CHU Caen, Université Caen UMR 1086, Caen, France, d Department of Pulmonology, VU University Medical Center, Amsterdam, The Netherlands,

Transcription

1 EPITOME-2: An open-label study assessing the transition to a new formulation of intravenous epoprostenol in patients with pulmonary arterial hypertension Olivier Sitbon, MD, a Marion Delcroix, MD, b Emmanuel Bergot, MD, c Anco B. Boonstra, MD, d John Granton, MD, e David Langleben, MD, f Pilar Escribano Subías, MD, g Nazzareno Galiè, MD, h Thomas Pfister, PhD, i Jean-Christophe Lemarié, MSc, j and Gérald Simonneau, MD a Paris, and Caen, France; Leuven, Belgium; Amsterdam, The Netherlands; Toronto, and Montreal, Canada; Madrid, Spain; Bologna, Italy; and Allschwil, Switzerland Background Continuous infusion of epoprostenol is the treatment of choice in patients with pulmonary arterial hypertension in functional classes III to IV. However, this treatment's limitations include instability at room temperature. A new epoprostenol formulation offers improved storage conditions and patient convenience. Methods The EPITOME-2 trial was an open-label, prospective, multicenter, single-arm, phase IIIb study. Patients with pulmonary arterial hypertension on long-term, stable epoprostenol therapy were transitioned from epoprostenol with glycine and mannitol excipients (Flolan; GlaxoSmithKline, Durham, NC) to epoprostenol with arginine and sucrose excipients (Veletri; Actelion Pharmaceuticals Ltd, Allschwil, Switzerland). Patients were followed up for 3 months, and dose adjustments were recorded. Efficacy measures included the 6-minute walk distance, hemodynamics assessed by right heart catheterization, and New York Heart Association functional class. Safety and tolerability of the transition were also evaluated. Quality of life was assessed using the Treatment Satisfaction Questionnaire for Medication. Results Forty-two patients enrolled in the study, and 1 patient withdrew consent before treatment; thus, 41 patients received treatment and completed the study. Six patients required dose adjustments. There were no clinically relevant changes from baseline to month 3 in any of the efficacy end points. Adverse events were those previously described with intravenous prostacyclin therapy. Treatment Satisfaction Questionnaire for Medication scores showed an improvement from baseline to month 3 in the domain of treatment convenience. Conclusions Transition from epoprostenol with glycine and mannitol excipients to epoprostenol with arginine and sucrose excipients did not affect treatment efficacy, raised no new safety or tolerability concerns, and provided patients with an increased sense of treatment convenience. (Am Heart J 2014;167: ) Intravenous (IV) epoprostenol sodium was first licensed as a pulmonary arterial hypertension (PAH) treatment in 1995 based on improved functional and exercise capacity and survival over conventional therapy in randomized controlled trials. 1,2 To date, IV epoprostenol is the only agent recommended as a first-line treatment for patients with severe PAH categorized as New York Heart Association (NYHA) functional class (FC) IV. 3,4 Owing to its short half-life in aqueous biological fluids, epoprostenol must be continuously administered through a central venous catheter using a portable pump. 5 Epoprostenol degradation is also rapid in aqueous solutions that are From the a Université Paris-Sud, INSERM U999, Centre de Référence de l'hypertension Pulmonaire Sévère, Service Pneumologie, Hôpital Bicêtre, Le Kremlin-Bicêtre, Paris, France, b Department of Pneumology, University Hospital of Leuven, Leuven, Belgium, c Centre de Compétence de l'hypertension Pulmonaire Sévère, Service de Pneumologie, CHU Caen, Université Caen UMR 1086, Caen, France, d Department of Pulmonology, VU University Medical Center, Amsterdam, The Netherlands, e Pulmonary Hypertension Programme at UHN, University of Toronto, Toronto, Canada, f Center for Pulmonary Vascular Disease, Division of Cardiology, Jewish General Hospital, McGill University, Montreal, Canada, g Unidad de Hipertensión Pulmonar, Servicio de Cardiología, Madrid, Spain, h Institute of Cardiology, University of Bologna, Bologna, Italy, i Department of Clinical Science, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland, and j Effi-stat, Paris, France. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited. Randomized controlled trial registration no. NCT Submitted November 23, 2012; accepted August 13, Reprint requests: Olivier Sitbon, MD, Service de Pneumologie et Soins Intensifs, Hôpital de Bicêtre, 78, rue du Général Leclerc, Le Kremlin-Bicêtre, Paris, France. olivier.sitbon@bct.aphp.fr /$ - see front matter 2014, The Authors. Published by Mosby, Inc. All rights reserved.

