http://www.jhltonline.

org

One-year experience with intravenous treprostinil for

pulmonary arterial hypertension
Raymond L. Benza, MD,a Victor F. Tapson, MD,b Mardi Gomberg-Maitland, MD, MSc,c
Abigail Poms, RRT,b Robyn J. Barst, MD,d and Vallerie V. McLaughlin, MDe

From the aDivision of Cardiovascular Diseases, Allegheny General Hospital, Pittsburgh, Pennsylvania; bDivision of Pulmonary and Critical
Care Medicine, Duke University Medical Center, Durham, North Carolina; cSection of Cardiology, University of Chicago, Chicago, Illinois;
d
Barst Consulting, New York, New York; and the eDivision of Cardiovascular Medicine, University of Michigan Health System, Ann Arbor,
Michigan.

KEYWORDS: BACKGROUND: Intravenous (IV) epoprostenol has been the mainstay of therapy in advanced
treprostinil; pulmonary arterial hypertension (PAH). Continuous IV treprostinil has several potential advantages
prostacyclin; over IV epoprostenol; however, there has been a lack of published long-term efficacy and safety data on
pulmonary arterial hy- IV treprostinil in PAH.
pertension METHODS: We conducted a 48-week, multicenter, prospective, open-label, uncontrolled, study of
continuous IV treprostinil in 16 patients on no prior PAH specific therapy at baseline (de novo), or 31
patients transitioned at baseline from IV epoprostenol (transition). The primary end point was change in
exercise capacity assessed by the 6-minute walk distance (6MWD) test.
RESULTS: In de novo patients, IV treprostinil increased the mean ⫾ standard error 6MWD by 125 m
from 332 ⫾ 21 m at baseline to 457 ⫾ 26 m at Week 48. There were also improvements in the
secondary end points of Naughton-Balke treadmill time, Borg Dyspnea Score, and hemodynamics at
Week 48 compared with baseline. In 23 patients transitioned from IV epoprostenol with 48-week
follow-up data, 6MWD, hemodynamic measures, and World Health Organization functional class at
Week 48 were all stable compared with baseline. Side effects were generally mild and consistent with
those reported with prostacyclin treatment. During the study, 5 patients died of causes not considered
related to the therapy, and 7 discontinued due to adverse events.
CONCLUSIONS: In this open-label trial, continuous IV treprostinil for 1 year appears to be safe and
effective in de novo PAH patients and those transitioned from IV epoprostenol.
J Heart Lung Transplant 2013;32:889–896
r 2013 International Society for Heart and Lung Transplantation. All rights reserved.

