Journal of Cardiovascular Pharmacology™
`41:293–299 © 2003 Lippincott Williams & Wilkins, Inc., Philadelphia
`
`Efficacy and Safety of Treprostinil: An Epoprostenol Analog for
`Primary Pulmonary Hypertension
`
`*Vallerie V. McLaughlin, †Sean P. Gaine, ‡Robyn J. Barst, §Ronald J. Oudiz,
`储Robert C. Bourge, ¶Adaani Frost, #Ivan M. Robbins, **Victor F. Tapson,
`††Michael D. McGoon, ‡‡David B. Badesch, §§Jeff Sigman, §§Robert Roscigno,
`§§Shelmer D. Blackburn, §§Carl Arneson, 储储Lewis J. Rubin, and *Stuart Rich, on behalf
`of the Treprostinil Study Group
`
`*Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Illinois; †Johns Hopkins Hospital, Baltimore, Maryland;
`‡Columbia University College of Physicians and Surgeons, New York, New York; §Harbor-UCLA Medical Center,
`Los Angeles, California; 储University of Alabama at Birmingham, Birmingham, Alabama; ¶Methodist Hospital,
`Baylor Medical College, Houston, Texas; #Vanderbilt University Medical Center, Nashville, Tennessee; **Duke
`University Medical Center, Durham, North Carolina; ††Mayo Clinic, Rochester, Minnesota; ‡‡University of
`Colorado Health Sciences Center, Denver, Colorado; §§United Therapeutics Corporation, Research Triangle Park,
`North Carolina; and 储储University of California at San Diego, San Diego, California, U.S.A.
`
`Summary: Intravenous epoprostenol is currently FDA approved for manage-
`ment of primary pulmonary hypertension, but it requires intravenous infusion
`and is associated with adverse effects. The objective of this study was to
`evaluate the effects of an epoprostenol analog, treprostinil, for management of
`pulmonary hypertension. Ten tertiary care academic institutions with pulmo-
`nary hypertension programs participated in these pilot trials. In the first trial,
`intravenous epoprostenol and intravenous treprostinil were compared. In the
`second trial, intravenous treprostinil and subcutaneous treprostinil were com-
`pared. In the third trial, subcutaneous treprostinil was compared with placebo
`infusion during an 8-week period. Intravenous epoprostenol and intravenous
`treprostinil resulted in a similar reduction in pulmonary vascular resistance
`acutely (22% and 20%, respectively). Intravenous treprostinil and subcutane-
`ous treprostinil also demonstrated comparable short-term decrease in pulmo-
`nary vascular resistance (23% and 28%, respectively). The placebo-controlled
`8-week trial demonstrated a mean improvement of 37 ± 17 m as measured by
`the 6-minute walk distance in patients receiving treprostinil compared with a
`6 ± 28 m reduction in those receiving placebo. There were trends toward an
`improvement in cardiac index and pulmonary vascular resistance index in the
`treprostinil group. Subcutaneous treprostinil has favorable hemodynamic ef-
`fects when given acutely and in the short term. Treprostinil can be given
`safely to an ambulatory patient with a novel subcutaneous delivery pump
`system. Key Words: Pulmonary arterial hypertension—Hemodynamics—
`Epoprostenol—Prostacyclin.
`
`Received December 3, 2001; accepted July 16, 2002.
`Supported by United Therapeutic Corporation, Research Triangle
`Park, North Carolina.
`Current affiliation for Dr. Gaine: Mater Misericordiae Private Hos-
`pital, Dublin, Ireland.
`
`Address correspondence and reprint requests to Dr. Vallerie V.
`McLaughlin at the Rush-Presbyterian-St. Luke’s Medical Center, 1725
`W. Harrison Street, Suite 020 Chicago, IL 60612, U.S.A. E-mail:
`vmclaugh@rush.edu
`
`293
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`
`IPR2021-00406
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`
`

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`294
`
`V. V. MCLAUGHLIN ET AL.
