Transition From IV Epoprostenol to Subcutaneous Treprostinil in Pulmonary Arterial Hypertension

CHEST

Original Research PULMONARY HYPERTENSION

Transition From IV Epoprostenol to Subcutaneous Treprostinil in Pulmonary Arterial Hypertension* A Controlled Trial Melvyn Rubenfire, MD†; Vallerie V. McLaughlin, MD, FCCP; Roblee P. Allen, MD, FCCP; Greg Elliott, MD; Myung H. Park, MD; Michael Wade, PhD; and Robert Schilz, DO, PhD

Background: We determined the relative efficacy of subcutaneous (SC) treprostinil in stable World Health Organization class II and III patients transitioned from IV epoprostenol. Methods: This was an 8-week, multicenter, randomized study in which patients were transitioned from IV epoprostenol to SC treprostinil or placebo over a period of up to 14 days and monitored carefully during and after the transition period for signs of deterioration. Patients with clinical deterioration were returned promptly to epoprostenol. Placebo or SC treprostinil doses were titrated in response to symptoms. Time to adjudicated clinical deterioration was compared between treatment groups, and exercise capacity, symptoms of disease, and safety were assessed throughout the study. Results: Twenty-two patients were enrolled and completed the study. Seven of 8 patients (88%) withdrawn to placebo had clinical deterioration, while only 1 of 14 patients (7%) withdrawn to SC treprostinil had clinical deterioration (p ⴝ 0.00023 based on a treatment comparison of time to deterioration). Analyses of exercise capacity and symptoms strongly supported the efficacy of SC treprostinil in epoprostenol-treated patients. Adverse events consisted of painful infusion site reactions and anticipated prostacyclin side effects. Conclusions: SC treprostinil is effective in pulmonary arterial hypertension and prevents clinical deterioration and maintains functional status in patients transitioned from epoprostenol. (CHEST 2007; 132:757–763) Key words: prostacyclin; pulmonary hypertension; withdrawal trial Abbreviations: AE ⫽ adverse event; PAH ⫽ pulmonary arterial hypertension; SC ⫽ subcutaneous; WHO ⫽ World Health Organization

umerous studies have shown that IV prosN tacyclin (epoprostenol sodium) is effective in 1– 6

the treatment of pulmonary arterial hypertension (PAH). However, epoprostenol therapy is limited by its short half-life7 and lack of stability at room temperature, and is challenging for patients. Sudden cardiopulmonary collapse can occur with infusion interruption.8 Research into stable analogues of prostacyclin for PAH therapy has led to the approval of subcutaneous (SC)- and IV-administered treprostinil9 –16 and to iloprost, which can be administered by inhalation.17 SC-administered treprostinil has been shown to be www.chestjournal.org

effective and safe in PAH,12,13 and in 2002 received a provisional approval from the US Food and Drug For editorial comment see page 741 Administration for World Health Organization (WHO) functional class II-IV. However, in the pivotal controlled efficacy trial,12 the effect of SC treprostinil on exercise capacity was modest, as dosing was suboptimal because of infusion site pain and lack of experience with “best practice” dose titrations. To obtain formal confirmatory evidence of the benefit of SC treprostinil in PAH patients, the CHEST / 132 / 3 / SEPTEMBER, 2007

