Medical Therapy in Chronic Thromboembolic Pulmonary Hypertension

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1 Medical Therapy in Chronic Thromboembolic Pulmonary Hypertension Joanna Pepke-Zaba 1, Xavier Jais 2, and Richard Channick 3 1 Pulmonary Vascular Diseases Unit, Papworth Hospital, Cambridge, United Kingdom; 2 Department of Pulmonology, Bicêtre Hospital, Université Paris Sud, Le Kremlin Bicêtre, France; and 3 Pulmonary Hypertension and Thromboendarterectomy Program, Massachusetts General Hospital, Boston, Massachusetts Abstract Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but life-threatening condition resulting from unresolved thromboembolic obstructions. Pulmonary endarterectomy surgery is currently the standard of treatment, as it is potentially curative; however, not all cases are amenable to surgical intervention due to distal distribution of the organized thromboembolic material or the presence of comorbidities. Up to one-third of patients have persistent or recurrent pulmonary hypertension after pulmonary endarterectomy. In addition to the occlusive organized thromboembolic material, there is a small-vessel vasculopathy in nonoccluded parts of the pulmonary circulation that is histologically similar to that described in pulmonary arterial hypertension. This observation has led to frequent off-license use of approved pulmonary arterial hypertension therapies in CTEPH. Small uncontrolled trials have investigated prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors in CTEPH with mixed results. A phase III study of the endothelin receptor antagonist bosentan met only one of its two coprimary end points. The first large randomized controlled trial showing a positive treatment effect was the Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase Stimulator Trial (CHEST). This study led to the licensing of riociguat for use in inoperable or persistent recurrent CTEPH. Rigorous randomized controlled trials of medical therapy for CTEPH are needed, and several are underway or planned. In the future, outcomes research may be facilitated by identification of novel end points specific to CTEPH. Keywords: pulmonary circulation; thromboembolism; vasodilator agents; riociguat; pulmonary vascular resistance (Received in original form December 8, 2015; accepted in final form March 16, 2016 ) Correspondence and requests for reprints should be addressed to Joanna Pepke-Zaba, M.D., Ph.D., Pulmonary Vascular Diseases Unit, Papworth Hospital, Cambridge CB23 3RE, UK. joanna.pepkezaba@papworth.nhs.uk Ann Am Thorac Soc Vol 13, Supplement 3, pp S248 S254, Jul 2016 Copyright 2016 by the American Thoracic Society DOI: /AnnalsATS AS Internet address: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by the presence of organized fibrous tissue (chronic thromboembolic material) occluding varying degrees of the pulmonary arterial tree (1, 2). When these lesions are surgically accessible, CTEPH is potentially curable by means of pulmonary endarterectomy (3). However, not all cases of CTEPH are amenable to pulmonary endarterectomy, either due to a distal, inaccessible location of the organized thromboembolic material or due to the presence of prohibitive comorbidities. In addition, depending on the definition, between 16.7 and 35% of patients undergoing endarterectomy are left with residual pulmonary hypertension after surgery (4, 5). Patients with nonoperable (6) or residual pulmonary hypertension are likely to carry a worse prognosis. Although the mechanisms of distal disease or residual pulmonary hypertension are not certain, there are data suggesting that a microarteriopathy similar to pulmonary arterial hypertension (PAH) may occur (1, 7). This observation underlies the rationale for treating these patients with PAH therapies. Optimal medical treatment for CTEPH consists of anticoagulants, diuretics, and oxygen in cases of heart failure or hypoxemia. Lifelong anticoagulation is recommended, although no data exist on the efficacy and safety of new oral anticoagulants. In addition to the occlusive organized thromboembolic material, there is a smallvessel vasculopathy in nonoccluded parts of the pulmonary circulation that is histologically similar to that described in PAH (1, 7). These two distinct processes may both contribute to the elevation in pulmonary vascular resistance (8). The small-vessel remodelling is believed to be a secondary process arising from changes to pulmonary artery blood flow and consequent vessel wall tension caused by the more proximal occlusive chronic thromboembolic material (9). Similarities S248 AnnalsATS Volume 13 Supplement 3 July 2016

