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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Am J Cardiol. Author manuscript; available in PMC 2007 September 8.
Published in final edited form as:
PMCID: PMC1974790
NIHMSID: NIHMS27918

Transition of Stable Pediatric Patients With Pulmonary Arterial Hypertension from Intravenous Epoprostenol to Intravenous Treprostinil

D. Dunbar Ivy, MD,* Lori Claussen, BSN, RN, and Aimee Doran, MS, RN, CPNP

Abstract

Intravenous epoprostenol was the first agent approved by the United States Food and Drug Administration for the management of pulmonary arterial hypertension (PAH). However, epoprostenol therapy carries the risks of a short half-life (<6 minutes) and side effects, including jaw pain, flushing, and headache. Recently, intravenous treprostinil has been studied, primarily in adults with PAH, and found to provide effective therapy. The effects of continuous intravenous treprostinil were retrospectively evaluated in 13 children with stable PAH who had been treated with epoprostenol for >1 year. Children were transitioned in the hospital over 24 hours using a rapid or slow strategy. The children were a mean age of 11 years (range 3 to 17) and were transitioned to treprostinil from August 2004 to August 2005. The baseline 6-minute walking distance was on average 516 ± 115 m (n = 9) and did not change after transition. Patients were treated with treprostinil for 1.1 ± 0.5 years. There were 2 deaths, and 2 patients transitioned to other therapy. Seven patients experienced ≥1 central-line infection. Despite a higher dose of treprostinil, the side effects were subjectively diminished. In conclusion, treprostinil provides an alternative therapy in children with PAH, with fewer side effects. However, evaluation regarding rates of infection requires further exploration.

Intravenous epoprostenol was the first agent approved by the United States Food and Drug Administration for the management of pulmonary arterial hypertension (PAH). Although epoprostenol has improved long-term survival in patients with PAH,17 its therapy is complicated by several factors, including dose-limiting side effects such as flushing, headache, and nausea. Because of its very short half-life in blood (<6 minutes), there is a risk for rebound PAH, which may be life threatening, with abrupt or inadvertent interruption.8,9 Treprostinil, a prostacyclin analog, was initially indicated as a continuous subcutaneous therapy and was subsequently approved for intravenous infusion for those not able to tolerate subcutaneous infusion.10,11 Site pain, often associated with subcutaneous treprostinil, has often prevented this route of administration in pediatric patients. Recently, treprostinil has also been indicated to diminish the rate of clinical deterioration in patients requiring transition from epoprostenol.11 Treprostinil possesses physiochemical properties that make its use more convenient, including stability at room temperature and longer elimination half-life (4.4 hours).12 In a recent clinical trial evaluating the transition from epoprostenol to intravenous treprostinil, primarily in adult patients with PAH, results at week 12 showed no significant difference between exercise capacity at baseline (while receiving epoprostenol) and week 12 (while receiving intravenous treprostinil).11

Method and Results

This was a retrospective analysis designed to evaluate the safety and tolerability of transitioning pediatric patients with PAH receiving stable intravenous epoprostenol doses to intravenous treprostinil. All patients were enrolled in an institutional review board–approved protocol, A Prospective Evaluation of Adolescents and Children With Pulmonary Arterial Hypertension (PEACH). This protocol allows follow-up analysis of pediatric patients with PAH receiving different therapies. Patients considered for transition to treprostinil were treated with epoprostenol for >1 year and expressed an interest in transitioning because of the pharmacologic benefits of treprostinil (longer half-life, room temperature, and 48-hour stability of drug in solution). All patients received insurance approval and were hospitalized overnight for the transition from epoprostenol to treprostinil. Patients were transitioned using 1 of 2 methods: slow or rapid. Initially, patients were transitioned using a slow transition, and as experience was gained, a rapid transition was generally used. During slow transitions, treprostinil was initiated at the original epoprostenol dose, and the epoprostenol dose was decreased by half. Every 1 to 2 hours, the epoprostenol dose was decreased by 10 ng/kg/min, and the treprostinil dose was increased by 5 to 10 ng/kg/min, depending on symptoms and side effects, until epoprostenol was discontinued. The rapid transition method involved discontinuing epoprostenol and initiating treprostinil at the original epoprostenol dose. Dose escalation of treprostinil continued every 20 to 60 minutes by 5 to 10 ng/kg/min while monitoring symptoms and side effects. With both transition methods, the goal was to achieve a dose of treprostinil 1.25 to 1.75 times that of epoprostenol by the completion of the transition. After discharge from the hospital, outpatient dose titration was based on patients’ symptoms and prostanoid side effects. Patients received regular and frequent telephone calls. Adverse events were evaluated using a 4-point scale (0 = no discomfort or interference with daily activity; 1 = mild discomfort but no interference; 2 = moderate discomfort sufficient to reduce or affect daily activity; and 3 = severe, incapacitating discomfort with inability to perform normal daily activities).

