SUNDAY: Scandinavian Trial of Uncomplicated Aortic Dissection Therapy
Study Details
Study Description
Brief 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 optimal medical therapy (OMT) alone or TEVAR in addition to OMT. The primary outcome is 5-year survival, while secondary outcomes include neurological events, aortic-related mortality, in addition to subgroup analyses based on the extent of treatment.
Sample size calculations based on previous reports indicate the need to include approximately 632 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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N/A |
Detailed 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 optimal medical therapy (OMT) alone or TEVAR in addition to OMT. The primary outcome is 5-year survival, while secondary outcomes include neurological events, aortic-related mortality, in addition to 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 OMT or OMT + TEVAR are equivalent.
- Background
The incidence of a Stanford type-B thoracic aortic dissection (TBAD) is estimated at 3.9 - 4.0 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 Investigaton 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 OMT group and 88.9% in the TEVAR plus OMT 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 determine whether TEVAR in the subacute phase of uTBAD impacts overall survival at five years.
Secondary Objectives
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To determine the risk of aortic-related mortality.
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To determine the risk of neurological injury, either stroke or paraplegia, among patients who received TEVAR treatment, but also those who were treated with OMT.
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To determine the proportion of patients with uTBAD randomized to OMT who crossed over to TEVAR treatment within 5 years due to development of an aortic complication.
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To determine, based on subgroup analyses, whether extent of treatment is associated with either improved survival or neurological injury.
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To determine the associated risk of reinterventions for patients with uTBAD treated with TEVAR.
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To determine the associated changes in quality-of-life.
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To determine the 10-year overall survival and aortic-related mortality.
Endpoint Definitions
Primary endpoint: All-cause mortality.
Secondary endpoints:
Aortic-related mortality: Death as a result from aortic rupture or organ malperfusion.
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. Spinal cord ischemia is defined as either ischemic or hemorrhagic resulting in paraparesis or paraplegia.
Reintervention: Any open or endovascular intervention after the original TEVAR procedure that was related to the dissection or a complication of the initial procedure.
Rationale for objectives and endpoint selection
Despite evidence from retrospective and descriptive studies suggesting long-term benefits for early TEVAR intervention among uTBAD patients, the underlying unanswered question is whether TEVAR confers a benefit of survival. The two previous RCTs, mentioned above, were underpowered to address this issue. A demotion of this important endpoint of overall survival to a secondary status would limit the value of this trial.
Therapeutic Agents and their Definitions
Optimal Medical Therapy (OMT)
Contemporary optimal 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 centres/surgical team, based on the individual patient's prior and current therapy and tolerance to various medical regimens. While the goal is to reduce the systolic blood pressure between 100 - 120 mm Hg and the pulse rate below 60 beats/minute, the advocated first-line therapy consists of beta-blockade, with calcium channel antagonists and/or renin-angiotensin inhibitors as alternatives. Pain relief is furthermore up to the discretion of the physicians and patients.
Thoracic Endovascular Aortic Repair (TEVAR)
Patients randomized to TEVAR therapy will undergo placement of an endovascular stentgraft in the descending thoracic aorta. 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 patients are allowable under the allocation to the TEVAR patient cohort, as this reflects real-world considerations and the question at hand based on analysis of an intention-to-treat.
The trial is a randomized, open label, clinical trial with parallel assignment of patients in multiple centres in Denmark, Sweden, Norway, and Finland. Recruited patients will be randomized to either OMT exclusively or TEVAR + OMT.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| No Intervention: Medical Therapy Patients will be treated with optimal medical therapy, i.e., antihypertensives, pulse-rate regulators, and pain medication. |
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| Active Comparator: Stent Therapy Patients will be treated with both optimal medical therapy, in addition to placement of a thoracic endovascular aortic repair stent graft. |
Device: TEVAR
A TEVAR stent graft will be placed in the descending aorta in order to cover the primary entry of the dissection.
Other Names:
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Outcome Measures
Primary Outcome Measures
- Survival [Five years]
Overall survival
Secondary Outcome Measures
- Aortic-related mortality [Five years]
Death as a result from aortic rupture or organ malperfusion
- Neurological injury [Five years]
Cerebrovascular accidents and/or spinal cord ischemia
- Crossover [Five years]
The proportion of patients who cross over from OMT to TEVAR
- Reintervention [Five years]
The number of open or endovascular interventions after the original TEVAR, including crossovers, that were related to the dissection. Categorised as planned or unplanned.
- EQ-5D-5L [Five years]
Quality of life.
Eligibility Criteria
Criteria
Inclusion Criteria:
All patients, aged 18 or greater, admitted or referred to the participating vascular surgery centres with an acute (< 14 days) or subacute (<90 days) uncomplicated type B aortic dissection.
Exclusion Criteria:
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Patients presenting with a complicated type B aortic dissection.
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Patients previously treated in their descending aorta, either open surgery or TEVAR.
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Patients with pre-existing thoracoabdominal aortic aneurysm.
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Patients with an established connective tissue disease at the time of randomization, including but not limited to Marfans and Loeys-Dietz syndrome.
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Patients with bilaterally occluded iliac arteries.
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Patients with a clinically estimated life expectancy < 2 years.
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Patients with dementia.
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Pregnant or nursing patients.
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Patients with current sepsis.
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Patients currently participating in other clinical interventional trials.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Aarhus University Hospital | Aarhus | Denmark | 8200 |
Sponsors and Collaborators
- University of Aarhus
Investigators
- Principal Investigator: Jacob W Budtz-Lilly, MD PhD, Aarhus University Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 8240