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(Chest. 2004;126:1377-1381.)
© 2004 American College of Chest Physicians

Sustained Symptomatic, Functional, and Hemodynamic Benefit With the Selective Endothelin-A Receptor Antagonist, Sitaxsentan, in Patients With Pulmonary Arterial Hypertension*

A 1-Year Follow-up Study

David Langleben, MD; Andrew M. Hirsch, MD; Eileen Shalit, RN; Lyda Lesenko, RN and Robyn J. Barst, MD

* From the Center for Pulmonary Vascular Disease (Drs. Langleben and Hirsch, and Ms. Shalit and Ms. Lesenko), Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Quebec, Canada; and Division of Pediatric Cardiology (Dr. Barst), New York Presbyterian Hospital, Columbia University College of Physicians and Surgeons, New York, NY.

Correspondence to: David Langleben, MD, Room E-258, Jewish General Hospital, 3755 Cote Ste Catherine, Montreal, Quebec Canada H3T 1E2; e-mail: david.langleben{at}mcgill.ca


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To examine the long-term efficacy and safety of the selective endothelin-A receptor (ET-A) antagonist, sitaxsentan sodium, after 1 year of therapy in patients with pulmonary arterial hypertension (PAH).

Design: The study was a Canadian, open-label extension of at least 1-year total of active therapy (sitaxsentan, 100 mg/d), following a preceding, blinded, 12-week placebo controlled trial of sitaxsentan (placebo, or sitaxsentan, 100 mg/d or 300 mg/d), which had then been followed by a blinded active-therapy continuation study (sitaxsentan, 100 mg/d or 300 mg/d).

Patients: Eleven patients with PAH were enrolled. The condition of one patient worsened at 7 months of therapy, and the patient transferred to epoprostenol therapy. The remaining 10 patients (idiopathic [n = 3], connective tissue disease [n = 3], congenital heart disease [n = 4]) completed the evaluation after 1 year of active therapy.

Interventions: The end points of the study included the 6-min walk test, World Health Organization (WHO) functional class, and cardiopulmonary hemodynamic parameters.

Results: After 1 year of sitaxsentan therapy, there were significant improvements in 6-min walk distance (50-m treatment effect), WHO functional class, and hemodynamics, as compared to baseline. There were no serious adverse events, and no instances of hepatotoxicity or bleeding.

Conclusion: Long-term selective ET-A blockade with sitaxsentan sodium is safe and may improve exercise capacity, functional class, and hemodynamics in patients with PAH.

Key Words: congenital heart disease • endothelin • endothelin receptors • pulmonary hypertension • scleroderma • sitaxsentan


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The various disorders that cause vascular remodeling of precapillary pulmonary vessels lead to increased pulmonary vascular resistance (PVR), pulmonary hypertension (PH) and, ultimately, death from right-heart failure. Because they share many common histologic features, and presumably many similar pathophysiologic processes, these disorders have been grouped into the diagnostic category of "pulmonary arterial hypertension" (PAH) by the World Health Organization (WHO).1 The disorders within PAH include idiopathic (primary) PAH, PAH related to connective tissue disease (CTD), PAH related to congenital heart disease, and some other types of PAH that were formerly termed secondary PH.

The 20-year search for mediators of PH has identified many abnormalities,2 but thus far only agents ameliorating the abnormalities of the prostanoid and endothelin (ET) pathways have resulted in safe and efficacious therapies.34 ET-1 is a potent vasoconstrictor and cellular mitogen, and increased local pulmonary levels of ET-1 expression and production appear to contribute to the vascular abnormalities in PAH.567 ET-1 signaling is transduced through two receptor subtypes. Binding of ET-1 to the ET-A receptor (ET-A) and ET-B receptor (ET-B) on smooth muscle induces vasoconstriction and proliferation. In contrast, ET-B on endothelial cells has a moderating role, by clearing ET-1,8 and by inducing production of the vasodilator and antiproliferative agents, prostacyclin and nitric oxide.9 Animal models of vascular disease that have deficient ET-B function have worsening of the vascular abnormalities.1011 Thus, preservation of ET-B function by selective ET-A antagonism may be preferable to nonselective ET-A and ET-B antagonism, although this hypothesis remains to be tested in clinical studies.

