Sitaxsentan for the Treatment of Pulmonary Arterial Hypertension: A 1-Year, Prospective, Open-Label Observation of Outcome and Survival

doi:10.1378/chest.07-0767

Chest

Volume 134, Issue 4, October 2008, Pages 775-782

https://doi.org/10.1378/chest.07-0767 Get rights and content

Background

Despite advances in the management of pulmonary arterial hypertension (PAH), the mortality rate remains excessive. Long-term efficacy evaluations are needed to guide therapeutic management. The purpose of this study is to present 1-year observational data with two endothelin antagonists, sitaxsentan and bosentan, in a prospective, open-label study.

Methods

The present study was a prospective, international, multicenter, randomized, open-label extension of the Sitaxsentan To Relieve Impaired Exercise-2 trial. All-cause mortality, time to discontinuation (all causes) from monotherapy, time to discontinuation due to adverse events, time to elevations in and time to discontinuation due to elevated hepatic transaminases, and time to first clinical worsening event were evaluated. Patients initially receiving sitaxsentan at 50 mg were excluded from the main analysis. The distributions of time-to-event variables are estimated using Kaplan-Meier methods, and treatment effects are evaluated using the Cox proportional hazards model.

Results

Patients treated with sitaxsentan at 100 mg had 96% overall survival and a 34% risk for a clinical worsening event by 1 year. In addition, there was a 6% risk of elevated aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels > 3 × upper limit of normal range (ULN) at 1 year and a 15% risk of discontinuation due to adverse events. Patients treated with bosentan had 88% overall survival and a 40% risk of a clinical worsening event by 1 year. In addition, there was a 14% risk for elevated AST and/or ALT levels > 3 × ULN at 1 year and a 30% risk of discontinuation due to adverse events.

Conclusions

At 1 year, sitaxsentan therapy appears safe and efficacious for patients with PAH; reductions in mortality and the risk for clinical worsening events provide support for durability of efficacy.

Section snippets

Patients

Two hundred twenty-nine patients aged 12 to 78 years in WHO functional class II-IV with idiopathic PAH (IPAH) or PAH associated with connective tissue disease (PAH-CTD) or PAH associated with a congenital heart defect (PAH-CHD) were enrolled in STRIDE-2X. Additional inclusion criteria have been published previously.⁷ The study was conducted according to ethical principles stated in the Declaration of Helsinki (1996) and applicable guidelines on good clinical practice. The protocol was approved

Demographics

The sitaxsentan and bosentan treatment groups in the analysis population were comparable with regards to baseline characteristics (Table 1). Patients ranged in age from 14 to 78 years (mean, 54 years), and approximately 77% were female. Approximately 60% of patients had IPAH, 30% had PAH-CTD, and 10% had PAH-CHD. Baseline characteristics of patients in predefined subgroups were similar.

The overall treatment population of 229 patients was randomized to sitaxsentan (n = 145) or standard-dose

Discussion

We report 1-year results with the selective ET-A receptor antagonist sitaxsentan coupled with 1-year outcomes with the nonselective ET-A/ET-B receptor antagonist bosentan in a broad class of PAH patients (inclusion of IPAH [approximately 60%] and associated PAH conditions, ie, PAH-CTD [approximately 30%] and PAH-CHD [approximately 10%] with baseline functional class II-IV). It is important to recognize that although the STRIDE-2X study looked at patients who initiated treatment with sitaxsentan

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Cited by (97)

