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Published on 17 August 2010

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Bosentan for treatment of pulmonary arterial hypertension

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This article reviews the pathophysiology and epidemiology of pulmonary arterial hypertension (PAH) and agents for the treatment of PAH, including the endothelin-1 antagonist bosentan

Eric Kerkhove
PharmD
Pharmacy Practice Resident
Immanuel Medical Center, Omaha
USA

Mikayla Spangler
PharmD BCPS
Assistant Professor Department of
Pharmacy Practice
Omaha, USA

Shailendra K Saxena
MD PhD
Assistant Professor Department of Family Medicine
Omaha, USA

Birgit Khandalavala
MD
Assistant Professor Department of Family Medicine
Creighton University School of Medicine
Omaha, USA

Bosentan is an endothelin-receptor antagonist, indicated for the treatment of pulmonary arterial hypertension (PAH) with WHO class II to IV symptoms (see Table 1). PAH affects one to five persons per one million in Europe.[1] PAH may be idiopathic in nature, or secondary to underlying disease states. PAH is defined as a mean pulmonary artery pressure >25mm Hg at rest and a pulmonary wedge pressure <15mm Hg measured by cardiac catheterisation. Signs and symptoms are highly variable.
Patients with PAH commonly present with signs of exertional dyspnea, angina, fatigue and orthopnea. Signs of disease progression include dyspnea at rest, leg swelling, anorexia and plethora. Doppler echocardiography can be used as a noninvasive screening test or to follow disease progression. Right-heart catheterisation is the gold standard for diagnosis of PAH and can also assess for pulmonary reactivity, guiding treatment options. Patients should be evaluated for chronic pulmonary embolism through the use of ventilation perfusion lung scans. Exercise capacity in patients with PAH can be assessed through testing 6-minute walk distance (6MWD). Serial monitoring of the 6MWD is a useful indicator of disease progression or treatment efficacy.
PAH involves several molecular events, including hypertrophy, fibrosis, inflammation, constricting factors, loss of relaxing factors and a pro-coagulant state. Multiple biological mediators contribute to these molecular events, resulting in PAH. These changes are mediated by nitric oxide (NO), prostacyclin (PGI2), serotonin (5-HT) and endothelin-1 (ET-1). ET-1 is a potent vasoconstrictor acting via the endothelin receptors ETa (resulting in vasoconstriction and sodium retention) and ETb (resulting in NO release, natriuresis and dieresis). ET-1’s action results in smooth muscle proliferation and vasoconstriction. Levels of ET-1 are increased in persons with PAH and correlate with the severity of disease and overall prognosis.1
Treatment is aimed at alleviating symptoms, increasing quality of life and preventing disease progression.[2,3] Although improvement in survival is important, many patients initially present with advanced disease and may only achieve short-term mortality reductions. Patients who are less severely ill may have better outcomes, but this has yet to be substantiated in clinical trials. Current treatment options include supplementing endogenous vasodilators, inhibiting endogenous vasoconstrictors and limiting the risk for thrombosis.[2,3] Anticoagulation is recommended in patients with PAH due to the increased risk factors for thrombosis in these patients (ie, right-sided heart failure, sedentary lifestyle and increased thrombotic markers). In patients who have undergone right-sided heart catheterisation that have a high degree of vasoreactivity, calcium channel blockers (CCBs) are the treatment of choice. Between 5–10% of patients will show a benefit with CCBs. Dihydropyridine CCBs are the favoured class, as they lack negative inotropic effects. Phosphodiesterase-5 inhibitors such as sildenafil have been shown to be beneficial in PAH at increasing vasodilation and decreasing cellular proliferation. PGI2 analogues are strong vasodilators of all vascular beds. They are also potent inhibitors of platelet aggregation and possess antiproliferative activity. Finally, endothelin antagonists are used to reverse activation of the ET-1 symptoms, preventing vasoconstriction and cellular proliferation. The purpose of this review is to evaluate the use of bosentan, an ET-1 antagonist active at both ETa and ETb.

