Review
Chronic thromboembolic pulmonary hypertension Marius M Hoeper, Michael M Madani, Norifumi Nakanishi, Bernhard Meyer, Serghei Cebotari, Lewis J Rubin
Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but debilitating and life-threatening complication of acute pulmonary embolism. CTEPH results from persistent obstruction of pulmonary arteries and progressive vascular remodelling. Not all patients presenting with CTEPH have a history of clinically overt pulmonary embolism. The diagnostic work-up to detect or rule out CTEPH should include ventilation-perfusion scintigraphy, which has high sensitivity and a negative predictive value of nearly 100%. CT angiography usually reveals typical features of CTEPH, including mosaic perfusion, part or complete occlusion of pulmonary arteries, and intraluminal bands and webs. Patients with suspected CTEPH should be referred to a specialist centre for right-heart catheterisation and pulmonary angiography. Surgical pulmonary endarterectomy remains the treatment of choice for CTEPH and is associated with excellent long-term results and a high probability of cure. For patients with inoperable CTEPH, various medical and interventional therapies are being developed.
Introduction Chronic thromboembolic pulmonary hypertension (CTEPH) is defined as raised mean pulmonary artery pressure (of at least 25 mm Hg at rest) caused by persistent obstruction of pulmonary arteries after pulmonary embolism that has not resolved despite at least 3 months of therapeutic anticoagulation.1 Occasionally patients present with clinical and diagnostic features of CTEPH, including widespread obstruction of pulmonary arteries, but have no pulmonary hypertension. Formally, this presentation should not be classified as CTEPH and instead may be termed chronic thromboembolic disease, although the management of these patients is usually similar to that of patients with classic CTEPH. Non-resolving acute pulmonary embolism is the most common cause of CTEPH, and can occur after one or multiple episodes. CTEPH might occasionally develop owing to in-situ pulmonary artery thrombosis, which could be associated with inflammation of the vessel walls.2 CTEPH is underdiagnosed, which is problematic because many affected patients can be effectively treated by surgical pulmonary endarterectomy (PEA). For patients who are not surgical candidates, medical and interventional treatments have been developed and specialist centres can now offer tailored therapies for almost all affected patients. In this Review we summarise the available information on the diagnosis and treatment of CTEPH.
Epidemiology, natural history, and pathogenesis Incomplete resolution of pulmonary embolism is not uncommon. In fact, despite effective therapeutic anticoagulation, more than 50% of patients have residual perfusion defects 6 months after diagnosis of pulmonary embolism.3 Most of these patients, however, do not develop manifest chronic pulmonary hypertension. Even patients who present with signs of pulmonary hypertension during an episode of acute pulmonary embolism are unlikely to develop CTEPH, and in most of these patients, echocardiography shows complete recovery of right ventricular function within 6 weeks.4 Some
patients, however, present with persistent pulmonary hypertension and others develop pulmonary hypertension after an asymptomatic interval that can last from several months to years.5 Of note, marked pulmonary hypertension is not a feature of acute pulmonary embolism because the nonadapted right ventricle cannot generate high pressures. Thus, whenever patients present with seemingly acute pulmonary embolism and signs of severe pulmonary hypertension, CTEPH is likely already to have been present. The estimated prevalence of CTEPH after acute pulmonary embolism is 0·1–4·0% after 2 years.4–8 The risk of developing CTEPH is increased in patients who have recurrent venous thromboembolism, large perfusion defects, and echocardiographic signs of pulmonary hypertension at the initial presentation. Development of CTEPH is not associated with common risk factors for venous thromboembolism, such as factor V Leiden, factor II mutation, or a prothrombin 20210G→A gene mutation.9,10 An important exception is the presence of antiphospholipid antibodies, which predispose patients to acute venous thromboembolism and CTEPH.1,9,11 Distinct clinical disorders that are deemed to be risk factors include
Lancet Respir Med 2014 Published Online June 2, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70089-X Department of Respiratory Medicine, Hannover Medical School and German Centre for Lung Research (DZL), Hannover, Germany (Prof M M Hoeper MD); Department of Cardiothoracic Surgery (Prof M M Madani MD) and Department of Respiratory Medicine (Prof L J Rubin MD), University of California, San Diego, CA, USA; Department of Cardiovascular Medicine, National Cardiovascular Centre, Osaka, Japan (Prof N Nakanishi MD); and Department of Radiology (B Meyer MD) and Department of Cardiovascular, Thoracic and Transplantation Surgery (S Cebotari MD), Hannover Medical School, Hannover, Germany Correspondence to: Prof Marius M Hoeper, Department of Respiratory Medicine, Hannover Medical School, 30623 Hannover, Germany hoeper.marius@mh-hannover. de
