Transitioning From IV Epoprostenol to
`Subcutaneous Treprostinil in Pulmonary
`Arterial Hypertension*
`
`Jean-Luc Vachie´ry, MD; Nicholas Hill, MD, FCCP; Diane Zwicke, MD, FCCP;
`Robyn Barst, MD; Shelmer Blackburn, MD; and Robert Naeije, MD
`
`Objective: Continuous IV epoprostenol (prostacyclin) therapy improves survival and quality of
`life in patients with pulmonary arterial hypertension (PAH). IV epoprostenol therapy may be
`limited by serious complications related to the need for an implanted central venous catheter,
`and its chemical instability and short half-life. Treprostinil is a longer-acting prostacyclin analog,
`chemically stable, and suitable for continuous subcutaneous administration. We report successful
`transitioning to subcutaneous treprostinil of patients who presented with life-threatening
`complications of IV epoprostenol delivery.
`Design: Open, uncontrolled study.
`Setting: ICUs and departments of cardiology at academic hospitals.
`Patients: Eight patients with PAH treated with continuous IV epoprostenol.
`Intervention: Transition to subcutaneous treprostinil following an empiric protocol.
`Results: Transition to treprostinil was achieved successfully in 21 to 96 h, with no major adverse
`side effects, and no change in the improved clinical status achieved with IV epoprostenol. Doses
`of epoprostenol before transition ranged from 3.5 to 75 ng/kg/min (mean, 27 ng/kg/min). Doses
`of
`treprostinil at completion of
`the transition ranged from 3 to 65 ng/kg/min (mean,
`22 ng/kg/min). Four to 11 months later, the patients remained clinically improved. In spite of
`mild-to-moderate infusion site pain, all patients reported an improved sense of comfort and
`well-being.
`Conclusion: Patients with PAH can be safely transitioned from treatment with IV epoprostenol to
`subcutaneous treprostinil.
`(CHEST 2002; 121:1561–1565)
`
`Key words: anorexigens; congenital heart disease; connective tissue disease; epoprostenol; HIV infection; portal
`hypertension; primary pulmonary hypertension; pulmonary arterial hypertension; treprostinil
`
`Abbreviations: NYHA ⫽ New York Heart Association; PAH ⫽ pulmonary arterial hypertension
`
`C ontinuous IV epoprostenol (prostacyclin) ther-
`
`apy improves functional state, exercise capacity,
`pulmonary hemodynamics, and survival in patients
`
`*From the Departments of Cardiology (Dr. Vachie´ry) and Patho-
`physiology (Dr. Naeije), Erasme University Hospital, Brussels,
`Belgium; Rhode Island Hospital (Dr. Hill), Providence, RI; St
`Luke’s Medical Center (Dr. Zwicke), Milwaukee, WI; the De-
`partment of Pediatrics (Dr. Barst), Columbia Presbyterian Med-
`ical Center, New York, NY; and United Therapeutics Corpora-
`tion (Dr. Blackburn), Research Triangle Park, NC.
`This study was supported by United Therapeutics Corporation,
`Research Triangle Park, NC.
`Drs. Vachie´ry, Hill, Zwicke, Barst, and Naeije were principal
`investigators and/or members of the steering committee of a
`randomized controlled trial of the efficacy and safety of trepros-
`tinil in pulmonary arterial hypertension and, as such, received
`indirect support from United Therapeutics Corporation. Dr.
`Blackburn is an employee of United Therapeutics Corporation.
`Manuscript received July 23, 2001; revision accepted October 30,
`2001.