`
`Management of primary pulmonary hypertension
`(PPH) is problematic. Intravenous epoprostenol
`(Flolan®, Glaxo-SmithKline, Research Triangle Park,
`NC, U.S.A.) is currently FDA approved for patients with
`advanced PPH. Epoprostenol is a potent vasodilator of
`the systemic and pulmonary arteries and is a potent in-
`hibitor of platelet aggregation. Previous studies have
`demonstrated that in the short term (12 weeks), epopro-
`stenol improves exercise tolerance, symptoms, hemody-
`namics, and survival in patients with PPH who are func-
`tional class III and IV and refractory to conventional
`therapy (1,2). Longer-term therapy with epoprostenol
`has been demonstrated to lower pulmonary vascular re-
`sistance beyond the level achieved in the short term (3).
`Despite its benefits, epoprostenol therapy is associated
`with a number of obstacles. Since the drug is unstable at
`pH values below 10.5, it cannot be given orally, and
`continuous intravenous infusion is necessary due to
`its short half-life. Serious complications, particularly
`catheter-related infections and temporary interruption of
`the infusion due to malfunction of the pump or dislodg-
`ment of the central venous catheter, have been reported
`(1,3). These complications can be potentially life threat-
`ening and underscore the need for an alternative mode of
`drug delivery.
`More recently, bosentan (Tracleer) has been approved
`by the FDA for management of pulmonary arterial hy-
`pertension (4). A 16-week placebo-controlled trial dem-
`onstrated an improvement in exercise tolerance and an
`increased time to clinical worsening. Treprostinil (Re-
`modulin, United Therapeutics, Research Triangle Park,
`NC, U.S.A.) is an epoprostenol analog with a half-life of
`3 hours and is stable at room temperature (5). Animal
`studies suggest that its hemodynamic effects appear
`similar to epoprostenol (6,7). We chose to take advan-
`tage of these properties and evaluate the feasibility for
`continuous subcutaneous infusion of treprostinil in pa-
`tients with PPH.
`This article reports a series of clinical trials designed
`to assess the utility of the chronic subcutaneous admin-
`istration of treprostinil. The objective of the first trial was
`to compare the immediate hemodynamic effects of in-
`travenous treprostinil with those of intravenous epopro-
`stenol in patients with PPH who were functional class III
`or IV. The objective of the second trial was to compare
`the short-term hemodynamic effects of intravenous
`treprostinil with those of subcutaneous treprostinil in pa-
`tients with PPH. Based on the results of these studies
`indicating comparable efficacy with subcutaneous and
`intravenous treprostinil, a third study was undertaken.
`This study was a multicenter, double-blinded, placebo-
`
`J Cardiovasc Pharmacol™, Vol. 41, No. 2, 2003
`
`controlled chronic pilot trial. The objectives of this third
`trial were to assess the safety of chronically administered
`continuous subcutaneous infusion of treprostinil in pa-
`tients with PPH and to assess the efficacy of treprostinil
`on exercise capacity and hemodynamics.
`
`METHODS
`
`All three trials enrolled patients with PPH based on the
`criteria of the National Institutes of Health Registry on
`PPH (8). For all three trials, the inclusion criteria were
`New York Heart Association functional class III or IV
`despite conventional therapy, a mean pulmonary artery
`pressure greater than or equal to 25 mm Hg, a pulmonary
`capillary wedge pressure or left ventricular end diastolic
`pressure of less than or equal to 15 mm Hg, and a pul-
`monary vascular resistance of greater than 3 Wood units.
`Right heart catheterization was performed with a triple-
`lumen flow-directed catheter via the internal jugular or
`femoral vein and left in place for monitoring (trials 1 and
`2). Standard hemodynamic measures were evaluated at
`select times throughout the study. All patients (or parents
`for patients aged less than 18 years) provided informed
`consent approved by the Institutional Review Board of
`each of the participating institutions.
