Safety and efficacy of sitaxsentan 50 and 100 mg in patients with pulmonary arterial hypertension

doi:10.1016/j.pupt.2011.10.002

Pulmonary Pharmacology & Therapeutics

Volume 25, Issue 1, February 2012, Pages 33-39

https://doi.org/10.1016/j.pupt.2011.10.002 Get rights and content

Abstract

Objective

To assess safety and efficacy of sitaxsentan 50 and 100 mg in patients with pulmonary arterial hypertension (PAH).

Background

Sitaxsentan is a highly selective endothelin-A receptor antagonist that was recently withdrawn by the manufacturer because of a pattern of idiosyncratic liver injury.

Methods

Before sitaxsentan withdrawal, this 18-week double-blind, placebo-controlled study randomized patients with PAH to receive placebo or sitaxsentan 50 or 100 mg once daily. The primary efficacy endpoint was change from baseline in 6-min walk distance (6MWD) at week 18. Changes in World Health Organization (WHO) functional class and time to clinical worsening (TTCW) were secondary endpoints. The primary efficacy analysis was powered for sitaxsentan 100 mg versus placebo.

Results

Of 98 randomized patients, 61% were WHO functional class II at baseline. Improvement from baseline to week 18 in 6MWD occurred with sitaxsentan 100 but not 50 mg; a strong placebo effect was observed. At week 18, WHO functional class was improved or maintained in more patients receiving sitaxsentan 100 mg than placebo (P = 0.038); 0% versus 12% of patients deteriorated, respectively. TTCW was not significantly different for 100-mg sitaxsentan patients than placebo (P = 0.090). Adverse events (AEs) occurring more frequently with sitaxsentan (50 or 100 mg) included headache, peripheral edema, dizziness, nausea, extremity pain, and fatigue; most AEs were of mild or moderate severity.

Conclusion

Sitaxsentan 100 mg improved functional class but not 6MWD in PAH patients who were mostly WHO functional class II at baseline. No patient receiving sitaxsentan 100 mg experienced clinical worsening; sitaxsentan was well tolerated.

Introduction

Pulmonary arterial hypertension (PAH) is a rare and ultimately fatal disorder of the pulmonary vasculature [1], [2]. Because PAH is difficult to diagnose, the majority of patients are identified with functional class III and IV disease [3], [4]. Only recently have trials investigated outcomes using populations with substantial numbers of patients with functional class II disease [5], [6], [7], [8].

The pathogenesis of PAH is incompletely understood [9], [10]. Conventional treatments for PAH include vasodilators, digoxin, diuretics, anticoagulants, supplemental oxygen, and calcium-channel blockers (in selected patients) [11]. Disease-specific treatments for PAH include prostacyclins and prostacyclin analogs, phosphodiesterase type 5 inhibitors (PDE5i), and endothelin receptor antagonists (ETRAs) [11]; these drugs, alone or in combination, have been established as first-line therapy for the majority of PAH patients [12].

Sitaxsentan is a highly selective ETRA (6500-fold more selective for ET_A than ET_B receptors [13]) with a high oral bioavailability and long duration of action enabling once-daily dosing [13]. Selective inhibition may provide benefits by preserving vasodilator and clearance functions specific to ET_B receptors while preventing vasoconstriction and cellular proliferation mediated by ET_A [14]. In the first of 2 randomized, double-blind, placebo-controlled studies examining the efficacy and safety of treatment in PAH patients, Sitaxsentan to Relieve ImpaireD Exercise (STRIDE)-1, sitaxsentan 100 or 300 mg significantly improved 6-min walk distance (6MWD), functional class, and hemodynamic measures compared with placebo; no liver function abnormalities were reported for the 100-mg dose [15]. In the second trial (STRIDE-2), 6MWD was significantly improved compared with placebo for sitaxsentan 100 mg but not 50 mg [16]. Likewise, World Health Organization (WHO) functional class significantly improved with sitaxsentan 100 mg only. The incidences of elevated hepatic transaminase levels were comparable for all treatment groups, including placebo. Our study (STRIDE-4) further evaluates the efficacy and safety of the lower dose range of sitaxsentan (50 or 100 mg) compared with placebo when added to conventional PAH treatment to better define the therapeutic dose.

This study was conducted before the recent market withdrawal of sitaxsentan because of the recognition of a pattern of idiosyncratic liver injury. Findings from this study provide additional support of ETRAs as an effective class of agents for patients with PAH, particularly in a predominantly functional class II study population.