2 in endothelin 1 biology in idiopathic PAH and CTEPH have been demonstrated (10 12). Moreover, an imbalance between pulmonary artery vasoconstrictors and vasodilators is supported by studies showing that many patients with CTEPH have a positive acute vasoreactive response after a vasodilator challenge (13 17). Two studies investigating the use of nebulized iloprost in CTEPH have reported acute vasoreactive responses after vasodilatory challenges both during preoperative evaluation and when given immediately after pulmonary endarterectomy (18, 19). In a recent publication describing the use of the I-neb Adaptive Aerosol Delivery system, similar acute vasoreactive responses were seen in both disease groups (20). Pulmonary Arterial Hypertension Targeted Therapies in Chronic Thromboembolic Pulmonary Hypertension Current licensed therapies for PAH include: prostanoids, phosphodiesterase type 5 inhibitors, endothelin receptor antagonists, and a soluble guanylate cyclase stimulator. Although there have been favorable results seen in case series and small phase 2 studies in patients with CTEPH, until recently these results have not been replicated in larger phase 3 trials (Table 1). Despite this paucity of trial data, many of these therapies are used off license in the treatment of CTEPH. In the prospective contemporary European and Canadian CTEPH Registry, 37.9% of patients (28.3% in the operable group vs. 53.8% in the nonoperable group) started at least one PAH-targeted therapy at the time of diagnosis (21). PAH-targeted therapy is used in four distinct clinical situations in patients with CTEPH: 1. Distal CTEPH not amenable to pulmonary endarterectomy. 2. Residual pulmonary hypertension after endarterectomy. 3. Nonoperable CTEPH due to medical comorbidities or having surgery declined by the patient. 4. Bridging therapy to endarterectomy in those with hemodynamically severe disease. Determination of operability is subjective and center dependent. Therefore, many clinical trials have grouped together these first three categories even though the pathophysiological processes causing disease is different among them. A few studies also included patients who declined surgery despite having accessible disease (22, 23). Inoperable and Residual Chronic Thromboembolic Pulmonary Hypertension: Retrospective and Open-Label Studies Prostanoids Initial case series describing the use of intravenous prostacyclin included small numbers of patients with CTEPH (24, 25). Two small studies described the use of intravenous epoprostenol in inoperable or residual pulmonary hypertension (26, 27). These studies reported improvements in both hemodynamic parameters and functional status after 3 months of therapy. This was maintained over the period of the observation (median, mo) (26) (Table 1). Ono and colleagues reported improvements in hemodynamic parameters after 2 months of therapy with the orally stable prostacyclin analog beraprost in distal CTEPH compared with patients treated conventionally with anticoagulants (28). In contrast, no significant change in hemodynamic parameters was seen by Vizza and colleagues. However, a significant improvement in 6-minute-walk distance and functional class after 3 months of therapy with beraprost was reported (29). Lang and colleagues reported the use of subcutaneously infused treprostinil in patients with inoperable CTEPH or residual pulmonary hypertension after pulmonary Table 1. Selected noncontrolled studies investigating the efficacy of pulmonary arterial hypertension targeted therapies in chronic thromboembolic pulmonary hypertension Drug Reference Study Design Duration of Follow Up (mo) Patients (n) WHO FC Baseline (m) Effect on Baseline PVR (dyn $ s/cm 5 ) Effect on PVR (%) Intravenous epoprostenol Subcutaneous treprostinil Sildenafil Riociguat Cabrol et al., 2007 (26) Skoro-Sajer et al., 2007 (31) Ghofrani et al., 2003 (32) Hoeper et al., 2005 (35) Hughes et al., 2006 (36) Bonderman et al., 2005 (22) Seyfarth et al., 2007 (59) Post et al., 2009 (60) Ghofrani et al., 2010 (23) Retrospective cohort 3 23 III IV m 2, (i) 221 Prospective cohort 6 25 III IV m Prospective cohort m 1, (i) 230 Prospective cohort 3 19 II IV m Retrospective cohort II IV m Prospective cohort 6 16 II IV m Prospective cohort 6 12 III m 1, Retrospective cohort >24 18 III IV m Prospective cohort 3 42 II III m Definition of abbreviations: = 6-minute-walk distance; (i) = indexed; PVR = pulmonary vascular resistance; WHO FC = World Health Organization functional class. Pepke-Zaba, Jais, and Channick: Therapy in CTEPH S249

