the Tei index have diagnostic utility before and after PTE, studies have shown that others such as TAPSE lose their utility postoperatively [48, 49].

Ventilation-Perfusion scintigraphy Ventilation-perfusion (V/Q) scintigraphy is one of the most widely available and sensitive tests for the detection of CTEPH. Despite advances in CT and MRI imaging modalities, The V/Q scan remains the preferred screening test for the diagnosis of CTEPH. V/Q scintigraphy is an imaging technique used to differentiate between CTEPH and other causes of pulmonary hypertension by detecting the presence of perfusion defects. The presence of multiple perfusion - 11 -

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defects suggests CTEPH as the likely diagnosis, whereas a normal V/Q scan can be used to rule out CTEPH. With CTPA, defects in chronic thromboembolic disease appear differently compared to solitary PE, and thus require additional training and special attention to detect these subtle differences. Furthermore, V/Q scintigraphy, when compared to CTPA, requires less radiation exposure and avoids potential complications related to the use of intravenous contrast [50]. In a study of 227 patients suspected of having CTEPH, V/Q scan had a sensitivity of 9697.4% and specificity of 90-95%, while CTPA showed a sensitivity and specificity of 51% and 99%, respectively [51]. V/Q scintigraphy does not anatomically localize the extent of disease, and thus cannot be used to determine if the defect is amenable to surgery. The benefit of the V/Q scan is the ease at which the results of the test can be interpreted (either normal or abnormal), making this imaging modality the preferred screening study in the evaluation of patients with pulmonary hypertension for CTEPH.

Catheter-based pulmonary angiography Catheter-based pulmonary angiography, with digital subtraction to improve vessel contrast, is the gold standard for confirming the diagnosis of CTEPH. The diagnostic technique combines both adequate visualization of the pulmonary vasculature with quantitative hemodynamic assessment via right heart catheterization. Though contrast does pose a risk of renal damage and anaphylaxis in some individuals, the amount of contrast can be minimized based on a patient’s cardiac output. In comparison to acute PE, five specific angiographic findings are suggestive of a diagnosis of CTEPH: pouch defects, pulmonary artery webs and bands, intimal irregularities, abrupt vascular narrowing, and lobar or segmental vessel obstruction at their origin [52]. In most CTEPH patients, two or more of these angiographic irregularities are present [22]. The advantage of catheter-based pulmonary angiography with digital subtraction is that this diagnostic modality provides an accurate, preoperative assessment of thrombus location and surgical accessibility. - 12 -

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Right heart catheterization (RHC) with hemodynamic assessment should be performed at the time of pulmonary angiography to quantify the degree of pulmonary hypertension, and assess responsiveness to vasodilator therapy. Decreased mPAP following nitric oxide (NO) inhalation can be indicative of an increase in long-term survival in CTEPH patients following PTE [53]. Differentiating elevated pulmonary artery pressures resulting from pre-existing PAH versus elevated pressures from acute PE remains a common challenge for the cardiologist. Gradual changes in symptoms and stepwise elevation in mPAP are more often indicators of chronic disease. PAH elicited with exercise, but not present at rest, may be an early indicator of chronic thromboembolic disease [54]. In patients suspected with CTEPH with only modest pulmonary hypertension by RHC, measurements should be completed following a short period of exercise. Exercise can cause a disproportionate elevation in mPAP in CTEPH patients due to the lack of compensatory pulmonary artery distension and recruitment seen in patients without disease.

Computed tomography pulmonary angiography Computed tomography pulmonary angiography (CTPA) has some benefits over conventional catheter-based pulmonary angiography. CTPA is a non-invasive screening tool that avoids the need for directed catheter access. In addition, with advances in CT technology, CTPA can provide high-resolution images that highlight pulmonary vessel wall thickness and additional details of surround structures that cannot be appreciated by conventional angiography [55]. Furthermore, CT imaging can screen for underlying mediastinal disease and reveal evidence of mosaic perfusion patterns and bronchial artery collaterals, vessel detail not always evident by other forms of angiography [56]. When compared to V/Q scintigraphy, CTPA is limited by a sensitivity of detecting CTEPH of 51% compared to >96% sensitivity with a V/Q scan [51]. Thus, CTPA therefore is best utilized in many centers for operability assessment; to detect CTEPH in vessels that are accessible for surgical PTE. CTPA is beneficial for detecting - 13 -

