Chronic thromboembolic pulmonary hypertension

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

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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

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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

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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.

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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<0·0001), but no improvements were seen in 6 min walking distance or other clinical outcomes.67 Despite these negative results, lack of other evidence, and the fact that these drugs have not been licensed for this indication, pulmonary hypertension guidelines do recommend the cautious use of endothelin-receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclin analogues in patients with inoperable CTEPH.41,70 Some retrospective series suggest improved long-term survival in patients with inoperable CTEPH who received targeted medical therapy with phosphodiesterase-5 inhibitors, endothelin-receptor antagonists, or prostacyclin analogues, compared with historical control groups, but confirmation by prospective randomised studies is pending.30,71 In 2013, riociguat became the first drug approved for the treatment of inoperable CTEPH, including persistent or recurrent disease after PEA. Riociguat acts by stimulating soluble guanylate cyclase activity, by which it exerts vasodilatory and antiproliferative effects on vascular smooth-muscle cells.72 In an uncontrolled phase 2 study, riociguat had similar effects on haemodynamics and exercise capacity in patients with CTEPH and those with pulmonary artery hypertension.73 The ensuing phase 3 study, CHEST-1,74 included 261 patients who had persistent or recurrent pulmonary hypertension after PEA or peripheral, inoperable disease. The findings from CHEST-1 confirmed those of the phase 2 study. Riociguat was associated with significant improvements in 6 min walking distance

(placebo-corrected treatment effect showed an increase of 46 m, p<0·0001) pulmonary vascular resistance, functional class, and concentrations of the N-terminal fragment of probrain natriuretic peptide after 16 weeks of treatment.74 The drug was generally well tolerated, with headache, dizziness, dyspepsia, and nasopharyngitis being the most frequent side-effects. Additionally, four (2%) of 175 patients in the riociguat group experienced episodes of haemoptysis. Whether this adverse effect was related to the study medication was unclear, but a warning was added to local prescribing information. Extension studies and postapproval registry data will provide further information on the safety of riociguat. The approval of riociguat for patients with inoperable CTEPH closes an important therapeutic gap, but at the same time aggravates the issue of use of medications in patients with CTEPH rather than referral to an expert centre for assessment for potential invasive diagnostic procedures and the perspective of major surgery. Even before the approval of riociguat, medications, particularly phosphodiesterase type 5 inhibitors, were being widely used in patients with CTEPH before referral even though there was no clinical benefit, and the time to surgery was substantially extended.75 It must be borne in mind that surgery remains the only curative option for CTEPH. Benefits from medical therapy have been shown only in patients with truly inoperable disease, and whether riociguat or other drugs for pulmonary artery hypertension improve long-term outcomes in patients with CTEPH is unclear. Thus, operability or inoperability should be determined as soon as possible by specialised multidisciplinary teams that include physicians, radiologists, and expert surgeons.38 Although drug therapy is approved for patients with inoperable CTEPH and for patients with persistent or recurrent pulmonary hypertension after PEA, the evidence is not yet robust for the latter group; the subgroup analyses of BENEFIT67 and CHEST-174 showed no significant effects in patients with residual or recurrent pulmonary hypertension. Neither trial, however, was powered for subgroup analyses. Medical therapy to reduce pulmonary vascular resistance before PEA has been explored, as high values Number of Mean (SD) PVR (dyn s/cm–⁵) In-hospital Long-term survival procedures mortality Before PEA

After PEA

Madani et al29

500

719 (383)

253 (149)

2·2%

82% at 5 years, 75% at 10 years

Mayer et al47

386

728 (N/A)

NA

4·7%

93% at 1 year

Corsico et al51

157

1140 (517)

327 (238)

11·5%

Berman et al52*

411

693 (372)

308 (254)

5·4%

91% at 1 year, 88% at 3 years

Camous et al53†

181

880 (370)

485 (210)

3·7%

NA

84% at 5 years

PVR=pulmonary vascular resistance. PEA=pulmonary endarterectomy. NA=not available. *Data from patients younger than 70 years. †Data from a cohort of patients without antiphospholipid syndrome.

