Researchers Evaluate the Effect of Ambrisentan on Digital Blood Flow in Patients with Systemic Sclerosis using Laser Doppler Perfusion Imaging

Researchers from the Hunter Holmes McGuire VA Medical Center, Richmond, VA, and the Department of Rheumatic and Immunologic Diseases, Orthopedics and Rheumatology Institute, Cleveland Clinic, OH, have recently released results from a clinical trial that evaluated the use of ambrisentan, a selective endothelin type A receptor antagonist, on increasing blood flow in patients with limited systemic sclerosis (SSc) using laser Doppler perfusion imaging (LDPI).  The study entitled “Evaluation of the effect of ambrisentan on digital microvascular flow in patients with systemic sclerosis using laser doppler perfusion imaging: a 12-week randomized double-blind placebo controlled trial,” was published March 5^th in the on-line edition of Arthritis Research & Therapy.

Background Terminology:

• Ischemia: is a restriction in blood supply to tissues that causes a shortage of oxygen and glucose that the tissues need to stay alive. It is most often caused by problems with blood vessels, resulting in damage to or dysfunction of tissue
• Vasodilators: is the the widening of blood vessels that allows for an increase in blood flow to the surrounding tissues.
• Endothelin type A receptor antagonist (ETA-antagonists): drugs that block the vasoconstricting properties of Endothelin type A (ETA) causing vasodilation and increased blood flow
• Laser doppler perfusion imaging (LDPI): imaging technique that gives a direct measure of the circulation of the blood in the smallest blood vessels, known as capillaries

RP is a condition (not a disease) that is characterized as a loss of blood flow (vasoconstriction) to the extremities.  The patients will most often times notice their fingers and/or toes becoming white or blue when they are cold leading to a tingling and numbing sensation, and in severe cases a complete loss of feeling. This condition affects women more often than men (5 to 1).  When the condition occurs without any underlying cause it is known as primary RP, otherwise when it is accompanied by another medical condition it is referred to as secondary RP.  For the 100,000 patients who are diagnosed with scleroderma in the US, secondary RP is a condition that 90% struggle with.

Current treatments are only marginally effective in reducing the ischemia caused by RP in SSc patients. Previous research has shown that ETA-antagonists may have an effect on the vascular disease caused by RP.

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About the Study:

In this study, researchers chose a particular ETA-antagonist, ambrisentan, to test whether significant improvement in vascular blood flow to the digits would be observed if used to treat the effects of secondary RP in a sample of SSc patients.

They enrolled 20 patients with limited SSc and put them in the following treatment groups:

• 15 patients received ambrisentan 5 mg daily for 1 month and then 10 mg daily for 2 months
• 5 received a placebo

Each patient had 3 clinic visits: baseline, 1 week, and 12 weeks.  At each visit Participants filled out three questionnaires: Scleroderma-Health Assessment Questionnaire (S-HAQ), Raynaud Condition Score (RCS), and Pain-Visual Analog Scale (P-VAS); and LDPI was used to obtain blood flow measurements of the digits.

The results of this study showed that there were no significant differences in improved blood flow to the digits, associated with the continuous use of ambrisentan for 3 months in comparison to a placebo.  There was however differences in patients perceived disease severity, measured from their answers to the RCS and S-HAQ scores.  To these patients there was a feeling of improvement while in the study.

In discussing their findings the authors wrote, “The discrepancy between the lack of improvement in blood flow and improvement in the RCS and S-HAQ scores remains unexplained, but suggests that these subjective measures of symptomatic improvement of Raynaud phenomenon and of functional status may not be entirely mediated through reversal of digital ischemia, but possibly through other factors such as improvement in hand function and overall quality of life. This decoupling might be perceived to hint at some off target effects of ambrisentan not involving vasodilatory or anti proliferative pathways.”