Sonja Bartolome, MD

Chronic thromboembolic pulmonary hypertension (CTEPH) is an elevation in pulmonary vascular resistance (PVR) resulting from chronic, “scarred-in” thromboembolic material partially occluding the pulmonary arteries. This vascular obstruction, over time, results in failure of the right ventricle and early mortality.

CTEPH was first characterized in an autopsy series from the Massachusetts General Hospital in 1931. On these postmortem examinations, it was noted that the affected patients had large pulmonary artery vascular obstruction, but also normal pulmonary parenchyma distal to this vascular obstruction and extensive bronchial collateral blood flow (Means J. Ann Intern Med. 1931;5:417). Although this observation set the groundwork for the theory that surgically removing the vascular obstruction to this preserved lung tissue could improve the condition of these patients, it would take until the mid-20th century until imaging and cardiac catheterization techniques allowed the recognition of the disease in real time.

CTEPH is thought to begin with an acute pulmonary embolus, but in approximately 3.4% of patients, rather than resolving over time, the thrombus will organize and incorporate into the pulmonary artery intimal layer (Simonneau G, et al. Eur Respir Rev. 2017;26:160112) A history of venous thromboembolism in a patient with persistent dyspnea should spur a screening evaluation for CTEPH; 75% of patients with CTEPH have a history of prior known acute pulmonary embolus and 56% of patients report a prior diagnosis of deep venous thrombosis. An acute pulmonary embolus will fibrinolyse early with the vast majority of the vascular obstruction resolving by the third month. Therefore, if the patient continues to report a significant exercise limitation after 3 months of therapeutic anticoagulation therapy, or has concerning physical exam signs, a workup should be pursued. The initial evaluation for CTEPH begins with a transthoracic echocardiogram (TTE) and ventilation/perfusion (V/Q) scintigraphy. A retrospective study comparing V/Q scan and multidetector CT scan revealed that V/Q scanning had a sensitivity and specificity of 97% and 95% for CTEPH, while CTPA had good specificity at 99% but only 51% sensitivity (Tunariu N, et al. J Nuc Med. 2007;48(5):680). If these are abnormal, then right-sided heart catheterization and invasive biplane digital subtraction pulmonary angiography are recommended. These studies confirm the diagnosis, grade its severity, and allow an evaluation for surgically accessible vs distal disease. Some CTEPH centers utilize additional imaging techniques, such as magnetic resonance angiography, optical resonance imaging, spectral CT scanning with iodine perfusion images, and intravascular ultrasound. These modalities and their place in the diagnostic algorithm are under investigation.

The goal of the initial evaluation process is to determine if the patient can undergo surgical pulmonary thromboendarterectomy (PTE), because in experienced hands, this procedure ensures the best long-term outcome for the patient. The first pulmonary thromboendarterectomy was performed at the University of California San Diego in 1970. Because the disease involves the intimal layer of the pulmonary artery, the surgery had to involve not just removal of the intravascular obstruction but also a pulmonary artery intimectomy. Surgical mortality rates were high in the initial experience. In 1984, a review of 85 worldwide cases reported an average mortality rate of 22%, and as high as 40% in some centers (Chitwood WR, Jr, et al. Clin Chest Med. 1984;5(3):507).

 

Over the ensuing years, refinements in surgical technique, the utilization of deep hypothermia and cardiac arrest during the procedure, development of new surgical instruments, and standardization of surgical selection and postoperative care have improved surgical mortality to <5% in experienced centers. Long-term outcomes of successful PTE surgery remain good, with 90% 3-year survival vs 70% for those who do not undergo surgery and are medically treated. Importantly, 90% of postoperative patients report functional class I or II symptoms at 1 year (Condliffe R, et al. Am J Reslpir Crit Care Med. 2008:177(10);1122). Because of this difference in early mortality and symptoms, PTE surgery remains the treatment of choice for CTEPH.

