Scandinavian trial of Uncomplicated Aortic Dissection Therapy

An acute aorta dissection (AD) is the sudden tearing of the inner layer of the
aorta and, depending on its location and severity, can lead to frank rupture or
often times to splitting of the aorta into several lumens, typically two, a
true and a false lumen. There is a timeframe for ADs, that is, they are
classified according to their chronicity: acute, <= 14 days, subacute, 15-90
days, and chronic,> 90 days.

For the sake of simplicity, there are essentially three types of ADs.
Dissections more proximal, or closer to the heart and proximal to the left
subclavian artery are termed Type A dissections, and these almost always
require immediate open surgery. There are then two types of dissections in the
descending aorta, which are labelled Type B aorta dissection (TBAD), which are
divided into either complicated (cTBAD) or uncomplicated (uTBAD). According to
the European Society of Vascular Surgery, a complication is defined as the
presence of one or more of the following: rupture, hypotension/shock, organ
malperfusion, rapid aortic expansion, paraplegia/paraparesis, or intractable
pain or hypertension.1,2 As these cTBADs pose an immediate threat to survival,
prompt intervention, either open surgery or endovascular (minimally
invasive-catheter-based) treatment, is also necessary. The final group of
dissections, the uTBADs, invoke a more varying and unpredictable clinical
trajectory. These individuals have traditionally been treated conservatively
with medication and *watchful waiting*, and there is currently no high level of
evidence regarding the best treatment. This paradigm may need changes, based on
some of the findings described below.

The incidence of TBADs is estimated at 3.9 - 6.0 per 100,000 person years,
although this may be an underestimate. 1,3,4 Approximately 50-60% of these are
uncomplicated. The average age in a recent analysis was approximately 57 years,
although ranges have been reported from 36 to 97 years. 5,6 The ratio of men to
women is approximately 1.5 :1,6 while the mortality of ADs varies depending on
its type, acuity, and method of repair (more below). The economic burden on
healthcare systems and the psychological impact are considerable. It has been
shown that the median and total yearly costs to treat ADs have increased beyond
the rate of inflation, while rehabilitation constitutes a significant portion
of these costs. 7 Meanwhile, individuals surviving an AD have reported poorer
levels of mental health and sexual function. 8

Open aortic surgery has previously played a role in TBAD treatment, but its
dismal outcomes, particularly when compared to medical treatment, were what led
to a more conservative strategy of medical therapy and watching waiting, as
mentioned above. 9-11 The use of medical therapy includes blood pressure
lowering medicine, typically β -blockers, in order to mitigate the stress on
the aorta and the potential pressure on the various false lumens, as well as
pain relief and anti-anxiety medications. 1, 12

The introduction of TEVAR, a minimally invasive and catheter-based technique
for placing a stent graft across the aortic tear, has radically changed the
treatment of aortic disease, and is now the recommended therapy for many aortic
pathologies.13, 14 Its use in the treatment of uTBADs, however, is uncertain.
The dilemma centers around the balance of the relatively satisfactory
short-term outcomes with medical therapy, against the subsequent relatively
poorer long-term outcomes. That is, in-hospital survival for those treated with
medical therapy is reported at 90%.15 In contrast, the survival at five years
has been reported at 79.3%, and approximately 30% of the surviving cohort
ultimately require treatment at some point which, notably often becomes more
technically challenging with increased risks.16, 17 Indeed, some experts have
commented that the term *uncomplicated* is a blatant misnomer, and that the
complication is really, in effect, just waiting to happen.16 The
counterproposal is that early TEVAR treatment confers prompt aortic remodeling
and avoids the inevitable progression to complex aortic disease, rupture, and
death. The benefit of TEVAR, however, comes with associated up-front risks of
an invasive procedure, which are not benign. The risks of TEVAR include
inadvertent rupture, paraplegia, further operations, and death, among
others.18,19

This clinical dilemma is perhaps well-reflected by a recent international
survey of cardiovascular specialists regarding the preferred treatment of
uTBADs. When asked regarding their preferred strategy, 54.8% of respondents
answered that they do not routinely use TEVAR, while 37.4% were in favor of
routine TEVAR treatment. Moreover, 88.6% of respondents agreed that equipoise,
or perhaps an agreement to disagree, was present and that an RCT was
warranted.20

Thus, it would appear logical that a(n) RCT would resolve this issue. There
are, in fact, two industry-affiliated studies assessing early TEVAR in uTBAD.
The statistically underpowered Acute Dissection: Stent graft OR Best medical
therapy (ADSORB) trial randomized a total of 61 individuals from 17 European
centres. As noted, it was underpowered to discern differences in survival, but
they found that TEVAR was associated with improved remodeling of the aorta,
which many believe is reason enough to offer this treatment.21 The
Investigation of Stent Grafts in Aortic Dissection (INSTEAD) trial included 140
uTBAD participants and was primarily powered for analysis of two-year
outcomes,22 later extended to a five-year analysis. The overall survival at two
years was statistically equivalent, while the five-year analysis showed a
non-significant absolute reduction in all-cause mortality of 8.2% for those who
underwent TEVAR. Interestingly, they also showed that 26.5% of the cohort
randomized to medical therapy ultimately crossed-over to the intervention of
TEVAR.