Thirteen patients (mean age 11 years; range 3 to 17) were transitioned from epoprostenol to treprostinil from August 2004 to August 2005. Demographic information and results are listed in Table 1. The data cut-off date was August 31, 2006. All patients were receiving ≥1 of the following conventional therapies for their PAH: calcium channel blockers (n = 2), diuretics (n = 6), digoxin (n = 4), warfarin (n = 11), clopidogrel (n = 1), oxygen (n = 7), bosentan (n = 2), and sildenafil (n = 12). At the time of transition, the mean epoprostenol dose was 36 ± 13 ng/kg/min (range 8 to 55), and the mean time receiving epoprostenol was 2.6 ± 2.9 years (range 1.2 to 9.5). All patients were considered to be stabilized on their doses of epoprostenol at the time of transition. Seven patients underwent slow transitions, and 6 patients underwent rapid transitions. Immediately after initial transition to treprostinil (12 to 24 hours), the mean dose of treprostinil was 51.4 ± 20 ng/kg/min (range 10 to 83). The mean treprostinil doses at 6 and 12 months were 79 ± 35 ng/kg/min (range 29 to 150; n = 12) and 86 ± 40 ng/kg/min (range 12 to 150; n = 11). The mean 6-minute walking distance was 516 ± 115 m (n = 9) at baseline, 513 ± 110 m (n = 9) at 6 months, and 564 ± 84 m (n = 8) at 12 months and was not different (Figure 1). Each patient’s World Health Organization functional class was unchanged at the 6- (n = 13) and 12-month (n = 12) visits. Two patients experienced slight decreases in their functional classifications during the initial 6-month period. Over time and with increased doses of treprostinil, these 2 patients’ functional classifications returned to baseline. Two deaths occurred, 1 at 2 months (patient 1) from pneumonia and another from thrombosis related to systemic infection (patient 9). Two patients were transitioned to inhaled ilo-prost, 1 because of recurrent central-line infections after 1 year (patient 7) and the other for convenience or patient preference at 6 months (patient 10). Cardiac catheterization before transition revealed a mean pulmonary arterial pressure of 52 ± 13 mm Hg (range 26 to 69) and was repeated after transition in 6 patients, with a mean pulmonary pressure of 49 ± 13 mm Hg (range 29 to 65). The mean pulmonary pressure/systemic pressure ratio was 0.82 ± 0.46 at baseline and 0.70 ± 0.11 at follow-up.

Figure 1
Patients’ 6-minute walking distances (in meters).
Table 1
Patient characteristics and clinical data

The rapid and slow transition methods were well tolerated, with no serious adverse events. Pallor was common with both methods and was reduced with the continued up-titration of treprostinil. Patients did not have the same degree of facial and palmar flushing present after transition. Headache was more common with slow transitions. Typical prostacyclin-related side effects, including headache, rash, diarrhea, jaw pain, leg pain, and gastrointestinal disturbances, were experienced while taking epoprostenol (Figure 2). Six to 12 months after transition, mean severity scores decreased by >50% for rash, diarrhea, headache, jaw pain, and gastrointestinal adverse events compared with baseline; leg pain tended to increase. Seven patients experienced ≥1 central-line infection, 1 patient with gram-positive bacilli and 6 with gram-negative bacilli. All 7 patients required replacement of their central venous catheters.

