Treprostinil for severe inoperable chronic thromboembolic pulmonary hypertension

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1 Journal of Thrombosis and Haemostasis, 5: ORIGINAL ARTICLE Treprostinil for severe inoperable chronic thromboembolic pulmonary hypertension N. SKORO-SAJER,* D. BONDERMAN,* F. WIESBAUER,* E. HARJA,* J. JAKOWITSCH,* W. KLEPETKO, M. P. KNEUSSLà and I. M. L A N G * *Division of Cardiology, Vienna General Hospital, Medical University of Vienna, Vienna; Cardiothoracic Surgery, Vienna General Hospital, Medical University of Vienna, Vienna; and àwilhelminenspital der Stadt Wien, Vienna, Austria To cite this article: Skoro-Sajer N, Bonderman D, Wiesbauer F, Harja E, Jakowitsch J, Klepetko W, Kneussl MP, Lang IM. Treprostinil for severe inoperable chronic thromboembolic pulmonary hypertension. J Thromb Haemost 2007; 5: Summary. Background: Chronic thromboembolic pulmonary hypertension (CTEPH) results from non-resolving pulmonary thromboemboli that are resistant to plasmatic anticoagulation. Because of a secondary pulmonary arteriopathy accompanying major vessel obstruction, the disorder may be a target for vasodilator therapy. Objectives: In an open-label uncontrolled study, we investigated the prostacyclin analog treprostinil given s.c. in patients with severe inoperable CTEPH. Methods: Between September 1999 and September 2005, 25 patients were included if their World Health Organization (WHO) functional classwasiiioriv,iftheirsix-minutewalkingdistance(6- MWD) 380 m, and if they had undergone at least one hospitalization for right heart decompensation within the prior six months, albeit not within one month before treatment start. Right heart catheterization was performed at baseline and after a minimum of 12 months (range: months) of treatment. Treprostinil plasma concentrations were determined after at least six months of treatment. A historical group of 31 patients at our center with inoperable CTEPH matched for disease severity was used for comparative analyses. Results: Treprostinil-treated patients demonstrated significant improvements in 6-MWD (P ¼ 0.01), WHO functional class (P ¼ 0.001), B- type brain natriuretic peptide plasma levels (P ¼ 0.02), cardiac outputs (P ¼ 0.007) and pulmonary vascular resistances (P ¼ 0.01) after 19 ± 6.3 months. Treprostinil plasma concentrations correlated with drug dose (P < 0.001), indicating stable absorption over time. Long-term survival was significantly better than in controls. Conclusions: Treprostinil improves exercise capacity, hemodynamics and survival in patients with Correspondence: Irene Lang, Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Währinger Gu rtel 18-20, 1090 Vienna, Austria. Tel.: ; fax: ; irene.lang@meduniwien.ac.at, nika.skoro-sajer@meduniwien.ac.at Received 8 October 2006, accepted 22 December 2006 severe inoperable CTEPH. We speculate that the effects may be explained by a combined vasodilatatory, platelet-antagonistic and potential antiproliferative action of the drug. Keywords: chronic thromboembolic pulmonary hypertension, prostacyclin analog. Introduction Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by non-resolving organized thromboemboli obstructing the pulmonary vascular bed [1]. These thrombi are resistant to thrombolytic therapy and chronic plasmatic anticoagulation. An increase in pulmonary vascular resistance (PVR), right ventricular overload, and eventually right ventricular failure ensue. The treatment of choice for CTEPH is pulmonary endarterectomy (PEA), providing a potential cure for the disease [2]. However, about 50% of patients at our center are not candidates for surgery, mainly because of distal location of thromboemboli. In addition, approximately 10% of patients who undergo PEA obtain no relief and maintain a pulmonary hypertensive state or experience recurrent pulmonary hypertension (PH). Despite recent advances in the treatment of pulmonary arterial hypertension (PAH) [3], medical treatments have not been recommended for inoperable CTEPH, because of the concept that a predominantly major vessel obstructive arteriopathy would not be suitable for vasodilators. Furthermore, a major drawback of i.v. prostacyclin therapy is the need for a permanent central venous access that increases the risk of infection ( per patient per year [4]), thrombosis and new major vessel thromboembolism. Treprostinil (Remodulin Ò, United Therapeutics, Research Triangle Park, NC, USA) is a stable prostacyclin analog with similar acute hemodynamic effects as epoprostenol [5]. Treprostinil has an s.c. elimination half-life of 4.6 h [6] and is chemically stable at room temperature with a neutral ph, permitting continuous s.c. infusion. In the 468-patient 12-week double blind, placebo-controlled PAH trial, treprostinil improved exercise capacity, indices of dyspnea, signs and

