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Long-Term Tadalafil Therapy Is Effective in Pulmonary Arterial Hypertension: Presented at ERS

By Evelyn Harvey

VIENNA, Austria -- September 14, 2009 -- Long-term treatment of pulmonary arterial hypertension (PAH) with once-daily oral tadalafil improves exercise tolerance significantly and delays clinical worsening, according to a study presented here at the 19th Annual Congress of the European Respiratory Society (ERS).

Results of the Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST)-1 and 2 study was presented by Ronald J. Oudiz, MD, Los Angeles Biomedical Research Institute, Harbor UCLA Medical Center, Torrance, California, on September 13.

The narrowing of the pulmonary arterial lumens in PAH is thought to be caused partly by excess vasoconstriction. Tadalafil works by inhibiting phosphodiesterase 5, thereby increasing cyclic guanosine monophosphate levels and modulating vasodilation and vascular cell proliferation. Current PAH therapies are limited by frequent doses, inconvenient delivery systems, or monitoring concerns.

The PHIRST studies therefore aimed to evaluate tadalafil as a once-daily oral therapy for PAH. In PHIRST-1, 405 patients with PAH arising from various causes were treated with oral tadalafil 2.5, 10, 20, or 40 mg daily or placebo for 16 weeks. All subjects were aged >=12 and had resting mean pulmonary arterial pressure >=25 mm Hg and a 6-minute walk distance (6MWD) results between 150 and 450 m. Concomitant therapy with bosentan <=125 mg twice daily was permitted, but use of epoprostenol, iloprost, or treprostinil was prohibited.

Significant improvement was seen in 6MWD at 16 weeks in the 40-mg tadalafil group (P < .001), rank stratified according to cause of PAH and bosentan use.

Time to clinical worsening also improved in this group (P = .041). No statistically significant effects were seen for tadalafil compared with placebo in World Health Organization (WHO) functional class improvement, which appeared to be associated with bosentan use in a post hoc analysis.

A total of 357 patients subsequently enrolled in PHIRST-2, a 52-week double-blind extension study of tadalafil 20 or 40 mg daily. Previous treatments included 75 patients who received placebo in PHIRST-1 and 132 for whom PHIRST-1 tadalafil dosage was maintained.

The increases in 6MWD observed at 16 weeks were maintained to week 52 of PHIRST-2 (week 68 overall) in the 241 patients who completed the study. The mean change in 6MWD at 16 weeks in PHIRST-1 was 37 m (95% confidence interval [CI], 30-44) and at 44 weeks was 38 m (95% CI, 29-47). In patients who remained on tadalafil 20 or 40 mg throughout both studies, 19% and 9%, respectively, deteriorated by at least 1 WHO functional class.

Similar safety profiles were obtained in PHIRST-1 and -2. Tadalafil was well tolerated at all doses, with 74 severe adverse events (AEs) reported in equal proportion across treatment groups. Discontinuation rates were approximately 16% in all groups. Three deaths occurred but were unrelated to tadalafil use. No differences in AEs were associated with bosentan use.

Both PHIRST studies demonstrated the safety and efficacy of oral tadalafil 40 mg daily in improving exercise tolerance and time to clinical worsening in PAH.

"Tadalafil 40 mg once daily offers a clinically meaningful addition to the currently approved treatment options," the authors wrote. They noted that the favourable effects were also evident in the bosentan-treated group, supporting the use of combination therapy in PAH.

Tadalafil was approved for use in PAH treatment in the United States in May 2009.

Funding for this study was provided by Eli Lilly and Company.

[Presentation title: Effect of Once-Daily Tadalafil on Exercise Capacity and Clinical Deterioration With Up to 68 Weeks of Treatment in Patients With PAH. Abstract E1486/E1487]

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