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concept of a novel, small, carefully monitored, controlled withdrawal trial emerged after discussions among the Food and Drug Administration, the treprostinil sponsor, and physicians who treat patients with PAH. Patients stable on epoprostenol were to be transitioned to SC treprostinil or placebo and carefully monitored for signs of clinical deterioration, following which they would be returned promptly to epoprostenol therapy for the duration of the study. *From the University of Michigan Health System (Drs. Rubenfire and McLaughlin), Ann Arbor, MI; UC Davis Medical Center (Dr. Allen), Sacramento, CA; LDS Hospital and the University of Utah (Dr. Elliot), Salt Lake City, UT; University of Maryland School of Medicine (Dr. Park), Baltimore, MD; United Therapeutics Corporation (Dr. Wade), Research Triangle Park, NC; and University Hospitals of Cleveland (Dr. Schilz), Cleveland, OH. †For the Treprostinil Phase 4 Study Group: R. Clayton, RN, and S. McDevitt, RN; MSN, University of Michigan, Ann Arbor, MI; L. Latham, RN, and L. Slaughter RN, University Hospitals of Cleveland, Cleveland, OH; A. Hoso, RN, UC Davis Medical Center, Sacramento, CA; N. Kitterman, RN, LDS Hospital, Salt Lake City, UT; B. Harris, RN, and M. Franklin, LNP, Oschner Clinic, New Orleans, LA; J. Sigman, C. Arneson, M.Stat, W. DellaMaestra, S. McSwain, D. Preston, DVM, and R. Jeffs, PhD, United Therapeutics Corporation, Research Triangle Park, NC. This work was performed at the University of Michigan Health System, UC Davis Medical Center, LDS Hospital and the University of Utah, and the University of Maryland School of Medicine. Dr. Rubenfire has served as principal investigator of research projects sponsored by Pfizer, United Therapeutics, Encysive, and CoTherix, and Dr. Rubenfire has owned stock in United Therapeutics. Dr. McLaughlin has served as a consultant, speaker, and/or member of the advisory board for Actelion, CoTherix, Encysive, Myogen, Pfizer, and United Therapeutics, and has received grant support from Actelion, CoTherix, Encysive, Lung Rx, Pfizer, and United Therapeutics. Dr. Allen has been reimbursed as a consultant from several companies, including Actelion, Encysive, and CoTherix. He has also received grant/contract support from Actelion, Myogen, United Therapeutics, and Emphasys Medical. Dr. Allen is also on speakers’ bureaus for Bristol-Myers Squibb and Boehringer-Ingleheim. Dr. Elliot has served as a principal investigator of research projects sponsored by Pfizer, United Therapeutics, CoTherix, and Encysive, and has served as a consultant, speaker, and/or member of advisory boards for Actelion, CoTherix, Encysive, and United Therapeutics. Dr. Park has participated as a speaker in scientific meetings or courses organized and financed by Actelion, CoTherix, GlaxoSmithKline, Pfizer, and United Therapeutics. Dr. Wade is an employee of United Therapeutics. Dr. Schilz serves as a consultant and lecturer for commercial sponsors, as well as serves on advisory boards. He also has industry-sponsored grants. Members of the Data Safety Monitoring Board include B. Brundage, MD, chair; M. McGoon, MD; and P. Westfall, PhD. Discontinuation Events Adjudication Committee members are R. Bourge, MD, chair; V. Tapson, MD; and N. Hill, MD. Manuscript received August 28, 2006; revision accepted February 13, 2007. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Melvyn Rubenfire, MD, University of Michigan, 24 Frank Lloyd Wright Dr, Ann Arbor, MI 48106-0363; e-mail: [email protected] DOI: 10.1378/chest.06-2118 758

