O R I G I N A L R E S E A R C H
`
`Safety and efficacy of transition from inhaled treprostinil to
`parenteral treprostinil in selected patients with pulmonary
`arterial hypertension
`
`Ioana R. Preston,1 Jeremy Feldman,2 James White,3 Veronica Franco,4 David Ishizawar,5
`Charles Burger,6 Aaron B. Waxman,7 Nicholas S. Hill1
`
`1Tufts Medical Center, Boston, Massachusetts, USA; 2St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, USA; 3University
`of Rochester Medical Center, Rochester, New York, USA; 4Ohio State University, Columbus, Ohio, USA; 5University of Pittsburgh
`Medical Center, Pittsburgh, Pennsylvania, USA; 6Mayo Clinic, Jacksonville, Florida, USA; 7Brigham and Women’s Hospital, Bos-
`ton, Massachusetts, USA
`
`Abstract: Guidelines for the treatment of pulmonary arterial hypertension (PAH) recommend sequential
`add-on therapy for patients who deteriorate or fail to improve clinically. However, it is not known whether
`these patients also benefit from transitioning from inhaled prostacyclins to parenteral prostacyclins. We
`sought to characterize PAH patients receiving inhaled treprostinil who were transitioned to parenteral tre-
`prostinil. We conducted a multicenter retrospective study at 7 PAH centers and collected reasons, methods,
`safety, and outcome of patients transitioned from inhaled treprostinil to parenteral treprostinil. Twenty-six
`patients with pulmonary hypertension in group 1, 4, or 5 transitioned from inhaled treprostinil to parenteral
`treprostinil (10 intravenous, 16 subcutaneous). Twenty-four patients were also on one or two oral therapies.
`Reasons for transition were clinical deterioration, lack of clinical improvement, and pregnancy (19, 6, and
`1 patients, respectively). Transitions occurred in hospital, clinic, or home (17, 7, and 2 patients, respectively).
`Parenteral infusion was started after the last inhaled treatment at maintenance dose (13 patients), after the
`inhaled therapy was downtitrated to 18 μg (6 patients), or with an overlap of inhaled downtitration with par-
`enteral uptitration (7 patients). The transition was safe; side effects included symptoms of prostacyclin over-
`dose. Patients were followed for 3–18 months. At 3 months, 8 patients improved, 17 maintained their func-
`tional class, and 1 continued to deteriorate. In conclusion, selected PAH patients can be safely transitioned
`from inhaled treprostinil to parenteral treprostinil using a variety of methodologies in different settings with
`the expectation that patients will improve or at least remain clinically stable.
`
`Keywords: prostacyclin analogues, goal-oriented therapy, multicenter study.
`
`Pulm Circ 2014;4(3):456-461. DOI: 10.1086/677360.
`
`I N T R O D U C T I O N
`Pulmonary arterial hypertension (PAH) is a progressive
`disease that leads to right ventricular failure and death.
`Three classes of drugs are currently available for the treat-
`ment of PAH: prostanoids, phosphodiesterase-5 inhibi-
`tors, and endothelin receptor antagonists. Current PAH
`treatment uses a goal-oriented approach, which targets im-
`provements in various markers of disease that are impor-
`tant predictors of outcome, such as New York Heart Asso-
`ciation (NYHA) functional class,1 6-minute walk distance
`(6MWD),2 and certain hemodynamic parameters, such as
`cardiac output and right atrial pressure.3 Current recommen-
`
`dations include step-up therapy if patients fail to meet tar-
`gets or deteriorate.4 In addition, adding or switching to a
`drug from one class to another and changing the route of
`administration of drugs that have multiple routes of deliv-
`ery are considerations when the current treatment is poorly
`tolerated or ineffective. However, there is no clear consen-
`sus on how and when to make these changes or specifically
`what therapies to add or substitute.
`Within the class of prostanoids, three related com-
`pounds with different pharmacologic structures are cur-
`rently available in the United States: epoprostenol, which
`
`Address correspondence to Dr. Ioana R. Preston, Tufts Medical Center, 800 Washington Street, Box 257, Boston, MA 02111, USA. E-mail:
`ipreston@tuftsmedicalcenter.org.
`
`Submitted January 6, 2014; Accepted April 16, 2014; Electronically published August 12, 2014.
`© 2014 by the Pulmonary Vascular Research Institute. All rights reserved. 2045-8932/2014/0403-0012. $15.00.
`
`IPR2021-00406
`United Therapeutics EX2090
`
`

