IcoSApent ethyL to slow down aortic VAlve stenosis proGrEssion

Aortic valve stenosis (AVS) is the most prevalent form of valvular heart
disease in developed countries. Due to changing demographics, the incidence is
expected to rise considerably over the next decades. AVS is characterized by a
long asymptomatic period, in which valvular fibrosis and calcification occurs,
but subsequent dysfunction of the valve often remains undetected. Once stenosis
becomes severe, it may lead to clinical manifestations including angina, heart
failure, or syncope. For symptomatic severe AVS, the only treatment option is
surgical or transcatheter valve replacement. Therefore, medical treatment to
slow down the progression of AVS is a large unmet clinical need.

The pathophysiology of AVS has long been considered degenerative, but in recent
years it has become clear that development and progression of AVS is an active
disease process. Current understanding is that its pathophysiology consists of
two stages; an initiation phase of aortic valve sclerosis, akin to
atherosclerosis, where traditional cardiovascular risk factors such as
LDL-cholesterol (LDL-c), obesity and diabetes mellitus play a role. Once a
certain degree of valve sclerosis, stiffening and microcalcification has
developed, a second propagation stage sets in where progressive valve
dysfunction and shear stress lead to accelerated macrocalcification and further
stenosis. Nevertheless, statins, the quintessential class of
anti-atherosclerotic medication were ineffective in slowing down disease
progression among patients with moderate AVS. It is hypothesized that this was
caused by the fact that the typical patient population to be targeted in AVS
trials, i.e. those with mild to moderate AVS detected as an incidental finding
during echocardiography that is performed for other reasons, is already in the
second stage of progressive calcification where lipid-lowering therapies are no
longer able to modify disease progression. In order to be effective in this
disease stage, treatment strategies should target the progressive
procalcification pathways ensuing in the aortic valve. Until now, no such
treatment exists.

Genetic association studies have identified the rs174547 variant at the FADS1/2
locus as a potentially causal risk factor for AVS. FADS1 and FADS2 encode
enzymes that regulate desaturation steps in both *-3 and *-6 fatty acid
metabolism. In the *-6 pathway, these steps lead to the formation of
arachidonic acid (AA), a precursor of a range of proinflammatory mediators such
as tromboxanes, prostaglandins, and leukotrienes. In the *-3 pathway, FADS1 and
2 facilitate the formation of eicosapentaenoic acid (EPA) and docosahexaenoic
acid (DHA), which can initiate a number of anti-inflammatory pathways,
including the formation of resolvins. FADS1 variants associate with
inflammation, type 2 diabetes mellitus, and coronary artery disease, and it is
hypothesized that this is mediated by affecting inflammatory pathways. For the
FADS1/2 variant rs174547, the protective C allele was associated with higher
FADS2 transcripts contributing to, overall, higher DHA content in human aortic
valves.11 However, within the same valve, DHA was decreased in calcified versus
noncalcified tissue. These data suggest that DHA-derived anti-inflammatory
mediators such as resolvins protect against calcification in aortic valves.
This concept is further supported by the observation that EPA, a precursor of
DHA in the *-3 pathway, attenuated arterial calcification in two rat models.
Also, DHA-derived resolvin E1 inhibited Chem23-mediated calcification of
vascular smooth muscle cells in vitro.14 Furthermore, within the same aortic
valve, calcified parts had a lower content of *-3 fatty acids such as EPA and
DHA compared to noncalcified parts, and this corresponded with dysregulation of
the *-3 pathway-derived anti-inflammatory mediator resolvin E1. Taken together,
these data imply that the *-3 fatty acid pathway products EPA and DHA, via
anti-inflammatory mediators such as resolving E1, play a pivotal role in
protecting the aortic valve from calcification. This potential of EPA and DHA
to inhibit calcification pathways is unique compared to other
anti-atherosclerotic therapies such as statins, which have been shown to
enhance calcification, at least in coronary atherosclerosis.

