Safety and Efficacy of Transition from Systemic Prostanoids to Inhaled Treprostinil in Pulmonary Arterial Hypertension

Safety and Efficacy of Transition from Systemic Prostanoids to Inhaled Treprostinil in Pulmonary Arterial Hypertension Vinicio A. de Jesus Perez, MDa,*, Erica Rosenzweig, MDb, Lewis J. Rubin, MDc, David Poch, MDc, Abubakr Bajwa, MDd, Myung Park, MDe, Mohit Jain, MDf, Robert C. Bourge, MDf, Kristina Kudelko, MDa, Edda Spiekerkoetter, MDa, Juliana Liu, NPa, Andrew Hsia, and Roham T. Zamanian, MDa Pulmonary arterial hypertension (PAH) is a disease characterized by increased pulmonary pressures and chronic right heart failure. Therapies for moderate and severe PAH include subcutaneous (SQ) and intravenous (IV) prostanoids that improve symptoms and quality of life. However, treatment compliance can be limited by severe side effects and complications related to methods of drug administration. Inhaled prostanoids, which offer the advantage of direct delivery of the drug to the pulmonary circulation without need for invasive approaches, may serve as an alternative for patients unable to tolerate SQ/IV therapy. In this retrospective cohort study we collected clinical, hemodynamic, and functional data from 18 clinically stable patients with World Health Organization group I PAH seen in 6 large national PAH centers before and after transitioning to inhaled treprostinil from IV/SQ prostanoids. Before transition 15 patients had been receiving IV or SQ treprostinil (mean dose 73 ng/kg/min) and 3 patients had been on IV epoprostenol (mean dose 10 ng/kg/min) for an average duration of 113 ⴞ 80 months. Although most patients who transitioned to inhaled treprostinil demonstrated no statistically significant worsening of hemodynamics or 6-minute walk distance, a minority demonstrated worsening of New York Heart Association functional class over a 7-month period. In conclusion, although transition of patients from IV/SQ prostanoids to inhaled treprostinil appears to be well tolerated in clinically stable patients, they should remain closely monitored for signs of clinical decompensation. © 2012 Published by Elsevier Inc. (Am J Cardiol 2012;110:1546 –1550)

Pulmonary arterial hypertension (PAH) is a disease characterized by abnormal increase in pulmonary pressures that, if untreated, leads to chronic right heart failure and death. Since the introduction of epoprostenol in 1995, prostanoids have been used to improve the functional status, hemodynamic profile, and quality of life of patients with moderate and severe forms of PAH.1,2 There are 3 prostanoids approved for use in a Stanford University, Stanford, California; bColumbia University, New York, New York; cUniversity of California, San Diego, California; dUniversity of Florida, Gainesville, Florida; eUniversity of Maryland, Baltimore, Maryland; fUniversity of Alabama at Birmingham, Birmingham, Alabama. Manuscript received April 2, 2012; revised manuscript received and accepted July 4, 2012. Dr. de Jesus Perez was supported by a K12 grant from the National Institutes of Health and a Career Development Award from the Robert Wood Johnson Foundation. Dr. Spielerketter was supported by K12 and K08 awards from the National Institutes of Health. Dr. Rubin has served as consultant for United Therapeutics, Silver Spring, Maryland/LungRx, Actelion, Basel, Switzerland, Pfizer, New York, New York, GlaxoSmithKline, Br entford, Middlesex, UK, Gilead, Foster City, California, Bayer, Pittsburgh, Pennsylvania, GeNo, New Delhi, India, and AIRES, San Diego, California and serves on the scientific advisory board of United Therapeutics. Dr. Rosenzweig has received research support from Pfizer. Dr. Bourge has served as consultant to Medtronic, Inc., Medtronic, Minneapolis. Dr. Zamanian receives research funds from Actelion, Gilead, and United Therapeutics and is a consultant for Gilead and United Therapeutics Pharmaceuticals. *Corresponding author: Tel: 1-650-723-0318; fax: 1-650-498-6288. E-mail address: [email protected] (V.A. de Jesus Perez).

