Epoprostenol given as a continuous intravenous (IV) infusion has been shown to improve exercise capacity, quality of life, and hemodynamics, and to prolong survival in patients with New York Heart Association (NYHA) functional class III-IV idiopathic pulmonary arterial hypertension (IPAH, formerly called primary pulmonary hypertension) that have not responded to conventional medical therapy.1-3 Epoprostenol has also been shown to improve exercise capacity in patients with pulmonary arterial hypertension (PAH) associated with scleroderma.4 Improvements with epoprostenol have also been reported in patients with PAH associated with congenital left-to-right shunts,5 portal hypertension.6 and HIV infection.7 Despite these favorable outcomes, continuous IV infusion of epoprostenol is far from ideal as a treatment for severe PAH. Epoprostenol is chemically unstable and requires delivery via continuous IV infusion with frequent changes of medication reservoir. In addition, due to epoprostenol's very short half-life (~3 to 6 min), pump malfunctions, which may cause abrupt therapy interruption, can produce life-threatening rebound pulmonary hypertension and death.8
Treprostinil is a tricyclic benzindene prostacyclin analogue with similar pharmacologic actions as epoprostenol.9,10 Treprostinil has been approved for continuous subcutaneous infusion in the treatment of NYHA functional class II-IV PAH patients in the United States and class III IPAH patients in most European countries. It possesses several potential advantages over epoprostenol in terms of chemical stability at room temperature and increased half-life (terminal half life of 4.5 hours). However, subcutaneous administration is associated with pain at the infusion site, which can be intolerable in some patients, leading to discontinuation of therapy.11 Studies have demonstrated bioequivalence of IV and subcutaneous treprostinil delivery,12 which has led to the US Food and Drug Administration approval of treprostinil administered by the IV route in case of intolerable subcutaneous infusion site pain. By establishing bioequivalence between the two routes of administration the efficacy data gathered for subcutaneous treprostinil can also be applied to the IV route.
In this study, we investigated whether stable PAH patients on IV epoprostenol could be safely transitioned to IV treprostinil using a rapid switch protocol that consisted of a direct switch of the epoprostenol medication reservoir with the treprostinil medication reservoir.
This 12 week open-label trial was conducted at 2 referral centers to evaluate the safety and efficacy of transition from IV epoprostenol to IV treprostinil therapy using a rapid switch protocol. The protocol received approval from the ethics committees at each institution, and each patient gave informed and signed consent before entry into the study. The primary objective was to determine the feasibility of transitioning patients from IV epoprostenol to IV treprostinil by assessing exercise capacity as assessed by the 6 minute walk test (6MWT) at week 12. Secondary efficacy endpoints included changes from baseline to week 12 in NYHA functional class, Borg dyspnea score, and hemodynamic parameters recorded by right-heart catheterization. Tolerance and safety were assessed by spontaneous adverse events reporting and a specific prostacyclin-related side effects questionnaire.
Patients were evaluated by physical examination, 6MWT, Borg dyspnea scale, and assessment of specific prostacyclin-related side effects questionnaire at baseline (before transition) and at weeks 6 and 12. Right heart catheterization was performed at baseline and at week 12. At the end of the 12 weeks, patients were given the option of continuing on IV treprostinil or returning to epoprostenol.
Eligible patients were between 18 and 65 years of age with stable NYHA functional class I or II IPAH, familial PAH, connective tissue disease-associated PAH, or PAH related to repaired congenital left-to-right shunt. All patients had received epoprostenol therapy for at least 3 months before enrollment and at a stable dose for at least 1 month before transitioning to IV treprostinil. In addition, all patients were on optimal doses of conventional therapies for their PAH, including endothelin-receptor antagonists, calcium channel blockers, anticoagulants, diuretics, digoxin, and oxygen.
Patients were hospitalized for transition from IV epoprostenol to IV treprostinil. In all patients, the portable CADD-Legacy (Sims Deltec Inc.) infusion pump was used to infuse epoprostenol and treprostinil. Treprostinil was diluted in sterile saline in the dosing reservoir, and an appropriate flow rate was chosen to achieve a 48 hour interval between subsequent treprostinil reservoir changes. The infusion of treprostinil was initiated by direct switching of the medication reservoir from epoprostenol to treprostinil.