Methods
A search of PubMed with the search terms ‘bosentan’ and ‘pulmonary hypertension’ was performed using the limit of clinical trials only and ages 19 and above. In addition, the National Guidelines Clearinghouse was accessed for recent guidelines pertaining to the treatment of PAH. Finally, the bibliographies of relevant guidelines were cross-referenced with the PubMed results. Twenty studies were identified in the literature, of which six are discussed below.

Discussion
The six studies identified were chosen for this review due to their double-blind, randomised nature, large sample size or patient-orientated primary outcomes. Other studies that were not included had smaller sample sizes, disease-orientated outcomes or open-label study design.
In a double-blind, placebo-controlled study by Channick et al,[4] 32 patients with WHO functional class III PAH were assigned to bosentan 62.5mg twice-daily for four weeks then 125mg twice-daily thereafter or placebo. This was the first randomised placebo-controlled study assessing chronic administration of bosentan for PAH. The 6MWD improved by 70 metres at 12 weeks in patients receiving bosentan compared to a decrease of 6 metres in placebo (difference of 76 metres [95% CI 0.6–1.4], p<0.0001). Patients receiving bosentan also had improved to WHO class II (43%) or remained in class III (57%). In patients receiving placebo, only one patient improved to WHO class II (9%), 73% remained in WHO class III and two patients deteriorated to class IV (18%). Bosentan had a significant effect on WHO functional class compared to placebo (p= 0.019). Adverse events were similar between groups.
The second relevant article was by Rubin et al[5] who conducted a double-blind, placebo-controlled study (BREATHE-1) with 213 patients with PAH (WHO class III and IV). The goal of BREATHE-1 was to evaluate bosentan’s effect on more severe disease (WHO class IV) and to evaluate the safety and efficacy of a higher dose (250mg twice-daily). The patients received placebo or bosentan 62.5mg twice-daily for four weeks followed by either bosentan 125mg or 250mg twice-daily for a minimum of 12 weeks. The 6MWD difference between placebo and the combined bosentan groups was 44 metres (95% CI, 21–67; p<0.001). Patients also experienced an increased time to clinical worsening with bosentan (p =0.002). The bosentan group had a dose-dependent effect on hepatic enzyme function compared to placebo. Compared to 2% in the placebo group, 4% of the 125mg group (p =1.0) and 14% of the 250mg bosentan group (p =0.03) had elevations in hepatic enzymes. This enzyme elevation was dose-dependent.
A case-control study comparing cohort data from bosentan clinical trials to historical data from similar patients treated with epoprostenol, a prostacyclin analogue also used to treat PAH, was completed by Sitbon et al.[6] The objective was to determine if starting therapy with bosentan negatively influenced long-term outcomes compared to initiating therapy with epoprostenol. The epoprostenol group had more severe disease compared to the bosentan cohort at baseline. Kaplan–Meier survival analysis of the two groups at one and two years were 97% and 91% for bosentan compared to 91 and 84% in epoprostenol (log rank, p=0.022).
In addition, retrospective data from patients treated with epoprostenol were matched with prospective bosentan patients using baseline haemodynamic data. Due to the epoprostenol group’s more severe disease at baseline, case-control matching rules were biased against the bosentan group. Unmatched bosentan patients with better haemodynamic variables were excluded while unmatched epoprostenol patients with worse haemodynamic variables were excluded. Kaplan–Meier survival analysis of the two matched case-control cohorts was nearly identical (HR 1.03; 95% CL (0.446, 2.114). After Cox regression analysis based on baseline haemodynamic differences between the two groups was performed, the hazard ratio between the two groups consistently favoured bosentan over epoprostenol. The authors concluded that initial therapy with bosentan did not adversely affect long- term outcomes in patients with PAH compared to epoprostenol.[6]
Provencher et al[7] conducted a retrospective long-term analysis evaluating 99 patients with PAH in New York Heart Association (NYHA) functional class III/IV treated with bosentan. The goal of this study was to evaluate the long-term efficacy of bosentan on patients not benefiting from the close follow-up seen during clinical trials. At four months, NYHA class improved in 48% of patients, remained stable in 42% and deteriorated in 9%. The 6MWD increased from 322+105 metres at baseline, to 364+109 metres at four months and remained stable at 12 months (p<0.001). At one year, six patients had died, nine had prostanoid therapy added to bosentan and one patient was lost to follow-up. In addition, 21 patients had not received a full year of bosentan at the study’s cut-off date. In these patients, their 6MWD had no further improvements from their four-month follow-up. Three patients required discontinuation due to abnormal hepatic function.

