**8. Treatment of CTEPH**

Several therapies have been used for CTEPH patients since the initial discovery of this clinical entity [85, 86]. In recent years scientific societies have unanimously endorsed surgical inter‐ vention with PEA as the preferred treatment for CTEPH because of the significant improve‐ ment in survival for the majority of patients and long-term improved outcomes.

PAH specific medications have been investigated in CTEPH, though the number of patients studied is much smaller than those enrolled in PAH clinical trials. These studies have shown safety of several therapies, and varying degrees of benefit. Medical therapies are often considered for use in inoperable patients, or for patients who have residual pulmonary hypertension after surgery.

The decision to use a specific medication in patients with CTEPH who cannot undergo surgery or who present with residual PH after surgical intervention should be made after an evaluation by a referral center. In addition, these patients should remain under close clinical monitoring.

#### **8.1. Surgical approach**

#### *8.1.1. Preparation of patients before pulmonary endarterectomy*

After diagnostic evaluation, PEA is the treatment of choice for symptomatic patients with proximal CTEPH. The preoperative assessment of patients scheduled for PEA involves evaluating the presence of associated left heart disease with echocardiography to assess LV size and function as well as coronary angiography to exclude coronary artery disease in the appropriate patient [87]. Patients are also evaluated for significant concurrent disorders such as malignancy, using age-appropriate targeted screening, based on careful consideration of the symptoms presented. Patients are usually maintained on systemic anticoagulation immediately before surgery, although the actual protocol depends on local experience and preference of the expert center. Supplemental oxygen and diuretics are often administered to optimize the patient's oxygen and volume status. Thromboendarerectomy is the treatment of choice for symptomatic patients with CTEPH when surgically feasible. In some of these patients, particularly those with severe pulmonary hypertension and right ventricular failure, medical treatment pre-PEA with parenteral prostanoids (eg epoprostenol) may be initiated as a bridge to endarterectomy [87, 88, 89].

#### *8.1.2. Pulmonary Endarterectomy (PEA)*

Pulmonary endarterectomy is the preferred treatment for patients with CTEPH because of the potential for cure and complete resolution of PH and its complications. PEA has the potential to restore near normal cardiopulmonary function. Patient selection for surgery depends on the extent and location of the organized thrombus in relation to the degree of pulmonary hyper‐ tension. When the thrombus is situated in a proximal location, it represents the ideal condition for surgery, but if the thrombus is more distal, the intervention becomes more difficult.

#### *8.1.2.1. Surgical strategy*

helpful in the selection of patients for PEA. Type I disease is characterised by a clear central thrombus; type II consists of the thickening of the intima and fibrous reticulum in a main or segmental bronchus, without thrombus in a main vessel; type III is limited to segmental or sub-segmental regions and type IV involves only peripheral vessels and is not an operable disease.[80, 81]. In addition, pulmonary angiography is not free of significant risk in the context of severe pulmonary hypertension. Therefore, some security measures should be taken [82, 83]. The biplane acquisition technique should be used whenever possible. The systematic use of the side view is extremely useful in determining the location and extent of anatomical

Pulmonary angioscopy is used as an adjunct to pulmonary angiography. In the early years of endarterectomy, pulmonary angioscopy was used more frequently. More recent‐ ly, it has been replaced by other, less invasive imaging techniques [84]. The technique in‐ volves the introduction of the angioscope through an introducer, preferably in the right internal jugular vein, then through the right atrium and right ventricle and the right and left pulmonary arteries, where it can be guided in each lobe of the arteries. The distal bal‐ loon is inflated with carbon dioxide, which obstructs blood flow transiently and allows

Several therapies have been used for CTEPH patients since the initial discovery of this clinical entity [85, 86]. In recent years scientific societies have unanimously endorsed surgical inter‐ vention with PEA as the preferred treatment for CTEPH because of the significant improve‐

PAH specific medications have been investigated in CTEPH, though the number of patients studied is much smaller than those enrolled in PAH clinical trials. These studies have shown safety of several therapies, and varying degrees of benefit. Medical therapies are often considered for use in inoperable patients, or for patients who have residual pulmonary

The decision to use a specific medication in patients with CTEPH who cannot undergo surgery or who present with residual PH after surgical intervention should be made after an evaluation by a referral center. In addition, these patients should remain under close clinical monitoring.