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proximal pulmonary artery thromboembolic disease, but disease confined to the distal segmental pulmonary arteries may be missed using CTPA as a screening modality. Using 320slice CT technology, the sensitivity for detecting disease in distal segmental vessels was lower when compared to disease limited to main or lobar branches of the pulmonary vasculature (86% vs. 97%, respectively) [57]. Recent use of multi-detector CTPA, however, has shown sensitivity for detecting CTEPH-related disease in main/lobar and segmental vessels at 100% and 100%, respectively [55]. Compared to the gold standard of diagnosis, pulmonary digital subtraction angiography (PDSA), the sensitivity and specificity of CTPA to detect CTEPH in main/lobar vessels were 97.0% and 97.1%, respectively [57]. High-quality multi-detector CTPA can be used as an alternative to conventional pulmonary angiography in centers with extensive CTEPH experience. At more experienced centers, CTEPH diagnosed using CTPA will often be deemed operable for PTE. However, due to the limitations of CTPA, using this screening modality alone may miss patients with disease that can benefit from medical therapy. With advances in CT imaging, the role of CTPA as a screening method for CTEPH may increase in the future.

Functional Assessment Cardiopulmonary exercise testing (CPX) is a non-invasive tool that provides measurements of cardiorespiratory function, including expiratory ventilation, carbon dioxide output, and oxygen uptake, along with EKG and blood pressure readings. For the cardiologist, the maximum oxygen uptake at peak exercise (VO2) is reflection of the highest attainable rate of gas exchange, and is a standard expression of capacity for endurance. CTEPH patients often experience

worsening

hypoxemia

with

exercise.

This

hypoxemia

is

the

result

of

ventilation/perfusion (V/Q) mismatch and an inadequate cardiac output response to exercise. Thus, in CTEPH patients, CPX testing is frequently abnormal with results showing decreased mixed venous oxygen saturation and decreased peak VO2 [58]. In some patients with normal echocardiograms at rest following acute PE, CPX can provide a complementary evaluation of - 14 -

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the degree of cardiopulmonary compromise and dead space ventilation. In a study of 42 patients with CTEPH, a third with normal echocardiograms were found to have pathological CPX results [59]. These results are in accord with a subsequent study that utilized CPX as a means of evaluating symptomatic patients with negative results on echocardiogram. Again, approximately one third of patients with negative results on echocardiogram following acute PE were found to have pathological findings on CPX and of these patients, approximately 25% had abnormal pulmonary perfusion by V/Q scan [60]. The results of both studies suggest that CPX is a useful complementary tool for the diagnosis of CTEPH, but that CPX testing must be followed up by either V/Q scan or pulmonary angiography. An additional test that be utilized in the evaluation of a patient for possible CTEPH is the six minute walk test (6MWT). The 6MWT has particular diagnostic utility in CTEPH patients because it has been found to represent clinical and hemodynamic disease severity [61]. In some centers, the 6MWT is routinely performed before and after PTE, and the 6-minute walk distance is used to assess prognosis and response to therapy. In a prospective study of 116 patients, mPAP, pulmonary vascular resistance (PVR), HR, peak VO2, and 6-minute walk distance were recorded in 37 patients before and after PTE. Baseline change in HR during 6MWT was significantly associated with PVR one year post-PTE, and multivariate analysis showed an association of percent heart rate reserve (HRR) during 6MWT with residual pulmonary hypertension [62].

Pulmonary function testing Pulmonary function studies (PFTs) are part of the diagnostic workup of CTEPH, but alone do not provide sufficient evidence for the diagnosis of CTEPH. In a small cohort of patients with CTEPH, a modest reduction in the vital capacity and pulmonary membrane diffusion capacity was found in comparison to those with primary PAH [63]. Many of these patients also had modest reductions in diffusing capacity of carbon monoxide (DLCO), a finding - 15 -

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that seems to be attributed to the loss in functional capillary exchange surface area and disturbances in the blood gas barrier. However, severe reductions in DLCO were associated with significant pulmonary vascular bed compromise and were associated with alternative diagnoses to CTEPH. In a different study, approximately 20% of CTEPH patients exhibited mild restrictive defects on PFTs, most likely due to parenchymal scarring from previous lung infarction [64]. Though CTEPH patients can exhibit a restrictive pattern on PFTs, additional studies have shown that normal values cannot exclude CTEPH as a diagnosis [7].