3 endarterectomy (30). In this retrospective study, a significant improvement in functional class and 6-minute-walk test was described after 1 year of treatment and was maintained at 36 months. Skoro-Sajer and colleagues compared the outcome of long-term subcutaneous treprostinil therapy to a historical cohort of patients with inoperable CTEPH who did not receive any vasodilator therapy (31). Improvement was reported in hemodynamic parameters along with a survival benefit in the treprostinil group compared with the historical control group (Table 1). Phosphodiesterase 5 Inhibitors The only drug in this class with published data in CTEPH is sildenafil. In an open-label study of 12 patients with distal CTEPH, a significant reduction in pulmonary vascular resistance index and a significant improvement in 6-minute-walk test after 6 months of treatment with sildenafil were observed (32). In a large open-label study of 104 patients with inoperable CTEPH, similar benefits after 3 months of sildenafil therapy were reported (33). The increase in 6-minute-walk distance was maintained after 1 year of therapy, although 7% of these patients required the addition of inhaled iloprost due to clinical worsening (Table 1). Endothelin Receptor Antagonists The only drug in this class with published data in CTEPH is bosentan, a dual endothelin receptor antagonist. Small open-label studies demonstrated improvements in hemodynamic parameters and 6-minutewalk distance after 3 months of therapy with bosentan (22, 34, 35). After these preliminary studies, a multicentre European retrospective cohort of 47 patients with distal CTEPH reported improvement in the 6-minute-walk distance of 52 m at 1 year after bosentan therapy (36). Hirashiki and colleagues retrospectively investigated the functional effect of 3 to 6 months of bosentan on distal CTEPH through cardiopulmonary exercise testing (37). They found that bosentan did not increase peak VO 2 in patients with CTEPH (Table 1). Soluble Guanylate Cyclase Stimulators The first study with riociguat in CTEPH primarily assessed safety and pharmacokinetic outcomes (38). This study was followed up by an uncontrolled openlabel phase II study that showed significant improvements in 6-minute-walk test and hemodynamic parameters (23) (Table 1). Randomized Controlled Trials Prostanoids The Aerosolized Iloprost Randomized Study included 33 patients with CTEPH (39). Although the study reported an overall positive treatment effect, post hoc analysis of CTEPH subgroup showed no difference compared with the placebo control group. Phosphodiesterase 5 Inhibitors In a small double-blind placebo-controlled study of sildenafil in 19 patients with distal CTEPH or residual pulmonary hypertension after pulmonary endarterectomy, the authors found a significant reduction in pulmonary vascular resistance (40). However, there was no statistically significant improvement in 6-minute-walk test distance after 12 weeks of therapy. In the open-label 12-month extension phase of this study, a significant reduction in pulmonary vascular resistance and a significant increase in 6-minute-walk test compared with baseline were demonstrated (Table 2). Endothelin Receptor Antagonists In contrast to sildenafil and prostanoids, the dual endothelin receptor antagonist bosentan was studied in a large double-blind placebo-controlled randomized clinical trial. In the Effects in Inoperable Forms of CTEPH (BENEFiT) study, 157 patients were enrolled and 149 completed 16 weeks of treatment with bosentan or placebo (41). In this study, pulmonary vascular resistance was reduced significantly (2146 dyn $ s/cm 5 ) after16weeksoftherapyinthetreatment group but increased by 30 dyn $ s/cm 5 in the control group. In a subgroup analysis, patients with residual pulmonary hypertension had a larger drop in pulmonary vascular resistance than those with distal CTEPH. However, despite this improvement in hemodynamic parameters in the treatment group, no significant improvement in 6-minute-walk distance was observed at 16 weeks. Adverse events reported in the trial included peripheral edema (13 vs. 7.5% in placebo control group) and abnormal