Before 2001, approved pharmacotherapy for pulmonary
arterial hypertension (PAH) consisted of continuous intra-
venous (IV) epoprostenol sodium (Flolan; GlaxoSmithK-
line, Research Triangle Park, NC).1 Since 2001, oral,
inhaled, and alternatively infused medications have been
approved based on improved exercise capacity.2–5 Even
with many new therapies, PAH remains a life-threatening
Reprint requests: Raymond L. Benza, MD, Division of Cardiovascular
Diseases, Allegheny General Hospital, Pittsburgh, PA 15212. Telephone:
412-359-3584.
E-mail address: rbenza@wpahs.org
1053-2498/$ - see front matter r 2013 International Society for Heart and Lung Transplantation. All rights reserved.
http://dx.doi.org/10.1016/j.healun.2013.06.008
disease.6–8 The expanded treatment armamentarium has
many advantages to individualizing treatment but also
increases the complexity of choosing the most appropriate
therapy.
Although prostacyclin therapy is deemed the most
effective treatment available for moderate to severe PAH,
current data suggest a sub-optimal use of parenteral therapy
in high-risk patients.9 Recent data from the Registry to
Evaluate Early and Long-term PAH Disease Management
(REVEAL) registry indicate that 40% of patients who died
with World Health Organization (WHO) Functional Class
IV limitations were never treated with a parenteral
890 The Journal of Heart and Lung Transplantation, Vol 32, No 9, September 2013
prostanoid. Although these data cannot fully be explained,
they underscore the need to consider initiation of prostacy-
clin therapy in high-risk patients and to overcome barriers to
their use.10
Traditionally, intravenous (IV) epoprostenol has been
considered the most effective treatment, particularly for
advanced PAH, despite requiring a daily mixing regimen
and cooling with ice packs. Treprostinil sodium (Remod-
ulin; United Therapeutics Corp, Research Triangle Park,
NC) was subsequently developed as an alternative to
epoprostenol due to increased stability. Treprostinil sodium
is available for sub-cutaneous (SC) or IV administration and
has anti-platelet aggregation and pulmonary and systemic
vascular bed vasodilatory properties, similar to those of
epoprostenol. Bioequivalence and linearity of dosing exists
between IV and SC treprostinil.11,12 In previous studies, SC
treprostinil increased exercise capacity, improved indices of
dyspnea, reduced signs and symptoms of PAH, and
improved cardiopulmonary hemodynamics in patients with
PAH, but may have a more favorable safety and
convenience profile compared with IV epoprostenol.5,13
As with epoprostenol, these beneficial effects are dose-
related and independent of PAH etiology.14–17 For patients
unable to tolerate SC treprostinil infusion, IV administration
is an option.
Although the pharmacodynamics of epoprostenoln and
treprostinil may be qualitatively similar, they differ in
their pharmacokinetic profile. Treprostinil has a longer
half-life (elimination t½ of 4.5 hours; distribution t½ of 40
minutes vs t½ of 2 to 3 minutes for epoprostenol); thereby,
it may avoid abrupt hemodynamic effects in the event of
infusion disruption and may impart greater safety. Tre-
prostinil also demonstrates chemical stability at physio-
logic pH and at an ambient temperature of up to 1041F,
thus alleviating the need for ice packs as required by
Flolan, the available epoprostenol at the time of this study.
The 48-hour infusion interval for IV administration allows
for drug preparation and cassette replacement every other
day. These characteristics make treprostinil favorable for
IV use and suggest that it may have safety and
convenience advantages over some forms of epoprostenol
for appropriate PAH patients.11,18–20 Parenteral prostanoid
therapy is considered appropriate for advanced PAH
patients at higher risk of death.21
In a 12-week open label observational trial, we
previously reported that IV treprostinil appears to be safe
and effective in treatment-naïve patients as initial
therapy22 and in patients transitioned from IV epoproste-
nol monotherapy to IV treprostinil monotherapy.23 The
48-week safety and efficacy results of the open-label IV
treprostinil extension trial are presented here to inform
physicians treating PAH that this form of parenteral
prostacyclin does provide a lasting effect, as measured by
traditional end points, and to report the long-term toler-
ability of the drug.
n
Flolan and Veletri are 2 available epoprostenols today. At the time that
this study was done, only Flolan was available.
Methods and materials
The clinical study was approved by each investigator’s respective
Investigational Review Board. All patients provided written
informed consent.
Patient population
This is an update of the previously published 12-week study. The
extension study, with data updated to 48 weeks, consisted of
patients aged 12 to 65 years with symptomatic PAH that was
idiopathic, heritable, related to connective-tissue disease, or related
to underlying congenital heart disease despite treatment with anti-
coagulants, cardiac glycosides, diuretics, supplemental oxygen,
and calcium channel blockers, as described for the original 12-
week report.22,23 Newly diagnosed WHO Functional Class II, III,
or IV patients not previously treated with specific targeted PAH
therapies (de novo) with a baseline 6-minute walk distance
(6MWD) 4 50 m who were clinically stable for 4 1 month
before study enrollment were eligible. Transition patients receiving