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`Pulmonary Circulation
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`Volume 4
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`Number 3
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`September 2014
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`| 457
`
`is administered via continuous intravenous infusion; ilo-
`prost, administered via the inhaled route; and treprostinil,
`administered via inhaled and continuous intravenous or
`subcutaneous infusion routes. Two open-label multicen-
`ter clinical trials supported the safety of transitioning from
`epoprostenol to intravenous or subcutaneous treprostinil
`with maintenance of clinical stability in selected patients.5,6
`Conversely, similar to a prior report showing that transi-
`tion from parenteral prostacyclins to oral therapies is not
`always successful in an otherwise stable patient,7 transition
`from parenteral prostacyclins to inhaled treprostinil in sta-
`ble patients was associated with deterioration in 4 out of
`the 18 patients studied retrospectively.8 These reports sug-
`gest that certain patients respond differentially not only to
`different therapies but also to the same drug when admin-
`istered by a different route. It is also not known whether
`parenteral forms of treprostinil can still be effective when
`there has been a lack or loss of response to the inhaled
`form. In this multicenter retrospective study, we sought to
`characterize PAH patients receiving inhaled treprostinil
`who, in the opinion of the investigator, required transition
`to parenteral treprostinil, with the aim of assessing the safety
`and clinical efficacy of this transition.
`
`M E T H O D S
`A multicenter retrospective chart review was performed
`at 7 PAH centers with extensive experience in using all
`PAH-specific therapies, including inhaled and parenteral
`prostanoids for the management of PAH. The study was
`approved by the institutional review board (IRB) at Tufts
`Medical Center, and local IRB approvals were obtained by
`each center prior to collection of data. Clinical data were
`collected between April 2007 and March 2012 from con-
`secutive adult patients with PAH with World Health Orga-
`nization groups 1, 4, and 54 who were transitioned from
`inhaled treprostinil to parenteral treprostinil (intravenous
`or subcutaneous routes). The reason and method for tran-
`sition were determined at each center by the local PAH
`team, without a prespecified protocol. Data included base-
`line demographics, location of transition, reasons and meth-
`ods for transition, assessments of PAH severity within 1 month
`before and 3 to 6 months after transition, adverse events en-
`countered during and after transition, and long-term out-
`comes. In our statistical analyses, demographic and clini-
`cal characteristics are presented in a descriptive fashion as
`
`means standard deviations and ranges.
`
`R E S U L T S
`Baseline characteristics
`Twenty-six patients underwent transition from inhaled tre-
`prostinil to parenteral treprostinil. Demographic data are
`
`presented in Table 1. The majority of patients had idio-
`pathic, heritable, or drug- and toxin-associated PAH; were
`treated with inhaled treprostinil in combination with one
`or two oral PAH therapies (Table 2); and had poor func-
`tional capacity as evidenced by a low 6MWD and an ad-
`
`Table 1. Demographic and clinical characteristics
`of patients transitioned
`
`Characteristics
`
`No.
`
`No. of patients (F/M)
`
`Age, years, mean  SD (range)
`Type of PAH, n
`IPAH, HPAH, drugs/toxins
`PAH-CTD
`PAH-CHD
`PoPH
`CTEPH
`PAH WHO Group 5a
`NYHA FC in the month prior
`to transition, n
`
`1
`2
`3
`4
`6MWD within 1 month before transition
`
`(n = 20 patients), m, mean 
`
`SD (range)
`Reason for transition, n
`Clinical deterioration
`Lack of clinical improvementb
`Pregnancy
`Place of transition, n
`In hospital
`Outpatient clinic
`Home
`
`26 (17/9)
`
`53  14 (19–85)
`
`13
`3
`2
`5
`1
`2
`
`0
`7
`17
`2
`
`287  152 (55 – 498)
`
`19
`6
`1
`
`17 (10 SQ, 7 IV)
`7 (4 SQ, 3 IV)
`2 (SQ)
`
`Note: 6MWD: 6-minute walk distance; CTEPH: chronic throm-
`boembolic pulmonary hypertension; F: females; HPAH: herita-
`ble pulmonary arterial hypertension; IPAH: idiopathic pulmo-
`nary arterial hypertension; IV: intravenous; M: males; NYHA
`FC: New York Heart Association functional class; PAH: pulmo-
`nary arterial hypertension; PAH-CHD: congenital heart disease–
`associated pulmonary arterial hypertension; PAH-CTD: connec-
`tive tissue disease–associated pulmonary arterial hypertension;
`PoPH: portopulmonary hypertension; SD: standard deviation;
`SQ: subcutaneous; WHO: World Health Organization.
`a The two patients in group 5 had sarcoidosis and polyneu-
`ropathy, organomegaly, endocrinopathy, monoclonal protein, and
`skin changes (POEMS) syndrome, respectively.
`b One patient who was transitioned for inadequate response
`also complained of cough.
`
`

