REVIEW URRENT C OPINION
Chronic thromboembolic pulmonary hypertension: evolution in management Barbara L. LeVarge a and Richard N. Channick b
Purpose of review Chronic thromboembolic pulmonary hypertension (CTEPH) is an important cause of pulmonary hypertension. Although surgery is potentially curative, some patients present with inoperable disease. In these patients, medical therapies for pulmonary arterial hypertension are increasingly being used. Recent findings The pathobiology of CTEPH development remains incompletely understood; however, evidence supports both large and small vessel disorder in patients with the disease. Surgical thromboendarterectomy is an increasingly well tolerated and often curative procedure and is the management strategy of choice for most patients. Although excellent outcomes in surgical management have been noted, the role of medical management in selected patients with inoperable or recurrent or persistent disease after surgery is increasing. A recent large, randomized controlled clinical trial of riociguat in CTEPH demonstrated improvements in exercise capacity, functional class, and hemodynamics. A safe, effective angioplasty approach to CTEPH is being pursued in addition. Summary The approach to CTEPH management in the operable patient remains surgical, without clear benefit to preoperative pulmonary arterial hypertension-specific therapy at this time. Patients with inoperable disease or pulmonary hypertension following thromboendarterectomy, however, should be considered for medical management, with riociguat currently having the strongest evidence specific to CTEPH. Keywords chronic thromboembolic pulmonary hypertension, pulmonary embolism, pulmonary thromboendarterectomy
INTRODUCTION
INCIDENCE AND RISK FACTORS
Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary hypertension characterized by obstruction of the pulmonary vasculature resulting from impaired thrombus resolution and remodeling following acute pulmonary embolism. In comparison to pulmonary arterial hypertension (PAH), there are major differences not only in pathophysiology but also importantly in management, as CTEPH represents a potentially curable form of pulmonary hypertension by pulmonary thromboendarterectomy (PTE, also known as PEA). CTEPH and PAH have similarities, particularly in the realm of small vessel changes; thus, there has been increasing interest in a medical approach for some patients. Recent data support functional and hemodynamic improvements in inoperable or recurrent or persistent pulmonary hypertension patients who are treated with PAH-specific therapies. This article reviews current knowledge of the disease, with a focus on new evidence for the role of medical therapy.
Although the incidence of CTEPH is unknown, the disease is, no doubt, underdiagnosed. In a prospective study by Pengo et al. [1], 3.8% of patients developed symptomatic CTEPH within 2 years of first pulmonary embolism. Subsequent estimates of CTEPH incidence have varied according to study population, with range 0.6–4.6% when diagnosis requires catheterization [2–6]. The risk of developing CTEPH after acute pulmonary embolism is greater in those with recurrent pulmonary
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a
Department of Pulmonary and Critical Care Medicine, Beth Israel Deaconess Medical Center and bDepartment of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA Correspondence to Barbara LeVarge, MD, Department of Pulmonary and Critical Care Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA. Tel: +1 617 667 5864; e-mail: [email protected] Curr Opin Pulm Med 2014, 20:400–408 DOI:10.1097/MCP.0000000000000088 Volume 20 Number 5 September 2014
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CTEPH: evolution in management LeVarge and Channick
KEY POINTS CTEPH is critical to consider in the differential diagnosis of precapillary pulmonary hypertension. Although the pathophysiology of CTEPH remains incompletely understood, it is clear that patients develop both large vessel organized thrombus and microvascular disorder. The radionucleotide ventilation-perfusion scan is the preferred screening test, and pulmonary angiography is used to confirm diagnosis and assess operability. In appropriate surgical candidates, pulmonary thromboendarterectomy improves functional status and exercise capacity and provides a cure for many patients with CTEPH. As some individuals present with inoperable disease or have pulmonary hypertension persisting after thromboendartectomy, an evidence-supported role for medical therapy is emerging.
embolism, unprovoked event, larger clot burden, and younger age [1,2,7]. Other CTEPH case control and cohort studies have identified additional risk factors, including splenectomy [8–10], ventriculoatrial shunts [8,9], infected pacemakers [9], chronic inflammatory conditions [8], non-O blood groups [9,11], thyroid replacement [9], malignancy [9], elevated factor VIII and von Willebrand factor (vWF) levels [12,13], and lupus anticoagulant or antiphospholipid antibodies [9,14].
resistance has also been established in CTEPH [20]. The increased risk of CTEPH in patients with infected pacemakers and ventriculo-atrial shunts may relate to poor resolution of clot in the setting of staphylococcal infection [21]. It is clear that the pathophysiology of CTEPH involves more than simply chronic mechanical obstruction of proximal pulmonary arteries. An important ‘small vessel’ component, with microvascular changes similar to those seen in PAH, is often present in both the unobstructed vascular bed and vessels distal to the chronic obstruction [22]. Blauwet et al. [23] described endarterectomy specimens from 54 patients; organized or organizing thrombus, occasionally of multiple ages, was noted, with intimal findings including collagen and elastin deposition, chronic inflammation, hemosiderin, atherosclerosis, and calcification. A study of 200 patients undergoing PTE revealed non-CTEPH disorder in five patients (pulmonary artery sarcoma in two, metastatic germ cell tumor in one, and arteritis in two patients). In addition to histopathologic changes of the previous study, notable cellularity, particularly in areas of recanalization and rarely associated with cellular atypia, was described [24]. The observed small vessel abnormalities, including intimal thickening, medial hypertrophy, and plexiform lesions, share similarities with PAH of other causes [25 ,26,27]. These disorders are thought to predominate in the small vessels downstream of patent pulmonary arteries, with paucity of vasculature noted distal to vessels occluded by chronic thromboembolism [25 ]. Presence of a large burden of small vessel vasculopathy may limit the degree of hemodynamic improvement that will occur following PTE and serves as the rationale for pulmonary vasodilator therapy in some CTEPH patients. &
&
PATHOPHYSIOLOGY AND DISORDER Although acute pulmonary embolism is a clear risk factor for CTEPH, there remains incomplete understanding of the mechanism behind why a subset of patients do not resolve acute thromboembolism, although most do. Recanalization of the embolic obstruction is an important step in acute pulmonary embolism resolution; this process relies on angiogenesis with new vessel penetration into the thrombus. Paucity of vessels is a feature of endarterectomy specimens, promoting hypothesis of impaired angiogenesis [15]. Abnormal fibrinogens with resistance to lysis also may be important, with demonstration of impaired fibrinolysis and/or fibrinogen gene mutations in some CTEPH patients [16–18]. The role of inflammation in CTEPH is also being investigated. C-reactive protein increases CTEPH but not PAH smooth muscle cell proliferation in vitro, with enhanced inflammatory cell adhesion and endothelin and vWF secretion by endothelial cells [19]. Correlation between monocyte chemoattractant protein-1 levels and pulmonary vascular
CLINICAL FEATURES Most but, importantly, not all CTEPH patients will have history of venous thromboembolism. In the international CTEPH registry, 25% of patients did not have prior history of acute pulmonary embolism [11]. As with other forms of pulmonary hypertension, patients with CTEPH typically present with progressive dyspnea and exercise intolerance. Later symptoms of exertional syncope or edema relate to limitation in exertional right ventricular (RV) output and RV failure. Physical examination findings depend on severity and commonly include jugular venous distension, murmur of tricupsid regurgitation, prominent pulmonic component of S2, RV heave, and edema or ascites. A relatively unique physical finding in CTEPH is the presence
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FIGURE 1. Radionucleotide perfusion scan of a patient with chronic thromboembolic pulmonary hypertension. Numerous perfusion defects, involving all lobes, right lung greater than left, are demonstrated. No defects were seen on the patient’s corresponding ventilation images.