liver function tests (7.8 vs. 1.3%) (Table 2). Soluble Guanylate Cyclase Stimulators The first large randomized controlled trial showing a positive treatment effect in CTEPH was the Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase Stimulator Trial (CHEST1). This study Table 2. Randomized controlled trials investigating the efficacy of pulmonary arterial hypertension targeted therapies in chronic thromboembolic pulmonary hypertension Drug Reference Duration of Follow Up (mo) Patients (n) WHO FC Baseline (m) Effect on P Value Baseline PVR (dyn $ s/cm 5 ) Effect on PVR P Value Sildenafil Riociguat Suntharalingam et al., 2008 (40) Jaïs et al., 2008 (41) Ghofrani et al., 2013 (42) 3 19 II IV * m * 227% II IV * 12.2 m * 224%, II IV * 146 m, * 231%,0.001 Definition of abbreviations: = 6-minute-walk distance; PVR = pulmonary vascular resistance; WHO FC = World Health Organization functional class. *Baseline value in the treatment group. effect of study drug over placebo. S250 AnnalsATS Volume 13 Supplement 3 July 2016

4 result led to the licensing of riociguat for use in nonoperable and residual CTEPH (42). This multicenter placebo-controlled study recruited 261 patients with distal or residual CTEPH. A central adjudication committee prospectively reviewed the patients eligibility before enrollment in the study. In the initial 16-week placebocontrolled phase of the study (CHEST1), patients were titrated up to 2.5 mg three times a day of riociguat, dependent on systemic systolic blood pressure or symptoms of hypotension. The authors reported a placebo-adjusted increase in 6-minute-walk distance of 46 m (95% confidence interval [CI], m) in favor of the treatment group. Subgroup analysis suggested that the improvement in 6-minute-walk distance was greatest in the distal CTEPH group (54 m; 95% CI, m), compared with the residual postoperative group (27 m; 95% CI, 210 to 63 m). Secondary outcomes, including hemodynamic parameters and changes in functional class, were also significantly improved in the treatment group. A composite time to clinical worsening parameter was not significantly different between the two groups (Table 2). Hemoptysis was reported in 2% and hypotension in 9% of patients on riociguat. The CHEST2 study was the open-label, single-group extension phase of the CHEST1 study (43). In this extension study, all eligible patients completing the CHEST1 study were titrated up to a maximum dose of riociguat 2.5 mg three times a day. The maximum dose was achieved for 82% of patients from the CHEST1 treatment group and 90% of the original placebo group. Overall, 237 patients entered CHEST2. At 1 year of CHEST2, mean treatment duration in the trial was 83 weeks, and cumulative treatment exposure was 378 patient-years. The 6-minute-walk distance had changed by 159 (658) m for the former riociguat group (n = 114), 137 m (669) in the former placebo group (n = 58), and 151 m (662) in the overall population (n = 172). Eight (3%) adverse events and four (2%) serious adverse events of hemoptysis, including one fatality, were reported. Hypotension (1%) and syncope (2%) were reported as serious adverse events. An open-label phase 3b long-term surveillance study, the Early Access Study, was initiated to assess the long-term safety and clinical effects of riociguat in a setting more closely related to real-life clinical practice. At the data cutoff, 238 patients had been included in this study, 168 (71%) with inoperable CTEPH and 70 (29%) with persistent or recurrent pulmonary hypertension after endarterectomy (44). Hypotension and hemoptysis were both reported in 1% of patients as serious adverse events. Coadministration of sildenafil and riociguat is now contraindicated due to the increased risk of hemoptysis and hypotension with coadministration (45). In a retrospective exploratory analysis of the CHEST1 data, D Armini and colleagues investigated the effect of riociguat on responder threshold criteria (46). Threshold values of those criteria are associated with clinical response to treatment and correlate with survival in patients with PAH. At baseline, the proportion of patients meeting these threshold criteria was similar. However, at the end of the study, significantly more patients in the riociguat treatment arm met these criteria. Riociguat increased the proportion of patients with a 6-minutewalk distance greater than 380 m, World Health Organization class I or II, and pulmonary vascular resistance