2 484 N. Skoro-Sajer et al symptoms of PH, cardiopulmonary hemodynamics and quality of life [7]. A recent retrospective European study [8], and a US European study [9] involving a large group of patients with PH have demonstrated significant benefits of treprostinil treatment with regard to exercise capacity and survival. The major objective of the present study was to analyze efficacy of long-term treprostinil in the difficult subset of severe inoperable CTEPH. The main concern against this treatment has been loss of efficacy because of local side effects over weeks of single skin site usage. Therefore, we measured treprostinil plasma levels in parallel with six-minute walking distance (6- MWD), World Health Organization (WHO) functional class, B-type brain natriuretic peptide (BNP), hemodynamics, and pain visual analog scales. Methods Study population The study was designed as a single-center prospective uncontrolled observational cohort study. The criteria for CTEPH diagnosis and PEA at our institution have been previously described [10]. In brief, the diagnosis was based upon PH in the presence of an abnormal ventilation/perfusion scan with one or more segmental-sized or larger mismatched perfusion defects, an abnormal pulmonary angiography showing typical findings of CTEPH and at least three months of effective anticoagulation prior to inclusion. Criteria for inclusion were inoperable CTEPH (distal disease or persistent/recurrent PH following PEA, and severe comorbidities precluding a surgical approach) in WHO functional classes (as modified for PAH from the New York Heart Association classification) III and IV [11], 6-MWD 380 m and at least one hospitalization for right heart decompensation within the previous six months, not within one month before treatment start, mean pulmonary artery pressure (MPAP) >25mmHg,aPVR>500dynesscm )5, in the presence of a pulmonary wedge pressure < 15 mmhg. S.c. treprostinil therapy was chosen instead of i.v. prostacyclin because of the threat of thromboembolism associated with Hickman catheters in this patient population. Patients were excluded if they suffered from interstitial lung disease with total lung capacity < 60% predicted, or forced expiratory volumen/forced vital capacity (FEV1/FVC) ratio of < 50%, mental illnesses, inability to operate the s.c. infusion pump, evidence of valvular heart disease, pericardial constriction, left ventricular dysfunction, renal dysfunction (serum creatinine > 2.5 mg dl )1 [12]), and uncontrolled sleep apnea. The Ethics Committee of the Medical University of Vienna approved the study, and patients signed informed consent. A historical group of 31 patients (diagnosed between September 1994 and September 1999, and who did not receive any specific PH medication) matched for disease severity by hemodynamic assessment, WHO functional class and 6-MWD served for comparative survival analyses. Both groups, the study group and the historical group, were stable on conventional therapy or had been optimized for at least one month before enrolment. Conventional therapy included oral anticoagulation at an International Normalized Ratio of 2 3, diuretics, supplemental oxygen and digitalis. This treatment has been practised at our institution over the past three decades and was not changed during the observation period. Treprostinil therapy Patients were instructed in the use of the positive pressure microinfusion pump (MiniMed, Sylmar, CA, USA, or Disetronic, Roche, France). Starting at 2 ng kg )1 min )1, doses were increased over 12 weeks to a maximum dose with an acceptable side effect profile. Dose adjustments were performed every three months from then on, and were based on signs and symptoms of PH. Infusion site changes were performed every 26 ± 8 days. Efficacy Efficacy endpoints were 6-MWD, functional class, BNP plasma levels and hemodynamics. 6-MWD, functional class and BNP plasma levels were assessed every three months. A fluorescence immunoassay was performed for quantification of BNP levels (Triage BNP Test, Biosite Diagnostics, Inc., USA). Right heart catheterization at baseline and after at least 12 months of treatment was performed as previously described [13]. Treprostinil plasma concentration Treprostinil plasma concentration was measured after at least six months of treprostinil treatment, at 29 ± 15 months of treatment. Plasma measurements were performed at two time points in every single patient, one in the first week (7 ± 4 days) and one in the third week (22 ± 9 days) after infusion site change, by liquid liquid extraction with subsequent analysis by LC-API/MS/MS (Alta Analytical Laboratory, El Dorado Hills, CA, USA) [14]. To examine the influence of s.c. tissue on treprostinil absorption, abdominal s.c. adipose tissue thickness (SAT) within the upper and lower epigastrical areas was measured in mm with a Lipometer TM (Moeller Messtechnik, Graz, Austria), an optical device with a sensor head containing lightemitting diodes. Local side effects, tolerability and pain management Side effects were monitored by annual questionnaires, and at every visit. Local pain questionnaires were obtained twice during the observation period after a minimum of six months of therapy, and at one year. A pain visual analog scale was used. Mild pain corresponds to a score of less than 30, moderate pain to a score between 31 and 54 and severe pain scores above 55 [15,16]. The standards for the treatment of infusion site pain were hot/cold compresses and topical