`Correspondence to: Robert Naeije, MD, Laboratory of Physiol-
`ogy, Erasmus Campus, CP 604, Route de Lennik 808, B-1070
`Brussels, Belgium; e-mail: rnaeije@ulb.ac.be
`
`with primary pulmonary hypertension.1– 6 Similar
`clinical effects of epoprostenol have been reported in
`patients with pulmonary hypertension associated
`with connective tissue disease7,8 and congenital heart
`defects.9 The treatment therefore appears indicated
`in pulmonary arterial hypertension (PAH) as re-
`cently defined by a World Health Organization-
`sponsored consensus conference.10 However, due to
`its short half-life and chemical instability, long-term
`epoprostenol therapy requires a permanently im-
`planted central venous catheter and a portable infu-
`sion pump, exposing the patients to a series of
`complications including catheter-related embolism
`or thrombosis, infection, and delivery system mal-
`functions resulting in poorly tolerated, rapid over-
`dosing or underdosing.1–9 Accordingly, alternative
`modes of administration and longer acting prostacy-
`clin derivatives are currently under investigation.
`Favorable results have been reported with trepros-
`
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`
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`
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`

`tinil, a chemically stable prostacyclin analog with a
`longer half-life, administered as a long-term subcu-
`taneous infusion.11 This report describes the success-
`ful first transition to subcutaneous treprostinil of
`eight patients with PAH who presented with life-
`threatening complications of long-term IV epopros-
`tenol therapy.
`
`Materials and Methods
`
`Eight patients with severe PAH who had initial clinical im-
`provement (improved symptoms, exercise capacity) with long-
`term IV epoprostenol administration, but presented with life-
`threatening complications of
`this
`treatment, gave written
`informed consent to the study. All patients were followed up at
`centers experienced in long-term IV epoprostenol therapy, and
`which had participated in a randomized controlled trial11 of
`long-term subcutaneous treprostinil therapy in New York Heart
`Association (NYHA) class III and IV patients with PAH.
`An empiric transition protocol was agreed on and approved by
`the local institutional review boards. Patients were hospitalized
`throughout the transition process. The transitions were per-
`formed in an intensive care or telemetry setting, with continuous
`monitoring of clinical status, including ECG and BP. While in
`the hospital and receiving a prescribed dose of epoprostenol,
`each patient was initiated on a dose of treprostinil (generally
`ⱕ 5 ng/kg/min) equal to not more than one half of the current
`epoprostenol dose. Treprostinil was maintained at this dose for at
`least 6 h. During this time, the dose of epoprostenol was reduced
`slowly,
`in not more than 2-ng/kg/min decrements, based on
`appearance of prostacyclin-related signs and symptoms. With the
`patient in clinically stable condition, treprostinil was increased
`further, by no more than one half of the current dose, and
`maintained for at least 6 h while epoprostenol was further
`reduced based on prostacyclin-related events. Symptoms of
`insufficient or excess prostacyclin were managed with adjust-
`ments to the IV epoprostenol dose. This process was continued
`until epoprostenol was discontinued. Symptoms of prostacyclin
`overdosing were facial flush, headache,
`jaw pain, abdominal
`cramping, diarrhea, and hypotension. Symptoms of prostacyclin
`underdosing were fatigue, dyspnea, chest pain, and pallor. Clin-
`ical state, NYHA functional class, and exercise capacity were
`evaluated before and after the transition, and then at least every
`3 months. Exercise capacity was evaluated using a standard
`unencouraged 6-min walk test.12
`Treprostinil, available in a ready-to-use parenteral solution,
`was administered subcutaneously using a positive-pressure mi-
`
`croinfusion pump (MiniMed; Sylmar, CA). The catheter was
`placed by the patient in the subcutaneous tissue of the abdominal
`wall, changing the infusion site location every 3 days. Epoproste-
`nol, provided as a lyophilized powder for dilution with glycine
`buffer, was administered through a permanently implanted cen-
`tral venous catheter, using a portable infusion pump. Conven-
`tional therapy included coumarin derivatives with doses adapted
`for an international normalized ratio between 1.5 and 2.5, and
`diuretics and/or digitalis as needed.
`The results are expressed individually or as mean ⫾ SE. Stu-
`dent’s paired t tests were used for statistical analysis.
