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Bosentan for patients with chronic thromboembolic pulmonary hypertension
European Journal of Internal Medicine 20 (2009) 24 – 29 www.elsevier.com/locate/ejim
Original article
Bosentan for patients with chronic thromboembolic pulmonary hypertension Fabio Giuseppe Vassallo a , Metka Kodric a , Cleante Scarduelli b , Sergio Harari c , Alfredo Potena d , Angelo Scarda a , Marco Piattella d , Roberto Cassandro c , Marco Confalonieri a,⁎ a
Department of Pneumology, University Hospital of Trieste, Trieste, Italy b Pneumology Unit, Hospital of Bozzolo-Mantova, Mantova, Italy c Department of Pneumology, Hospital S.Giuseppe, Milan, Italy d Respiratory Unit, Arcispedale S.Anna, Ferrara, Italy
Received 18 August 2007; received in revised form 28 November 2007; accepted 9 March 2008 Available online 29 April 2008
Abstract Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive disease leading to worsening functional status and reduced survival for those patients who cannot undergo pulmonary endarterectomy (PEA). Pharmacotherapy with novel drugs for pulmonary hypertension may be useful in treating patients who are poor candidates for surgery, but there are still few clinical data on medical therapy for CTEPH. The aim of this prospective open-label, multicenter, study is to compare the efficacy of 1-year bosentan treatment to standard drugs in nonoperated patients with CTEPH. Patients and methods: Thirty-four nonoperated patients with CTEPH were enrolled. Functional assessment included 6 minute walk test (6MWT), Borg index, WHO classification, arterial blood gases and echocardiography systolic pulmonary artery pressure (sPAP). Seventeen patients received bosentan (62.5 mg bid for 4 weeks and then 125 mg bid); 17 patients were treated with standard therapy alone. Results: At admission sPAP was 76.18 +/− 5.96 mmHg in bosentan group and 71.48 +/− 3.71 mmHg in controls, paO2 64.68 +/− 2.25 mmHg in bosentan group, and 59.52 +/− 2.05 mmHg in controls, 6MWT 297.53 +/− 34.25 mt in bosentan group, and 268.47 +/− 36.54 mt in controls. After 12 months there were significant differences between the groups in the 6MWT (+ 57.24 +/− 22.21 m vs −73.13 +/− 21.23 m, p b 0.001), dyspnoea index (Borg score 4.29 +/− 0.49 vs 7.06 +/− 0.32, p b 0.001) and oxygenation (paO2 65.93 +/− 3.76 mmHg vs 48.48 +/ − 1.31 mmHg, p b 0.001). The sPAP was stable after 12 months of bosentan (76.18 +/− 5.96 mmHg vs 71.00 +/− 5.41 mmHg, p = 0.221) in contrast to controls (71.48 +/− 3.71 mmHg vs 80.44 +/− 4.70 mmHg, p = 0.029). Conclusion: The data of this open-label study in nonoperated CTEPH patients suggest an improvement in functional outcomes adding Bosentan to diuretics and oral anticoagulants. No improvement was observed using only standard drugs after 1-year. © 2008 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. Keywords: Chronic thromboembolic pulmonary hypertension; Bosentan; Endothelin; Pulmonary hypertension; Thromboembolism; Six-minutes walking test
1. Introduction Chronic thromboembolic pulmonary hypertension (CTEPH) is a major although underdiagnosed cause of ⁎ Corresponding author. Department of Pulmonology (SC Pneumologia), University Hospital of Trieste, Strada di Fiume 447, 34100 Trieste, Italy. Tel.: +39 0403994665; fax: +39 0403994668. E-mail address: [email protected] (M. Confalonieri).
progressive elevation of pulmonary arterial pressure and vascular resistances, ultimately leading to right ventricular dysfunction and death [1–3]. Vascular re-canalization by pulmonary endarterectomy (PEA) is the elective treatment when the thrombi are accessible and there is no serious concomitant lung disease, but not all the patients are eligible for surgery [4]. Nonoperated patients are usually treated only with oral anticoagulation, diuretics and supplemental oxygen for
0953-6205/$ - see front matter © 2008 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2008.03.008
F.G. Vassallo et al. / European Journal of Internal Medicine 20 (2009) 24–29
hypoxemia with poor results [5–7], although generally progression to death is more slowly than idiopathic pulmonary hypertension [8]. The availability of novel drugs for pulmonary hypertension may represent a useful therapeutic alternative in treating patients who are poor candidates for surgery, but there are still few clinical data on pharmacotherapy, most of them from retrospective and uncontrolled studies [9]. The aim of this prospective, multicentre, open-label study is to compare the one-year efficacy of bosentan plus standard therapy to standard therapy alone in patients with inoperable CTEPH. 2. Materials and methods 2.1. Setting The multicenter study was conducted in four Pulmonary Hospital Units in Northern Italy (Department of Pulmonology, University Hospital, Trieste; Department of Pulmonology, San Giuseppe Hospital, Milan, Department of Pulmonology, General Hospital, Mantova; Department of Respiratory Disease, University Hospital, Ferrara) in the period from March 2005 to March 2007. 2.2. Study design and diagnostic procedures This open-label, prospective, nonrandomized study enrolled consecutive symptomatic patients with inoperable CTEPH and WHO class [8] II to IV comparing bosentan plus conventional drug therapy to conventional therapy alone. Patients were assigned to treatment with bosentan or standard therapy according to the local policy about the use of bosentan for CTEPH, that was different in the Centres involved into the study (Milan and Trieste allowed the use of bosentan for CTEPH, whilst Ferrara and Mantova did not). The diagnosis of CTEPH was established by echocardiography and ventilation/perfusion lung scanning and/ or multislice computed tomography. Pulmonary angiography and right heart catheterization were not mandatory for each patient. Nevertheless, they were regularly performed when needed to clarify the diagnosis of proximal clot load and operability. Inclusion criteria were a systolic pulmonary arterial pressure (sPAP) of more than 40 mmHg as estimated by Doppler echocardiography, and the absence of other diseases known to cause or to be associated with secondary pulmonary hypertension as for example severe obstructive lung disease with a FEV1/FVC ratio of less than 0.5 after bronchodilator, or idiopathic pulmonary fibrosis diagnosed according the ATS/ERS criteria [10]. Patients should have no liver laboratory abnormalities or any contraindication or known or suspected hypersensitivity to bosentan. Prior to enrolment pulmonary endarterectomy was discussed by a panel of experts (surgeons, radiologists and pneumologists) and excluded in case of diffuse peripheral