Key messages • Chronic thromboembolic pulmonary hypertension (CTEPH) is caused by persistent obstruction of pulmonary arteries following pulmonary embolism • CTEPH is an important differential diagnosis in patients with unexplained dyspnoea and pulmonary hypertension • Ventilation-perfusion scintigraphy is the key imaging tool to determine or rule out CTEPH and has a higher sensitivity than contrast-enhanced CT • Patients with suspected or documented CTEPH should be referred to specialised centres, where the diagnosis can be established and operability determined • Pulmonary endarterectomy is the preferred treatment for CTEPH, as it is curative in most patients • Riociguat, which stimulates soluble guanylate cyclase activity, is the first drug to be approved for patients with inoperable CTEPH • Balloon pulmonary angioplasty is a potential new treatment option for patients with inoperable CTEPH and is being assessed in specialist centres
www.thelancet.com/respiratory Published online June 2, 2014 http://dx.doi.org/10.1016/S2213-2600(14)70089-X
1
Review
myeloproliferative disorders, splenectomy, inflammatory bowel disease, chronic osteomyelitis, and the presence of permanent central venous lines, pacemakers or ventriculoatrial shunts.11–14 These disorders are associated with chronic inflammation, increased risk of repeated blood-stream infections, or both, which probably contribute to non-dissolution of thromboembolic material.1 Proinflammatory molecules, such as C-reactive protein, might also participate in the development of CTEPH.15 Additionally, direct infection of thrombotic material by blood-borne pathogens could also be important, especially in patients with pacemakers, permanent central venous lines, or ventriculoatrial shunts.16 The exact mechanisms that prevent complete dissolution of the thromboembolic material are complex and incompletely understood. Usually, resolution of large clots is orchestrated in two steps, starting with rapid fibrinolysis followed by a cellular response that leads to ingrowth of monocytes and endothelial progenitor cells and initiates neovascularisation of the thrombus.17–19 The process can be altered at any of these steps and, therefore, the factors predisposing the development of CTEPH vary between individuals.10,20,21 On the basis of experimental data and analysis of samples obtained from PEA in human beings, several groups proposed a misguided vascular remodelling process that involved defective angiogenesis and delayed thrombus resolution associated with endothelial dysfunction and endothelialmesenchymal transition as the key mechanism in the development of CTEPH.1,22–24 Several animal models have improved understanding of specific features of CTEPH, but no model truly mimics human disease.25 Occlusion of pulmonary arteries by thromboembolic material is the initial trigger of CTEPH. Non-dissolution of thromboembolic material eventually results in the formation of organised scar tissue, sometimes termed fibrous clots, and intraluminal webs and bands, which partly or completely obstruct pulmonary arteries. As a consequence, the pulmonary blood flow is redistributed to non-occluded vessels, which become exposed to high intravascular pressures and shear stress, resulting in endothelial dysfunction and vascular remodelling of precapillary arteries. These changes resemble those seen in pulmonary arterial hypertension.26 These microvascular changes explain why CTEPH is a progressive disease, even in the absence of recurrent thromboembolic events. If left untreated, the outlook for patients with CTEPH is dismal. Median survival is less than 2 years in patients who have mean pulmonary artery pressure higher than 30 mm Hg at diagnosis.27,28 Right-heart failure is the most frequent cause of death. Advances in management have improved outcomes, but CTEPH remains a potentially fatal condition, especially when surgery is not an option.29,30
Symptoms and diagnosis As in other forms of pulmonary hypertension, progressive dyspnoea on exertion is the predominant 2
symptom of CTEPH. Additionally, patients might present with fatigue, syncope, haemoptysis, and signs of right-heart failure. CTEPH should be considered in all patients who have a history of clinically overt acute pulmonary embolism, although around 25% of patients diagnosed as having CTEPH have no documented acute pulmonary embolism events.31 Thus, CTEPH should be considered in any patient with otherwise unexplained pulmonary hypertension. The diagnostic approach for CTEPH starts with transthoracic echocardiography to assess the likelihood of pulmonary hypertension, followed by ventilationperfusion scintigraphy to detect or rule out perfusion defects. Ventilation-perfusion scanning remains the preferred imaging tool because of its high sensitivity and a negative predictive value of virtually 100%.32 Thus CTEPH is generally ruled out if the scan is normal.32 The presence of multiple perfusion defects is strongly suggestive of CTEPH but can also occur in other disorders, such as pulmonary veno-occlusive disease, pulmonary vasculitis, fibrosing mediastinitis, or malignant disease.33–35 Multidetector CT angiography usually reveals indirect and direct signs of CTEPH. Indirect signs include a mosaic perfusion pattern of the lung parenchyma and the presence of dilated bronchial arteries. Direct