3 Subcutaneous treprostinil in CTEPH 485 application of three ointments containing various anaesthetics: formula A: ketoprofen 10%, lidocaine 5%, gabapentin 6%, pluronic lecithin organogel 30% ad 30.0; formula B: formula A plus ketamin 5%; formula C: formula B plus amitryptilin 2%. Statistics Results are expressed as mean ± SD. The two-sided alphalevel of 0.05 was used to determine statistical significance. Changes from baseline to the follow-up assessments were analyzed by single-sample t-test. A correlation Z-test was used for relating treprostinil plasma concentration and BNP plasma levels to other efficacy parameters. For the assessment of confounding, we first fit a univariate model, examining the association of treprostinil and other variables with overall mortality. Then, we carried out multiple bivariate analyses with treprostinil and one of the following covariates together in the model: gender, age, PVR, cardiac index (CI), 6-MWD and functional class. Confounding was judged to be present if the crude point estimate was changed by more than 10% by the second covariate [17]. The time of observation started when treprostinil or conventional therapy was initiated. Those factors that confounded the association were included in the multivariate model in addition to age and gender. This approach was chosen in order to obtain the most parsimonious statistical mode. The Kaplan Meier method was used to estimate the proportion of patients surviving at each time point. Patients switched to epoprostenol were censored as dead at the time of the survival analysis. The single patients who underwent bilateral lung transplantation, and those patients whodiedweresetto0 mfor6-mwd,orclassifiedaswhoiv. The results are expressed as hazard ratios with 95% confidence interval. The log-rank test was used to test for statistical significance. Patients who underwent lung transplantation were considered as censored at the date of transplantation. Results Baseline clinical characteristics and hemodynamic variables Clinical characteristics, exercise capacity and hemodynamic measurements at baseline are shown in Table 1. Between 15 September 1999 and 15 September 2005, 28 patients fulfilled the inclusion criteria and were treated with s.c. treprostinil. At our center, the standard of care for medical treatment of CTEPH has been prostacyclin, which, until bosentan was launched in the Fall of 2002, has been the only drug approved for the treatment of PAH in Austria. In the period between July 2003 and July 2004, inoperable CTEPH patients were treated with bosentan in an off-label experimental study [10]. During this period, no patients were found suitable for the treprostinil study. Three patients terminated therapy after 12 ± 6 weeks because of intolerable pain at a dose of 7.7 ± 3.5 ng kg )1 min )1 (range: ng kg )1 min )1 ), and were excluded. Out of 25 study patients (16 females and 9 males, age 58 ± 13 years) who had clinical symptoms of PH Table 1 Baseline characteristics of patients with inoperable chronic thromboembolic pulmonary hypertension compared with the control group. Comparisons between the treprostinil-treated group and a historical control group were made using the unpaired Student t-test. Data are presented as the number of patients, or respective mean value ± SD for 42 ± 52 months, six patients suffered from severe PH 2.0 ± 0.8 years after PEA, two patients suffered from recurrent disease, while the remaining patients were diagnosed as primarily inoperable. In the control group, 24 patients suffered from surgically inaccessible CTEPH, and seven had PH after PEA. Prior to the initiation of treprostinil, 11 patients were classified as WHO III and 14 patients as WHO IV. Long-term follow-up of patients Treprostiniltreated patients (n ¼ 25) P-value Control group (n ¼ 31) Female/male 16/9 n.s. 25/6 Age (years) 59 ± 13 n.s. 62 ± 15 Functional class III/IV 11/14 n.s. 15/16 6-MWD (m) 260 ± 111 n.s. 294 ± 136 BDS 6.2 ± 2.1 n.s. 5.8 ± 2.4 BNP (pg ml )1 ) 284 ± 201 n.s. 288 ± 298 MPAP (mmhg) 52 ± 10 n.s. 47 ± 14 MRAP (mmhg) 12 ± 5 n.s. 12 ± 8 CI (L min )1 m )2 ) 2.1 ± 0.5 n.s. 2.3 ± 0.7 PVR (dynes s cm )5 ) 924 ± 347 n.s. 890 ± 255 S v O 2 (%) 55 ± 10 n.s. 54 ± 11 Heart rate (beats per min) 81 ± 11 n.s. 81 ± 12 Functional class ¼ World Health Organization functional class; 6- MWD, six-minute walking distance; BDS, Borg Dyspnea Score; BNP, B-type brain natriuretic peptide; MPAP, mean pulmonary artery pressure; MRAP, mean right atrial pressure; CI, cardiac index; PVR, pulmonary vascular resistance; S v O 2, mixed venous saturation. Functional class, 6-MWD and BNP Patients were followed for a mean period of 24 ± 18 months (range: 6 72 months). Mean treprostinil dose at six months was 21 ± 5ngkg )1 min )1 (range: ng kg )1 min )1 ). Functional class improved in 13 patients and was unchanged in 12 patients. The mean increase in 6-MWD was 59 m (260 ± 111 m at baseline and 319 ± 117 m at follow up, P ¼ 0.01). At 12 months, the mean treprostinil dose was 28 ± 10 ng kg )1 min )1 (range: ng kg )1 min )1, n ¼ 19). Five patients were classified as functional class II, 13 patients remained in class III and one patient in class IV. The mean increase in the 6-MWD was 105 m (from 271 ± 107 to 376 ± 89 m). BNP plasma levels had decreased from 270 ± 197 pg ml )1 (range: pg ml )1 ) to 180 ± 78 pg ml )1 (range: pg ml )1, P ¼ 0.02). Follow-up right heart catheterization was performed in 19 patients (10 females and 9 males, age 57.2 ± 10.5 years) after 19 ± 6.3 months, at a mean treprostinil dose of 37.7 ± 9.6 ng kg )1 min )1 (range: ng kg )1 min )1 ; see Table 2). The results of the hemodynamic measurements are summarizedintable2.

4 486 N. Skoro-Sajer et al Table 2 Change of hemodynamic variables from baseline to follow-up at the maximum tolerated treprostinil dose, assessed using the paired Student t-test. Values are mean (±SD) changes from baseline Variable (n ¼ 19) Change from baseline P-value A SPAP (mmhg) )7.8 ± 17 n.s. DPAP (mmhg) )0.8 ± 10.2 n.s. MPAP (mmhg) )3.5 ± 9.2 n.s. MRAP (mmhg) )1.7 ± 3.4 n.s. CO (L min )1 ) 0.7 ± CI (L min )1 m )2 ) 0.3 ± S v O 2 (%) 3.7 ± 9.1 n.s. PVR (dynes s cm )5 ) )116 ± RVEDP (mmhg) )3.5 ± HR (beats per min) )1 ± 0.3 n.s. SBP (mmhg) )8.2 ± DBP (mmhg) )3.5 ± Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Day 14 SPAP, systolic pulmonary artery pressure; DPAP, diastolic pulmonary artery pressure; MPAP, mean pulmonary artery pressure; MRAP, mean right atrial pressure; CO, cardiac output; CI, cardiac index; S v O 2, mixed venous saturation; PVR, pulmonary vascular resistance; RVEDP, right ventricular end-diastolic pressure; HR, heart rate; SBP, systolic blood pressure; DBP, diastolic blood pressure. B Treprostinil therapy was associated with significant improvements in cardiac output (CO; 3.8 ± 0.9 to 4.6 ± 1.5 L min )1, P ¼ 0.007), CI (2.1 ± 0.5 to 2.4 ± 0.6 L min )1 m )2, P ¼ 0.02) and PVR (924.6 ± 347 to ± dynes s cm )5, P ¼ 0.01), whereas systolic, diastolic and MPAPs did not change significantly from baseline. Changes in BNP plasma levels correlated with changes in functional class (r ¼ 0.407, P < 0.01) and right ventricular end-diastolic pressure (r ¼ 0.46, P < 0.05). Local side effects and tolerability Abdominal infusion site pain was the most common adverse event (86%), followed by infusion site erythema (76%) and hematoma (34%). There were two cases of infusion site abscesses requiring surgical incision and treatment with oral antibiotics, with no serious adverse consequences. Diarrhea (n ¼ 3), jaw pain (n ¼ 1) and flushing (n ¼ 1) were mild and transient. The analyses of the pain visual analog scales are shown in Fig. 1A,B. Pain levels decreased in the second year of treatment (P ¼ 0.04). Treprostinil plasma concentration As plasma levels of treprostinil (29 ± 15 months of treatment) correlated with the actual s.c. dose at both time points (P < 0.001; Fig. 2), a linear pharmacokinetic profile of treprostinil can be assumed. Our data are comparable to data reported in normal subjects over 28 days [18]. Plasma concentrations were not dependent on abdominal s.c. adipose tissue thickness. Treprostinil plasma concentrations were correlated with improvements in 6-MWD (r ¼ 0.479, P ¼ 0.03). Outcome At 24 ± 20 months follow-up, 19 patients remained on long-term treprostinil treatment, five patients had died after 27 ± 10 weeks (24 36 weeks), and one patient Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Day 14 Fig. 1. Box plots of pain visual analog scales in the (A) first and (B) second year of treatment, within a randomly chosen 14-day observation period, illustrated on the x-axis. The y-axis depicts the pain scale. plasma concentration (ng ml 1 ) dose (ng kg 1 min 1 ) Fig. 2. Correlation between treprostinil plasma concentration (ng ml )1 ) and continuous s.c. dose in ng kg )1 min )1 22 ± 9 days after infusion site change (after 29 ± 15 months of treatment). had undergone successful lung transplantation after seven months of treatment. Cause of death was right heart failure in four patients, and one patient died from breast cancer.