2 American Heart Journal Volume 167, Number 2 Sitbon et al 211 typically used for IV administration. Therefore, epoprostenol sodium is formulated as a lyophilized powder that needs to be reconstituted and diluted before IV infusion. Degradation of epoprostenol in solution is slowed by elevated ph and refrigerated temperatures. Flolan(GlaxoSmithKline, Durham, NC) is an epoprostenol sodium formulation that contains the excipients glycine and mannitol (epoprostenol GM). Freshly prepared solutions of epoprostenol GM must be administered within 8 to 12 hours at room temperature or within 24 hours if maintained at 2 C to 8 C using frozen gel packs. 6,7 As a result, patients on epoprostenol GM therapy need to prepare fresh IV solution and change the medication cassettes every 12 hours, or every 24 hours if using frozen gel packs. 6,7 The inconvenience of epoprostenol therapy could be alleviated to some degree by eliminating the need for frozen gel packs and decreasing the frequency of fresh medication preparation and changing medication cassettes. Based on a previous formulation, 8 a new formulation of epoprostenol sodium has been developed (Veletri; Actelion Pharmaceuticals Ltd, Allschwil, Switzerland) containing the excipients arginine and sucrose (epoprostenol AS). The new formulation results in an improved stability of epoprostenol in solution. Depending on the concentration, the IV solutions maintain the potency of epoprostenol at room temperature for up to 72 hours, when freshly prepared, or up to 48 hours after refrigerated storage for up to 8 days. 9 A pharmacokinetic comparison of epoprostenol GM and epoprostenol AS demonstrated that the formulations met the criteria for bioequivalence. 10 The objectives of EPITOME-2 were to assess dose adjustments and the effects on efficacy, safety and tolerability, and quality of life of patients with PAH transitioning from epoprostenol GM to the new formulation, epoprostenol AS. Methods Trial design This prospective, multicenter, single-arm, open-label, phase IIIb study was conducted at 8 centers in 6 countries (Belgium, Canada, France, Italy, the Netherlands, and Spain) to assess the effects of transitioning patients on stable epoprostenol GM therapy to epoprostenol AS on: dose adjustment, efficacy, safety and tolerability, and quality of life, for 3 months after the transition. The study was conducted in accordance with the Declaration of Helsinki and its amendments and the laws and regulations of the countries conducting the study, as well as following the International Conference on Harmonization Good Clinical Practice guidelines. The protocol received approval from the ethics committees at each institution, and each patient provided signed informed consent before study entry. The trial was registered at (EPITOME-2 registration number: NCT ) and was sponsored by Actelion Pharmaceuticals Ltd, which was responsible for designing the protocol and data collection under the leadership of the independent study investigators. Medical writing assistance was provided by a professional medical writer paid by the sponsor. All authors received the original study data, reviewed and interpreted the data, agreed on manuscript content, and reviewed and revised all drafts. All authors approved the final version and agreed to submission. Participants Patients 18 years or older with idiopathic or heritable PAH, or PAH associated with connective tissue disease or induced by drugs and toxins, were enrolled. Eligibility criteria were defined to enroll stable patients whose disease was reasonably well controlled. All patients must have been receiving epoprostenol GM treatment for at least 12 months before study entry and have been on a stable dose for at least the past 3 months. Concomitant PAH-specific therapies including bosentan, ambrisentan, sitaxentan, sildenafil, and tadalafil were permitted if patients were already receiving these therapies for 90 days and on a stable dose for 30 days before enrollment. Calcium-channel blockers, diuretics, oxygen (if on a stable dose 30 days before enrollment), and oral anticoagulants were permitted. Women of childbearing potential were included if they were using a reliable method of contraception. Exclusion