Table 1: Results of pulmonary endarterectomy in expert centres

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Figure 3: Results of balloon pulmonary angioplasty in a man aged 31 years with inoperable distal chronic thromboembolic pulmonary hypertension (A) Pulmonary angiography and (B, C) C-arm CT showed predominantly small-vessel disease with intraluminal webs and bands (black arrows in C) and CT showed high-grade stenosis at the origin of the segmental artery A2 (green arrows in B and C). (D) Selective angiography of the right upper lobe during balloon placement (arrows) showed that the segmental artery was blocked and there was no distal contrast enhancement. (E) Immediately after balloon pulmonary angioplasty, contrast enhancement was improved. (F) Improved venous return after balloon pulmonary angioplasty, which is a typical early sign of successful treatment.

are an independent risk factor for postoperative mortality.76 Several small studies have shown that drugs used for pulmonary artery hypertension might improve haemodynamics in surgical candidates,64,77,78 but no evidence indicates improved postoperative outcomes.75 In individuals with a high mortality risk, this strategy could be applied if physicians and surgeons agree and if it does not delay surgery. No data indicate the efficacy of medical therapy in patients with proximal CTEPH who are deemed to have operable disease but who do not undergo PEA because of 6

severe comorbidities or because they decline surgery. These patients are generally excluded from randomised, controlled trials. Evidence from studies in other patients suggests that haemodynamic improvement can be expected in this population, but the clinical effects remain unclear. Drugs for treatment of pulmonary artery hypertension are generally well tolerated by CTEPH patients; it might, therefore, be appropriate to treat patients with operable disease similarly to patients with truly inoperable distal disease, bearing in mind the gaps in the available evidence.

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Balloon pulmonary angioplasty A potential treatment option for CTEPH is balloon pulmonary angioplasty. This technique was first described in 2001,79 but was not widely adopted despite promising results, mainly because it was associated with major, possibly fatal, complications, especially reperfusion oedema and pulmonary haemorrhage. The technique has, however, begun to gain widespread interest after development in several Japanese centres.80–82 The concept is straightforward and uses a standard balloon angioplasty technique. The targeting of only one area during each treatment session minimises the risk and, therefore, three to five treatment sessions are usually required. The balloon size is always smaller than the diameter of the target vessel because the main aim is to reopen vessels occluded by bands and webs and not to dilate them (figure 3). Segmental and subsegmental vessels are the main target areas. Japanese and European centres have demonstrated impressive haemodynamic improvements (table 2), along with improvements in exercise capacity, concentrations of brain natriuretic peptide in plasma, and reversal of right-ventricular remodelling.80–84 Serious complications, including fatal pulmonary haemorrhage, have been observed but are rare, and an inverse relationship between major complications and centre experience has been reported.81 Periprocedural mortality has ranged from none to 10%, but was 1·5% in the largest series (table 2). During observation periods of up to 3 years, re-stenosis has been seen only occasionally,81 and stenting has not seemed necessary, but the long-term results must be assessed further. Balloon pulmonary angioplasty remains an experimental procedure with insufficient long-term data to allow widespread use. As with medical therapy, balloon pulmonary angioplasty presents potential opportunities and risks at the same time. Physicians who favour interventional treatments might choose this treatment rather than referring patients to expert centres first to have operability of CTEPH assessed. At the same time, the risk of serious complications would be expected to increase if the balloon angioplasty were adopted by non-expert centres, because the technique and selection of patients require expertise and advanced imaging technology. For main and lobar CTEPH, surgery will remain the most effective therapy overall, as it will when a substantial number of segmental or subsegmental pulmonary arteries are fully occluded. Even after successful balloon pulmonary angioplasty, residual pulmonary hypertension frequently persists, and most patients who have undergone this procedure have received medical treatments used in pulmonary artery hypertension before and after intervention.80–82 Most of the leading CTEPH and PEA centres worldwide have added or will soon add balloon pulmonary angioplasty to their therapeutic options. These centres

Number of Mean (SD) PVR (dyn s/cm–5) Periprocedures procedural mortality Before intervention

Long-term survival

After intervention

Kataoka et al80

29

NA

NA

3·4%

NA

Mizoguchi et al81

68

942 (367)

327 (151)

1·5%

97% after 2·2 (SD 1·4) years

Sugimura et al82

12

627 (236)

310 (73)

0

100% at 1 year

Fukui et al83

20

889 (365)

490 (221)

0

NA

Andreassen et al84 20

704 (320)

472 (288)

10%

85% after 51 (SD 30) months

PVR=pulmonary vascular resistance. NA=not available.