5 Subcutaneous treprostinil in CTEPH Postmortem autopsy verification was performed in all patients. Two deaths occurred three months after switching to i.v. epoprostenol. At our institution, switching to the i.v. application is recommended in cases in whom the necessary dose increases for stabilization cannot be achieved via the s.c. route. The cause of death in the control group (n ¼ 26) was right heart failure. Overall survival rates at one, two, three and five years were 80%, 80%, 80% and 53% (Fig. 3), respectively, compared with untreated patients showing survival rates of 67%, 43%, 37% and 16%, respectively (P ¼ 0.02). In the univariate and multivariate analyses, baseline functional class and treprostinil treatment were predictors of survival. While class IV was associated with high overall mortality, treprostinil treatment significantly reduced the risk of death in these patients. These associations were independent of gender, age, PVR, CI or 6- MWD (Table 3). Discussion Treprostinil treated Untreated Time in months of follow-up Subject Treprostinil treated at risk, n Untreated Fig. 3. Kaplan Meier survival estimates in 25 patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH), starting at the initiation of treprostinil therapy. For comparison, survival data are also shown for an untreated control group with inoperable CTEPH matched for disease severity, who did not receive vasodilator therapy. In the group of patients treated with treprostinil (dashed line), the overall survival rates at one, two, three and five years were 80%, 80%, 80% and 53%, respectively, compared with 67%, 43%, 37% and 16% (P ¼ 0.02 by the log-rank test; solid line). Our study provides novel data on the long-term outcome, management and survival in patients with severe inoperable CTEPH in functional classes III and IV, with a 6-MWD 380 m and at least one recent hospitalization for right heart decompensation. This subset of PH has never been studied under an s.c. prostacyclin therapy. We investigated the effect of long-term treprostinil therapy for more than two years uptitrating the dose based on the patientsõ symptoms. In our study, survival was significantly and independently improved by treprostinil therapy, and dependent on the functional class at the initial presentation [19]. Treprostiniltreated patients demonstrated significant improvements in Table 3 Cox proportional hazard model assessing the univariate association and multivariate cox proportional hazard model (shown in italics) assessing the association of different factors with overall mortality in chronic thromboembolic pulmonary hypertension (CTEPH) patients Odds ratio 95% CI P-value Treprostinil therapy Gender Age PVR CI MWD Functional class PVR, pulmonary vascular resistance; CI, cardiac index; 6-MWD, sixminute walking distance. Only those factors that confounded the association of treprostinil with overall mortality were included in the multivariate model. 6-MWD, WHO functional class and BNP plasma levels. In addition, cardiac outputs, PVRs and right ventricular enddiastolic pressures improved, while MPAP decreased, albeit not statistically significantly. Because of five deaths and one transplantation prior to completion of 12 months of treatment, only 19 patients underwent follow-up right heart catheterizations, causing a bias in the information on hemodynamic changes. Small patient numbers and the uncontrolled nature of our investigation are sensible limitations of this study. PH early in CTEPH is a direct consequence of the loss of functional pulmonary capillaries because of major pulmonary vessel obstruction with non-resolving thrombi. Over time, however, gradual hemodynamic and symptomatic decline has been observed because of development of a secondary pulmonary hypertensive arteriopathy involving predominantly small precapillary pulmonary vessels [20], resembling idiopathic PAH [21]. For all these reasons, a historical CTEPH patient control group was considered most suitable for an estimation of survival. This group dates from the time prior to vasodilator treatments at our institution, which started in According to our experience, CTEPH accounts for a substantial number of patients in a pulmonary vascular center. Recently, it has been shown that CTEPH occurs in 3.8% of cases after symptomatic pulmonary embolism [22], and is more common than expected [23]. In addition, in our center, approximately 50% of patients with CTEPH are not candidates for PEA. About 10% of patients do not benefit from surgery, possibly because of distal thrombi or significant small vessel arteriopathy [2]. Additional theoretical efficacy of prostacyclins for CTEPH may be derived from the platelet antagonistic effects of prostacyclins, because a pathophysiologic role of platelets in CTEPH has been implicated for cases associated with splenectomy in which elevated platelet numbers are circulating [24,25].