`
`Results
`
`The baseline characteristics of the patients are
`summarized in Table 1. Five of the patients had
`primary pulmonary hypertension, which was associ-
`ated with fenfluramine ingestion in three patients
`and associated with HIV infection in one patient.
`One patient had pulmonary hypertension associated
`with portal hypertension, one patient had a congen-
`ital left-to-right cardiac shunt, and one patient had
`scleroderma. All patients had been severely ill,
`NYHA class III or IV, before the institution of IV
`epoprostenol therapy. Mean pulmonary artery pres-
`sure ranged from 31 to 88 mm Hg (mean ⫾ SE,
`58 ⫾ 8 mm Hg). After 3 to 15 months of epoproste-
`nol therapy, seven patients were NYHA class II and
`one patient had improved from NYHA class IV to
`class III. Severe complications justifying transition to
`subcutaneous treprostinil included recurrent central
`venous catheter-related sepsis in five patients; severe
`headache, jaw pain, abdominal cramping, and diar-
`rhea preventing an increase in epoprostenol dose in
`the presence of clinical deterioration in one patient;
`recurrent cerebral air emboli with residual left pa-
`ralysis in one patient; and several episodes of syn-
`cope due to the short half-life and accidental discon-
`nections of the IV line in one patient.
`The doses of epoprostenol at transition, the initial
`treprostinil dose, the treprostinil dose at completion
`of transition, and the time needed to complete
`the transition are presented in Table 2. The dose
`
`Table 1—Patient Characteristics*
`
`Patient
`No.
`
`Age,
`yr
`
`Gender
`
`Diagnosis
`
`Initial
`NYHA Class
`
`Time Receiving IV
`Epoprostenol, mo
`
`Current NYHA
`Class
`
`Epoprostenol
`Complications
`
`Sepsis
`39
`IV
`PPH
`Female
`39
`1
`Headache
`21
`IV
`PPH
`Female
`54
`2
`Sepsis
`31
`IV
`PPH
`Male
`35
`3
`Cerebral emboli, hemiplegia
`4.5
`III
`VSD, PDA
`Female
`30
`4
`Sepsis
`II
`36
`IV
`Portal hypertension
`Male
`32
`5
`Recurrent syncope
`II
`29
`III
`PPH/HIV
`Female
`48
`6
`Sepsis
`II
`25
`III
`CTD
`Female
`54
`7
`Sepsis
`II
`21
`III
`PPH
`Female
`52
`8
`*PPH ⫽ primary pulmonary hypertension; VSD ⫽ ventricular septal defect; PDA ⫽ patent ductus arteriosus; CTD ⫽ connective tissue disease.
`
`II
`III
`II
`
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`
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`

`Table 2—Doses of Epoprostenol and Treprostinil,
`and Duration of Transition in Eight Patients With
`Severe PAH
`
`Patient
`No.
`
`Epoprostenol
`Dose,
`ng/kg/min
`
`Initial
`Treprostinil
`Dose,
`ng/kg/min
`
`Final
`Treprostinil
`Dose,
`ng/kg/min
`
`Time to
`Transition,
`h
`
`1
`2
`3
`4
`5
`6
`7
`8
`
`15
`13
`18
`3.5
`75
`26
`26
`40
`
`4
`4
`6
`1
`5
`5
`4.2
`5.45
`
`7
`10
`16
`3
`65
`16
`23
`36.6
`
`23
`22
`21
`24
`96
`56
`50
`54
`
`of epoprostenol at transition ranged from 3.5 to
`75 ng/kg/min (mean, 27 ng/kg/min), and the dose of
`treprostinil at completion of transition ranged from 3
`to 65 ng/kg/min (mean, 22 ng/kg/min). Moderate
`symptoms of excess prostacyclin delivery were
`promptly relieved by reduction of the IV epoproste-
`nol infusion rate. There were no other side effects of
`the transition. Clinical status and NYHA functional
`class were unchanged after the transition. Heart rate
`(from 75 ⫾ 3 to 76 ⫾ 4 beats/min), mean systemic
`BP (from 79 ⫾ 4 to 82 ⫾ 4 mm Hg), and distance
`walked in 6 min (from 496 ⫾ 45 to 486 ⫾ 29 m,
`n ⫽ 5) were unchanged posttransition from the im-
`provement experienced with IV epoprostenol (Table
`3; p ⫽ not significant 6 to 8 weeks posttransition vs
`within 1 week prior to transition, Student’s paired t
`test). The 6-min walk test could not be performed in
`patient 4, was refused by one patient because of local
`infusion site pain, and one patient did not have a
`pretransition test.