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localization of thrombi, important co-morbidity or patient refusal, otherwise patients were referred to surgery. At baseline, all patients underwent physical examination, determination of World Health Organization (WHO) functional classification [8], appropriate imaging, echocardiography, ECG, 6-min walking test [11], pulmonary function testing [12] with the assessment of maximal expiratory flowvolume loops, lung volumes, total lung capacity and measures of carbon monoxide (CO) transfer [13], arterial blood gas analysis and laboratory assessment of liver function. Patients who understood and agreed with the purpose of the study were enrolled and gave their written informed consent, developed in conformity with the Hospital Ethic Committees. Bosentan group patients received bosentan (62.5 mg orally bid for the first 4 weeks and then 125 mg bid) associated to standard therapy (oral anticoagulation, diuretics and supplemental oxygen for hypoxemia). Liver function tests were checked on a monthly basis and every 2 weeks after any increased of bosentan dose. Bosentan doses were reduced when significant liver dysfunction occurred i.e. sustained increase of transaminases more than 3 times the upper limit of the normal range (ULN) or the drug was discontinued if it recurred after restarting the drug. Control group patients were treated with standard therapy alone: oral anticoagulation, diuretics and supplemental oxygen for hypoxemia. The primary end-points were those of the 6 minutes walking test, functional WHO class, and baseline arterial oxygenation after 1 yr treatment; the secondary end-point was the assessment of systolic PAP by echocardiography after 1 yr treatment. The primary and secondary outcome variables were reassessed after 3, 6 and 12 months in both groups. Patients were asked to refer to our centres for any health problem in order not to miss any adverse effect during the treatment. 2.3. Statistical analysis Analysis was performed using Statview for Windows (Version 5.0.1., SAS Institute Inc., SAS Campus Drive, Cary, NC 27513) and MedCalc (Version 7.2.1.0, MedCalc Software, Mariakerke, Belgium). Data were expressed as mean and standard error of the mean (SEM). The Wilcoxon rank test was used to compare the baseline, and 3-month, 6month and 12-month variables within the two groups. The comparisons of the variables between the two groups were performed using the Mann–Whitney test. Categorical data were analyzed by the Chi-square test. A p-value of less than 0.05 was considered significant. 3. Results Seventy-one patients with secondary pulmonary hypertension were diagnosed during the study period. Thirty-
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Table 1 Patients' characteristics at baseline
Number Age, years Female/male WHO class II/III/IV, n° 6 MWT, m 6 MWT, % of predicted by sex (F/M)30 sPAP, mmHg paO2, mmHg SaO2, % Borg score after 6MWT INR
Bosentan group
Control group
p-value
17 64.88 (46–83) 15/2 1/14/2 297.53 ± 34.25 58.37/58.62
17 62.78(26–79) 8/9 3/12/2 268.47 ± 36.54 46.80/51.57
NA 0.6098 0.0103 0.5616 0.5658 NA
76.18 ± 5.96 64.68 ± 2.25 93.04 ± 0.80 5.59 ± 0.50 2.6 ± 0.3
71.48 ± 3.71 59.52 ± 2.05 89.57 ± 0.74 5.77 ± 0.43 2.5 ± 0.4
0.5081 0.0994 0.0032 0.7898 0.8429
Normal values, adjusted for sex, of the 6-minute walking test are obtained from reference [30]. Data are presented as mean (range) or mean ± SEM. NA = not applicable or not assessed. WHO: World Health Organization; 6 MWT: 6-minute walking test; sPAP: systolic pulmonary artery pressure; paO2: partial arterial oxygen pressure; SaO2: arterial oxygen saturation; INR: International Normalized Ratio of prothrombin time.
three patients were excluded from the study by other diseases known to cause secondary hypertension: 10 patients had COPD, 8 patients had connective tissue disease, 1 patient had congenital heart disease, 9 patients had idiopathic pulmonary fibrosis, 1 patient with sarcoidosis. Other 9 patients were excluded by the study because they were found suited for PEA. Thirty-four patients with CTEPH were enrolled in the study and 17 (50%) were commenced on bosentan; the other 17 (50%) patients were included in the control group. We collected data from all of the patients with only one exception; 1 patient (2.94%) in the control group died during the study at month 10 for acute myocardial infarction and heart failure. Patients' characteristics in the two groups are listed in Table 1. All procedures were performed by all the patients except for the one patent who died after 10 months failing to follow assessment at 12 months. Two patients (11.76% of the bosentan group) experienced a significant transaminases elevation respectively at month 2 and month 10 and dis-
Fig. 2. Progression of 6MWT in the two groups. Data are expressed as mean and bars represent standard error of the mean (SEM).
continued the study drug until the values normalized. Baseline data were not significantly different in the two groups, but we observed a significant prevalence of females in the bosentan group (p = 0.010). From month 6 to month 12 the two groups showed significant changes in the following parameters: 6MWT distance (347 ± 35 m vs. 220 ± 31 m, respectively in the bosentan group and controls, p = 0.012), paO2 (64.0 ± 4.1 mmHg vs. 53.1 ± 1.3 mmHg, respectively bosentan-treated patients and controls, p = 0.016), and Borg's dyspnea score (4.5 ± 0.3 vs. 6.3 ± 0.3, bosentan vs. controls, p = 0.001). A significant improvement in the functional class in the bosentan group was observed after 1 yr of treatment (p = 0.027) while it was deteriorated in the control group (Fig. 1). There was a progressive improvement in the 6MWT distance from baseline to month 12 (+ 57 ± 22 m, p = 0.023) in the bosentan group; whilst, in the control group there was a worsening performance from baseline to month 12 (− 73 ± 21 m, p = 0.001) (Fig. 2). The perception of dyspnoea was progressively improved in the bosentan group from baseline to month 12 (4.29 ± 0.49 after 1 year, p = 0.048); whilst in the control group there was a worsening (7.06 ± 0.32, p = 0.029) (Fig. 3). A significantly different trend of oxygenation from month 3 to month 12 was observed in the two group of treatment. The bosentan group showed a stabilization in the
Fig. 1. Comparison of WHO classes in the two groups at baseline and after 12 months.
