Cardiac CT for therapeutic stratification in low gradient presumed severe aortic stenosis with preserved left ventricular ejection fraction

Calcific aortic stenosis (AS) has become the most frequent valvular heart
disease encountered in Europe and North America affecting approximately 2% to
4% of people over 65 years of age(1-3). This corresponds to approximately 3
million people with AS in Europe alone. One in five will eventually progress to
symptomatic AS representing 600.000 patients. Left untreated, severe AS is
associated with a dismal prognosis with median survival averaging only 2, 3 and
5 years after symptom onset of angina, syncope and heart failure (4).

Both, the ESC and ACC/AHA cardiology societies have endorsed guidelines on
valvular heart disease emphasizing the need for aortic valve replacement (AVR)
once symptoms develop or in case of impaired left ventricular (LV) function
(5,6). Surgical replacement of the aortic valve reduces symptoms and improves
survival in patients with severe AS (7,8) and in the absence of serious
comorbidities, the procedure is associated with low operative mortality (9).
However, in clinical practice, at least 30% of patients with severe symptomatic
AS do not undergo surgical AVR because of advanced age, LV dysfunction or the
presence of multiple comorbidities (10-12).

Transcatheter aortic valve replacement (TAVR) represents a less invasive
procedure than surgical AVR (13,14) with similar 1 year survival rates (15).
Doppler echocardiography is the preferred technique for assessing AS severity
providing transvalvular jet velocities, pressure gradients and aortic valve
area (AVA) (6,16).

According to current guidelines severe AS is defined as an AVA <=1 cm2 (AVA
indexed to body surface area (BSA) <=0.6 cm2/m2), a transaortic mean gradient >=
40 mmHg or a peak velocity >= 4 m/s (5,6). However, approximately 30-45% of
patients with preserved LVEF present with paradoxically discordant low mean
transvalvular pressure gradients (<40 mmHg), despite AVA <=1 cm2, posing
significant diagnostic and therapeutic challenges (17-19). Indeed, in a recent
substudy of the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) trial,
Jander et al. reported that patients with low mean gradient (LG) (<40 mmHg)
severe AS (AVA <=1 cm2) and normal LVEF (>=50%) had similar outcome compared to
patients with moderate AS (20).

Paradoxical LG severe AS with preserved LVEF can occur in the presence of both
normal flow (NF) with LV stroke volume index (SVI) > 35 ml/m2 and low flow (LF)
with LV SVI <= 35 ml/m2 (21,22). A recent study of 1704 consecutive severe AS
patients stratified by gradient and SVI demonstrated that patients with NF/LG
severe AS with preserved LVEF had a favorable outcome with medical management
with no survival benefit associated with AVR (23). Indeed, peroperative aortic
valve (AV) inspection frequently reveals only minor AV calcifications in
patients with LG severe AS and preserved LVEF, while these patients frequently
suffer a protracted postoperative course, including increased risk of heart
failure and mortality. The entity of paradoxical LG (<40 mmHg) severe AS (AVA
<=1 cm2) with preserved LVEF (>=50%) (24) is associated with small ventricular
size, marked LV hypertrophy, a history of hypertension (6), higher LV
hemodynamic afterload, increased concentric remodeling (25,26), decreased
ventricular cavity size (23), reduced LV longitudinal function (27-29),
increased myocardial fibrosis (28) and elevated brain natriuretic peptide level
(29).

Previous studies have indicated that the average rate of progression of
calcific AS is a reduction in valve area of about 0.1 cm2 per year and an
average increase in mean gradient of 7 mmHg (30-32). Recently, the natural
progression of AVA and mean gradient was assessed after two years follow up in
116 patients with either mild, moderate or severe AS with the severe AS group
subdivided in patients with low and high mean gradient (33). Annual decreases
in AVA were -0.16 ± 0.15 cm2 for mild AS, -0.08 ± 0.15 cm2 for moderate AS,
-0.03 ± 0.07 cm2 for low gradient severe AS and -0.03 ± 0.07 cm2 for high
gradient severe AS (p=0.004 between groups). Annual increases in mean gradient
were 1 ± 3 mmHg for mild AS, 1.8 ± 5 mmHg for moderate AS, 4.8 ± 9 mmHg for low
gradient severe AS and 1.5 ± 7 mmHg for high gradient AS. At 2 years follow up
no patients had died and 25% of patients in the LG severe AS group progressed
to high gradient severe AS (33). In the moderate AS group, 24% progressed to
low gradient and 13% progressed to high gradient severe AS respectively. From
the perspective of progression to high gradient severe AS, low gradient AS
patients appeared to be more advanced than moderate AS patients, which suggests
that low gradient severe AS might represent an intermediate stage between
moderate AS and high gradient severe AS (33).

Apart from representing a distinct entity, inconsistent grading of AS severity
with low gradient severe AS can also result from several mechanisms, including
small body size and the tendency of Doppler measurements to underestimate flow,
resulting in eventual underestimation of AVA and erroneous assumption of *low
flow conditions*. In addition, severity thresholds for AVA and mean pressure
gradient recommended in current guidelines are inherently inconsistent and
generation of a mean gradient of 40 mmHg requires a valve area closer to 0.8
cm2 than 1.0 cm2 (24). Discordantly low mean transvalvular pressure gradients
and severe AS according to AVA <=1 cm2 can also result from an underestimation
of AVA due to the erroneous assumption of a circular shape of the LV outflow
tract (LVOT) with 2-dimensional echocardiography (16,34). Using the continuity
equation, the AVA is calculated based on the ratio between the Doppler stroke
volume and the post-aortic valve flow. Doppler stroke volume relies crucially
on accurate estimation of the LVOT area (LVOT area) according to the formula:
Doppler stroke volume = LVOTarea x LVOT flow. On 2-dimensional
echocardiography, the LVOT area is derived from LVOT diameter measurements made
on the parasternal long axis view and the assumption that the LVOT is circular.
However, recent computed tomography (CT) studies demonstrate that the LVOT is
elliptical and not circular, and as a consequence, measurements made using
echocardiography underestimate the true LVOT area and hence also LV stroke
volume and AVA (35,36).

