Sildenafil to Tadalafil in Pulmonary Arterial Hypertension (SITAR)

Sildenafil (Revatio) received approval for treatment of pulmonary arterial hypertension
based upon the results of the SUPER1 study that randomized patients to sildenafil 20, 40 or
80 mg tid or matching placebo. 1 For the open label extension study, all patients received
80 mg tid. Following analysis of the data, the FDA approved 20 mg tid, indicating that
"higher doses are not recommended" (Revatio PDR package insert). Although there was no
significant difference between dosing groups in the overall cohort with regard to 6 minute
walk, patients with idiopathic PAH did have a greater hemodynamic effect at the 80 mg tid
dose, raising the possibility that the maximum approved dose was not the maximally
hemodynamically effective dose for at least some patient subsets. This has resulted in a
confusing situation with some clinicians treating patients with sildenafil doses
substantially above the FDA recommended dose, which creates issues of cost and insurance
coverage. Some patients receive up to five 20 mg Revatio (sildenafil for PH) tablets tid,
increasing cost fivefold (RPFrantz, unpublished data).

Tadalafil (Adcirca) received FDA approval for treatment of PAH in May 2009, and will be
available for this indication in August 2009. The pivotal Pulmonary Arterial Hypertension
and Response to Tadalafil (PHIRST) study randomized 405 patients with WHO group I PAH who
were either treatment naïve or on background therapy with bosentan, to receive placebo, 2.5,
10, 20 or 40 mg daily.2 A dose response was observed, with 40 mg daily meeting the primary
endpoint of improvement in 6 minute walk at 16 weeks (placebo-corrected treatment effect 33
m, p < 0.01), while the composite time to clinical worsening endpoint was also met. The FDA
approved dose of tadalafil for PAH is 40 mg (two 20 mg tablets) daily. 20 mg daily improved
median walk distance nearly as much as the 40 mg dose, but just missed the required p value
based upon the statistical plan. The PHIRST trial is the first placebo controlled trial to
document an incremental benefit of phosphodiesterase-5 inhibition in patients already
receiving an endothelin receptor antagonist. This has important implications for the
concept of combination therapy in PAH.

Since tadalafil can be administered once daily, and the cost of the therapy is less than for
sildenafil, it is anticipated that many patients will transition from sildenafil to
tadalafil. The goal of this prospective and retrospective study is to gather observational
data regarding how that switch is made, tolerability of the switch, and, to the extent
possible with this methodology, assess clinical effects of the switch.