criteria included the following: need for emergency care, known or suspected pulmonary veno-occlusive disease, use of IV inotropic agents, prostacyclin treatment other than epoprostenol GM, tachycardia with a heart rate N120 beats/ min at rest, a history of myocardial infarction, left-sided heart disease or a chronic bleeding disorder, a central venous line infection within 90 days of screening and/or a history of recurring line infections, any factor that might interfere with treatment compliance, or any known concomitant life-threatening disease with a life expectancy of b12 months. Patients were screened for eligibility up to 14 days before study entry. Intervention, transition, and dosing procedure Reconstituted solutions of epoprostenol AS were immediately diluted and administered within 24 hours. Patients were hospitalized for the transition, which was done by directly replacing the medication cassette containing epoprostenol GM with a cassette containing epoprostenol AS at the infusion pump. The dose of epoprostenol AS at the time of transition was requested to be similar (±10%) to the last dose of epoprostenol GM. The concentration of epoprostenol AS in the IV solution and the infusion rate were eventually adjusted to allow for administration from one cassette over a period of 24 hours (without cooling). Cassette volumes were either 50 or 100 ml. Patients were monitored in the hospital for any changes to vital signs and symptoms of PAH, before and after transition. They were discharged when their treating physician determined them to be clinically stable and trained on epoprostenol AS preparation and administration. Length of hospital stay was determined by the investigator but was expected to be between 1 and 3 days. Dose adjustments were permitted throughout the study, as per the investigator's judgment, to balance maximum tolerability and clinical benefit. Treatment could be temporarily or permanently discontinued if assessed necessary by the investigator. Outcomes Efficacy assessments were conducted at baseline and month 3 and included 6-minute walk distance (6MWD), Borg dyspnea score, NYHA FC, and N-terminal pro brain natriuretic peptide (NT-proBNP) levels, and hemodynamics. The hemodynamic parameters of right atrial pressure, cardiac output, mean

3 212 Sitbon et al American Heart Journal February 2014 Table I. Patient demographic, clinical, and hemodynamic characteristics at baseline Figure 1 Characteristic (n = 41) Mean ± SD Median (range) Age (y) 44.8 ± ( ) Female, n (%) 30 (73.2) Body mass index (kg/m 2 ) 26.0 ± ( ) PAH etiology, n (%) Idiopathic PAH 31 (75.6) Heritable PAH 5 (12.2) PAH associated with 2 (4.9) connective tissue disease PAH induced by drugs 3 (7.3) and toxins NYHA FC, n (%) I 2 (4.9) II 30 (73.2) III 9 (22.0) IV 0 Time since diagnosis (y) 7.1 ± ( ) Time since epoprostenol 4.6 ± ( ) GM initiation (y) 6MWD (m) ± ( ) Borg dyspnea score 4.0 ± ( ) NT-proBNP (ng/l) ± ( ) Hemodynamics Right atrial pressure 7.9 ± ( ) (mm Hg) Mean pulmonary artery 51.9 ± ( ) pressure (mm Hg) mpcwp (mm Hg), 10.2 ± ( ) Cardiac index 3.3 ± ( ) (L/min per m 2 ) Pulmonary vascular ± ( ) resistance (dyne s cm 5 ), Heart rate (beats/min) 81.4 ± ( ) Systolic/diastolic blood pressure (mm Hg) ± 13.7/ 68.1 ± ( )/ 69.0 ( ) mpcwp, Mean pulmonary capillary wedge pressure. n = 40. n = 37. Mean pulmonary capillary wedge pressure as pulmonary vascular resistance could not be measured in 4 patients. pulmonary artery pressure, and mean pulmonary capillary wedge pressure were measured by right heart catheterization. Epoprostenol AS safety and tolerability were assessed by recording adverse events (AEs) throughout the study and at 24 hours (all AEs) and 30 days (serious AEs only) after study end and vital signs (heart rate, blood pressure, body weight). Epoprostenol AS dose adjustments were allowed throughout treatment. Patients' quality of life was evaluated using the abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9) at baseline and month 3, to obtain the patients' perception of treatment effectiveness, treatment convenience, and global satisfaction. 