Pulmonary Arterial Hypertension (PAH)

Excessive vasoconstriction and excessive cellular proliferation play important roles in the pathogenesis of pulmonary arterial hypertension (PAH). Endothelin-1 (ET-1) is a potent vasoconstrictor that also promotes the proliferation of pulmonary artery smooth muscle cells. Patients with PAH have elevated levels of plasma ET-1, which correlate with disease severity and prognosis. Furthermore, the clearance of ET-1 in the pulmonary vasculature is reduced in patients with PAH.1 Bosentan was the first endothelin receptor antagonist (ERA) to be approved by the US Food and Drug Administration (FDA) in 2001.2 Ambrisentan and macitentan gained FDA approval in 2007 and 2013, respectively.3,4

Letairis (Ambrisentan)

Letairis® (ambrisentan) is an FDA-approved ERA indicated for the treatment of patients with PAH in World Health Organization (WHO) group 1 with WHO class II or III symptoms to improve exercise capacity and delay clinical worsening. It comes in 5- and 10-mg unscored, film-coated tablets.3 The efficacy of Letairis was demonstrated in two 12-week randomized, double-blind, placebo-controlled, multicenter studies (ARIES-1 and ARIES-2)5 in 393 patients with PAH in WHO group 1. Patients were assigned either placebo, 5 mg, or 10 mg of Letairis in ARIES-1 and either placebo, 2.5 mg, or 5 mg of Letairis in ARIES-2. Changes in 6-minute walk distance were measured at week 12, which showed significant improvements in all patients treated with Letairis compared to those given placebo. There was also a significant delay in the time to clinical worsening in the Letairis group. Clinical worsening was reported in 3% of patients in the Letairis group and 10% in the placebo group (hazard ratio [HR], 0.28; P =.044) in ARIES-1. In ARIES-2, 6% of patients administered Letairis experienced clinical worsening vs 22% of those given placebo (HR, 0.3; P =.006).3 

The recommended dosage of Letairis is 5 mg once a day with or without food. The dose may be increased to 10 mg if 5 mg is well tolerated. Common adverse reactions include peripheral edema, nasal congestion, sinusitis, flushing, palpitations, nasopharyngitis, abdominal pain, and constipation. Severe adverse events include serious liver injury. Monthly monitoring is recommended, and treatment should be discontinued if liver aminotransferases exceed 5 times the upper limit of normal (ULN), bilirubin is more than 2 times the ULN, or there are signs and symptoms of liver dysfunction. Monitoring hemoglobin levels at 1 month and periodically thereafter is also recommended, as Letairis may cause anemia. Decreased sperm count has also been reported in patients taking endothelin receptor antagonists. Letairis is completely contraindicated during pregnancy because it can cause fetal harm, and patients should be put on adequate contraception during treatment. It is recommended that patients measure hemoglobin at the initiation of treatment within 1 month and periodically thereafter due to decreases in hemoglobin observed among patients. Also, fluid retention may require intervention.3   

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Tracleer (Bosentan)

Tracleer® (bosentan) is an FDA-approved, dual ERA for type A and B receptors indicated for the treatment of patients with PAH in WHO group 1 to improve exercise ability and decrease clinical worsening.2,6 It comes in 62.5- and 125-mg tablets. The efficacy of Tracleer was established in 2 randomized, double-blind, placebo-controlled, multicenter studies (BREATHE-1 and Study 351). BREATHE-1 compared twice daily doses of 125 mg and 250 mg of Tracleer vs placebo, and Study 351 compared twice daily doses of 125 mg of Tracleer vs placebo. In both trials, Tracleer resulted in significant increases in exercise ability as measured by 6-minute walk distance at 3 months (Study 351) or 4 months (BREATHE-1). Study 351 demonstrated that treatment with Tracleer also resulted in an increased cardiac index and reductions in pulmonary arterial pressure, pulmonary vascular resistance, and mean right atrial pressure. The time to clinical worsening was also significantly prolonged in patients treated with Tracleer in BREATH-1 (6% vs 20% in the placebo group [P =.0015]) and Study 351 (0% vs 27% in the placebo group [P =.033]).2

The recommended dose of Tracleer is 62.5 mg twice daily with or without food for 4 weeks, followed by an increase to 125 mg twice daily. Patients over the age of 12 years weighing <40kg are kept at a maintenance dose of 62.5mg. Common adverse reactions include respiratory tract infection and anemia. Tracleer is contraindicated during pregnancy and in patients with a hypersensitivity to Tracleer, and it should not be used in patients receiving cyclosporine A or glyburide. Liver transaminases should be measured prior to initiating therapy and monitored monthly. Treatment should be discontinued if transaminases are elevated and accompanied by elevated bilirubin (>2x ULN) or signs and symptoms of liver injury or dysfunction.2 

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Opsumit (Macitentan)

Opsumit® (macitentan) is a dual ERA indicated for the treatment of patients with PAH in WHO group 1 to reduce the risks of disease progression and hospitalization for PAH. It comes in 10-mg tablets, with a recommended dose of 10 mg once daily.4 The effect of macitentan on the progression of PAH was demonstrated in a multicenter, long-term, placebo-controlled study in 742 patients with symptomatic PAH in WHO functional classes II-IV.7 Treatment with Opsumit resulted in a 45% reduction (HR, 0.55; 97.5% CI, 0.39-0.76; P <.0001) in the occurrence of the primary study endpoint, which was time to the first occurrence of death, a significant morbidity event (defined as atrial septostomy, lung transplantation, or initiation of intravenous or subcutaneous prostanoids), or “other worsening of PAH.” The risk of PAH-related death or hospitalization was reduced by 50% in the Opsumit group compared to that in the placebo group (HR, 0.50; 97.5% CI, 0.34-0.75; P <.0001).4

Opsumit is completely contraindicated during pregnancy, and patients should be put on adequate contraception during treatment. The most common adverse reactions are anemia, nasopharyngitis/pharyngitis, bronchitis, headache, influenza, and urinary tract infection. Opsumit is associated with hepatotoxicity and liver failure. Baseline liver enzymes should be monitored as clinically indicated.4

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1. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation. 2009;119(16):2250-2294. doi:10.1161/CIRCULATIONAHA.109.192230

2. Tracleer. Prescribing information. Actelion Pharmaceuticals US, Inc.; 2016. Accessed May 10, 2022.

3. Letairis. Prescribing information. Gilead Sciences, Inc.; 2009. Accessed May 10, 2022.

4. Opsumit. Prescribing information. Actelion Pharmaceuticals US, Inc.; 2019. Accessed May 10, 2022.

5. ARIES – ambrisentan in patients with moderate to severe pulmonary arterial hypertension (PAH). ClinicalTrials.gov. September 14, 2004. Updated March 8, 2010. Accessed May 10, 2022.

6. Yaghi S, Novikov A, Trandafirescu T. Clinical update on pulmonary hypertension. J Investig Med. 2020;68(4):821-827. doi:10.1136/jim-2020-001291

7. Study of macitentan (ACT-064992) on morbidity and mortality in patients with symptomatic pulmonary arterial hypertension (SERAPHIN). ClinicalTrials.gov. April 17, 2008. Updated September 28, 2015. Accessed May 10, 2022.

Reviewed by Debjyoti Talukdar, MD, on 5/26/2022.