Despite the advances in PTE surgery, some patients are not operative candidates either due to surgically inaccessible disease or due to comorbidities. In 2001, Feinstein and colleagues described a series of 18 CTEPH cases treated with balloon pulmonary angioplasty (BPA). Promising hemodynamics effects were reported; however, the procedure had an unacceptable complication rate in which 11 patients developed reperfusion lung injury, 3 patients required mechanical ventilation, and 1 patient died. In the ensuing years, Japanese and Norwegian groups have independently developed and improved techniques for BPA. The procedure is done in a series of sessions (average four to six), 1 to 4 weeks apart, where small (2-3 mm) balloons are directed toward distal, diseased pulmonary vessels. Common complications include reperfusion injury, vessel injury, hemoptysis, and, more rarely, respiratory failure. Still, early experience suggests this procedure decreases pulmonary vascular resistance over time, improves right ventricular function, and improves patients’ symptoms (Andreassen A, et al. Heart. 2013;99(19):1415). The experience with this procedure is limited but growing in the United States, with only a handful of centers currently performing BPAs and collecting data.

Lifelong anticoagulation, oxygen, and diuretics for right-sided heart failure are recommended for patients with CTEPH. The first successful large phase III medication study for CTEPH was the CHEST-1 trial published in 2013. This was a multicenter, randomized, placebo-controlled trial of the soluble guanylate cyclase stimulator riociguat. The study enrolled 261 patients with inoperable CTEPH or persistent pulmonary hypertension after surgery. The primary end point was 6-minute walk distance at 12 weeks. The treatment group showed a 46 m improvement (P<.001). Secondary end points of pulmonary vascular resistance, NT-proBNP level, and functional class also improved. This pivotal trial led to the FDA approval of riociguat for inoperable or persistent postoperative CTEPH.

MERIT-1, a phase II, randomized placebo-controlled double trial of macitentan (an oral endothelin receptor antagonist) was recently completed. It enrolled 80 patients with inoperable CTEPH. The primary endpoint was pulmonary vascular resistance at week 16, expressed as a percentage of baseline. At week 16, the patients in the treatment arm had a PVR 73% of baseline vs 87.2% in the treatment group. This medication is not yet FDA-approved for the treatment of inoperable CTEPH (Ghofrani H, et al. Lancet Respir Med. 2017;5(10):785-794).

Pulmonary hypertension medication has been postulated as a possible way to “pretreat” patients before pulmonary thromboendarterectomy surgery, perhaps lowering preoperative pulmonary vascular resistance and surgical risk. However, there are currently no convincing data to support this practice, and medical treatment has been associated with a possible counterproductive delay in surgery. A phase II study including CTEPH patients with high PVR for preoperative treatment with riociguat vs placebo is currently enrolling to determine if “induction” treatment with medication prior to surgery reduces risk or delays definitive surgery. Occasionally, patients are found who have persistent thrombus but not pulmonary hypertension. Chronic thromboembolic disease (CTED) is a recently coined term describing patients who have chronic thromboembolism on imaging but have normal resting hemodynamics. Whether CTED represents simply unresolved clot that will never progress to CTEPH or is an early point on the continuum of disease not well-defined and a controversial topic among experts. At many centers, patients with CTED and symptoms will undergo exercise testing to look for exercise -induced pulmonary hypertension or an increase in dead space ventilation as a cause of their symptoms. A retrospective series of carefully chosen CTED patients who underwent PTE surgery reported improvements in symptoms and overall quality of life, without increased complications (Taboada D, et al. Eur Respir J. 2014 44(6):1635). The operation carries risk, however, and further work into the epidemiology and prognosis of CTED is required before operative intervention can be recommended.

In conclusion, CTEPH is a disease that rarely occurs after an acute PE but when undiagnosed and untreated portends a poor prognosis. The definitive treatment for this disease is surgical PTE, but to achieve the best outcomes, this procedure needs to be performed at expert centers with multidisciplinary team experience. Patients who are poor operative candidates or with surgically inaccessible disease may be considered for balloon pulmonary angioplasty. For patients without more curative options, medication improves exercise tolerance. The field of CTEPH has been rapidly expanding over the last decade, leading to better patient outcomes and more treatment options.

Dr. Bartolome is Associate Professor, Pulmonary and Critical Care Medicine; Director, CTEPH Program; and Associate Director, PH Program; UT Southwestern Medical Center, Dallas, Texas.