11 The TSQM-9 scores range from 0 to 100, where higher scores reflect improved perception of these parameters. At the end of the 3-month study, patients had the opportunity to continue treatment with epoprostenol AS as part of an open-label extension. Statistical methods A small sample size was anticipated, and so no formal statistical hypothesis was set for this exploratory study. The all-treated set, which included all enrolled patients who received the study drug, Dose of epoprostenol with AS excipients during the study for patients who required dose adjustments. was used for all analyses. Patient demographics and clinical characteristics, dosing, efficacy, and treatment satisfaction end point assessments were summarized descriptively by arithmetic means with SDs and medians with ranges for continuous variables. Categorical variables were described using proportions. The geometric mean of the percentage ratio (month 3/baseline) and its 95% confidence limits (CLs) were used to estimate the level of change from baseline to month 3 for efficacy end points and vital signs. The mean of the difference (month 3 minus baseline) and its 95% CL were used to estimate the level of change from baseline to month 3 for the treatment satisfaction end points. Results Patient disposition and baseline characteristics Forty-two patients enrolled in EPITOME-2. One patient withdrew consent before receiving study treatment. Therefore, the all-treated analysis set comprised 41 patients. All 41 patients completed the study and enrolled in the EPITOME-2 open-label extension study. The baseline characteristics of the patients are shown in Table I. The baseline 6MWD of 500 m was consistent, with most patients being in NYHA FC II at enrollment. A high proportion of patients (n = 33; 80.5%) were taking oral PAH-specific therapy at baseline, including endothelin receptor antagonists (n = 7; 17.1%), phosphodiesterase-5 inhibitors (n = 9; 22.0%), and combination therapy of endothelin receptor antagonists and phosphodiesterase-5 inhibitors (n = 17; 41.5%). Other background therapies at baseline included anticoagulants (n = 34; 82.9%), diuretics (n = 32, 78.0%), potassium-sparing agents (n = 21; 51.2%), and oxygen (n = 8; 19.5%). Epoprostenol AS dosing The mean period of hospital stay for the transition from epoprostenol GM to epoprostenol AS was 1.7 ± 0.5 days.

4 American Heart Journal Volume 167, Number 2 Sitbon et al 213 Table II. Change in hemodynamic and clinical parameters and vital signs at baseline to month 3 after the switch from epoprostenol GM to epoprostenol AS Parameter Mean ± SD Change from baseline Median (range) Percentage ratio, month 3/ baseline (95% CL) Hemodynamics RAP (mm Hg) 0.8 ± ( 9.0 to 6.0) 86.0 ( ) mpap (mm Hg) 0.2 ± ( 20.0 to 17.0) 98.6 ( ) mpwcp (mm Hg), 0.2 ± ( 9.0 to 7.0) ( ) Cardiac index (L/min per m 2 ) 0.0 ± ( 1.0 to 1.4) ( ) PVR (dyne s cm 5 ), 8.0 ± ( to 232.7) 98.0 ( ) Clinical parameters 6MWD (m) 5.3 ± ( 62.0 to 69.0) 99.1 ( ) Borg dyspnea score 0.7 ± ( 4.0 to 1.0) 80.1 ( ) NT-proBNP (ng/l) 13.6 ± ( to ) 97.8 ( ) Vital signs Heart rate (beats/min) 1.5 ± ( 20.0 to 35.0) ( ) Systolic/Diastolic blood pressure (mm Hg) 4.0 ± 14.3/ 0.9 ± ( 37.0 to 34.0)/0.0 ( 31.0 to 26.0) ( )/98.0 ( ) RAP, Right atrial pressure; mpap, mean pulmonary artery pressure; mpcwp, mean pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance. n = 36. mpcwp as PVR could not be measured in 5 patients. n = 40. The mean dose of epoprostenol AS at baseline was 29.9 ± 15.1 ng kg 1 min 1. Two patients started epoprostenol AS on a slightly higher dose than their last dose of epoprostenol GM. One patient went from epoprostenol GM 9 ng kg 1 min 1 to epoprostenol AS 10 ng kg 1 min 1 and the other from epoprostenol GM 26 ng kg 1 min 1 to epoprostenol AS 27 ng kg 1 min 1. For 1 patient, the initial epoprostenol AS dose of 23 ng kg 1 min 1 was slightly lower than the previous epoprostenol GM dose of 25 ng kg 1 min 1. The mean dose at month 3 was 30.2 ± 15.0 ng kg 1 min 1. Most patients (n = 35; 85.4%) remained on their initial dose throughout the 3-month study. Six patients required dose adjustments during the study (Figure 1). Four patients required dose increases during the study period because of relapse or worsening of PAH, dyspnea, dyspnea upon exertion, chest discomfort, and/or fatigue. One of these patients started epoprostenol