MICA: Prevention of Aortic Stenosis (PAS) Pilot Trial

We plan to conduct a pilot randomised placebo controlled double-blind cross-over trial to determine whether sevelamer lowers serum phosphate in patients with aortic stenosis.

Aortic stenosis is a serious heart condition with no known means of prevention. It is caused by progressive deposition of calcium phosphate crystals on the aortic valve, leading to obstruction of blood flow from the heart. Death follows symptoms of cardiac insufficiency in most cases unless the valve is surgically replaced. About 1.3 million people over age 75 have aortic stenosis in the UK, about one quarter of whom are severely affected. This number is expected to double over the next few decades as the population ages. There is a need for a preventive treatment.

The phosphate binding drug, sevelamer, reduces blood phosphate by blocking dietary absorption. Treatment is licensed in patients with kidney failure to lower the high phosphate (2-3 x physiological levels) which results from failed renal excretion and leads to bone disease. Treatment reduces calcium phosphate, raising the possibility of extending its use in the prevention of aortic stenosis, by slowing or arresting valve calcification, in all people with the disorder. It is not known whether sevelamer lowers serum phosphate in patients with aortic stenosis whose phosphate levels are within the physiological range.

In the proposed pilot trial, sevelamer, at low dose (2.4g/day) and high dose (7.2g/day) will be compared with placebo in 72 patients with aortic stenosis. The cross-over design (each person is their own control) provides the statistical power to assess efficacy in lowering phosphate with few subjects and the 2 doses allow the trade-off between efficacy and tolerability to be assessed. The study will be double-blind; neither the participants nor the investigators will know whether the placebo or the sevelamer is being taken or at what dose, until the end of the study, allowing an unbiased comparison of the treatments.

The pilot study, in addition to assessing efficacy and acceptability, will also develop the recruitment pathways for a definitive trial, to assess the effect of sevelamer on the progression of aortic stenosis, with a view to repurposing this drug for the prevention of aortic stenosis in the population.

We plan to conduct a pilot randomised placebo controlled double-blind cross-over trial to determine whether sevelamer lowers serum phosphate in patients with aortic stenosis.

Aortic stenosis is a serious heart condition with no known means of prevention. It is caused by progressive deposition of calcium phosphate crystals on the aortic valve, leading to obstruction of blood flow from the heart. Death follows symptoms of cardiac insufficiency in most cases unless the valve is surgically replaced. About 1.3 million people over age 75 have aortic stenosis in the UK, about one quarter of whom are severely affected. This number is expected to double over the next few decades as the population ages.

The phosphate binding drug, sevelamer, reduces blood phosphate by blocking dietary absorption. Treatment is licensed in kidney failure to lower the high phosphate (2-3 x physiological levels) which results from failed renal excretion and leads to bone disease. Treatment reduces calcium phosphate, raising the possibility of extending its use in the prevention of aortic stenosis, by slowing or arresting valve calcification, in all people with the disorder. It is not known whether sevelamer lowers serum phosphate in patients with aortic stenosis whose phosphate levels are within the physiological range.

In the proposed pilot trial, sevelamer, at low dose (2.4g/day) and high dose (7.2g/day) will be compared with placebo in 72 patients with aortic stenosis. The cross-over design (each person is their own control) provides the statistical power to assess efficacy in lowering phosphate with few subjects and the 2 doses allow the trade-off between efficacy and tolerability to be assessed.

The pilot study, in addition to assessing efficacy, will also develop the recruitment pathways for a definitive trial, to assess the effect of sevelamer on the progression of aortic stenosis, with a view to repurposing this drug for the prevention of aortic stenosis in the population.

The proposed pilot study is a first step to determine whether sevelamer is effective in lowering serum phosphate in patients with aortic stenosis, and the effect of dose. If the results are favourable, this would pave the way for a definitive trial to determine whether sevelamer reduces the progression of aortic stenosis.

The ultimate aim is the prevention of aortic stenosis and its serious clinical consequences. Patients with aortic stenosis would, therefore, be the principal beneficiaries. Reducing the need for aortic valve surgery also has health economic benefits, given that this is an expensive and the most commonly performed surgical valve procedure (67,500 open heart operations were performed in the USA last year).

There would be a commercial impact. Even though sevelamer has recently become a generic drug, which has resulted in substantial reductions in drug cost, its use in patients with aortic stenosis would broaden the market substantially (an estimated 7 million affected individuals in the USA and EU) and represent a new indication for its use.

There is a potential public health impact, if a safe and effective preventive treatment were available because this would open the door to screening for aortic stenosis, which affects about 12% of people over age 75, with a view to prevention at a population level.