The endothelin system as target for therapeutic interventions in cardiovascular and renal disease
2020, Clinica Chimica Acta
Endothelins including its most abundant isoform, endothelin-1 (ET-1), are peptides acting as vasoconstrictors when binding to ET_A and ET_B receptors, and, in addition to their distinct roles in normal physiology, endothelins have a central role in the pathophysiology of many diseases including cardiovascular and renal diseases. Endothelin-1 (ET-1), the most potent vasoconstrictor in the cardiovascular system, regulates basal vascular tone and glomerular hemodynamics. ET-1 is involved also in vascular and cardiac hypertrophy, inflammation, and in the development and progression of cardiovascular diseases - e.g. essential hypertension, atherosclerosis, coronary artery disease, congestive heart failure, pulmonary arterial hypertension and cerebrovascular disease and renal diseases - e.g. acute renal failure, polycystic kidney disease and chronic kidney disease. Not surprisingly, the ET system has become a target for therapeutic interventions that now include a few already established and some new promising agents. In this narrative review, we summarize physiologic properties of the ET system, focusing especially on ET-1, and its role in the pathophysiology of ET system activated diseases, and discuss the potentials of therapeutic interventions targeting the ET system in cardiovascular and renal diseases. While ET receptor antagonists have already revolutionized the management of idiopathic pulmonary arterial hypertension, so far, this class of drugs have failed as medication for congestive heart failure. Clinical trials continue to explore new applications of endothelin receptor antagonists in treatment-resistant hypertension and chronic kidney disease and have shown some benefits in the latter group by reducing proteinuria; however, they have not been approved yet. We conclude that larger clinical trials are needed to validate the use of ET receptor antagonists in ET system activated diseases.
Endothelin antagonism and uric acid levels in pulmonary arterial hypertension: Clinical associations
2014, Journal of Heart and Lung Transplantation
Citation Excerpt :
Briefly, patients with PAH were randomized 1:1:1:1 to receive sitaxentan 50 or 100 mg or matched placebo orally once daily, or open-label bosentan 125 mg twice daily for 18 weeks. STRIDE-2X was an open-label extension of STRIDE-2.18 Patients were eligible if they completed the STRIDE-2 trial or had prematurely discontinued placebo or sitaxentan 50 mg in STRIDE-2 because of lack of clinical response.
Elevated serum uric acid is detected in pulmonary arterial hypertension (PAH) and is associated with poor patient outcomes. High serum uric acid is an independent risk factor for cardiovascular disease and renal impairment. We analyzed the effects of endothelin receptor antagonism on serum uric acid in PAH patients participating in the Sitaxentan to Relieve Impaired Exercise (STRIDE)-2/2X trial, and the impact of uric acid on 6-minute walk distance (6MWD), time to clinical worsening (TtCW) and survival.
In the 18-week, double-blind, placebo-controlled STRIDE-2 trial, 246 PAH patients were randomized and received matched placebo, sitaxentan 50 or 100 mg orally once daily, or open-label bosentan 125 mg twice daily. STRIDE-2X was a 1-year, open-label extension of STRIDE-2.
Baseline serum uric acid was similar between groups. Increased serum uric acid was a significant risk factor for 1-year mortality and TtCW. Compared with placebo, sitaxentan 50 and 100 mg and bosentan all reduced serum uric acid (p < 0.05). Reduced serum uric acid correlated with increased 6MWD (p = 0.0037).
Endothelin receptor antagonism reduces serum uric acid in PAH patients, and this reduction is associated with improved survival and longer TtCW. Further prospective studies are needed to investigate the pathogenic role of serum uric acid in PAH and its prognostic potential.
Evaluation of the predictive value of a clinical worsening definition using 2-year outcomes in patients with pulmonary arterial hypertension: A REVEAL registry analysis
2013, Chest
Time to clinical worsening has been proposed as a primary end point in clinical trials of pulmonary arterial hypertension (PAH); however, neither standardized nor validated definitions of clinical worsening across PAH trials exist. This study aims to evaluate a proposed definition of clinical worsening within a large prospective, observational registry of patients with PAH with respect to its value as a predictor of proximate (within 1 year) risk for subsequent major events (ie, death, transplantation, or atrial septostomy).
We assessed overall 2-year survival and survival free from major events to determine the relationship between clinical worsening and major events among adults with hemodynamically defined PAH (N = 3,001). Freedom from clinical worsening was defined as freedom from worsening functional class (FC), a ≥ 15% reduction in 6-min walk distance (6MWD), all-cause hospitalization, or the introduction of parenteral prostacyclin analog therapy.