of pulmonary flow ‘bruits’ heard over the posterior lung fields. These bruits are heard in approximately one-third of patients with CTEPH, and when present, generally correlate with operable disease [Channick R, personal communication].
DIAGNOSIS All patients with unexplained pulmonary hypertension should undergo evaluation for CTEPH as the cause, regardless of presence or absence of a history of prior thromboembolic episodes [28]. The radionuclide ventilation-perfusion scan is the screening test of choice to distinguish CTEPH from other forms of pulmonary hypertension (Fig. 1). Tunariu et al. [29] performed a head-to-head comparison of radionuclide ventilation or perfusion and computed tomography angiogram (CTA) in 227 patients, using pulmonary angiography as gold standard. Radionuclide ventilation or perfusion scanning had sensitivity of 96–97% with specificity of 90–95%, whereas sensitivity for CTA was only 51% [29]. Disease confirmation with pulmonary angiography is usually the next step in diagnosis. Typical angiographic features of CTEPH include complete 402
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branch vessel obstructions, pouches, webs, and intimal irregularities (Fig. 2) [30]; location and extent of findings factor into decisions regarding surgical accessibility. Pulmonary angiography also allows for direct hemodynamic assessment when combined with right heart catheterization; severity of pulmonary hypertension provides information regarding surgical risk [31]. Acute response to inhaled nitric oxide (iNO) can also be assessed at this time, with evidence that greater iNO-mediated decrease in mean pulmonary artery pressure (mPAP) corresponds to improved post-PTE outcomes [32]. In some cases, CTA may be sufficient and avoid the need for pulmonary angiography, although right heart catheterization should still be performed. Additional imaging techniques under investigation include dual-energy computed tomography [33] and MRI [34–36]; these may find a larger role in either the screening or diagnosis of CTEPH in the future.
SURGICAL TREATMENT Pulmonary thromboendarterectomy remains the procedure of choice for the treatment of CTEPH. Volume 20 Number 5 September 2014
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FIGURE 2. Anteroposterior and lateral views of the right pulmonary artery on angiography, correlating with the perfusion scan shown in Fig. 1. Pouch defects (shaded arrow) and numerous webs or bands (open arrow) with poststenotic dilatations are noted throughout the right main pulmonary artery and its branches.
The earliest true endarterectomy procedures were performed in the 1960s, with subsequent refinement over the following years [37]. Current techniques utilize median sternotomy, cardiopulmonary bypass, and periods of deep hypothermic circulatory arrest to maintain a bloodless field while endarterectomy is performed (Fig. 3). Recently, some centers have successfully performed PTE using antegrade cerebral perfusion to avoid complete circulatory arrest [38]. However, a recent trial randomizing patients in this regard noted no difference in cognitive function between groups [39]. International registry data demonstrated 4.7% in-hospital mortality in 384 patients between 2007 and 2009 [11]. Recent data from the University of California-San Diego reported mortality of only 2.2% among 500 patients undergoing PTE between 2006 and 2010 [40]. Mortality data vary with center experience, circulatory arrest duration, preoperative 6MWD, and pre and postoperative pulmonary vascular resistance (PVR) [41]. Potential complications of PTE include reperfusion pulmonary edema, persistent pulmonary hypertension, infection, neurologic complications, and pericardial effusion [41,42 ]. Endarterectomy has consistently been associated with impressive improvements in functional class, exercise capacity, and hemodynamics, with immediate normalization of pulmonary artery pressures in many. Of 157 patients analyzed by Corsico et al. [43], prevalence of functional class III/IV shifted from 97% preoperatively to 12% at 3 months postoperative; mean 6MWD increased &
dramatically from 95 to 342 m during that same time period (P < 0.001 for both comparisons). Mayer et al. [41] reported improvement in 6MWD from 362 to 459 m within 1 year of PTE. Recent experience from the San Diego group showed postoperative improvements in mPAP (45.5 to 26.0 mmHg) and cardiac output (4.3 to 5.6l/min) [40]. Improvements in PVR (preoperative to end of ICU stay) from the international registry and San Diego groups were 736 to 248 dyn-s-cm5 and 719 to 253 dyn-s-cm5, respectively [40,41].
PERCUTANEOUS TREATMENT Interventional angioplasty techniques for management of CTEPH were introduced by Feinstein et al. [44] in 2001. Eighteen patients, deemed inoperable because of surgical inaccessibility or comorbid illness, were treated with balloon dilations of affected segments. One patient died, and 11 developed reperfusion pulmonary edema. Improvements in mPAP, 6MWD, and functional class were noted [44]. Several recent series have been published, with consistent reports of hemodynamic improvements, though high rates of reperfusion pulmonary edema and mortality up to 10% in one series [45–47]. Fukui et al. [48] recently reported on 20 patients undergoing balloon angioplasty for inoperable CTEPH, with gains achieved in several parameters, including mPAP, PVR, cardiac index (CI), 6MWD, and cardiac MRI findings. Importantly, no deaths or major complications occurred in this series [48]. Further study in the role of percutaneous techniques in the
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FIGURE 3. Surgical thromboendarterectomy specimens, obtained from same patient whose imaging is shown in Figs 1 and 2. Fibrotic and thrombotic material, extending into segmental pulmonary arteries, was dissected out at the time of surgery.
management of CTEPH is needed, as with refinements in technique and more long-term data, balloon angioplasty may emerge as an effective treatment option when performed by experienced operators in comprehensive centers [49].