signs are organised emboli, partial filling defects or complete obstruction of pulmonary arteries, and bands and webs (figure 1).36,37 Of note, similar findings might be seen in patients with non-embolic thrombi, tumours, or vasculitis of pulmonary arteries.38,39 MRI is a suitable alternative method to CT angiography for the diagnostic work-up of CTEPH,40 but is not widely used. If imaging suggests the presence of CTEPH, patients should be referred to a specialist centre for further assessment, including right-heart catheterisation and pulmonary angiography. If logistics allow, these two invasive procedures should be combined to keep inconvenience and risk of complications to a minimum. Pulmonary angiography should be done at a centre that assesses patients’ suitability for surgery to avoid the need for repeat procedures. Whether survivors of acute pulmonary embolism should be followed up systematically to detect the development of CTEPH at an early stage is a matter of debate. In view of the high frequency of acute pulmonary embolism and the low, albeit important, risk of developing CTEPH, general screening after acute pulmonary embolism is not recommended.41–43 The threshold for a diagnostic workup, however, should be low in patients who remain symptomatic after an episode of acute pulmonary embolism. Echocardiography remains the preferred diagnostic tool if pulmonary hypertension is suspected, but a diagnostic approach that combines no characteristics of right-ventricular strain on electrocardiogram with normal plasma concentrations of the N-terminal fragment of probrain
www.thelancet.com/respiratory Published online June 2, 2014 http://dx.doi.org/10.1016/S2213-2600(14)70089-X
Review
A
D
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Figure 1: Imaging and histopathology of chronic thromboembolic pulmonary hypertension (A) Perfusion scan showing multiple bilateral segmental and subsegmental perfusion defects. (B) Mosaic perfusion and (C) enlarged bronchial arteries on chest CT. (D) Multidetector CT showing intravascular filling defects in the left lower lobe artery. (E) Right-sided pulmonary angiography showing partly and completely occluded vessels. (F) Histological sample showing typical webs.
natriuretic peptide has a negative predictive value of 99% (95% CI 97–100) for CTEPH.44
but the presence or absence of vena cava filters had no effect on 1-year survival after PEA in the CTEPH registry of the International CTEPH Association.47
Treatment Although never assessed in clinical trials, the need for lifelong anticoagulation for patients with CTEPH is undisputed, even in patients who underwent successful PEA. The target international normalised ratio is 2·0–3·0. Vitamin K antagonists remain the most widely used drugs to treat CTEPH. Subcutaneous lowmolecular-weight heparins or fondaparinux and novel anticoagulants are suitable alternative drugs, especially in patients in whom a stable international normalised ratio is difficult to maintain with vitamin K antagonists, although none has been systematically tested in patients with CTEPH. The use of filters in the inferior vena cava remains controversial.45 In the past, these filters were used regularly, particularly after PEA. Increasingly, centres use vena cava filters only when therapeutic anticoagulation is not feasible or when recurrent venous thromboembolism occurred despite sufficient anticoagulation.46 Prospective studies have not been done,
Pulmonary endarterectomy In only a few centres worldwide are more than 20 PEA surgeries performed per year.42 Unlike pulmonary embolectomy for acute pulmonary embolism (Trendelenburg’s procedure), PEA is a true endarterectomy and is almost always bilateral, which involves general anaesthesia, the use of cardiopulmonary bypass, and deep hypothermia (usually 20°C) because episodes of complete circulatory arrest are required to prevent collateral blood flow into the operation field.46,48 The pulmonary arteries are opened inside the pericardium, from where endarterectomy is performed as far distal as possible, beyond the levels of the segmental and subsegmental arteries (figure 2).46 In experienced centres, the short-term and long-term results of PEA are excellent, but there is a clear reciprocal relation between a centre’s experience and the mortality rate.47 In high-volume centres, the in-hospital mortality is now less than 5%.29,47,48–51 In one centre that had performed
www.thelancet.com/respiratory Published online June 2, 2014 http://dx.doi.org/10.1016/S2213-2600(14)70089-X
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A
B
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Figure 2: Pulmonary endarterectomy in a man aged 51 years with chronic thromboembolic pulmonary hypertension (A) Preoperative pulmonary angiograms show widespread pulmonary vascular obstruction by intraluminal scar tissue in both lungs. These findings are supported by (B) scar tissue removed during surgery and (C) preoperative ventilation-perfusion scintigraphy. (D) Postoperative ventilation-perfusion scintigraphy showed notable improvement in lung perfusion. The pulmonary vascular resistance dropped from 853 dyn s/cm–5 before surgery to 119 dyn s/cm–5 after surgery. New York Heart Association functional class improved from III to I shortly after surgery.