There are several TEVAR stents on the market, while only three are used in
Scandinavia. Despite minor design and structural differences, the underlying
principle of construction is the same, as are the associated risks.
Importantly, all devices used in Scandinavia and in this trial are currently
CE-marked for the pathology indicated and treated in this project. According to
the EU regulation, Article 103 (2017/745), endorsed by the Medical Device
Coordination Group (MDCG), all of the stent grafts used in this trial are
categorized as Class III.

The TEVAR stent grafts used in this trial are designed for the endovascular
repair of lesions in the descending thoracic aorta. When placed, the stent
graft provides an alternative conduit for blood flow within the vasculature by
excluding the lesion from blood flow and pressure. They may be used as a single
device or in multiple device combinations to accommodate the intended treatment
site. All of the devices used in this trial are composed of two components: an
implantable stent graft and a disposable delivery system. The stent graft is
preloaded into the delivery system, which is inserted endoluminally via the
femoral or iliac artery and tracked through the vascular system to deliver the
stent graft at the target site.

This project aims to answer whether or not standard medical therapy (SMT) and
early TEVAR treatment for participants with an uncomplicated Type B aortic
dissection (uTBAD) is superior to SMT alone. Survival at five years is the
primary outcome for analysis. Secondary outcomes include aortic-related
mortality, neurological events, hospital readmissions, reinterventions, and an
economic analysis in conjunction with quality of life.
The impact of these findings, irrespective of various benefits or not, will
have a major impact on future care. Multiple scenarios are possible, each of
which will better inform us as to the health of the participant and the
economic resources req

Primary Objective: The primary objective of the study is to determine the
superiority of TEVAR versus SMT in reducing the incidence of all-cause
mortality.

Secondary Objectives: The secondary objectives of the study are:
• To compare the risk of aortic-related mortality.
• To compare the risk of neurological injury, including stroke or paraplegia.
• To compare the proportion and indication of subjects who underwent an aortic
intervention within 5 years due to development of an aortic complication.
• To compare the number of disease-related readmissions during follow-up. To
compare, based on subgroup analyses, whether extent of TEVAR is associated with
either improved survival or neurological injury.
• To compare the associated risk of reinterventions, including those subjects
who were initially randomized to SMT and subsequently required an aortic
intervention.
• To compare the associated changes in quality-of-life.
• To compare the 10-year overall survival and aortic-related mortality.
• To compare the costs.

The trial is a randomized, open label, clinical trial with parallel assignment
of participants in multiple clinical centres in Denmark, Sweden, Norway,
Iceland, Finland and the Netherlands. Recruited participants will be randomized
to either SMT exclusively or TEVAR + SMT.

Contemporary standard medical therapy for TBAD consists of antihypertensive
agents and pain relief. The choice of the specific agents will be left to the
discretion of the individual treatment sites/surgical team, based on the
individual subject*s prior and current therapy and tolerance to various medical
regimens. While the goal is to reduce the systolic blood pressure to between
100 - 120 mm Hg and the pulse rate below 60 beats/minute in the acute phase,
the advocated first-line therapy consists of intravenous β-blockade, with
calcium channel antagonists and/or renin-angiotensin inhibitors as
alternatives. Pain relief is furthermore critical in order to mitigate
activation of the sympathetic nervous system and resultant tachycardia and
blood pressure elevation. Anxiolytic medication may also be used in this role.

Long-term SMT is essential and, although not evaluated in any clinical trials,
the target blood pressure is 120/80 mmHg.15 All subjects will be equipped with
a home blood pressure apparatus in order to measure and record their values. As
detailed below, these measurements will be recorded in the electronic database
for all subjects at follow-up consultations.

Clearly, medical therapy for aortic dissection is a complex and unresolved
research topic in and of itself, and individual-specific therapy can only be
supported by guidelines from the European Society of Vascular Surgery and the
European Society of Cardiology. Consideration in the trial was given to the
connotations of *best* or *optimal* medical therapy, as well as kindred RCT
protocols, e.g. Asymptomatic Carotid Surgery Trial-1 (ACST-1), 24 and the
ramifications of these definitions vis-à-vis endpoint determination. Because of
the recognized local differences in medical therapy and the interest in
maintaining the pragmatic nature of this trial, it was determined that the
terminology of *standard medical therapy* is most appropriate.