`
`TRIAL DESIGNS
`
`Trial 1
`This was a multicenter, open-label, acute trial de-
`signed to compare the effects of intravenous epopros-
`tenol and intravenous treprostinil. Following right heart
`catheterization, epoprostenol was administered intrave-
`nously beginning at 2 ng/kg/min and increased every 15
`to 30 minutes in 2-ng/kg/min increments to a maximum
`tolerated dose while serial hemodynamic measurements
`were obtained. Following a 90-minute epoprostenol-free
`washout period, intravenous treprostinil was initiated at 5
`ng/kg/min for 30 minutes and increased every 30 min-
`utes to 10, 20, 30, 40, and 60 ng/kg/min. The dose-
`ranging procedure was continued until a dose was
`achieved that produced side effects that warranted reduc-
`tion or discontinuation of the infusion; this was consid-
`ered the nontolerated dose. A 90-minute maintenance
`infusion was continued at 10 to 20 ng/kg/min below the
`nontolerated dose and followed by a 120-minute trepro-
`stinil-free washout period. The catheters were removed,
`and the patients were observed for 24 hours in a post-
`treatment phase.
`
`Trial 2
`This was a multicenter, open-label, acute trial de-
`signed to compare the effects of intravenous treprostinil
`
`

`

`EFFICACY AND SAFETY OF TREPROSTINIL
`
`295
`
`and subcutaneous treprostinil. Following right heart cath-
`eterization, patients received a 10 ng/kg/min intravenous
`dose of treprostinil for 75 min, followed by a 150-minute
`washout period. Baseline measurements were again ob-
`tained. Patients then received subcutaneous treprostinil
`in fixed doses of 5, 10, and 20 ng/kg/min (cohorts 1, 2,
`and 3, respectively) for 150 minutes. This was followed
`by a 150-minute washout period. The catheters were re-
`moved, and the patients were observed in the hospital for
`24 hours following completion of the treatment. Serial
`plasma samples (5 ml each) were collected at baseline,
`15, 30, 60, and 75 minutes during the intravenous trepro-
`stinil infusion, at 5, 10, 15, 30, 60, 90, and 120 minutes
`during the washout, at baseline, 15, 30, 60, 90, 120, and
`150 minutes during the subcutaneous treprostinil infu-
`sion, and at 5, 10, 15, 30, 60, 90, 120, and 150 minutes
`during the washout for pharmacokinetic determinations.
`
`Trial 3
`This was a multicenter, double-blinded, parallel, pla-
`cebo-controlled, 2:1 randomized, 8-week trial. Patients
`underwent a screening practice and baseline 6-minute
`walk test during which they had to walk 50 to 450 m to
`be included. Borg Dyspnea Score and Dyspnea Fatigue
`Rating were obtained in conjunction with the 6-minute
`walk. Right heart catheterization was performed within 2
`days of the walk test at baseline and at the end of 8
`weeks. After baseline evaluation, patients were random-
`ized in a 2:1 fashion to receive either subcutaneous
`treprostinil or placebo. The dose of treprostinil was ini-
`tiated at 2.5 to 5.0 ng/kg/min and was adjusted in incre-
`ments of 2.5 to 5.0 ng/kg/min every 24 hours based on
`response to therapy and side effects to a maximum dose
`of 20 ng/kg/min. Patients were observed in the hospital
`during initiation of therapy and were trained by a clinical
`nurse specialist on preparation of the study medication
`and operation of the ambulatory infusion pump. After
`hospital discharge, the dose was increased by no more
`than 5 ng/kg/min each week. Right heart catheterization
`and the 6-minute walk were repeated after 8 weeks.
`
`Statistical analysis
`Data are presented as mean ± SE. All patients having
`a baseline cardiac catheterization are included in the
`analyses of demographics and baseline characteristics.
`Patients completing the epoprostenol and treprostinil
`dose-ranging segments in trial 1 were considered in the
`evaluation of changes in hemodynamic measurements
`from baseline to maximum tolerated dose (n ⳱ 14). In
`trial 2, the patients completing the 150-minute subcuta-
`neous treprostinil dosing segment were considered for
`the analysis of changes in hemodynamics from baseline
`
`(n ⳱ 20). The percent change in hemodynamics from
`baseline was calculated after intravenous treprostinil ad-
`ministration, and then a second baseline measure was
`obtained after the washout period and was used to cal-
`culate the percent change with subcutaneous treprostinil
`administration.