Magnetic resonance imaging Magnetic resonance imaging (MRI) is not currently recommended as a screening test for CTEPH in patients with pulmonary hypertension. Over the years, traditional MRI has evolved into an imaging modality that can assess both the pulmonary vasculature and the functional capacity of the heart. Cardiac MRI can offer measurements of mass, stroke volume, and ejection fraction with relatively high accuracy and precision and is currently utilized to evaluate RV dysfunction and RV workload [65]. Recent developments in magnetic resonance (MR) techniques include four-dimensional (4D) flow studies that map both direction and speed of blood flow. Recent analysis of hemodynamic flow changes within the pulmonary arteries has shown normalization of pulmonary arterial flow by 4D flow MRI in a patient with CTEPH following PTE [66]. The role of 4D flow MRI as a screening tool for the detection of CTEPH, however, has not been studied extensively. Likewise, there is limited data on the use of 3D contrast-enhanced lung perfusion MRI in the diagnosis of CTEPH. In a study of 132 patients from the ASPIRE registry, MR perfusion had a sensitivity of 97% and specificity of 92% in correctly diagnosing CTEPH compared to CTPA (sensitivity 94% and specificity 98%) [67].

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Treatment Role of Surgical Therapy Surgery is the only definitive treatment for CTEPH. The gold standard therapy for patients with CTEPH and a surgically accessible thrombus is PTE. Before surgery can occur, however, an operability assessment must be performed. With recent developments using PAHtargeted therapies and balloon pulmonary artery angioplasty (BPA) for the treatment of CTEPH, the role of a major operative procedure such as PTE is under greater scrutiny than in the past. PTE remains the established method of treatment for patients with operable CTEPH due to decreased mortality rates, excellent outcomes, and hemodynamic improvement, particularly when performed in experienced centers. A simplified therapeutic algorithm for the treatment of CTEPH is shown in Figure 2. The preoperative assessment should include the location of the thrombi, the extent of vessel obstruction, the current hemodynamic status of the patient, and the impact of the patient’s comorbidities on the risk of surgery [68]. In particular, patients with severe pulmonary hypertension and those with decompensated right heart failure from CTEPH are at greater risk for an adverse surgical outcome [69]. A patient with underlying significant obstructive or restrictive lung disease would not be a candidate for PTE given that reperfusion of abnormal lung parenchyma would result in minimal symptomatic relief for the patient. Direct contraindications to PTE include small-vessel disease with PVR out of proportion to the degree of obstruction, expected postoperative reduction in PVR <50%, and significant perioperative risk. Though advanced age is not a contraindication to surgery, a retrospective study showed that both total hospital days and ICU stay was greater in patients >70 years of age with inhospital mortality rate of 4.6% in patients <70 years and 7.8% in those patients >70 years [70]. The preoperative assessment also includes radiographic assessment of the extent of the disease in addition to quantitative hemodynamic assessment. The use of radiologic imaging

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such as CTPA and echocardiography to assess the degree of disease and its hemodynamic impact is largely based on clinical experience. RHC with pulmonary angiography not only allows visualization of the thrombi, but also provides an assessment of mPAP and PVR. A PVR <10001200 dyn/s/cm-5 is a preoperative indicator of a favorable postsurgical outcome [71]. In a single institution study of more than 2,700 patients, the San Diego group reported a declining overall operative mortality risk of 2.2%, with a mortality rate of 4.1% in patients with preoperative PVR >1000 dyn/s/cm-5 compared to 1.6% in patients with preoperative PVR <1000 dyn/s/cm-5 [29]. In a similar separate study, overall in-hospital mortality following PTE was 4% in patients with preoperative PVR >1200 dyn/s/cm-5 and decompensated right heart failure upon initial presentation [72]. Though some centers have reported higher mortality rates in patients with PVR >1000-1200 dyn/s/cm-5, this hemodynamic cutoff value is not a direct contraindication for PTE. One attempt to lower preoperative PVR is through the use of vasodilator therapy. When comparing short-term responses to inhaled nitric oxide therapy, long-term use of vasodilators such as bosentan and sildenafil has shown no benefit to accurately predict hemodynamic postoperative status or postsurgical outcomes following PTE [73]. PTE necessitates a median sternotomy, cardiopulmonary bypass, and deep hypothermia with intermittent circulatory arrest [74]. The median sternotomy allows access to pulmonary arteries, assures removal of the chronic thrombus, and prevents disruption of bronchial artery collateral flow. The dissection of the pulmonary arteries occurs intrapericardially without entering the pleural cavity. Cardiopulmonary bypass with temporary circulatory arrest (limited to 20-minute intervals) is employed to allow for dissection of the thrombus from the pulmonary vessel and for better visualization of the surgical field. Fundamentally, the purpose of using deep hypothermic circulatory arrest is to reduce PVR. Recently, alternative approaches have been explored to reduce the neurological complications of circulatory arrest and hypothermia. These alternative techniques include the use of moderate rather than deep hypothermia, antegrade unilateral cerebral artery perfusion with and without total circulatory - 18 -