[[HPE51.26]]

The BENEFiT study[8] evaluated bosentan in 157 patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Mortality in patients with CTEPH is >50% at one year if untreated. Bosentan has shown promise in open-label studies in CTEPH, but this is the first double-blind, randomised, placebo-controlled study to evaluate its safety and efficacy. Patients with WHO class II, III or IV PAH were randomised 1:1 to bosentan or placebo. Patients receiving bosentan were given an initial dose of 62.5mg twice-daily for four weeks, increasing to 125mg twice-daily thereafter. The primary endpoints were change in pulmonary vascular resistance (PVR) and 6MWD from baseline to 16 weeks. Patients experienced a significant change in PVR of -24.1 % (95% CI -31.5 to -16%; p<0.0001). However, patients only experienced an increase of 2.2 metres 6MWD (p=0.5449). The authors concluded that while patients’ haemodynamics improved, lack of improvement in exercise capacity necessitates further study of bosentan in CTEPH.
Galie et al[9] conducted a study in patients with mildly symptomatic WHO functional class II PAH (the EARLY study). One hundred and eighty-five patients were enrolled in this double-blind, randomised controlled trial evaluating PVR and 6MWD at baseline and six months. At six months, patients in the bosentan group had a PVR of 83.2% of baseline, compared to 107.5% of baseline in the placebo group (treatment effect -22.6%, 95% CI -33.5 to -10; p<0.0001). The 6MWD decreased in the placebo group by 7.9 metres and increased in the bosentan group by 11.2 metres. Despite this difference, the treatment effect was not statistically significant (p=0.758). Bosentan was also associated with a delay in time to clinical worsening. However, 70% of patients experienced an adverse event (compared to 65% in placebo). The most common adverse events in the bosentan group were elevated liver function tests (13%) and nasopharyngitis (8%). The authors concluded that bosentan may be beneficial in WHO functional class II for maintaining functional class and patient haemodynamic parameters.
Bosentan’s safety and efficacy in PAH has been demonstrated in multiple retrospective and prospective studies. Its use as a first line agent compared to epoprostenol has been shown to be effective. Further areas of study include its place in therapy compared to other PAH therapies such as PDE-5 inhibitors, inhaled PGI2 analogues and selective ETa-1 antagonists. In addition, its place in combination therapy has yet to be ascertained.

Conclusion
Bosentan is an endothelin antagonist indicated for use in patients with WHO functional class II–IV. In clinical trials, bosentan improved or maintained WHO functional class and increased exercise capacity shown through increased 6MWD. Pulmonary haemodynamics and other markers of PAH disease status also improved. Bosentan is started at 62.5mg twice-daily for four weeks and can be titrated to 125mg or 250mg twice-daily. Elevated liver enzymes may require discontinuation or dose reduction. Liver function tests should be done at baseline and monthly thereafter. Bosentan is pregnancy category X and females of childbearing age should have monthly pregnancy testing and be advised to use back-up methods of birth control.

References
1. Deprio JT. Pharmacotherapy: a pathophysiological approach. New York: McGraw-Hill; 2008.
2. McLaughlin V et al. J Am Coll Cardiol 2009;53:1573–1619.
3. Badesch D et al. Chest 2007;131:1917–28.
4. Channick R et al. Lancet 2001;358:1119–23.
5. Rubin L et al. N Engl J Med 2002;346:896–903.
6. Sitbon O et al. Brit Med J 2005;60:1025–30.
7. Provencher S et al. Eur Heart J 2006;27:589–95.
8. Jais X et al. J Am Coll Cardiol 2008;52:2127–34.
9. Galie N et al. Lancet 2008;371:2093–2100.



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