less than 500 dyn $ s/cm 5 from 37, 34, and 25% at baseline to 58, 57, and 50% at Week 16, respectively, whereas little change was observed in placebo-treated patients. Bridging Therapy to Pulmonary Endarterectomy A seemingly logical application of medical therapy for CTEPH is a bridging treatment for those patients who await pulmonary endarterectomy. Nagaya and colleagues investigated the use of intravenous prostacyclin in 33 patients with severe CTEPH, a group recognized to be more likely to have distal vasculopathy and a more distal distribution of thromboembolic disease, while waiting for pulmonary endarterectomy (47). After therapy, pulmonary vascular resistance fell by 422 dyn $ s/cm 5. However, no difference in hemodynamic parameters was seen after surgery, suggesting no long-term benefits of bridging therapy with prostacyclin. Bridging therapy with epoprostenol was also investigated in a small case series of nine patients with operable CTEPH. The response to therapy in this study was mixed, with three patients deteriorating clinically (48). Reesink and colleagues studied the effect of bosentan as a bridging therapy to pulmonary endarterectomy (49). In this single blinded randomized controlled trial comparing bosentan to no therapy, 13 patients in the treatment arm significantly improved total pulmonary resistance and 6-minute-walk test after 16 weeks of treatment before surgery compared with no statistical change in the control arm. The authors concluded that bosentan was an effective bridging therapy to endarterectomy. The potential downside of bridging therapy was demonstrated by Jensen and colleagues, who reviewed consecutive patients undergoing endarterectomy at the University of California, San Diego between 2005 and 2007 (50). Of the 355 patients undergoing pulmonary endarterectomy, 111 patients were on medication for PAH before surgery. Patients were divided into those receiving and those not on any bridging therapy targeting PAH. The two groups were well matched hemodynamically, except for a slightly higher mean pulmonary artery pressure in the bridged group than in the control group (50 mm Hg vs. 46 mm Hg; P = 0.02). Although there was a limited decrease in mean pulmonary artery pressure with drug therapy by the time of referral for consideration of surgery, there were no differences in hemodynamic parameters between the two groups after endarterectomy. Importantly, the bridging therapy group had a significantly longer median time to referral for consideration of surgery. Survival in Patients with Chronic Thromboembolic Pulmonary Hyertension Treated Medically: Observational Data Many retrospective studies have investigated the impact of therapies targeting PAH on survival in CTEPH. Some studies compared survival between cohorts treated with conventional therapy and those treated with conventional therapy plus a combination of therapies targeting PAH (51, 52). Others compared PAH-targeted therapy with published results of historical cohorts composed of patients for whom therapy targeted at PAH was not available (53). In a UK-wide study of all patients diagnosed with CTEPH between 2001 and 2006, 3-year survival for those treated with Pepke-Zaba, Jais, and Channick: Therapy in CTEPH S251

5 pulmonary endarterectomy was 76 versus 70% for those treated medically for distal CTEPH (P = 0.023) (5). Since 2003, 90% of patients with distal CTEPH were treated with an off-license either monotherapy or combination of PAH-targeted therapies. There were no significant differences between the two groups with regard to hemodynamic parameters or functional outcomes. A subanalysis comparing those diagnosed within the first 2 years and those diagnosed subsequently showed a significant increase in the use of medications targeted at PAH and improved survival in both the operated and distal CTEPH groups in the later cohort. It should be noted, however, that the earlier distal CTPEH group had a higher proportion of patients in World Health Organization class 4 than the latter group. Therefore, it is difficult to attribute this improvement in survival to just the availability of PAH-targeted therapies. Similarly, in an analysis of survival in inoperable CTEPH, Saouti and colleagues report improved survival in a cohort of patients diagnosed after 2003; again, this later group had better hemodynamic parameters than the historical group (54). Conversely, Nishimura and colleagues showed improved