In the 2 years of follow-up, 583 patients died. Four hundred twenty-six died after a documented clinical worsening event, including FC worsening (n = 128), a ≥ 15% reduction in 6MWD (n = 118), all-cause hospitalization (n = 370), or introduction of a prostacyclin analog (n = 91). Patients who experienced clinical worsening had significantly poorer subsequent 1-year survival postworsening than patients who did not worsen (P < .001).
Clinical worsening was highly predictive of subsequent proximate mortality in this analysis from an observational study. These results validate the use of clinical worsening as a meaningful prognostic tool in clinical practice and as a primary end point in clinical trial design.
ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov
Relationship between baseline ET-1 plasma levels and outcome in patients with idiopathic pulmonary hypertension treated with bosentan
2013, International Journal of Cardiology
To address if baseline endothelin-1 (ET-1) plasma levels might predict clinical worsening (CW) in patients with idiopathic pulmonary hypertension (IPAH) treated with bosentan.
Forty-four consecutive patients with IPAH (WHO classes II–III) were included in this study. After an initial assessment (clinical status, pulmonary hemodynamics, samples for adrenomedullin (ADM), ET-1 and brain natriuretic peptide (BNP) plasma levels), patients were treated with bosentan and followed-up for CW.
We observed CW in 24 patients. Actuarial rates of freedom from CW were 74% at 1 year, 56% at 2 years, and 43% at 3 years. Patients with CW had a worse WHO functional class (II/III; no-CW 14/6 vs CW 5/19, p = 0.002), six-minute walk-test distance (no-CW 439 + 94 m vs CW 385 + 82 m, p = 0.04), mean pulmonary artery pressure (no-CW 47.4 + 10.6 mm Hg vs CW 56 + 12.6 mm Hg, p = 0.02) and pulmonary vascular resistance (PVR no-CW 12.5 + 4.8 WU vs CW 16.4 + 6.3 WU, p = 0.03) than the no-CW group. Moreover ET-1 (no-CW 14.1 + 4.2 pg/ml vs CW 21.3 + 6.3 pg/ml, p = 0.0001), ADM (no-CW 14.9 + 7 pg/ml vs CW 21.5 + 10.4 pg/ml p = 0.002) and BNP (no-CW 82.8 + 35.3 pg/ml vs CW 115.4 + 39.6 pg/ml, p = 0.007) plasma levels were significantly higher in the CW group than in the no-CW group. The multivariate Cox proportional hazards model identified WHO class III (RR 4.6, 95%CI 14.6–1.45), ET-1 plasma levels (RR 1.1, 95%CI 2.05–1.01) and PVR (RR 1.2, 95%CI 1.3–1.03) as independent risk factors for CW.
These data confirm the high rate of CW in patients with IPAH treated with bosentan and document the impact of the endothelin system on CW of these patients.
Hemodynamic Stability After Transitioning Between Endothelin Receptor Antagonists in Patients With Pulmonary Arterial Hypertension
2013, Canadian Journal of Cardiology
Maintenance of a favourable hemodynamic profile is central to therapeutic success in pulmonary arterial hypertension (PAH). There is little information about the safety of transitioning patients between oral therapies for PAH. Endothelin receptor antagonists (ERAs) have been a therapeutic mainstay in PAH, providing benefit to many patients. Three ERAs, bosentan, sitaxsentan, and ambrisentan have been approved for clinical use. Sitaxsentan was voluntarily withdrawn from the market in late 2010 resulting in the need to quickly transition a large number of stable patients.
We transitioned 30 clinically stable patients to either ambrisentan or bosentan. Patients underwent a right heart catheterization, measurement of serum N-terminal pro-brain natriuretic peptide (NT-proBNP), and assessment of functional class before changing ERA and again 4 months later. We present a retrospective analysis of those data.
Of the 30 patients transitioned (15 to ambrisentan, 15 to bosentan), 23 had complete hemodynamic data. No significant change was observed in the groups in right atrial, mean pulmonary artery, and pulmonary artery wedge pressures, or in cardiac output, pulmonary vascular resistance, or NT-proBNP levels. There was no change in World Health Organization functional class. Four ambrisentan and 2 bosentan-treated patients reported fluid retention, and 3 bosentan-treated patients had elevation of hepatic transaminases. Two of the patients had a right atrial pressure increase of ≥5 mm Hg, and 4 had pulmonary artery wedge pressure increase of ≥5 mm Hg.
Transitioning between ERAs in stable PAH patients does not result in hemodynamic or clinical deterioration during the first 4 months posttransition. A minority of patients have developed increased cardiac filling pressures.
Le maintien d'un profil hémodynamique favorable est essentiel au succès thérapeutique de l'hypertension artérielle pulmonaire (HAP). Peu d'informations existent sur l'innocuité de la transition vers les différents traitements oraux de l'HAP chez les patients. Les antagonistes des récepteurs de l'endothéline (ARE) ont été un pilier thérapeutique de l'HAP s'avérant un avantage chez plusieurs patients. Trois (3) ARE, le bosentan, le sitaxsentan et l'ambrisentan ont été approuvés pour utilisation clinique. Le sitaxsentan a été volontairement retiré du marché à la fin de 2010, ce qui a entraîné la nécessité d'une transition rapide chez un grand nombre de patients stables.