2700 operations overall, the in-hospital mortality for the last 500 consecutive operations, performed between 2006 and 2010, was 2·2% and none of the last 260 patients died (table 1).29 105 of these patients had peripheral disease (Jamieson type III) before surgery. Cognitive function is usually not impaired after surgery despite periodical circulatory arrest, and the procedure can be performed with acceptable risks in very old patients.49,52 Additionally, PEA can be combined with other cardiac operations.46,54 Postoperative haemodynamics become normal or near normal in most patients after PEA. Several groups have reported that more than 80% of patients improve to New York Heart Association functional class I or II after PEA.51,55,56 Residual or recurrent pulmonary hypertension after surgery remains the most important cause of postoperative morbidity and mortality.47,57 In the International CTEPH Registry, 64 (16∙7%) of 384 patients had persistent pulmonary hypertension, defined as mean pulmonary artery pressure of at least 25 mm Hg at the end of intensive care.46 Skoro-Sajer and colleagues58 reported persistent pulmonary hypertension defined by a 4
mean pulmonary artery pressure of at least 25 mm Hg and a pulmonary vascular resistance of more than 400 dyn s/cm–⁵ in 14 (31%) of 45 patients 1 year after surgery. Freed and co-workers56 found raised mean pulmonary artery pressures (30 mm Hg or more 3 months after surgery) in 95 (31%) of 306 patients who underwent surgery between 1997 and 2007. In that series, postoperative pulmonary hypertension was associated with impaired exercise capacity, but, surprisingly, not with decreased 5-year survival (90·3% vs 89·9% in discharged patients with a postoperative mean pulmonary artery pressures less than 30 mm Hg vs 30 mm Hg or higher).56 In the only long-term study on haemodynamics after PEA, Corsico and colleagues51 noted persistent pulmonary hypertension in 12 (24%) of 49 patients who had pulmonary vascular resistance of more than 500 dyn s/cm–⁵ after 4 years. The clinical relevance of residual pulmonary hypertension after PEA has not been fully explored, but these data suggest that persistent or recurrent pulmonary hypertension is a potential problem that physicians should bear in mind, especially in patients who present with progressive dyspnoea, signs of right heart failure, or both.
www.thelancet.com/respiratory Published online June 2, 2014 http://dx.doi.org/10.1016/S2213-2600(14)70089-X
Review
Targeted medical therapy Therapeutic advances in pulmonary arterial hypertension59 and the similarities between the peripheral vasculopathy in this disorder and CTEPH mean that medical therapy of CTEPH has been widely explored. Various case series and uncontrolled studies initially suggested beneficial effects of endothelin-receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclin analogues.60–66 Randomised controlled trials, however, produced mostly disappointing results.67–69 Sildenafil is probably the compound most widely used to treat patients with inoperable CTEPH, but there has been only one randomised control trial of this compound, which showed no change in 6 min walking distance but was associated with significant improvements in functional class and haemodynamics.68 Those results, however, were based on only 17 eligible patients and, therefore, the study lacked statistical power to determine clinically relevant effects. The first large, randomised, double-blind, controlled trial in this field was the BENEFiT trial,67 which assessed the safety and efficacy of 16 weeks’ treatment with bosentan, an endothelin-receptor antagonist, versus placebo in patients with either inoperable CTEPH or persistent or recurrent pulmonary hypertension after PEA. Pulmonary vascular resistance improved significantly (placebo-corrected change from baseline –24·1%, p
Chronic thromboembolic pulmonary hypertension Marius M Hoeper, Michael M Madani, Norifumi Nakanishi, Bernhard Meyer, Serghei Cebotari, Lewis J Rubin
Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but debilitating and life-threatening complication of acute pulmonary embolism. CTEPH results from persistent obstruction of pulmonary arteries and progressive vascular remodelling. Not all patients presenting with CTEPH have a history of clinically overt pulmonary embolism. The diagnostic work-up to detect or rule out CTEPH should include ventilation-perfusion scintigraphy, which has high sensitivity and a negative predictive value of nearly 100%. CT angiography usually reveals typical features of CTEPH, including mosaic perfusion, part or complete occlusion of pulmonary arteries, and intraluminal bands and webs. Patients with suspected CTEPH should be referred to a specialist centre for right-heart catheterisation and pulmonary angiography. Surgical pulmonary endarterectomy remains the treatment of choice for CTEPH and is associated with excellent long-term results and a high probability of cure. For patients with inoperable CTEPH, various medical and interventional therapies are being developed.