Given the availability of several targeted medical therapies for PAH and the similarities in histopathology between PAH and CTEPH, there is strong rationale for utilizing these therapies in patients with inoperable disease or postoperative pulmonary hypertension.
MEDICAL TREATMENT Although CTEPH management is surgical for most patients, increasing evidence for use of medical therapies in this disease is emerging. Medical therapy should not be thought of as a substitute for PTE in appropriate surgical candidates. It should be considered in those with inoperable disease (36.4% of CTEPH patients in an international registry [11]) or recurrence or persistence of pulmonary hypertension following PTE. Although unproven, medical therapy may also have a role in optimizing patients prior to PTE. A management algorithm, presented at the 2013 World Symposium on Pulmonary Hypertension, is shown in Fig. 4 [50 ]. All therapeutic strategies, medical and surgical, must be combined with lifelong anticoagulation with vitamin K antagonists (VKAs), with INR target of 2.0 to 3.0, to prevent new in-situ thrombus formation and embolic disease. As experience with the novel oral anticoagulants in the CTEPH and PAH populations is still quite limited, and as important drug interactions with PAH-specific therapies may exist, it is premature to consider these agents as acceptable alternatives to VKAs [51]. &&
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PROSTANOIDS Intravenous epoprostenol use for inoperable CTEPH was studied retrospectively by Cabrol et al. [52] in 27 patients. After mean followup of 20 months and at mean epoprostenol dose of 30 ng/kg/min, improvements in functional class, hemodynamics, and 6MWD (þ58 m) were seen [52]. Skoro-Sajer et al. [53] studied subcutaneous treprostinil in 28 patients with inoperable or recurrent or persistent CTEPH. Three patients discontinued therapy because of infusion site pain. After mean followup of 19 months and at mean treprostinil dose of 38 ng/kg/ min, significant improvements in CI and PVR (116 dyn-s-cm5) were noted. Improvements in 6MWD (þ 59 m at 6 months), functional class, and brain natriuretic peptide (BNP) levels were reported, and, in comparison to a historical group of CTEPH patients, mortality benefits were also suggested [53].
ENDOTHELIN RECEPTOR ANTAGONISTS The first large double-blind, placebo-controlled clinical trial in CTEPH (BENEFIT) randomized 157 Volume 20 Number 5 September 2014
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CTEPH Diagosis Continue lifelong anticoagulation
Operability assessment by CTEPH team
Non-operable
Operable
Recommend 2nd opinion by experienced center
Pulmonary endarterectomy
Targeted medical therapy
Referral for lung transplantation
Persistent symptomatic pulmonary hypertension
PTPA?
FIGURE 4. Proposed management algorithm for chronic thromboembolic pulmonary hypertension. Presented at the 2013 World Symposium on Pulmonary Hypertension. CTEPH, chronic thromboembolic pulmonary hypertension; PTPA, percutaneous transluminal pulmonary angioplasty. Reproduced with permission from [50 ]. &&
patients with inoperable (72%) or recurrent or persistent CTEPH to bosentan or placebo. The two primary endpoints were change in 6MWD and change in PVR. After 16 weeks, PVR decreased by a mean of 146 dyn-s-cm5 in the treatment group and increased by 30 dyn-s-cm5 in the placebo group, with resulting treatment effect on PVR of 24.1% (P < 0.0001). Effect on 6MWD was only þ 2.2 m, nonsignificant. Differences in CI and BNP were also found, in favor of bosentan [54]. Bosentan use in CTEPH was further evaluated in a meta-analysis by Becattini et al. [55], which included findings from the randomized controlled trial. Eleven papers (269 patients on bosentan therapy) were analyzed. Two hundred thirty patients (85.5%) were inoperable and the remainder had recurrence or persistence following PTE. After 3–6 months of bosentan, a weighted mean increase in 6MWD of 35.9 m (P < 0.001) was observed. The authors further noted positive shifts in functional class and decrease in BNP. Hemodynamic data were available for up to 185 patients; increase in CI of 8% (0.23 l/min/m2) and decrease in mPAP of 5.8% (2.6 mmHg) were both significant. For those with available PVR data (n ¼ 164), there was decrease of 20% (160 dyn-s-cm5) [55]. The ARIES-3 study investigated effects of ambrisentan on a diverse population of patients with pulmonary hypertension, including 29 with CTEPH. Analysis of this subgroup showed mean 17 m improvement in 6MWD, with nonsignificant decrease in BNP, after 24 weeks of therapy [56].
PHOSPHODIESTERASE TYPE-5 INHIBITORS An early uncontrolled study looked at effects of sildenafil in 12 patients with severe inoperable CTEPH over 6 months. Increase in 6MWD (312 to 366 m, P ¼ 0.02) and CI (2.0 to 2.4 l/min/m2, P ¼ 0.009) and decrease in PVR index (1935 to 1361 dyn-s-cm5/m2, P ¼ 0.004) were observed [57]. A subsequent larger study examined 104 inoperable patients over 12 months; the authors demonstrated improvements in similar parameters, including 6MWD (310 to 366 m, P ¼ 0.0005) and hemodynamics [58]. Suntharalingam et al. [59] performed a doubleblind, placebo-controlled pilot study of sildenafil in 19 patients with inoperable or recurrent CTEPH. At 12 weeks, increase in 6MWD was not significant, although there were significant improvements in functional class and PVR. Change to open-label dosing occurred at the conclusion of the trial; after 12 months, patients had favorable change in 6MWD, BNP, CI, and PVR [59].