IV epoprostenol at baseline (minimum treatment period of
3 months) had to have been on a stable epoprostenol dose for
1 month and have WHO Functional Class II or III disease status at
baseline. Exclusion criteria were similar to those in the 12-week
study.22
Study design
All patients were hospitalized at the start of the 48-week study. A
central catheter was placed in de novo patients for continuous IV
treprostinil (initial dose of 2.0 ng/kg/min). Transition patients had
2 separate IV catheters, and treprostinil was up-titrated as the
epoprostenol (Flolan) dose was down-titrated, with vital sign
monitoring over a 24- to 48-hour period. Investigators increased
the treprostinil doses as tolerated by the treatment-related side
effects to manage dyspnea as effectively as possible throughout
the study.
Outcome measures
The primary efficacy end point was exercise capacity as assessed
by the 6MWD test, the standard at the time this study was done.
The test was repeated at Weeks 6, 12, 24, 36, and 48. Secondary
efficacy end points included time on the Naughton-Balke treadmill
test, Borg Dyspnea Score, and WHO functional classification,
assessed at Weeks 6, 12, 24, 36, and 48. Hemodynamic
assessments were performed at baseline, Week 12, and Week 48.
Adverse events (AEs) and standard laboratory hematology and
blood chemistry assessments were made at baseline and at Weeks
12 and 48.
Statistical analysis
Continuous data are presented as mean ⫾ standard deviation (or
standard error) and categorical data are presented in frequency and
percentage. All paired changes from baseline to Weeks 12 and 48
for each end point are summarized with descriptive statistics. The
Kaplan-Meier method was used to estimate overall survival and
treatment success defined as free from death, lung transplantation,
atrial septostomy, or discontinuation of IV treprostinil. To avoid
the potential of biasing the results of this uncontrolled study with a
small sample size, no imputation for missing values was used.
Benza et al. IV Treprostinil for PAH
Figure 1 Disposition of study patients at 1 year. AEs, adverse events.
Results
Patients and IV treprostinil dosing
The disposition of patients is shown in Figure 1. Of the 47
patients with PAH who were enrolled between February
2003 and September 2004, 16 were de novo and 31 were
transitioned from chronic IV epoprostenol† at baseline. An
AE caused 7 patients to discontinue (2 de novo and
5 transition). Forty patients entered the post-Week 12
extension period of the study; ff these, 34 completed the trial
through Week 48, 5 died, and 1 was lost to follow-up. In the
de novo group, 11 of the 16 patients completed 48 weeks of
therapy with a mean exposure of 314 ⫾ 118 days. Of 31
transition patients, 23 completed at least 48 weeks, with a
mean exposure of 308 ⫾ 124 days. Baseline characteristics
are reported in Table 1. The mean time on IV epoprostenol
in the transition group at baseline was 219 ⫾ 177 weeks,
with a mean IV epoprostenol dose at baseline of 41 ⫾ 4
ng/kg/min. The dose of IV treprostinil increased from
baseline through Week 48 to a mean of 98 ng/kg/min in the
de novo group and 111 ng/kg/min in the transition group,
respectively (Table 2).
Exercise capacity
The mean 6MWD increased by 125 m from 332 ⫾ 21 m at
baseline to 457 ⫾ 26 m in the 11 of 16 de novo patients who
completed the 6MWD at Week 48 (Figure 2A). In the 23 of
31 patients transitioned from IV epoprostenol who com-
pleted a Week 48 6MWD, the mean distance was
stable (mean change of –0.5 ⫾ 9 m from the baseline of
444 ⫾ 18 m; Figure 2B). In de novo patients who completed
†
All patients who were transitioned from epoprostenol were receiving
Flolan; Veletri and the TEVA generic epoprostenol were not available at the
time the study was done.
891
the Week 48 Naughton-Balke treadmill test, the time
increased by 333 seconds from 323 ⫾ 39 seconds at
baseline to 656 ⫾ 59 seconds (Figure 3A). Treadmill time
for transition patients at Week 48 was stable, with a 19 ⫾
35-second change from 549 ⫾ 60 seconds at baseline to
530 ⫾ 56 seconds (Figure 3B). Patients with data measured
at both time points (baseline and Week 12 and baseline and
Week 48) were included in exercise capacity analyses, and
thus, the number of individuals varies for each analysis.
The mean Borg Dyspnea Score improved from 4.3 ⫾
0.8 at baseline to 2.4 ⫾ 0.7 at Week 48 in de novo patients
(n ¼ 10) but was unchanged in transition patients (2.2 ⫾
0.4 at baseline and 2.1 ⫾ 0.4 at Week 48; n ¼ 22; data not
shown).
WHO Functional Class
Data were available for 11 de novo patients and 23
transition patients at Week 48. In the de novo group,
1 patient (9%) improved from Class IV at baseline to Class
III, and 8 patients (73%) improved from Class III to Class II.
Functional class was unchanged in 2 patients, and no
patients decreased in functional class in the de novo group.
In the transition group, 13 patients (57%) had no change, 3
(13%) improved from Class III to Class II, and 5 (22%)
improved from Class II to Class I. Two patients (9%)
declined from Class II to Class III (Table 3).
Hemodynamics
Fourteen de novo and 27 transition patients were assessed at
baseline. At Week 48, in the de novo group (n ¼ 11), mean
pulmonary artery pressure decreased by 17%, cardiac index
increased by 56%, and pulmonary vascular resistance index
decreased by 50%. No hemodynamic changes occurred in
any parameter among the 22 transition patients (Table 4).
892 The Journal of Heart and Lung Transplantation, Vol 32, No 9, September 2013