`Also in trial 2, individual patient pharmacokinetic pa-
`rameters during intravenous treprostinil and subcutane-
`ous treprostinil dosing were determined from the corre-
`sponding plasma treprostinil concentration versus time
`profile. The noncompartmental routine in WinNonlin
`was used for the pharmacokinetic analysis. All pharma-
`cokinetic parameters were determined from treprostinil
`concentration values based on actual blood sampling
`times (not nominal times as described in the protocol). In
`trial 3, 6-minute walk data were analyzed in an intention-
`to-treat analysis of all randomized patients utilizing a
`parametric analysis of variance (ANOVA). Patients who
`died, exited the study prematurely due to clinical dete-
`rioration, or underwent transplantation were assigned a
`value of 0 m; patients who did not have a week 8 walk
`due to an adverse event, withdrawal of consent, or who
`were lost to follow-up evaluation were assigned the last
`observation carried forward as their 8-week value. Other
`efficacy parameters (Borg dyspnea score, dyspnea fa-
`tigue score, and hemodynamic measurements) were ana-
`lyzed utilizing available data, and treatment group dif-
`ferences in the changes from baseline were assessed
`using the Wilcoxon rank sum test.
`
`RESULTS
`
`Baseline demographics for each of the trials are dis-
`played in Table 1. Baseline hemodynamic measurements
`for trials 1 and 2 are shown in Table 2, and for trial 3 in
`Table 3.
`
`Trial 1
`Fourteen patients were enrolled. The maximum toler-
`ated doses of intravenous epoprostenol and intravenous
`treprostinil were 6.4 ± 0.8 ng/kg/min and 24.6 ± 4.0
`ng/kg/min, respectively. Dose-limiting adverse effects
`were similar for epoprostenol and treprostinil and in-
`cluded headache, nausea, chest pain, jaw pain, backache,
`and restlessness. Epoprostenol and treprostinil produced
`similar increases in cardiac output and decreases in the
`mean pulmonary artery pressure. There was a 22% re-
`duction in pulmonary vascular resistance with epopros-
`tenol and a 20% reduction with treprostinil (p ⳱ NS for
`epoprostenol vs. treprostinil). There were no serious ad-
`verse events related to treprostinil during the dose-
`
`J Cardiovasc Pharmacol™, Vol. 41, No. 2, 2003
`
`

`

`296
`
`V. V. MCLAUGHLIN ET AL.
`
`TABLE 1.
`Baseline demographics
`
`Trial 1
`IV epoprostenol
`vs. IV treprostinil
`
`Trial 2
`IV treprostinil vs.
`SC treprostinil
`
`Trial 3
`SC treprostinil
`vs. placebo
`
`Centers, n
`Patients, n
`Age, years
`Age range, years
`Female, %
`Male, %
`NYHA III, %
`NYHA IV, %
`
`4
`14
`35 ± 12
`12–57
`10 (71)
`4 (29)
`13 (93)
`1 (7)
`
`NYHA ⳱ New York Heart Association.
`
`10
`25
`42 ± 11
`22–71
`20 (80)
`5 (20)
`19 (76)
`6 (24)
`
`3
`26
`37 ± 17
`12–73
`21 (81)
`5 (19)
`25 (96)
`1 (4)
`
`ranging segment of the study. One patient experienced a
`serious adverse event during the maintenance infusion.
`Having successfully completed the dose-ranging study,
`the patient was maintained at 16 ng/kg/min. Forty-five
`minutes into the maintenance infusion, the patient expe-
`rienced an increase in pulmonary artery pressure and
`severe hypoxia, possibly related to an increase in right-
`to-left flow through a documented patent foramen ovale.
`The infusion was terminated, and the patient subse-
`quently recovered.
`
`Trial 2
`Twenty-five patients were enrolled. The changes in
`hemodynamic parameters with intravenous treprostinil
`
`TABLE 2.