Introduction Chronic thromboembolic pulmonary hypertension (CTEPH) is defined as raised mean pulmonary artery pressure (of at least 25 mm Hg at rest) caused by persistent obstruction of pulmonary arteries after pulmonary embolism that has not resolved despite at least 3 months of therapeutic anticoagulation.1 Occasionally patients present with clinical and diagnostic features of CTEPH, including widespread obstruction of pulmonary arteries, but have no pulmonary hypertension. Formally, this presentation should not be classified as CTEPH and instead may be termed chronic thromboembolic disease, although the management of these patients is usually similar to that of patients with classic CTEPH. Non-resolving acute pulmonary embolism is the most common cause of CTEPH, and can occur after one or multiple episodes. CTEPH might occasionally develop owing to in-situ pulmonary artery thrombosis, which could be associated with inflammation of the vessel walls.2 CTEPH is underdiagnosed, which is problematic because many affected patients can be effectively treated by surgical pulmonary endarterectomy (PEA). For patients who are not surgical candidates, medical and interventional treatments have been developed and specialist centres can now offer tailored therapies for almost all affected patients. In this Review we summarise the available information on the diagnosis and treatment of CTEPH.
Epidemiology, natural history, and pathogenesis Incomplete resolution of pulmonary embolism is not uncommon. In fact, despite effective therapeutic anticoagulation, more than 50% of patients have residual perfusion defects 6 months after diagnosis of pulmonary embolism.3 Most of these patients, however, do not develop manifest chronic pulmonary hypertension. Even patients who present with signs of pulmonary hypertension during an episode of acute pulmonary embolism are unlikely to develop CTEPH, and in most of these patients, echocardiography shows complete recovery of right ventricular function within 6 weeks.4 Some
patients, however, present with persistent pulmonary hypertension and others develop pulmonary hypertension after an asymptomatic interval that can last from several months to years.5 Of note, marked pulmonary hypertension is not a feature of acute pulmonary embolism because the nonadapted right ventricle cannot generate high pressures. Thus, whenever patients present with seemingly acute pulmonary embolism and signs of severe pulmonary hypertension, CTEPH is likely already to have been present. The estimated prevalence of CTEPH after acute pulmonary embolism is 0·1–4·0% after 2 years.4–8 The risk of developing CTEPH is increased in patients who have recurrent venous thromboembolism, large perfusion defects, and echocardiographic signs of pulmonary hypertension at the initial presentation. Development of CTEPH is not associated with common risk factors for venous thromboembolism, such as factor V Leiden, factor II mutation, or a prothrombin 20210G→A gene mutation.9,10 An important exception is the presence of antiphospholipid antibodies, which predispose patients to acute venous thromboembolism and CTEPH.1,9,11 Distinct clinical disorders that are deemed to be risk factors include
Lancet Respir Med 2014 Published Online June 2, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70089-X Department of Respiratory Medicine, Hannover Medical School and German Centre for Lung Research (DZL), Hannover, Germany (Prof M M Hoeper MD); Department of Cardiothoracic Surgery (Prof M M Madani MD) and Department of Respiratory Medicine (Prof L J Rubin MD), University of California, San Diego, CA, USA; Department of Cardiovascular Medicine, National Cardiovascular Centre, Osaka, Japan (Prof N Nakanishi MD); and Department of Radiology (B Meyer MD) and Department of Cardiovascular, Thoracic and Transplantation Surgery (S Cebotari MD), Hannover Medical School, Hannover, Germany Correspondence to: Prof Marius M Hoeper, Department of Respiratory Medicine, Hannover Medical School, 30623 Hannover, Germany hoeper.marius@mh-hannover. de
Key messages • Chronic thromboembolic pulmonary hypertension (CTEPH) is caused by persistent obstruction of pulmonary arteries following pulmonary embolism • CTEPH is an important differential diagnosis in patients with unexplained dyspnoea and pulmonary hypertension • Ventilation-perfusion scintigraphy is the key imaging tool to determine or rule out CTEPH and has a higher sensitivity than contrast-enhanced CT • Patients with suspected or documented CTEPH should be referred to specialised centres, where the diagnosis can be established and operability determined • Pulmonary endarterectomy is the preferred treatment for CTEPH, as it is curative in most patients • Riociguat, which stimulates soluble guanylate cyclase activity, is the first drug to be approved for patients with inoperable CTEPH • Balloon pulmonary angioplasty is a potential new treatment option for patients with inoperable CTEPH and is being assessed in specialist centres