Nous avons assuré la transition vers l'ambrisentan ou le bosentan chez 30 patients cliniquement stables. Les patients ont subi un cathétérisme cardiaque droit, une mesure de la concentration sérique du propeptide natriurétique de type B N-terminal (NT-proBNP : N-terminal pro-brain natriuretic peptide) et une évaluation de la classe fonctionnelle avant le changement d'ARE ainsi que 4 mois plus tard. Nous présentons une analyse rétrospective de ces données.
Parmi ces 30 patients ayant effectué la transition (15 à l'ambrisentan, 15 au bosentan), 23 avaient des données hémodynamiques complètes. Dans les groupes, aucun changement significatif n'a été observé dans la pression auriculaire droite, la pression artérielle pulmonaire moyenne et la pression capillaire pulmonaire, ni dans le débit cardiaque, la résistance vasculaire pulmonaire ou les concentrations de NT-proBNP. Il n'y a eu aucun changement dans la classe fonctionnelle de l'Organisation mondiale de la santé. Quatre (4) patients traités à l'ambrisentan et 2 traités au bosentan ont rapporté une rétention hydrique, et 3 patients traités au bosentan ont eu une augmentation des transaminases hépatiques. Deux (2) des patients ont eu une augmentation de la pression auriculaire droite ≥5 mm Hg, et 4 ont eu une augmentation de la pression capillaire pulmonaire ≥5 mm Hg.
La transition vers les différents ARE chez les patients ayant une HAP stable n'entraînait pas de détérioration hémodynamique ou clinique au cours des 4 premiers mois suivant la transition. Une augmentation des pressions de remplissage cardiaque est apparue chez une minorité de patients.
Prognostic factors in severe pulmonary hypertension patients who need parenteral prostanoid therapy: The impact of late referral
2012, Journal of Heart and Lung Transplantation
Citation Excerpt :
This bias could justify the results obtained, because incident cases have a worst prognosis than prevalent patients.26 The good survival in the open-label phase of the randomized controlled study has created the wrong conclusion that oral therapy represents a definite cure for PAH, but survival is satisfactory only when other drugs are promptly added in case of clinical worsening, which is a common experience during oral monotherapy.10,12–16 In real-world clinical practice, most PAH patients are still dying on monotherapy, with only a few being escalated to parenteral prostanoids, as documented by specialty pharmacy service providers,27 confirming a delayed use of prostanoids usually not available in the non-expert centers.
Oral drugs have made the treatment of pulmonary hypertension (PH) feasible in non-expert centers, which could delay patient access to prostanoid therapy.
Fifty-seven consecutive patients with precapillary PH received a prostanoid in our center. Data at prostanoid initiation included modality of center referral, medical history, New York Heart Association [NYHA] class, exercise capacity, echocardiographic parameters, and hemodynamics.
Overall survival at 1, 2, and 3 years was 85%, 69%, 55%, respectively. Non-survivors had worse NYHA class III/IV (17/12) than survivors (27/1; p < 0.01) and exercise capacity on 6-minute-walk distance (254 ± 114 vs 354 ± 91 meters; p < 0.01). Non-survivors were more frequently referred on oral therapy (83% vs 36%; p < 0.01) and had a higher rate of urgent prostanoid treatment (69% vs 17%; p < 0.0001). Multivariate analysis (hazard ratio [95% confidence interval]) found the independent prognostic factors were urgent prostanoid therapy (2.0 [1.1–3.9]) and NYHA class (3.5 [1.5–8.2]). Survivors had a significant response to prostanoid, improving NYHA class from 2.8 ± 0.4 to 2.3 ± 0.5 (p = 0.002), 6-minute walk distance from 354 ± 91 to 426 ± 82 meters (p = 0.0001), and pulmonary hemodynamics (pulmonary artery pressure from 56 ± 13 to 44 ± 18 mm Hg [p < 0.05]; cardiac index from 2.0 ± 1.2 to 3.1 ± 1.2 liters/min/m² [p = 0.002], and pulmonary vascular resistance from 17 ± 10 to 8 ± 6 WU [p = 0.001]).
Referral of patients on oral treatment to a tertiary PH center is delayed and significantly affects prognosis.

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The authors have no conflicts of interest to disclose.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

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Chest

Original ResearchPulmonary Arterial HypertensionSitaxsentan for the Treatment of Pulmonary Arterial Hypertension: A 1-Year, Prospective, Open-Label Observation of Outcome and Survival

Background

Methods

Results

Conclusions

Section snippets

Patients

Demographics

Discussion

Chest

Pharmacol Ther

J Am Coll Cardiol

J Heart Lung Transplant

J Heart Lung Transplant

Chest

Pulmonary arterial hypertension

N Engl J Med

Treatment of pulmonary arterial hypertension

N Engl J Med

Long-term outcome with first-line bosentan therapy in idiopathic pulmonary arterial hypertension

Eur Heart J

Roles of endothelin ETA and ETB receptors in the pathogenesis of monocrotaline-induced pulmonary hypertension

J Cardiovasc Pharmacol

Original Research
Pulmonary Arterial Hypertension
Sitaxsentan for the Treatment of Pulmonary Arterial Hypertension: A 1-Year, Prospective, Open-Label Observation of Outcome and Survival