`Baseline hemodynamics
`
`Trial 1
`IV epoprostenol
`vs. IV treprostinil
`(n ⳱ 14)
`
`Trial 2
`IV epoprostenol
`vs. SC treprostinil
`(n ⳱ 25)
`
`RAPm, mm Hg
`PAPm, mm Hg
`PCWPm, mm Hg
`CO, l/min
`CI, l/min/m2
`PVR, Units
`PVRI, Units/m2
`SAPm, mm Hg
`MV Sat, %
`SaO2, %
`
`10 ± 1
`56 ± 5
`12 ± 1
`4.6 ± 0.5
`2.5 ± 0.2
`11.0 ± 1.7
`19.2 ± 2.5
`9.38 ± 2.9
`66 ± 3
`95 ± 1
`
`10 ± 1
`63 ± 4
`12 ± 2
`3.8 ± 0.3
`2.1 ± 0.1
`15.5 ± 2.2
`28.1 ± 3.7
`92.8 ± 2.8
`59 ± 2
`95 ± 1
`
`CI, cardiac index; CO, cardiac output; MV Sat, mixed venous satu-
`ration; PAPm, mean pulmonary artery pressure; PCWPm, mean pul-
`monary capillary wedge pressure; PVR, pulmonary vascular resistance;
`PVRI, pulmonary vascular resistance index; RAPm, mean right atrial
`pressure; SAPm, mean systemic arterial pressure; SaO2, systemic ar-
`terial saturation.
`
`J Cardiovasc Pharmacol™, Vol. 41, No. 2, 2003
`
`infusion at 10 ng/kg/min and subcutaneous treprostinil at
`5, 10, and 20 ng/kg/min (cohorts 1, 2, and 3) are shown
`in Table 4. Five patients were prematurely withdrawn
`from this study due to intolerable local side effects from
`the subcutaneous treprostinil infusion: 1 in cohort 1, 1 in
`cohort 2, and 3 in cohort 3. There were 5 patients in
`cohort 1, 12 in cohort 2, and 3 in cohort 3. As the 20-
`ng/kg/min dose in cohort 3 was poorly tolerated, addi-
`tional patients were enrolled in cohort 2 to better define
`the hemodynamic effects of the maximal tolerated dose.
`Data reported are for those 20 patients who completed
`the subcutaneous treprostinil infusion. A dose of 10
`ng/kg/min was identified as the maximal tolerated sub-
`cutaneous dose acutely. Dose-limiting side effects of
`subcutaneous treprostinil were similar to intravenous
`treprostinil and included nausea, vomiting, headache,
`dizziness, and anxiety. Changes in hemodynamic mea-
`sures were similar for intravenous treprostinil and sub-
`cutaneous treprostinil at the maximal tolerated dose (co-
`
`TABLE 3.
`Baseline hemodynamics and exercise capacity, trial 3 (sc
`treprostinil vs. placebo)
`
`RAPm, mm Hg
`PAPm, mm Hg
`PCWPm, mm Hg
`CI, l/min/m2
`MV Sat, %
`PVRI, Units/m2
`Exercise, meters
`Borg dyspnea score
`
`Placebo
`(n ⳱ 9)
`
`10 ± 1
`64 ± 6
`10 ± 1
`2.4 ± 0.2
`61.7 ± 2.8
`24.7 ± 3.0
`384 ± 27
`+2.4 ± 0.7
`
`Treprostinil
`(n ⳱ 17)
`
`9 ± 1
`59 ± 4
`8 ± 1
`2.3 ± 0.2
`62.1 ± 3.0
`24.8 ± 2.6
`373 ± 25
`+3.2 ± 0.3
`
`p
`
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`
`CI, cardiac index; MV Sat, mixed venous saturation; PAPm, mean
`pulmonary artery pressure; PCWPm, mean pulmonary capillary wedge
`pressure; PVRI, pulmonary vascular resistance index; RAPm, mean
`right atrial pressure.
`
`

`

`EFFICACY AND SAFETY OF TREPROSTINIL
`
`297
`
`TABLE 4.