Table 1 Baseline Demographic and Hemodynamic Character- Table 2 Summary of Dosing

istics
Dose (ng/kg/min)
IV epoprostenol Patients No. Mean ⫾ SE (range)
Variablesa De novo transition
De novo patients 16a
Age, years 45 (26–59) 43 (12–68) Discharge 15 5 ⫾ 2 (2–8)
Week 12 14 41 ⫾ 4 (20–62)
White ethnicity 11 (69) 23 (74) Week 24 9 66 ⫾ 7 (34–96)
Female sex 16 (100) 22 (71) Week 48 11 98 ⫾ 9 (54–155)
Etiology of PAH Transition patients 31a
Idiopathic 8 (50) 21 (68) Baseline IV epoprostenol dose 31 41 ⫾ 4 (10–97)
Connective tissue disease 6 (38) 6 (19) Discharge 30 47 ⫾ 4 (15–115)
Congenital heart disease 2 (13) 4 (13) Week 12 27 83 ⫾ 7 (24–180)
Borg Dyspnea Score 4.4 ⫾ 2.3 2.1 ⫾ 1.7 Week 24 18 95 ⫾ 11 (24–225)
WHO Functional Class Week 48 23 111 ⫾ 10 (24–208)
II 0 23 (74)
IV, intravenous; SE, standard error.
III 14 (88) 8 (26) a
Not all patients were monitored at each time point.
IV 2 (13) 0
Weeks on IV epoprostenol 0 219 ⫾ 177
Digoxin use 4 (25) 17 (55)
Bosentan use 1 (6) 12(39) pneumonia, renal insufficiency associated with systemic
Sildenafil use 0 0 lupus erythematosus, and a sub-dural hematoma in 1 patient
6-minute walk distance, m 307 ⫾ 115 441 ⫾ 81 that occurred before trial enrollment. All but 1 of these
Naughton treadmill time, sec 319 ⫾ 125b 580 ⫾ 271 patients subsequently received IV epoprostenol. Of the
7 patients who discontinued the study due to adverse events,
Mean PAP, mm Hg 58 ⫾ 15 46 ⫾ 12 1 died of cardiac arrest 1 month after discontinuation
Mean RAP, mm Hg 12 ⫾ 5 6⫾4 attributable to worsening of a sub-dural hematoma.
Cardiac index, liters/min/m2 1.7 ⫾ 0.4 3.0 ⫾ 0.8
Bosentan (Tracleer; Actelion Pharmaceuticals Ltd Allsch-
PVRI, units  m2 29 ⫾ 10 13 ⫾ 5
wil/Basel, Switzerland) was initiated in this 4 days after IV
IV, intravenous; PAH, pulmonary arterial hypertension; PAP, treprostinil was discontinued. The remaining 6 patients were
pulmonary artery pressure; PVRI, pulmonary vascular resistance index;
alive at the time of the 48-week analysis.
RAP, right atrial pressure; WHO, World Health Organization.
a
Continuous data are shown as mean (range) or as mean ⫾ standard There were 35 serious adverse events (SAEs) in 17 of the
deviation and categoric data as number (%). 47 patients (36%). Transition patients had 2 catheter-related
b
Continuous data, mean ⫾ SD; categorical data, n (%). local site infections and 2 bloodstream infections (BSIs).