0002-9149/12/$ – see front matter © 2012 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.amjcard.2012.07.012

World Health Organization (WHO) group I PAH: epoprostenol, iloprost, and treprostinil.2 Although the first 2 are administered exclusively by intravenous (IV) and inhaled routes, respectively, the latter is available in IV, inhaled, and subcutaneous (SQ) forms.3– 6 Despite their efficacy, long-term use of IV prostanoids may be complicated by adverse side effects including recurrent line infections, patient noncompliance, and challenges related to proper preparation and maintenance of prostanoid infusion.7,8 Although inhaled prostanoids are approved for use only in WHO group I PAH with specific indications related to functional status, it is unclear whether this approach could also be offered to patients who may not be candidates for long-term use of these agents. In the present study we sought to evaluate whether patients with stable PAH receiving IV/SQ prostanoid infusions could be safely transitioned to inhaled treprostinil with maintenance of efficacy and with a similar safety profile. Methods The institutional review board of Stanford University reviewed and approved the collection of clinical data for this study (Stanford University institutional review board number 12338). Informed consent was obtained from all patients before participation. A multicenter retrospective chart review study was performed in which clinical data from patients with WHO group I PAH who were initially started on IV/SQ treprostinil or IV epoprostenol and later switched to inhaled treprostinil were collected from 6 large www.ajconline.org

Miscellaneous/Transition from IV to Inhaled Prostanoids

PAH centers (New York-Presbyterian/Columbia University; University of California, San Diego; Stanford University; University of Alabama, Birmingham; University of Maryland; and University of Florida) with extensive experience in the use of all forms of prostanoids for management of PAH. Most patients (90%) who underwent transition to inhaled prostanoids had severe side effects and recurrent line infections despite aggressive palliative efforts by a multidisciplinary care team and the remainder (10%) were unable to make optimal use of systemic therapy because of superimposed clinical and/or social adversities. Before initiation of transition, all patients were counseled by their PAH care team on the limited evidence in support of transitioning to inhaled prostanoids after achieving clinical stability on systemic prostanoids and underwent assessment to determine whether they were clinically fit to tolerate the potential stress involved in the transition. Clinical fitness was judged by persistent improvement in hemodynamic values, 6-minute walk distance, New York Heart Association (NYHA) functional class, and quality of life after initiation of prostanoid therapy that had remained unchanged for ⱖ1 year. All patients transitioning to inhaled therapy had been on IV or SQ prostanoids for an average period of 9 years. In addition to prostanoids, most patients were receiving other PAH therapies including oral vasodilators, diuretics, and digoxin at the time of transition. Methods used for transition from IV/SQ to inhaled therapy varied among different centers. The most commonly used strategy was initiation of inhaled treprostinil and simultaneous weaning off the IV or SQ prostanoid (i.e., “wean start”) as an inpatient or an outpatient. Inhaled treprostinil was started at a rate of 3 puffs every 6 hours and increased every day as tolerated to a final goal of 9 puffs 4 times/day. Once weaning of the prostanoid infusion was complete, patients were screened with echocardiography, 6-minute walk distance, NYHA functional class, and laboratory tests (i.e., creatinine and brain natriuretic peptide or N-terminal pro– brain natriuretic peptide measurements). In some centers a right heart catheterization was also performed to document hemodynamics after transition. Patients were followed at 1- and 3-month intervals during which these noninvasive parameters were documented and compared to those before and after prostanoid transition. In some centers reassessment including cardiac catheterization was targeted for 3 to 6 months after discontinuation of IV epoprostenol. Statistical analysis was performed using unpaired t tests and chi-squared analysis for trends. A p value ⬍0.05 was chosen to represent statistically significant differences. Results Eighteen patients (14 women, 4 men) underwent transition from IV/SQ prostanoids to inhaled treprostinil (Table 1). Most patients had been on prostanoid infusions for approximately 113 ⫾ 80 months before transitioning to inhaled therapy. All these patients had WHO group I PAH in which the cause was predominantly idiopathic (n ⫽ 8, 44%) or related to connective tissue disease (n ⫽ 5, 28%) or portopulmonary hypertension (n ⫽ 2, 11%). Most patients were in NYHA functional class II (n ⫽ 14, 78%) or III (n ⫽