The development of bosentan, a nonselective ET-A and ET-B antagonist, has represented a significant advance in the therapeutic armamentarium for PAH.1213 Recently, the first large randomized trial14 of an orally active ET-A selective antagonist, using sitaxsentan sodium, also demonstrated significant improvement in functional capacity, hemodynamics, and symptoms in patients with PAH. Although a 1-year follow-up study15 has been reported for bosentan, there have been no long-term data available for sitaxsentan. We now present a 1-year follow-up of a Canadian cohort of patients with PAH treated with sitaxsentan.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Design and Patient Population
The Sitaxsentan To Relieve Impaired Exercise (STRIDE)-1 study was a placebo-controlled, double-blind, randomized, 12-week study of placebo vs sitaxsentan (Encysive Corporation; Houston, TX), 100 mg/d po or 300 mg/d po.14 Sixty patients were randomized to placebo treatment; 55 patients were randomized to sitaxsentan, 100 mg/d; and 63 patients were randomized to sitaxsentan, 300 mg/d. All patients had the option of continuing in an extension safety trial while the STRIDE-1 study was still enrolling new patients. Patients who had received 100 mg/d or 300 mg/d of sitaxsentan in the STRIDE-1 study were continued on the same dose, while patients who received placebo treatment in the STRIDE-1 study were randomized to either 100 mg/d or 300 mg/d of sitaxsentan in a blinded fashion. Following completion of the 12-week STRIDE-1 trial, and prior to the positive results of the study being reported,14 the decision was taken by the sponsors to terminate the extension study. However, at the Jewish General Hospital, under a Canadian compassionate-use protocol approved by Health Canada and the Jewish General Hospital Research Ethics Review Board, and with written, informed consent, all our patients (n = 11) were permitted to continue on open-label sitaxsentan, 100 mg/d. They underwent a monthly follow-up, and a reassessment of end points 1 year after starting active therapy. Thus, for placebo-treated patients in the STRIDE-1 study, reassessment was performed 1 year after starting the extension protocol (baseline). For those who had received sitaxsentan, at either dose, during the STRIDE-1 protocol, reassessment was performed 1 year after having started the STRIDE-1 study (baseline). For those patients (n = 6) who had been receiving sitaxsentan at the start of the STRIDE-1 study, we also had 3-month data (83 days) representing an evaluation at the completion of the STRIDE-1 study. The Canadian open-label treatment study was begun without breaking the treatment codes of the STRIDE-1 study or its extension trial. However, with completion and locking of the STRIDE-1 study and extension databases, we were unblinded as to the treatment of the patients before they had reached the 1-year total treatment interval, with the exception of one patient who had been treated for approximately 13 months by the time of unblinding. The assessments of functional class and functional capacity were performed by individuals who were blinded as to the patient’s therapy.

End Points
We employed the standard end points used in many previous PAH therapy trials, including distance walked in 6 min,16 World Health Organization (WHO) functional class, and hemodynamic parameters at cardiac catheterization: mean pulmonary arterial pressure (Ppa), cardiac output, pulmonary artery wedge pressure, mean systemic BP, and PVR.12131415171819 The evaluations were performed before starting therapy, and at 1 year. Monthly measurements of serum aspartate aminotransferase, alanine aminotransferase, and bilirubin were performed due to reported hepatotoxicity with ET-receptor antagonists.12131418