www.thelancet.com/respiratory Published online June 2, 2014 http://dx.doi.org/10.1016/S2213-2600(14)70089-X
1
Review
myeloproliferative disorders, splenectomy, inflammatory bowel disease, chronic osteomyelitis, and the presence of permanent central venous lines, pacemakers or ventriculoatrial shunts.11–14 These disorders are associated with chronic inflammation, increased risk of repeated blood-stream infections, or both, which probably contribute to non-dissolution of thromboembolic material.1 Proinflammatory molecules, such as C-reactive protein, might also participate in the development of CTEPH.15 Additionally, direct infection of thrombotic material by blood-borne pathogens could also be important, especially in patients with pacemakers, permanent central venous lines, or ventriculoatrial shunts.16 The exact mechanisms that prevent complete dissolution of the thromboembolic material are complex and incompletely understood. Usually, resolution of large clots is orchestrated in two steps, starting with rapid fibrinolysis followed by a cellular response that leads to ingrowth of monocytes and endothelial progenitor cells and initiates neovascularisation of the thrombus.17–19 The process can be altered at any of these steps and, therefore, the factors predisposing the development of CTEPH vary between individuals.10,20,21 On the basis of experimental data and analysis of samples obtained from PEA in human beings, several groups proposed a misguided vascular remodelling process that involved defective angiogenesis and delayed thrombus resolution associated with endothelial dysfunction and endothelialmesenchymal transition as the key mechanism in the development of CTEPH.1,22–24 Several animal models have improved understanding of specific features of CTEPH, but no model truly mimics human disease.25 Occlusion of pulmonary arteries by thromboembolic material is the initial trigger of CTEPH. Non-dissolution of thromboembolic material eventually results in the formation of organised scar tissue, sometimes termed fibrous clots, and intraluminal webs and bands, which partly or completely obstruct pulmonary arteries. As a consequence, the pulmonary blood flow is redistributed to non-occluded vessels, which become exposed to high intravascular pressures and shear stress, resulting in endothelial dysfunction and vascular remodelling of precapillary arteries. These changes resemble those seen in pulmonary arterial hypertension.26 These microvascular changes explain why CTEPH is a progressive disease, even in the absence of recurrent thromboembolic events. If left untreated, the outlook for patients with CTEPH is dismal. Median survival is less than 2 years in patients who have mean pulmonary artery pressure higher than 30 mm Hg at diagnosis.27,28 Right-heart failure is the most frequent cause of death. Advances in management have improved outcomes, but CTEPH remains a potentially fatal condition, especially when surgery is not an option.29,30
Symptoms and diagnosis As in other forms of pulmonary hypertension, progressive dyspnoea on exertion is the predominant 2
symptom of CTEPH. Additionally, patients might present with fatigue, syncope, haemoptysis, and signs of right-heart failure. CTEPH should be considered in all patients who have a history of clinically overt acute pulmonary embolism, although around 25% of patients diagnosed as having CTEPH have no documented acute pulmonary embolism events.31 Thus, CTEPH should be considered in any patient with otherwise unexplained pulmonary hypertension. The diagnostic approach for CTEPH starts with transthoracic echocardiography to assess the likelihood of pulmonary hypertension, followed by ventilationperfusion scintigraphy to detect or rule out perfusion defects. Ventilation-perfusion scanning remains the preferred imaging tool because of its high sensitivity and a negative predictive value of virtually 100%.32 Thus CTEPH is generally ruled out if the scan is normal.32 The presence of multiple perfusion defects is strongly suggestive of CTEPH but can also occur in other disorders, such as pulmonary veno-occlusive disease, pulmonary vasculitis, fibrosing mediastinitis, or malignant disease.33–35 Multidetector CT angiography usually reveals indirect and direct signs of CTEPH. Indirect signs include a mosaic perfusion pattern of the lung parenchyma and the presence of dilated bronchial arteries. Direct signs are organised emboli, partial filling defects or complete obstruction of pulmonary arteries, and bands and webs (figure 1).36,37 Of note, similar findings might be seen in patients with non-embolic thrombi, tumours, or vasculitis of pulmonary arteries.38,39 MRI is a suitable alternative method to CT angiography for the diagnostic work-up of CTEPH,40 but is not widely used. If imaging suggests