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Selective endothelinA receptor antagonism with sitaxsentan for pulmonary arterial hypertension associated with connective tissue disease
  1. Reda E Girgis (rgirgis{at}jhmi.edu)
  1. Johns Hopkins University, School of Medicine, United States
    1. Adaani E Frost (frost{at}bcm.tmc.edu)
    1. Baylor College of Medicine and the Methodist Hospital, United States
      1. Nicholas S Hill (nhill{at}tufts-nemc.org)
      1. Tufts New England Medical Center, United States
        1. Evelyn M Horn (emh3{at}columbia.edu)
        1. Department of Medicine, Columbia University College of Physicians & Surgeons, United States
          1. David Langleben (david.langleben{at}mcgill.ca)
          1. Sir Mortimer B. Davis Jewish General Hospital, Canada
            1. Vallerie V Mc Laughlin (vmclaugh{at}med.umich.edu)
            1. University of Michigan Health System, United States
              1. Ronald J Oudiz (oudiz{at}humc.edu)
              1. Harbor-UCLA Medical Center, UCLA Geffen School of Medicine, United States
                1. Ivan M Robbins (ivan.robbins{at}vanderbilt.edu)
                1. Vanderbilt University Medical Center, United States
                  1. James R Seibold (jseibold{at}med.umich.edu)
                  1. University of Michigan Health System, United States
                    1. Shelley Shapiro (sshapiro{at}hsc.usc.edu)
                    1. VA Greater Los Angeles Healthcare System, UCLA Geffen School of Medicine, United States
                      1. Victor F Tapson (tapso001{at}mc.duke.edu)
                      1. Duke University Medical Center, United States
                        1. Robyn J Barst (rjb3{at}columbia.edu)
                        1. Department of Pediatrics, Columbia University College of Physicians & Surgeons, United States

                          Abstract

                          Introduction Endothelin receptor antagonism has become an important component in the treatment of pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD). The purpose of this study was to analyze the safety and effectiveness of sitaxsentan, a selective antagonist of the ETA receptor, in a cohort of PAH-CTD patients. Short-term clinical and hemodynamic effects as well as longer-term follow up data are presented.

                          Methods A post hoc subgroup analysis was performed on 42 patients who had PAH associated with CTD amongst 178 patients enrolled in a 12 week double-blind randomized clinical trial of sitaxsentan versus placebo. Data from 33 patients assigned to sitaxsentan 100 mg or 300 mg daily were pooled and compared with nine placebo-treated patients. Forty one patients entered the blinded extension where all patients received either 100 mg or 300 mg sitaxsentan once daily.

                          Results Sitaxsentan treated patients had an increase in six minute walk distance of 20 ± 52 (SD) meters from baseline to week 12 (P= 0.037) whereas the placebo group had a decrease of 38 ± 84 m resulting in a 58 meter placebo subtracted treatment effect (P = 0.027). Parallel improvements in quality of life and hemodynamics were also observed. No patient discontinued drug during the 12-week trial. In the blinded extension (median treatment duration 26 weeks), more patients were functional class (FC) I II vs. III IV (P < 0.0001) at end of study compared with start of active therapy. Elevated hepatic transaminase levels occurred in two patients.

                          Conclusions Sitaxsentan appears to be efficacious in patients with PAH associated with CTD.

                          • endothelin
                          • exercise capacity
                          • hemodynamics
                          • pulmonary hypertension
                          • scleroderma

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