`All patients experienced varying degrees of ery-
`
`Table 3—NYHA Classification and 6-min Walk Test
`Prior to and After Transition*
`
`NYHA Class
`Prior to
`Transition
`
`NYHA Class
`After
`Transition
`
`6-min Walk
`Prior to
`Transition, m†
`
`6-min Walk
`After
`Transition, m‡
`
`Patient
`No.
`
`II
`III
`II
`NA
`II
`II
`II
`II
`
`528
`325
`563
`NA
`NA
`482
`583
`242
`
`II
`1
`III
`2
`II
`3
`NA
`4
`II
`5
`II
`6
`II
`7
`II
`8
`*NA ⫽ not assessed.
`†6-minute walk test was conducted within 1 week prior to transition.
`‡6-minute walk test follow-up ranged from 6 to 8 weeks after
`transition.
`
`496
`404
`555
`NA
`639
`449
`525
`NA
`
`thema, swelling, and pain at the treprostinil infusion
`site at the completion of the transition. The maxi-
`mum pain rating was mild in one patient with the
`lowest dose of epoprostenol, but was moderate to
`severe in the seven other patients. The pain was
`treated with topical cooling and corticosteroid or
`nonsteroidal anti-inflammatory drug ointments, oral
`paracetamol
`(acetaminophen), and/or other oral
`nonsteroidal anti-inflammatory drugs. Two patients
`received paracetamol-codeine preparations, briefly.
`Two other patients were treated with short courses
`(2 mg/kg/d) of oral prednisolone, which appeared to
`be very effective. The local pain markedly improved
`after a few weeks in six patients. The only other side
`effect of subcutaneous treprostinil therapy reported
`was minor infusion site hematoma, occurring in four
`patients.
`Follow-up after transition to treprostinil ranged
`from 4 to 11 months. Clinical state, NYHA functional
`class, and 6-min walk distances
`remained un-
`changed, except in one NYHA class III patient who
`slowly deteriorated in spite of continuous increases
`of treprostinil, but improved moderately after an
`atrial septostomy. This patient had been deteriorat-
`ing while receiving IV epoprostenol.
`
`Discussion
`
`The present results demonstrate that the transi-
`tion from IV epoprostenol to subcutaneous trepros-
`tinil
`is safe, with excellent intermediate (4 to 11
`months) results,
`in patients with severe PAH in
`whom epoprostenol therapy is effective but compli-
`cated by life-threatening side effects.
`Severe PAH is a rapidly progressive and fatal
`disease that remains incurable.13 However, patient
`outcome has been improved in recent years by
`several therapeutic advances.13 The most significant
`advance has unquestionably been in the introduction
`of long-term IV epoprostenol therapy.1–10,13 How-
`ever, this treatment is not without complications.
`Due to its short half-life (1 to 2 min) and chemical
`instability, epoprostenol can only be administered via
`IV, and thus requires a permanently implanted
`central venous catheter and a portable infusion
`pump, as well as refrigeration during administration.