AS on a dose slightly higher than the last epoprostenol GM dose. Two patients had dose reductions during the study. In 1 patient, the dose was reduced because of high cardiac output, measured by right heart catheterization. This patient started epoprostenol AS on a dose slightly lower than the last epoprostenol GM dose. The other patient experienced increased skin sensitivity, jaw pain, flushing, and foot pain, for which the dose was reduced. The mean exposure time to epoprostenol AS was 87.7 ± 4.9 days. Efficacy outcomes Transitioning patients from epoprostenol GM to epoprostenol AS produced no distinct absolute changes from baseline to month 3 in hemodynamics (Table II). The change from baseline for pulmonary vascular resistance expressed as the geometric mean of the percentage ratio of month 3/baseline values had a 95% CL of 91.3% to 105.2% (close to 100%), suggesting that hemodynamics remained stable overall. On an individual patient level, changes at month 3 from baseline varied within a clinically expected range (Figure 2A). Change from baseline to month 3 and the geometric mean of the percentage ratio of month 3/baseline in other efficacy measures demonstrated no relevant changes in these parameters (Table II). Figure 2B shows individual changes in 6MWD for each patient from baseline to month 3. The NT-proBNP levels measured at baseline were within a wide range of between 26 and 6770 ng/l (Table I). The geometric mean of the percentage ratio month 3/baseline showed no relevant change (Table II). Most patients (n = 35; 87.5%) remained in the same NYHA FC from baseline to month 3, after the transition to epoprostenol AS. Functional class improved in 1 patient from FC III to II. Four patients experienced FC worsening, 1 from FC I to II and 3 from FC II to III (Figure 3); one of these 3 patients also required a dose increase. Table III provides further information on the clinical parameters of these 4 patients. Safety and tolerability All patients switched from epoprostenol GM to epoprostenol AS completed the study. Most AEs were of mild (63.0%) or moderate (32.0%) intensity. The most common AEs, defined as those occurring in at least 3 (7.3%) patients, were typical of IV prostacyclin therapy (Table IV). Three patients experienced device-/catheter-related infections, including 1

5 214 Sitbon et al American Heart Journal February 2014 Figure 2 Individual changes from baseline to month 3 for pulmonary vascular resistance (A; n = 36) and 6MWD (B; n = 40). EoT, end of treatment. Figure 3 New York Heart Association FC at baseline and month 3 in patients transitioned from epoprostenol with GM excipients to epoprostenol with AS excipients. n = 40 patients; 1 patient was not assessed for FC at month 3. case of suppuration at the outside cutaneous orifice of the catheter. All 3 were local infections, and there was no evidence of bacteremia. Six serious AEs occurred during epoprostenol AS therapy, 4 of these were associated with the drug delivery system, including 3 device connection issues including damage, and 1 of the aforementioned device-related infections. The 4 serious events resolved without sequelae. The remaining 2 serious AEs were diverticulitis requiring Hartmann resection (n = 1) and right ventricular failure (n = 1) and were ongoing at study end. None of the serious AEs were considered related to epoprostenol AS treatment as judged by the investigator. Patients' vital signs of heart rate, systolic/diastolic blood pressure, and body weight showed no clinically significant changes from baseline to month 3 (Table II). Quality of life Treatment satisfaction data were collected for 38 patients and were not available for 3 patients as the center failed to administer the TSQM-9. The mean ± SD perception of treatment effectiveness was 78.2 ± 12.6 at baseline and 74.7 ± 17.6 at month 3, representing a mean change of 3.5 (95% CL 8.7 to 1.7). The mean ± SD for global satisfaction was 71.8 ± 18.4 at baseline and 75.2 ± 15.6 at month 3, representing a change of 3.4 (95% CL 1.3 to 8.1). In contrast, patients' mean perception of treatment convenience increased from 53.6 ± 15.8 at baseline to 66.4 ± 17.0 at month 3, where the mean change was 12.7 ± 20.0 (95% CL ). Discussion In EPITOME-2, transitioning patients with PAH from IV epoprostenol GM to epoprostenol AS occurred without any safety or tolerability issues, or major changes to the patients' hemodynamic or clinical conditions. For most patients, no dose adjustments were required, and they received a stable dose of epoprostenol AS throughout the study. Adverse events were typical of IV prostacyclin use. These data are similar to other studies assessing the transition from IV epoprostenol GM to IV

