This randomized, open-label, two-armed controlled study addresses the question of whether
thoracic endovascular aortic repair (TEVAR) alters 5-year survival among patients with an
uncomplicated Stanford type-B aortic dissection (uTBAD). Patients will be randomized to
either standard medical therapy (SMT) alone or TEVAR in addition to SMT. The primary
outcome is 5-year survival, while secondary outcomes include aortic-related mortality,
neurological events, quality of life, costs, re interventions and readmissions. in
addition, subgroup analyses based on the extent of treatment.
Primary hypothesis:
The null hypothesis for this trial states that the five-year survival results for
patients treated with either SMT or SMT + TEVAR are equivalent.
- Background
The incidence of a Stanford type-B thoracic aortic dissection (TBAD) is estimated at 3.9
- 6.0 per 100,000 person years, although this may be an underestimate. These account for
approximately 30-40% of all types of aorta dissection. The diagnosis of TBAD is further
classified with respect to time: acute, ≤ 14 days, subacute, 15-90 days, and chronic, >
90 days. Approximately 40-50% of ABDs are considered complicated which, according to the
European Society of Vascular Surgery, is defined as the presence of one or more of the
following: rupture and/or hypotension/shock, organ malperfusion, rapid aortic expansion,
paraplegia/paraparesis, peri-aortic haematoma, or intractable pain or hypertension. In
the absence of these complications, the dissection is considered uncomplicated.
In-hospital survival for these patients has been reported as approximately 90%.
The management of TBADs is dependent upon the above-mentioned factors, i.e., complicated
or uncomplicated, acute or chronic, as well as accompanying comorbidities. An underlying
and universal component for all these patients is optimal medical therapy, which includes
antihypertensive therapy, typically beta-blockers, in order to mitigate aortic wall
stress and false lumen pressures, as well as pain relief. Furthermore, lifestyle
improvements and cardiovascular risk profile modification are recommended.
The introduction of thoracic endovascular aortic repair (TEVAR) in 1994 radically changed
the treatment of thoracic aortic pathology, and TEVAR is now the recommended therapy for
complicated TBADs, thoracic aortic aneurysms, and traumatic thoracic transections, among
others. To date, the use of TEVAR in the treatment of uncomplicated TBAD is uncertain, if
not controversial. Several analyses have found that TEVAR confers improved aortic
remodeling and possibly survival, albeit with the implied and inherent procedural risks
of intervention, including paraplegia, retrograde dissection, and death.
There are two relevant randomized clinical trials (RCTs), addressing the issue of early
TEVAR among TBAD patients. The Acute Dissection: Stent graft OR Best medical therapy
(ADSORB) trial, notably underpowered, randomized a total of 61 patients from 17 European
centres with acute uTBAD. There were no aortic ruptures at 1-year in either arm of the
trial, while TEVAR was associated with improved thrombosis of the false lumen and
reduction of its lumen. The Investigation of Stent Grafts in Aortic Dissection (INSTEAD)
trial included 140 patients in the subacute phase. The overall survival at two years was
statistically equivalent, 95.6% in the medical arm and 88.9% in the TEVAR plus medicine
group. The long-terms results from the extended INSTEAD-XL found a non-significant
absolute reduction in all-cause mortality of 8.2% at five years for those patients who
underwent TEVAR.
The conclusions from the retrospective and above-mentioned RCTs have not been persuasive
enough for the European Society of Vascular Surgery to render a higher recommendation
than "TEVAR may be selectively considered" for those patients presenting with
uncomplicated type B aortic dissections. This is furthermore echoed by a recent
international survey regarding preferred treatment of uTBAD, in which 54.8% of
respondents answered that they do not routinely use TEVAR, as opposed to 37.4% who prefer
this strategy; moreover, 88.6% of respondents agreed that equipoise was present and that
an RCT was warranted.
Research Objectives
Primary Objective
• To compare the overall survival at five years between subjects treated with SMT or SMT
Secondary Objectives
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.
Endpoint Definitions
Primary endpoint:
All-cause mortality.
Secondary endpoints:
Aortic-related mortality: Death as a result from aortic rupture or organ malperfusion, or
death due to aortic intervention.
