Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05215587 |
| Other study ID # |
8240 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
May 24, 2023 |
| Est. completion date |
December 31, 2030 |
Study information
| Verified date |
February 2024 |
| Source |
University of Aarhus |
| Contact |
Jacob W Budtz-Lilly, MD PhD |
| Phone |
45 28147705 |
| Email |
jacoblilly[@]clin.au.dk |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The introduction of thoracic endovascular aortic repair (TEVAR) in 1994 has radically changed
the treatment of thoracic aortic pathology, and TEVAR is now the recommended therapy for
"complicated" TBADs and other thoracic aorta diseases. To date, the use of TEVAR in the
treatment of "uncomplicated" dissections (uTBAD) is uncertain, although it is presumed that a
prophylactic procedure can prevent later complex surgery and early death. Several analyses
have found that TEVAR confers improved aortic remodeling and possibly survival, although
these were underpowered for this specific outcome. In addition, there are several reports
regarding the uncertain benefit or harm of this intervention in the vascular surgery
community. Put another way, there is equipoise, and the need for robust evidence in the form
of a randomized clinical trial has been clearly iterated by the European Society of Vascular
Surgery.
This randomized, open-label, two-armed controlled study directly addresses this question of
whether TEVAR alters 5-year survival among patients with an 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.
Sample size calculations based on previous reports indicate the need to include approximately
554 patients. Patients will be recruited from multiple centres in Scandinavia. Based on the
population (24 million) and incidence of uTBAD (approximately 480 per year), and depending on
the total number of participating centres, a conservative estimate of two to three years is
required for enrolment.
Description:
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.
2. 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 +
subacute TEVAR.
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:
1. 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.
2. The Hospital and Anxiety Depression Score (HADS).
3. 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.