Chronic thromboembolic pulmonary hypertension (CTEPH) is an elevation in pulmonary vascular resistance (PVR) resulting from chronic, “scarred-in” thromboembolic material partially occluding the pulmonary arteries. This vascular obstruction, over time, results in failure of the right ventricle and early mortality.

CTEPH was first characterized in an autopsy series from the Massachusetts General Hospital in 1931. On these postmortem examinations, it was noted that the affected patients had large pulmonary artery vascular obstruction, but also normal pulmonary parenchyma distal to this vascular obstruction and extensive bronchial collateral blood flow (Means J. Ann Intern Med. 1931;5:417). Although this observation set the groundwork for the theory that surgically removing the vascular obstruction to this preserved lung tissue could improve the condition of these patients, it would take until the mid-20th century until imaging and cardiac catheterization techniques allowed the recognition of the disease in real time.

CTEPH is thought to begin with an acute pulmonary embolus, but in approximately 3.4% of patients, rather than resolving over time, the thrombus will organize and incorporate into the pulmonary artery intimal layer (Simonneau G, et al. Eur Respir Rev. 2017;26:160112) A history of venous thromboembolism in a patient with persistent dyspnea should spur a screening evaluation for CTEPH; 75% of patients with CTEPH have a history of prior known acute pulmonary embolus and 56% of patients report a prior diagnosis of deep venous thrombosis. An acute pulmonary embolus will fibrinolyse early with the vast majority of the vascular obstruction resolving by the third month. Therefore, if the patient continues to report a significant exercise limitation after 3 months of therapeutic anticoagulation therapy, or has concerning physical exam signs, a workup should be pursued. The initial evaluation for CTEPH begins with a transthoracic echocardiogram (TTE) and ventilation/perfusion (V/Q) scintigraphy. A retrospective study comparing V/Q scan and multidetector CT scan revealed that V/Q scanning had a sensitivity and specificity of 97% and 95% for CTEPH, while CTPA had good specificity at 99% but only 51% sensitivity (Tunariu N, et al. J Nuc Med. 2007;48(5):680). If these are abnormal, then right-sided heart catheterization and invasive biplane digital subtraction pulmonary angiography are recommended. These studies confirm the diagnosis, grade its severity, and allow an evaluation for surgically accessible vs distal disease. Some CTEPH centers utilize additional imaging techniques, such as magnetic resonance angiography, optical resonance imaging, spectral CT scanning with iodine perfusion images, and intravascular ultrasound. These modalities and their place in the diagnostic algorithm are under investigation.

The goal of the initial evaluation process is to determine if the patient can undergo surgical pulmonary thromboendarterectomy (PTE), because in experienced hands, this procedure ensures the best long-term outcome for the patient. The first pulmonary thromboendarterectomy was performed at the University of California San Diego in 1970. Because the disease involves the intimal layer of the pulmonary artery, the surgery had to involve not just removal of the intravascular obstruction but also a pulmonary artery intimectomy. Surgical mortality rates were high in the initial experience. In 1984, a review of 85 worldwide cases reported an average mortality rate of 22%, and as high as 40% in some centers (Chitwood WR, Jr, et al. Clin Chest Med. 1984;5(3):507).

 

Over the ensuing years, refinements in surgical technique, the utilization of deep hypothermia and cardiac arrest during the procedure, development of new surgical instruments, and standardization of surgical selection and postoperative care have improved surgical mortality to <5% in experienced centers. Long-term outcomes of successful PTE surgery remain good, with 90% 3-year survival vs 70% for those who do not undergo surgery and are medically treated. Importantly, 90% of postoperative patients report functional class I or II symptoms at 1 year (Condliffe R, et al. Am J Reslpir Crit Care Med. 2008:177(10);1122). Because of this difference in early mortality and symptoms, PTE surgery remains the treatment of choice for CTEPH.