Survival

The 48-week survival for de novo patients was 75%, and

treatment success was 69%, as defined by freedom from
death, lung transplantation, atrial septostomy, or discontin-
uation of IV treprostinil (Figure 4A). For transition patients,
the 48-week survival was 94% and treatment success was
77% (Figure 4B).

Safety

Five patients died (3 de novo and 2 transition) during the

study, but the investigators concluded no deaths were
related to treprostinil. The cause of death was progression of
PAH in 3 patients, hemoptysis in 1, and adrenal hemorrhage
in 1. Of the 2 transition patients who died, 1 death was
deemed related to progression of PAH and the other to
hemoptysis. Of the total number of patients who died, half
Figure 2 Change in 6-minute walk distance from baseline to
showed an increase in CI and half showed a decrease in CI. Week 48 is shown in the (A) de novo and (B) transition patients.
A drop in CI could not explain the number of deaths that The 6-minute walk distance (mean ⫾ standard error) is compared
occurred. for 14 de novo and 27 transition patients at baseline and Week 12
Six transition patients and 1 de novo patient discontinued and for 11 de novo and 23 transition patients at baseline and Week
the study due to AEs. Four transition patients experienced 48. All changes p o 0.005 for de novo patients and p ¼ not
leg pain. Other events leading to discontinuation were significant for transition patients.
Benza et al. IV Treprostinil for PAH 893

headache (45%), jaw pain (45%), diarrhea (36%), nausea

(32%), flushing (23%), peripheral edema (19%), back pain
(19%), loose stools (17%), and palpitations (17%). Extrem-
ity pain was described as severe in 1 de novo patient and in
6 transition patients (13%). Headache was described as
severe in 5 transition patients (16%). Diarrhea, nausea,
flushing, and loose stools were reported more frequently in
de novo patients than in transition patients.