SOLUBLE GUANYLATE CYCLASE STIMULATORS The only drug that is United States Food and Drug Administration (FDA) approved for patients with CTEPH (inoperable or persistent or recurrent pulmonary hypertension) is riociguat, a novel soluble guanylate cyclase stimulator. Approval of riociguat resulted from the recent CHEST-1 study, a 16-week, phase 3 multicenter double-blind,
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placebo-controlled clinical trial. Two hundred and sixty-one patients with inoperable (72%) or persistent or recurrent CTEPH were randomized to riociguat or placebo. The primary endpoint, change in 6MWD, was significantly improved in the riociguat group compared with placebo (least-squares mean difference 46 m, P < 0.001, Fig. 5). Secondary outcomes were also improved in the riociguat-treated patients, including changes in PVR (mean difference of 246 dyn-s-cm5), BNP, and functional class. Potential adverse effects of note included hypotension, dizziness, headache, dyspepsia, and diarrhea [60 ]. Riociguat is prescribed with a dose-escalation protocol. A treatment dose of 0.5 or 1 mg three times daily is started; provided signs or symptoms of hypotension do not develop, this dose can be increased every 2 weeks to a maximum of 2.5 mg three times daily. Riociguat cannot be taken with nitrates or phosphodiesterase type-5 inhibitors, and it is contra-indicated in pregnancy. &&
MEDICAL THERAPY AS A BRIDGE TO PULMONARY THROMBOENDARTERECTOMY Mortality of PTE is greater in patients with more severe baseline hemodynamic abnormalities. In one large series, those with preoperative PVR more than 1000 dyn-s-cm5 had mortality of 10.1%, compared with 1.3% when PVR was less than 1000 [61]. Concern of high mortality and desire to improve outcomes in these very severe patients led to investigations using medical therapy preoperatively. 406
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Nagaya et al. [62] treated 12 CTEPH patients with PVR more than 1200 dyn-s-cm5 with intravenous epoprostenol, to an average dose of 6 ng/kg/min, for a mean of 46 days prior to PTE. Epoprostenol significantly increased cardiac output and decreased PVR (by 28%), right atrial pressure, and BNP. One patient had persistent pulmonary hypertension postoperatively and died. Bosentan treatment prior to PTE was tested in a controlled study, during which pre-PTE patients were randomized to a 16-week period of bosentan (n ¼ 13) or usual care (n ¼ 12). Hemodynamics and 6MWD improved in those on bosentan prior to surgery; however, PTE outcomes were overall similar between the two groups [63]. Jensen et al. [63] retrospectively reviewed all PTE referrals at a single center between 2005 and 2007 and noted an increasing prevalence of medical therapy use (up to 37% of referrals during 2007). There were no significant differences in outcomes between those with or without preoperative medical therapy. However, those on medical therapy had longer time to referral (8.9 versus 4.4 months, P < 0.01), raising concern that use of medical therapy could delay potentially curative surgery [64].
CONCLUSION CTEPH is an important diagnosis to consider in the evaluation of exertional intolerance and pulmonary hypertension. Most but not all patients have had prior episode of acute pulmonary embolism. In addition to anticoagulation, assessment of candidacy for PTE surgery is key to appropriate management of the CTEPH patient. In operable patients, PTE surgery is unequivocally the treatment of choice and may be curative; percutaneous alternatives are also being investigated. However, as the pathobiology of the disease also includes small vessel vasculopathy similar to PAH and as some patients will be inoperable or have persistent or recurrent pulmonary hypertension despite PTE, there is an emerging role for medical management. Acknowledgements None. Conflicts of interest None declared.
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Historical perspective: surgery for chronic thromboembolic disease. Semin Thorac Cardiovasc Surg 2006; 18:218–222. 38. Thomson B, Tsui SS, Dunning J, et al. Pulmonary endarterectomy is possible and effective without the use of complete circulatory arrest the UK experience in over 150 patients. Eur J Cardiothorac Surg 2008; 33:157–163. 39. Vuylsteke A, Sharples L, Charman G, et al. Circulatory arrest versus cerebral perfusion during pulmonary endarterectomy surgery (PEACOG): a randomised controlled trial. Lancet 2011; 378:1379–1387. 40. Madani MM, Auger WR, Pretorius V, et al. Pulmonary endarterectomy: recent changes in a single institution’s experience of more than 2,700 patients. Ann Thorac Surg 2012; 94:97–103. 41. Mayer E, Jenkins D, Lindner J, et al. Surgical management and outcome of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry. J Thorac Cardiovasc Surg 2011; 141:702– 710. 42. Jenkins DP, Madani M, Mayer E, et al. Surgical treatment of chronic throm& boembolic pulmonary hypertension. Eur Respir J 2013; 41:735–742. This paper reviews techniques and current outcomes of surgical pulmonary thromboendartectomy and its key role in the management of chronic thromboembolic pulmonary hypertension. 43. Corsico AG, D’Armini AM, Cerveri I, et al. Long-term outcome after pulmonary endarterectomy. Am J Respir Crit Care Med 2008; 178:419–424. 44. Feinstein JA, Goldhaber SZ, Lock JE, et al. Balloon pulmonary angioplasty for treatment of chronic thromboembolic pulmonary hypertension. Circulation 2001; 103:10–13. 45. Andreassen AK, Ragnarsson A, Gude E, et al. Balloon pulmonary angioplasty in patients with inoperable chronic thromboembolic pulmonary hypertension. Heart 2013; 99:1415–1420. 46. Mizoguchi H, Ogawa A, Munemasa M, et al. Refined balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv 2012; 5:748–755. 47. Kataoka M, Inami T, Hayashida K, et al. Percutaneous transluminal pulmonary angioplasty for the treatment of chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv 2012; 5:756–762. 48. Fukui S, Ogo T, Morita Y, et al. Right ventricular reverse remodelling after balloon pulmonary angioplasty. Eur Respir J 2014; 43:1394–1402. 49. Hoeper MM. Chronic thromboembolic pulmonary hypertension at the crossroad. Eur Respir J 2014; 43:1230–1232. 50. Kim NH, Delcroix M, Jenkins DP, et al. Chronic thromboembolic pulmonary && hypertension. J Am Coll Cardiol 2013; 62:D92–99. This paper reviews recent developments and discussions of the chronic thromboembolic pulmonary hypertension task force as presented at the 2013 World Symposium on Pulmonary Hypertension in Nice, France. 51. Bertoletti L, Delavenne X, Montani D. Antithrombotics in pulmonary hypertension: more work needed before we turn to newer agents! Eur Respir J 2013; 41:775–777. 52. Cabrol S, Souza R, Jais X, et al. Intravenous epoprostenol in inoperable chronic thromboembolic pulmonary hypertension. J Heart Lung Transplant 2007; 26:357–362. 53. Skoro-Sajer N, Bonderman D, Wiesbauer F, et al. Treprostinil for severe inoperable chronic thromboembolic pulmonary hypertension. J Thromb Haemost 2007; 5:483–489.