the presence of CTEPH, patients should be referred to a specialist centre for further assessment, including right-heart catheterisation and pulmonary angiography. If logistics allow, these two invasive procedures should be combined to keep inconvenience and risk of complications to a minimum. Pulmonary angiography should be done at a centre that assesses patients’ suitability for surgery to avoid the need for repeat procedures. Whether survivors of acute pulmonary embolism should be followed up systematically to detect the development of CTEPH at an early stage is a matter of debate. In view of the high frequency of acute pulmonary embolism and the low, albeit important, risk of developing CTEPH, general screening after acute pulmonary embolism is not recommended.41–43 The threshold for a diagnostic workup, however, should be low in patients who remain symptomatic after an episode of acute pulmonary embolism. Echocardiography remains the preferred diagnostic tool if pulmonary hypertension is suspected, but a diagnostic approach that combines no characteristics of right-ventricular strain on electrocardiogram with normal plasma concentrations of the N-terminal fragment of probrain
www.thelancet.com/respiratory Published online June 2, 2014 http://dx.doi.org/10.1016/S2213-2600(14)70089-X
Review
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Figure 1: Imaging and histopathology of chronic thromboembolic pulmonary hypertension (A) Perfusion scan showing multiple bilateral segmental and subsegmental perfusion defects. (B) Mosaic perfusion and (C) enlarged bronchial arteries on chest CT. (D) Multidetector CT showing intravascular filling defects in the left lower lobe artery. (E) Right-sided pulmonary angiography showing partly and completely occluded vessels. (F) Histological sample showing typical webs.
natriuretic peptide has a negative predictive value of 99% (95% CI 97–100) for CTEPH.44
but the presence or absence of vena cava filters had no effect on 1-year survival after PEA in the CTEPH registry of the International CTEPH Association.47
Treatment Although never assessed in clinical trials, the need for lifelong anticoagulation for patients with CTEPH is undisputed, even in patients who underwent successful PEA. The target international normalised ratio is 2·0–3·0. Vitamin K antagonists remain the most widely used drugs to treat CTEPH. Subcutaneous lowmolecular-weight heparins or fondaparinux and novel anticoagulants are suitable alternative drugs, especially in patients in whom a stable international normalised ratio is difficult to maintain with vitamin K antagonists, although none has been systematically tested in patients with CTEPH. The use of filters in the inferior vena cava remains controversial.45 In the past, these filters were used regularly, particularly after PEA. Increasingly, centres use vena cava filters only when therapeutic anticoagulation is not feasible or when recurrent venous thromboembolism occurred despite sufficient anticoagulation.46 Prospective studies have not been done,
Pulmonary endarterectomy In only a few centres worldwide are more than 20 PEA surgeries performed per year.42 Unlike pulmonary embolectomy for acute pulmonary embolism (Trendelenburg’s procedure), PEA is a true endarterectomy and is almost always bilateral, which involves general anaesthesia, the use of cardiopulmonary bypass, and deep hypothermia (usually 20°C) because episodes of complete circulatory arrest are required to prevent collateral blood flow into the operation field.46,48 The pulmonary arteries are opened inside the pericardium, from where endarterectomy is performed as far distal as possible, beyond the levels of the segmental and subsegmental arteries (figure 2).46 In experienced centres, the short-term and long-term results of PEA are excellent, but there is a clear reciprocal relation between a centre’s experience and the mortality rate.47 In high-volume centres, the in-hospital mortality is now less than 5%.29,47,48–51 In one centre that had performed
www.thelancet.com/respiratory Published online June 2, 2014 http://dx.doi.org/10.1016/S2213-2600(14)70089-X
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A
B
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Figure 2: Pulmonary endarterectomy in a man aged 51 years with chronic thromboembolic pulmonary hypertension (A) Preoperative pulmonary angiograms show widespread pulmonary vascular obstruction by intraluminal scar tissue in both lungs. These findings are supported by (B) scar tissue removed during surgery and (C) preoperative ventilation-perfusion scintigraphy. (D) Postoperative ventilation-perfusion scintigraphy showed notable improvement in lung perfusion. The pulmonary vascular resistance dropped from 853 dyn s/cm–5 before surgery to 119 dyn s/cm–5 after surgery. New York Heart Association functional class improved from III to I shortly after surgery.