`

`458
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`|
`
`Inhaled treprostinil to parenteral treprostinil in PAH
`
`Preston et al.
`
`Table 2. Background therapies of patients transitioned
`
`Therapy
`
`Concomitant PAH-specific therapy
`None
`PDE-5i
`ERAs
`PDE-5i + ERAs
`Anticoagulation
`Duration of inhaled treprostinil before
`
`transition, months, mean  SD (range)
`
`Dose of inhaled treprostinil at the time
`of transition
`
`μg × 4 times/day, mean  SD (range)
`No. of breaths × 4 times/day, mean 
`
`SD (range)
`
`No.
`
`2
`15
`3
`6
`13
`
`12.7  5.7 (2–50)
`
`56  10 (18–90)
`9.3  1.6 (3–15)
`
`Note: ERAs: endothelin receptor blockers; PAH: pulmonary
`arterial hypertension; PDE-5i: phosphodiesterase-5 inhibitors; SD:
`standard deviation.
`
`vanced NYHA functional class prior to transition (Table 1).
`At the time of transition, patients had been on inhaled tre-
`prostinil for at least 2 months, 23 of them were receiving
`the recommended dose of 54 μg (9 puffs) 4 times a day or
`higher, and most were on a combination with one or two
`oral therapies (Table 2). The most common reason for
`transition to parenteral treprostinil was clinical deteriora-
`tion, followed by lack of clinical improvement on the cur-
`rent regimen (Table 1). No patients were transitioned to
`infusion therapy because of intolerance or noncompliance
`with inhaled treprostinil. One patient became pregnant
`while on a combination of inhaled treprostinil and sil-
`denafil without experiencing clinical deterioration or an in-
`adequate response. She was transitioned to intravenous tre-
`prostinil until her successful delivery and then was switched
`back to the inhaled route.
`
`maining 7 patients, the inhaled dose was downtitrated
`while the parenteral infusion was started at 2– 4 ng/kg/
`min and uptitrated. Inhalation was then stopped when
`the parenteral infusion rate reached 10–20 ng/kg/min, an
`overlap process that took 1–13 days. All oral PAH-specific
`therapies were continued throughout the transition to par-
`enteral treprostinil.
`
`Follow-up after transition
`At 3 months after transition, 8 patients had improved their
`NYHA functional class (Fig. 1A; 7 patients improved from
`functional class 3 to 2 and 1 from 4 to 3), and 17 main-
`tained their functional class. One patient with portopul-
`monary hypertension remained in functional class 4 and
`died from end-stage liver failure soon after the transition.
`Among the 12 patients who had 6MWDs 1 month before
`and 3–6 months after transition, 4 had at least a 10% im-
`provement, another 4 maintained their walks within 10%
`pretransition, and the last 4 had a decline of at least 10%
`(Fig. 1B). Brain natriuretic peptide (BNP) was measured in
`13 patients prior to transition (average 496  388, range
`
`20–1,201 pg/mL). Among the 9 patients who had BNP
`measurements 1 month before and 3–6 months after tran-
`sition, 8 patients showed improvements (Fig. 1C).
`
`Hemodynamic assessments
`Fifteen patients underwent hemodynamic assessment by
`right heart catheterization 0–60 days before transition,
`with 12 of the 15 being performed within 30 days of tran-
`sition (Table 3). The 15 patients in whom hemodynamics
`were assessed were in NYHA functional classes 2 (6 pa-
`tients), 3 (7 patients), and 4 (2 patients). The majority of
`patients had moderate to severe hemodynamic impair-
`ment, with 11 of the 15 having a pulmonary vascular re-
`sistance greater than or equal to 8 Wood units. Eleven
`
`after transition (range 0.5–10 months). Of those 11 pa-
`
`patients had right heart catheterizations 5  3 months
`tients, 7 were evaluated before (0.5  0.4 months) and
`after (5.6  3 months; range 2–10 months) the transition
`
`Transition methods
`More than half of transitions occurred in the hospital
`(Table 1). The majority of patients started the transition
`while they were on 54 μg 4 times a day of inhaled tre-
`prostinil. The method of transition was highly variable from
`center to center. In 13 patients, the parenteral infusion started
`at 2–4 ng/kg/min 6 hours after the last inhalation at the
`maintenance dose, and it was followed by uptitration of
`the parenteral therapy. In an additional 6 patients, inhaled
`treprostinil was weaned off over several days, and paren-
`teral infusion was started at 2–4 ng/kg/min after the last
`inhalation of 18 μg of treprostinil (3 breaths). In the re-
`
`(Fig. 2). Six of the 7 patients showed improved hemody-
`namics at follow-up. Patient 3, who had PAH associated
`with rheumatoid arthritis, improved from NYHA func-
`tional class 4 to NYHA functional class 3 for 6 months
`after the transition, after which she deteriorated, showed
`severe hemodynamic impairment at follow-up assessment,
`and underwent bilateral lung transplantation.
`
`Long-term outcomes
`Patients were followed for 3–18 months. The dose of par-
`enteral treprostinil at the last assessment was 26  20 ng/
`
`kg/min (range 2–78 ng/kg/min). Three patients died 3,
`
`