Aortic intervention: Any open surgical or endovascular intervention performed in any
anatomical location, performed for the following indications, which are related to the
aortic pathology: aneurysmal degeneration, visceral ischemia, lower extremity ischemia,
rupture, or any of the criteria listed above under the definition of a complicated TBAD.
Neurological injury: These are divided into two categories: cerebrovascular accidents
(CVA) and spinal cord ischemia (SCI). CVAs are defined according to the Society for
Vascular Surgery reporting standards and classified as any central neurological
complication, ischemic and hemorrhagic. For this project, the modified Rankin scale will
be used for classifying stroke severity. Spinal cord ischemia is defined as either
ischemic or hemorrhagic resulting in paraparesis or paraplegia. The modified Tarlov
scoring scale will be used for the grading of any spinal cord injuries.
Reintervention: Any open or endovascular intervention after the original TEVAR procedure
that was related to the dissection. These should be categorized as either planned
reintervention, e.g., a staged procedure, or unplanned, which indicates a complication
from the original procedure, a failure of the device, or progression of disease.
Quality of life: The quality of life will be assessed with the three following
self-assessment forms:
The EuroQOL-5D-5L instrument from the EuroQol Group, comprised of five dimensions
with five levels of scoring that can be combined into a five-digit number of
description.
The Hospital and Anxiety Depression Score (HADS).
The 12-Item Short-Form (12-SF) Health Survey.
Economic evaluation: The economic evaluation will be performed from a payer/healthcare
point of view, including resource use associated with healthcare, intervention and
medication, whereas broader potential consequences for society, i.e., effects on
productivity, will not be included. During the course of the trial, the accumulated costs
will be measured per treatment arm from the participating hospital´s
administrative/controlling/billing systems. As far as possible, the following resource
use items will be included and captured as accumulated costs from the hospital's
cost-per- subject system on all outpatient and inpatient visits:
costs for healthcare staff
subject -specific costs for primary and secondary endovascular and surgical
procedures postoperative care unit costs
costs of drugs during surgery and postoperative care
costs of anaesthetic procedures and blood transfusions
additional diagnostic procedures from the radiology and clinical physiology
departments and from clinical chemistry.
The costs for healthcare staff will comprise the full wage costs, including costs for
social security. Costs for each endovascular and surgical procedure will be retrieved
individually, and, as far as possible, be based on the price per minute according to the
hospital's cost-per- subject systems.
Changes in health status will be assessed in terms of quality-adjusted life-years
(QALYs), which combine the time spent in a specific health state with the corresponding
self-assessed health-related quality of life (HRQoL), as derived from the EuroQOL
EQ-5D-5L questionnaire. Time is measured in years and the HRQoL is measured on an index
scale ranging from 0 (equivalent to being dead) to 1 (best possible health state). The
total number of QALYs will be calculated by multiplying the HRQoL index score (QALY
weight) by the time spent in each health state. Group differences in total costs will be
calculated and divided by the difference in QALYs in the interval from baseline until end
of study, and the incremental cost-effectiveness ratio will be calculated as follows:
(CostTEVAR -CostSMT)/(QALYsTEVAR - QALYsSMT)=ΔCost/ΔQALY.
Rationale for objectives and endpoint selection
Despite evidence from retrospective and descriptive studies suggesting long-term benefits
for early TEVAR intervention among uTBAD subjects, the underlying unanswered question is
whether TEVAR confers a benefit of survival. The two previous RCTs, mentioned above, were
underpowered to address this issue. Despite potential theoretical and procedural
advantages of various composite endpoints, it was determined that a trial based on a
clearly expressed question with a binary outcome will have the most clinical impact.
Similarly, focus on the albeit interesting, but not essential, endpoint of aortic
morphological changes and imaging findings, would complicate the pragmatic design of this
trial.
Study Design
The trial is a randomized, open label, clinical trial with parallel assignment of
subjects in multiple sites in Denmark, Sweden, Norway, Iceland, and Finland. Recruited
subjects will be randomized to either SMT exclusively or TEVAR + SMT.