Section snippets

Study design

This 18-week randomized, double-blind, placebo-controlled study evaluated efficacy and safety of sitaxsentan 50 or 100 mg compared with placebo once daily. Patients were randomized 1:1:1 to receive sitaxsentan 50 mg, sitaxsentan 100 mg, or placebo in addition to conventional treatment (including calcium-channel blockers, digitalis, diuretics, anticoagulants, and/or oxygen).

Efficacy measures (6MWD, WHO functional class, and Borg Dyspnea Score) were assessed at baseline and weeks 6, 12, and 18.

Patients

This study was conducted between December 2003 and November 2004; 98 patients were randomized at 11 sites in Mexico, Argentina, Brazil, Spain, and Poland. Patient disposition is summarized in Fig. 1; 89% of patients completed the study.

Baseline demographic characteristics were similar between groups (Table 1). Most patients had idiopathic PAH (68%) and the majority were Hispanic (54%). A greater proportion of patients in the placebo group had PAH–CHD; conversely, more patients in the

Discussion

In this study of PAH patients mostly (61%) in WHO functional class II, all patients receiving sitaxsentan 100 mg retained or improved their WHO functional class status and none experienced a clinical worsening event. There was no significant effect of sitaxsentan 100 mg on 6MWD; sitaxsentan 50 mg appeared subtherapeutic. Sitaxsentan was generally well tolerated.

Other ETRAs have similarly produced mixed efficacy results in clinical trials. Ambrisentan 2.5–10 mg significantly improved 6MWD and

Acknowledgments

This study was funded by Encysive Pharmaceuticals Inc., now part of Pfizer Inc, New York, NY, USA. Editorial assistance was provided by Tiffany Brake, PhD, at Complete Healthcare Communications, Inc., and was funded by Pfizer Inc.

The institution employing Dr. Sandoval and Dr. Pulido has received research grants from United Therapeutics, Actelion Pharmaceuticals, Pfizer Inc, Gilead (formerly Myogen Ltd.), and Encysive Pharmaceuticals. Dr. Sandoval has received consultant honoraria from Encysive

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Cited by (33)

