Continuing Education Activity

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but potentially curable condition characterized by progressive exercise intolerance. The disorder should be considered in patients with worsening exercise capacity in the absence of predictable risk factors like previous acute pulmonary embolism. The diagnosis relies on combining imaging modalities with a ventilation/perfusion scan as the initial screening tool.

The diagnostic criteria include specific hemodynamic parameters and evidence of chronic pulmonary embolism on imaging. Treatment options include medical therapy for pulmonary arterial hypertension and surgical intervention, with pulmonary endarterectomy being the preferred surgical approach in eligible patients. CTEPH presents diagnostic and management challenges. Treatment delays correlate with high mortality rates, underscoring the importance of timely intervention. Surgical options demonstrate improved outcomes, necessitating comprehensive evaluation of potential candidates. Awareness of alternative management strategies for nonsurgical candidates, such as pulmonary balloon angioplasty, targeted medical therapy, and lifelong anticoagulation, is essential.

This activity for healthcare professionals is designed to enhance learners' competence in evaluating and managing CTEPH. Participants gain proficiency in recognizing the signs and symptoms of this disorder, which may be initially nonspecific and overlap with other cardiopulmonary conditions. Valuable insights regarding CTEPH treatment options will be gained, encompassing acute and long-term management strategies to improve symptoms and outcomes. At the end of the activity, learners become prepared to collaborate effectively within an interprofessional team caring for patients with CTEPH.

Objectives:

• Identify patients at risk for chronic thromboembolic pulmonary hypertension based on clinical history, symptoms, and risk factors.

• Develop a clinically appropriate diagnostic plan for a patient with possible chronic thromboembolic pulmonary hypertension.

• Select individualized therapeutic interventions for patients with chronic thromboembolic pulmonary hypertension.

• Implement effective interprofessional communication and coordination strategies to streamline care delivery and ensure comprehensive evaluation and treatment of patients with chronic pulmonary embolic hypertension.

Introduction

Chronic Thromboembolic Pulmonary Hypertension Overview

Chronic thromboembolic pulmonary hypertension (CTEPH) is a potentially life-threatening condition associated with high morbidity and mortality.[1] However, advances in medical and surgical treatments have markedly improved the outcomes.[2][3] CTEPH is a form of precapillary pulmonary hypertension associated with chronic thromboembolic disease. This condition falls under the World Health Organization's group 4 pulmonary hypertension classification.[4] 

Acute pulmonary embolism, particularly when coupled with additional risk factors such as prothrombotic tendencies, recurrent thromboembolic events, genetic predisposition, and patient characteristics like comorbidities, has the potential to evolve into chronic thromboembolic disease over time. Chronic thromboembolism can result in CTEPH. Overt right heart failure can ensue if this condition is untreated at advanced stages. Thus, a low threshold is necessary when monitoring at-risk individuals for the development of CTEPH. Untreated cases eventually lead to significant functional capacity limitations and premature death due to worsening hemodynamics.[5][6]

Pulmonary Circulation

Understanding the anatomical features involved in CTEPH pathophysiology provides insights into how thromboembolic obstructions impact pulmonary hemodynamics, gas exchange, and right heart function. The pulmonary circulation involves the network of blood vessels transporting blood between the heart and lungs for oxygenation. This circulation begins at the right side of the heart. The right ventricle injects deoxygenated blood into the pulmonary arteries. The pulmonary arteries then branch into smaller vessels, eventually reaching the pulmonary capillaries within the lung parenchyma.

Gas exchange occurs in the pulmonary capillaries. Carbon dioxide is released from the capillary blood into the alveoli to be exhaled, while inhaled oxygen diffuses into the blood to be carried back to the heart. Once oxygenated, blood travels toward the left atrium via the pulmonary veins.

The pulmonary circulation is normally a low-pressure system compared to the systemic circulation. The right ventricle only needs to pump blood a short distance into the lungs' highly compliant blood vessels and back. This anatomy is well-adapted for efficient gas exchange, ensuring that blood is adequately oxygenated before systemic distribution. Additionally, the pulmonary vasculature is highly responsive to oxygen level changes, allowing for blood flow fine-tuning to match the body's metabolic demands.

