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Type B aortic dissection - Intervention vs. best medical treatment
Christoph Nienaber
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Thoracic endografting has evolved from an alternative to surgery in high-risk patients to encompassing a range of thoracic aortic diseases such as acute and chronic dissection, intramural haematoma, penetrating ulcer, traumatic injury myocotic aneurysms and anastomotic aneurysms.
The successful management with thoracic stent grafting of aortic dissection necessitates that the proximal entry tears are sealed by placing the device in the true lumen across the entry tear. This inhibits both proximal communications and flow to the false lumen. As a result depressurisation of the false lumen occurs thereby facilitating reconstruction of the true channel. Not only does this induced proximal thrombosis of false lumen support repositioning of the dissection lamella, but it enables progressive caudal thrombosis and fibrosis of the false lumen resulting in stent-induced aortic remodelling.
Treatment options
Normally, type B chronic aortic dissection is treated with antihypersensitivity drugs, with surgery (both elective and emergency) it is considered an option in complicated cases. Although approximately 85% of patients who have antihypersensitivity treatment leave hospital, the five year mortality rate is estimated to be 50% often the result of the expansion of the false lumen (and the subsequent development of a thoracic aneurysm) or retrograde progression of dissection. In addition, there is a 14% to 67% risk of irreversible spinal cord injury or postoperative mortality following surgery. Many of these patients also have serious co-morbidities such as coronary artery disease, emphysema, high blood pressure or diabetes. These conditions make it difficult, if not impossible, for them to survive open surgical repair.
However, the data from the International Registry of Aortic Dissection showed a one-year mortality rate of <5% following endograft placement for the treatment of type B aortic dissection (figure 1). This is because endovascular procedure has the potential for less complications and better outcomes in both elective and emergency endograft treatment.
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Figure 1
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Figure 2
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The INSTEAD trial
As a result, the Investigation of Stent Grafts in Patients With type B Aortic Dissection (INSTEAD) study was designed as a prospective randomised thoracic clinical study, to compare one-year outcomes of patients treated for aortic dissection with an endograft (Medtronic Talent Thoracic Stent Graft System) in addition to tailored antihypertensive treatment to patients managed only with conventional antihypertensive treatment alone. The purpose of the study is to assess the role of endografts in uncomplicated patients with type B dissection and determine how this course of treatment compares to conventional (antihypertensive) treatment. The exclusion and inclusion criteria are listed in Tables I and II. Due to the difficulty in evaluating the role of endografts in reconstruction and healing of the dissection, patients with type B aortic dissection and spontaneous flase lumen were excluded. Patency of the false lumen was measured at baseline by MRI, CT or TEE. The study involves 136 patients with type B aortic dissections, and is taking place at 11 clinical sites in four European countries - Austria, Germany, France and Italy (Appendix A). All participating physicians had performed at least ten endovascular repair procedures for aortic type B dissection as primary operators.
The Talent Thoracic Stent Graft is introduced through a small opening in the femoral artery of the leg and advanced under fluoroscopic guidance to the site of the thoracic aortic aneurysm or dissection. The delivery system is tracked over the wire to the predetermined position aiming to seal the entry tear. Once in place, the stent graft expands to fit within the diameter of the aorta, thereby excluding the aneurysm or the false lumen, by providing a new path for blood. Transoesophageal ultrasound and angiographic imaging established closure of the entry tear(s), stent apposition and flow condition in the excluded false lumen.
Outcomes measures, follow-up and recruitment
The primary outcome measure is all-cause mortality. Secondary outcome variables (ancillary end points) include conversion to stent and/or surgery, induced thrombosis of the false lumen, cardiovascular morbidity, aortic expansion (>5 mm/y of maximum diameter including true and false lumen), quality of life, and length of intensive care unit and hospital stay. All study patients are scheduled for follow-up visits at three, 12, and 24 months post-randomisation. The INSTEAD study began in February 2002 and completed its recruitment of 136 consecutive patients in May 2005.
The primary outcome analysis will be the comparison of survival curves for all-cause mortality between the two study groups on an intent-to-treat basis. Survival curves will be plotted, and the statistical difference between the curves will be assessed by nonparametric log rank test statistics.
Secondary end-points of the INSTEAD study do not form the basis for sample size determination, therefore there may or may not be sufficient power to demonstrate statistical difference or equivalence between the two study groups.
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Figure 3
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Figure 4
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Power calculation
The study is designed to find an 18% difference in mortality over one year between the two types of treatment. The null hypothesis would mean no difference in mortality between the two treatment groups. The null hypothesis will be rejected in favour of one alternative if a difference in mortality between the two treatment arms reveals a P value <.05 and/or if the 95% CI of the difference will not include zero. Allowing for a type I error of 5% (a = .05), a sample of 136 patients (68 per arm) will give an 80% power to reject the null hypothesis, calculated under the assumption that the group undergoing stent-graft treatment plus antihypertensive medications has an expected one-year mortality of 5%.
The one-year mortality rate is expected to be 23% or even higher with antihypertensive treatment alone, based on the observed difference in outcomes of patients with stable type B aortic dissection who underwent either elective stent-graft placement or antihypertensive treatment and were followed for two years (both treatment arms had 80 patients each).
Discussion
Dissection of the aorta is a life-threatening condition as a result of the separation of the aortic media layer and creation of true and false lumina. Both the extent of dissection and the number of communication sites may vary as much as anatomical and clinical sequelae. Patients with complicated type B aortic dissection have been shown to benefit from early endovascular interventions avoiding events associated with high early mortality such as imminent rupture and malperfusion syndrome.
Thus, based on observational evidence, emergency cases are shown to benefit from early stent-graft therapy. Conversely, outcome analysis of stable type B aortic dissection after stent-graft placement has not been assessed in a prospective trial yet.
Despite medical therapy with antihypertensive drugs for uncomplicated type B dissection, surgical or endovascular interventions have been shown to benefit patients suffering from impending rupture, refractory hypertension, localised large false aneurysm, continued pain, or malperfusion syndrome.
The INSTEAD trial is the first randomised trial using endograft treatment of chronic type B aortic dissection to investigate two year outcomes of endovascular vs. conservative therapy. The study design excluded emergency cases of impending rupture and malperfusion (already known to benefit from endovascular treatment) and allowed time for custom-made devices to be supplied. Therefore, patients considered to benefit from and subjected to emergency interventions were not eligible for the INSTEAD trial.
Sample size figures were drawn from 12-month outcome data collected from the principal investigator's series of 80 previous patients in local databases at the Hamburg and Rostock University hospitals. A Kaplan-Meier life-table analysis shows at 12 months a risk of death in the those patients who received a stentgraft of 5.1% vs. a historic mortality of 27.5% with conventional therapy. Secondary end-points include conversion to open or endovascular repair and significant expansion of aortic diameter. Moreover, successful aortic remodeling, length of hospitalisation, and quality of life will be assessed to allow cost-effectiveness measurements.
Although a small series of studies have suggested the superiority of endovascular therapy in comparison with surgery for type B aortic dissection and the case can be made for stent induced aortic remodelling, answers maybe provided by the multi-centre randomised INSTEAD trial that has now completed recruitment.
Interim data
Interim date demonstrating the distribution of available data, demographics and history of co-morbitdities can be seen in Figures 2, 3 and 4, respectively. As this data is an interim analysis and not all have been collected (baseline data and discharge data is still pending for two and four patients respectively) and cleaned so far, this data is presented blinded for the study arms. It is important to note that this is uncleaned data and are susceptible to further modifications during the adjudication process.
Full one-year data will be presented in Fall 2006.
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Inclusion and Exclusion criteria
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