After diagnostic evaluation, PEA is the treatment of choice for symptomatic patients with proximal CTEPH. The preoperative assessment of patients scheduled for PEA involves

ment in survival for the majority of patients and long-term improved outcomes.

proximal embolic obstruction and, therefore, surgical accessibility.

*7.5.3. Pulmonary angioscopy*

152 Pulmonary Hypertension

visualization of the vascular bed [84].

**8. Treatment of CTEPH**

hypertension after surgery.

**8.1. Surgical approach**

*8.1.1. Preparation of patients before pulmonary endarterectomy*

PEA is performed during total circulatory arrest under conditions of profound hypothermia. This is required to enable visibility in the distal pulmonary arterial branches, which would otherwise be subject to back-bleeding during the endarterectomy due to the development of a systemic-to-pulmonary artery circulation at the precapillary level. A relatively recent technical advance is the introduction of video-assisted pulmonary endarterectomy, which uses a video camera connected to a rigid angioscope [90, 91]. Video technology is beneficial because it provides a source of light, allows visualization of the distal pulmonary vascular tree, and facilitates a close view of the surgery by the assistant surgeons.

#### *8.1.2.2. Surgical procedure*

After a median sternotomy, followed by a vertical pericardiotomy, the patient is placed on cardiopulmonary bypass with hypothermia at 18 to 20 ° C. Before the cardiopulmonary bypass the patient's head is wrapped in a blanket with circulating cold water at 4° C. [90, 91]. This blanket has a thermometer and a device for regulating the water circulation. After the cardiopulmonary bypass has been started vents are placed in the pulmonary artery and the right superior pulmonary vein. The right pulmonary artery is dissected between the aorta and the superior vena cava and is mobilised within the pericardial reflection. During a first period of circulatory arrest, the plane is circumferentially followed down to the segmental and sometimes subsegmental branches of each lobe using special suction dissectors, until a complete endartectomy is achieved. Once the field has been prepared, the endarterectomy precedes with the aid of a microscopic aspirator with a rounded tip. The surgical specimen often resembles the arborization of pulmonary arteries, sometimes containing a mixture of fresh and old clots. The pulmonary artery pressures are commonly reduced immediately after surgery. The patient is reperfused for approximately 15 min with cardiopulmonary bypass, while the arteriotomy is closed with a back-and-forth running suture. An arteriotomy is performed on the left pulmonary artery and the endarterectomy is repeated in the left lung within another period of circulatory arrest. The final stage comprises reperfusion during closure of the left pulmonary artery, de-airing of the cardiac chambers, unclamping of the aorta, and slow rewarming of the patient to 37°C. [92, 93].

*8.1.5. Postoperative outcomes*

to 12 months after PEA.

procedure [100].

*8.1.6. Long-term outcomes*

quality of life [101].

**8.2. Medical therapy**

Despite the potential for life-threatening complications, the perioperative mortality of pa‐ tients undergoing lung PEA has improved in recent years. The first results of an interna‐ tional CTEPH registry, which included 386 consecutive patients with newly diagnosed CTEPH undergoing surgery showed a significant and sustained decrease in PVR from 736 to 248 dyn s cm-5, which was accompanied by substantial improvements in WHO functional class and exercise capacity at 1 year [97]. Reported rates of residual PH after PEA (mean PAP> 30 mmHg) were 16.7% and 31%, respectively. More recently, a greatly reduced surgical mortality rate of 2.2% was reported [98]. Perioperative mortality in pa‐ tients undergoing pulmonary endarterectomy at the University of California at San Diego was 17% for the first 200 patients who underwent operation from 1970 to 1990 [98]. In a series from UCSD from 1998 until 2002, 500 patients underwent pulmonary endarterecto‐ my, with a rate of hospital mortality of 4.4% [98]. The preoperative factors that may ad‐ versely affect surgical outcomes include age over 70 years, the presence of multiple comorbidities, preoperative pulmonary vascular resistance, severe heart failure with high right atrial pressure, and prolonged duration of pulmonary hypertension before surgery [99]. In order to detect persistent or recurrent pulmonary hypertension, systematic moni‐ toring surveys are needed. Right heart catheterization is recommended for a period of 6