Consistent with previous experience transitioning patients from IV epoprostenol to subcutaneous treprostinil,13 patients were initially transitioned to IV treprostinil at the same dose of IV epoprostenol (1:1 ng/kg/min basis). After a 24 hour monitoring period, patients were discharged from the hospital. Outpatient dose titration was performed throughout the study on the basis of PAH symptoms whilst targeting a 2-fold increase at week 12. This 2-fold increase in dose was based on clinical experience described by Gomberg-Maitland et al14 in which patients were safely and effectively transitioned from epoprostenol to IV treprostinil using this same dosing strategy over a 12 week treatment period. Patients were contacted at least weekly to record both clinical symptoms of PAH and prostacyclin-related side effects. The dose of IV treprostinil was systematically increased on a weekly basis unless this was prevented by drug-related side effects. The dose of treprostinil could also be decreased as needed on the basis of drug-related side effects.
Study population, dosing, and outcome data are presented as mean ± SD. Changes in baseline to week 12 for primary and secondary endpoints were tested using the Wilcoxon signed-rank test with P values based on 2-sided tests, and values <0.05 were considered significant. No imputation was used for missing values.
Twelve patients, including 7 with IPAH, 4 with familial PAH, and 1 with PAH associated with repaired atrial septal defect were enrolled between November 2004 and March 2005. Baseline characteristics of patients are shown in Table 1. Two patients were NYHA functional class I, and 10 were class II.
After transition to IV treprostinil at the same dose as epoprostenol, all patients received further increases in their treprostinil dose over the 12 week period. At week 6, the mean dose of treprostinil was 52 ± 28 ng/kg/min (range, 24-133 ng/kg/min); at week 12, it was 62 ± 30 ng/kg/min (range, 23-139 ng/kg/min). The individual dose increase range was between 1.5- and 3.0-fold compared with the baseline epoprostenol dose. All 12 patients chose to remain on IV treprostinil at the end of the 12 week period.
There was no statistically significant difference between the mean 6MW distance at baseline on IV epoprostenol (561 ± 89 m) and that performed at either week 6 (543 ± 91 m; P = 0.06) or week 12 on IV treprostinil (576 ± 96 m; P = 0.13). Individual patient data are shown in Figure 1. There was no significant change in the Borg dyspnea score, which was 3.4 ± 2.5 at baseline, 3.9 ± 1.8 at week 6 (P = 0.28), and 4.1 ± 2.5 at week 12 (P = 0.10). All 12 patients were NYHA functional class II at week 12 as compared with baseline, with two patients shifting from class I at baseline to class II at week 12, despite similar 6MWT.
Hemodynamic parameters are presented in Table 2. There were no significant changes in hemodynamic parameters between baseline and week 12.
Tolerance and Safety
All patients successfully completed the rapid switch transition, and there were no serious adverse events and no unexpected adverse events on the basis of the known safety profile of prostacyclins. Patients were clinically stable and had no acute adverse effects upon completing the rapid switch transition. Two patients subsequently reported severe adverse events judged as serious (requiring hospitalization) but not attributable to treprostinil during the 12 week study; one patient experienced hemoptysis, and one developed a catheter-related infection. Both events resolved with treatment, and the patients continued in the study. Four of twelve patients spontaneously reported 6 mild or moderate adverse experiences judged as attributable to treprostinil: headache, flushing, pain, rash, or vertigo. In addition, 10 patients completed questionnaires at baseline and week 12 to separately elicit specific prostacyclin-related side effects whilst on epoprostenol and then treprostinil, respectively (Table 3). There were 5 specific prostacyclin-related side effects reported at baseline whilst still on epoprostenol: jaw pain, flushing, diarrhea, rash, and foot pain. After 12 weeks on IV treprostinil, there were no new reports of specific prostacyclin-related side effects. With one exception, side effects in all cases had either resolved or were reported to be less severe. The number of patients reporting jaw pain, flushing, diarrhea, and rash at week 12 were 1, 4, 2, and 1, respectively, compared with 6, 6, 6, and 2 at baseline. The number of patients reporting foot pain at week 12 also decreased from 2 to 1, but this patient reported increased severity from mild foot pain to severe.