Statistical Analysis
Data are presented as mean ± SD, with median, ranges, and 95% confidence intervals (CIs). To examine the differences in hemodynamic end points and 6-min walk distance between baseline and 1 year, the Wilcoxon signed-rank test was used. For evaluation of the group change in WHO functional class between baseline and 1 year, a Fisher Exact Test was used. Two-tailed p values < 0.05 were considered significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Patient Population
Eleven patients entered the open-label protocol. One of the patients with CTD-related PAH deteriorated clinically at 7 months of active therapy; she was transferred to epoprostenol therapy but died from progressive PAH. The data for the remaining 10 patients are presented in Tables 1, 2 . Of the 10 remaining patients, 3 patients had idiopathic PAH, 3 patients had CTD-related PAH, and 4 patients had PAH associated with congenital heart disease. Four patients received placebo during the STRIDE-1 study, three patients received 100 mg/d of sitaxsentan, and three patients received 300 mg/d of sitaxsentan. There were no demographic differences between ex-placebo patients and ex-sitaxsentan patients. All patients had been exposed to active sitaxsentan therapy for approximately 1 year (mean, 374 ± 20 days; range, 363 to 430 days) at the time of the 1-year evaluation, with the exception of the first patient, who had received approximately 14 months of sitaxsentan because we had not yet been unblinded as to her initial therapy by the time she had been treated for 1 year.


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  		Table 1.. Baseline Characteristics of Patients Who Completed the Study*

 

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  		Table 2.. Treatment Dose and Duration of Sitaxsentan for Each Patient Who Completed the Study

 
End Points
Treatment with sitaxsentan significantly improved the 6-min walk distance over the 1-year period (Fig 1 ). The baseline 6-min walk distance was 386 ± 116 m (median, 357 m; 95% CI, 303 to 468), and 436 ± 82 m (median, 397 m; 95% CI, 377 to 494) after 1 year (p = 0.04; improvement, 50 m). There were similar improvements in the hemodynamic parameters (Fig 2 ). Although mean Ppa did not change during the 1 year of therapy (at baseline, 44 ± 14 mm Hg; median, 42.5 mm Hg; 95% CI, 34 to 54) vs at 1 year (45 ± 15 mm Hg; median, 41.5 mm Hg; 95% CI, 34 to 56; p = 0.5), there were significant improvements in cardiac output and PVR. Cardiac output increased from 4.3 ± 0.9 L/min (median, 4.49 L/min; 95% CI, 3.7 to 5.0) at baseline to 5.4 ± 1.1 L/min (median, 5.22 L/min; 95% CI, 4.6 to 6.1) [p = 0.009]; and PVR fell from 742 ± 341 dyne·cm·s–5 (median, 613 dyne·s·cm–5; 95% CI, 498 to 987) at baseline to 585 ± 246 dyne·s·cm–5 (median, 502 dyne·s·cm–5; 95% CI, 409 to 762) after 1 year of therapy (p = 0.04). There was no significant change in mean pulmonary artery wedge pressure (6 ± 3 mm Hg; median, 7 mm Hg; 95% CI, 4 to 8) at baseline vs 7 ± 4 mm Hg (median, 8 mm Hg; 95% CI, 5 to 10) at 1 year. Similarly, mean systemic BP did not change (84 ± 13 mm Hg; median, 79 mm Hg; 95% CI, 75 to 93) at baseline vs 83 ± 13 mm Hg (median, 79 mm Hg; 95% CI, 73 to 92) at 1 year. At baseline, one patient was in WHO functional class II and nine patients were in WHO functional class III. At 1 year, all 10 patients were in WHO functional class II (p < 0.01). For those patients for whom data were available, there were no differences between 12 weeks and 1 year of treatment, with the results of some patients returning slightly toward, but still better than, baseline, and other patients showing ongoing improvement.



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  		Figure 1.. Distance walked in 6 min (meters) before starting sitaxsentan therapy (baseline), at 12 weeks (where available), and after 1 year of therapy. Points represent individual patients. The numbers are group means ± SD at baseline and 1 year. There was a significant improvement over 1 year as compared to baseline (p = 0.04).

 


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  		Figure 2.. Mean Ppa (top), cardiac output (middle), and PVR (bottom) before starting sitaxsentan therapy (baseline), at 12 weeks (where available), and after 1 year of therapy. Points represent individual patients. The numbers are group means ± SD at baseline and 1 year. There was a significant improvement over 1 year in cardiac output (p = 0.009) and PVR as compared to baseline (p = 0.04). NS = not significant.