Concomitant pulmonary hypertension-specific

therapy

At the start of the study, 13 patients (12 transitions, 1 de

novo) were already receiving bosentan (Tracleer). Three
patients (2 transitions, 1 de novo) started bosentan (Tracleer)
after discontinuing the study due to AEs. One transition
patient was started on sildenafil (Revatio; Pfizer, New York,
Figure 3 Change in treadmill test time from baseline to Week NY) during the study at 45 weeks after discontinuing
48 is shown in the (A) de novo and (B) transition patients. bosentan (Tracleer), and 1 transition patient started sildenafil
Treadmill walk time (mean ⫾ standard error) compared with (Revatio) after discontinuing the study due to AEs. Six
baseline (in 15 de novo and 27 transition) at Week 12 (in 14 de patients (5 transitions, 1 de novo) began Flolan upon
novo and 26 transition) and Week 48 (in 10 de novo and 20
discontinuing the study due to AEs.
transition patients). All changes p o 0.01 for de novo patients and
Two patients received sildenafil as concomitant therapy.
p ¼ not significant for transition patients.
Sildenafil (Revatio) added to the regimen in 1 patient who
was receiving oral bosentan (Tracleer) plus IV treprostinil
None of the de novo patients had any clinically significant for 11 months. The second patient transitioned back to IV
catheter-related infections or BSIs. Pneumonia developed in epoprostenol, and bosentan (Tracleer) was added at Month
2 patients (1 in each study arm). The remaining 29 SAEs 3 and sildenafil (Revatio) at Month 4 of follow-up.
were each reported in individual patients: 13 in de novo
patients and 16 in transition patients.‡ Thirty-three of the Discussion
SAEs were not considered attributable to treprostinil,
whereas 2 (hematoma and non-cardiac chest pain) were In 2004, the Food and Drug Administration approved
considered possibly attributable to treprostinil. During the continuous IV treprostinil for PAH patients with New York
study, there were 35.23 patient-years of treprostinil Heart Association (NYHA) Functional Class II, III, and IV
exposure, providing a calculated rate of 0.198 infections signs and symptoms. The label was further expanded in
per patient per year. 2006 to include an indication for diminishing the rate of
AEs are summarized in Table 5. The most frequent AE clinical deterioration in patients requiring transition from
was extremity pain (generally lower extremity), reported in continuous IV epoprostenol to IV treprostinil.24 In the de
72% of patients. The location of the extremity pain appears novo patients who remained on the therapy, the extension
to differ from that experienced with epoprostenol. Of 13 study results demonstrated increased exercise capacity
premature discontinuations, only 4 listed “foot pain” or “leg assessed by the standard 6MWD test after 1 year of therapy
pain” as the reason. Other frequently reported AEs were with IV treprostinil. The 6MWD test had prognostic
importance and real world application. It is a key end point
in the recently published and validated REVEAL and
French predictive equations8 and is used widely in the
Table 3 World Health Organization Classification
community, along with other factors, to make decisions
Matched baseline Week 48 regarding therapy augmentation.
Variable (No.) (No.) The Naughton-Balke treadmill walk time, Borg Dyspnea
Score, NYHA Functional Class and hemodynamics also
De novo 11 improved. These findings at 48 weeks are in accordance
Class I 0 0
with our previous reports after 12 weeks of IV treprostinil
Class II 0 8
Class III 10 3 ‡
Class IV 1 0 One case each of adrenal hemorrhage, adrenal insufficiency, atrial
fibrillation, bacteremia, bronchitis, candidiasis, catheter placement, catheter
Transition 23
related complications, catheter sepsis, cerebrovascular accident, dizziness,
Class I 0 5 dyspnea, fluid overload, hemoptysis, hematoma, intracardiac thrombus,
Class II 19 15 mental status change, non-cardiac chest pain, pericardial effusion, pleural
Class III 4 3 effusion, pneumonia (viral), renal insufficiency, right heart failure, sinus
Class IV 0 0 arrhythmia, staphylococcal bacteremia, staphylococcal infection, sub-dural
hematoma, sub-dural hematoma, urinary tract infection, and urosepsis.
894 The Journal of Heart and Lung Transplantation, Vol 32, No 9, September 2013

Table 4 Hemodynamic Parameters–Baseline and One Year

De novob (N ¼ 11) Transition (N ¼ 22)c

Parametera Baseline Week 12 Week 48 Baseline Week 12 Week 48

Mean RAP (mm Hg) 12 ⫾ 1 12 ⫾5 8 ⫾ 1 5 ⫾ 1 6 ⫾4 6 ⫾ 1
Mean PAP (mm Hg) 58 ⫾ 5 54 ⫾13 48 ⫾ 4 45 ⫾ 3 50 ⫾ 13 48 ⫾ 3
CI, liters/min/m2 1.6 ⫾ 0.1 2.2 ⫾ 0.6 2.5 ⫾ 0.2 3.1 ⫾ 0.2 2.6 ⫾0.6 3.2 ⫾ 0.2
PVRI, units ∙ m2 32 ⫾ 3 20 ⫾9 16 ⫾ 2 13 ⫾ 1 16.2 ⫾6 13 ⫾ 1
CI, cardiac index; PAP, pulmonary artery pressure; PVRI, pulmonary vascular resistance index; RAP, right atrial pressure.
a
Data are shown as mean ⫾ standard error.
b
De novo changes p o 0.05.
c
Catheterization was not performed on 1 patient due to patient refusal.

