Tadalafil, a competitive inhibitor of phosphodiesterase 5, improved exercise capacity and had an acceptable safety profile in patients with pulmonary arterial hypertension (PAH) in a 16-week, phase 3 double-blind, placebo-controlled trial (PHIRST-1 study). In the long-term extension study (PHIRST-2), the six-minute walk distance (6MWD) was maintained over the 52-week period. We report clinical worsening for subjects remaining on tadalafil 20-mg or tadalafil 40-mg for entire 68-week treatment period across the 2 studies.
Across both studies there were 82 patients on 20-mg tadalafil and 79 patients on the 40-mg dose. Clinical worsening was defined as death, lung transplantation, atrial septostomy, new chronic treatment for PAH, worsening of WHO functional class or hospitalization due to worsening of PAH.
In the initial 16-week study, there was a significant delay in clinical worsening for the patients in the 40-mg tadalafil group compared to placebo (p = 0.038; relative risk reduction 68%). Over the 52-week extension period, fewer subjects experienced clinical worsening with tadalafil 40-mg (n = 13, 16%) than with 20-mg (n = 15, 18%). Over both studies, numerically fewer subjects experienced clinical worsening with tadalafil 40-mg (n = 17, 22%) than with 20-mg (n = 23, 28%). In addition, fewer subjects who remained on tadalafil 40-mg across both studies (9%) compared to those who remained on tadalafil 20-mg across both studies (19%) experienced worsening WHO functional class. This observation was more pronounced in those subjects not taking concomitant bosentan, with 6% worsening on tadalafil 40-mg compared to 31% on tadalafil 20-mg.
During the entire 68-week treatment, the probability of remaining free of clinical worsening tended to be greatest in the tadalafil 40-mg treatment group. A smaller proportion of patients taking the 40-mg dose experienced a decline in WHO functional class.
The delay in clinical worsening seen in patients taking tadalafil 40-mg over the 68-week treatment period is consistent with the improvement in 6MW distance seen over this time, and suggests durable clinical benefit for tadalafil in PAH treatment.
Ronald Oudiz, Consultant fee, speaker bureau, advisory committee, etc. - Lecture Fees/Honoraria from Actelion, Gilead, LungRx, Pfizer, United Therapeutics - Research Support for Actelion, Bayer, Gilead, Eli Lilly, LungRx, Pfizer, United Therapeutics -Mike Wade and Carl Arneson are employees of United Therapeutics Corp.; Product/procedure/technique that is considered research and is NOT yet approved for any purpose. Tadalafil is not yet approved.