2700 operations overall, the in-hospital mortality for the last 500 consecutive operations, performed between 2006 and 2010, was 2·2% and none of the last 260 patients died (table 1).29 105 of these patients had peripheral disease (Jamieson type III) before surgery. Cognitive function is usually not impaired after surgery despite periodical circulatory arrest, and the procedure can be performed with acceptable risks in very old patients.49,52 Additionally, PEA can be combined with other cardiac operations.46,54 Postoperative haemodynamics become normal or near normal in most patients after PEA. Several groups have reported that more than 80% of patients improve to New York Heart Association functional class I or II after PEA.51,55,56 Residual or recurrent pulmonary hypertension after surgery remains the most important cause of postoperative morbidity and mortality.47,57 In the International CTEPH Registry, 64 (16∙7%) of 384 patients had persistent pulmonary hypertension, defined as mean pulmonary artery pressure of at least 25 mm Hg at the end of intensive care.46 Skoro-Sajer and colleagues58 reported persistent pulmonary hypertension defined by a 4
mean pulmonary artery pressure of at least 25 mm Hg and a pulmonary vascular resistance of more than 400 dyn s/cm–⁵ in 14 (31%) of 45 patients 1 year after surgery. Freed and co-workers56 found raised mean pulmonary artery pressures (30 mm Hg or more 3 months after surgery) in 95 (31%) of 306 patients who underwent surgery between 1997 and 2007. In that series, postoperative pulmonary hypertension was associated with impaired exercise capacity, but, surprisingly, not with decreased 5-year survival (90·3% vs 89·9% in discharged patients with a postoperative mean pulmonary artery pressures less than 30 mm Hg vs 30 mm Hg or higher).56 In the only long-term study on haemodynamics after PEA, Corsico and colleagues51 noted persistent pulmonary hypertension in 12 (24%) of 49 patients who had pulmonary vascular resistance of more than 500 dyn s/cm–⁵ after 4 years. The clinical relevance of residual pulmonary hypertension after PEA has not been fully explored, but these data suggest that persistent or recurrent pulmonary hypertension is a potential problem that physicians should bear in mind, especially in patients who present with progressive dyspnoea, signs of right heart failure, or both.
www.thelancet.com/respiratory Published online June 2, 2014 http://dx.doi.org/10.1016/S2213-2600(14)70089-X
Review
Targeted medical therapy Therapeutic advances in pulmonary arterial hypertension59 and the similarities between the peripheral vasculopathy in this disorder and CTEPH mean that medical therapy of CTEPH has been widely explored. Various case series and uncontrolled studies initially suggested beneficial effects of endothelin-receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclin analogues.60–66 Randomised controlled trials, however, produced mostly disappointing results.67–69 Sildenafil is probably the compound most widely used to treat patients with inoperable CTEPH, but there has been only one randomised control trial of this compound, which showed no change in 6 min walking distance but was associated with significant improvements in functional class and haemodynamics.68 Those results, however, were based on only 17 eligible patients and, therefore, the study lacked statistical power to determine clinically relevant effects. The first large, randomised, double-blind, controlled trial in this field was the BENEFiT trial,67 which assessed the safety and efficacy of 16 weeks’ treatment with bosentan, an endothelin-receptor antagonist, versus placebo in patients with either inoperable CTEPH or persistent or recurrent pulmonary hypertension after PEA. Pulmonary vascular resistance improved significantly (placebo-corrected change from baseline –24·1%, p