Etiology

Several theories regarding CTEPH's etiology exist. This condition develops similarly to deep vein thrombosis and acute pulmonary embolism in that organized thrombus material embolizes in the pulmonary circulation, causing vascular remodeling and subsequent pulmonary arterial hypertension. Current medical literature reports statistical associations with phospholipid antibodies, lupus anticoagulant, and elevated factor VIII levels, suggesting hypercoagulability and venous thrombosis state as predisposing factors.[7] Moreover, elevated levels of prothrombotic factor VIII were reported in 41% of patients with CTEPH.[8]

Multiple risk factors have been associated with CTEPH:[9]

• A previous history of pulmonary embolism (odds ratio is increased 19.0 times)
• Young age (odds ratio increases 1.79 times per decade of age)
• A large perfusion defect (odds ratio increases 2.22 times per decile decrement in perfusion on lung scan)

Acute pulmonary embolism is reported in nearly 90% of individuals with CTEPH, with recurrent pulmonary embolism found in almost half of all cases.[10] Pulmonary embolism clots usually resolve spontaneously to restore pulmonary circulation. However, the factors contributing to incomplete pulmonary embolus resolution in some cases remain unknown. Several mechanisms have been suggested, including difficulty in lysing large clots entirely or, in some cases, the embolic substance having more fibrin-rich material and red blood cells that make them more resistant to breakdown.

Other CTEPH risk factors include recurrent embolic events, thrombophilias, immunological disorders, ventriculoatrial shunts, pacemakers, peripherally inserted central catheter ("PICC lines"), malignancy, inflammatory bowel disease, splenectomy, chronic osteomyelitis, right ventricular dysfunction, large arterial thrombi, diabetes, hypothyroidism, younger age, acute pulmonary embolism with more significant perfusion defect, and idiopathic pulmonary embolism.[11][12] Determining whether these patients already harbored undiagnosed pulmonary hypertension or had CTEPH masquerading as acute pulmonary embolism presents a considerable challenge.[13] 

Epidemiology

Limited studies delve into CTEPH's epidemiology.[14] The condition's incidence is estimated to be 2% to 6%, and its prevalence is around 26 to 38 cases per million.[15] The annual CTEPH incidence is estimated to be 1% at 6 months following pulmonary embolism and 3% at 1 year.[9] The development of CTEPH is rare 2 years after an acute pulmonary embolism episode.[16]

In the US, CTEPH's incidence after the initial pulmonary embolism event ranges from 0.1% to 9.1%.[17] A meta-analysis showed that <1% of all patients with a prior diagnosis of pulmonary embolism have CTEPH at the population level. CTEPH is frequently misdiagnosed, and its prevalence is underestimated due to limited clinician awareness and the so-called "honeymoon period"—the time interval between pulmonary embolism episodes and the onset of CTEPH symptoms.[18]  

The European Society of Cardiology and the European Respiratory Society recently introduced a new term, "chronic thromboembolic pulmonary disease" (CTEPD), which is independent of the presence of pulmonary hypertension. Patients with CTEPD have similar symptoms, perfusion defects, and pulmonary vessel obstructions with or without pulmonary hypertension at rest. CTEPD is estimated to be present in 20% of individuals suspected of CTEPH.[19] These patients usually present younger than those with CTEPH and have a better functional status based on the 6-minute walk test distance.

Pathophysiology

The pathophysiology of CTEPH is still unclear. According to the generally accepted theory, CTEPH emerges following one or multiple pulmonary embolism episodes, predominantly from venous thrombosis.[20] The condition may also arise due to in situ thrombosis in the lung from primary arteriopathy and endothelial dysfunction, similar to PAH. This hypothesis may explain why up to 63% of patients with CTEPH do not have a history of acute pulmonary embolism (see Image. Chronic Thromboembolic Pulmonary Hypertension Proposed Pathophysiology).[21] 

Histopathology

The histopathology slides of several patients diagnosed with CTEPH who underwent thromboendarterectomy show small vessel arteriopathy, microvascular thrombosis, intimal proliferation, and reduced pulmonary artery cross-sectional area from thrombosis.[22] 

History and Physical

CTEPH symptoms may include breathlessness, chest pain, dizziness, fainting, and fatigue. These symptoms may be mild initially but can worsen without treatment. The most common presenting symptoms are exertional dyspnea and declining exercise tolerance. Other infrequent symptoms include cough, episodic hemoptysis, atypical chest pain, and palpitations.[23] 

The physical examination may be nonspecific during CTEPH's early stages. In most cases, the diagnosis of CTEPH is established only in the later stages of the disease, when symptoms and signs of right ventricular dysfunction, such as peripheral edema, exertional chest pain, dyspnea during exercise, peripheral edema, dizziness, or syncopal episodes, have already appeared.