F.G. Vassallo et al. / European Journal of Internal Medicine 20 (2009) 24–29
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Fig. 3. Borg dyspnoea score in the two groups. Data are expressed as mean and bars represent standard error of the mean (SEM).
paO2 from baseline to month 12 (65.93 ± 3.76 mmHg, p = 0.786); while in the control group the values fell from baseline to 1-year (48.48 ± 1.31 mmHg, p b 0.001)(Fig. 4). Comparable results were observed after 12 months for the SaO2 (91.69 ± 1.26 vs 83.18 ± 1.09 in the bosentan group and control group, respectively, p b 0.001). The systolic pulmonary artery pressure (PAPs) in the bosentan group remained stable, even showing a slight improvement, from baseline at month 3 (67.40 ± 6.93 mmHg, p = 0.474), month 6 (66.93 ± 5.42 mmHg, p = 0.310) and month 12 (71.00 ± 5.41 mmHg, p = 0.221). In the control group sPAP worsened from baseline to month 3 (76.86 ± 6.37 mmHg, p = 0.620), month 6 (76.69 ± 4.24 mmHg, p = 0.005) and month 12 (80.44 ± 4.70 mmHg, p = 0.029) (Fig. 5). 4. Discussion The results of our study suggest that nonoperated patients with CTEPH could benefit treatment with bosentan plus conventional therapy. In fact, 1-yr bosentan therapy seems to slow the functional deterioration and disease progression in CTEPH patients whilst medical conventional therapy alone did not. Only the bosentan therapy improved 6-min walking distance, oxygenation, Borg dyspnea index, and WHO functional class, whilst the not-bosentan cohort did not improve after 1-year. Bosentan was well tolerated and no
Fig. 4. Oxygenation at rest (paO2 in mmHg) in the two groups. Data are expressed as mean and bars represent standard error of the mean (SEM).
Fig. 5. Systolic pulmonary artery pressure (sPAP) in the two groups. Data are expressed as mean and bars represent standard error of the mean (SEM).
patient had to stop treatment definitely because of adverse effects. Only two patients experienced transient transaminases elevation and had to taper temporarily the dose. Our results are in accordance with other previous uncontrolled studies [14–17]. Surgical pulmonary endarterectomy (PEA) is the elective treatment when the thrombi are accessible and there is no serious concomitant lung disease [18,19], with a peri-operative mortality rate of 5–11%, which is directly proportionate to preoperative pulmonary vascular resistances [20]. Untreated patients have a poor outcome with 90% mortality rate after 5 years from the diagnosis if the mean pulmonary artery pressure is superior to 30 mmHg [21]. Furthermore, there is an inverse correlation between survival and the degree of pulmonary hypertension at presentation [21]. Also CTEPH-predisposing medical conditions and chronic inflammatory disorders may influence prognosis negatively [21–23]. Nevertheless, the use of bosentan in nonoperated patients with CTEPH may have a pathopysiologic rationale [22]. The secondary arteriopathy that develops in CTEPH is similar to that seen in idiopathic pulmonary hypertension [6]. As in other forms of severe pulmonary hypertension, the endothelin system is activated in patients with CTEPH and may contribute to pulmonary vasoconstriction as well as vascular remodelling [24,25]. Plasma levels of endothelin-1 are elevated in this group of patients, and upregulation of type B endothelin receptors on pulmonary arterial smooth muscle cells has been demonstrated [7]. A substantial proportion of patients with CTEPH is considered inoperable due to significant distal thromboembolic pathology, or is classified as representing poor candidacy for PEA surgery due to concomitant vascular arteriopathy [22,26]. Patients in the latter group often suffer from persistent or residual pulmonary hypertension (PH) after PEA [27,28]. Although there is no doubt that eligible patients with CTEPH should undergo PEA, it is currently uncertain how to best manage patients with surgically inaccessible or otherwise inoperable disease. Medical therapies currently used in the management of post-pulmonary embolism patients (anticoagulants, diuretics, digitalis, calcium-channel
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blockers) do not affect underlying disease processes in CTEPH. Current recommended treatment of post-pulmonary embolism patients includes the life-long administration of anticoagulant therapy to reduce the risk of recurrent pulmonary embolism, but this therapy does not seem to influence survival given the reported 3-yr mortality of 90% in cases with severe pulmonary hypertension [21]. Advanced medical therapies acting on relevant underlying mechanisms of disease may have a rational role and provide functional benefits in CTEPH as shown in idiopathic pulmonary artery hypertension [22]. The results of our study suggest that the treatment with the oral dual endothelin receptor antagonist bosentan may represent a beneficial alternative in nonoperated CTEPH patients, especially with regard to oxygenation that did not worsen during a 1-year treatment period. The effect of bosentan on systolic pulmonary artery pressure seems to lead to a substantial stabilization, whilst conventional drug therapy alone failed to stop pulmonary artery pressure progressive increase. The limitations of this study are the lack of a double-blind randomized placebo-controlled design, the lack of scheduled invasive haemodynamic assessment and pulmonary angiography for every patient. Right heart catheterization remains the gold standard for the diagnosis of pulmonary hypertension [22], but Doppler echocardiography has already been used with reliable results to monitor the efficacy of specific therapeutic intervention in patients with pulmonary hypertension [29,30]. Moreover, all the patients in our study had a very high systolic PAP (mean 70 mmHg), making us enough confident to exclude false positive cases, even if PAP was assessed by echo without a direct haemodynamic measurement. Comparable results to ours were also obtained in other, open-label, uncontrolled studies showing an average increase of 6-min walking distance from 73 m to 54 m respectively after 3 and 6 months of bosentan [14,15,24]. In conclusion, the data of this study suggest that bosentan added to standard therapy may improve the functional outcomes of patients with CTEPH, so representing a safe and effective therapeutic option when PEA cannot be performed. 5. Learning points • Chronic thromboembolic pulmonary artery hypertension (CTEPH) is a progressive disease leading to worsening functional status and reduced survival to those patients who cannot undergo surgical pulmonary endarterectomy (PEA). • Unfortunately, there are several patients with CTEPH who are not eligible for PEA. • Data on alternative therapies to PEA for patients with inoperable CTEPH are limited in the literature. • This study suggests bosentan as an effective treatment for nonoperated CTEPH patients. Bosentan improves exercise capacity, dyspnoea index, oxygenation and slowed haemodynamic deterioration in CTEPH patients who cannot undergo PEA.