BMI and Treatment Response in Patients With Pulmonary Arterial Hypertension: A Meta-analysis
2022, Chest
Citation Excerpt :
This study used individual participant data from 18 phase III randomized placebo-controlled trials of therapies for PAH submitted to the U.S. Food and Drug Administration (FDA) for approval from 2000 to 2015 (Table 1).32-47
Obesity is increasingly prevalent in pulmonary arterial hypertension (PAH) but is associated with improved survival, creating an “obesity paradox” in PAH. It is unknown if the improved outcomes could be attributable to obese patients deriving a greater benefit from PAH therapies.
Does BMI modify treatment effectiveness in PAH?
Using individual participant data, a meta-analysis was conducted of phase III, randomized, placebo-controlled trials of treatments for PAH submitted for approval to the U.S. Food and Drug Administration from 2000 to 2015. Primary outcomes were change in 6-min walk distance (6MWD) and World Health Organization (WHO) functional class.
A total of 5,440 participants from 17 trials were included. Patients with overweight and obesity had lower baseline 6MWD and were more likely to be WHO functional class III or IV. Treatment was associated with a 27.01-m increase in 6MWD (95% CI, 21.58-32.45; P < .001) and lower odds of worse WHO functional class (OR, 0.58; 95% CI, 0.48-0.70; P < .001). For every 1 kg/m² increase in BMI, 6MWD was reduced by 0.66 m (P = .07); there was no significant effect modification of treatment response in 6MWD according to BMI (P for interaction = .34). Higher BMI was not associated with odds of WHO functional class at end of follow-up; however, higher BMI attenuated the treatment response such that every 1 kg/m² increase in BMI increased odds of worse WHO functional class by 3% (OR, 1.03; P for interaction = .06).
Patients with overweight and obesity had lower baseline 6MWD and worse WHO functional class than patients with normal weight with PAH. Higher BMI did not modify the treatment response for change in 6MWD, but it attenuated the treatment response for WHO functional class. PAH trials should include participants representative of all weight groups to allow for assessment of treatment heterogeneity and mechanisms.
Efficacy and tolerability of pharmacological interventions for pulmonary arterial hypertension: A network meta-analysis
2018, Pulmonary Pharmacology and Therapeutics
Citation Excerpt :
After reviewing full texts, 16 articles with insufficient data were removed and 14 articles were excluded in consideration of a lack of network connections with EAP or placebo. Finally, 43 RCTs met the inclusion criteria and were retrieved for data extraction [18–60]. The searching progress was shown in Fig. 1.
This network meta-analysis (NMA) is designed to compare the efficacy and tolerability of various therapies and combinations for pulmonary arterial hypertension (PAH).
We conducted a systematic search in databases PubMed, Embase, and Cochrane Library. Treatment efficacy and tolerability were compared by synthesizing direct and indirect evidence. The surface under the curve ranking area was utilized to rank multiple interventions.
A total of 43 randomized clinical trials were included in our NMA. With regard to efficacy outcomes, including 6 min walking distance (6MWD), functional class amelioration (FCA), death, clinical worsening (CW), pulmonary vascular resistance (PVR), mean pulmonary artery pressure (mPAP), cardiac index (CI), and mean right atrial pressure (mRAP), endothelin receptor antagonists (ERA), phosphodiesterase 5 inhibitor (PDE-5Is), ERA combined with PDE-5Is (EAP), and prostacyclin analogs (PGI) combined with ERA (PAE) performed better than others. Meanwhile PAP and PGE demonstrated better than others in tolerability. Overall, EAP and PAE showed good efficacy and were well-tolerated among all therapies.
Overall, we recommend EAP as the optimal choice for patients with PAH in clinical practice and PAE as suboptimal in view of their desirable performance in efficacy. Most of the combination therapies performed better than monotherapies.
Comparative efficacy and acceptability of endothelin receptor antagonists for pulmonary arterial hypertension: A network meta-analysis
2017, International Journal of Cardiology
Citation Excerpt :
Finally, publication bias evaluated using the comparison-adjusted funnel plot. As suggested by the literature flow diagram (Fig. 1), a total of 10 articles that satisfied the inclusion criteria mentioned earlier were screened from the initially retrieved 1175 articles [6-10, 12, 15-17, 31]. All of the 10 eligible articles were randomized clinical trials that involved inter-therapy comparisons of the efficacy and/or acceptability among Primary PAH therapies including bosentan, sitaxsentan, macitentan, ambrisentan and placebo.
Endothelin receptor antagonists (ERAs) such as ambrisentan, sitaxsentan, bosentan and macitentan are primary drug therapies for pulmonary arterial hypertension (PAH) patients. However, the optimal drugs for PAH remained controversial due to heterogeneous nature of randomized control trials (RCTs).
Apart from traditional meta-analysis, network meta-analysis (NMA) was performed in this study for multiple comparisons among PAH therapies. The 6 minute walking distance (6MWD) and clinical worsening were efficacy outcomes whereas serious adverse effects (SAE) and all-cause discontinuation were acceptability outcomes. The weighted mean difference (WMD) and odds ratio (OR) along with their 95% confidence interval (95% CI) or 95% credible interval (95% CrI) were used to evaluate the positive and negative effects of these therapies on PAH patients.