Auscultation findings include an accentuated second heart sound (P2), S4 gallop, and systolic ejection click over the pulmonary artery. However, the presence of pulmonary flow murmurs over the lung fields is more CTEPH-specific. This manifestation is described as subtle, high-pitched bruits with blowing quality, accentuated on inspiration and usually heard while holding the breath. These bruits arise from obstruction of medium-to-large pulmonary arteries.[24]

With the progression of pulmonary hypertension, a tricuspid regurgitation murmur, pedal edema, jugular venous distention, hepatomegaly, ascites, and other right ventricular failure symptoms appear. Hypoxemia is common in CTEPH due to ventilation-perfusion mismatching.[25] The level of hypoxia correlates with pulmonary vascular resistance, mean pulmonary artery pressure (PAP), and degree of vascular obstruction.

Evaluation

Diagnostic tests should be reserved for patients presenting with new or persistent symptoms, ie, dyspnea or exercise intolerance, after at least 3 months of anticoagulation.[26] Early diagnosis of this condition is challenging due to the initially nonspecific symptoms and delayed specific manifestations.

The initial evaluation of a dyspneic patient usually includes a chest x-ray, which may be normal in early CTEPH. In contrast, late CTEPH chest radiography often shows pulmonary hypertension signs, cardiac chamber enlargement, and segmental oligemia with pleuroparenchymal scarring.[27]

A CTEPH suspicion based on chest computed tomography (CT) findings of an obstructive thrombus, venous thromboembolism history, or characteristic bruits may be confirmed by ventilation/perfusion (V/Q) scanning, echocardiography, and pulmonary function tests. Diagnostic confirmation requires combining techniques, such as right heart catheterization and CT pulmonary angiography.

Transthoracic echocardiography primarily diagnoses pulmonary hypertension but is nonspecific, as it cannot differentiate between acute and chronic pulmonary embolism.[28] V/Q scanning has high sensitivity (90% to 100%) and specificity (94% to 100%) and is a first-line screening tool for diagnosing CTEPH.[29][30] Hence, a normal V/Q scan can reliably exclude the diagnosis of chronic venous thromboembolism. However, V/Q scanning may underestimate the size of pulmonary vascular obstruction in central locations and other V/Q mismatch etiologies.

Diagnostic criteria for CTEPH include mean PAP over 20 mm Hg, pulmonary arterial wedge pressure below 15 mm Hg, pulmonary vascular resistance greater than 3 Woods units (>240 dynes per second per cm), and evidence of chronic pulmonary embolism on CT or V/Q scan.

Right heart catheterization with conventional pulmonary angiography is the gold standard in diagnosing CTEPH, especially since a negative CT scan cannot exclude the condition.[31] Novel techniques such as dual-energy CT, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and optical coherence tomography are valuable diagnostic tools for evaluating patients with CTEPH. Digital subtraction techniques for pulmonary angiography are the gold standard in confirming a CTEPH diagnosis and determining surgical eligibility. The combination of different diagnostic tools can provide additional information and assist in ruling out other conditions, planning interventions, and assessing treatment response.

Treatment / Management

Patients with CTEPH should be evaluated and treated in an adequately equipped center by a specialized team of experts. All patients with suspected CTEPH should be prescribed anticoagulation for at least 3 months. The disease can regress during this period, and significant hemodynamic improvement or complete resolution of pulmonary hypertension may occur. Symptom resolution confirms a CTEPH diagnosis and distinguishes it from subacute pulmonary embolism, which often involves small pulmonary vessels. Diagnostic confirmation paves the way for definitive management.