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Disorders of the pulmonary circulation 54. Jais X, D’Armini AM, Jansa P, et al. Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension: BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension), a randomized, placebo-controlled trial. J Am Coll Cardiol 2008; 52:2127–2134. 55. Becattini C, Manina G, Busti C, et al. Bosentan for chronic thromboembolic pulmonary hypertension: findings from a systematic review and meta-analysis. Thromb Res 2010; 126:e51–e56. 56. Badesch DB, Feldman J, Keogh A, et al. ARIES-3: ambrisentan therapy in a diverse population of patients with pulmonary hypertension. Cardiovasc Ther 2012; 30:93–99. 57. Ghofrani HA, Schermuly RT, Rose F, et al. Sildenafil for long-term treatment of nonoperable chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2003; 167:1139–1141. 58. Reichenberger F, Voswinckel R, Enke B, et al. Long-term treatment with sildenafil in chronic thromboembolic pulmonary hypertension. Eur Respir J 2007; 30:922–927. 59. Suntharalingam J, Treacy CM, Doughty NJ, et al. Long-term use of sildenafil in inoperable chronic thromboembolic pulmonary hypertension. Chest 2008; 134:229–236.
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60. Ghofrani HA, D’Armini AM, Grimminger F, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 2013; 369:319–329. The CHEST-1 study is a randomized, double-blind, placebo-controlled clinical trial which demonstrated efficacy of riociguat in a large group of patients with inoperable or recurrent chronic thromboembolic pulmonary hypertension. 61. Jamieson SW, Kapelanski DP, Sakakibara N, et al. Pulmonary endarterectomy: experience and lessons learned in 1,500 cases. Ann Thorac Surg 2003; 76:1457–1462; . 62. Nagaya N, Sasaki N, Ando M, et al. Prostacyclin therapy before pulmonary thromboendarterectomy in patients with chronic thromboembolic pulmonary hypertension. Chest 2003; 123:338–343. 63. Reesink HJ, Surie S, Kloek JJ, et al. Bosentan as a bridge to pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension. J Thorac Cardiovasc Surg 2010; 139:85–91. 64. Jensen KW, Kerr KM, Fedullo PF, et al. Pulmonary hypertensive medical therapy in chronic thromboembolic pulmonary hypertension before pulmonary thromboendarterectomy. Circulation 2009; 120:1248–1254.
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Chronic thromboembolic pulmonary hypertension: evolution in management Barbara L. LeVarge a and Richard N. Channick b
Purpose of review Chronic thromboembolic pulmonary hypertension (CTEPH) is an important cause of pulmonary hypertension. Although surgery is potentially curative, some patients present with inoperable disease. In these patients, medical therapies for pulmonary arterial hypertension are increasingly being used. Recent findings The pathobiology of CTEPH development remains incompletely understood; however, evidence supports both large and small vessel disorder in patients with the disease. Surgical thromboendarterectomy is an increasingly well tolerated and often curative procedure and is the management strategy of choice for most patients. Although excellent outcomes in surgical management have been noted, the role of medical management in selected patients with inoperable or recurrent or persistent disease after surgery is increasing. A recent large, randomized controlled clinical trial of riociguat in CTEPH demonstrated improvements in exercise capacity, functional class, and hemodynamics. A safe, effective angioplasty approach to CTEPH is being pursued in addition. Summary The approach to CTEPH management in the operable patient remains surgical, without clear benefit to preoperative pulmonary arterial hypertension-specific therapy at this time. Patients with inoperable disease or pulmonary hypertension following thromboendarterectomy, however, should be considered for medical management, with riociguat currently having the strongest evidence specific to CTEPH. Keywords chronic thromboembolic pulmonary hypertension, pulmonary embolism, pulmonary thromboendarterectomy
INTRODUCTION
INCIDENCE AND RISK FACTORS
Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary hypertension characterized by obstruction of the pulmonary vasculature resulting from impaired thrombus resolution and remodeling following acute pulmonary embolism. In comparison to pulmonary arterial hypertension (PAH), there are major differences not only in pathophysiology but also importantly in management, as CTEPH represents a potentially curable form of pulmonary hypertension by pulmonary thromboendarterectomy (PTE, also known as PEA). CTEPH and PAH have similarities, particularly in the realm of small vessel changes; thus, there has been increasing interest in a medical approach for some patients. Recent data support functional and hemodynamic improvements in inoperable or recurrent or persistent pulmonary hypertension patients who are treated with PAH-specific therapies. This article reviews current knowledge of the disease, with a focus on new evidence for the role of medical therapy.
Although the incidence of CTEPH is unknown, the disease is, no doubt, underdiagnosed. In a prospective study by Pengo et al. [1], 3.8% of patients developed symptomatic CTEPH within 2 years of first pulmonary embolism. Subsequent estimates of CTEPH incidence have varied according to study population, with range 0.6–4.6% when diagnosis requires catheterization [2–6]. The risk of developing CTEPH after acute pulmonary embolism is greater in those with recurrent pulmonary
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a
Department of Pulmonary and Critical Care Medicine, Beth Israel Deaconess Medical Center and bDepartment of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA Correspondence to Barbara LeVarge, MD, Department of Pulmonary and Critical Care Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA. Tel: +1 617 667 5864; e-mail: [email protected] Curr Opin Pulm Med 2014, 20:400–408 DOI:10.1097/MCP.0000000000000088 Volume 20 Number 5 September 2014
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CTEPH: evolution in management LeVarge and Channick
KEY POINTS CTEPH is critical to consider in the differential diagnosis of precapillary pulmonary hypertension. Although the pathophysiology of CTEPH remains incompletely understood, it is clear that patients develop both large vessel organized thrombus and microvascular disorder. The radionucleotide ventilation-perfusion scan is the preferred screening test, and pulmonary angiography is used to confirm diagnosis and assess operability. In appropriate surgical candidates, pulmonary thromboendarterectomy improves functional status and exercise capacity and provides a cure for many patients with CTEPH. As some individuals present with inoperable disease or have pulmonary hypertension persisting after thromboendartectomy, an evidence-supported role for medical therapy is emerging.