`

`Pulmonary Circulation
`
`Volume 4
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`Number 3
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`September 2014
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`| 459
`
`Figure 1. Clinical characteristics before and after transition. A, All 26 patients had New York Heart Association functional class
`(NYHA FC) assessments before and 3 months after transition. B, Among the 12 patients who underwent a 6-minute walk distance
`(6MWD) test, 8 showed stability or improvement. C, Brain natriuretic peptide (BNP) levels were measured in 9 patients before and
`3–6 months after the transition.
`
`3.8, and 6.8 months after transition, of metastatic carcinoid
`with pulmonary embolism, end-stage liver disease, and pul-
`monary embolism, respectively. One patient underwent lung
`transplantation after 10 months of intravenous therapy, and
`another patient with portopulmonary hypertension under-
`went liver transplantation.
`
`Safety of the transition
`The transition process was not associated with any seri-
`ous adverse events, and there were no hemodynamic ad-
`verse outcomes. Three of the 7 patients who had an over-
`lap transition experienced prostacyclin overdose symptoms,
`which were controlled by decreasing more rapidly or per-
`manently discontinuing the inhaled form. Six of the 19 pa-
`tients in whom the transition did not involve an overlap
`
`Table 3. Hemodynamic characteristics of the 15 patients
`tested before transition
`
`Hemodynamic parameter
`
`mRAP, mmHg
`mPAP, mmHg
`PAWP, mmHg
`CO, L/min
`CI, L/min/m2
`PVR, Wood units
`
`Mean  SD (range)
`10.4  4.1 (5–18)
`57  12.4 (39–88)
`12  5.2 (55–25)
`5.2  2.3 (2.3–12.7)
`2.67  0.97 (1.3–5.6)
`9.9  5.1 (4 –25)
`
`Note: CI: cardiac index; CO: cardiac output; mPAP: mean
`pulmonary artery pressure; mRAP: mean right atrial pressure;
`PAWP: pulmonary artery wedge pressure; PVR: pulmonary vas-
`cular resistance; SD, standard deviation.
`
`had overdose symptoms and the infusion was temporarily
`downtitrated to control the side effects. These symptoms in-
`cluded nausea, vomiting, headaches, diarrhea, or jaw pain.
`An additional side effect was pain at the site of the subcuta-
`neous infusion (5 patients).
`
`D I S C U S S I O N
`We report here the experience of 7 experienced PAH cen-
`ters that successfully transitioned selected PAH patients
`from inhaled treprostinil to parenteral treprostinil. We chose
`to include transition to both intravenous treprostinil and
`subcutaneous treprostinil, since the two forms of paren-
`teral delivery provide similar pharmacokinetic profiles.9
`Selected patients had moderate to severe functional and
`hemodynamic impairment at the time of transition, de-
`spite therapy with a combination of inhaled treprostinil
`and one or two oral therapies in the majority of cases. The
`assessment of lack of clinical improvement or worsening
`of the disease varied from center to center and from patient
`to patient, with only selected patients undergoing complete
`noninvasive and invasive testing. All had reported NYHA
`functional class in combination with at least one other test:
`6MWD, serologic (BNP), or hemodynamic assessment.
`The location of transition varied among centers. In all
`patients transitioned to intravenous treprostinil, the tran-
`sition occurred in the hospital or outpatient setting, while
`transition to the subcutaneous form occurred in the inpa-
`tient setting, outpatient clinic, or home. Similarly, the tran-
`sition method consisted of an overlap of the two drugs, stop-
`ping the inhaled form and starting the parenteral form at
`low dose, or downtitrating the inhaled form to the lowest
`
`