`Percent change from baseline, Trial 2 (IV treprostinil vs. SC treprostinil)
`
`IV 10
`ng/kg/min
`
`5 Cohort 1
`SC 5 ng/kg/min
`
`10 Cohort 2
`SC 10 ng/kg/min
`
`20 Cohort 3
`SC 20 ng/kg/min
`
`n
`RAPm, %
`PAPm, %
`PCWPm, %
`CI, %
`PVRI, %
`SAPm, %
`MVO2, %
`SaO2, %
`
`20
`−11 ± 31
`−7 ± 12
`3 ± 30
`+15 ± 17
`−22 ± 15
`−4 ± 8
`+9 ± 21
`−3 ± 11
`
`5
`+27 ± 68
`+4 ± 7
`+3 ± 9
`+6 ± 16
`+2 ± 27
`+1 ± 3
`−3 ± 9
`−1 ± 2
`
`12
`−20 ± 46
`−13 ± 12
`−1 ± 24
`+20 ± 22
`−26 ± 21
`−3 ± 9
`+6 ± 8
`0 ± 2
`
`3
`13 ± 63
`−8 ± 8
`−20 ± 8
`+7 ± 3
`−15 ± (NA)
`−9 ± 11
`+6 ± 19
`−1 ± 2
`
`Values shown as mean ± SD.
`CI, cardiac index; MV Sat, mixed venous saturation; PAPm, mean pulmonary artery
`pressure; PCWPm, mean pulmonary capillary wedge pressure; PVRI, pulmonary vascular
`resistance index; RAPm, mean right atrial pressure; SAPm, mean systemic arterial pres-
`sure; SaO2, systemic arterial saturation.
`
`hort 2). In the intravenous treprostinil and subcutaneous
`treprostinil 10-ng/kg/min cohort, there was a 6% and
`13% decrease in mean pulmonary artery pressure and a
`23% and 28% decrease in pulmonary vascular resistance,
`respectively. Pharmacokinetic data were available for 4
`patients in cohort 1, 8 patients in cohort 2, and 3 patients
`in cohort 3, and are displayed in Table 5.
`
`Trial 3
`Twenty-six patients were enrolled. There were no sta-
`tistically significant differences in baseline hemodynam-
`ics or walk distance between the placebo and the trepro-
`stinil groups (Table 3). Two patients in the treprostinil
`group did not complete the study due to intolerable side
`effects. One patient had hypotension with the initiation
`of treprostinil and was withdrawn from the study and
`treated with intravenous epoprostenol. The other patient
`had intolerable pain at the site of the subcutaneous infu-
`sion. Of the remaining patients, 15 were on a mean dose
`of 13.0 ± 3.1 ng/kg/min of treprostinil (range, 2.5–50),
`while the 9 patients receiving placebo were on 38.9 ± 6.7
`
`TABLE 5.
`Plasma half-life of treprostinil, trial 2
`
`Cohort 1
`(n ⳱ 4)
`
`Cohort 2
`(n ⳱ 8)
`
`Cohort 3
`(n ⳱ 3)
`
`IV
`dosing
`
`SC
`dosing
`
`IV
`dosing
`
`SC
`dosing
`
`IV
`dosing
`
`SC
`dosing
`
`T1/2 min
`Mean
`SD
`
`41.7
`60.8
`
`65.1
`48.0
`
`35.4
`31.7
`
`117.2
`89.4
`
`25.6
`12.1
`
`55.1
`20.1
`
`ng/kg/min (range, 20–75) at the end of the 8-week pe-
`riod. Clinically significant adverse effects and local ad-
`verse effects related to the subcutaneous infusion were
`common (Table 6). In general, these effects occurred
`with the initiation of the drug and were short lived.
`Treprostinil had a favorable effect on hemodynamics and
`exercise tolerance (Table 7). While none of these favor-
`able effects associated with treprostinil reached statisti-
`cal significance, there was a 20% decrease in pulmonary
`vascular resistance index during the 8-week period.
`There was a trend toward improvement of 37 ± 17 m in
`the 6-minute walk distance in patients receiving trepro-
`stinil for 8 weeks (from 373 m to 411 m) compared with
`a 6 ± 28 m decrease in those receiving placebo (379 m at
`week 8 compared with 384 m at baseline; p ⳱ NS). In
`addition, there was a trend toward improvement in the
`Borg Dyspnea Scale from 3.2 to 3.1 in the treprostinil
`
`TABLE 6.