therapy.22 In stable patients who transitioned from IV
epoprostenol to IV treprostinil and continued to receive IV
treprostinil therapy, efficacy was maintained while on
IV treprostinil, as measured by exercise capacity, WHO
Functional Class, and hemodynamics after 1 year, which
may suggest comparable efficacy of the 2 prostanoids.23 In
light of this apparent equivalence, IV treprostinil may have
some potential advantages over present formulations of
Figure 4 Kaplan-Meier estimates show (A) treatment success
at 1 year, defined as freedom from death, lung transplantation,
atrial septostomy, or discontinuation of intravenous treprostinil, for
de novo and transition patients, and (B) survival for the de novo
and transition patients.
epoprostenol, including a longer half-life and avoidance of
acute discontinuation events (Flolan, Veletri [Actelion],
generic epoprostenol), ease of use (Flolan, generic epopros-
tenol), and stability at room temperature (Flolan, generic
epoprostenol). The currently available thermostable epo-
prostenol (Veletri) may be delivered at some concentrations
up to 24 hours before cassette changes compared with
diluted treprostinil, which is stable at room temperature for
up to 48 hours, thus requiring cassette changes every other
day. This may be considered advantageous from both a
patient’s and a physician’s perspective in some instances.
Thus, IV treprostinil may be an appropriate therapy for
some patients and important in the PAH treatment
armamentarium.
This 48-week study provides efficacy and safety
information for IV treprostinil in patients followed up
prospectively. It is not intended to provide direct compa-
rative data to IV epoprostenol, which remains the only PAH
therapy shown to have a survival benefit in a controlled trial
(12-week randomized open-label study in Class III and IV
PAH patients) and in long-term retrospective analyses of
2 large observational trials.1,14 IV treprostinil may provide
this benefit over time as well. This 1-year IV study, a 10-
year SC study by Lang et al,25,26 and the long-term study by
Barst et al27 demonstrate that first-line treprostinil provides
long-term tolerability and long-term effects on functional
class, 6MWD, hemodynamics, and survival.
This study suggests that dosing with IV treprostinil may
need to be more aggressive than was previously reported
with the SC pivotal trials. Recent studies support doses of
1.5 to 2 times that of epoprostenol.20,23,28 However, careful
titration based on clinical symptoms and AEs remains
paramount.
The most frequent AEs of IV treprostinil were those
commonly attributed to prostacyclin therapy. Severity and
character of extremity pain and jaw pain may vary from one
prostanoid to another as well as in each individual patient.
Most patients in prior studies reported less severe AEs with
IV treprostinil than with IV epoprostenol.20,22
The rate of serious catheter infection was 0.198 events
per patient per year, which is comparable to the described
rate of 0.32 infection and sepsis AEs per patient per year
for epoprostenol.29 Approximately 10% of patients receiv-
ing IV treprostinil for 1 year experienced a serious catheter
infection and/or bacteremia, which is consistent with
Benza et al. IV Treprostinil for PAH 895

