From the Guidelines
The recommended treatment for pulmonary arterial hypertension (PAH) involves a multifaceted approach tailored to disease severity, with initial therapy typically including calcium channel blockers for vasoreactive patients, and most patients requiring PAH-specific medications such as phosphodiesterase-5 inhibitors, endothelin receptor antagonists, prostacyclin analogs, or soluble guanylate cyclase stimulators, as outlined in the 2019 Chest guideline update 1.
Treatment Approach
The treatment approach for PAH is guided by the severity of the disease and the patient's response to initial therapy. The following medications are commonly used:
- Phosphodiesterase-5 inhibitors: sildenafil (20 mg every 8 h) and tadalafil (40 mg once daily) 1
- Endothelin receptor antagonists: bosentan (125 mg twice daily), ambrisentan (5 or 10 mg once daily), and macitentan (10 mg once daily) 1
- Prostacyclin analogs: epoprostenol (2 ng/kg/min IV infusion), treprostinil (0.25 mg bid or 0.125 mg tid oral, or 18-54 mg inhaled 4 times daily), and iloprost (2.5 or 5.0 mg inhaled 6-9 times daily) 1
- Soluble guanylate cyclase stimulators: riociguat (0.5-1.0 mg every 8 h oral) 1
Combination Therapy
Combination therapy is often necessary, with many patients starting on dual therapy with an endothelin receptor antagonist plus a phosphodiesterase-5 inhibitor. The choice of combination therapy depends on the patient's disease severity, response to initial therapy, and tolerability of the medications.
Supportive Measures
Supportive measures include:
- Diuretics for fluid management
- Oxygen supplementation for hypoxemia
- Anticoagulation in selected cases
- Pulmonary rehabilitation, which may improve exercise capacity and quality of life in patients with PAH, as suggested by the 2013 American Thoracic Society/European Respiratory Society statement 1
Advanced Disease
For advanced disease unresponsive to medical therapy, lung transplantation may be considered. Treatment aims to reduce pulmonary vascular resistance, improve right ventricular function, enhance exercise capacity, and ultimately improve survival by targeting the underlying pathophysiological mechanisms of vasoconstriction, cellular proliferation, and vascular remodeling that characterize PAH.
From the FDA Drug Label
Treprostinil is indicated for the treatment of pulmonary arterial hypertension (PAH; WHO Group 1) to diminish symptoms associated with exercise Ambrisentan tablets are indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1): To improve exercise ability and delay clinical worsening. Epoprostenol for injection is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise capacity.
The recommended treatments for pulmonary arterial hypertension are:
- Treprostinil (SQ): to diminish symptoms associated with exercise 2
- Ambrisentan (PO): to improve exercise ability and delay clinical worsening 3
- Epoprostenol (IV): to improve exercise capacity 4
From the Research
Treatment Options for Pulmonary Arterial Hypertension
The treatment for pulmonary arterial hypertension (PAH) typically involves a combination of medications and lifestyle changes. Some of the recommended treatment options include:
- Endothelin receptor antagonists (ERAs) such as bosentan, ambrisentan, and macitentan 5, 6, 7
- Phosphodiesterase-5 inhibitors (PDE-5 inhibitors) such as sildenafil, tadalafil, and vardenafil 5, 8
- Prostacyclin analogs such as epoprostenol, treprostinil, and iloprost 5, 9
Clinical Practice Guidelines
Clinical practice guidelines recommend oral endothelin receptor antagonist or phosphodiesterase inhibitor therapy in mild to moderate PAH 5. Epoprostenol is specifically suggested as first-line therapy in moderate to severe PAH patients (ie, World Health Organization/New York Heart Association functional class III-IV) 5, 9. However, treprostinil may be an alternative option in these severe PAH patients 5.
Pharmacokinetics and Drug Interactions
The pharmacokinetics of bosentan, a dual endothelin receptor antagonist, have been studied in healthy subjects and patients with PAH 6. The drug is approximately 98% bound to albumin and has a terminal half-life of 5.4 hours. Bosentan is mainly eliminated from the body by hepatic metabolism and subsequent biliary excretion of the metabolites. The pharmacokinetics of bosentan are dose-proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) 6. A study has also developed a LC-MS method to determine the concentrations of five PAH drugs (PDE-5 inhibitors: sildenafil and tadalafil, ERAs: bosentan, macitentan, and ambrisentan) from plasma samples 8.
Evidence-Based Pharmacologic Management
A review of the available information on PAH, including its pathophysiology, classification of its severity, current treatment options, drug interactions, pharmacokinetics, and cost considerations, has been published 9. The results of clinical trials of the available treatments are summarized, and a suggested treatment algorithm is provided as a guide to the medical management of PAH. The review suggests that oral therapies such as sildenafil and bosentan have been effective in patients with mild to moderate symptoms, while infusions of the prostacyclin analogues epoprostenol and treprostinil appear to be the treatment of choice for moderate to severe PAH 9.