embolism, unprovoked event, larger clot burden, and younger age [1,2,7]. Other CTEPH case control and cohort studies have identified additional risk factors, including splenectomy [8–10], ventriculoatrial shunts [8,9], infected pacemakers [9], chronic inflammatory conditions [8], non-O blood groups [9,11], thyroid replacement [9], malignancy [9], elevated factor VIII and von Willebrand factor (vWF) levels [12,13], and lupus anticoagulant or antiphospholipid antibodies [9,14].
resistance has also been established in CTEPH [20]. The increased risk of CTEPH in patients with infected pacemakers and ventriculo-atrial shunts may relate to poor resolution of clot in the setting of staphylococcal infection [21]. It is clear that the pathophysiology of CTEPH involves more than simply chronic mechanical obstruction of proximal pulmonary arteries. An important ‘small vessel’ component, with microvascular changes similar to those seen in PAH, is often present in both the unobstructed vascular bed and vessels distal to the chronic obstruction [22]. Blauwet et al. [23] described endarterectomy specimens from 54 patients; organized or organizing thrombus, occasionally of multiple ages, was noted, with intimal findings including collagen and elastin deposition, chronic inflammation, hemosiderin, atherosclerosis, and calcification. A study of 200 patients undergoing PTE revealed non-CTEPH disorder in five patients (pulmonary artery sarcoma in two, metastatic germ cell tumor in one, and arteritis in two patients). In addition to histopathologic changes of the previous study, notable cellularity, particularly in areas of recanalization and rarely associated with cellular atypia, was described [24]. The observed small vessel abnormalities, including intimal thickening, medial hypertrophy, and plexiform lesions, share similarities with PAH of other causes [25 ,26,27]. These disorders are thought to predominate in the small vessels downstream of patent pulmonary arteries, with paucity of vasculature noted distal to vessels occluded by chronic thromboembolism [25 ]. Presence of a large burden of small vessel vasculopathy may limit the degree of hemodynamic improvement that will occur following PTE and serves as the rationale for pulmonary vasodilator therapy in some CTEPH patients. &
&
PATHOPHYSIOLOGY AND DISORDER Although acute pulmonary embolism is a clear risk factor for CTEPH, there remains incomplete understanding of the mechanism behind why a subset of patients do not resolve acute thromboembolism, although most do. Recanalization of the embolic obstruction is an important step in acute pulmonary embolism resolution; this process relies on angiogenesis with new vessel penetration into the thrombus. Paucity of vessels is a feature of endarterectomy specimens, promoting hypothesis of impaired angiogenesis [15]. Abnormal fibrinogens with resistance to lysis also may be important, with demonstration of impaired fibrinolysis and/or fibrinogen gene mutations in some CTEPH patients [16–18]. The role of inflammation in CTEPH is also being investigated. C-reactive protein increases CTEPH but not PAH smooth muscle cell proliferation in vitro, with enhanced inflammatory cell adhesion and endothelin and vWF secretion by endothelial cells [19]. Correlation between monocyte chemoattractant protein-1 levels and pulmonary vascular
CLINICAL FEATURES Most but, importantly, not all CTEPH patients will have history of venous thromboembolism. In the international CTEPH registry, 25% of patients did not have prior history of acute pulmonary embolism [11]. As with other forms of pulmonary hypertension, patients with CTEPH typically present with progressive dyspnea and exercise intolerance. Later symptoms of exertional syncope or edema relate to limitation in exertional right ventricular (RV) output and RV failure. Physical examination findings depend on severity and commonly include jugular venous distension, murmur of tricupsid regurgitation, prominent pulmonic component of S2, RV heave, and edema or ascites. A relatively unique physical finding in CTEPH is the presence
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FIGURE 1. Radionucleotide perfusion scan of a patient with chronic thromboembolic pulmonary hypertension. Numerous perfusion defects, involving all lobes, right lung greater than left, are demonstrated. No defects were seen on the patient’s corresponding ventilation images.
of pulmonary flow ‘bruits’ heard over the posterior lung fields. These bruits are heard in approximately one-third of patients with CTEPH, and when present, generally correlate with operable disease [Channick R, personal communication].
DIAGNOSIS All patients with unexplained pulmonary hypertension should undergo evaluation for CTEPH as the cause, regardless of presence or absence of a history of prior thromboembolic episodes [28]. The radionuclide ventilation-perfusion scan is the screening test of choice to distinguish CTEPH from other forms of pulmonary hypertension (Fig. 1). Tunariu et al. [29] performed a head-to-head comparison of radionuclide ventilation or perfusion and computed tomography angiogram (CTA) in 227 patients, using pulmonary angiography as gold standard. Radionuclide ventilation or perfusion scanning had sensitivity of 96–97% with specificity of 90–95%, whereas sensitivity for CTA was only 51% [29]. Disease confirmation with pulmonary angiography is usually the next step in diagnosis. Typical angiographic features of CTEPH include complete 402
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branch vessel obstructions, pouches, webs, and intimal irregularities (Fig. 2) [30]; location and extent of findings factor into decisions regarding surgical accessibility. Pulmonary angiography also allows for direct hemodynamic assessment when combined with right heart catheterization; severity of pulmonary hypertension provides information regarding surgical risk [31]. Acute response to inhaled nitric oxide (iNO) can also be assessed at this time, with evidence that greater iNO-mediated decrease in mean pulmonary artery pressure (mPAP) corresponds to improved post-PTE outcomes [32]. In some cases, CTA may be sufficient and avoid the need for pulmonary angiography, although right heart catheterization should still be performed. Additional imaging techniques under investigation include dual-energy computed tomography [33] and MRI [34–36]; these may find a larger role in either the screening or diagnosis of CTEPH in the future.