6 American Heart Journal Volume 167, Number 2 Sitbon et al 215 Table III. Clinical and hemodynamic data of patients with FC deterioration Patient FC deterioration 6MWD (m) mpap (mm Hg) Cardiac index (L/min per m 2 ) PVR (dyne s cm 5 ) BL Mo 3 BL Mo 3 BL Mo 3 BL Mo 3 1 I-II II-III II-III II-III mpap, Mean pulmonary artery pressure; PVR, pulmonary vascular resistance; BL, baseline; Mo 3, month 3. Table IV. Adverse events occurring in more than 5% of patients AE (n = 41) Epoprostenol AS, n (%) Patients with 1 AE 32(78) Headache 12 (29.3) Nasopharyngitis 7 (17.1) Jaw pain 6 (14.6) Flushing/Hot flush 6 (14.6) Dyspnea/Dyspnea upon exertion 5 (12.2) Device connection issue 3 (7.3) Epistaxis 3 (7.3) Extremity pain 3 (7.3) Palpitations 3 (7.3) treprostinil. 12,13 These studies followed 2 different switch protocols: rapid switch, with a direct exchange of one treatment for another, as in EPITOME-2, 13 or slow switch, with simultaneous up- and down-titration of each study drug. 12 In both 3-month studies, transition from epoprostenol GM to treprostinil occurred with maintenance of clinical status and without serious treprostinilrelated AEs. However, the mean dose of IV treprostinil at study end was twice that of epoprostenol GM that patients were transitioned from, which is likely to reflect the differences in the active agents in the 2 treatments. In contrast, in EPITOME-2, the mean epoprostenol AS dose at study end was close to that at study start; however, in this study, there is no change in the pharmacologically active agent. After continued epoprostenol use, the effect can decline requiring dose escalation to maintain treatment benefits. However, it is not known if this is caused by tachyphylaxis or PAH's progressive nature. 14 Many patients enrolled in the study had been diagnosed as having PAH for some years and had been receiving longterm epoprostenol treatment. Four patients required dose increases during the study because of disease progression symptoms. Although the eligibility criteria for study participation were intended to enroll stable patients, dose adjustments were not unexpected. Indeed, the dose of epoprostenol AS was slightly increased from the last epoprostenol GM dose at transition in 2 patients. Two patients required dose decreases, one because of typical IV prostacyclin AEs and the other because of an elevated hemodynamic effect. It is unlikely that the dose adjustments were caused by differences in exposure to epoprostenol between the 2 formulations of epoprostenol sodium. A recently published study in healthy volunteers demonstrated that the pharmacokinetic, pharmacodynamic, safety, and tolerability characteristics of epoprostenol GM and epoprostenol AS were similar. 10 In particular, the plasma concentration time curves of the primary metabolites of epoprostenol GM and epoprostenol AS were similar in shape and almost superimposable for both formulations. Changes in FC were not expected during this study because enrolled patients were considered to be on stable prostacyclin therapy. Functional class remained stable in most, with 1 patient showing an improvement in FC. Of the 4 patients who experienced worsening FC, 1 moved from FC I to II, a differentiation that can be difficult and subjective and has not been made in a recent study. 