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arrest, and aortic bronchial artery occlusion with balloon catheter [75-78]. Despite these studies, none have proven to be superior to traditional PTE surgery. Patients undergoing PTE can experience two unique complications that can significantly impair gas exchange. Pulmonary artery steal syndrome, which refers to the postoperative redistribution of pulmonary arterial blood flow to newly endarterectomized segments with subsequent

V/Q

mismatch,

can

occur

in

up

to

70%

of

patients

undergoing

thromboendarterectomy [79]. Treatment is supportive and this vascular phenomenon resolves in most patients with no supplemental oxygen needed two weeks after hospital discharge [80]. Reperfusion pulmonary edema is another complication that can occur in up to 30% of patients following PTE, with fluid collecting in areas of the lung from which proximal thromboemboli were removed [81]. It can occur up to 72 hours after surgery with varying severity and treatment is mainly supportive. Average ICU length of stay from reperfusion pulmonary edema is 4 days with a postoperative length of stay of 14 days [82]. Reperfusion pulmonary edema and pulmonary artery steal syndrome can occur together. In this situation, the hypoxemia can be profound and extracorporeal membrane oxygenation (ECMO) can be helpful as a supportive measure for patients. Veno-arterial ECMO is necessary in cases of hemodynamic instability, while venovenous ECMO is sufficient in patients with primarily reperfusion injury [83, 84]. In patients with RV failure, ECMO has been used for hemodynamic support with a median duration of treatment of 5 days and reported survival up to 57% [85]. Recent reports of in-hospital mortality rates for PTE are 2.2% from a single center series in the US [29] and 4.7% according across multiple European surgical centers [69]. The longterm prognosis following PTE still remains favorable compared to non-operable medical management. In a prospective study of 679 patients, 3-year estimated survival rates in operable patients were 89% (95% CI, 86-92) and only 70% (95% CI, 64-76) in non-operable patients [86]. Further, it was found that in both operated and non-operated patients, PAH-targeted medical therapy did not affect survival rates significantly. Recent studies from Europe show 5-year - 19 -

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survival rates at approximately 90% [87, 88]. During the postoperative course, an improvement in hemodynamics can lead to reverse RV remodeling, with eventual return of both normal systolic and diastolic RV function. In a retrospective study of 72 patients, RV reverse remodeling, as measured by improvement in RV volumes and mass with MRI, was observed for 3 months in patients who underwent PTE surgery [89]. Postoperative improvements in hemodynamic status can also be measured by assessing functional capacity. Both the 6-minute walk distance and the New York Heart Association (NYHA) functional class are significantly improved following PTE and these beneficial effects are seen years following surgery [90]. In a study of patients with symptomatic CTEPH and baseline mPAP <25 mmHg following PTE, surgical intervention resulted in a significant improvement in both functional status and quality of life with 95% of patients at either NYHA functional class I or II at 6 months follow-up [91]. Not all patients show continued hemodynamic improvement following PTE. Late adverse effects from PTE include residual elevation in mPAP and recurrent pulmonary hypertension in patients who initially showed improvement. Estimates of residual pulmonary hypertension vary between 5-35% of patients following PTE [71, 90]. Postoperative decreases in PVR by at least 50% to a PVR <500 dyn/s/cm-5 have more favorable postsurgical outcomes [92]. In a study of 500 patients, those with PVR >500 dyn/s/cm-5 had an in-hospital mortality rate of 10.3% compared to 0.9% in patients with PVR <500 dyn/s/cm-5 [29]. Long-term studies are warranted to determine what level of residual pulmonary hypertension negatively impacts functional status in patients after surgery. Recurrent pulmonary hypertension in patients with persistent functional impairment may be candidates for medical therapy.