Materials and Methods We conducted an 8-week, multicenter, randomized, placebocontrolled withdrawal trial in which PAH patients stable on epoprostenol therapy were transitioned to study drug (SC treprostinil or placebo, 2:1) over a period of up to 14 days (Table 1). Informed consent for the study protocol was obtained in writing, utilizing the document and protocol approved by each participating author’s institutional review board. Patients remained hospitalized during the transition period and for at least 24 h after the epoprostenol infusions were terminated. Those who could not complete the transition to study drug or who had clinical deterioration were returned to continuous IV epoprostenol. Assessments were conducted at baseline, prior to discharge after the transition period, and at weeks 4 and 8. The primary end point was time to clinical deterioration as determined by the investigator, and was supported by objective criteria. The Discontinuation Events Adjudication Committee adjudicated each deterioration event and all premature discontinuations from study drug. Prospective secondary end-points included the 6-min walk test with Borg dyspnea score, dyspnea fatigue index, symptoms of PAH, and cardiovascular hospitalizations. Eligibility criteria included the following: age 18 to 75 years; WHO functional class II or III; stable symptoms for 30 days; baseline 6-min walk distance of at least 250 m; and PAH diagnosis limited to idiopathic/familial, or associated with scleroderma, congenital systemic to pulmonary shunt, HIV, or portal hypertension. Patients must have been receiving epoprostenol therapy for ⱖ 3 months, with no dose changes within 15 days, and a current dose of 10 to 75 ng/kg/min. Because of the placebo control and minimal experience for withdrawal from epoprostenol or conversion to SC treprostinil at the time of the study, the withdrawal dosing scheme was more conservative than has subsequently been used clinically (Table 1). Inability to discontinue epoprostenol within 14 days was considered study drug treatment failure. Any need to increase the epoprostenol dose during the transition period, or clinical deterioration after the transition period despite study drug dose increases were considered treatment failure. Patients were instructed not to discuss infusion site pain with the investigator, and investigators were instructed not to examine study drug infusion sites. Statistical Analysis Study population and dosing data are presented as mean ⫾ SD; outcome data are presented as mean ⫾ SE. The planned enrollment under the protocol, as amended, was approximately 39 patients. This provided 90% power at a significance level of 0.05 (two sided) to detect a 4.5-fold increase in the median time to clinical deterioration from a placebo median time of 3.45 weeks, assuming exponential distributions. A prospectively planned interim analysis of the primary end point was conducted after the first 21 patients completed the study, and enrollment was suspended after the 22nd patient was enrolled based on the interim results. The primary efficacy end point, time to adjudicated clinical deterioration, was tested using the exact (permutation distribution-based) method of the log-rank test, as performed using statistical software (StatXact-4; Cytel Software Corporation; Cambridge, MA).18 Results of the distributions of time to clinical deterioration were displayed using a Kaplan-Meier plot. For the interim analysis, the primary end point was tested using a Pocock boundary.19 For the 6-min walk test, in addition to measuring the distance traversed during the test, dyspnea was assessed by each patient at the completion of the test using a 10-point scale, the Borg dyspnea score. Dyspnea fatigue index changes from baseline were compared between groups using the Wilcoxon rankOriginal Research

Table 1—Recommended Transition Period Dose Changes Dose Transition Day 1 2 3 4 5 6 7

Epoprostenol Dose

Study Drug Dose

Unchanged 80% starting epoprostenol dose 60% starting epoprostenol dose 40% starting epoprostenol dose 20% starting epoprostenol dose 5% starting epoprostenol dose 0

10% starting epoprostenol dose 30% starting epoprostenol dose 50% starting epoprostenol dose 70% starting epoprostenol dose 90% starting epoprostenol dose 110% starting epoprostenol dose 110% starting epoprostenol dose plus additional 5 to 10% as needed Additional 5 to 10% as needed Additional 5 to 10% as needed Additional 5 to 10% as needed Additional 5 to 10% as needed Additional 5 to 10% as needed Additional 5 to 10% as needed Additional 5 to 10% as needed

8* 9* 10* 11* 12* 13* 14*

0 0 0 0 0 0 0

*As needed. Patients must remain hospitalized at least 24 h after epoprostenol dose has been discontinued.

sum test. Imputations were used for analysis of secondary end points. Imputing missing data using prespecified rules is helpful in the case of controlled trials that allow rescue therapy when missing data are expected and patients could die or become severely ill without rescue.

Results Study Patients Twenty-two patients were enrolled and completed the study between October 2002 and August 2005. Fourteen patients were randomized to treprostinil, and 8 were randomized to placebo. Treatment groups were well matched for demographics, medical history, and baseline epoprostenol dose (Table 2), and were typical of a PAH study population. Nine-

teen of the patients were women, and 16 patients had idiopathic or familial PAH. In the treprostinil group, nine patients were WHO class II and five patients were WHO class III for dyspnea/fatigue; while in the placebo group, three patients were WHO class II, four patients were class III, and one patient was WHO class I. Mean durations of epoprostenol therapy were 3.2 ⫾ 0.68 years and 3.4 ⫾ 0.95 years in the treprostinil and placebo groups, respectively. Study Drug and Epoprostenol Dosing Summary dosing and outcome data are shown in Table 3. All 14 patients randomized to SC treprostinil completed the transition to study drug. Of the eight patients randomized to placebo, five patients