 
Safety
There were no serious adverse events during the year of therapy in the 10 patients. Side effects attributable to sitaxsentan therapy included headache, peripheral edema, nasal congestion, and nausea, in frequencies similar to those previously reported for ET-receptor antagonist therapy.131418 Notably, there were no occurrences of liver function abnormalities, and there were no management difficulties or complications related to the known sitaxsentan/warfarin interaction.14


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The natural history of PAH is one of ongoing deterioration. The objectives of therapy are to improve functional capacity and survival. This is the first study to present long-term outcome data with a selective ET-A antagonist, sitaxsentan, in patients with PAH. Although the cohort was small and from a single center, there were significant improvements in exercise capacity, functional class, and hemodynamics at 1 year.

Historically, phase II or III placebo-controlled trials of therapy in PAH have not extended beyond 12 to 16 weeks in duration, because of concern regarding the placebo group, as well as the expectation of demonstrating significant benefit within that time period. However, concern has been expressed that improvement at 12 weeks or 16 weeks should not lead to the assumption of long-term benefit. Indeed, a recent trial20 of beraprost sodium showed benefit at 3 months and 6 months of therapy, which was lost at 9 months and 12 months of therapy. Thus, assessment of long-term efficacy is very important. Long-term benefit has been reported with calcium- channel blockade and with epoprostenol,2122232425 and bosentan in idiopathic PAH and PAH related to CTD.15 We now demonstrate long-term improvement and clinical stability from selective ET-A blockade, using sitaxsentan, over a 1-year period.

We found a 50-m improvement in 6-min walk distance with sitaxsentan, which was comparable to that previously reported for bosentan (60 m).15 Epoprostenol has been reported to provide even greater benefit (142-m increase) at 1 year.24 However, our patient cohort was slightly different from that of previous PAH studies; in the STRIDE-1 study, there was no upper exclusion limit for baseline 6-min walk test distance, which has traditionally been set at 450 m. Moreover, the STRIDE-1 study included patients with PAH related to congenital heart disease. Indeed, if analysis was confined to the patients in our Canadian cohort who met the traditional criteria of previous studies, ie, baseline 6-min walk < 450 m and idiopathic PAH or PAH related to CTD, the increase in 6-min walk distance was 81 m (314 ± 83 m at baseline; 395 ± 56 m at 1 year; n = 5, p = 0.07). Furthermore, functional class improved in 10 of the 11 patients. Thus, sitaxsentan is safe and effective in the long-term treatment of PAH. Comparative trials are needed to assess whether the strategy of selective ET-A antagonism is superior to that of nonselective ET-A and ET-B antagonism.


   Acknowledgements
 
We thank the staff of the Jewish General Hospital Cardiac Catheterization Laboratory for their generous assistance.


   Footnotes
 
Drs. Langleben, Hirsch, and Barst have been investigators or consultants for Encysive Pharmaceuticals Corporation, and Ms. Shalit and Ms. Lesenko have served as coordinators for studies sponsored by Encysive Pharmaceuticals Corporation.

Dr. Langleben is a Chercheur Boursier Clinicien National (National Research Scholar) of the Fonds de la Recherche en Sante du Quebec.

This work was supported in part by the Bank of Montreal Center for the Study of Heart Disease in Women, at the Jewish General Hospital.

Abbreviations: CI = confidence interval; CTD = connective tissue disease; ET = endothelin; ET-A = endothelin-A receptor; ET-B = endothelin-B receptor; PAH = pulmonary arterial hypertension; PH = pulmonary hypertension; Ppa = pulmonary arterial pressure; PVR = pulmonary vascular resistance; STRIDE = Sitaxsentan To Relieve Impaired Exercise; WHO = World Health Organization

Received for publication January 27, 2004. Accepted for publication May 21, 2004.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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