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The danger inherent in the initiation of specific medical treatment of pulmonary hypertension without consultation with a surgeon is that potentially operable patients are not referred to a center of expertise, and they do not respond to medical treatment or are sent to surgery at an advanced stage, which is associated with a significantly increased risk. Before starting treatment, it must be established that the patients are appropriate candidates for the surgical

Changes in short and long term patient outcomes are generally favorable after PEA. Indeed, functional and hemodynamic results are very encouraging. Most patients who were New York Heart Association (NYHA) class III or IV preoperatively became class I or II after surgery and were able to resume normal activities. A significant reduction and standardization of both pulmonary artery pressure and resistance may also be affected. In the largest series to date, the mean pulmonary artery pressure decreased from 46 mm Hg to 28 mm Hg and the mean pulmonary vascular resistance decreased from 893 to 285 dyne/s-1, [98]. Similar improvements were observed in right ventricular function by echocardiography, exercise capacity, and

Pulmonary endarterectomy is the treatment of choice for patients with CTEPH; unfortunately, it cannot be performed in all CTEPH patients because of the inaccessibility of distal lesions or the presence of concomitant life-threatening diseases. [102]. In addition, patients with CTEPH

#### *8.1.3. PEA in patients with distal CTEPH*

The potential benefits of PEA are uncertain in patients with distal arterial obstruction and associated CTEPH. Studies have focused specifically on this issue by comparing clinical and hemodynamic results of surgery in patients with CTEPH and proximal thrombosis or distal thrombosis [94]. In a study of patients evaluated for CTEPH, 83 patients were considered for thrombo-endarterectomy [95], 40 patients underwent the procedure of whom 14 had distal lesions affecting small vessels. In these 14 subjects, PEA was associated with improvement of the baseline dyspnea index. However, the distal thrombo-endarterectomy was associated with increased perioperative mortality and severe residual PH post-thrombo-endarterectomy. Currently, there is no clear consensus on optimal management of distal chronic thromboem‐ bolic disease with associated PH. [94].

#### *8.1.4. Management of patients after surgery*

This is a crucial element for the success of the pulmonary PEA. Although pulmonary hemo‐ dynamics improved immediately after surgery in most patients, the postoperative course may be complicated. Complications are usually not related to any specific aspect of the heart surgery (pericardial effusion, arrhythmia, atelectasis, wound infection), or specific to the pulmonary thromboendarterectomy [96]. The postoperative course is marked mainly by the risk of pulmonary edema-like lesionswhich may appear up to 72 hours after surgery in the areas where the thromboembolic obstruction was removed [96, 97]. This pulmonary edema is of varying severity, ranging from a simple acute hypoxemia transition to a fatal hemorrhagic complication sometimes requiring prolonged mechanical ventilation. Other complications encountered are right heart failure due to persistent PH, the dehiscence of an arteriotomy suture during an episode of PAH, nosocomial pneumonia, hemoptysis, which will be easily treated by embolization, or phrenic nerve paralysis which might prolong mechanical ventila‐ tion.

Reethrombosis in the region of the thromboendarterectomy is a rare but known complication, especially in unilateral obstruction, which justifies the initiation of anticoagulant therapy as early as possible after the operation. Patients often continue to improve functionally and hemodynamicly in the months after the operation.

#### *8.1.5. Postoperative outcomes*

precedes with the aid of a microscopic aspirator with a rounded tip. The surgical specimen often resembles the arborization of pulmonary arteries, sometimes containing a mixture of fresh and old clots. The pulmonary artery pressures are commonly reduced immediately after surgery. The patient is reperfused for approximately 15 min with cardiopulmonary bypass, while the arteriotomy is closed with a back-and-forth running suture. An arteriotomy is performed on the left pulmonary artery and the endarterectomy is repeated in the left lung within another period of circulatory arrest. The final stage comprises reperfusion during closure of the left pulmonary artery, de-airing of the cardiac chambers, unclamping of the