Role of Medical Management The most common medical treatments used for CTEPH include anticoagulants, diuretics, and oxygen supplementation for hypoxemia. Anticoagulation is prescribed in most - 20 -

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CTEPH patients to prevent recurrent VTE. Lifelong anticoagulation with vitamin K antagonists with a goal INR=2-3 is recommended, and currently no guidelines are available regarding the use of direct oral anticoagulants in CTEPH. Though multiple studies have shown that indefinite anticoagulation decreases the risk of recurrent VTE in patients with unprovoked or idiopathic PE [93, 94], data is lacking for the widespread use of long-term anticoagulation in CTEPH. The role of medical therapy for the treatment of CTEPH is increasing as more studies are performed using PAH-targeted therapies. Pulmonary vasodilators and remodeling agents lower the PVR and mPAP, thus improving exercise capacity and oxygenation. Therefore, pulmonary vasodilators should be considered in patients with inoperable CTEPH or in those with persistent PAH following PTE. PAH-targeted medical therapy for patients with operable CTEPH is not recommended. Medications used in CTEPH are similar to those used to treat idiopathic PAH and include prostanoids, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and soluble guanylate cyclase stimulants. As in PAH, plasma levels of endothelin-1 closely correlate with the severity of disease and the hemodynamic status in CTEPH patients [40]. Furthermore, the histopathological appearance of distal arteries in CTEPH patients closely resembles those in patients with idiopathic PAH [95]. With persistent PH following PTE in almost a quarter of patients, the need for medical therapy in CTEPH is growing. Data from randomized control trials suggest that medical therapy for patients with inoperable CTEPH has symptomatic benefits (Table 1). For inoperable CTEPH and those with residual PAH following PTE, medical therapy is recommended with riociguat as the first drug to show positive primary endpoints in a randomized control trial for both of these indications. Riociguat is an oral medication taken three times daily and belongs to a class of soluble guanylate cyclase stimulants [96]. It requires dose titration to decrease the risk of systemic hypotension and does not alter prothrombin time when used in conjunction with warfarin [97]. In one of the largest randomized control trials in CTEPH to date, the CHEST-1 trial found that - 21 -

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following 16 weeks of treatment, patients treated with riociguat had improvement in 6-minute walk distance, PVR, WHO functional class, and NT-proBNP [98]. Subgroup analysis found that treatment effects were less pronounced in patients with persistent PAH following PTE. Followup data from the open-label, long-term extension of this trial (CHEST-2) reported that prolonged therapy for up to two years with riociguat resulted in similar exercise and functional status benefits and a favorable safety profile [99, 100]. The use of endothelin receptor antagonists in CTEPH is common and occurs in approximately 20% of patients following initial PTE evaluation. In the BENEFiT randomized placebo-controlled trial, 157 patients with either inoperable CTEPH or persistent CTEPH following PTE were randomly assigned to either placebo or oral bosentan for 16 weeks [101]. Compared to placebo, bosentan therapy was associated with decreased PVR and improved cardiac index. Oral bosentan did not show improvement in exercise capacity. A systematic review of ten observational studies and the BENEFiT trial found that in inoperable CTEPH patients, oral bosentan was associated with improvement in baseline exercise capacity as measured by the 6MWT, as well as decreased mPAP and increased cardiac index compared to controls [102]. Given this promising data, the MERIT-1 trial with macitentan, a newer generation endothelin receptor antagonist, is currently underway in patients with inoperable CTEPH with the primary endpoint being the change in PVR 16 weeks after therapy compared to placebo. In a double-blind, placebo-controlled trial, 19 patients with inoperable CTEPH were randomly assigned either the phosphodiesterase-5 inhibitor sildenafil or placebo [103]. At 12 weeks, no improvement was observed in exercise capacity, but the sildenafil group had a better WHO functional class and decreased PVR. At this time, all subjects were provided with openlabel sildenafil and offered repeat follow-up at 12 months. It was found that sildenafil afforded significant improvements in 6-minute walk distance, quality of life scores, cardiac index, PVR, and N-terminal prohormone of brain natriuretic peptide (NT-proBNP). Similar improvements in PVR and 6-minute walk distance were observed in an open-label uncontrolled clinical trial of - 22 -

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104 patients with inoperable CTEPH treated with sildenafil [104]. A small number of studies report benefit from prostanoids in patients with inoperable CTEPH. Improvements in PVR, mPAP, and exercise capacity have been shown in a small study with the prostacyclin analogue epoprostenol [105]. Similarly, studies with treprostinil and iloprost suggest significant hemodynamic and functional benefit [106, 107]. In an open-label study of 28 patients with inoperable CTEPH, treprostinil administration resulted in significant improvements in 6-minute walk distance, WHO functional class, NT-proBNP, cardiac output, and PVR [106]. Furthermore, it was found that long-term survival was significantly better than in controls. Medical therapy in CTEPH should not be considered as a replacement for PTE. There is some evidence that medical therapy can be used in patients with severe life-threatening CTEPH as a therapeutic bridge to definitive PTE. In a case series of 12 patients with severe CTEPH as defined as PVR >1200 dyn/s/cm-5, a continuous IV infusion of epoprostenol was administered for a mean of 46 days prior to surgery [108]. A 28% decrease from baseline was seen in PVR preoperatively, however, no postoperative benefits were observed. The role of bridging with medical therapy and the delay for definitive treatment with PTE has not been sufficiently studied and should be reserved for additional investigation.