`Clinically significant adverse effects, trial 3 (sc treprostinil
`vs. placebo)
`
`Placebo
`n (%)
`
`Treprostinil
`n (%)
`
`Vomiting
`Hypotension
`Bradycardia
`Vasovagal
`Syncope
`Insomnia
`Infusion site erythema/induration
`Infusion site pain
`
`0 (0)
`0 (0)
`0 (0)
`2 (22)
`3 (33)
`3 (33)
`2 (22)
`2 (22)
`
`4 (24)
`4 (24)*
`2 (12)
`0 (0)
`1 (6)
`1 (6)
`16 (94)
`15 (88)*
`
`Placebo, n ⳱ 9; treprostinil n ⳱ 17.
`*One patient was withdrawn from the study.
`
`p
`
`NS
`NS
`NS
`NS
`NS
`NS
`0.0004
`0.0016
`
`J Cardiovasc Pharmacol™, Vol. 41, No. 2, 2003
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`

`

`298
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`V. V. MCLAUGHLIN ET AL.
`
`TABLE 7.
`Hemodynamic/exercise capacity change from baseline, trial 3
`(sc treprostinil vs. placebo)
`
`RAPm, mmHg
`PAPm, mmHg
`MV Sat, %
`CI, l/min/m2
`PVRI, Units/m2
`Exercise, meters
`Borg Dyspnea Scale
`
`Placebo
`(n ⳱ 9)
`
`−2 ± 1
`−2 ± 1
`−2 ± 1
`−0 ± 0.2
`+0.2 ± 1.9
`−6 ± 28
`+1.0 ± 0.8
`
`Treprostinil
`(n ⳱ 15)
`
`−1 ± 1
`0 ± 3
`−2 ± 2
`+0.4 ± 0.2
`−4.8 ± 1.4
`+37 ± 17
`0.0 ± 0.4
`
`p
`
`NS
`NS
`NS
`0.065
`0.065
`NS
`NS
`
`CI, cardiac index; MV Sat, mixed venous saturation; PAPm, mean
`pulmonary artery pressure; PVRI, pulmonary vascular resistance index;
`RAPm, mean right atrial pressure.
`
`group compared with a worsening of 2.4 to 3.4 in the
`placebo group. The Dyspnea Fatigue Rating improved
`from 6.3 in the treprostinil group to 7.1, while it wors-
`ened from 6.3 to 5.6 in the placebo group. These trends
`were not statistically significant. Other adverse events,
`including headache, diarrhea, flushing, jaw pain, and
`foot pain, were common with treprostinil administration
`as they are with epoprostenol.
`
`DISCUSSION
`
`The trials reported here demonstrate that treprostinil
`appears to be effective and in a small pilot study may be
`comparable with epoprostenol in the short term for the
`management of PPH. When compared with intravenous
`epoprostenol, intravenous treprostinil produced a similar
`decrease in pulmonary vascular resistance (22% vs. 20%,
`respectively). In fact, given the estimated half-life of
`intravenous treprostinil determined in trial 2 (25.6–41.7
`minutes), the effect of intravenous treprostinil in trial 1
`may have been underestimated as the dose was increased
`at 30-minute intervals. To test whether the effects ob-
`served from intravenous treprostinil could be reproduced
`with subcutaneous administration, the second trial com-
`pared acutely administered doses of 10 ng/kg/min intra-
`venous treprostinil with subcutaneous treprostinil given
`at doses of 5, 10, and 20 ng/kg/min. Although the small-
`est dose of 5 ng/kg/min did not have a significant effect,
`the higher doses of 10 ng/kg/min and 20 ng/kg/min re-
`sulted in a 26% and 16% decrease in total pulmonary
`resistance, respectively. This study also demonstrated
`that the apparent biologic half-life of subcutaneous
`treprostinil was in the range of 55 to 117 minutes. This
`trial supported the hypothesis that the effects of subcu-
`taneous treprostinil were similar to intravenous treprosti-
`nil. The small number of patients, the unblinded nature,
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`J Cardiovasc Pharmacol™, Vol. 41, No. 2, 2003
`
`and the confounding factor of spontaneous variation in he-
`modynamics that may occur during the many hours re-
`quired to complete these studies limit both of these trials.