The potential benefits of PEA are uncertain in patients with distal arterial obstruction and associated CTEPH. Studies have focused specifically on this issue by comparing clinical and hemodynamic results of surgery in patients with CTEPH and proximal thrombosis or distal thrombosis [94]. In a study of patients evaluated for CTEPH, 83 patients were considered for thrombo-endarterectomy [95], 40 patients underwent the procedure of whom 14 had distal lesions affecting small vessels. In these 14 subjects, PEA was associated with improvement of the baseline dyspnea index. However, the distal thrombo-endarterectomy was associated with increased perioperative mortality and severe residual PH post-thrombo-endarterectomy. Currently, there is no clear consensus on optimal management of distal chronic thromboem‐

This is a crucial element for the success of the pulmonary PEA. Although pulmonary hemo‐ dynamics improved immediately after surgery in most patients, the postoperative course may be complicated. Complications are usually not related to any specific aspect of the heart surgery (pericardial effusion, arrhythmia, atelectasis, wound infection), or specific to the pulmonary thromboendarterectomy [96]. The postoperative course is marked mainly by the risk of pulmonary edema-like lesionswhich may appear up to 72 hours after surgery in the areas where the thromboembolic obstruction was removed [96, 97]. This pulmonary edema is of varying severity, ranging from a simple acute hypoxemia transition to a fatal hemorrhagic complication sometimes requiring prolonged mechanical ventilation. Other complications encountered are right heart failure due to persistent PH, the dehiscence of an arteriotomy suture during an episode of PAH, nosocomial pneumonia, hemoptysis, which will be easily treated by embolization, or phrenic nerve paralysis which might prolong mechanical ventila‐

Reethrombosis in the region of the thromboendarterectomy is a rare but known complication, especially in unilateral obstruction, which justifies the initiation of anticoagulant therapy as early as possible after the operation. Patients often continue to improve functionally and

aorta, and slow rewarming of the patient to 37°C. [92, 93].

*8.1.3. PEA in patients with distal CTEPH*

154 Pulmonary Hypertension

bolic disease with associated PH. [94].

*8.1.4. Management of patients after surgery*

hemodynamicly in the months after the operation.

tion.

Despite the potential for life-threatening complications, the perioperative mortality of pa‐ tients undergoing lung PEA has improved in recent years. The first results of an interna‐ tional CTEPH registry, which included 386 consecutive patients with newly diagnosed CTEPH undergoing surgery showed a significant and sustained decrease in PVR from 736 to 248 dyn s cm-5, which was accompanied by substantial improvements in WHO functional class and exercise capacity at 1 year [97]. Reported rates of residual PH after PEA (mean PAP> 30 mmHg) were 16.7% and 31%, respectively. More recently, a greatly reduced surgical mortality rate of 2.2% was reported [98]. Perioperative mortality in pa‐ tients undergoing pulmonary endarterectomy at the University of California at San Diego was 17% for the first 200 patients who underwent operation from 1970 to 1990 [98]. In a series from UCSD from 1998 until 2002, 500 patients underwent pulmonary endarterecto‐ my, with a rate of hospital mortality of 4.4% [98]. The preoperative factors that may ad‐ versely affect surgical outcomes include age over 70 years, the presence of multiple comorbidities, preoperative pulmonary vascular resistance, severe heart failure with high right atrial pressure, and prolonged duration of pulmonary hypertension before surgery [99]. In order to detect persistent or recurrent pulmonary hypertension, systematic moni‐ toring surveys are needed. Right heart catheterization is recommended for a period of 6 to 12 months after PEA.

The danger inherent in the initiation of specific medical treatment of pulmonary hypertension without consultation with a surgeon is that potentially operable patients are not referred to a center of expertise, and they do not respond to medical treatment or are sent to surgery at an advanced stage, which is associated with a significantly increased risk. Before starting treatment, it must be established that the patients are appropriate candidates for the surgical procedure [100].

#### *8.1.6. Long-term outcomes*

Changes in short and long term patient outcomes are generally favorable after PEA. Indeed, functional and hemodynamic results are very encouraging. Most patients who were New York Heart Association (NYHA) class III or IV preoperatively became class I or II after surgery and were able to resume normal activities. A significant reduction and standardization of both pulmonary artery pressure and resistance may also be affected. In the largest series to date, the mean pulmonary artery pressure decreased from 46 mm Hg to 28 mm Hg and the mean pulmonary vascular resistance decreased from 893 to 285 dyne/s-1, [98]. Similar improvements were observed in right ventricular function by echocardiography, exercise capacity, and quality of life [101].