Role of Balloon Pulmonary Artery Angioplasty Another alternative therapy in select patients with surgically inaccessible distal disease or recurrent PAH following PTE is balloon pulmonary artery angioplasty (BPA). In a study of 68 patients with inoperable CTEPH undergoing BPA, an average of 4 separate BPA procedures were performed in each patient to reduce the risk of reperfusion injury [109]. Following these procedures, improvement was observed in WHO functional class and mPAP. However, 60% of patients developed reperfusion injury after BPA and four required transient mechanical ventilation. In a separate series of 29 patients with CTEPH who underwent BPA, both WHO functional class and mPAP improved [110]. Of the 51 total procedures performed, 53% resulted - 23 -

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in reperfusion pulmonary edema with one patient requiring intubation and transient mechanical ventilation. It has recently been suggested that the effects of BPA are comparable to surgical endarterectomy due to recent changes in angioplasty techniques [111]. As percutaneous BPA carries significant risk of reperfusion injury, however, this intervention should only be performed at experienced, specialized centers. In surgically amenable patients, surgical treatment with PTE remains the gold standard. Inoperable CTEPH patients should be treated medically with riociguat. Additional studies need to be performed to determine the role of BPA in inoperable CTEPH.

Conclusion CTEPH is a rare and potentially fatal disease that can be potentially cured with surgery. Patients with progressive dyspnea on exertion and other symptoms of right heart failure should undergo echocardiography to assess right ventricular function and pulmonary pressures, followed by V/Q scintigraphy and pulmonary angiography/right heart catheterization to confirm the diagnosis. Surgically amenable patients should be referred for experienced CTEPH centers, as PTE remains the gold standard for treatment. Inoperable CTEPH patients or those with residual PAH post PTE should be treated medically with riociguat. Ongoing studies will further determine the role of medical therapy and BPA in CTEPH.

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Acknowledgements The authors have no financial or proprietary interest in the subject matter of this article.

Author disclosure: Dr Mandras reports serving as a consultant or paid advisory board member for Actelion Pharmaceuticals US, Inc, and Bayer Pharmaceuticals. Dr Mandras also reports receipt of lecture fees on behalf of Actelion Pharmaceuticals US, Inc, and Gilead Pharmaceuticals.

