Treprostinil is a prostacyclin analog. The researchers point out that while patients and caregivers are often deterred by the disadvantages of parenteral prostanoids, “the ease of delivery of inhaled treprostinil, combined with the clinical benefits as demonstrated here, might expand the prostanoid treatment options for PAH patients,” said lead author Dr. Valerie V. McLaughlin from University of Michigan Health System, Ann Arbor, Michigan and colleagues.
In the randomized TRIUMPH trial, the researchers enrolled 235 patients with PAH who had been receiving a stable dose of bosentan or sildenafil for at least 3 months. All subjects had New York Heart Association (NYHA) functional class III or IV symptoms and a 6-minute walk distance of 200 to 450 meters.
For 12 weeks, they received either treprostinil (up to 9 breaths, or 54 mcg, by nebulizer) or placebo, four times a day.
The primary endpoint, 6-minute walk distance, increased by 21.6 meters in the inhaled treprostinil group and by 3.0 meters in the placebo group. “The improvement…was greatest in those in the lowest quartile for baseline,” the researchers reported.
In addition, 31% of patients in the treatment group vs 12% in the placebo group could walk at least 50 meters further on the 6-minute-walk test at 12 weeks.
Overall, the improvement in 6MWD was 19 meters better with inhaled treprostinil than with placebo at week 6, and 20 meters better at week 12.
But while patients on bosentan had statistically significant gains in exercise capacity from adding treprostinil, patients taking sildenafil did not. On the 6-minute walk test, for example, patients in the bosentan subgroup had improvements of 22 meters at 6 weeks and 25 meters at 12 weeks, compared to 11 and 9 meters at 6 and 12 weeks, respectively for the sildenafil subgroup.
Inhaled treprostinil was associated with significant improvements in quality of life (as assessed by the Minnesota Living with Heart Failure questionnaire), but there were no differences between treatment and placebo groups Borg Dyspnea Score, NYHA functional classification, or PAH signs and symptoms at 12 weeks.
Levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), which correlate with hemodynamic severity and prognosis in PAH, decreased during treprostinil therapy but increased with placebo. There was a significant difference between the groups at week 12.
Cough was the most common adverse event, occurring in 54% of treprostinil patients and 29% of placebo patients. The treprostinil group had 11 serious adverse events, including worsening PAH, syncope, anemia, abdominal pain, diabetes mellitus, diarrhea, gastric ulcer, and right ventricular failure.
The researchers admit that their study design does not let them define “a mechanism (for treprostinil) or elucidate the role of continued therapy with bosentan or sildenafil.”
Even so, they conclude, “The improvement noted in these advanced but not end-stage patients with inhaled treprostinil suggests that such patients still have capacity to improve with inhaled prostanoid therapy.”
The study was funded by United Therapeutics Corporation, which markets inhaled treprostinil as Tyvaso. All but one author has served as received fees or research grants from the company.
J Am Coll Cardiol 2010;55:1915-1922.