`

`460
`
`|
`
`Inhaled treprostinil to parenteral treprostinil in PAH
`
`Preston et al.
`
`Figure 2. Hemodynamic characteristics before and after transition in 7 patients. Shown are changes in mean pulmonary artery (PA)
`pressures (A), cardiac index (CI; B), and pulmonary vascular resistance (PVR; C ). Follow-up assessment occurred 2–10 months after
`the transition.
`
`dose and then starting the parenteral form at a low dose
`followed by uptitration. Regardless of the method of transi-
`tion, all patients tolerated the process quite well, experienc-
`ing only occasional minor symptoms of prostacyclin excess
`and having no serious adverse events. Most importantly,
`most patients stabilized or improved clinically.
`The introduction of inhaled prostanoids (iloprost and
`treprostinil) has widened the choices of treatment for PAH
`patients. How the pharmacokinetics and the effectiveness
`of inhaled forms compare to parenteral forms of prosta-
`noids at the currently approved doses, however, has not
`been adequately studied. Comparing blood levels during
`infusion and after inhalation may be misleading because
`lung tissue levels after inhaled delivery are probably higher
`than circulating blood levels. Therefore, clinicians need to
`rely on clinical assessment as proof of response to therapy.
`In our cohort of 26 patients who failed to respond or expe-
`rienced a decline on inhaled treprostinil, one-third of pa-
`tients improved their functional class and only 1, who was
`in functional class 4 at the time of transition, failed to im-
`prove. This might indicate that lack or loss of response
`to the inhaled form suggests that the route of delivery or
`the dose currently used is somehow limiting efficacy. Con-
`versely, in selected patients intolerant of parenteral tre-
`prostinil infusion, transition to inhaled treprostinil can
`also be achieved. Of note, however, clinicians should exer-
`cise caution when making such a transition, as one small
`series reported a 22% rate of clinical worsening despite
`continuation of concomitant oral nonprostanoid therapies
`among patients transitioned from the parenteral route to
`the inhaled route.8
`Our report supports the notion that inhaled treprostinil
`and parenteral treprostinil are not always equivalent. As
`the maximum studied dose of inhaled treprostinil (54 μg
`
`4 times a day) is thought to be equivalent to approximately
`a 10-ng/kg/min infusion,10 patients who require low doses
`of prostanoids may remain stable or improve on the in-
`haled form, whereas those who require higher doses of pros-
`tanoid may benefit from transition to parenteral forms.
`Our study is limited by the retrospective design, lack
`of a standardized method of transition, small number of
`patients, and missing data, which precluded us from per-
`forming meaningful statistical analyses. On the other hand,
`data on the transition from inhaled treprostinil to paren-
`teral treprostinil are sparse, and to our knowledge, this is
`the only report thus far in the literature. Our data suggest
`that in selected patients who do not achieve and/or main-
`tain satisfactory improvements on inhaled treprostinil in
`combination with oral therapies, transition to parenteral tre-
`prostinil may be beneficial. In addition, our findings sup-
`port the notion that a number of different approaches to
`transitioning are safe and well tolerated and can take place
`in the hospital, outpatient clinic, or home, the latter for the
`subcutaneous route.
`In conclusion, our report provides important informa-
`tion to clinicians who treat patients with advanced PAH
`and are contemplating transitions from inhaled prostanoids
`to parenteral prostanoids. These can be done safely by experi-
`enced PAH teams, using a variety of methodologies in a num-
`ber of different settings with the expectation that patients
`will improve or at least remain clinically stable for months
`afterward. Future studies evaluating criteria for patient se-
`lection and timing of transitions as well as comparing dif-
`ferent methods are needed.
`
`A C K N O W L E D G M E N T S
`Preliminary results of this manuscript were presented at the
`2011 American College of Chest Physicians meeting.
`
`

`

`Pulmonary Circulation
`
`Volume 4
`
`Number 3
`
`September 2014
`
`| 461
`
`Source of Support: The study was funded by an unrestricted
`grant from United Therapeutics. United Therapeutics had no
`participation in data collection, analysis, or manuscript prepa-
`ration.
`
`Conflict of Interest: None declared.
`
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