Notably, 1 patient reported pump failure lasting 3 hours and did not complain of any clinical deterioration.
In this study, we demonstrated that stable PAH patients on long-term IV epoprostenol therapy could be easily and safely transitioned to the IV prostacyclin analogue treprostinil using a rapid switch protocol. Twelve weeks after transitioning from IV epoprostenol to IV treprostinil, functional class, exercise capacity assessed by the 6MWT, and hemodynamics assessed by right-heart catheterization remained stable.
The transition between IV epoprostenol and IV treprostinil was performed using a direct switch of the infusion pump medication reservoir. This is in contrast to a separate study in which the infusion of treprostinil was gradually increased through a peripherally positioned IV line whilst simultaneously reducing the dose of IV epoprostenol over a period of 24 to 48 hours.14 Rapid switch can be easily performed and is less time consuming; hence, it is a more advantageous approach.
On the basis of previous experience transitioning patients from IV epoprostenol to subcutaneous treprostinil,13 patients were initially transitioned on a 1:1 ng/kg/min basis. The transitions were performed safely in all patients without any significant clinical deterioration during initial hospitalization. Preliminary clinical experience reported by Gomberg-Maitland14 showed that the relative potency of IV treprostinil to IV epoprostenol was about 2:1. In this study, all patients received systematic dose increases on at least weekly intervals throughout the study, resulting in a 12 week dose of treprostinil of approximately twice the dose of epoprostenol before transitioning (62 versus 28 ng/kg/min). The mean 6MWT distance at week 6 was slightly lower than at baseline (543 m versus 561 m, respectively) but returned to above the baseline value at week 12 (576 m). This is possibly related to the treprostinil dose not having reached the target dose of 2-fold the baseline epoprostenol dose. Hemodynamic parameters were unchanged at week 12 in comparison with baseline, which is consistent with 6 minute walk distance at week 12 and evidence that the optimal treprostinil dose was achieved. However, it is not known whether a higher IV treprostinil dose could lead to further clinical and hemodynamic improvement. The limited sample size prevented formal comparison on the basis of etiology of disease, severity of disease, or initial epoprostenol.
The dose of treprostinil achieved in this study appears to be greater than subcutaneous doses previously reported (9.3 ng/kg/min at 12 weeks).11 The overall lower doses seen in patients treated with subcutaneous treprostinil may reflect a reluctance to increase the dose due to local infusion site pain and irritation. However, any relationship between treprostinil dose and subcutaneous site pain/irritation has not been established.
Intravenous treprostinil appeared to have a similar overall side effect profile to IV epoprostenol. However, most patients reported their prostacyclin-related side effects on IV treprostinil to be less severe compared to epoprostenol. In several patients, preexisting prostacyclin-related side effects experienced on IV epoprostenol were not experienced on IV treprostinil. Only 1 patient reported an increase in foot pain from mild to severe, but this did not result in dose reduction or discontinuation of IV treprostinil. This relatively better tolerance profile should be viewed with caution because the study was not controlled. However, no patients had to be transitioned back to epoprostenol during the study, and all patients chose to remain on IV treprostinil after completion of the study. This may be due to their better perception of the tolerance profile and also the improved treatment convenience. Indeed, quality of life may be improved by allowing reservoir change every 48 hours with treprostinil (without ice-packs) as compared with every 12 hours or 24 hours (with ice-packs) with epoprostenol.13,14 In addition, the longer half-life of treprostinil could prevent life-threatening events in case of sudden infusion interruption. To this extent, 1 patient in this study had a 3 hour pump failure without any clinical deterioration.
On the basis of this study, it appears safe to transition PAH patients from IV epoprostenol to IV treprostinil using a rapid switch protocol, which is more convenient than up-down titration employed previously. In all patients, baseline exercise capacity and hemodynamics remain stable at week 12. All 12 patients have elected to continue on IV treprostinil, and follow-up data will determine if the effects seen at week 12 are maintained after 1 year.
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