Table 2—Baseline Demographics and PAH History* Parameters Age, yr Gender Female Male Duration of PAH, yr Time at current WHO class, yr WHO classification Class I Class II Class III Six-minute walk distance, m Diagnosis Idiopathic PAH PAH associated with scleroderma PAH associated with congenital systemic-to-pulmonary shunt PAH associated with portopulmonary hypertension Duration of epoprostenol therapy, yr

Treprostinil (n ⫽ 14) 47.1 ⫾ 3.2

Placebo (n ⫽ 8) 42.6 ⫾ 4.1

12 (86) 2 (14) 4.4 ⫾ 0.85 1.4 ⫾ 0.41

7 (88) 1 (13) 3.5 ⫾ 0.96 1.6 ⫾ 0.82

0 (0) 9 (64) 5 (36) 436.6 ⫾ 26.2

1 (13) 3 (38) 4 (50) 423.9 ⫾ 30.6

10 (71) 2 (14) 1 (7) 1 (7) 3.2 ⫾ 0.68

6 (75) 1 (13) 0 (0) 1 (13) 3.4 ⫾ 0.95

*Data are presented as mean ⫾ SE or No. (%). www.chestjournal.org

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Table 3—Summary of Dosing and Outcome Data* Treatment Group Variables Completed transition from epoprostenol Yes No Mean time to complete transition, d Clinical deterioration Epoprostenol dose at baseline, ng/kg/min Mean study drug dose at transition, ng/kg/min Mean maximum study drug dose, ng/kg/min Maximum study drug dose as a percentage of baseline epoprostenol dose, %

Treprostinil (n ⫽ 14)

Placebo (n ⫽ 8)

14 (100) 0 (0) 7.0 ⫾ 0.4 (n ⫽ 14) 1 (7) 22.3 ⫾ 3.3 (n ⫽ 14) 25.3 ⫾ 3.5 (n ⫽ 14) 32.2 ⫾ 4.9 (n ⫽ 14) 152.6 ⫾ 20.3 (n ⫽ 14)

5 (63) 3 (38) 7.5 ⫾ 1.1 (n ⫽ 5) 7 (88) 30.0 ⫾ 5.6 (n ⫽ 8) 32.0 ⫾ 9.4 (n ⫽ 5) 37.3 ⫾ 6.0 (n ⫽ 8) 134.6 ⫾ 12.8 (n ⫽ 8)

*Data are presented as No. (%) or mean ⫾ SE.

(63%) completed the transition from epoprostenol, while three patients (38%) did not complete the transition to study drug (ie, could not be weaned off epoprostenol). Mean times to complete the transition to study drug in patients who completed the transition were 7 days and 7.5 days in the treprostinil and placebo groups, respectively. Mean maximum study drug doses were 32.2 ⫾ 4.9 ng/kg/min and 37.3 ⫾ 6.0 ng/kg/min for patients in the SC treprostinil and placebo groups, respectively. Primary End Point (Clinical Deterioration) Seven of 8 patients (88%) transitioned to placebo had clinical deterioration, compared to only 1 of 14 patients (7%) withdrawn to SC treprostinil therapy (Table 3). The only placebo-treated patient without clinical deterioration by week 8 was the lone WHO class I patient (sponsor-allowed protocol deviation). The SC treprostinil-treated patient with deterioration had a syncopal event during the transition period of the study. The patient was unblinded for safety reasons and was found to be receiving treprostinil. However, the patient declined to return to epoprostenol therapy and finished the study receiving SC treprostinil, a protocol violation. The patient was adjudicated as a study drug treatment failure because the syncopal event that led to unblinding was considered clinical deterioration. A second syncopal event in the treprostinil group (Table 4) was attributed to a blood draw. This patient remained stable for the remainder of the trial on an increased dose of SC treprostinil. Figure 1 shows a KaplanMeier plot of the distribution of time to clinical deterioration through week 8. The time to adjudicated clinical deterioration for each treatment group is displayed in days and is plotted against the percentage of patients without a clinical deterioration event in each group. The final primary analysis, which included all 22 randomized patients, yielded a nominal p value of 0.00023 in favor of treprostinil therapy. 760