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4, 22%) before transition. At baseline the average 6-minute walk distance of patients was 399 ⫾ 64 m. Regarding prostanoid infusions in use before transitioning, most patients (n ⫽ 15, 83%) were on treprostinil-based infusions at a mean dose of 73 ng/kg/min and the remainder (n ⫽ 3, 17%) was on epoprostenol at a mean dose of 10 ng/kg/min. Lower-range epoprostenol and treprostinil doses were seen in cases where the physician decided to wean the IV medication before the introduction of inhaled treprostinil. It is important to point out that, with the exception of 1 patient, most were on dual (n ⫽ 7, 39%) or triple (n ⫽ 10, 56%) therapy with an endothelin receptor antagonist (n ⫽ 10, 56%), a phosphodiesterase 5 inhibitor (n ⫽ 16, 89%), or a calcium channel blocker (n ⫽ 1, ⬍1%). After transition to inhaled treprostinil, during a mean follow-up period of 7 ⫾ 2 months, we found no difference in 6-minute walk distance (447 ⫾ 64 m at baseline vs 427 ⫾ 53 m at follow-up, p ⬎0.05) or brain natriuretic peptide (151 ⫾ 11 pg/ml at baseline vs 168 ⫾ 25 pg/ml at followup, p ⬎0.05). However, we did find a significant trend toward worsening NYHA functional class (n ⫽ 4, 22% at baseline, vs n ⫽ 6, 33% NYHA class III at follow-up, p ⫽ 0.006) and N-terminal pro– brain natriuretic peptide (n ⫽ 5, 354 ⫾ 65 pg/ml at baseline vs n ⫽ 5, 496 ⫾ 71 pg/ml at follow-up) after transition (Table 1). A subset of patients did undergo baseline and follow-up right heart catheterizations to document changes in hemodynamic variables after their transition to inhaled treprostinil (Table 1). Despite no evidence of statistically significant differences between hemodynamic variables at baseline and during follow-up right heart catheterizations, it is worth noting that a trend toward worsening cardiac index was documented (3.2 ⫾ 1.2 L/min/m2 at baseline vs 2.87 ⫾ 1.5 L/min/m2 at follow-up). One of the most common reasons our patients gave to justify their transition off IV/SQ prostanoids was the severity of side effects associated with these therapies. After transition there were no reports of diarrhea (n ⫽ 9 with IV/SQ prostanoids vs 0 with inhaled treprostinil) and most patients reported improvement in myalgia (n ⫽ 7 vs 1), nausea/vomiting (n ⫽ 5 vs 2) and headache (n ⫽ 4 vs 2). However, some patients developed new symptoms of cough (n ⫽ 0 vs 3) and syncope (n ⫽ 0 vs 3) after initiation of inhaled therapy (Table 2). These developments were concerning because 4 of these patients were considered to have worsening symptoms resulting in reinstitution of prostanoid infusions in 2 and addition of oral PAH therapies in the remainder. It is important to point out that after transition there was 1 patient death because of a myocardial infarction secondary to a massive gastrointestinal bleed. At the time this report was written, it is unclear whether there was a causal link between transition to inhaled treprostinil and development of gastrointestinal bleed in this patient. Discussion Since their introduction into the PAH treatment armamentarium ⬎1 decade ago, prostanoids have remained a vital component in the management of moderate to severe WHO group I PAH.2,9 The prostanoids approved by the Food and Drug Administration for use in the United States

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Table 1 Clinical and hemodynamics characteristics of the 18 patients included in the study Age (years)/Sex

Diagnosis

26/F 26/F

IPAH IPAH

29/F

IPAH

35/F

IPAH

37/M

IPAH

39/F

CTD-APAH

43/M 44/M 45/F

CHD-APAH PPHTN IPAH

47/F

HIV-APAH

49/M

D/T APAH

49/F

CTD-APAH

50/F 51/F 52/F 57/F

CTD-APAH IPAH PPHTN IPAH

60/F 68/F

CTD-APAH CTD-APAH

Oral Therapy sildenafil tadalafil diltiazem sildenafil bosentan sildenafil ambrisentan amlodipine sildenafil sildenafil bosentan sildenafil tadalafil ambrisentan sildenafil bosentan sildenafil ambrisentan sildenafil bosentan sildenafil bosentan sildenafil sildenafil bosentan bosentan tadalafil

Before Transition IV/SQ Therapy

Dose (ng/kg/min)

