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Long-Term Outcomes in Children With Pulmonary Arterial Hypertension Treated With Bosentan in Real-World Clinical Settings

https://doi.org/10.1016/j.amjcard.2010.06.064Get rights and content

Treatment algorithms in pediatric pulmonary arterial hypertension (PAH) are derived from clinical trials in adult populations and from clinical practice, but experience in children is limited. In this retrospective cohort study, we analyzed outcomes in a previously identified cohort of 86 consecutive children with PAH treated with bosentan as part of their treatment regimen. All children with idiopathic PAH or heritable PAH and PAH associated with congenital heart disease or connective tissue disease who started bosentan treatment from May 2001 to April 2003 in 2 tertiary pediatric referral centers were followed, with data collection ending August 2006. Eighty-six children (37 male, 49 female) 11 ± 5 years of age with idiopathic/heritable PAH (n = 36), PAH associated with congenital heart disease (n = 48), or PAH associated with connective tissue disease (n = 2) received bosentan as monotherapy (n = 42) or as an add-on to pre-existing continuous intravenous epoprostenol or subcutaneous treprostinil (n = 44). Median observation period was 39 months (range 2 to 60). Thirty-four patients (40%) received ≥1 additional PAH-specific therapy during follow-up. At end of data collection, 25 patients (29%) remained on bosentan, 43 (50%) had stopped bosentan, 11 (13%) had died while on bosentan, and 7 were lost to follow-up. At 4 years, the Kaplan-Meier estimate of disease progression in patients while on bosentan was 54% (7 patients at risk) with a survival estimate of 82% (16 patients at risk). Risk factors significantly associated with survival were World Health Organization functional class and indexed pulmonary vascular resistance. In conclusion, outcome in children with PAH managed with current treatment regimens appears favorable. However, despite current therapy options, disease progression remains a concern.

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Methods

This is a retrospective cohort study in 86 consecutive pediatric patients with PAH (≤18 years of age at bosentan initiation) who started bosentan from May 2001 to April 2003 with or without pre-existing continuous parenteral intravenous epoprostenol or subcutaneous treprostinil therapy at 2 tertiary referral centers in the United States (Columbia University Medical Center, New York, New York, and the Children's Hospital, Denver, Colorado). Follow-up data were collected retrospectively from

Results

In this cohort of 86 children with PAH, the median observation period, defined as time between initiation of bosentan and date of last clinical information capture before end of data collection, was 39 months (mean ± SD 35 ± 15, range 2 to 60).

Demographic characteristics at bosentan initiation have been presented previously7 (Table 1). Patients' ages ranged from 9 months to 18 years at the start of bosentan therapy. More patients with PAH-CHD were female and started bosentan as monotherapy.

Discussion

In this retrospective cohort study, we extended the observation period by 3 years in a previously identified cohort of 86 consecutive pediatric patients with PAH treated with bosentan monotherapy or as an add-on to pre-existing parenteral intravenous epoprostenol or subcutaneous treprostinil therapy.7 At the time these patients had bosentan initiated, bosentan was the only approved oral PAH therapy.

Historically, the prognosis for children with PAH appeared even worse than that for adults; the

Acknowledgment

The authors thank Sylvie Ertel, PhD, for medical writing assistance funded by Actelion Pharmaceuticals, Ltd. (Allschwil, Switzerland).

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    Dr. Ivy has served on advisory boards for Actelion, Basel, Switzerland; Gilead, Foster City, California; Pfizer, New York, New York; and United Therapeutics, Research Triangle Park, North Carolina; and receives grant support from Gilead. Dr. Berman Rosenzweig receives grant support from Actelion, Eli Lilly, Indianapolis, Indiana; Pfizer, Gilead and United Therapeutics and is a consultant for Actelion and United Therapeutics. Mr. Lemarié is a consultant for Actelion. Mrs. Brand and Dr. Rosenberg are employees of Actelion. Dr. Barst is a consultant for Actelion, Eli Lilly, Gilead, GSK, Middlesex, United Kingdom; Novartis, New York, New York; and Pfizer.

    This research was supported by Grant M01 RR00069 from the General Clinical Research Centers Program, National Center for Research Resources, National Institutes of Health, Bethesda, Maryland, and by Actelion Pharmaceuticals, Ltd., Allschwil, Switzerland.

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