Key Point:

New therapies currently under investigation—including endothelin receptor antagonists, prostacyclin analogs, and phosphodiesterase 5 inhibitors— may further improve the treatment of PAH in adults and children.

ORLANDO—The management of pulmonary arterial hypertension (PAH) remains challenging. Although several new therapies have been developed in the last decade, the disease is still difficult to treat. At the recent annual meeting of the American Thoracic Society, researchers described a number of studies—many of which are still ongoing—that will further improve our therapeutic options.¹

BOSENTAN

Oral therapy with the endothelin receptor antagonist bosentan may be an acceptable substitute for intravenous epoprostenol as first-line therapy for idiopathic PAH, suggest the results of a study that compared the two treatments in 485 patients with NYHA class III idiopathic PAH. “Starting treatment with bosentan rather than epoprostenol did not adversely affect outcomes,” stated lead author Olivier Sitbon, MD, a consultant in the Department of Respiratory and Intensive Care Medicine at the Antoine Beclere Hospital in Clamart, France.

In fact, the risk of death was 2.3 times higher among the 346 patients in the intravenous epoprostenol group than it was among the 139 patients receiving oral bosentan, even though the baseline survival estimates for the two groups were similar. Furthermore, the overall treatment adherence rates in the two groups were comparable: 87% at one year and 75% at two years. Thus, the use of oral bosentan could delay the need for intravenous epoprostenol in patients with class III idiopathic PAH, suggested Dr. Sitbon.

As monotherapy or as add-on therapy to long-term epoprostenol or treprostinil administration, bosentan “appears to be safe and may improve survival in children with PAH,” added Erika Berman-Rosenzweig, MD, an Assistant Professor of Pediatrics at the Columbia University College of Physicians and Surgeons in New York City. She and her colleagues reached that conclusion after they evaluated 86 infants and children ages 7 months to 18 years who had received bosentan monotherapy or add-on therapy for PAH during a two-year span.

Among the 44 children given monotherapy, the one- and two-year survival rates were 98% and 86%, respectively. Those rates were 97% and 90%, respectively, in 42 children who received add-on treatment. Survival in the two groups was similar to the estimated one- and two-year rates of 97% and 88%. Bosentan treatment was stopped due to adverse events (elevated hepatic transaminase levels) in only three cases.

OTHER ENDOTHELIN ANTAGONISTS

Sitaxsentan, an oral endothelin receptor antagonist currently under development, has been found to be effective for improving functional class in PAH patients, related Evelyn M. Horn, MD, an Associate Professor of Clinical Medicine at Columbia University College of Physicians and Surgeons. Dr. Horn was the lead investigator in a study of 170 patients with PAH who were treated with 100 mg or 300 mg of sitaxsentan once daily for a median of 26 weeks.

The health status of 53% of the 100-mg group and 44% of the 300-mg group improved by at least one NYHA functional class; this improvement most often occurred within the initial 12 weeks of therapy. However, a few patients got worse during sitaxsentan treatment, acknowledged Dr. Horn. “During treatment, 5% of patients deteriorated on 100 mg and 8% on 300 mg.” She concluded that the 100-mg dose should be chosen for clinical use due to its more favorable safety profile—specifically, a lower risk of liver function abnormalities.

In comparison with other PAH treatments, ambrisentan, another oral endothelin receptor antagonist, may offer two advantages: fewer drug interactions and a lower risk of liver toxicity, said Lewis J. Rubin, MD, Director of the Pulmonary Hypertension Program at the University of California, San Diego. During Dr. Rubin’s 24-week study of ambrisentan therapy in 64 patients with PAH, there were no apparent drug interactions, and in only four patients did transient serum aminotransferase elevations (levels more than three times the upper limit of normal) develop.

Furthermore, ambrisentan treatment significantly improved exercise capacity and World Health Organization (WHO) functional classification. The patients in the study received one of four ambrisentan doses—1, 2.5, 5, or 10 mg—for 12 weeks followed by a 12-week open-label dose adjustment period, noted Dr. Rubin.

TREPROSTINIL

In a prospective study of 17 PAH patients, Nika Skoro-Sajer, MD, and colleagues found that continuous subcutaneous administration of the long-acting prostacyclin analog treprostinil improved performance on the six-minute walk test by an average of more than 48% and increased the mean Borg dyspnea score by about 34%. In addition, it decreased plasma brain natriuretic peptide levels from a mean of 227 to 88.1 pg/mL. On average, the patients’ health status also improved by almost a full functional class.

These benefits were observed during a mean of 28.5 months of treprostinil therapy, which was given via a microinfusion pump at an average delivery rate of 35 ng/kg/min. In the patients in this study, PAH was idiopathic or secondary to congenital heart disease, connective tissue disease, or portopulmonary hypertension. “Treprostinil therapy is effective in patients with pulmonary arterial hypertension of various etiologies,” concluded Dr. Skoro-Sajer, who is a cardiology resident at Vienna General Hospital in Austria.

The addition of subcutaneous treprostinil to the phosphodiesterase 5 inhibitor sildenafil may improve treatment effectiveness, suggest the results of a pilot study by Mardi Gomberg-Maitland, MD, and colleagues. After at least six months of subcutaneous treprostinil plus 50 mg of oral sildenafil three times daily, the four PAH patients who have completed the study to date showed an average increase in their treadmill exercise tolerance of 45%.

“Sildenafil combined with treprostinil appeared to be well-tolerated,” reported Dr. Gomberg-Maitland, who is Associate Director of the Rush Heart Institute Center for Pulmonary Heart Disease in Chicago. Eight PAH patients have been enrolled in the study so far, she said; of these, four each were in WHO functional classes II and III at baseline.

—Timothy Begany

Reference
1. Galie N, Langleben D, Sitbon O, et al. Emerging therapies for pulmonary arterial hypertension. Presented at: annual meeting of the American Thoracic Society; May 23, 2004; Orlando, Fla.