6 488 N. Skoro-Sajer et al Because of the concept that a large-vessel obstruction is the predominant cause for CTEPH, few data exist on vasodilator treatments [26,27]. The only randomized data are from the Aerosolized Iloprost Randomized (AIR) study [28] where CTEPH patients did not statistically benefit from inhaled iloprost treatment. Several series have reported a beneficial effect of the oral dual endothelin receptor antagonist bosentan in CTEPH, albeit in less sick patients [10,29,30]. Improvements in 6-MWDs ranged from 80 to 100 m in all these three-to-six-month studies, with CIs improving from 2.1 to 2.5 L min )1 m )2, an observation that appears similar to the improvements maintained in the present study over the long term, albeit in very ill patients. One case series reported favorable effects with oral sildenafil [26]. Our expertise in treprostinil use, including the successful management of local pain at the infusion site, may explain, at least in part, the positive results observed. Absence of skin necroses and maintained efficacy over years were confirmed. Intolerability to local pain is unpredictable, but, if present, occurs early during the initiation period of therapy. Pain is minimized by infrequent site changes. Therefore, s.c. infusion was continued over weeks, thus deviating from what was practised during the pivotal trial. Because of the concern of efficacy loss because of infrequent site changes, we measured treprostinil plasma levels. As suggested in the pivotal trial [7], efficacy was dependent on treprostinil dose and plasma concentrations. It has been shown that treprostinil administered by s.c. infusion is rapidly and completely absorbed into the systemic circulation. Relatively modest differences in pharmacokinetic parameters between s.c. and i.v. treprostinil include a slightly longer time to maximum plasma level and a longer apparent plasma half-life following s.c. administration [31]. In the present study, continuous use over years did not appear to compromise absorption of the drug. Despite a requirement of more than double the dose when transitioning from i.v. epoprostenol to i.v. treprostinil [32], s.c. treprostinil therapy improved exercise capacity, WHO functional class and survival over an observation period of 24 ± 18 months of treatment, at a dose of only 37.7 ± 9.6 ng kg )1 min )1 (range: ng kg )1 min )1 ). In accord with these data, survival with s.c. treprostinil was comparable to that observed with i.v. epoprostenol in a multicenter study of 122 patients dosed at similar rates in three large European PH referral centers [8]. Despite the major drawback of an open-label uncontrolled design, and the observation that 1/5 of the patients succumbed to PH within one year, our study demonstrates the safety and efficacy of treprostinil over coumadin, and urges the need for randomized, placebo-controlled trials to confirm alternative treatments of severe inoperable CTEPH. Disclosure of Conflict of Interests This research was supported by the O sterreichischer Selbsthilfeverein Lungenhochdruck, proposal reference number FP and FWFS9406-B11 (to IML). References 1 Lang IM, Marsh JJ, Olman MA, Moser KM, Loskutoff DJ, Schleef RR. Expression of type 1 plasminogen activator inhibitor in chronic pulmonary thromboemboli. Circulation 1994; 89: Klepetko W, Mayer E, Sandoval J, Trulock EP, Vachiery JL, Dartevelle P, Pepke-Zaba J, Jamieson SW, Lang I, Corris P. Interventional and surgical modalities of treatment for pulmonary arterial hypertension. 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