DIagnostic and prognostic value of intracoronary physiologic indices and need for revascularisation in severe aortic VAlve disease (DIVA)

Currently, standard therapy for symptomatic severe aortic valve disease is
surgical aortic
valve replacement, which relieves symptoms and improves long-term survival. The
majority of aortic valve stenosis is degenerative, occurs in the elderly, often
involving co-morbidity and leading to (post)-operative morbidity and mortality.
In the Euro Heart Survey at least 30% of high-risk patients was rejected or not
referred for surgery[1]. Untreated symptomatic aortic valve stenosis has a poor
prognosis[2]. Therefore, less invasive transcatheter aortic valve implantation
(TAVI) has been developed. The first transcatheter implantation in humans was
performed in 2002[3]. Experience, technical development and careful patient
selection have improved the results. The transcatheter treatment of symptomatic
patients with severe aortic valve stenosis is a treatment that has been
established at the AMC-UVA in 2007 and has been performed under approval by the
medical ethical committee (institutional review board).

Since AS is a disease predominantly prevailing in the elderly population and
shares a large part of its pathophysiology, risk factors and prevalence with
atherosclerotic CAD, both diseases often co-exist in each patient and possibly
cause. Prevalence of CAD in patients with severe AS is described being up to
50-65%, depending on definitions used [4-7]. Sharing symptomatology, debate
about the need for revascularisation in patients who undergo a TAVI-procedure,
regarding treating symptoms, effecting prognosis and influencing costs is
ongoing[5, 6, 8, 9].

The left ventricle (LV) of patients with severe aortic valve stenosis shows
pathophysiological changes such as hypertrophy and increased stiffness or wall
stress, which may lead to diastolic dysfunction and subendocardial ischemia.
Ultimately, a severe aortic stenosis can cause a reduction in systolic left
ventricular function. By reducing the aortic pressure gradient with aortic
valve replacement, LV afterload is reduced. Direct improvements of
echocardiographic LV function and reduction in wall strain have been
described[10, 11]. Improvement of coronary flow (reserve) measured with
transoesophageal echocardiography has been described after both surgical and
percutaneous aortic valve replacement[12]. More recently, direct result
regarding invasively measured coronary flow (reserve) of transcatheter aortic
valve replacement is described in the AMC[13], as well as small cohorts in
Canada [14] and London [15]. Recent study shows accurate diagnostic properties
of FFR-measurements in patients with AS, concluding that the intra procedural
measurements after valve placement are the most reliable to assess lesion
severity[16]. However, these results are not described during longer follow-up.
The interventional Section Leadership Council of the American College of
Cardiology spoke out lately on performance of PCI before TAVI-treatment, but
states that the topic has never been profoundly investigated and does not
mention the influence of invasive coronary flow- and pressure measurements[17].

The diagnostic and prognostic value of intracoronary flow- and pressure
measurements (Fractional Flow Reserve (FFR), Coronary Flow Reserve (CFR),
instant Flow Reserve (iFR), MR (Microvascular Resistance)) has been described
in patients with stable CAD. In the FAME II cohort, FFR-guided PCI showed a
large, significant improved outcome over optimal medical therapy alone [18].
PCI in TAVI patients is described as feasible and safe[19, 20]. In a small case
series, FFR shows promise in assessing hemodynamic significance of coronary
lesions[21]. However, no data of the diagnostic and prognostic worth of these
measurements in patients with AS and LVH have been previously described in a
large cohort containing longer term follow-up measurements. The effects of
unloading of the left ventricle by TAVI-procedure on coronary hemodynamic (and
its* measurements) is not yet fully understood during longer follow-up [14, 15]
and it is reasonable to think this changes significantly after valve
replacement regarding left ventricular pressures and function of the coronary
microvasculature[13]. We use the combined flow- and pressure wire (Combowire, )
to fully understand the expected changes, where most other stated studies
namely use one of both measurements.

Following the current trend in treating lower surgical risk patients with TAVI,
the question whether to treat CAD in AS patients becomes more important. This
study seeks to provide insight in the changes of coronary hemodynamics,
probably influencing future clinical decision making.

This study is designed to assess diagnostic and prognostic value of
intracoronary flow- and pressure measurements in patients with severe aortic
valve stenosis and concomitant coronary artery disease, unravelling the
physiological impact on coronary hemodynamic of the TAVI-procedure. Answering
this physiological question will aid in the question whether CAD needs
treatment in patients with concomitant AS.

Single centre, exploratory study

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The added risk of this study, compared to standard clinical care, will be
minimal. In different centres performing TAVI, whether or not revascularisation
is performed in the work-up or after a TAVI is done by the operators* opinion
since no clear data exists until date. This study mimics the current strategy
in the AMC, by doing as less as possible coronary revascularisation in the
TAVI-workup since the biggest prognostic effect is expected from the TAVI
procedure and not from the possible PCI. This study adds safety by adding per
procedural and follow-up measurements for monitoring coronary lesions in
patients not treated with PCI.

However, patients will be exposed to a minimal extra radiation dose during
TAVI-procedure, since placing the wires for measuring flow- and pressure
parameters will take imaging and time. However, this radiation will be very
minimal, estimated an extra 3-4 minutes of fluoroscopy time, accounting for
approximately 2-3 mSV on top of the radiation dose for regular valve placement.
Comparing this to the background radiation in the Netherlands (2-3 mSV), with
taking the advanced age of the subjects into account, this risk could be
estimated as minimal.
In all patients, there will be a follow-up CAG with coronary measurements. The
follow-up CAG including the combined measurements is standard clinical care as
in other patients with coronary stenosis of unknown significance. This
re-catheterisation adds the (minimal) risks of the invasive procedure and
radiation exposure as earlier described once again.

The benefit of this study is a better understanding of mechanisms of LVF
improvement after TAVI, as well as identification of dissipating effects of
ventricular wall adaptation to aortic valve stenosis on functional parameters
of coronary hemodynamic, potentially influencing clinical decision-making.
Benefit for included patients will consist of better follow-up and better
understanding of the prognostic value (and effect on symptoms) of their
existing CAD. All the patients will be closely monitored, especially on
symptoms of progressing coronary artery disease and corresponding symptoms
after their TAVI-procedure.
This study could not be conducted in another group of patients.