References [1] Fedullo PF, Auger WR, Kerr RM, Rubin LJ. Chronic thromboembolic pulmonary hypertension. N Engl J Med 2001;345(20):1465–72. [2] Pengo V, Lensing AWA, Prins MH, Marchiori A, Davidson BL, Tiozzo F, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004;350:2257–64. [3] Doyle RL, MacCrory D, Chennick RN, Simonneau G, Conte J. Surgical treatment/interventions for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004;126:63s–71s. [4] Dartevelle P, Fadel E, Mussot S, Chapelier A, Hervé P, de Perrot M, et al. Chronic thromboembolic pulmonary hypertension. Eur Respir J 2004;23(4):637–48. [5] Ulrich S, Speich R, Domenighetti G, Geiser T, Aubert JD, Rochat T, et al. Bosentan therapy for chronic thromboembolic pulmonary hypertension. A national open label study assessing the effect of bosentan on haemodynamics, exercise capacity, quality of life, safety and tolerability in patients with chronic thromboembolic pulmonary hypertension (BOCTEPH-Study). Swiss Med Wkly 2007;137:573–80. [6] Kunieda T, Nakanishi N, Satoh T, Kyotani S, Okano Y, Nagaya N. Prognoses of primary pulmonary hypertension and chronic major vessel thromboembolic pulmonary hypertension determined from cumulative survival curves. Intern Med 1999;38:543–6. [7] Suntharalingam J, Machado RD, Sharples LD, Toshner MR, Sheares KK, Hughes RJ, et al. Demographic features, BMPR2 status and outcomes in distal chronic thromboembolic pulmonary hypertension. Thorax 2007;62:617–22. [8] Barst RJ, McGoon M, Torbicki A, Sitbon O, Krowka MJ, Olschewski H, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:S40–7. [9] Bresser P, Pepke-Zaba J, Jaïs X, Humbert M, Hoeper MM. Medical therapies for chronic thromboembolic pulmonary hypertension. Proc Am Thorac Soc 2006;3(7):594–600. [10] American Thoracic Society and European Respiratory Society. Idiopathic pulmonary fibrosis: diagnosis and treatment; international consensus statement. Am J Respir Crit Care Med 2000;161:646–64. [11] ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002;166:111–7. [12] American Thoracic Society. Lung function testing: selection of reference values and interpretative strategies. Am Rev Respir Dis 1991;144:1202–18. [13] ATS statement single-breath carbon monoxide diffusing capacity (transfer factor). Recommendations for a standard technique-1995 update. Am J Respir Crit Care Med 1995;152:2185–98. [14] Hoeper MM, Kramm T, Wilkens H, Schulze C, Schafers HJ, Welte T, et al. Bosentan therapy for inoperable chronic thromboembolic pulmonary hypertension. Chest 2005;128:2363–7. [15] Bonderman D, Nowotny R, Skoro-Sajer N, Jakowitsch J, Adlbrecht C, Klepetko W, et al. Bosentan therapy for inoperable chronic thromboembolic pulmonary hypertension. Chest 2005;128:2599–603. [16] Hughes RJ, Jais X, Bonderman D, Suntharalingam J, Humbert M, Lang I, et al. The efficacy of bosentan in inoperable chronic thromboembolic pulmonary hypertension: a 1-year follow-up study. Eur Respir J 2006;28:138–43. [17] Seyfarth HJ, Hummerschmidt S, Pankau H, Winkler J, Wirtz H. Long-term bosentan in chronic thromboembolic pulmonary hypertension. Respiration 2007;74(3):287–92. [18] Jamieson SW, Kapelanski DP, Sakakibara N, Manecke GR, Thistlethwaite PA, Kerr KM, et al. Pulmonary endarterectomy: experience and lessons learned in 1500 cases. Ann Thorac Surg 2003;76:1457–62. [19] Jamieson SW. Pulmonary thromboendarterectomy. Heart 1998;79: 118–20. [20] Moser KM, Auger WR, Fedullo PF. Chronic major-vessel thrombotic pulmonary hypertension. Circulation 1990;81:1735–43. [21] Riedel M, Stanek V, Widinsky J, Prerovsky I. Long term follow-up of patients with pulmonary thromboembolism: late prognosis and evolution of hemodynamic and respiratory data. Chest 1982;81:151–8.
F.G. Vassallo et al. / European Journal of Internal Medicine 20 (2009) 24–29 [22] Hoeper MM, Mayer E, Simonneau G, Rubin LJ. Chronic thromboembolic pulmonary hypertension. Circulation 2006;113:2011–20. [23] Kim NH, Fesler P, Channick RN, Knowlton KU, Ben-Yehuda O, Lee SH, et al. Preoperative partitioning of pulmonary vascular resistance correlates with early outcome after thromboendarterectomy for chronic thromboembolic pulmonary hypertension. Circulation 2004;109:18–22. [24] Reesink HJ, Meijer RC, Lutter R, Boosma F, Jansen HM, Kloek JJ, et al. Hemodynamic and clinical correlates of endothelin-1 in chronic thromboembolic pulmonary hypertension. Circulation J 2006;8:1058–63. [25] Bauer M, Wilkens H, Langer F, Schneider SO, Lausberg H, Schäfers HJ. Selective upregulation of endothelin B receptor gene expression in severe pulmonary hypertension. Circulation 2002;105:1034–6. [26] Bonderman D, Skoro-Sajer N, Jakowitsch J, Adlbrecht C, Dunkler D, Taghavi S, et al. Predictors of outcome in chronic thromboembolic pulmonary hypertension. Circulation 2007;115:2153–8.
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[27] Archibald CJ, Auger WR, Fedullo PF, Channick RN, Kerr KM, Jamieson SW, et al. Long-term outcome after pulmonary thromboendarterectomy. Am J Respir Crit Care Med 1999;160:523–8. [28] McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation 2006;114:1417–31. [29] Hinderliter AL, Willis 4th PW, Barst RJ, Rich S, Rubin LJ, Badesch DB, et al. Effects of long-term infusion of prostacyclin (epoprostenol) on echocardiographic measures of right ventricular structure and function in primary pulmonary hypertension. Circulation 1997;95:1479–86. [30] Galie N, Humbert M, Vachiery JL, Vizza CD, Kneussl M, Manes A, et al, Arterial Pulmonary Hypertension and Beraprost European (ALPHABET) Study Group. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized doubleblind, placebo-controlled trial. J Am Coll Cardiol 2002;39:1496–502.
