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




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 ± 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.


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. There are 3 prostanoids approved for use in World Health Organization (WHO) group I PAH: epoprostenol, iloprost, and treprostinil. 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. 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. 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 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 ≥1 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 = 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%).



Table 1

Clinical and hemodynamics characteristics of the 18 patients included in the study

















































































































































































































































































































































































































































































































































































































































Age (years)/Sex Diagnosis Oral Therapy Before Transition After Transition
IV/SQ Therapy Dose (ng/kg/min) NYHA Functional Class 6MWD BNP NT–pro-BNP mRAP mPAP mPCWP CI NYHA 6MWD BNP NT–pro-BNP mRAP mPAP mPCWP CI
26/F IPAH sildenafil epoprostenol 8 2 386 128 7 50 12 3.2 2 394 135 8 52 10 2.8
26/F IPAH tadalafil treprostinil 2 2 374 153 10 44 9 3.7 2 372 200
diltiazem
29/F IPAH sildenafil treprostinil 48 3 424 110 8 41 8 3 400 155 10 40 9 2.7
bosentan 3
35/F IPAH sildenafil treprostinil 56 2 469 300 11 47 10 3.7 2 444 502
ambrisentan
37/M IPAH amlodipine treprostinil 77 2 524 188 5 48 11 2.9 3 486 196 7 50 10 3
sildenafil
39/F CTD-APAH sildenafil treprostinil 48 3 434 400 9 54 9 2.7 3 421 570 10 53 9 2.2
bosentan
43/M CHD-APAH epoprostenol 7 2 498 155 7 40 13 3.3 2 440 172 8 42 10 2.9
44/M PPHTN sildenafil treprostinil 84 2 398 225 8 46 7 3.8 2 402 161
45/F IPAH tadalafil epoprostenol 15 2 412 349 8 43 8 2.7 2 395 415
ambrisentan
47/F HIV-APAH sildenafil treprostinil 68 3 502 167 9 49 8 3.1 2 456 290
bosentan
49/M D/T APAH sildenafil treprostinil 92 2 602 148 6 45 10 3 3 554 153 8 47 11 2.6
ambrisentan
49/F CTD-APAH sildenafil treprostinil 191 2 397 151 7 39 11 2.6 2 349 160 7 38 10 2.8
bosentan
50/F CTD-APAH sildenafil treprostinil 50 2 433 362 8 46 9 3.8 2 439 489 8 55 10 3.4
51/F IPAH bosentan treprostinil 83 2 466 138 10 51 9 3.2 3 433 140
52/F PPHTN sildenafil treprostinil 66 3 512 359 9 38 10 3.8 3 500 503 10 42 8 3.4
57/F IPAH sildenafil treprostinil 85 2 455 125 7 44 6 3.2 2 460 137
bosentan
60/F CTD-APAH bosentan treprostinil 64 2 377 145 8 49 12 3.1 2 354 161
68/F CTD-APAH tadalafil treprostinil 82 2 385 135 8 46 13 3.6 2 395 128

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Dec 7, 2016 | Posted by in CARDIOLOGY | Comments Off on Safety and Efficacy of Transition from Systemic Prostanoids to Inhaled Treprostinil in Pulmonary Arterial Hypertension

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