Despite the advances in PTE surgery, some patients are not operative candidates either due to surgically inaccessible disease or due to comorbidities. In 2001, Feinstein and colleagues described a series of 18 CTEPH cases treated with balloon pulmonary angioplasty (BPA). Promising hemodynamics effects were reported; however, the procedure had an unacceptable complication rate in which 11 patients developed reperfusion lung injury, 3 patients required mechanical ventilation, and 1 patient died. In the ensuing years, Japanese and Norwegian groups have independently developed and improved techniques for BPA. The procedure is done in a series of sessions (average four to six), 1 to 4 weeks apart, where small (2-3 mm) balloons are directed toward distal, diseased pulmonary vessels. Common complications include reperfusion injury, vessel injury, hemoptysis, and, more rarely, respiratory failure. Still, early experience suggests this procedure decreases pulmonary vascular resistance over time, improves right ventricular function, and improves patients’ symptoms (Andreassen A, et al. Heart. 2013;99(19):1415). The experience with this procedure is limited but growing in the United States, with only a handful of centers currently performing BPAs and collecting data.

Lifelong anticoagulation, oxygen, and diuretics for right-sided heart failure are recommended for patients with CTEPH. The first successful large phase III medication study for CTEPH was the CHEST-1 trial published in 2013. This was a multicenter, randomized, placebo-controlled trial of the soluble guanylate cyclase stimulator riociguat. The study enrolled 261 patients with inoperable CTEPH or persistent pulmonary hypertension after surgery. The primary end point was 6-minute walk distance at 12 weeks. The treatment group showed a 46 m improvement (P<.001). Secondary end points of pulmonary vascular resistance, NT-proBNP level, and functional class also improved. This pivotal trial led to the FDA approval of riociguat for inoperable or persistent postoperative CTEPH.

MERIT-1, a phase II, randomized placebo-controlled double trial of macitentan (an oral endothelin receptor antagonist) was recently completed. It enrolled 80 patients with inoperable CTEPH. The primary endpoint was pulmonary vascular resistance at week 16, expressed as a percentage of baseline. At week 16, the patients in the treatment arm had a PVR 73% of baseline vs 87.2% in the treatment group. This medication is not yet FDA-approved for the treatment of inoperable CTEPH (Ghofrani H, et al. Lancet Respir Med. 2017;5(10):785-794).

Pulmonary hypertension medication has been postulated as a possible way to “pretreat” patients before pulmonary thromboendarterectomy surgery, perhaps lowering preoperative pulmonary vascular resistance and surgical risk. However, there are currently no convincing data to support this practice, and medical treatment has been associated with a possible counterproductive delay in surgery. A phase II study including CTEPH patients with high PVR for preoperative treatment with riociguat vs placebo is currently enrolling to determine if “induction” treatment with medication prior to surgery reduces risk or delays definitive surgery. Occasionally, patients are found who have persistent thrombus but not pulmonary hypertension. Chronic thromboembolic disease (CTED) is a recently coined term describing patients who have chronic thromboembolism on imaging but have normal resting hemodynamics. Whether CTED represents simply unresolved clot that will never progress to CTEPH or is an early point on the continuum of disease not well-defined and a controversial topic among experts. At many centers, patients with CTED and symptoms will undergo exercise testing to look for exercise -induced pulmonary hypertension or an increase in dead space ventilation as a cause of their symptoms. A retrospective series of carefully chosen CTED patients who underwent PTE surgery reported improvements in symptoms and overall quality of life, without increased complications (Taboada D, et al. Eur Respir J. 2014 44(6):1635). The operation carries risk, however, and further work into the epidemiology and prognosis of CTED is required before operative intervention can be recommended.

In conclusion, CTEPH is a disease that rarely occurs after an acute PE but when undiagnosed and untreated portends a poor prognosis. The definitive treatment for this disease is surgical PTE, but to achieve the best outcomes, this procedure needs to be performed at expert centers with multidisciplinary team experience. Patients who are poor operative candidates or with surgically inaccessible disease may be considered for balloon pulmonary angioplasty. For patients without more curative options, medication improves exercise tolerance. The field of CTEPH has been rapidly expanding over the last decade, leading to better patient outcomes and more treatment options.

Dr. Bartolome is Associate Professor, Pulmonary and Critical Care Medicine; Director, CTEPH Program; and Associate Director, PH Program; UT Southwestern Medical Center, Dallas, Texas.