Surgical Treatment

Pulmonary endarterectomy (PEA) is a complex surgical intervention in selected operable patients. The procedure can normalize pulmonary hemodynamics and improve exercise capacity and survival.[32] Individuals who may benefit from the surgery include patients consenting to the procedure or with proximal thromboembolic burden, minimal comorbidities, and significant hemodynamic and ventilatory impairments.[33] 

The University of California-San Diego proposed a classification of CTEPH, which helps guide surgeons regarding the complexity and expertise needed for the treatment. The category level increases with increasing complexity. Level 0 includes patients without surgical evidence of chronic thromboembolic disease. Level 1 denotes blockade at the main pulmonary level. Levels 2, 3, and 4 show lobar, segmental, and subsegmental pulmonary artery obstruction, respectively.[34]

PEA removes obstructive and hardened thrombi and markedly improves hemodynamic measures such as mean PAP, pulmonary vascular resistance, and cardiac output. The procedure can reverse right ventricular remodeling due to right-sided cardiac function normalization.[35][36] CTEPH may persist in 5% to 35% of cases after PEA.[37] Notably, evidence suggests that patients may need to be on lifelong anticoagulation post-PEA to prevent further venous thromboembolism recurrence. Compared to direct-acting oral anticoagulants, vitamin K antagonists significantly lower recurrent thromboembolism risk.[38] Right ventricular function improves significantly after a PEA. Additionally, normalization of gas exchange, exercise capacity, and quality of life are reported.[33]

More than 30% of the patients are inoperable. However, pulmonary balloon angioplasty (BPA) may be a promising alternative for these patients.[39][40] Studies on BPA's effect on CTEPH patients continue after some have been completed. The Expert Consensus on the Evaluation and Treatment of Pulmonary Hypertension Using Balloon Pulmonary Angioplasty plans to conduct an international observational study regarding BPA's effect on patients with CTEPH at rest and during exercise. The International BPA registry currently has an ongoing prospective study evaluating BPA's efficacy and safety on patients with CTEPH. A 2019 meta-analysis showed that BPA was superior to riociguat therapy in improving exercise intolerance and hemodynamic parameters.[41]

BPA is known to cause general angioplasty complications like wire injury, vessel dissection, vessel rupture, and complications specific to lung angioplasty, including reperfusion pulmonary edema, pulmonary parenchymal bleeding, and hemothorax. However, the use of targeted vasodilators should be reserved for patients with right ventricular failure or severe pulmonary hypertension.

Medical Treatment

Current guidelines recommend using anticoagulants, diuretics, and oxygen if needed for optimal medical treatment of CTEPH. Patients with PEA contraindications or refractory pulmonary hypertension, despite surgical treatment, may improve pulmonary pressures from the targeted medical therapy riociguat. Bilateral lung transplantation is considered the last resort in people who are not PEA candidates, failed PEA, or have contraindications to targeted medical therapy with vasodilators.

Patients with a confirmed CTEPH diagnosis should be placed immediately on lifelong anticoagulation, which can also prevent in situ pulmonary artery thrombosis and further thromboembolism. The anticoagulants recommended by the Expert Panel and CHEST guidelines are as follows:

• First line: Direct oral anticoagulants dabigatran, rivaroxaban, apixaban or edoxaban
• Second line: Vitamin K antagonist therapy
• Third line: Low-molecular-weight heparin

Inferior vena cava filter placement should be considered in patients with CTEPH with an increased bleeding risk. Anticoagulation can be started once the bleeding tendency diminishes.[42]

PAH-targeted therapy in CTEPH includes the administration of endothelin-receptor antagonists, phosphodiesterase type-5 inhibitors, and prostanoids. Treprostinil and macitentan were extensively studied and proven beneficial in these patients.[43] The best PAH treatment option for individuals with CTEPH is riociguat, a guanylate-cyclase stimulator currently used in patients ineligible for surgery or with persistent disease post-PEA.

Differential Diagnosis

CTEPH is a curable disease, and clinicians should distinguish it from other conditions that may cause thrombotic and fibrotic pulmonary arterial changes. Notably, CTEPH must be differentiated from idiopathic pulmonary artery hypertension (IPAH).[44] On CT scan, IPAH lacks thromboembolic material or fibrotic obstructions in the pulmonary arteries but has significantly decreased segmental and subsegmental arterial diameter. A key IPAH finding is the presence of corkscrew-like pulmonary arteries, representing plexogenic arteriopathy.[45] A noninvasive test to differentiate between CTEPH and IPAH is possible using Doppler ultrasound. PAP waveforms differ significantly in patients with CTEPH and IPAH, with pulse pressure in CTEPH usually being markedly larger.