By synthesizing direct evidence from 10 studies with a total number of 2172 patients, we discovered that all of the four PAH therapies significantly increased the average 6MWD in comparison to the placebo (P-value < 0.05). Moreover, bosentan and ambrisentan both showed significant association with a decrease in the risk of clinical worsening compared to placebo. Regarding of all-cause discontinuation, ambrisentan is the only therapy which was significantly associated with a risk decrease compared to placebo. However, there was no sufficient evidence suggesting significant difference in any efficacy or acceptability outcomes between any two of the PAH therapies (P-value > 0.05).
Ambrisentan could be considered as the most appropriate therapy among the four ERAs for PAH patients. Bosentan also behaved well, but it is not as safe as ambrisentan.
In regard to Badiani and Messori, “Targeted Treatments for Pulmonary Arterial Hypertension: Interpreting Outcomes by Network Meta-analysis”
2016, Heart Lung and Circulation
Use of outcome measures in pulmonary hypertension clinical trials
2015, American Heart Journal
To evaluate the use of surrogate measures in pulmonary hypertension (PH) clinical trials and how it relates to clinical practice.
Studies of pulmonary arterial hypertension (PAH) employ a variety of surrogate measures in addition to clinical events because of a small patient population, participant burden, and costs. The use of these measures in PH drug trials is poorly defined.
We searched PubMed/MEDLINE/Embase for randomized or prospective cohort PAH clinical treatment trials from 1985 to 2013. Extracted data included intervention, trial duration, study design, patient characteristics, and primary and secondary outcome measures. To compare with clinical practice, we assessed the use of surrogate measures in a clinical sample of patients on PH medications at Duke University Medical Center between 2003 and 2014.
Between 1985 and 2013, 126 PAH trials were identified and analyzed. Surrogate measures served as primary endpoints in 119 trials (94.0%). Inclusion of invasive hemodynamics decreased over time (78.6%, 75.0%, 52.2%; P for trend = .02), while functional testing (7.1%, 60.0%, 81.5%; P for trend < .0001) and functional status or quality of life (0%, 47.6%, 62.8%; P for trend < .0001) increased in PAH trials over the same time periods. Echocardiography data were reported as a primary or secondary outcome in 32 trials (25.4%) with increased use from 1985-1994 to 1995-2004 (7.1% vs 35.0%, P = .04), but the trend did not continue to 2005-2013 (25.0%). In comparison, among 450 patients on PAH therapies at our institution between 2003 and 2013, clinical assessments regularly incorporated serial echocardiography and 6-minute walk distance tests (92% and 95% of patients, respectively) and repeat measurement of invasive hemodynamics (46% of patients).
The majority of PAH trials have utilized surrogate measures as primary endpoints. The use of these surrogate endpoints has evolved significantly over time with increasing use of patient-centered endpoints and decreasing or stable use of imaging and invasive measures. In contrast, imaging and invasive measures are commonly used in contemporary clinical practice. Further research is needed to validate and standardize currently used measures.
Clinical worsening as composite study end point in pediatric pulmonary arterial hypertension
2015, Chest
Clinical worsening (CW), an increasingly used composite end point in adult pulmonary arterial hypertension (PAH), has not yet been evaluated in pediatric PAH. This study aims to evaluate the usefulness of CW in pediatric PAH by assessing the event incidence and prognostic value of each separate component of CW and of the composite CW end point.
Seventy pediatric patients with PAH from the Dutch National Network for Pediatric Pulmonary Hypertension, who started PAH-targeted therapy between January 2000 and January 2014, were included in the study and underwent standardized follow-up. The following CW components were prospectively registered: death, lung transplantation (LTx), PAH-related hospitalizations, initiation of IV prostanoids, and functional deterioration (World Health Organization functional-class deterioration, > 15% decrease in 6-min walk distance, or both). The longitudinal event incidence and prognostic value were assessed for each separate component and their combination.
The end-point components of death, LTx, hospitalizations, initiation of IV prostanoids, and functional deterioration occurred with a longitudinal event rate of 10.1, 2.5, 21.4, 9.4 and 48.1 events per 100 person-years, respectively. The composite CW end point occurred 91.5 times per 100 person-years. The occurrences of either hospitalization, initiation of IV prostanoids, or functional deterioration were predictive of death or LTx (P ≤ .001 for each component). In this cohort, 1-, 3-, and 5-year transplant-free survival was 76%, 64%, and 56%, respectively. Freedom from CW at 1, 3, and 5 years was 43%, 22%, and 17%, respectively.
CW occurred with a high event incidence and each of the soft end-point components was predictive of death or LTx. This supports the usefulness of CW as a study end point in clinical trials in pediatric PAH.

View all citing articles on Scopus

¹: on behalf of the STRIDE-4 investigators.

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Safety and efficacy of sitaxsentan 50 and 100 mg in patients with pulmonary arterial hypertension

Abstract

Objective

Background

Methods

Results

Conclusion

Introduction

Section snippets

Study design

Patients

Discussion

Acknowledgments

Lancet

J Am Coll Cardiol

Clin Chest Med

Respir Med

J Am Coll Cardiol

Vascul Pharmacol

J Am Coll Cardiol

J Am Coll Cardiol

Lancet

Chest

Chest

J Am Coll Cardiol

Primary pulmonary hypertension. A national prospective study

Ann Intern Med

Primary pulmonary hypertension

N Engl J Med

Pulmonary arterial hypertension in France: results from a national registry

Am J Respir Crit Care Med

A USA-based registry for pulmonary arterial hypertension: 1982–2006

Eur Respir J