Chronic thromboembolic pulmonary hypertension (CTEPH) is an elevation in pulmonary vascular resistance (PVR) resulting from chronic, “scarred-in” thromboembolic material partially occluding the pulmonary arteries. This vascular obstruction, over time, results in failure of the right ventricle and early mortality.

CTEPH was first characterized in an autopsy series from the Massachusetts General Hospital in 1931. On these postmortem examinations, it was noted that the affected patients had large pulmonary artery vascular obstruction, but also normal pulmonary parenchyma distal to this vascular obstruction and extensive bronchial collateral blood flow (Means J. Ann Intern Med. 1931;5:417). Although this observation set the groundwork for the theory that surgically removing the vascular obstruction to this preserved lung tissue could improve the condition of these patients, it would take until the mid-20th century until imaging and cardiac catheterization techniques allowed the recognition of the disease in real time.

CTEPH is thought to begin with an acute pulmonary embolus, but in approximately 3.4% of patients, rather than resolving over time, the thrombus will organize and incorporate into the pulmonary artery intimal layer (Simonneau G, et al. Eur Respir Rev. 2017;26:160112) A history of venous thromboembolism in a patient with persistent dyspnea should spur a screening evaluation for CTEPH; 75% of patients with CTEPH have a history of prior known acute pulmonary embolus and 56% of patients report a prior diagnosis of deep venous thrombosis. An acute pulmonary embolus will fibrinolyse early with the vast majority of the vascular obstruction resolving by the third month. Therefore, if the patient continues to report a significant exercise limitation after 3 months of therapeutic anticoagulation therapy, or has concerning physical exam signs, a workup should be pursued. The initial evaluation for CTEPH begins with a transthoracic echocardiogram (TTE) and ventilation/perfusion (V/Q) scintigraphy. A retrospective study comparing V/Q scan and multidetector CT scan revealed that V/Q scanning had a sensitivity and specificity of 97% and 95% for CTEPH, while CTPA had good specificity at 99% but only 51% sensitivity (Tunariu N, et al. J Nuc Med. 2007;48(5):680). If these are abnormal, then right-sided heart catheterization and invasive biplane digital subtraction pulmonary angiography are recommended. These studies confirm the diagnosis, grade its severity, and allow an evaluation for surgically accessible vs distal disease. Some CTEPH centers utilize additional imaging techniques, such as magnetic resonance angiography, optical resonance imaging, spectral CT scanning with iodine perfusion images, and intravascular ultrasound. These modalities and their place in the diagnostic algorithm are under investigation.

The goal of the initial evaluation process is to determine if the patient can undergo surgical pulmonary thromboendarterectomy (PTE), because in experienced hands, this procedure ensures the best long-term outcome for the patient. The first pulmonary thromboendarterectomy was performed at the University of California San Diego in 1970. Because the disease involves the intimal layer of the pulmonary artery, the surgery had to involve not just removal of the intravascular obstruction but also a pulmonary artery intimectomy. Surgical mortality rates were high in the initial experience. In 1984, a review of 85 worldwide cases reported an average mortality rate of 22%, and as high as 40% in some centers (Chitwood WR, Jr, et al. Clin Chest Med. 1984;5(3):507).

 

Over the ensuing years, refinements in surgical technique, the utilization of deep hypothermia and cardiac arrest during the procedure, development of new surgical instruments, and standardization of surgical selection and postoperative care have improved surgical mortality to <5% in experienced centers. Long-term outcomes of successful PTE surgery remain good, with 90% 3-year survival vs 70% for those who do not undergo surgery and are medically treated. Importantly, 90% of postoperative patients report functional class I or II symptoms at 1 year (Condliffe R, et al. Am J Reslpir Crit Care Med. 2008:177(10);1122). Because of this difference in early mortality and symptoms, PTE surgery remains the treatment of choice for CTEPH.

