1	Comparison of Sitaxsentan and Bosentan in Pulmonary Arterial Hypertension Associated with Connective Tissue Diseases K. B. Highland, C. Strange, R. Girgis, C. Black
2	Introduction STRIDE-2X was a prospective, randomized, multicenter, open label extension study of STRIDE-2, investigating sitaxsentan 100 mg once-daily and bosentan twice-daily in patients with PAH. Here we report the pre-specified subgroup analyses and long-term results of patients with PAH associated with CTD receiving sitaxsentan 100 mg once-daily or bosentan 125 mg twice-daily in STRIDE-2/2X with drug exposure for up to one year.
3	STRIDE-2X: Study Design
4	Methods The primary analysis population for this presentation was defined as all treatment naïve patients who received at least 1 dose of sitaxsentan 100 mg or bosentan in either STRIDE-2 or its extension. STRIDE-2 included a sitaxsentan 50 mg arm that was up-titrated to 100 mg after the initial 18 week trial. To maintain comparability between the treatment naïve groups, this arm was removed for the primary analysis. Summarized results including this group is also presented here. Combination therapy was not allowed. Patients were discontinued if new PAH therapy was required (true Monotherapy trial). Baseline was determined at the time a patient received sitaxsentan or bosentan in either the lead‑in (STRIDE-2) or the extension study. All cause mortality included all patients in the analysis population, followed for 1-year. Kaplan Meier Analysis was performed; treatment effects are reported as Cox proportional hazard ratio and 95% confidence interval.
5	Methods The following endpoints were evaluated : Time to Discontinuation (all causes) from Monotherapy Time to Discontinuations Associated with Adverse Events Time to Discontinuations Associated with Elevated Liver Transaminases Sitaxsentan: AST/ALT >5×ULN Bosentan: Per Prescribing Information Time to Elevated Liver Transaminases (AST/ALT >3×ULN) Time to Clinical Worsening Adjudicated by 3^rd party blinded panel Defined as: Death, Hospitalization for PAH, Addition of Epoprostenol or Treprostinil, Atrial Septostomy, Transplantation, and a combined decline in WHO Class and >15% in 6MWD One-Year All Cause Mortality
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7	STRIDE-2X: Baseline Demographics CTD Subgroup
8	Time to Discontinuation from Monotherapy
9	Results: Time to Clinical Worsening
10	Time to Discontinuations Due to Adverse Events
11	Time to Elevated Hepatic Transaminases >3x ULN
12	Time to Discontinuations Due to Elevated Hepatic Transaminases
13	One-Year Survival
14	Relative Risk With and Without 50 mg Group at One-Year for Sitaxsentan vs. Bosentan CTD Subgroup
15	Relative Risk at One-Year for Sitaxsentan vs. Bosentan CTD and Non-CTD Subgroups
16	Limitations The STRIDE-2X trial was an open-label study and has the potential for bias for or against either treatment. Patient or investigator bias The study was not powered to determine differences in treatment effects. Successive randomizations with partial and uneven double-blind While subgroup analyses were pre-specified, this study was not primarily designed to look at PAH-CTD With the exception of survival, patients were not followed after discontinuation from the trial. 6 minute walk data and WHO functional class were not analyzed because these were not collected following discontinuation.
17	Conclusions The results of this long term, open label extension study suggest that sitaxsentan treated PAH-CTD patients may have a reduced relative risk with respect to bosentan treated PAH-CTD patients in: Time to discontinuation of monotherapy Time to clinical worsening Time to adverse events leading to discontinuations Time to LFT increase Time to discontinuation due to LFT increases Survival at 1 year
18	Backup/Additional Slides
19	Clinical Worsening Events
20	Adverse Events Leading to Discontinuation CTD Subgroup
21	Relative Risk With and Without 50 mg Group at One-Year for Sitaxsentan vs. Bosentan All Treated Patients
22	Relative Risk Reduction at One-Year for Sitaxsentan vs. Bosentan
23	Relative Risk Reduction at One-Year for Sitaxsentan vs. Bosentan