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[85] Berman M, Tsui S, Vuylsteke A, Snell A, Colah S, Latimer R, et al. Successful extracorporeal membrane oxygenation support after pulmonary thromboendarterectomy. Ann Thorac Surg. 2008;86:1261-7. [86] Delcroix M, Lang I, Pepke-Zaba J, Jansa P, D'Armini AM, Snijder R, et al. Long-Term Outcome of Patients With Chronic Thromboembolic Pulmonary Hypertension: Results From an International Prospective Registry. Circulation. 2016;133:859-71. [87] Saouti N, Morshuis WJ, Heijmen RH, Snijder RJ. Long-term outcome after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension: a single institution experience. Eur J Cardiothorac Surg. 2009;35:947-52; discussion 52. [88] Freed DH, Thomson BM, Berman M, Tsui SS, Dunning J, Sheares KK, et al. Survival after pulmonary thromboendarterectomy: effect of residual pulmonary hypertension. J Thorac Cardiovasc Surg. 2011;141:383-7. [89] Berman M, Gopalan D, Sharples L, Screaton N, Maccan C, Sheares K, et al. Right ventricular reverse remodeling after pulmonary endarterectomy: magnetic resonance imaging and clinical and right heart catheterization assessment. Pulmonary circulation. 2014;4:36-44. [90] Corsico AG, D'Armini AM, Cerveri I, Klersy C, Ansaldo E, Niniano R, et al. Long-term outcome after pulmonary endarterectomy. Am J Respir Crit Care Med. 2008;178:419-24. [91] Taboada D, Pepke-Zaba J, Jenkins DP, Berman M, Treacy CM, Cannon JE, et al. Outcome of pulmonary endarterectomy in symptomatic chronic thromboembolic disease. Eur Respir J. 2014;44:1635-45. [92] Keogh AM, Mayer E, Benza RL, Corris P, Dartevelle PG, Frost AE, et al. Interventional and surgical modalities of treatment in pulmonary hypertension. J Am Coll Cardiol. 2009;54:S67-77. [93] Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, Deitcher SR, et al. Longterm, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003;348:1425-34. [94] Kearon C, Ginsberg JS, Kovacs MJ, Anderson DR, Wells P, Julian JA, et al. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med. 2003;349:631-9. [95] Moser KM, Bloor CM. Pulmonary vascular lesions occurring in patients with chronic major vessel thromboembolic pulmonary hypertension. Chest. 1993;103:685-92. [96] Ghofrani HA, Humbert M, Langleben D, Schermuly R, Stasch JP, Wilkins MR, et al. Riociguat: Mode of action and clinical development in pulmonary hypertension. Chest. 2016. [97] Koress C, Swan K, Kadowitz P. Soluble Guanylate Cyclase Stimulators and Activators: Novel Therapies for Pulmonary Vascular Disease or a Different Method of Increasing cGMP? Curr Hypertens Rep. 2016;18:42. [98] Ghofrani H-A, D'Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, et al. Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension. N Engl J Med. 2013;369:319-29. [99] Simonneau G, D'Armini AM, Ghofrani HA, Grimminger F, Hoeper MM, Jansa P, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension: a long-term extension study (CHEST-2). Eur Respir J. 2015;45:1293-302. [100] Simonneau G, D'Armini AM, Ghofrani HA, Grimminger F, Jansa P, Kim NH, et al. Predictors of long-term outcomes in patients treated with riociguat for chronic thromboembolic pulmonary hypertension: data from the CHEST-2 open-label, randomised, long-term extension trial. The Lancet Respiratory medicine. 2016;4:372-80. [101] Jais X, D'Armini AM, Jansa P, Torbicki A, Delcroix M, Ghofrani HA, et al. Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension: BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension), a randomized, placebo-controlled trial. J Am Coll Cardiol. 2008;52:2127-34.

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[102] Becattini C, Manina G, Busti C, Gennarini S, Agnelli G. Bosentan for chronic thromboembolic pulmonary hypertension: findings from a systematic review and meta-analysis. Thromb Res. 2010;126:e51-6. [103] Suntharalingam J, Treacy CM, Doughty NJ, Goldsmith K, Soon E, Toshner MR, et al. Long-term use of sildenafil in inoperable chronic thromboembolic pulmonary hypertension. Chest. 2008;134:229-36. [104] Reichenberger F, Voswinckel R, Enke B, Rutsch M, El Fechtali E, Schmehl T, et al. Longterm treatment with sildenafil in chronic thromboembolic pulmonary hypertension. Eur Respir J. 2007;30:922-7. [105] Cabrol S, Souza R, Jais X, Fadel E, Ali RH, Humbert M, et al. Intravenous epoprostenol in inoperable chronic thromboembolic pulmonary hypertension. J Heart Lung Transplant. 2007;26:357-62. [106] Skoro-Sajer N, Bonderman D, Wiesbauer F, Harja E, Jakowitsch J, Klepetko W, et al. Treprostinil for severe inoperable chronic thromboembolic pulmonary hypertension. J Thromb Haemost. 2007;5:483-9. [107] Olschewski H, Simonneau G, Galie N, Higenbottam T, Naeije R, Rubin LJ, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 2002;347:322-9. [108] Nagaya N, Sasaki N, Ando M, Ogino H, Sakamaki F, Kyotani S, et al. Prostacyclin therapy before pulmonary thromboendarterectomy in patients with chronic thromboembolic pulmonary hypertension. Chest. 2003;123:338-43. [109] Mizoguchi H, Ogawa A, Munemasa M, Mikouchi H, Ito H, Matsubara H. Refined balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv. 2012;5:748-55. [110] Kataoka M, Inami T, Hayashida K, Shimura N, Ishiguro H, Abe T, et al. Percutaneous transluminal pulmonary angioplasty for the treatment of chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv. 2012;5:756-62. [111] Satoh T, Kataoka M, Inami T, Ishiguro H, Yanagisawa R, Shimura N, et al. Endovascular treatment for chronic pulmonary hypertension: a focus on angioplasty for chronic thromboembolic pulmonary hypertension. Expert Rev Cardiovasc Ther. 2016:1-6. [112] Hoeper MM, Barberà JA, Channick RN, Hassoun PM, Lang IM, Manes A, et al. Diagnosis, Assessment, and Treatment of Non-Pulmonary Arterial Hypertension Pulmonary Hypertension. J Am Coll Cardiol. 2009;54:S85-96.