Despite the advances in PTE surgery, some patients are not operative candidates either due to surgically inaccessible disease or due to comorbidities. In 2001, Feinstein and colleagues described a series of 18 CTEPH cases treated with balloon pulmonary angioplasty (BPA). Promising hemodynamics effects were reported; however, the procedure had an unacceptable complication rate in which 11 patients developed reperfusion lung injury, 3 patients required mechanical ventilation, and 1 patient died. In the ensuing years, Japanese and Norwegian groups have independently developed and improved techniques for BPA. The procedure is done in a series of sessions (average four to six), 1 to 4 weeks apart, where small (2-3 mm) balloons are directed toward distal, diseased pulmonary vessels. Common complications include reperfusion injury, vessel injury, hemoptysis, and, more rarely, respiratory failure. Still, early experience suggests this procedure decreases pulmonary vascular resistance over time, improves right ventricular function, and improves patients’ symptoms (Andreassen A, et al. Heart. 2013;99(19):1415). The experience with this procedure is limited but growing in the United States, with only a handful of centers currently performing BPAs and collecting data.

Lifelong anticoagulation, oxygen, and diuretics for right-sided heart failure are recommended for patients with CTEPH. The first successful large phase III medication study for CTEPH was the CHEST-1 trial published in 2013. This was a multicenter, randomized, placebo-controlled trial of the soluble guanylate cyclase stimulator riociguat. The study enrolled 261 patients with inoperable CTEPH or persistent pulmonary hypertension after surgery. The primary end point was 6-minute walk distance at 12 weeks. The treatment group showed a 46 m improvement (P<.001). Secondary end points of pulmonary vascular resistance, NT-proBNP level, and functional class also improved. This pivotal trial led to the FDA approval of riociguat for inoperable or persistent postoperative CTEPH.

MERIT-1, a phase II, randomized placebo-controlled double trial of macitentan (an oral endothelin receptor antagonist) was recently completed. It enrolled 80 patients with inoperable CTEPH. The primary endpoint was pulmonary vascular resistance at week 16, expressed as a percentage of baseline. At week 16, the patients in the treatment arm had a PVR 73% of baseline vs 87.2% in the treatment group. This medication is not yet FDA-approved for the treatment of inoperable CTEPH (Ghofrani H, et al. Lancet Respir Med. 2017;5(10):785-794).

Pulmonary hypertension medication has been postulated as a possible way to “pretreat” patients before pulmonary thromboendarterectomy surgery, perhaps lowering preoperative pulmonary vascular resistance and surgical risk. However, there are currently no convincing data to support this practice, and medical treatment has been associated with a possible counterproductive delay in surgery. A phase II study including CTEPH patients with high PVR for preoperative treatment with riociguat vs placebo is currently enrolling to determine if “induction” treatment with medication prior to surgery reduces risk or delays definitive surgery. Occasionally, patients are found who have persistent thrombus but not pulmonary hypertension. Chronic thromboembolic disease (CTED) is a recently coined term describing patients who have chronic thromboembolism on imaging but have normal resting hemodynamics. Whether CTED represents simply unresolved clot that will never progress to CTEPH or is an early point on the continuum of disease not well-defined and a controversial topic among experts. At many centers, patients with CTED and symptoms will undergo exercise testing to look for exercise -induced pulmonary hypertension or an increase in dead space ventilation as a cause of their symptoms. A retrospective series of carefully chosen CTED patients who underwent PTE surgery reported improvements in symptoms and overall quality of life, without increased complications (Taboada D, et al. Eur Respir J. 2014 44(6):1635). The operation carries risk, however, and further work into the epidemiology and prognosis of CTED is required before operative intervention can be recommended.

In conclusion, CTEPH is a disease that rarely occurs after an acute PE but when undiagnosed and untreated portends a poor prognosis. The definitive treatment for this disease is surgical PTE, but to achieve the best outcomes, this procedure needs to be performed at expert centers with multidisciplinary team experience. Patients who are poor operative candidates or with surgically inaccessible disease may be considered for balloon pulmonary angioplasty. For patients without more curative options, medication improves exercise tolerance. The field of CTEPH has been rapidly expanding over the last decade, leading to better patient outcomes and more treatment options.

Dr. Bartolome is Associate Professor, Pulmonary and Critical Care Medicine; Director, CTEPH Program; and Associate Director, PH Program; UT Southwestern Medical Center, Dallas, Texas.