Original article
Bosentan for patients with chronic thromboembolic pulmonary hypertension Fabio Giuseppe Vassallo a , Metka Kodric a , Cleante Scarduelli b , Sergio Harari c , Alfredo Potena d , Angelo Scarda a , Marco Piattella d , Roberto Cassandro c , Marco Confalonieri a,⁎ a
Department of Pneumology, University Hospital of Trieste, Trieste, Italy b Pneumology Unit, Hospital of Bozzolo-Mantova, Mantova, Italy c Department of Pneumology, Hospital S.Giuseppe, Milan, Italy d Respiratory Unit, Arcispedale S.Anna, Ferrara, Italy
Received 18 August 2007; received in revised form 28 November 2007; accepted 9 March 2008 Available online 29 April 2008
Abstract Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive disease leading to worsening functional status and reduced survival for those patients who cannot undergo pulmonary endarterectomy (PEA). Pharmacotherapy with novel drugs for pulmonary hypertension may be useful in treating patients who are poor candidates for surgery, but there are still few clinical data on medical therapy for CTEPH. The aim of this prospective open-label, multicenter, study is to compare the efficacy of 1-year bosentan treatment to standard drugs in nonoperated patients with CTEPH. Patients and methods: Thirty-four nonoperated patients with CTEPH were enrolled. Functional assessment included 6 minute walk test (6MWT), Borg index, WHO classification, arterial blood gases and echocardiography systolic pulmonary artery pressure (sPAP). Seventeen patients received bosentan (62.5 mg bid for 4 weeks and then 125 mg bid); 17 patients were treated with standard therapy alone. Results: At admission sPAP was 76.18 +/− 5.96 mmHg in bosentan group and 71.48 +/− 3.71 mmHg in controls, paO2 64.68 +/− 2.25 mmHg in bosentan group, and 59.52 +/− 2.05 mmHg in controls, 6MWT 297.53 +/− 34.25 mt in bosentan group, and 268.47 +/− 36.54 mt in controls. After 12 months there were significant differences between the groups in the 6MWT (+ 57.24 +/− 22.21 m vs −73.13 +/− 21.23 m, p b 0.001), dyspnoea index (Borg score 4.29 +/− 0.49 vs 7.06 +/− 0.32, p b 0.001) and oxygenation (paO2 65.93 +/− 3.76 mmHg vs 48.48 +/ − 1.31 mmHg, p b 0.001). The sPAP was stable after 12 months of bosentan (76.18 +/− 5.96 mmHg vs 71.00 +/− 5.41 mmHg, p = 0.221) in contrast to controls (71.48 +/− 3.71 mmHg vs 80.44 +/− 4.70 mmHg, p = 0.029). Conclusion: The data of this open-label study in nonoperated CTEPH patients suggest an improvement in functional outcomes adding Bosentan to diuretics and oral anticoagulants. No improvement was observed using only standard drugs after 1-year. © 2008 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. Keywords: Chronic thromboembolic pulmonary hypertension; Bosentan; Endothelin; Pulmonary hypertension; Thromboembolism; Six-minutes walking test
1. Introduction Chronic thromboembolic pulmonary hypertension (CTEPH) is a major although underdiagnosed cause of ⁎ Corresponding author. Department of Pulmonology (SC Pneumologia), University Hospital of Trieste, Strada di Fiume 447, 34100 Trieste, Italy. Tel.: +39 0403994665; fax: +39 0403994668. E-mail address: [email protected] (M. Confalonieri).
progressive elevation of pulmonary arterial pressure and vascular resistances, ultimately leading to right ventricular dysfunction and death [1–3]. Vascular re-canalization by pulmonary endarterectomy (PEA) is the elective treatment when the thrombi are accessible and there is no serious concomitant lung disease, but not all the patients are eligible for surgery [4]. Nonoperated patients are usually treated only with oral anticoagulation, diuretics and supplemental oxygen for
0953-6205/$ - see front matter © 2008 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2008.03.008
F.G. Vassallo et al. / European Journal of Internal Medicine 20 (2009) 24–29
hypoxemia with poor results [5–7], although generally progression to death is more slowly than idiopathic pulmonary hypertension [8]. The availability of novel drugs for pulmonary hypertension may represent a useful therapeutic alternative in treating patients who are poor candidates for surgery, but there are still few clinical data on pharmacotherapy, most of them from retrospective and uncontrolled studies [9]. The aim of this prospective, multicentre, open-label study is to compare the one-year efficacy of bosentan plus standard therapy to standard therapy alone in patients with inoperable CTEPH. 2. Materials and methods 2.1. Setting The multicenter study was conducted in four Pulmonary Hospital Units in Northern Italy (Department of Pulmonology, University Hospital, Trieste; Department of Pulmonology, San Giuseppe Hospital, Milan, Department of Pulmonology, General Hospital, Mantova; Department of Respiratory Disease, University Hospital, Ferrara) in the period from March 2005 to March 2007. 2.2. Study design and diagnostic procedures This open-label, prospective, nonrandomized study enrolled consecutive symptomatic patients with inoperable CTEPH and WHO class [8] II to IV comparing bosentan plus conventional drug therapy to conventional therapy alone. Patients were assigned to treatment with bosentan or standard therapy according to the local policy about the use of bosentan for CTEPH, that was different in the Centres involved into the study (Milan and Trieste allowed the use of bosentan for CTEPH, whilst Ferrara and Mantova did not). The diagnosis of CTEPH was established by echocardiography and ventilation/perfusion lung scanning and/ or multislice computed tomography. Pulmonary angiography and right heart catheterization were not mandatory for each patient. Nevertheless, they were regularly performed when needed to clarify the diagnosis of proximal clot load and operability. Inclusion criteria were a systolic pulmonary arterial pressure (sPAP) of more than 40 mmHg as estimated by Doppler echocardiography, and the absence of other diseases known to cause or to be associated with secondary pulmonary hypertension as for example severe obstructive lung disease with a FEV1/FVC ratio of less than 0.5 after bronchodilator, or idiopathic pulmonary fibrosis diagnosed according the ATS/ERS criteria [10]. Patients should have no liver laboratory abnormalities or any contraindication or known or suspected hypersensitivity to bosentan. Prior to enrolment pulmonary endarterectomy was discussed by a panel of experts (surgeons, radiologists and pneumologists) and excluded in case of diffuse peripheral
