What is the relationship between Ambrisentan (Endothelin receptor antagonist) and fluid retention?

From the Guidelines

Ambrisentan is associated with an increased incidence of peripheral edema, a form of fluid retention, as a common side effect. This medication, used to treat pulmonary arterial hypertension (PAH), works by blocking endothelin receptors, which helps dilate blood vessels in the lungs but can lead to peripheral edema in patients [ 1 ]. The fluid retention typically manifests as swelling in the ankles, feet, and legs, and may also contribute to weight gain. Patients taking ambrisentan should monitor for signs of worsening edema, rapid weight gain, or increasing shortness of breath, as these could indicate serious fluid retention requiring medical attention [ 1 ].

Management of Fluid Retention

To manage this side effect, healthcare providers may recommend:

• Limiting salt intake
• Elevating the legs when sitting
• Wearing compression stockings
• In some cases, adding a diuretic like furosemide 20-40 mg daily Dose adjustment of ambrisentan (typically available as 5 mg or 10 mg tablets) may be necessary if fluid retention becomes severe. The fluid retention occurs because endothelin receptor antagonists like ambrisentan affect sodium and water balance in the body, particularly through their effects on the kidneys and vascular permeability [ 1 ].

Key Considerations

It is essential to note that while ambrisentan can cause fluid retention, the incidence of this side effect may vary among different endothelin receptor antagonists [ 1 ]. Regular monitoring and management of fluid retention are crucial to minimize its impact on patients' quality of life and morbidity.

From the FDA Drug Label

5.3 Fluid Retention Peripheral edema is a known class effect of endothelin receptor antagonists, and is also a clinical consequence of PAH and worsening PAH. In the placebo-controlled studies, there was an increased incidence of peripheral edema in patients treated with doses of 5 or 10 mg ambrisentan compared to placebo [see Adverse Reactions (6. 1)]. Most edema was mild to moderate in severity. In addition, there have been postmarketing reports of fluid retention in patients with pulmonary hypertension, occurring within weeks after starting ambrisentan. Patients required intervention with a diuretic, fluid management, or, in some cases, hospitalization for decompensating heart failure If clinically significant fluid retention develops, with or without associated weight gain, further evaluation should be undertaken to determine the cause, such as ambrisentan or underlying heart failure, and the possible need for specific treatment or discontinuation of ambrisentan therapy.

The relationship between Ambrisentan and fluid retention is that Ambrisentan may cause fluid retention, as it is a known class effect of endothelin receptor antagonists. Key points include:

• Increased incidence of peripheral edema in patients treated with Ambrisentan compared to placebo
• Most edema was mild to moderate in severity
• Postmarketing reports of fluid retention in patients with pulmonary hypertension, occurring within weeks after starting Ambrisentan
• Patients may require intervention with a diuretic, fluid management, or hospitalization for decompensating heart failure if clinically significant fluid retention develops 2

From the Research

Relationship between Ambrisentan and Fluid Retention

• Ambrisentan, an endothelin receptor antagonist, has been associated with fluid retention, particularly peripheral edema, in patients with pulmonary arterial hypertension (PAH) 3, 4, 5, 6.
• In the ARIES-1 and ARIES-2 studies, edema-related adverse events were reported in 23% of patients treated with ambrisentan, compared to 14% of patients in the placebo group 3.
• Patients with edema tended to have a worse baseline World Health Organization (WHO) functional class and were older and heavier than those without edema 3.
• The incidence of peripheral edema, a common side effect of ambrisentan, was reported to be around 17% in clinical trials 6.
• In a real-world study, oedema was the most common side effect leading to cessation of ambrisentan therapy, occurring in 7% of patients 5.

Clinical Implications

• Despite the association with fluid retention, ambrisentan has been shown to provide clinical benefits in patients with PAH, including improved exercise capacity and reduced brain natriuretic peptide levels 3, 4, 7.
• The drug is generally well tolerated, with a low risk of liver function abnormalities 7, 6.
• However, patients should be monitored for signs of fluid retention, and the drug should be used with caution in patients with a history of edema or other conditions that may increase the risk of fluid retention 5, 6.