To print: Select File and then Print from your browser's menu --------------------------------------------------------------------------------------- Title: Tadalafil Improves Exercise Capacity and Delays Time to Clinical Worsening in Patients With Pulmonary Arterial Hypertension: Presented at ERS URL: http://www.pslgroup.com/dg/22E662.htm Doctor's Guide October 8, 2008
By Chris Berrie BERLIN -- October 8, 2008 -- Tadalafil 40 mg once daily is well tolerated, improves exercise capacity and health-related quality of life, and delays time to clinical worsening in patients with pulmonary arterial hypertension (PAH), according to a study presented here at the European Respiratory Society (ERS) 18th Annual Congress. These beneficial effects of tadalafil are seen whether the patient is treatment naïve or receiving background bosentan therapy, said study presenter Nazzareno Galie, MD, Institute of Cardiology, University of Bologne, Bologne, Italy. The results of the multicentre, randomised, double-blind, placebo-controlled, phase 3 study were presented on October 7 on behalf of the Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) study group. Treatment options for PAH target the prostacyclin, endothelin, or nitric oxide pathways, as these are involved in the pathobiology of this disease. According to Dr. Galie, tadalafil is a selective inhibitor of phosphodiesterase type 5 (PDE-5) that is orally administered once daily and that is approved for treatment of erectile dysfunction. The drug has been shown to reduce mean pulmonary artery pressure (mPAP) after single dosing. Dr. Galie and colleagues evaluated the safety and efficacy of tadalafil at once-daily doses of 2.5, 10, 20, and 40 mg compared with placebo in treatment-naïve or bosentan-treated patients with PAH. The study enrolled patients aged 12 years or older with idiopathic PAH or PAH associated with collagen vascular disease, anorexigen use or HIV, or surgical repair of congenital left-to-right shunt or atrial septal defects. Patients had a 6-minute-walk distance (6MWD) of 150 to 450 meters and were permitted to receive bosentan treatment. Exclusion criteria included other PAH aetiologies such as left-sided heart disease, severe hepatic and renal impairment, breast feeding or pregnancy, or use of prostacyclins or other PDE-5 inhibitors. The primary efficacy endpoint was change in 6MWD from baseline to week 16, while secondary endpoints were changes in World Health Organisation functional class (WHO-FC), Borg dyspnoea score (BDS), and time to clinical worsening. Additional health-related quality-of-life and cardiopulmonary haemodynamic assessments were included. Researchers randomised 82 patients to placebo and 323 patients to tadalafil (2.5 mg, n = 82; 10 mg, n = 80; 20 mg, n = 82; 40 mg, n = 79). Treatments were administered once daily for 16 weeks. The mean age of patients ranged from 52 to 55 years for the various groups, and 21% to 25% were men. Baseline clinical and haemodynamic characteristics across these treatment groups were similar, with a mean 6MWD of 337 to 352 meters, BDS of 2.1 to 2.4, and 30% to 35% with WHO-FC 1 or 2. Significance for mean placebo-corrected, treatment-improved 6MWD for the intention-to-treat population was met only with tadalafil 40 mg (+33 meters; P = .0004); no statistically significant changes in WHO-FC and BDS were seen in any of the treatment arms. There were no significant differences among tadalafil dosages in 6MWD changes, although significance was reached with tadalafil 40 mg versus placebo for changes in WHO-FC among bosentan-naïve patients (P = .025). Finally, tadalafil 40 mg achieved a significant 68% reduction in relative risk for time to clinical worsening compared with placebo (P = .041), and health-related quality-of-life measures saw the most consistent significant patient benefits (P <= .01). In addition, study results showed significant cardiopulmonary haemodynamic benefits for mPAP, pulmonary vascular resistance, and Cardiac Index (P < .05 for each). While indicating that there were very low levels of adverse events at all tadalafil doses, Dr. Galie said that headache was reported by 41.8% of patients in the 40-mg arm, 31.7% in the 20-mg arm, 37.5 in the 10-mg arm, 18.3% in the 2.5-mg arm, and 14.6% in the placebo arm. "In patients with PAH -- either naïve or on background bosentan therapy -- tadalafil 40 mg taken once daily was well tolerated, improved exercise capacity and health-related quality of life, and delayed time to clinical worsening." Funding for this study was provided by Eli Lilly. [Presentation title: Tadalafil Improves Exercise Capacity and Delays Time to Clinical Worsening in Patients With Pulmonary Arterial Hypertension (PAH). 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