Icosapent ethyl is a highly purified (>96%) form of EPA. In the REDUCE-IT
trial, high dose icosapent ethyl resulted in a 25% reduction in ischemic
cardiovascular events.18 Interestingly, Interestingly, this benefit is
considered to be only partly attributable to the moderate triglyceride-lowering
effect of EPA, with a substantial part of the cardiovascular benefit
potentially related to the anti-inflammatory effects of EPA. The subsequent
EVAPORATE trial investigated the effect of icosapent ethyl on coronary plaque
volume and composition, as captured by coronary computed tomography angiography
(CCTA) in 80 patients with atherosclerosis and elevated triglyceride levels.
Interestingly, icosapent ethyl resulted in remarkable reductions in plaque
volume, predominantly in high-risk non-calcified, low-density plaque volume. It
remains unknown whether icosapent ethyl also reduces plaque volume and improves
plaque composition in patients without hypertriglyceridemia.

We hypothesize that EPA administration results in upregulation of
anti-inflammatory mediators in the aortic valve, leading to inhibition of
pro-calcific pathways. We designed a proof-of-concept randomized, double-blind,
placebo-controlled trial to test the efficacy of icosapent ethyl in slowing
down the progression of aortic valve calcification and stenosis among patients
with mild to moderate AVS. As secondary and exploratory outcomes, we will test
the effect of icosapent ethyl on coronary plaque volumes and plaque
composition.

This study has been transitioned to CTIS with ID 2024-517342-33-01 check the CTIS register for the current data.

The primary objective is:
• to study the effect of icosapent ethyl on progression of aortic valve
calcification.

The secondary objectives are:
• to study the effect of icosapent ethyl on progression of aortic valve
stenosis.
• to study the effect of icosapent ethyl on coronary plaque volumes and plaque
composition.

This study is designed as a randomized, double-blind, placebo-controlled trial
investigating the efficacy and safety of icosapent ethyl in slowing down the
progression of aortic valve calcification (AVC) and stenosis among people with
mild to moderate AVS. Potentially eligible participants will be recruited at
the Amsterdam UMC Department of Cardiology or at Cardiologie Centra Nederland,
a network of independent outpatient clinics cooperating with Amsterdam UMC.
Potentially eligible participants will be invited to visit CURIUS, the clinical
trial unit of the Heartcenter Amsterdam UMC for a screening visit (screening
inclusion and exclusion criteria, signing informed consent). Eligible
participants who have signed informed consent will be invited for a first visit
which will comprise baseline echocardiography and cardiac CT, as well as blood
drawing. Subsequently, study participants will be randomized to treatment with
either icosapent ethyl or matching placebo (mineral oil capsules, comparable to
REDUCE-IT trial) for the duration of 24 months. At 1 month, a follow-up check
will be performed by telephone to screen for medication safety issues and
compliance. At 1 year, a follow-up visit will be comprise echocardiography and
drawing of blood. At 2 years, a closing visit will comprise echocardiography,
cardiac CT, and drawing of blood.

Patients will be randomized to treatment with either icosapent ethyl or
matching placebo (in a 1:1 ratio).

The study protocol comprises 2 cardiac CT scans, with associated radiation
exposure, as well as injection of iodine contrast, which carries a very small
risk of an allergic reaction. In addition, the protocol comprises 3 visits for
blood sampling and echocardiography, which are considered to carry negligible
risk.
Participants will be randomized to either icosapent ethyl or matching
placebo. In the clinical trials performed thus far, icosapent ethyl was not
associated with an increased risk of side-effects compared to placebo, although
it must be stated that placebo consisted of mineral oil (an FDA requirement, in
order to mimic the color and consistency of icosapent ethyl). In absolute
terms, there was a high rate of treatment-emergent gastrointestinal
side-effects (icosapent 33,0% vs placebo 35,1%), which included diarrhea (9,0%
vs 11,1%), constipation (5,4% vs 3,6%), and nausea (4,6% vs 4,8%). Adverse
events that occurred more frequently in participants taking icosapent ethyl
versus placebo were atrial fibrillation (5,3% vs 3,9%) and peripheral edema
(6,5% vs 5,0%). Serious adverse bleeding events occurred in 2.7% of
participants in the icosapent ethyl group vs 2.1% in the placebo group
(P=0.06). The rates of serious adverse events leading to discontinuation of the
trial drug or placebo did not differ significantly between the trial groups.
Importantly, in the REDUCE-IT trial icosapent ethyl was shown to reduce the
risk of cardiovascular events, including cardiovascular death, myocardial
infarction, and stroke, by 25%. Also, if the study hypothesis turns out to
correct, participants may benefit from delaying the progression of AVS, thereby
postponing the need for open heart surgery. Finally, the yield for participants
lies in the contribution to the development of a potentially effective
treatment option for AVS.