SURGICAL TREATMENT Pulmonary thromboendarterectomy remains the procedure of choice for the treatment of CTEPH. Volume 20 Number 5 September 2014
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FIGURE 2. Anteroposterior and lateral views of the right pulmonary artery on angiography, correlating with the perfusion scan shown in Fig. 1. Pouch defects (shaded arrow) and numerous webs or bands (open arrow) with poststenotic dilatations are noted throughout the right main pulmonary artery and its branches.
The earliest true endarterectomy procedures were performed in the 1960s, with subsequent refinement over the following years [37]. Current techniques utilize median sternotomy, cardiopulmonary bypass, and periods of deep hypothermic circulatory arrest to maintain a bloodless field while endarterectomy is performed (Fig. 3). Recently, some centers have successfully performed PTE using antegrade cerebral perfusion to avoid complete circulatory arrest [38]. However, a recent trial randomizing patients in this regard noted no difference in cognitive function between groups [39]. International registry data demonstrated 4.7% in-hospital mortality in 384 patients between 2007 and 2009 [11]. Recent data from the University of California-San Diego reported mortality of only 2.2% among 500 patients undergoing PTE between 2006 and 2010 [40]. Mortality data vary with center experience, circulatory arrest duration, preoperative 6MWD, and pre and postoperative pulmonary vascular resistance (PVR) [41]. Potential complications of PTE include reperfusion pulmonary edema, persistent pulmonary hypertension, infection, neurologic complications, and pericardial effusion [41,42 ]. Endarterectomy has consistently been associated with impressive improvements in functional class, exercise capacity, and hemodynamics, with immediate normalization of pulmonary artery pressures in many. Of 157 patients analyzed by Corsico et al. [43], prevalence of functional class III/IV shifted from 97% preoperatively to 12% at 3 months postoperative; mean 6MWD increased &
dramatically from 95 to 342 m during that same time period (P < 0.001 for both comparisons). Mayer et al. [41] reported improvement in 6MWD from 362 to 459 m within 1 year of PTE. Recent experience from the San Diego group showed postoperative improvements in mPAP (45.5 to 26.0 mmHg) and cardiac output (4.3 to 5.6l/min) [40]. Improvements in PVR (preoperative to end of ICU stay) from the international registry and San Diego groups were 736 to 248 dyn-s-cm5 and 719 to 253 dyn-s-cm5, respectively [40,41].
PERCUTANEOUS TREATMENT Interventional angioplasty techniques for management of CTEPH were introduced by Feinstein et al. [44] in 2001. Eighteen patients, deemed inoperable because of surgical inaccessibility or comorbid illness, were treated with balloon dilations of affected segments. One patient died, and 11 developed reperfusion pulmonary edema. Improvements in mPAP, 6MWD, and functional class were noted [44]. Several recent series have been published, with consistent reports of hemodynamic improvements, though high rates of reperfusion pulmonary edema and mortality up to 10% in one series [45–47]. Fukui et al. [48] recently reported on 20 patients undergoing balloon angioplasty for inoperable CTEPH, with gains achieved in several parameters, including mPAP, PVR, cardiac index (CI), 6MWD, and cardiac MRI findings. Importantly, no deaths or major complications occurred in this series [48]. Further study in the role of percutaneous techniques in the
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FIGURE 3. Surgical thromboendarterectomy specimens, obtained from same patient whose imaging is shown in Figs 1 and 2. Fibrotic and thrombotic material, extending into segmental pulmonary arteries, was dissected out at the time of surgery.
management of CTEPH is needed, as with refinements in technique and more long-term data, balloon angioplasty may emerge as an effective treatment option when performed by experienced operators in comprehensive centers [49].
Given the availability of several targeted medical therapies for PAH and the similarities in histopathology between PAH and CTEPH, there is strong rationale for utilizing these therapies in patients with inoperable disease or postoperative pulmonary hypertension.
MEDICAL TREATMENT Although CTEPH management is surgical for most patients, increasing evidence for use of medical therapies in this disease is emerging. Medical therapy should not be thought of as a substitute for PTE in appropriate surgical candidates. It should be considered in those with inoperable disease (36.4% of CTEPH patients in an international registry [11]) or recurrence or persistence of pulmonary hypertension following PTE. Although unproven, medical therapy may also have a role in optimizing patients prior to PTE. A management algorithm, presented at the 2013 World Symposium on Pulmonary Hypertension, is shown in Fig. 4 [50 ]. All therapeutic strategies, medical and surgical, must be combined with lifelong anticoagulation with vitamin K antagonists (VKAs), with INR target of 2.0 to 3.0, to prevent new in-situ thrombus formation and embolic disease. As experience with the novel oral anticoagulants in the CTEPH and PAH populations is still quite limited, and as important drug interactions with PAH-specific therapies may exist, it is premature to consider these agents as acceptable alternatives to VKAs [51]. &&
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PROSTANOIDS Intravenous epoprostenol use for inoperable CTEPH was studied retrospectively by Cabrol et al. [52] in 27 patients. After mean followup of 20 months and at mean epoprostenol dose of 30 ng/kg/min, improvements in functional class, hemodynamics, and 6MWD (þ58 m) were seen [52]. Skoro-Sajer et al. [53] studied subcutaneous treprostinil in 28 patients with inoperable or recurrent or persistent CTEPH. Three patients discontinued therapy because of infusion site pain. After mean followup of 19 months and at mean treprostinil dose of 38 ng/kg/ min, significant improvements in CI and PVR (116 dyn-s-cm5) were noted. Improvements in 6MWD (þ 59 m at 6 months), functional class, and brain natriuretic peptide (BNP) levels were reported, and, in comparison to a historical group of CTEPH patients, mortality benefits were also suggested [53].
ENDOTHELIN RECEPTOR ANTAGONISTS The first large double-blind, placebo-controlled clinical trial in CTEPH (BENEFIT) randomized 157 Volume 20 Number 5 September 2014
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CTEPH: evolution in management LeVarge and Channick
CTEPH Diagosis Continue lifelong anticoagulation
Operability assessment by CTEPH team
Non-operable
Operable
Recommend 2nd opinion by experienced center
Pulmonary endarterectomy
Targeted medical therapy
Referral for lung transplantation
Persistent symptomatic pulmonary hypertension
PTPA?