Six-Minute Walk and Borg Dyspnea Score In the principle analysis of 6-min walk distance alone (imputing the worst rank for clinical deterioration and those too ill to walk, and last observation for discontinuations due to an adverse event [AE]), mean walk distance differences comparing the week 8 visit and baseline were ⫺ 35.2 ⫾ 40.1 m in the treprostinil group and ⫺ 357.4 ⫾ 68.8 m in the placebo group (p ⫽ 0.0041) [Table 5]. The mean treatment effect in the SC treprostinil group was negatively affected by a decrease in 338 m in walk distance in a patient who inadvertently turned off the infusion pump on the day of the hall walk. Thirty-six hours after resuming study drug, her walk distance was unchanged from previous. Because week 8 6-min walk and Borg dyspnea score tests were conducted for most patients, including patients who

Table 4 —Most Frequent AEs in the Treprostinil Group* AEs

Treprostinil (n ⫽ 14) Placebo (n ⫽ 8)

Infusion site pain Nausea Headache Diarrhea Infusion site erythema Dizziness Flushing Upper respiratory infection Vomiting Pain in jaw Abdominal distension Pain in extremity Dyspnea Infusion site induration Infusion site swelling Injection site pruritis Pyrexia Syncope Infusion site warmth

13 (93) 6 (43) 6 (43) 7 (50) 10 (71) 6 (43) 6 (43) 5 (36) 4 (29) 4 (29) 3 (21) 3 (21) 2 (14) 3 (21) 3 (21) 2 (14) 2 (14) 2 (14) 2 (14)

3 (38) 6 (75) 5 (63) 3 (38) 0 (0) 3 (38) 3 (38) 1 (13) 1 (13) 1 (13) 1 (13) 1 (13) 1 (13) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)

*Data are presented as No. (%). Original Research

Figure 1. Kaplan-Meier plot of the distribution of change from baseline for time to clinical deterioration at week 8.

were terminated early from study drug, actual week 8 data (as opposed to imputed data for patients with clinical deterioration) were also compared to baseline data (Table 5). The principle analysis of the Borg dyspnea score (worst rank for clinical deterioration and those too ill to walk; last observation carried forward for discontinuations due to an AE) showed mean differences from baseline of 0.61 ⫾ 0.60 in the treprostinil group and 5.63 ⫾ 0.94 in the placebo group (p ⫽ 0.0017). Observed Borg score data were available for 12 patients randomized to SC treprostinil who finished week 8 receiving the study drug, and five placebotreated patients who were rescued and finished the study receiving epoprostenol therapy (Table 5). In the treprostinil group, the mean change in Borg score at week 8 was 0.17 ⫾ 0.33. In the placebo group, the mean change in Borg score at week 8 using observed data was ⫺ 0.70 ⫾ 1.22. One placebo-treated patient had a decrease of ⫺ 5.5 at week 8, accounting for much of the decline as well as the large SE in that group. Similar results were found using the dyspnea fatigue index (primary imputation; Table 5) Patients in the SC treprostinil group maintained their baseline status with a mean change of 0.1 ⫾ 0.6, compared to a mean change of ⫺ 5.8 ⫾ 1.1 in placebotreated patients (p ⫽ 0.0016). One would expect few overall changes between baseline and week 8 because most patients randomized to placebo were rescued with epoprostenol therapy prior to week 8, and most patients randomized to treprostinil were maintained on the study drug. Safety AEs were reported in all patients. There were 150 AEs in the SC treprostinil group (10.7 AEs per www.chestjournal.org