Another differential diagnosis is primary pulmonary arterial sarcoma, an extremely rare disease with nonspecific symptoms that make it hard to differentiate from CTEPH. Sarcoma appears as a solid lobulated mass in the central pulmonary arteries on CT or MRI and is unresponsive to anticoagulation treatment. Positron-emission tomography (PET) with F-fludeoxyglucose can be performed to distinguish sarcoma from CTEPH.[46]

In rare cases, right heart failure with acute pulmonary thromboembolism can mimic CTEPH. However, the emboli of acute thromboembolism form at an acute angle with the pulmonary artery wall, whereas the angle in CTEPH is often obtuse. Also, right ventricle hypertrophy, a chronic feature, is less likely to be seen in acute pulmonary embolism.[47]

Other CTEPH differential diagnoses include thrombosis in situ, Takayasu arteritis, congenital proximal pulmonary artery interruption, malignant and benign pulmonary artery tumors, Von Recklinghausen and Osler-Weber-Randu diseases, malignant and nonmalignant pulmonary artery tumors, arteritis, congenital pulmonary artery stenosis, and fibrosing mediastinitis.[48][49][50][51]

Prognosis

PEA is the best option for improving operable patients' survival rates. A 2017 study demonstrated the five-year survival rate after PEA to be 70% to 80%.[52] Hemodynamic severity and systolic PAP significantly improve after PEA.[53] The period between the last pulmonary embolism episode and PEA is considered a risk factor for in-hospital mortality, signifying the importance of timely diagnosis of CTEPH for a favorable outcome. CTEPH's long-term prognosis after surgical thrombus removal is currently excellent.

Complications

CTEPH itself is a complication of chronic thromboembolism. If left untreated, the condition can lead to severe right heart failure, significant shortness of breath, decreased exercise tolerance, syncope, and death, with a 3-year mortality rate estimated to be 90%.[51]

Deterrence and Patient Education

In the general population, preventive measures against acute pulmonary embolism help prevent CTEPH. Patients on prolonged hospitalization should be given appropriate anticoagulation during their visit. Inflatable compression devices or compression stockings may also help prevent clot formation. Individuals who travel frequently and have longer airplane time should ensure they walk about every 1 to 2 hours or change their seating positions regularly.

Meanwhile, patients diagnosed with CTEPH should be educated on medication adherence and follow-up before discharge. Close follow-up is crucial in patients with multiple comorbidities, as managing concurrent medical conditions helps significantly improve functional capacity. Patients traveling by air must be assessed for possible oxygen needs during the in-flight journey.

Pearls and Other Issues

CTEPH is a rare, dangerous, but potentially curable thromboembolic disease. The lack of predictable predisposing factors, including a prior medical history of acute pulmonary embolism, does not rule out this condition in patients with a progressive reduction in exercise tolerance. CTEPH should be considered in all patients with pulmonary hypertension, as this is the only potentially correctible PAH cause.

V/Q scanning is the first-line screening tool for diagnosing CTEPH. Diagnostic criteria for CTEPH include mean PAP greater than 20 mm Hg, pulmonary arterial wedge pressure less than 15 mm Hg, pulmonary vascular resistance greater than 3 Woods units, and evidence of chronic pulmonary embolism on CT, MRI, or V/Q scanning.

Current medical treatment for CTEPH primarily consists of PAH-targeted therapy and oral anticoagulation. PEA is the surgical treatment of choice in patients with CTEPH.

Enhancing Healthcare Team Outcomes

CTEPH is a difficult diagnosis, and the management is not straightforward. Treatment delays correlate with high mortality rates. Improved outcomes are evident with surgical treatments. All potential surgical candidates should undergo evaluation for surgical thromboendarterectomy. Clinicians should also be aware of the management options for patients who are not surgical candidates. Options include BPA, PAH-targeted medical therapy, and lifelong anticoagulation.

Primary care clinicians and nurses should educate patients on medication adherence and follow-up before discharge. Managing concurrent medical conditions helps significantly improve functional capacity in patients with multiple comorbidities; thus, close follow-up is crucial. If pharmacotherapy is indicated, a specialty pharmacist should assist with medication selection and dosing, especially when using novel agents. Clinicians and nurses should assess patients traveling by air for in-flight oxygen requirements.

Nurses and pharmacists should also be empowered to inform clinicians if thromboembolism prophylaxis may be indicated for hospitalized patients. Close communication between interprofessional team members is vital to ensure that the patient receives the current standard of care. The interprofessional team, including clinicians, specialists, nurses, and pharmacists, must collaborate to implement these measures and advance positive outcomes in treating CTEPH.