Table 2: Results of balloon pulmonary angioplasty in expert centres

CTEPH diagnosis (anticoagulation and referral to expert centre)

Operable

Inoperable (or patient refuses surgery)

Pulmonary endarterectomy

Drug therapy*

Haemodynamics normalised

No

Persistent symptoms

Yes Reassess once yearly†

Consider BPA (or LTx‡)

Figure 4: Treatment algorithm for CTEPH CTEPH=chronic thromboembolic pulmonary hypertension. BPA=balloon pulmonary angioplasty. LTx=lung transplantation. *As of 2014, riociguat is the only drug approved for the treatment of patients with inoperable CTEPH. †Time to reassessment varies between individuals. ‡Rarely performed in CTEPH.

are in the best position to further explore the safety and efficacy of this procedure and to determine which patients will benefit more from surgery or an interventional approach. Eventually, randomised controlled trials to compare approaches in selected patient populations will be required. Taken together, PEA remains the most clinically effective treatment for CTEPH, and in many patients it is the definitive and curative treatment. Balloon pulmonary angioplasty could be considered for patients deemed inoperable by an experienced surgeon, owing to predominant distal disease or comorbidities,38 or in those with persistent or recurrent pulmonary hypertension after PEA.84 If all treatment options fail, lung transplantation remains a viable treatment option for selected patients, but is now rarely performed. Figure 4 shows a treatment algorithm to aid decisions about whether to use surgical or medical therapy, balloon pulmonary angioplasty, or both.

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Search strategy and selection criteria References for this Review were identified through searches of PubMed for articles published from January, 1970, to January, 2014, with the search terms “chronic thromboembolic pulmonary hypertension”, “pulmonary endarterectomy”, “pulmonary thrombendarterectomy”, “balloon pulmonary angioplasty”, and “pulmonary embolism and pulmonary hypertension”. Articles of interest were selected on the basis of review by MMH and LJR. Relevant references cited in retrieved articles were also reviewed. Articles published in English or German were included.

Economic considerations The costs of PEA and balloon pulmonary angioplasty vary widely between centres and are difficult to assess as few data have been published. Comparison of the costs at two centres that perform PEA and balloon pulmonary angioplasty, in Osaka, Japan, and Hannover, Germany, provides the following estimates: in Osaka, the average full costs for PEA are around ¥5 800 000 (US$50 000) and for four balloon pulmonary angioplasty procedures (the median number of interventions required per patient) are ¥4 900 000 ($47 000); in Hannover, the average costs are around €29 000 ($40 000) and €27 000 ($37 000), respectively. The approximate annual costs for 2·5 mg riociguat three times per day in Germany are €50 000 ($70 000), but the price in Osaka is not available. Thus, medical therapy with riociguat is more expensive than PEA or balloon pulmonary angioplasty procedures (in Germany at least), but cost-effectiveness cannot be compared.

Conclusions CTEPH is a life-threatening complication of pulmonary embolism. Treatment differs substantially from that of other forms of pulmonary hypertension. A robust diagnostic workup in patients with unexplained pulmonary hypertension, therefore, should include appropriate imaging, including ventilation-perfusion scintigraphy. The final diagnosis of CTEPH requires right-heart catheterisation and pulmonary angiography, which should be done in expert centres, where the best therapeutic approach for affected patients will also be determined. PEA is the treatment of choice, and remains the only potentially curative approach. For patients with inoperable disease, riociguat is so far the only approved drug that improves haemodynamics and exercise capacity. Balloon pulmonary angioplasty is a potential new treatment option for selected patients with inoperable disease, but requires further assessment before its place in the treatment strategy for CTEPH can be determined. Contributors MMH conceived the Review and was responsible for its overall content. All other authors assisted with writing and editing. MMM, NN, BM, and LJR created some of the figures, and NN, SC, and LJR created some of the tables.

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