Initial studies in AS patients, using 3-dimensional echocardiography or CT
demonstrated that the introduction of the planimetered LVOT area in the
continuity equation leads to a significantly larger AVA compared with the use
of 2-dimensional echocardiogarphy derived LVOT diameter (37,38). Importantly,
Kamperidis et al. recently demonstrated that incorporation of CT-derived LVOT
area into the echocardiographic continuity equation (fusion AVAi) reclassified
52% of NF/LG and 12% LF/LG severe AS into moderate AS (21). Additionally,
assessment of AV calcium burden using coronary calcium computed tomography
recently discriminated between patients with true severe AS among patients with
inconsistently graded severe AS with low mean transvalvular pressure gradients
(21,39,40).

It is currently unknown whether it is safe to cancel or postpone AVR in
patients who are reclassified from severe to moderate AS based on incorporation
of CT-derived LVOT area into the continuity equation (fusion AVAi ). It is also
unknown whether a less invasive AVR using TAVR improves exercise capacity in
patients with echocardiographically NF/LG and LF/LG severe AS with preserved
LVEF reclassified to moderate AS by CT derived LVOT area. Recently, TAVR was
shown non-inferior to surgery in patients with severe AS at intermediate
surgical risk (41).

Therefore, the CAPTURE-AS trial will allocate patients with NF/ LG and LF/LG
severe AS with preserved LVEF and fusion AVA-derived reclassification from
severe to moderate AS with fusion AVA in the range of 1.0-1.2 cm2 to TAVR
in

Primary objective: The primary objective of this non-randomized intervention
trial is to investigate whether TAVR improves exercise capacity in patients
with preserved LVEF and NF/LG or LF/LG severe AS reclassified based on hybrid
CT/TTE-derived parameters from severe to moderate AS with fusion AVA of
1.0-1.20 cm2.
In addition, this trial will investigate whether conservative management is
safe in patients with preserved LVEF and NF/LG or LF/LG severe AS reclassified
based on hybrid CT/TTE-derived parameters from severe to moderate AS with
fusion AVA >1.20 cm2.
Furthermore, exercise capacity will be compared between patients referred for
TAVR based on fusion AVA <1.0 cm2 (6 minute walk test (6 MWT) and
cardiopulmonary exercise test (CPET) only to be performed at 6 months follow
up) and 1.0-1.2 cm2 (6 MWT and CPET and patients managed conservatively with
fusion AVA >1.2 cm2 (6 MWT and CPET).

Secondary objective: The secondary objectives of this trial are to assess in
all 6 groups of patients:
The change from baseline to 6 months in quality of life (QoL)(Kansas City
Cardiomyopathy Questionnaire), symptoms (New York Heart Association (NYHA)
class and cardiac structural and functional characteristics assessed with TTE
and biomarkers.

This study is a single center, non-randomized, intervention trial designed to
evaluate the efficacy of TAVR in improving exercise capacity in patients with
NF/LG and LF/LG severe AS with preserved LVEF reclassified based on hybrid
CT/TTE-derived parameters from severe to moderate AS with fusion AVA 1.0-1.20
cm2.

Patients with NF/LG and LF/LG severe AS with preserved LVEF reclassified based
on hybrid CT/TTE-derived parameters from severe to moderate AS with fusion AVA
>1.2 cm2 will be managed conservatively with echocardiographic follow up at 6
months.

Patients with NF/LG and LF/LG severe AS with preserved LVEF in whom fusion AVA
remains <1.0 cm2 will be referred for TAVR.

Included patients will be referred once for a cardiac CT. Even in the case a
patient does not want to participate, it may be necessary to conduct a cardiac
CT for diagnostic purposes.

During the study the following measurements will be conducted at baseline and
at 6 months: Echocardiography, blood sampling, exercise tests (CPET and 6 MWT)
and quality of life questionnaire.

In case aortic valve replacement is necessary, this will be conducted through
TAVI instead of surgery. TAVI is associated with lower periprocedural risk of
morbidity and mortality than surgery in this population.

Patients who are allocated to a conservative strategy based on fusion-AVA >1.2
cm2 could experience symptomatic deterioration in case of progressive AS.
Conservatively managed patients will closely be followed up by outpatient
visits and echocardiography and in the setting of rising mean gradient >40mmHg
will be referred for TAVI.

This study includes the following safety endpoints:

*Major Adverse Cardiovascular and Cerebral Events (MACCE-) free survival at 6
months.
*Occurrence of individual MACCE components from baseline to 6 months.
*Major Adverse Events (MAE) from baseline to 6 months.
*Conduction disturbances leading to pacemaker implantation after TAVI from
baseline to 6 months.
*Aortic valve related hospitalizations from baseline to 6 months.
*Cardiovascular mortality.
*Periprocedural neurological injury (TIA, CVA).