NYHA Functional Class

6MWD

BNP

8 2

2 2

386 374

128 153

treprostinil

48

3

424

110

treprostinil

56

2

469

treprostinil

77

2

524

treprostinil

48

3

434

epoprostenol treprostinil epoprostenol

7 84 15

2 2 2

498 398 412

155 225

treprostinil

68

3

502

167

treprostinil

92

2

602

148

treprostinil

191

2

397

151

treprostinil treprostinil treprostinil treprostinil

50 83 66 85

2 2 3 2

433 466 512 455

treprostinil treprostinil

64 82

2 2

377 385

epoprostenol treprostinil

NT–pro-BNP

300 188 400

349

362 138 359 125 145 135

6MWD ⫽ 6-minute walk distance (meters); BNP ⫽ brain natriuretic peptide (picograms per milliliter); CHD-APAH ⫽ congenital heart disease–associated pulmonary hypertension; CI ⫽ cardiac index (liters per minute per square meter); CTD-APAH ⫽ connective tissue disease–associated pulmonary hypertension; D/T APAH ⫽ drug- and toxin-associated pulmonary hypertension; HIV-APAH ⫽ human immunodeficiency virus–associated pulmonary hypertension; IPAH ⫽ idiopathic pulmonary arterial hypertension; mPAP ⫽ mean pulmonary artery pressure (millimeters of mercury); mPCWP ⫽ mean pulmonary capillary wedge pressure (millimeters of mercury); mRAP ⫽ mean right atrial pressure (millimeters of mercury); NT–pro-BNP ⫽ N-terminal pro– brain natriuretic peptide; PPHTN ⫽ portopulmonary hypertension.

can be administered as IV (epoprostenol and treprostinil) or SQ (treprostinil) and inhaled (treprostinil and iloprost) therapies.2 In addition to improving quality of life and symptoms related to right heart failure, prostanoids have been shown to significantly improve prognosis. It is worth noting, however, that epoprostenol is still the only therapy that has imparted a survival benefit in patients with NYHA functional class III and IV disease in 1 controlled study and 1 meta-analysis.10,11 Despite their well-established ability to improve clinical outcomes in PAH, use of prostanoid-based therapies is complicated by side effects ranging from severe local to systemic pain, line sepsis, thrombosis, and lifethreatening drug-induced pneumonitis.9,12 Therefore, although patients may demonstrate improvement in hemodynamics, biomarkers, and functional parameters, severity of these side effects may force some patients to decrease their compliance or stop prostanoid therapy altogether, thus increasing the risk for clinical decompensation and death. Despite sharing a similar side effect profile, inhaled prostanoids appear to be better tolerated and could potentially play an important role in patients who have been stabilized on IV/SQ prostanoids but cannot continue on these therapies. Although there are several reports in the literature that

have described successful transitions from IV to inhaled prostanoids in patients with clinically stable PAH, it is unclear whether clinical stability can be maintained long term and whether baseline clinical parameters can help predict which patients can tolerate this intervention. In this retrospective study, the largest to date, we have collected clinical data from 18 patients seen in PAH centers across the United States who underwent transition from IV or SQ prostanoids to inhaled treprostinil under the clinical supervision of their PAH doctors. Although our data allow us to comment only on treprostinil, several investigators have reported successful transitions to inhaled iloprost, thus supporting the possibility that this agent could also be used as an alternative should treprostinil not be an option.13,14 The approach used across the various centers to perform the transition from IV/SQ prostanoids to inhaled treprostinil relied on a comprehensive assessment of baseline hemodynamic and functional clinical parameters to establish that the disease was under control before weaning the prostanoid. Most patients who underwent the transition were in NYHA class II at baseline and had been on prostanoid therapy for an average of 9 years. The rate at which weaning from IV/SQ prostanoids occurred was center dependent and

Miscellaneous/Transition from IV to Inhaled Prostanoids

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Table 1 (continued) After Transition mRAP