survival in a more contemporary group (5-year survival, 87.3%) compared with an earlier group (5-year survival, 54.6 and 69.7%), even though the contemporary group had more severe hemodynamic parameters (55). They also demonstrated that therapy targeting PAH was an independent predictor of survival. Yoshimi and colleagues reported on survival of patients with potentially operable disease treated with PAH-targeted therapies (because of other factors precluding surgery) compared with those undergoing pulmonary endarterectomy. They found that those patients treated medically had a significantly lower survival rate (P = 0.014) (56). Long-term outcomes of operated versus nonoperated patients are available from the International Prospective Registry. In the registry, 404 (60%) patients underwent surgery. Another 275 (40%) patients did not undergo surgery; 61% of those patients received at least one specific therapy for PAH during follow up. For all patients, the followup period was 3 to 5 years. The nonoperated population was older, was predominantly women, had a lower FEV 1 and a lower 6-minute-walk distance, had less history of acute venous thromboembolism, and had more distal disease on angiography. In contrast, functional class and pulmonary hemodynamic parameters were similar between the two groups. Operated patients had a much better survival (89.3%) than nonoperated patients (70.5%) at 3 years. This difference was maintained after adjustment for age, sex, functional class, pulmonary hemodynamic parameters, and history of cancer (6). Scholzel and colleagues reported on time to clinical worsening in addition to survival in patients with inoperable CTEPH (57). In this study, clinical worsening was defined as death, need for intravenous therapy targeted at PAH, or a 15% drop in 6-minute-walk distance without change in functional class. Scholzel and colleagues reported an overall 3-year survival of 77%, and 3-year freedom from clinical worsening was 60% (57). Those without clinical worsening were also more likely to be on PAH-targeted therapy. Summary Pulmonary endarterectomy remains the treatment of choice for surgically accessible CTEPH. However, in patients who have inaccessible disease or residual pulmonary hypertension after surgery, PAH-targeted therapy may have a role to improve exercise capacity, functional class, and hemodynamics and delay clinical worsening. At present, only one therapy, riociguat, is approved for this indication, although other agents are being studied. There is insufficient evidence to support the use of PAH-targeted therapy as a bridge to pulmonary endarterectomy. Current evidence-based use of PAHtargeted therapy in CTEPH includes patients who are technically nonoperable and those who have persistent or recurrent pulmonary hypertension after pulmonary endarterectomy. The evidence from publish data continues to identify pulmonary endarterectomy as the treatment of choice for the majority of patients with CTEPH. However, there are only a few centers worldwide with the ability and experience to perform pulmonary endarterectomy. As a result, for patients with CTEPH in the regions where surgical management has not been well established, PAH-targeted therapy might be the only choice to improve exercise capacity. Accordingly, recent guidelines for the diagnosis and treatment of pulmonary hypertension also say that off-label use of PAH-targeted therapy may be considered in symptomatic patients who have inoperable CTEPH (58). Future Directions There are currently ongoing or planned randomized controlled trials of other medical therapies in patients with CTEPH. Although clinical trials end points have mirrored those in pulmonary arterial hypertension trials, it is possible that novel end points related to CTEPH will be more revealing. This will allow better predicting and interpreting the effects of interventions, both medical and surgical. In addition, better radiographic techniques and biomarker assessments may help identify patients at risk of small-vessel vasculopathy and residual CTEPH. Through improved phenotyping, we expect to improve risk stratification and allow more personalized management of patients with CTEPH. Further investigation of the effects of PAH-targeted therapies on the right ventricle in CTEPH is required. n Author disclosures are available with the text of this article at References 1 Moser KM, Bloor CM. 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