#### **8.2. Medical therapy**

Pulmonary endarterectomy is the treatment of choice for patients with CTEPH; unfortunately, it cannot be performed in all CTEPH patients because of the inaccessibility of distal lesions or the presence of concomitant life-threatening diseases. [102]. In addition, patients with CTEPH who have undergone endarterectomy may experience a gradual hemodynamic and sympto‐ matic decline related to a secondary hypertensive arteriopathy in the small precapillary pulmonary vessels. It has also been questioned what can be done to reduce risks from PEA surgery to improve outcomes in "high risk" patients with CTEPH with substantial impairment of pulmonary hemodynamics before surgery. Such patients may benefit from preoperative reduction of pulmonary vascular resistance by means of medical therapy. Conventional medical treatments, such as anticoagulation, diuretics, digitalis, and chronic oxygen therapy, show low efficacy in the treatment of CTEPH as they do not affect underlying disease proc‐ esses. Over the last decade, several novel therapies have been developed for pulmonary arterial hypertension (PAH), including prostacyclin analogs (epoprostenol, beraprost, iloprost, treprostinil), endothelin receptor antagonists (bosentan, sitaxsentan, ambrisentan), and phosphodiesterase-5 inhibitors (sildenafil, tadalafil). Evidence of efficacy in PAH, coupled with studies showing histopathologic similarities between CTEPH and PAH, provides a rationale to extend the use of some of these medications to the treatment of CTEPH. However, direct evidence from clinical trials in CTEPH is limited to date [103, 104].

**8.3. Management of patients who are not candidates for endarterectomy**

**8.4. Balloon angioplasty in patients with CTEPH**

**8.5. Review of transplantation in patients with CTEPH**

exercise capacity.

studied in CTEPH.

PEA remains the preferred approach for patients with CTEPH. Unfortunately, up to 50% of patients are not surgical candidates with the most common reasons for exclusion being distal chronic thromboembolic disease with surgical inaccessibility and significant comorbidities. Specific medical therapies for PAH in the future can be a real alternative for PEA CTEPH patients. Although the distinction between PAH and CTEPH is often clear, there are many similarities between the conditions, including the clinical presentation with progressive PH and RV failure, and overlapping pathophysiology. PAH and CTEPH may represent extremes of a continuum of disease based on several data sources such as the observation that micro‐ vascular arteriopathy with plexiform lesions may exist in the vascular bed of both obstructed and unobstructed patients with CTEPH [109]. The role of several medical therapies in these specific groups of patients with CTEPH has been explored in many small-uncontrolled studies.

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http://dx.doi.org/10.5772/54749

157

Early indications are that medical therapies may have promise in all these subgroups of patients with CTEPH, but the precise role of medical treatment in each situation remains unclear. Studies to date have not demonstrated the same level of efficacy in CTEPH as for patients with PAH [110]. Other CTEPH patients who might receive PAH medications include those awaiting lung transplantation. The currently available data do not justify the continua‐ tion of medical treatment in these patients if the waiting time to lung transplantation is long.

Some patients with CTEPH, despite proximal (main, lobar or segmental) pulmonary artery occlusion are not candidates for thromboendarterectomy or decline surgery. In these patients, balloon angioplasty is a therapeutic option to relieve the obstructed pulmonary artery and improve the degree of pulmonary hypertension. Uncontrolled case series [111] have demon‐ strated a short-term improvement in pulmonary hemodynamics, WHO functional class, and

Although angioplasty may be beneficial, the long term results have not been thoroughly

Concerned patients with CTEPH in functional class III / IV who are inoperable or have residual pulmonary hypertension post-PEA are referred for lung transplantation to improve their clinical outcomes. Although no studies specifically addressing this medical issue have been identified, patients with CTEPH were included in studies of lung transplantation for pulmo‐ nary hypertension, and in reports from international transplant registries [112]. The average survival for patients with idiopathic pulmonary hypertension undergoing lung transplanta‐ tion was 5.6 years. The absence of any direct evidence for lung transplantation compared to medical treatment, especially in patients with CTEPH, was noted. However, the health benefits of lung transplantation, and a high impact on morbidity and mortality in selected CTEPH patients was emphasized. The CTEPH patients who are inoperable or experience residual PH post-PEA and who remain in WHO functional class III or IV, despite optimal medical therapy,

The BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension) study was a double-blind, randomized, placebo-controlled study in CTEPH including patients with either inoperable CTEPH or persistent/recurrent pulmonary hyper‐ tension after PEA (>6 months after PEA). Independent coprimary end points were change in PVR as a percentage of baseline and change from baseline in 6-min walk distance after 16 weeks of treatment [105]. This study demonstrated a positive treatment effect of bosentan on hemodynamics in this patient population. No improvement was observed in exercise capacity. Further trials are needed to define the role of medical therapy in patients with CTEPH. In a retrospective study, the authors analyzed the effects of long-term intravenous epoprostenol in 27 consecutive functional class III (n = 20) or IV (n = 7) patients with inoperable distal CTEPH. After three months of epoprostenol, NYHA functional class improved by one class in 11 of 23 surviving patients, 6-minute walk distance increased by 66 m (p 0.0001) and hemodynamics also improved. At the last evaluation (20 ± 8 months), functional class was improved in 9 of 18 surviving patients with sustained improvement in 6-minute walk distance (+46 m, p = 0.03) and hemodynamic parameters. Survival at one, two and three years was 73%, 59% and 41%, respectively [88]. Epoprostenol has also been shown to improve hemodynamics in CTEPH patients prior to pulmonary thromboendarterectomy. In an open-label uncontrolled study, the prostacyclin analog treprostinil has been used in patients with severe inoperable CTEPH. Treprostinil improves exercise capacity, hemodynamics and survival in patients with severe inoperable CTEPH. We speculate that the effects may be explained by a combined vasodila‐ tory, platelet-antagonistic and potential antiproliferative action of the drug [106].

A double-blind, placebo-controlled, 12-week pilot study investigated the use of sildenafil, 40 mg three times daily, in 19 patients with inoperable CTEPH. Unfortunately, this study was inadequately powered to test the primary end-point (change in 6-min walk distance). More‐ over, there was no significant difference between the sildenafil and placebo groups (17.5 m improvement). Nevertheless, there were significant improvements in WHO functional class (p=0.025) and pulmonary vascular resistance (p=0.044) for the sildenafil-treated [107].

#### **8.3. Management of patients who are not candidates for endarterectomy**

who have undergone endarterectomy may experience a gradual hemodynamic and sympto‐ matic decline related to a secondary hypertensive arteriopathy in the small precapillary pulmonary vessels. It has also been questioned what can be done to reduce risks from PEA surgery to improve outcomes in "high risk" patients with CTEPH with substantial impairment of pulmonary hemodynamics before surgery. Such patients may benefit from preoperative reduction of pulmonary vascular resistance by means of medical therapy. Conventional medical treatments, such as anticoagulation, diuretics, digitalis, and chronic oxygen therapy, show low efficacy in the treatment of CTEPH as they do not affect underlying disease proc‐ esses. Over the last decade, several novel therapies have been developed for pulmonary arterial hypertension (PAH), including prostacyclin analogs (epoprostenol, beraprost, iloprost, treprostinil), endothelin receptor antagonists (bosentan, sitaxsentan, ambrisentan), and phosphodiesterase-5 inhibitors (sildenafil, tadalafil). Evidence of efficacy in PAH, coupled with studies showing histopathologic similarities between CTEPH and PAH, provides a rationale to extend the use of some of these medications to the treatment of CTEPH. However,

The BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension) study was a double-blind, randomized, placebo-controlled study in CTEPH including patients with either inoperable CTEPH or persistent/recurrent pulmonary hyper‐ tension after PEA (>6 months after PEA). Independent coprimary end points were change in PVR as a percentage of baseline and change from baseline in 6-min walk distance after 16 weeks of treatment [105]. This study demonstrated a positive treatment effect of bosentan on hemodynamics in this patient population. No improvement was observed in exercise capacity. Further trials are needed to define the role of medical therapy in patients with CTEPH. In a retrospective study, the authors analyzed the effects of long-term intravenous epoprostenol in 27 consecutive functional class III (n = 20) or IV (n = 7) patients with inoperable distal CTEPH. After three months of epoprostenol, NYHA functional class improved by one class in 11 of 23 surviving patients, 6-minute walk distance increased by 66 m (p 0.0001) and hemodynamics also improved. At the last evaluation (20 ± 8 months), functional class was improved in 9 of 18 surviving patients with sustained improvement in 6-minute walk distance (+46 m, p = 0.03) and hemodynamic parameters. Survival at one, two and three years was 73%, 59% and 41%, respectively [88]. Epoprostenol has also been shown to improve hemodynamics in CTEPH patients prior to pulmonary thromboendarterectomy. In an open-label uncontrolled study, the prostacyclin analog treprostinil has been used in patients with severe inoperable CTEPH. Treprostinil improves exercise capacity, hemodynamics and survival in patients with severe inoperable CTEPH. We speculate that the effects may be explained by a combined vasodila‐