15 Indeed, clinical characteristics of this patient for 3 months (Table III) are indicative of stable disease. For the 3 patients who moved from FC II to III, 1 of whom required a dose increase, the clinical and hemodynamic parameters are not consistent with overall disease deterioration. The mean 6MWD was relatively high at baseline, again confirming that EPITOME-2 patients were stable and receiving optimal PAH treatment. There was no clinically or statistically relevant change in 6MWD after the transition to epoprostenol AS, indicating that most patients' exercise capacity remained stable after the switch. The median levels of NT-proBNP were within the threshold that is proposed to be indicative of a good prognosis for patients with PAH. 16,17 The safety profile of epoprostenol AS observed in this study was consistent with that of epoprostenol GM. The most frequently observed AEs (headache, nasopharyngitis, pain) were those expected from a potent, parenteral vasodilator therapy, and the proportion of patients affected was consistent with previous reports. 1,2,6,7 During the study, 3 patients experienced local device-/catheter-related infections, one listed as a serious AE. Bloodstream infections were not reported. A

7 216 Sitbon et al American Heart Journal February 2014 low rate of bloodstream infections of 0.12 per catheter-days during treatment with epoprostenol was recently reported from the REVEAL REGISTRY, where 1,146 patients have received at least 1 dose of IV prostacyclin therapy. 18 Epoprostenol AS was designed to improve convenience and ease of use. Upon dilution to the final IV solution, epoprostenol AS can be administered at room temperature within 24 to 72 hours, depending on the final IV solution concentration. 9 For patients, these improvements are expected to translate into an increased convenience of epoprostenol therapy by offering the option of storage, omitting the use of frozen gel packs, and increasing the interval between medication preparations. Domain assessments of TSQM-9 showed that patients had an increased perception of treatment convenience after the transition to epoprostenol AS, without any relevant change in the other domains. A direct comparison between the clinical effects of the 2 epoprostenol sodium formulations cannot be made because this was an open-label, single-arm study in a limited patient number. In addition, the observation period in EPITOME-2 was too short to assess long-term effects. This study's results support the short-term safety and efficacy of epoprostenol AS, which appears to be similar to other epoprostenol formulations. An open-label extension of EPITOME-2 is ongoing to collect long-term safety data. Despite these limitations, the results of this study suggest that transitioning patients from epoprostenol GM to epoprostenol AS does not affect treatment efficacy, raises no new safety or tolerability concerns, and provides patients with a potentially more convenient formulation of IV epoprostenol therapy. Disclosures Medical writing support was provided by Rose Doyle, PhD (Elements Communications Ltd, Westerham, UK), sponsored by Actelion Pharmaceuticals Ltd. This work was supported by Actelion Pharmaceuticals Ltd. O. Sitbon has acted as a consultant for Actelion Pharmaceuticals Ltd, Bayer HealthCare, GlaxoSmithKline, Eli Lilly, Pfizer, and United Therapeutics. M. Delcroix has acted as a consultant for Actelion Pharmaceuticals Ltd, Bayer HealthCare, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, and United Therapeutics and is holder of the Actelion Chair for Pulmonary Hypertension at the University of Leuven. E. Bergot has received speaker fees and/or honoraria for consultations from Actelion Pharmaceuticals Ltd, Pfizer, and Eli Lilly. A. Boonstra, or his employer, has relationships with companies including Actelion Pharmaceuticals Ltd, Pfizer, Tefa, Sun Pharma, Bayer HealthCare, United Therapeutics, Therabel, Ferrer, Boehringer Ingelheim, GlaxoSmithKline, and Mondobiotech. In addition to being an investigator in trials involving these companies, relationships include financial reimbursement for consultancy services and membership of scientific advisory boards. P. Escribano Subias has acted as a consultant for Actelion Pharmaceuticals Ltd, Eli Lilly, GlaxoSmithKline, Pfizer, and Ferrer. N. Galiè has acted as a consultant for Actelion Pharmaceuticals Ltd, Bayer HealthCare, GlaxoSmithKline, Pfizer, and Eli Lilly. J. Granton has been an investigator in trials involving Actelion Pharmaceuticals Ltd, Eli Lilly, United Therapeutics, and GlaxoSmithKline and received unrestricted educational grants or support from Actelion Pharmaceuticals Ltd, Eli