`This carries risks of sepsis, thrombosis, paradoxical
`embolism, and interruptions of treatment due to
`accidental occlusions, perforations and dislodgments
`of the catheter, and pump malfunction.2– 4,6 –9 Addi-
`tionally, any interruption of delivery may be associ-
`ated with syncope, and even death, from an acute
`pulmonary hypertensive crisis.2– 4,6 –9 The present
`series of patients illustrates how patients who have
`had life-threatening complications such as recurrent
`
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`
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`

`sepsis, paradoxical embolism, and interruptions of
`drug delivery while receiving IV epoprostenol may
`be transitioned to therapy with longer acting prosta-
`cyclin analogs administered by an alternative deliv-
`ery route, with a reduction in the risk of
`life-
`threatening complications.
`Treprostinil is a stable prostacyclin analog with
`pharmacologic actions14,15 and acute pulmonary va-
`sodilating properties16 similar to prostacyclin. In
`contrast to prostacyclin, treprostinil
`is chemically
`stable at room temperature and neutral pH, has a
`longer half-life (3 to 4 h), and is thus suitable for
`subcutaneous administration. A recent multicenter,
`randomized, double-blind, placebo-controlled trial
`in 470 patients has shown that long-term subcutane-
`ous treprostinil therapy improves exercise capacity,
`symptoms of pulmonary hypertension, hemodynam-
`ics, and quality of life, and is safe and well tolerated
`in patients with PAH (primary or associated with
`congenital cardiac shunts or connective tissue dis-
`ease).11 However, as also noted in the present study,
`the treatment is frequently associated with local
`infusion site erythema, swelling, and pain. This side
`effect profile occasionally can be severe enough to
`alter quality of life and exercise capacity, but most
`often is controlled by topical cold packs, corticoste-
`roid or anti-inflammatory ointments, and oral anti-
`inflammatory and analgesic drugs. Two patients in
`the present study reported severe local pain that was
`satisfactorily controlled by a short course of high-
`dose corticosteroids. Infusion site reactions also tend
`to abate over time, generally after a few months. Of
`interest, all but one of the eight patients felt an
`improved sense of comfort and well-being soon after
`transition to subcutaneous treprostinil, despite the
`infusion site pain.
`The only other notable side effect of long-term
`subcutaneous treprostinil was the occurrence of
`hematomas at the infusion site. Four of eight pa-
`tients experienced such hematomas, none of which
`were severe enough to preclude continuation of the
`treatment. These infusion site hematomas are ex-
`plained by the combination of mechanical trauma,
`anticoagulation, and possibly the antiplatelet aggre-
`gate effects of prostacyclins. Infusion site problems,
`including irritation,
`infection, bleeding and pain,
`have also been reported in patients receiving contin-
`uous IV epoprostenol.2– 4,6 –9
`In one patient,
`transition to treprostinil was
`elected due to clinical deterioration that could not be
`treated with increased epoprostenol doses due to
`intolerable prostacyclin-related side effects including
`headache and diarrhea. Subcutaneous treprostinil
`allowed better control of the clinical state by pro-
`gressive increases in dose with no or only mild signs
`and symptoms of prostacyclin intolerance.
`
`In summary, subcutaneous treprostinil can be
`safely considered as an alternative option to IV
`epoprostenol therapy in patients with severe PAH
`who experience life-threatening complications while
`receiving IV epoprostenol or in patients who cannot
`tolerate dose increases. Transition to subcutaneous
`treprostinil can be safely achieved using an empirical
`protocol that accomplishes the transition over a brief
`time period with minimal adverse side effects.
`
`ACKNOWLEDGMENT: The authors thank Allison Widlitz,
`PA-C, Evelyn Horn, MD, and Amy Yoney, RN, Columbia
`Presbyterian Medical Center, New York, NY; Jeanne Houtchens,
`RN, RI Hospital, Providence, RI; Don Lobacz, RN, St. Luke’s
`Medical Center, Milwaukee, WI; Marie-Therese Gautier, RN,
`Erasme University Hospital, Brussels, Belgium; and James Crow,
`PhD, Robin Flinchbaugh, BS, and Kim Kusy, BS, United
`Therapeutics Corporation, Research Triangle Park, NC.
`
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`13 Fishman AP. Epoprostenol (prostacyclin), and pulmonary
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