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localization of thrombi, important co-morbidity or patient refusal, otherwise patients were referred to surgery. At baseline, all patients underwent physical examination, determination of World Health Organization (WHO) functional classification [8], appropriate imaging, echocardiography, ECG, 6-min walking test [11], pulmonary function testing [12] with the assessment of maximal expiratory flowvolume loops, lung volumes, total lung capacity and measures of carbon monoxide (CO) transfer [13], arterial blood gas analysis and laboratory assessment of liver function. Patients who understood and agreed with the purpose of the study were enrolled and gave their written informed consent, developed in conformity with the Hospital Ethic Committees. Bosentan group patients received bosentan (62.5 mg orally bid for the first 4 weeks and then 125 mg bid) associated to standard therapy (oral anticoagulation, diuretics and supplemental oxygen for hypoxemia). Liver function tests were checked on a monthly basis and every 2 weeks after any increased of bosentan dose. Bosentan doses were reduced when significant liver dysfunction occurred i.e. sustained increase of transaminases more than 3 times the upper limit of the normal range (ULN) or the drug was discontinued if it recurred after restarting the drug. Control group patients were treated with standard therapy alone: oral anticoagulation, diuretics and supplemental oxygen for hypoxemia. The primary end-points were those of the 6 minutes walking test, functional WHO class, and baseline arterial oxygenation after 1 yr treatment; the secondary end-point was the assessment of systolic PAP by echocardiography after 1 yr treatment. The primary and secondary outcome variables were reassessed after 3, 6 and 12 months in both groups. Patients were asked to refer to our centres for any health problem in order not to miss any adverse effect during the treatment. 2.3. Statistical analysis Analysis was performed using Statview for Windows (Version 5.0.1., SAS Institute Inc., SAS Campus Drive, Cary, NC 27513) and MedCalc (Version 7.2.1.0, MedCalc Software, Mariakerke, Belgium). Data were expressed as mean and standard error of the mean (SEM). The Wilcoxon rank test was used to compare the baseline, and 3-month, 6month and 12-month variables within the two groups. The comparisons of the variables between the two groups were performed using the Mann–Whitney test. Categorical data were analyzed by the Chi-square test. A p-value of less than 0.05 was considered significant. 3. Results Seventy-one patients with secondary pulmonary hypertension were diagnosed during the study period. Thirty-
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Table 1 Patients' characteristics at baseline
Number Age, years Female/male WHO class II/III/IV, n° 6 MWT, m 6 MWT, % of predicted by sex (F/M)30 sPAP, mmHg paO2, mmHg SaO2, % Borg score after 6MWT INR
Bosentan group
Control group
p-value
17 64.88 (46–83) 15/2 1/14/2 297.53 ± 34.25 58.37/58.62
17 62.78(26–79) 8/9 3/12/2 268.47 ± 36.54 46.80/51.57
NA 0.6098 0.0103 0.5616 0.5658 NA
76.18 ± 5.96 64.68 ± 2.25 93.04 ± 0.80 5.59 ± 0.50 2.6 ± 0.3
71.48 ± 3.71 59.52 ± 2.05 89.57 ± 0.74 5.77 ± 0.43 2.5 ± 0.4
0.5081 0.0994 0.0032 0.7898 0.8429
Normal values, adjusted for sex, of the 6-minute walking test are obtained from reference [30]. Data are presented as mean (range) or mean ± SEM. NA = not applicable or not assessed. WHO: World Health Organization; 6 MWT: 6-minute walking test; sPAP: systolic pulmonary artery pressure; paO2: partial arterial oxygen pressure; SaO2: arterial oxygen saturation; INR: International Normalized Ratio of prothrombin time.
three patients were excluded from the study by other diseases known to cause secondary hypertension: 10 patients had COPD, 8 patients had connective tissue disease, 1 patient had congenital heart disease, 9 patients had idiopathic pulmonary fibrosis, 1 patient with sarcoidosis. Other 9 patients were excluded by the study because they were found suited for PEA. Thirty-four patients with CTEPH were enrolled in the study and 17 (50%) were commenced on bosentan; the other 17 (50%) patients were included in the control group. We collected data from all of the patients with only one exception; 1 patient (2.94%) in the control group died during the study at month 10 for acute myocardial infarction and heart failure. Patients' characteristics in the two groups are listed in Table 1. All procedures were performed by all the patients except for the one patent who died after 10 months failing to follow assessment at 12 months. Two patients (11.76% of the bosentan group) experienced a significant transaminases elevation respectively at month 2 and month 10 and dis-
Fig. 2. Progression of 6MWT in the two groups. Data are expressed as mean and bars represent standard error of the mean (SEM).
continued the study drug until the values normalized. Baseline data were not significantly different in the two groups, but we observed a significant prevalence of females in the bosentan group (p = 0.010). From month 6 to month 12 the two groups showed significant changes in the following parameters: 6MWT distance (347 ± 35 m vs. 220 ± 31 m, respectively in the bosentan group and controls, p = 0.012), paO2 (64.0 ± 4.1 mmHg vs. 53.1 ± 1.3 mmHg, respectively bosentan-treated patients and controls, p = 0.016), and Borg's dyspnea score (4.5 ± 0.3 vs. 6.3 ± 0.3, bosentan vs. controls, p = 0.001). A significant improvement in the functional class in the bosentan group was observed after 1 yr of treatment (p = 0.027) while it was deteriorated in the control group (Fig. 1). There was a progressive improvement in the 6MWT distance from baseline to month 12 (+ 57 ± 22 m, p = 0.023) in the bosentan group; whilst, in the control group there was a worsening performance from baseline to month 12 (− 73 ± 21 m, p = 0.001) (Fig. 2). The perception of dyspnoea was progressively improved in the bosentan group from baseline to month 12 (4.29 ± 0.49 after 1 year, p = 0.048); whilst in the control group there was a worsening (7.06 ± 0.32, p = 0.029) (Fig. 3). A significantly different trend of oxygenation from month 3 to month 12 was observed in the two group of treatment. The bosentan group showed a stabilization in the
Fig. 1. Comparison of WHO classes in the two groups at baseline and after 12 months.