Lilly, Pfizer, United Therapeutics, and GlaxoSmithKline. J. Granton has also acted as a consultant and received charitable funding through a PH patient education fund from Actelion Pharmaceuticals Ltd. D. Langleben has acted as a present or past consultant and/ or a clinical investigator for Actelion Pharmaceuticals Ltd, Bayer HealthCare, GlaxoSmithKline, Eli Lilly, Novartis, Pfizer, and United Therapeutics. T. Pfister is an employee of Actelion Pharmaceuticals Ltd. J.C. Lemarié provided statistical support funded by Actelion Pharmaceuticals Ltd. G. Simonneau has acted as a consultant for Actelion Pharmaceuticals Ltd, GlaxoSmithKline, Pfizer, Eli Lilly, Novartis, and United Therapeutics. References 1. Rubin LJ, Mendoza J, Hood M, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial. Ann Intern Med 1990;112: Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med 1996;334: Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2009;34: Barst RJ, Gibbs JS, Ghofrani HA, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol 2009;54(1 Suppl):S Chaumais MC, Jobard M, Huertas A, et al. Pharmacokinetic evaluation of continuous intravenous epoprostenol. Expert Opin Drug Metab Toxicol 2010;6: Flolan US prescribing information. assets/us_flolan.pdf. 7. Flolan EMA Summary of Product Characteristics. europa.eu/docs/en_gb/document_library/referrals_document/ flolan_30/wc pdf. 8. Lambert O, Bandilla D, Iyer R, et al. Stability and microbiological properties of a new formulation of epoprostenol sodium when reconstituted and diluted. Drug Des Devel Ther 2012;6: Lambert O, Bandilla D. Stability and preservation effectiveness of a new formulation of epoprostenol sodium for the treatment of pulmonary arterial hypertension. Drug Des Devel Ther 2012;6: Nicolas LB, Gutierrez M, Dingemanse J. 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8 American Heart Journal Volume 167, Number 2 Sitbon et al 217 different formulations of epoprostenol sodium for injection in healthy male subjects. Clin Ther 2013;35: Bharmal M, Payne K, Atkinson MJ, et al. Validation of an abbreviated treatment satisfaction questionnaire for Medication (TSQM-9) among patients on antihypertensive medications. Health Qual Life Outcomes 2009;7: Gomberg-Maitland M, Tapson VF, Benza RL, et al. Transition from intravenous epoprostenol to intravenous treprostinil in pulmonary hypertension. Am J Respir Crit Care Med 2005;172: Sitbon O, Manes A, Jais X, et al. Rapid switch from intravenous epoprostenol to intravenous treprostinil in patients with pulmonary arterial hypertension. J Cardiovasc Pharmacol 2007;49: Barst R. How has epoprostenol changed the outcome for patients with pulmonary arterial hypertension? Int J Clin Pract 2009;64: Humbert M, Sitbon O, Yaïci D, et al. Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension. Eur Respir J 2010;36: Fijalkowska A, Kurzyna M, Torbicki A, et al. Serum N-terminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension. Chest 2006;129: Andreassen AK, Wergeland R, Simonsen S, et al. N-terminal pro B-type natriuretic peptide as an indicator of disease severity in a heterogeneous group of patients with chronic precapillary pulmonary hypertension. Am J Cardiol 2006;98: Kitterman N, Poms A, Miller DP, et al. Bloodstream infections in patients with pulmonary arterial hypertension treated with intravenous prostanoids: insights from the REVEAL REGISTRY. Mayo Clin Proc 2012;87: O N THE MOVE? Send us your new address at least 6 weeks ahead Don t miss a single issue of the journal! To ensure prompt service when you change your address, please photocopy and complete the form below. Please send your change of address notification at least 6 weeks before your move to ensure continued service. We regret we cannot guarantee replacement of issues missed because of late notification. JOURNAL TITLE: Fill in the title of the journal here. OLD ADDRESS: Affix the address label from a recent issue of the journal here. NEW ADDRESS: Clearly print your new address here. Name Address City/State/ZIP COPY AND MAIL THIS FORM TO: OR FAX TO: OR PHONE: OR Elsevier Health Sciences Division JournalCustomerService- Subscription Customer Service Outside the U.S., call usa@elsevier.com 3251 Riverport Lane, Maryland Heights, MO