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Tables Table 1. Medical Therapy Trials Conducted in Patients with Inoperable CTEPH Patient s (n)

Duratio n (mo)

Primary Endpoint(s )

Riociguat (0.5-2.5 mg TID PO)

261

4

6MWD

Increase in mean 6MWD by 39m in riociguat group compared to mean decrease of 6m in control

[98]

CHEST-2, RCT

Riociguat (2.5 mg TID PO)

237

24

6MWD NT-proBNP

Improvement in 6MWD and NT-proBNP and 93% overall survival seen after 2 years

[99, 100]

BENEFiT, RCT

Bosentan (62.5-125 mg BID PO)

157

4

PVR 6MWD

Improved PVR and cardiac index. No improvement in 6MWD

[101]

MERIT-1, RCT

Macitentan (10 mg QD PO)

---

4

PVR

Ongoing study

RCT

Sildenafil (40 mg TID PO)

19

3

6MWD

No change in 6MWD at 3 months. Decrease in PVR, improvement in WHO-FC.

[103]

Open label, uncontrolled

Sildenafil (50 mg TID PO)

104

12

6MWD

Reduction in PVR and mPAP after 3 months. Significant improvement in 6MWD after 12 months.

[104]

Retrospectiv e cohort

Epoprostenol (16-30 ng/kg/min IV)

27

3

6MWD PVR mPAP

[105]

Uncontrolled , prospective cohort

Treprostinil (11-42 ng/kg/min subcutaneou s infusion)

25

6-72

6MWD WHO-FC NT-proBNP PVR

Improvement in 6MWD, PVR, and mPAP Significant improvement in 6MWD, WHO-FC, NTproBNP, and PVR.

Drug class

Study

Therapy

Soluble guanylate cyclase stimulants

CHEST-1, RCT

Endothelin receptor antagonists

Phosphodiesteras e-5 inhibitors

Prostanoids

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Result

Reference(s )

[106]

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RCT

Iloprost (2.55 mcg 6-9 times/day, inhaled)

203

3

6MWD NYHA-FC

Improved 6MWD, NYHA-FC. No difference in hemodynamic s between iloprost and placebo.

[107]

Abbreviations: QD = once daily, BID = twice daily, TID = three times daily, PO = per os, IV = intravenous, 6MWD = 6-minute walk distance, NT-proBNP = N-terminal prohormone of brain natriuretic peptide, PVR = pulmonary vascular resistance, mPAP = mean pulmonary arterial pressure, RCT = randomized control trial, WHO-FC = World Health Organization functional class, NYHA-FC = New York Heart Association functional class

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Figures Figure 1. Diagnostic Algorithm for the Patient with Suspected CTEPH.

Symptoms suspicious for PAH in a patient with PE after 6 months of anticoagulation

Echocardiogram with increased PA pressure, RVH, RVE, RAE with normal LV systolic, diastolic function and valves

Perfusion defects on V/Q scan?

No

Yes

CTEPH Excluded Catheter-Based Pulmonary Angiogram with Right Heart Catheterization, CTPA, MRA

Diagnosis Confirmed

Refer to Expert Center for consideration for PTE and/or medical therapy

Modified with permission, from Hoeper et al [112 ] Abbreviations: CTEPH= Chronic thromboembolic pulmonary hypertension; CTPA= Computed tomography pulmonary angiography; LV= left ventricular; PA= pulmonary artery; PAH= pulmonary arterial hypertension; PE= pulmonary embolism; PTE= pulmonary thromboendarterectomy; RAE=right atrial enlargement; RVE= right ventricular enlargement; RVH=right ventricular hypertrophy; MRA=magnetic resonance angiography; V/Q= ventilation-perfusion.

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Figure 2. Therapeutic Approach to the Management of the Patient with CTEPH.

Confirmed diagnosis of CTEPH

Surgically accessible thrombotic occlusions

Yes

No

Contraindications to surgery

No

PTE

Yes

Initiate medical therapy with pulmonary vasodilators

Recurrent symptomatic PAH

Refer for lung transplantation evaluation

Modified with permission, from Hoeper et al [112 ] Abbreviations: CTEPH= Chronic thromboembolic pulmonary hypertension; PAH= pulmonary arterial hypertension; PTE= pulmonary thromboendarterectomy

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