patient treated) and 68 AEs in the placebo group (8.5 AEs per patient treated), of which moderate or severe were reported in 79% of treprostinil-treated patients and 75% of placebo-treated patients. AEs reported by more than one patient in the treprostinil treatment group are shown in Table 4. Nearly all SC treprostinil-treated patients (93%) reported infusion site pain, as did three placebo-treated patients (38%). Infusion site pain was reported as moderate or severe in nine SC treprostinil-treated patients and one placebo-treated patient, and one SC treprostiniltreated patient withdrew consent because of moderate infusion site pain and erythema. A serious AE of “increase in PAH symptoms” was reported in the SC treprostinil-treated patient whose infusion pump was found to be turned off at the week 8 visit. In the placebo group, three patients had serious AEs (two instances of worsening PAH, and one case of right ventricular failure) that were associated with adjudicated clinical deterioration events. Eight of the nine discontinuations were due to adjudicated clinical deterioration events, seven of them in the placebo group. Moderate infusion site pain and erythema were listed as the reasons for study drug termination in a SC treprostinil-treated patient, who withdrew consent and was returned to epoprostenol therapy. Seven of the nine patients who discontinued from study drug did so within the first 2 weeks of the study. Discussion We found that SC treprostinil prevents clinical deterioration in stable patients with PAH who are withdrawn from epoprostenol therapy. Seven of eight epoprostenol-treated patients who were withdrawn to placebo had clinical deterioration during the 8-week study period. Of these patients, three could not be weaned off epoprostenol therapy, and two others had clinical deterioration within a few days of the termination of epoprostenol infusion; one patient had clinical deterioration within 28 days, and another patient had clinical deterioration at 39 days. The lone patient who was weaned off epoprostenol and did not have clinical deterioration with placebo therapy was the only study patient with mild (WHO class I) PAH symptoms at baseline. In contrast, all 14 patients randomized to SC treprostinil were weaned off epoprostenol, and only 1 of these patients had a clinical deterioration event. This patient declined to return to epoprostenol therapy (a protocol violation) and was continued on treprostinil for the duration of the study. The primary end point, time to clinical deterioration, was highly significant in favor of treprostinil (p ⫽ 0.00023). Secondary efficacy end points strongly supported CHEST / 132 / 3 / SEPTEMBER, 2007

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Table 5—Summary of Secondary Efficacy End Point Findings* Change From Baseline Parameters† Six-minute walk distance, m Primary imputation Observed data Borg dyspnea score Primary imputation Observed data Dyspnea fatigue index Primary imputation Observed data

Treprostinil (n ⫽ 14)

Placebo (n ⫽ 8)

p Value

⫺ 35.2 ⫾ 40.1 ⫺ 12.5 ⫾ 33.6 (n ⫽ 12)

⫺ 357.4 ⫾ 68.8 1.6 ⫾ 12.3 (n ⫽ 5)

0.004

0.61 ⫾ 0.60 0.17 ⫾ 0.33 (n ⫽ 12)

5.63 ⫾ 0.94 ⫺ 0.70 ⫾ 1.22 (n ⫽ 5)

0.0017

⫺ 5.8 ⫾ 1.1 0.0 ⫾ 0.7 (n ⫽ 6)

0.0016

0.1 ⫾ 0.60 ⫺ 0.1 ⫾ 0.5 (n ⫽ 12)

*Data are presented as mean ⫾ SE. †Primary imputation is the worst rank for clinical deterioration and being too ill to walk, and last observation carried forward for all others. Observed data are actual results for treprostinil-treated patients who remained on study drug (n ⫽ 12), or placebo-treated patients who were rescued and receiving epoprostenol at the week 8 visit (n ⫽ 6), and who completed the assessment at week 8.