direct evidence from clinical trials in CTEPH is limited to date [103, 104].

156 Pulmonary Hypertension

tory, platelet-antagonistic and potential antiproliferative action of the drug [106].

(p=0.025) and pulmonary vascular resistance (p=0.044) for the sildenafil-treated [107].

A double-blind, placebo-controlled, 12-week pilot study investigated the use of sildenafil, 40 mg three times daily, in 19 patients with inoperable CTEPH. Unfortunately, this study was inadequately powered to test the primary end-point (change in 6-min walk distance). More‐ over, there was no significant difference between the sildenafil and placebo groups (17.5 m improvement). Nevertheless, there were significant improvements in WHO functional class PEA remains the preferred approach for patients with CTEPH. Unfortunately, up to 50% of patients are not surgical candidates with the most common reasons for exclusion being distal chronic thromboembolic disease with surgical inaccessibility and significant comorbidities. Specific medical therapies for PAH in the future can be a real alternative for PEA CTEPH patients. Although the distinction between PAH and CTEPH is often clear, there are many similarities between the conditions, including the clinical presentation with progressive PH and RV failure, and overlapping pathophysiology. PAH and CTEPH may represent extremes of a continuum of disease based on several data sources such as the observation that micro‐ vascular arteriopathy with plexiform lesions may exist in the vascular bed of both obstructed and unobstructed patients with CTEPH [109]. The role of several medical therapies in these specific groups of patients with CTEPH has been explored in many small-uncontrolled studies.

Early indications are that medical therapies may have promise in all these subgroups of patients with CTEPH, but the precise role of medical treatment in each situation remains unclear. Studies to date have not demonstrated the same level of efficacy in CTEPH as for patients with PAH [110]. Other CTEPH patients who might receive PAH medications include those awaiting lung transplantation. The currently available data do not justify the continua‐ tion of medical treatment in these patients if the waiting time to lung transplantation is long.

#### **8.4. Balloon angioplasty in patients with CTEPH**

Some patients with CTEPH, despite proximal (main, lobar or segmental) pulmonary artery occlusion are not candidates for thromboendarterectomy or decline surgery. In these patients, balloon angioplasty is a therapeutic option to relieve the obstructed pulmonary artery and improve the degree of pulmonary hypertension. Uncontrolled case series [111] have demon‐ strated a short-term improvement in pulmonary hemodynamics, WHO functional class, and exercise capacity.

Although angioplasty may be beneficial, the long term results have not been thoroughly studied in CTEPH.

#### **8.5. Review of transplantation in patients with CTEPH**

Concerned patients with CTEPH in functional class III / IV who are inoperable or have residual pulmonary hypertension post-PEA are referred for lung transplantation to improve their clinical outcomes. Although no studies specifically addressing this medical issue have been identified, patients with CTEPH were included in studies of lung transplantation for pulmo‐ nary hypertension, and in reports from international transplant registries [112]. The average survival for patients with idiopathic pulmonary hypertension undergoing lung transplanta‐ tion was 5.6 years. The absence of any direct evidence for lung transplantation compared to medical treatment, especially in patients with CTEPH, was noted. However, the health benefits of lung transplantation, and a high impact on morbidity and mortality in selected CTEPH patients was emphasized. The CTEPH patients who are inoperable or experience residual PH post-PEA and who remain in WHO functional class III or IV, despite optimal medical therapy, should be referred for lung transplantation evaluation. Because there can be significant delays until transplantation, early referral is important.

[4] Moser KM, Braunwald NS. Successful surgical intervention in severe chronic throm‐

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