Sildenafil to Tadalafil in Pulmonary Arterial Hypertension (SITAR)
Sildenafil to Tadalafil in Pulmonary Arterial Hypertension (SITAR)
Assess tolerability, transition methods and clinical effects of transition from sildenafil
 (Revatio) to tadalafil (Adcirca) for treatment of pulmonary arterial hypertension.
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 unpublished data).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.
Inclusion Criteria:

 -  Treatment for PAH with sildenafil at a dose of 20mg tid or greater for at least 30
 days

 -  Clinical decision to convert from sildenafil to tadalafil therapy

 -  Patient consents to study participation (for patients who have already transitioned
 from sildenafil to tadalafil therapy prior to study initiation or identification of
 the patient, if the patient has provided consent for use of their medical record for
 research, retrospective review of the transition process will be performed. When
 possible, these patients will be approached about prospective data collection for the
 study if the transition occurred less than 3 months prior to consideration of
 prospective study participation)

 Exclusion Criteria:

 -  Non-group I PAH

 -  Age less than 18