To that end, all sites, investigators, and subjects will be informed of the
blood pressure target-oriented nature of this treatment and the following
recommendations from the European Society of Vascular Surgery: Initial therapy
consists of β-blockers. In subjects who do not respond to β-blockers or who do
not tolerate the drug, calcium channel antagonists and/or renin-angiotensin
inhibitors can be used as alternatives.1 In addition to these recommendations
for hypertension, efforts should be made to alter and improve lifestyle and
cardiovascular risk profiles, including smoking cessation, weight control, and
potential treatment of other comorbidities such as diabetes mellitus and
ischemic heart disease.

Subjects randomized to TEVAR therapy will undergo placement of an endovascular
stentgraft in the descending thoracic aorta. When placed, the stent graft
provides an alternative conduit for blood flow within the vasculature by
excluding the lesion from blood flow and pressure. They may be used as a single
device or in multiple device combinations to accommodate the intended treatment
site. All of the devices used in this trial are composed of two components: an
implantable stent graft and a disposable delivery system. The stent graft is
preloaded into the delivery system, which is inserted endoluminally via the
femoral or iliac artery and tracked through the vascular system to deliver the
stent graft at the target site.

Each device is supplied with an instructions-for-use (IFU), wherein
specifications of device material, contraindications, warnings and precautions,
and imaging safety information are provided.
Importantly, all devices used in this trial are currently CE-marked for the
pathology indicated and treated in this project.

The selection of the stent graft is left to the discretion of the treating
physicians. While the implicit goal of TEVAR in dissection treatment is to
treat the primary tear, certain adjunct proximal and/or distal procedures are
often required, e.g., coverage of the left subclavian artery with or without a
supplementary left subclavian artery revascularization, e.g., left carotid
artery-to-left subclavian artery bypass/transposition or fenestration to left
subclavian artery. Any or all adjunct procedures deemed necessary or beneficial
by the treating physicians and subjects are allowable under the allocation to
the TEVAR subject cohort, as this reflects real-world considerations and the
question at hand based on analysis of an intention-to-treat. This includes
distal or proximal aortic sealing, as well as Provisional Extension To Induce
Complete Attachment (PETTICOAT) or Stent-Assisted Balloon-Induced Intimal
Disruption and Relamination in Aortic Dissection Repair (STABILISE). 25, 26

The benefits of TEVAR treatment for a participant with an uTBAD are based on
the previously discussed RCTs above, the ADSORB and INSTEAD-XL trials, in
addition to several retrospective studies.21, 22 There are two main benefits:
first, it is well-documented that TEVAR treatment improves aortic remodeling
and delays the progression of disease. While SMT may be sufficient to maintain
early overall survival, the transformation of an acute/sub-acute dissection to
a chronic dissection entails a new pathological entity, i.e., a
thoracoabdominal aorta aneurysm, which is technically more challenging to treat
with increased associated risks. TEVAR intervention, on the other hand, delays
this process, thus reducing the yearly risk of rupture, which increases to
approximately 12.5-18.8% once the aortic diameter reaches a diameter of 6.0
cm.36

The second benefit is overall survival. The INSTEAD-XL trial demonstrated this,
using their prespecified use of a Landmark analysis for mortality. Between two
and five years, the survival for TEVAR participants was 100% versus 83.1% for
the SMT cohort.16 Their test for interaction between treatment effect and time
was moreover significant, suggesting a late survival benefit for TEVAR. The use
of the Landmark statistical analysis has had limited impact in altering
international guidelines regarding treatment of uTBADs, hence the need for the
present proposed trial.

The risk of TEVAR intervention is implicit in the very analysis performed in
the INSTEAD-XL trial, revealed when the Landmark analysis is replaced by the
standard Kaplan-Meier analysis, i.e., the starting point is moved back to day
zero. When this analysis is performed, the overall survival still appears to
benefit TEVAR participants, but the statistical p-value was nonsignificant. In
other words, there were *up-front* risks of death within the first year,
although none of these events were documented as periprocedural. Within one
year, there were five deaths (7.5%) in the TEVAR cohort and two deaths (3.0%)
in the SMT cohort, p=0.44. In addition to the risk of death, there were three
cases of neurological injury documented (1 paraplegia, 1 major stroke, and 1
transient paraparesis).

These risks must also be considered for those individuals initially treated
with SMT who ultimately cross over to TEVAR (26.5% within five years). Indeed,
the risk of rupture, or aorta-specific mortality, is significantly greater for
those on SMT, and any potential indication for aortic intervention may be
associated with increased risks, particularly in cases of acuity.

It is in this light that the benefit-risk rationale supports the potential
benefit of preemptive TEVAR treatment. Based on prior clinical research, there
appear to be both advantages and disadvantages for both treatment arms (the
control and intervention groups). However, these advantages and disadvantages
cannot be directly compared, leading to a potential bias towards one of the
groups. In summary, the intervention group entails perioperative risks, which
may be offset by better long-term survival and fewer subsequent aorta-related
interventions. This tension provides a solid foundation for conducting this
randomized study.