`The third trial was a pilot study of the short-term ef-
`fects of treprostinil in patients with PPH. During an
`8-week period, there was a trend toward an increase in
`cardiac index and a decrease in pulmonary vascular re-
`sistance index in patients treated with treprostinil com-
`pared with placebo, although the differences were not
`statistically significant. There was also a nonsignificant
`improvement in exercise tolerance of 37 ± 17 m. This
`compares favorably with the 47-m improvement demon-
`strated in a much larger 12-week trial of intravenous
`epoprostenol for PPH management (1). Trends toward
`improvements in assessment of effort were also demon-
`strated, suggesting that treated patients walked further
`with fewer symptoms. Adverse effects of the short-term
`use of treprostinil included headache, diarrhea, flushing,
`jaw pain, and foot pain, all of which also occur com-
`monly with chronic intravenous epoprostenol therapy.
`However, there were also injection site adverse effects,
`including erythema and pain. One patient was prema-
`turely withdrawn from the trial because of pain related to
`the injection site. Although this was a placebo-controlled
`trial, the frequency of infusion site reaction may have made
`true blinding difficult. This trial also demonstrated that
`treprostinil can be given safely in an ambulatory patient,
`using a novel subcutaneous delivery pump system.
`Subcutaneous treprostinil has several important ad-
`vantages over intravenous epoprostenol. It obviates the
`need for central venous access, and thus complications
`related to epoprostenol delivery, such as local and sys-
`temic infections, paradoxical emboli, and thrombosis, do
`not occur. Because of its short half-life, abrupt discon-
`tinuation of intravenous epoprostenol can lead to re-
`bound pulmonary hypertension, cardiovascular collapse,
`and death. However, because of its longer half-life and
`mode of delivery, abrupt discontinuation of treprostinil
`appears safe. Treprostinil does not need to be reconsti-
`tuted daily as does epoprostenol. In addition, the infusion
`pump is much smaller than the pump required for epo-
`prostenol initiation. Patients may prefer both these ad-
`vantages. The most significant adverse effects of trepro-
`stinil are pain and erythema at
`the subcutaneous
`administration site. Although most patients reported pain
`and erythema, only one patient withdrew from the
`8-week trial because of site pain.
`
`CONCLUSIONS
`
`This series of trials demonstrated that intravenous and
`subcutaneous treprostinil produce similar hemodynamic
`
`

`

`EFFICACY AND SAFETY OF TREPROSTINIL
`
`299
`
`effects when administered acutely, and the effects are
`comparable with intravenous epoprostenol administered
`acutely. We have also demonstrated the safety and effi-
`cacy of subcutaneous treprostinil given during an 8-week
`period in a small pilot trial of 26 patients with PPH.
`Based on these trials, a large international trial of trepro-
`stinil in patients with PPH, pulmonary hypertension as-
`sociated with collagen vascular diseases, and pulmonary
`hypertension associated with congenital heart disease
`was undertaken and has recently been reported (9).
`
`Acknowledgments: Other participants in the Trepro-
`stinil Study Group: Traci Housten-Harris, R.N., M.S.
`(University of Maryland Medical Center); Cathy
`Droogan, R.N., Veronica Lewis, R.N., Stella Goudie,
`R.N. (Columbia-Presbyterian Medical Center); Dina
`Hess, R.N., Maureen Panella, R.N. (Rush-Presbyterian-
`St. Luke’s Medical Center); Joy Beckmann, R.N., Daisy
`Camanga, R.N., Linda Magre, R.N. (Harbor-UCLA
`Medical Center); Cathy Severson, R.N., Kristy Mona-
`han, R.N. (Mayo Clinic); Kristine Wynne, R.N. (Univer-
`sity of Colorado Health Sciences Center); Terry Casey-
`Cato, R.N. (Vanderbilt University Medical Center);
`Abby Krichman, R.R.T., Michelle Johnson, R.N. (Duke
`University Medical Center); Helena Purl, R.N. (Method-
`ist Hospital, Baylor College of Medicine); Barry K. Ray-
`burn, M.D., Raymond L. Benza, M.D., Brian Foley,
`M.D., Marc Aaron, M.D., Amy Trimble, R.N., Melanie
`Smith, R.N., Amanda White, R.N., Amy Trimble, R.N.
`(University of Alabama, Birmingham); and James W.
`Crow, PhD.
`
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