What is Pulmonary Arterial Hypertension (PAH)?

From the Guidelines

Pulmonary arterial hypertension (PAH) should be treated with a combination of medications targeting different pathways, with first-line therapy often including phosphodiesterase-5 inhibitors or endothelin receptor antagonists, and supportive care including oxygen therapy, diuretics, and anticoagulation in selected cases, as recommended by the most recent guidelines 1. The treatment of PAH typically involves a combination of medications, including:

• Phosphodiesterase-5 inhibitors like sildenafil (20mg three times daily) or tadalafil (40mg once daily)
• Endothelin receptor antagonists such as ambrisentan (5-10mg daily) or bosentan (62.5mg twice daily for 4 weeks, then 125mg twice daily) For more severe cases, prostacyclin analogs like epoprostenol (continuous IV infusion starting at 2ng/kg/min and gradually increased) or treprostinil (subcutaneous or IV) may be necessary 1. Supportive care includes:
• Oxygen therapy for hypoxemia
• Diuretics for fluid retention
• Anticoagulation in selected cases Regular follow-up with a PAH specialist is essential, including:
• Echocardiograms
• 6-minute walk tests
• Right heart catheterizations to monitor disease progression These medications work by promoting vasodilation, preventing vascular remodeling, and improving cardiac output. Early diagnosis and aggressive treatment are crucial as PAH causes progressive right ventricular dysfunction through increased pulmonary vascular resistance, ultimately leading to right heart failure if not properly managed 1. The clinical classification of PAH has been simplified and now includes group 1, PAH; group 2, PH due to left heart disease; group 3, PH due to lung diseases and/or hypoxia; group 4, PH due to PA obstructions; and group 5, PH with unclear and/or multifactorial mechanisms 1. The diagnosis of PAH remains challenging due to its nonspecific symptoms, and a careful history evaluation is critical to evaluate for risk factors for PAH, including family history, history of drugs and toxins associated with PAH 1.

From the FDA Drug Label

Two 12-week, randomized, double-blind, placebo-controlled, multicenter studies were conducted in 393 patients with PAH (WHO Group 1).

The primary study endpoint was 6-minute walk distance.

In both studies, treatment with ambrisentan resulted in a significant improvement in 6-minute walk distance for each dose of ambrisentan and the improvements increased with dose.

Pulmonary Arterial Hypertension (PAH) treatment with ambrisentan resulted in a significant improvement in 6-minute walk distance.

• The improvements increased with dose.
• An increase in 6-minute walk distance was observed after 4 weeks of treatment with ambrisentan, with a dose-response observed after 12 weeks of treatment.
• Improvements in walk distance with ambrisentan were smaller for elderly patients (age ≥65) than younger patients and for patients with secondary PAH than for patients with idiopathic or heritable PAH. 2

From the Research

Definition and Prevalence of Pulmonary Arterial Hypertension

• Pulmonary arterial hypertension (PAH) is a subtype of pulmonary hypertension (PH), characterized by pulmonary arterial remodeling 3.
• The prevalence of PAH is approximately 10.6 cases per 1 million adults in the US 3.
• PAH is hemodynamically defined by right heart catheterization demonstrating a mean pulmonary artery pressure greater than 20 mm Hg, a pulmonary artery wedge pressure of 15 mm Hg or lower, and a pulmonary vascular resistance of 3 Wood units or greater 3.

Symptoms and Treatment of Pulmonary Arterial Hypertension

• Early presenting symptoms of PAH are nonspecific and typically consist of dyspnea on exertion and fatigue 3.
• Currently approved therapy for PAH consists of drugs that enhance the nitric oxide-cyclic guanosine monophosphate biological pathway, prostacyclin pathway agonists, and endothelin pathway antagonists 3.
• Combination drug therapy that targets more than one biological pathway has shown demonstrable improvement in morbidity and mortality compared with single-pathway targeted monotherapy 3, 4.

Emerging Therapies and Treatment Algorithms

• Emerging therapies and new directions in the treatment of PAH include the introduction of sotatercept as a second-line therapy, leading to a revised definition of maximal medical therapy 5.
• The treatment algorithm for PAH has been updated to include agents from four therapeutic groups: phosphodiesterase-5 inhibitors/soluble guanylate cyclase stimulators, endothelin receptor antagonists, prostacyclin pathway agents, and sotatercept 5.
• Other updates include the elimination of a distinct pathway for patients with cardiopulmonary comorbidities in favor of an individualized approach, and a reduction in the initial patient assessment risk categories from three to two 5.

Drug Quantification and Combination Therapy

• Combination treatment with endothelin receptor antagonists (ERA) and phosphodiesterase 5 inhibitors (PDE5I) has improved efficacy of PAH therapy, but drug-drug interactions and variable exposure can influence plasma levels 6.
• A method for the simultaneous quantification of ERA and PDE5I in human plasma has been developed, allowing for the assessment of trough drug and metabolite levels in PAH patients 6.
• The combination of ERA and PDE5I has been shown to be beneficial in PAH treatment, with macitentan and bosentan being potent antagonists of vasoconstriction in pulmonary arteries 4.