Table 5 Adverse Events University College of Physicians & Surgeons), Susie

McDevitt, RN, MSN, ACNP (University of Michigan),
All adverse events No. (%) and Victoria Belka, RN, BSN (University of Chicago), as
(N ¼ 47) well as Carl Arneson, MStat, for statistical advice. The
Extremity paina 34 (72) authors also acknowledge the untimely death of coauthor
Headache 21 (45) Robyn J. Barst, MD, and recognize her significant
Jaw pain 21 (45) contributions to the field.
Diarrhea 17 (36) R.L.B. has received educational grants and/or compen-
Nausea 15 (32) sations for scientific symposia from Actelion, United
Flushing 11 (23) Therapeutics, Gilead, Ikaria, and GeNo; is a paid speaker
Peripheral edema 9 (19) for Actelion, United Therapeutics, and Gilead; and serves on
Back pain 9 (19) advisory board committees for Ikaria and United Therapeu-
Loose stools 8 (17) tics.
Palpitations 8 (17)
V.F.T. has served as a paid consultant for and has
Serious adverse events
Any serious adverse event 17 (36)
received educational grants and/or compensation for
Catheter-related local-site infections 2 (6) scientific symposia from Actelion, Bayer, Gilead, Long
Central line infection 2 (6) LLC, Novartis, and United Therapeutics; and was a paid
Pneumonia 2 (6) speaker for and serves on advisory board committees for
a
Actelion, Gilead, and United Therapeutics.
Includes foot, arm, leg, toe. M.G.-M. has received research grant support from
Actelion, Gilead, GlaxoSmithKline, Medtronic, Novartis,
literature reports for risks of in-line infection and sepsis with and United Therapeutics over the last 12 months, and has
chronic indwelling central venous catheters. Although the served as a consultant on DSMB, Steering Committees, and
overall incidence of this severe complication is very low, for Clinical Events Committees for Actelion, Gilead, Ikaria,
there is concern about an increased number of gram- Medtronic, Novartis, Pfizer, and United Therapeutics. She
negative BSIs.29 This concern initially led to the delay in does not do any promotional speaking and has received
publication of these results to the present time. Now that a honorarium for travel from United Therapeutics and
catheter care guideline in PAH is available and the use of a Excelsior for attendance at International Conferences and
closed-hub system with maintenance of dry catheter hub from ABcomm, Healthmatters CME, and Medscape for
connections along with the changing the diluent of CME-related events.
treprostinil to the more alkaline epoprostenol diluent has A.P. has served as a paid consultant for Actelion,
significantly reduced the incidence of catheter-related BSIs, Novartis, GSK, and United Therapeutics; is a paid speaker
the authors felt compelled to proceed with the publication of for Actelion, Gilead, and United Therapeutics; and serves on
these longer term results.30–32 the advisory board committees for Actelion, Bayer, Lung
Limitations to this study include the small sample size LLC, Novartis, and United Therapeutics.
and the open-label uncontrolled study design. In addition, R.J.B. served as a paid consultant/scientific advisor for
the results reported here reflect a selection bias of patients Actelion, Bayer, Eli Lilly, Ikaria, Gilead, Merck, Novartis,
who tolerated the drug and completed at least 48 weeks of Pfizer, and VentriPoint; was a paid speaker for Actelion and
therapy. The data presented here are for 34 of the initial 47 Gilead; and owned stock in VentriPoint.
patients enrolled in the study. The dosing titration was not V.V.M. has served as a paid consultant for Actelion,
standardized but was based on patient symptoms and Bayer, Gilead, and United Therapeutics, has received
physician judgment. This, along with the interpatient educational grants and/or compensation for scientific
variability, may have contributed to differences in dosing. symposia from Actelion, Bayer and Novartis; and is a paid
In conclusion, this prospective open-label observational speaker for Actelion (ended 10/11), Gilead, and United
1-year study supports the safety and efficacy of IV Therapeutics.
treprostinil in de novo and epoprostenol-transition PAH None of the authors has an equity interest in any
patients for up to1 year of treatment. It is imperative that in pharmaceutical company or any other conflicts of interest to
compromised patients at high risk of death, that early use of disclose.
prostacyclins, such as IV treprostinil, not be delayed and
that they continue to be used as front-line therapy.
References

Disclosure statement
This investigator-initiated study was supported by United
Therapeutics Corporation, Research Triangle Park, North
Carolina. The authors thank the study coordinators from
each of the centers involved: Ginger Ward, RN (Duke
University Medical Center), Daniela Brady, RN (Columbia
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