the efficacy of SC treprostinil therapy. Analyses of the 6-min walk with Borg dyspnea score (combined and separate) and dyspnea fatigue index, comparing baseline and week 8 data and imputing worst rank to patients with clinical deterioration were strongly favorable to SC treprostinil therapy. Further, most analyses of these end points carrying forward last observations around the time of clinical deterioration were statistically significant, or approached significance, in favor of treprostinil. While the study was not powered to compare SC treprostinil and IV epoprostenol, the study design does allow a descriptive comparison by examining secondary end points in patients completing the study. Baseline exercise capacity and shortness of breath measures were similar to week 8 results in both treatment groups, suggesting that subcutaneous treprostinil maintained the clinical status of patients who were receiving optimal epoprostenol therapy at baseline. The mean maximum dose of treprostinil required to maintain the clinical benefit of epoprostenol during the 8-week period was 153% of the baseline epoprostenol dose on the basis of nanograms per kilogram per minute. This is slightly greater than previous initial dosing reported by Vachiery and colleagues.20 Safety findings were consistent with previous studies1,2,13,14 of SC treprostinil and epoprostenol in PAH patients. Infusion site-related adverse events were anticipated in the treprostinil group and were also reported in the placebo group, and infusion site issues did not appear to affect the interpretation of study efficacy end points. At the time of design of this study, there were no good alternative options for the PAH patients requiring epoprostenol. This study was designed to evaluate a potential option by assessing the efficacy of optimal dosing of SC treprostinil in PAH patients 762

who were stable on epoprostenol. The benefit/risk ratio was carefully considered by the sponsor, investigators, and an independent Data Safety Monitoring Board prior to and during the study. The decision of whether the benefit/risk ratio was appropriate for a potential study patient balanced the possibility that carefully monitored patients with deterioration with SC treprostinil or placebo would not respond to resumption of epoprostenol, against long-term advantages of SC treprostinil. Limitations of the study included the small patient numbers, the possibility of inadvertent unblinding due to SC infusion site pain, and a short duration without long-term follow-up. However, our safety and efficacy data are consistent with a number of published uncontrolled studies using treprostinil. Lang et al21 reported an increase in 6-min walk distance from 305 ⫾ 11 m at baseline to 444 ⫾ 29 m at the 49- to 54-month time point in 99 patients (WHO class II-IV) with PAH and 23 patients with chronic thromboembolic pulmonary hypertension treated with SC treprostinil. Two additional reports of IV treprostinil are also comparable to our data since SC infusion is bioequivalent to IV treprostinil at steady state, at least at low doses in normal volunteers.11 These uncontrolled trials suggest that treprostinil has effects on exercise capacity similar to those of epoprostenol when dosed appropriately in PAH patients previously untreated with a prostacyclin-class medication,14 and also maintained or improved the clinical status of patients for 1 year after transition from epoprostenol therapy.15 At least one additional small uncontrolled transition study16 has demonstrated safe transition from epoprostenol to IV treprostinil using a “rapid switch” protocol. This method involved swapping the infusion pump cassette containing epoprostenol for a cassette containing treprostinil without gradual dose Original Research

titrations of the medications, and was safe and efficacious over 12 weeks.16 Since the implementation of this study, uncontrolled studies21,22 in several hundred patients have reported improved symptoms as well as a survival advantages for PAH and chronic thromboembolic pulmonary hypertension in patients receiving long-term SC treprostinil therapy similar to those observed with epoprostenol based on registry survival curves for untreated patients. Long-term IV epoprostenol therapy is the treatment of choice and very effective in high-risk (WHO class IV) patients with PAH, but not without several disadvantages, including frequent catheter infections and life-threatening bacteremia, and a large pump requiring frequent cassette changes and or ice for stability. Our results and those of Vachiery et al20 support the safety and feasibility of transitioning from epoprostenol to SC treprostinil in patients having difficulty with IV therapy. Transitioning to oral therapies in selected low-risk patients with programmed gradual weaning off prostacyclin is another attractive option, but one whose safety and long-term efficacy are yet to be established.23 Steiner et al23 reported successful gradual weaning off IV epoprostenol (8 of 17 attempted) and SC treprostinil (2 of 5 attempted) in 10 of 22 patients who had begun bosentan 2 to 12 months prior to attempted weaning. We agree with Steiner et al,23 who caution that weaning IV or SC prostacyclin exposes patients to risks of rapid and unpredictable deterioration, after which reinstitution of prostacyclin may no longer be effective. References 1 McLaughlin VV, Genthner DE, Panella MM, et al. Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. N Engl J Med 1998; 338:273–277 2 Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996; 334:296 –301 3 Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. Ann Intern Med 2000; 132:425– 434 4 Sanchez O, Humbert M, Sitbon O, et al. Treatment of pulmonary hypertension secondary to connective tissue diseases. Thorax 1999; 54:273–277 5 Rosenzweig EB, Kerstein D, Barst RJ. Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects. Circulation 1999; 99:1858 –1865 6 McLaughlin VV, Barst RJ, Rich S, et al. Efficacy and safety of UT-15, a prostacyclin analog, for primary pulmonary hypertension [abstract]. Eur J Cardiol 1999; 20:486