FIGURE 4. Proposed management algorithm for chronic thromboembolic pulmonary hypertension. Presented at the 2013 World Symposium on Pulmonary Hypertension. CTEPH, chronic thromboembolic pulmonary hypertension; PTPA, percutaneous transluminal pulmonary angioplasty. Reproduced with permission from [50 ]. &&
patients with inoperable (72%) or recurrent or persistent CTEPH to bosentan or placebo. The two primary endpoints were change in 6MWD and change in PVR. After 16 weeks, PVR decreased by a mean of 146 dyn-s-cm5 in the treatment group and increased by 30 dyn-s-cm5 in the placebo group, with resulting treatment effect on PVR of 24.1% (P < 0.0001). Effect on 6MWD was only þ 2.2 m, nonsignificant. Differences in CI and BNP were also found, in favor of bosentan [54]. Bosentan use in CTEPH was further evaluated in a meta-analysis by Becattini et al. [55], which included findings from the randomized controlled trial. Eleven papers (269 patients on bosentan therapy) were analyzed. Two hundred thirty patients (85.5%) were inoperable and the remainder had recurrence or persistence following PTE. After 3–6 months of bosentan, a weighted mean increase in 6MWD of 35.9 m (P < 0.001) was observed. The authors further noted positive shifts in functional class and decrease in BNP. Hemodynamic data were available for up to 185 patients; increase in CI of 8% (0.23 l/min/m2) and decrease in mPAP of 5.8% (2.6 mmHg) were both significant. For those with available PVR data (n ¼ 164), there was decrease of 20% (160 dyn-s-cm5) [55]. The ARIES-3 study investigated effects of ambrisentan on a diverse population of patients with pulmonary hypertension, including 29 with CTEPH. Analysis of this subgroup showed mean 17 m improvement in 6MWD, with nonsignificant decrease in BNP, after 24 weeks of therapy [56].
PHOSPHODIESTERASE TYPE-5 INHIBITORS An early uncontrolled study looked at effects of sildenafil in 12 patients with severe inoperable CTEPH over 6 months. Increase in 6MWD (312 to 366 m, P ¼ 0.02) and CI (2.0 to 2.4 l/min/m2, P ¼ 0.009) and decrease in PVR index (1935 to 1361 dyn-s-cm5/m2, P ¼ 0.004) were observed [57]. A subsequent larger study examined 104 inoperable patients over 12 months; the authors demonstrated improvements in similar parameters, including 6MWD (310 to 366 m, P ¼ 0.0005) and hemodynamics [58]. Suntharalingam et al. [59] performed a doubleblind, placebo-controlled pilot study of sildenafil in 19 patients with inoperable or recurrent CTEPH. At 12 weeks, increase in 6MWD was not significant, although there were significant improvements in functional class and PVR. Change to open-label dosing occurred at the conclusion of the trial; after 12 months, patients had favorable change in 6MWD, BNP, CI, and PVR [59].
SOLUBLE GUANYLATE CYCLASE STIMULATORS The only drug that is United States Food and Drug Administration (FDA) approved for patients with CTEPH (inoperable or persistent or recurrent pulmonary hypertension) is riociguat, a novel soluble guanylate cyclase stimulator. Approval of riociguat resulted from the recent CHEST-1 study, a 16-week, phase 3 multicenter double-blind,
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placebo-controlled clinical trial. Two hundred and sixty-one patients with inoperable (72%) or persistent or recurrent CTEPH were randomized to riociguat or placebo. The primary endpoint, change in 6MWD, was significantly improved in the riociguat group compared with placebo (least-squares mean difference 46 m, P < 0.001, Fig. 5). Secondary outcomes were also improved in the riociguat-treated patients, including changes in PVR (mean difference of 246 dyn-s-cm5), BNP, and functional class. Potential adverse effects of note included hypotension, dizziness, headache, dyspepsia, and diarrhea [60 ]. Riociguat is prescribed with a dose-escalation protocol. A treatment dose of 0.5 or 1 mg three times daily is started; provided signs or symptoms of hypotension do not develop, this dose can be increased every 2 weeks to a maximum of 2.5 mg three times daily. Riociguat cannot be taken with nitrates or phosphodiesterase type-5 inhibitors, and it is contra-indicated in pregnancy. &&
MEDICAL THERAPY AS A BRIDGE TO PULMONARY THROMBOENDARTERECTOMY Mortality of PTE is greater in patients with more severe baseline hemodynamic abnormalities. In one large series, those with preoperative PVR more than 1000 dyn-s-cm5 had mortality of 10.1%, compared with 1.3% when PVR was less than 1000 [61]. Concern of high mortality and desire to improve outcomes in these very severe patients led to investigations using medical therapy preoperatively. 406
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Nagaya et al. [62] treated 12 CTEPH patients with PVR more than 1200 dyn-s-cm5 with intravenous epoprostenol, to an average dose of 6 ng/kg/min, for a mean of 46 days prior to PTE. Epoprostenol significantly increased cardiac output and decreased PVR (by 28%), right atrial pressure, and BNP. One patient had persistent pulmonary hypertension postoperatively and died. Bosentan treatment prior to PTE was tested in a controlled study, during which pre-PTE patients were randomized to a 16-week period of bosentan (n ¼ 13) or usual care (n ¼ 12). Hemodynamics and 6MWD improved in those on bosentan prior to surgery; however, PTE outcomes were overall similar between the two groups [63]. Jensen et al. [63] retrospectively reviewed all PTE referrals at a single center between 2005 and 2007 and noted an increasing prevalence of medical therapy use (up to 37% of referrals during 2007). There were no significant differences in outcomes between those with or without preoperative medical therapy. However, those on medical therapy had longer time to referral (8.9 versus 4.4 months, P < 0.01), raising concern that use of medical therapy could delay potentially curative surgery [64].
CONCLUSION CTEPH is an important diagnosis to consider in the evaluation of exertional intolerance and pulmonary hypertension. Most but not all patients have had prior episode of acute pulmonary embolism. In addition to anticoagulation, assessment of candidacy for PTE surgery is key to appropriate management of the CTEPH patient. In operable patients, PTE surgery is unequivocally the treatment of choice and may be curative; percutaneous alternatives are also being investigated. However, as the pathobiology of the disease also includes small vessel vasculopathy similar to PAH and as some patients will be inoperable or have persistent or recurrent pulmonary hypertension despite PTE, there is an emerging role for medical management. Acknowledgements None. Conflicts of interest None declared.
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