mPAP

mPCWP

CI

NYHA

6MWD

BNP

7 10

50 44

12 9

3.2 3.7

2 2

394 372

8

41

8

3

400

2

444

NT–pro-BNP

mRAP

mPAP

mPCWP

CI

135 200

8

52

10

2.8

155

10

40

9

2.7

7

50

10

10

53

9

2.2

8

42

10

2.9

11

47

10

3 3.7

5

48

11

2.9

3

486

9

54

9

2.7

3

421

7 8 8

40 46 43

13 7 8

3.3 3.8 2.7

2 2 2

440 402 395

172 161

9

49

8

3.1

2

456

290

6

45

10

3

3

554

153

8

47

11

2.6

7

39

11

2.6

2

349

160

7

38

10

2.8

8 10 9 7

46 51 38 44

9 9 10 6

3.8 3.2 3.8 3.2

2 3 3 2

439 433 500 460

489

8

55

10

3.4

503

10

42

8

3.4

8 8

49 46

12 13

3.1 3.6

2 2

354 395

primarily based on clinical stability and patient tolerance. In most centers weaning was performed under the supervision of a PAH care team over a period of days and inhaled treprostinil was initiated at the same time (wean start). The rate at which weaning occurs has been variable across published studies ranging from rapid to slow wean of IV epoprostenol followed by the introduction of oral or inhaled therapy in patients who remain clinically stable after weaning. One study described the attempt to transition 3 inpatients from IV epoprostenol to iloprost by making a rapid stepwise decrease of IV epoprostenol (1-ng/kg/min steps every 3 to 10 hours) concurrent with repeated inhalations of aerosolized iloprost (150 to 300 ␮g/day with 6 to 18 inhalations per day). Despite using high doses of iloprost all patients in this particular study developed signs consistent with decompensated right heart failure that corrected after reinitiating epoprostenol.15 Another group reported successful transition from IV epoprostenol (baseline dose 24 ng/ kg/min) to iloprost in a patient with portopulmonary hypertension using a more conservative approach by starting inhalations of iloprost 2.5 ␮g every 2 hours and rapidly titrating to 5 ␮g and the epoprostenol dose was simultaneously decreased from 24 to 5 ng/kg/min at a rate of 1 ng/kg/min per day as an outpatient after which the patient was admitted to the hospital to finish weaning the epoprostenol.13 Likewise, a study by Melnick et al14 described the successful transition of 13 pediatric patients from IV

502 196 570

3

415

140 137 161 128

epoprostenol to a combination of oral or oral/inhaled agents by first halting increases in epoprostenol for ⬎6 months before adding oral or inhaled therapy to document tolerability to epoprostenol dosage stabilization. An important difference between this last study and the present study is that most patients were transitioned to oral therapies: only 1 of the 13 patients was started on iloprost, whereas the remaining patients were started on calcium channel blockers, bosentan, or sildenafil alone or in combination. Although most patients appeared to be stable on inhaled treprostinil 7 months after transitioning, we did observe significant worsening in NYHA functional class, N-terminal pro– brain natriuretic peptide, and deteriorating hemodynamic parameters in some patients. Twenty-two percent of patients (4 of 17) developed worsening PAH on inhaled therapy and needed to return to parenteral therapy. The decision to return to IV therapy was made mainly on account of worsening NYHA functional class as determined by the PAH specialist at follow-up visits. It is worth noting that in the study by Melnick et al14 the patient started on iloprost also had a trend toward worsening mean pulmonary artery pressure and cardiac index compared to other patients who were exclusively on oral therapies. In our study most of our patients were already on oral therapies and in 2 of them the dosage of these agents had to be adjusted based on concerns for clinical decompensation. Although our present study is not powered to identify clinical parameters that could reliably highlight patients at risk for

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Table 2 Side effect profile before and after transition to inhaled treprostinil Side Effects Diarrhea Myalgia Fatigue Nausea/vomiting Dizziness Headache Chest pain Syncope Cough

Systemic Prostanoids (n)

Inhaled Prostanoids (n)

9 7 5 5 4 4 2 0 0

0 1 4 2 4 2 2 3 3

deteriorating after transitioning to inhaled treprostinil, it raises concerns over the amount of therapeutic control that can be achieved with inhaled therapies and argues for aggressive surveillance of these patients with serial echocardiography, 6-minute walk distance, and other validated prognosis markers and emerging clinical tools such as the REVEAL risk score to rapidly identify those patients whose transition may fail.16 –18 It is our opinion that if the clinician observes worsening of functional and hemodynamic parameters, this should not delay the decision to restart IV/SQ prostanoids if clinically indicated. Our study is limited by its retrospective nature, lack of a control group, short follow-up time, and small size of our patient population. An important limitation inherent to the study design is the lack of a standardized transition protocol across the various PAH centers. However, we have attempted to summarize the relevant steps taken in each of the 6 centers and stress those areas in which caution should be exercised whenever attempting such a transition. Another limitation is our lack of a systematic method to capture the full range of symptoms exhibited by the patients during transition. To address this limitation we sought to capture clinical changes that were severe enough to be highlighted in the medical record as different before and after transition. Nevertheless, despite these limitations, our data provide important information for clinicians who manage adult patients with PAH and may help them counsel patients who may be unable to tolerate or continue IV/SQ prostanoid therapies in the long term. Future studies focused on longterm outcomes after transition and powered to identify the presence of risk factors for early failure of this intervention are necessary to elaborate on and validate our findings. 1. Gomberg-Maitland M, Preston IR. Prostacyclin therapy for pulmonary arterial hypertension: new directions. Semin Respir Crit Care Med 2005;26:394 – 401. 2. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol 2009;53:1573–1619. 3. Simonneau G, Barst RJ, Galie N, Naeije R, Rich S, Bourge RC, Keogh A, Oudiz R, Frost A, Blackburn SD, Crow JW, Rubin LJ; Treprostinil

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