Figure 2
Side effects and symptoms evaluated with epoprostenol (immediately before transition) and at 6 and 12 months after the transition to treprostinil. White bars, baseline; black bars, 6 months; hatche bars, 12 months. GI = gastrointestinal.

Discussion

The purpose of this retrospective analysis was to evaluate the tolerability and safety of transitioning stable pediatric patients with PAH from epoprostenol to treprostinil. Stable patients were safely transitioned in the hospital with close observation, with further dose escalation of treprostinil on an outpatient basis. Although rapid and slow transitions were well tolerated, slow transition theoretically may be safer for patients with more severe disease. Assessments at 6 and 12 months after transition demonstrated that exercise capacity (assessed by the 6-minute walk test), functional class, hemodynamics, and echocardiographically estimated right ventricular systolic pressure were essentially unchanged compared with baseline. Patients require close monitoring to ensure adequate dose escalation the first 6 months to maintain efficacy. Of the typical prostanoid side effects, 5 of 6 (headache, rash, diarrhea, jaw pain, and gastrointestinal disturbances) diminished from baseline (with epoprostenol) compared with 6 and 12 months after transition, with leg pain the only exception. In general, treprostinil had a better adverse effect profile than epoprostenol, and these fewer side effects may lead to improved quality of life. Greater tolerability of treprostinil may also allow improved dosing, which may be beneficial to patients, but long-term studies are required. The longer half-life of treprostinil also allows a lower likelihood of rebound effects with inadvertent interruption. The number of central-line infections is very concerning and is under investigation. Ongoing evaluation regarding rates of infection and use of solutions for 48 hours at room temperature is required. Continued long-term clinical, physiologic, and psychosocial evaluations of children receiving all therapies for PAH are required.

Acknowledgments

This study was supported in part by Grant M01-RR00069 from the General Clinical Research Center, National Center for Research Resources, National Institutes of Health, Bethesda, Maryland.

References

1. Barst RJ, McGoon M, Torbicki A, Sitbon O, Krowka MJ, Olschewski H, Gaine S. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43:40S–47S. [PubMed]
2. Rashid A, Ivy D. Pulmonary hypertension in children. Current Pae-diatr. 2006;16:237–247.
3. D’Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Godring RM, Groves BM, Kernis JT, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115:343–349. [PubMed]
4. Barst RJ, Rubin LJ, McGoon MD, Caldwell EJ, Long WA, Levy PS. Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med. 1994;121:409–415. [PubMed]
5. Shapiro SM, Oudiz RJ, Cao T, Romano MA, Beckman XL, Georgiou D, Mandayam S, Ginzton LE, Brundage BH. Primary pulmonary hypertension: improved long-term effects and survival with continuous intravenous epoprostenol infusion. J Am Coll Cardiol. 1997;30:343–349. [PubMed]
6. McLaughlin VV, Genthner DE, Panella MM, Rich S. Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. N Engl J Med. 1998;338:273–277. [PubMed]
7. Badesch DB, Abman SH, Ahearn GS, Barst RJ, McCrory DC, Simonneau G, McLaughlin VV. Medical therapy for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:35S–62S. [PubMed]
8. Badesch DB, McLaughlin VV, Delcroix M, Vizza CD, Olschewski H, Sitbon O, Barst RJ. Prostanoid therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43:56S–61S. [PubMed]
9. McLaughlin VV, Gaine SP, Barst RJ, Oudiz RJ, Bourge RC, Frost A, Robbins IM, Tapson VF, McGoon MD, Badesch DB, et al. Efficacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension. J Cardiovasc Pharmacol. 2003;41:293–299. [PubMed]
10. Laliberte K, Arneson C, Jeffs R, Hunt T, Wade M. Pharmacokinetics and steady-state bioequivalence of treprostinil sodium (Remodulin) administered by the intravenous and subcutaneous route to normal volunteers. J Cardiovasc Pharmacol. 2004;44:209–214. [PubMed]
11. Gomberg-Maitland M, Tapson VF, Benza RL, McLaughlin VV, Krichman A, Widlitz AC, Barst RJ. Transition from intravenous epoprostenol to intravenous treprostinil in pulmonary hypertension. Am J Respir Crit Care Med. 2005;172:1586–1589. [PubMed]