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Fig. 3. Borg dyspnoea score in the two groups. Data are expressed as mean and bars represent standard error of the mean (SEM).
paO2 from baseline to month 12 (65.93 ± 3.76 mmHg, p = 0.786); while in the control group the values fell from baseline to 1-year (48.48 ± 1.31 mmHg, p b 0.001)(Fig. 4). Comparable results were observed after 12 months for the SaO2 (91.69 ± 1.26 vs 83.18 ± 1.09 in the bosentan group and control group, respectively, p b 0.001). The systolic pulmonary artery pressure (PAPs) in the bosentan group remained stable, even showing a slight improvement, from baseline at month 3 (67.40 ± 6.93 mmHg, p = 0.474), month 6 (66.93 ± 5.42 mmHg, p = 0.310) and month 12 (71.00 ± 5.41 mmHg, p = 0.221). In the control group sPAP worsened from baseline to month 3 (76.86 ± 6.37 mmHg, p = 0.620), month 6 (76.69 ± 4.24 mmHg, p = 0.005) and month 12 (80.44 ± 4.70 mmHg, p = 0.029) (Fig. 5). 4. Discussion The results of our study suggest that nonoperated patients with CTEPH could benefit treatment with bosentan plus conventional therapy. In fact, 1-yr bosentan therapy seems to slow the functional deterioration and disease progression in CTEPH patients whilst medical conventional therapy alone did not. Only the bosentan therapy improved 6-min walking distance, oxygenation, Borg dyspnea index, and WHO functional class, whilst the not-bosentan cohort did not improve after 1-year. Bosentan was well tolerated and no
Fig. 4. Oxygenation at rest (paO2 in mmHg) in the two groups. Data are expressed as mean and bars represent standard error of the mean (SEM).
Fig. 5. Systolic pulmonary artery pressure (sPAP) in the two groups. Data are expressed as mean and bars represent standard error of the mean (SEM).
patient had to stop treatment definitely because of adverse effects. Only two patients experienced transient transaminases elevation and had to taper temporarily the dose. Our results are in accordance with other previous uncontrolled studies [14–17]. Surgical pulmonary endarterectomy (PEA) is the elective treatment when the thrombi are accessible and there is no serious concomitant lung disease [18,19], with a peri-operative mortality rate of 5–11%, which is directly proportionate to preoperative pulmonary vascular resistances [20]. Untreated patients have a poor outcome with 90% mortality rate after 5 years from the diagnosis if the mean pulmonary artery pressure is superior to 30 mmHg [21]. Furthermore, there is an inverse correlation between survival and the degree of pulmonary hypertension at presentation [21]. Also CTEPH-predisposing medical conditions and chronic inflammatory disorders may influence prognosis negatively [21–23]. Nevertheless, the use of bosentan in nonoperated patients with CTEPH may have a pathopysiologic rationale [22]. The secondary arteriopathy that develops in CTEPH is similar to that seen in idiopathic pulmonary hypertension [6]. As in other forms of severe pulmonary hypertension, the endothelin system is activated in patients with CTEPH and may contribute to pulmonary vasoconstriction as well as vascular remodelling [24,25]. Plasma levels of endothelin-1 are elevated in this group of patients, and upregulation of type B endothelin receptors on pulmonary arterial smooth muscle cells has been demonstrated [7]. A substantial proportion of patients with CTEPH is considered inoperable due to significant distal thromboembolic pathology, or is classified as representing poor candidacy for PEA surgery due to concomitant vascular arteriopathy [22,26]. Patients in the latter group often suffer from persistent or residual pulmonary hypertension (PH) after PEA [27,28]. Although there is no doubt that eligible patients with CTEPH should undergo PEA, it is currently uncertain how to best manage patients with surgically inaccessible or otherwise inoperable disease. Medical therapies currently used in the management of post-pulmonary embolism patients (anticoagulants, diuretics, digitalis, calcium-channel
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blockers) do not affect underlying disease processes in CTEPH. Current recommended treatment of post-pulmonary embolism patients includes the life-long administration of anticoagulant therapy to reduce the risk of recurrent pulmonary embolism, but this therapy does not seem to influence survival given the reported 3-yr mortality of 90% in cases with severe pulmonary hypertension [21]. Advanced medical therapies acting on relevant underlying mechanisms of disease may have a rational role and provide functional benefits in CTEPH as shown in idiopathic pulmonary artery hypertension [22]. The results of our study suggest that the treatment with the oral dual endothelin receptor antagonist bosentan may represent a beneficial alternative in nonoperated CTEPH patients, especially with regard to oxygenation that did not worsen during a 1-year treatment period. The effect of bosentan on systolic pulmonary artery pressure seems to lead to a substantial stabilization, whilst conventional drug therapy alone failed to stop pulmonary artery pressure progressive increase. The limitations of this study are the lack of a double-blind randomized placebo-controlled design, the lack of scheduled invasive haemodynamic assessment and pulmonary angiography for every patient. Right heart catheterization remains the gold standard for the diagnosis of pulmonary hypertension [22], but Doppler echocardiography has already been used with reliable results to monitor the efficacy of specific therapeutic intervention in patients with pulmonary hypertension [29,30]. Moreover, all the patients in our study had a very high systolic PAP (mean 70 mmHg), making us enough confident to exclude false positive cases, even if PAP was assessed by echo without a direct haemodynamic measurement. Comparable results to ours were also obtained in other, open-label, uncontrolled studies showing an average increase of 6-min walking distance from 73 m to 54 m respectively after 3 and 6 months of bosentan [14,15,24]. In conclusion, the data of this study suggest that bosentan added to standard therapy may improve the functional outcomes of patients with CTEPH, so representing a safe and effective therapeutic option when PEA cannot be performed. 5. Learning points • Chronic thromboembolic pulmonary artery hypertension (CTEPH) is a progressive disease leading to worsening functional status and reduced survival to those patients who cannot undergo surgical pulmonary endarterectomy (PEA). • Unfortunately, there are several patients with CTEPH who are not eligible for PEA. • Data on alternative therapies to PEA for patients with inoperable CTEPH are limited in the literature. • This study suggests bosentan as an effective treatment for nonoperated CTEPH patients. Bosentan improves exercise capacity, dyspnoea index, oxygenation and slowed haemodynamic deterioration in CTEPH patients who cannot undergo PEA.
