Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Combined Analysis of Outcomes of Sitaxentan Treatment of Pulmonary Arterial Hypertension (PAH) Associated with Systemic Sclerosis (Scleroderma).

Seibold5,  James R., Matucci-Cerinic6,  Marco, Louie3,  Michael, Watt3,  Stephen, Teal4,  Simon A., Liu1,  Xuexuan, Hwang3,  Lie-Ju

Aerotek, Houston, TX
Cardiology, Montreal Jewish Hospital, Montreal, Canada
Pfizer Inc, New York, NY
Pfizer Ltd, Tadworth, Surrey, UK
Rheumatology, University of Connecticut, Farmington, Farmington, CT
University of Florence, Firenze, Italy

Background:

PAH is a leading cause of mortality and late disease morbidity in scleroderma. In PAH, endothelin (ET)-1 is a key vasoconstrictor, predominantly via ETA receptors, and ET receptor antagonists are established therapies. Sitaxentan sodium is a once daily, orally bioavailable, highly selective (6500:1 ETA vs ETB) ET-receptor antagonist. This report is a post-hoc analysis of pooled data from the STRIDE (Sitaxentan To Relieve ImpaireD Exercise) 1, 2, and 4 trials. The aim is to describe the efficacy and safety of oral sitaxentan 100 mg once daily (QD; the currently approved dose in the European Union, Canada, and Australia) vs bosentan 125 mg twice daily (BID) and placebo in patients with PAH-scleroderma.

Methods:

The STRIDE trials were double-blind, randomized, placebo-controlled trials of sitaxentan use in patients aged 12–75 years with WHO FC II–IV (predominantly II and III) idiopathic PAH or PAH associated with connective tissue disease or congenital heart disease. The trials ranged from 12 to 18 weeks in duration. The bosentan comparator arm in STRIDE- 2 was open-label.

Summary of the Results:

Fifty four patients with scleroderma were included in the pooled, post-hoc analyses. Except for a higher mean (± SD) age in the sitaxentan group vs the bosentan group (62± 8 vs 55±15 y; P=0.0493), demographics and baseline disease severity were not statistically different across the 3 treatment groups. All patients were WHO FC II or III at baseline except for 1 FC IV placebo-recipient. Change in 6 minute walk distance (6MWD) and WHO FC, and time to clinical worsening were as follows:

 Placebo (N = 15)Bosentan 125 mg bid (N = 15)Sitaxentan 100 mg QD (N = 24)
Mean (SD) change in 6 MWD, m-22 (79.0)-14 (110.4)18 (48.9)
  Placebo-subtracted difference 739
  Bosentan-subtracted difference  32
    P-value vs placebo NSNS
    P-value vs bosentan   
Change in WHO FC, n (%)   
  Improved1 (7%)3 (20%)6 (25%)
  No Change13 (87%)8 (53%)18 (75%)
  Deteriorated1 (7%)4 (27%)0 (0%)
    P-value vs placebo NSNS
    P-value vs bosentan   
  Response*14 (93%)11 (73%)24 (100%)
    P-value vs placebo NSNS
    P-value vs bosentan  0.011
Clinical Worsening, n (%)3 (20%)7 (47%)0 (0%)
    P-value vs placebo† NS0.033
    P-value vs bosentan†  0.002
NS = nonsignificant.
*Improved or no change.
P-values from log rank test for time to clinical worsening.

All therapies were well tolerated. For the safety analysis population (16 placebo, 24 sitaxentan 100 mg QD, and 16 bosentan 125 mg BID), the incidence of ALT/AST >3×ULN was 6% (placebo), 0% (sitaxentan), and 19% (bosentan). The incidence of discontinuations due to adverse events was 0% (placebo), 0% (sitaxentan) and 13% (bosentan).

Conclusions:

Sitaxentan 100 mg QD appears to be an effective and well tolerated therapy for patients with PAH-scleroderma. Sitaxentan 100 mg QD significantly reduced the incidence of clinical worsening events, with fewer discontinuations due to adverse events and fewer cases of elevated ALT/AST compared with bosentan. These findings warrant further investigation in a large, prospective study.

To cite this abstract, please use the following information:
Seibold, James R., Matucci-Cerinic, Marco, Louie, Michael, Watt, Stephen, Teal, Simon A., Liu, Xuexuan, et al; Combined Analysis of Outcomes of Sitaxentan Treatment of Pulmonary Arterial Hypertension (PAH) Associated with Systemic Sclerosis (Scleroderma). [abstract]. Arthritis Rheum 2010;62 Suppl 10 :565
DOI: 10.1002/art.28334

Abstract Supplement

Meeting Menu

2010 ACR/ARHP