Bosentan (Tracleer®), the first oral dual endothelin receptor antagonist, is clinically beneficial in patients with pulmonary arterial hypertension secondary to systemic sclerosis (SSc-PAH), although pulmonary hemodynamics and pulmonary function test results remained stable during treatment, according to a new study of this difficult-to-gather cohort in the January issue of the Journal of Rheumatology.¹

"Our study adds validity to published randomized controlled trials showing that 3 months' treatment with bosentan improves function during ordinary activities in patients with PAH secondary to systemic scleroderma," concludes the research team, led by Amit Joglekar, MD, a fellow in the division of pulmonary and critical care medicine at the University of Medicine and Dentistry of New Jersey Scleroderma Program in New Brunswick, New Jersey. "Although bosentan appears beneficial in treating PAH patients with SSc, continued assessment of its efficacy and safety is needed."

Improvements in class, not lung function

The retrospective analysis included 23 SSc-PAH patients with PAH at baseline (defined as PA systolic pressure [PASP] >e;45 mm Hg by echocardiogram or mean PA pressure >25 mm Hg at rest by cardiac catheterization) and World Health Organization (WHO) functional classes II–IV. Patients took 62.5 mg of bosentan twice daily for 1 month and then 125 mg twice daily. Outcomes measured were WHO functional class, PASP, and pulmonary function tests (PFT) at 3-month intervals for 18 months.

Reduction in WHO class by at least one rank was 57% at 3 months and none worsened, the study showed. However, after 9 months, WHO class tended to worsen compared to baseline. Baseline PASP was 54 ± 2 mm Hg (n = 21) and did not change significantly with therapy. Restriction (total lung capacity 76% ± 4% of predicted) and reduced diffusing capacity (39% ± 3% of predicted) were unchanged during therapy. Hepatic toxicity has been considered an issue with bosentan therapy, and abnormal transaminases in two patients (9%) required the discontinuation of the drug in both.

Study has value and limitations

"This is the first study to specifically look at systemic scleroderma patients with PAH rather than all comers with PAH and subsets of patients with scleroderma," points out Aryeh Fischer, MD, assistant professor of medicine in the division of rheumatology at the National Jewish Medical and Research Center and the University of Colorado Health Sciences Center, both in Denver, Colorado. "It's one more piece of data looking at a difficult cohort to gather," he says. "Any study we get in patients with SSc-PAH is hard to come by, so this is valuable."

The new study appears to support the use of bosentan, as patients did improve by functional class. "The gold standard markers of overall lung function include the 6-minute walk test and the pulmonary function test, and this study did not have the 6-minute walk test, so that's a real limitation," Dr. Fischer tells CIAOMed.

"The fact that lung function did not improve makes you raise your eyebrows a little bit," he admits. "Clinicians would still say, ‘why use the drug?' and a realistic answer is that patients felt a little bit better," Dr. Fischer says. "The biggest limitation of this study is that it is retrospective with a small number of patients, so we can't make definitive sweeping recommendations in either direction."

More therapeutic choices for managing PAH, but greater complexity

In general, there are more therapeutic options for treating PAH today. The choice used to be just oxygen therapy, but now physicians may consider bosentan, the phosphodiesterase type 5 inhibitor sildenafil (Revatio), and, in the future, sixastanten (Thelin), which selectively blocks only the endothelial-A receptor. (Bosentan blocks both the endothelial-A and endothelial-B receptors.)

"These choices may make treatment decisions more complicated for a non-PAH expert," Dr. Fischer says. For this reason, he explains, "early recognition is key in PAH and may provide more options for therapy." The availability of oral therapies also improves patient willingness and compliance.

Is combination therapy the future of PAH?

"Whether or not this whole PAH field is going to go the way of immunosuppression therapy and chemotherapy, where we find we need to use combined agents to maximize treatment is, at this point, unknown," Dr. Fischer says. "If a patient is not responding to one agent and if we can establish the safety and efficacy of combinations, people should start looking at combined therapies."

Reference

1. Joglekar A, Tsai FS, McCloskey DA, et al. Bosentan in pulmonary arterial hypertension secondary to scleroderma. J Rheumatol. 2006;33:61-68.