References [1] Fedullo PF, Auger WR, Kerr RM, Rubin LJ. Chronic thromboembolic pulmonary hypertension. N Engl J Med 2001;345(20):1465–72. [2] Pengo V, Lensing AWA, Prins MH, Marchiori A, Davidson BL, Tiozzo F, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004;350:2257–64. [3] Doyle RL, MacCrory D, Chennick RN, Simonneau G, Conte J. Surgical treatment/interventions for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004;126:63s–71s. [4] Dartevelle P, Fadel E, Mussot S, Chapelier A, Hervé P, de Perrot M, et al. Chronic thromboembolic pulmonary hypertension. Eur Respir J 2004;23(4):637–48. [5] Ulrich S, Speich R, Domenighetti G, Geiser T, Aubert JD, Rochat T, et al. Bosentan therapy for chronic thromboembolic pulmonary hypertension. A national open label study assessing the effect of bosentan on haemodynamics, exercise capacity, quality of life, safety and tolerability in patients with chronic thromboembolic pulmonary hypertension (BOCTEPH-Study). Swiss Med Wkly 2007;137:573–80. [6] Kunieda T, Nakanishi N, Satoh T, Kyotani S, Okano Y, Nagaya N. Prognoses of primary pulmonary hypertension and chronic major vessel thromboembolic pulmonary hypertension determined from cumulative survival curves. Intern Med 1999;38:543–6. [7] Suntharalingam J, Machado RD, Sharples LD, Toshner MR, Sheares KK, Hughes RJ, et al. Demographic features, BMPR2 status and outcomes in distal chronic thromboembolic pulmonary hypertension. Thorax 2007;62:617–22. [8] Barst RJ, McGoon M, Torbicki A, Sitbon O, Krowka MJ, Olschewski H, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:S40–7. [9] Bresser P, Pepke-Zaba J, Jaïs X, Humbert M, Hoeper MM. Medical therapies for chronic thromboembolic pulmonary hypertension. Proc Am Thorac Soc 2006;3(7):594–600. [10] American Thoracic Society and European Respiratory Society. Idiopathic pulmonary fibrosis: diagnosis and treatment; international consensus statement. Am J Respir Crit Care Med 2000;161:646–64. [11] ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002;166:111–7. [12] American Thoracic Society. Lung function testing: selection of reference values and interpretative strategies. Am Rev Respir Dis 1991;144:1202–18. [13] ATS statement single-breath carbon monoxide diffusing capacity (transfer factor). Recommendations for a standard technique-1995 update. Am J Respir Crit Care Med 1995;152:2185–98. [14] Hoeper MM, Kramm T, Wilkens H, Schulze C, Schafers HJ, Welte T, et al. Bosentan therapy for inoperable chronic thromboembolic pulmonary hypertension. Chest 2005;128:2363–7. [15] Bonderman D, Nowotny R, Skoro-Sajer N, Jakowitsch J, Adlbrecht C, Klepetko W, et al. Bosentan therapy for inoperable chronic thromboembolic pulmonary hypertension. Chest 2005;128:2599–603. [16] Hughes RJ, Jais X, Bonderman D, Suntharalingam J, Humbert M, Lang I, et al. The efficacy of bosentan in inoperable chronic thromboembolic pulmonary hypertension: a 1-year follow-up study. Eur Respir J 2006;28:138–43. [17] Seyfarth HJ, Hummerschmidt S, Pankau H, Winkler J, Wirtz H. Long-term bosentan in chronic thromboembolic pulmonary hypertension. Respiration 2007;74(3):287–92. [18] Jamieson SW, Kapelanski DP, Sakakibara N, Manecke GR, Thistlethwaite PA, Kerr KM, et al. Pulmonary endarterectomy: experience and lessons learned in 1500 cases. Ann Thorac Surg 2003;76:1457–62. [19] Jamieson SW. Pulmonary thromboendarterectomy. Heart 1998;79: 118–20. [20] Moser KM, Auger WR, Fedullo PF. Chronic major-vessel thrombotic pulmonary hypertension. Circulation 1990;81:1735–43. [21] Riedel M, Stanek V, Widinsky J, Prerovsky I. Long term follow-up of patients with pulmonary thromboembolism: late prognosis and evolution of hemodynamic and respiratory data. Chest 1982;81:151–8.
F.G. Vassallo et al. / European Journal of Internal Medicine 20 (2009) 24–29 [22] Hoeper MM, Mayer E, Simonneau G, Rubin LJ. Chronic thromboembolic pulmonary hypertension. Circulation 2006;113:2011–20. [23] Kim NH, Fesler P, Channick RN, Knowlton KU, Ben-Yehuda O, Lee SH, et al. Preoperative partitioning of pulmonary vascular resistance correlates with early outcome after thromboendarterectomy for chronic thromboembolic pulmonary hypertension. Circulation 2004;109:18–22. [24] Reesink HJ, Meijer RC, Lutter R, Boosma F, Jansen HM, Kloek JJ, et al. Hemodynamic and clinical correlates of endothelin-1 in chronic thromboembolic pulmonary hypertension. Circulation J 2006;8:1058–63. [25] Bauer M, Wilkens H, Langer F, Schneider SO, Lausberg H, Schäfers HJ. Selective upregulation of endothelin B receptor gene expression in severe pulmonary hypertension. Circulation 2002;105:1034–6. [26] Bonderman D, Skoro-Sajer N, Jakowitsch J, Adlbrecht C, Dunkler D, Taghavi S, et al. Predictors of outcome in chronic thromboembolic pulmonary hypertension. Circulation 2007;115:2153–8.
29
[27] Archibald CJ, Auger WR, Fedullo PF, Channick RN, Kerr KM, Jamieson SW, et al. Long-term outcome after pulmonary thromboendarterectomy. Am J Respir Crit Care Med 1999;160:523–8. [28] McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation 2006;114:1417–31. [29] Hinderliter AL, Willis 4th PW, Barst RJ, Rich S, Rubin LJ, Badesch DB, et al. Effects of long-term infusion of prostacyclin (epoprostenol) on echocardiographic measures of right ventricular structure and function in primary pulmonary hypertension. Circulation 1997;95:1479–86. [30] Galie N, Humbert M, Vachiery JL, Vizza CD, Kneussl M, Manes A, et al, Arterial Pulmonary Hypertension and Beraprost European (ALPHABET) Study Group. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized doubleblind, placebo-controlled trial. J Am Coll Cardiol 2002;39:1496–502.