ETA and AT1 Antagonism in ANCA-vasculitis (SPARVASC)
brief summary
ANCA-associated vasculitis is an autoimmune disease that causes damage to blood vessels. This leads to organ damage with the number of organs affected and the severity of damage varying significantly between patients. Vasculitis patients also have a very high risk of heart attacks and strokes, called cardiovascular disease. A chemical called 'endothelin', produced by the blood vessels, causes vessels to stiffen and raises blood pressure and this associates with cardiovascular risk. The investigators have previously shown that by blocking the effects of endothelin you reduce vessel stiffness, lower blood pressure and improve vessel function. However, these studies only blocked endothelin for a few hours. Now, the investigators would like to see if it is possible to maintain these benefits by blocking endothelin for longer. Sparsentan is a tablet that blocks endothelin and lowers blood pressure. The investigators plan to give sparsentan to patients with vasculitis for 6 weeks. To determine if any beneficial effects of sparsentan are due to blood pressure lowering the investigators will give another group of vasculitis patients a tablet called irbesartan which lowers blood pressure but does not block endothelin. The investigators will compare the results between the two groups.
detailed description
ANCA-associated vasculitis is an autoimmune disease that causes direct damage to the vascular endothelium. Recent improvements in the immunosuppressive drugs used have improved short term outcomes but this has not translated to improved longer term outcomes. This is largely due to the significantly increased rates of cardiovascular disease experienced by this group of patients. For vasculitis patients in long-term remission the commonest cause of death is cardiovascular disease.
Autoimmune damage to the endothelium causes endothelial dysfunction and this associates with future risk of cardiovascular disease.
Endothelin-1 is a peptide produced by the endothelium. It is the most potent endogenous vasoconstrictor. It raises blood pressure, causes arterial stiffness and endothelial dysfunction, impairs fibrinolytic capacity and is pro-inflammatory.
Previous work has demonstrated that short term blockade of endothelin receptors improves vessel stiffness and fibrinolytic capacity.
The investigators will conduct a randomised, double blind, active control, parallel group study. 40 patients with ANCA-associated vasculitis in long-term remission will be recruited. 20 will be treated with 6 weeks of the endothelin-A receptor and angiotensin-1 receptor blocker sparsentan and 20 will be treated with the angiotensin-1 receptor blocker irbesartan.
Patients will undergo a forearm blood flow study before and after 6 weeks of treatment. This will assess endothelial function and allow the investigators to assess if the improvement in endothelial function noted with short term endothelin receptor blockade previously is maintained longer term.
official title
Effects of Simultaneous ETA & AT1 Receptor Antagonism on Endothelial Function & Vascular Stiffness in ANCA-associated Vasculitis (SPARsentan in VASCulitis - SPARVASC)