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7 Data JL, Molony BA, Meinzinger MM, et al. Intravenous infusion of prostacyclin sodium in man: clinical effects and influence on platelet adenosine diphosphate sensitivity and adenosine 3⬘:5⬘-cyclic monophosphate levels. Circulation 1981; 64:4 –12 8 Humbert M, Sanchez O, Fartoukh M, et al. Short-term and long-term epoprostenol (prostacyclin) therapy in pulmonary hypertension secondary to connective tissue diseases: results of a pilot study. Eur Respir J 1999; 13:1351–1356 9 McNulty MJ, Sailstad JM, Steffen RP. The pharmacokinetics and pharmacodynamics of the prostacyclin analog 15AU81 in the anesthetized beagle dog. Prostaglandins Leukot Essent Fatty Acids 1993; 43:159 –166 10 Steffen RP, de la Mata M. The effects of 15AU81, a chemically stable prostacyclin analog, on the cardiovascular and rennin-angiotensin systems of anesthetized dogs. Prostaglandins Leukot Essent Fatty Acids 1999; 43:277–286 11 Laliberte K, Arneson C, Jeffs R, et al. Pharmacokinetics and steady-state bioequivalence of treprostinil sodium (Remodulin®) administered by the intravenous and subcutaneous route to normal volunteers. J Cardiovasc Pharmacol 2004; 44:209 –2144 12 Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension. Am J Respir Crit Care Med 2002; 165:800 – 804 13 McLaughlin VV, Gaine SP, Barst RJ, et al. Efficacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension. J Cardiovasc Pharmacol 2003; 41:293–299 14 Tapson VF, Barst RJ, Gomberg-Maitland M, et al. Long-term safety and efficacy of intravenous treprostinil for pulmonary arterial hypertension [abstract]. American Thoracic Society 2005; 2:A204 15 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; 172:1586 –1598 16 Sitbon O, Manes A, Jais X, et al. Rapid switch from intravenous epoprostenol to intravenous treprostinil in patients with pulmonary arterial hypertension [abstract]. Presented at ATS International Conference, San Diego, CA, May 19 –24, 2006 17 Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002; 347:322–329 18 Mehta C, Patel N: StatXact 4 for Windows user manual. Cambridge, MA: Cytel Software Corporation, 1999 19 Pocock SJ. Group sequential methods in the design and analysis of clinical trials. Biometrika 1977; 64:191–199 20 Vachiery JL, Hill N, Zwicke D, et al. Transitioning from IV epoprostenol to subcutaneous treprostinil in pulmonary arterial hypertension. Chest 2002; 121:1561–1565 21 Lang I, Gomez-Sanchez M, Kneussl M, et al. Efficacy of long-term subcutaneous treprostinil sodium therapy in pulmonary hypertension. Chest 2006; 129:1636 –1643 22 Gibbs JRS, Arneson CP. Chronic infusion of treprostinil is safe and appears to prolong survival over a three-year period in patients with pulmonary arterial hypertension [abstract]. Circulation 2002; 106(suppl II):575 23 Steiner MK, Preston IR, Klinger JR, et al. Conversion to bosentan from prostacyclin infusion therapy in pulmonary arterial hypertension: a pilot study. Chest 2006; 130:1471– 1480

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