EARNEST Study

Background

Aortic dissection is a life-threatening emergency, occurring in men and women in all age groups. UK incidence of thoracic aortic dissection is increasing along with the number of patients receiving treatment.[1] Published incidence of aortic dissection varies, between 0.5–6.3 per 100,000 person years.[2] The Well-executed Oxford Vascular Study,[3] the most relevant to this proposal estimated an incidence of 6 per 100,000 person years for all dissections with 15/52 events due to TBAD. Therefore, one may estimate that there will be 1,163 people with TBAD dissections each year in the UK, more than 60% will be uTBADs.[4]

In aortic dissection, a primary tear or defect in the intimal lining of the aorta or bleeding within the media of the aorta results in separation or dissection of the layers of the aortic wall. The dissection may progress proximally or distally. Two or more distinct channels form - the true and false lumen. Dissection entry tears distal to the left subclavian artery and dissection extending through the thoracic and often the abdominal aorta (see left figure) are classified as Stanford type B aortic dissections (TBAD). Immediate complications occur in some patients with TBAD due to a restriction of blood flow through the true lumen causing malperfusion of the end organs (e.g., gut, kidney, spine, lower limbs); direct occlusion of the branches of the aorta by the intimal flap (lamella); or from aortic dilatation and rupture of the thin, fragile wall of the false lumen. Immediate treatment is needed. TBAD patients without major complications, with uTBAD, are conventionally treated medically, with BP management and entered onto a surveillance programme. European Society of Vascular Surgery guidance supports this treatment strategy.[5]

With conservative treatment of uTBAD, approximately 1/3 of patients develop late aneurysmal change with risk of rupture. Therefore, if fit, patients with known aortic expansion are offered an operation when the aorta reaches 5.5-6cm in diameter. These procedures are usually complex, extensive operations and carry a significant risk of death. The 30-day mortality rate in the effective treatment of thoracic aortic aneurysms (ETTAA) study was 6.7% after endovascular treatment and 11.1% after open surgery for chronic aneurysms of the aorta. Major complications such as paraplegia, stroke, myocardial infarction, respiratory failure and renal failure are frequent.[6, 7] The cost to the NHS is significant. In addition, the quality of life of patients under surveillance may be significantly impaired.

 Rationale

A review of the evidence assessing the use of TEVAR early after uTBAD reveals two RCTs involving 201 patients,[8, 9] registry studies involving nearly 2000 patients,[4, 10, 11] a propensity matched analysis of 145 patients,[12] and a systematic review with 14,706 patients,[13].

One RCT [9] involving 61 patients showed that TEVAR was safe, with no mortality or stroke. In this study, incomplete false lumen thrombosis (and hence a much higher chance of late dilatation) was found in 43% of the stenting group but 97% of the medically treated group. Forty-five percent of the medically treated group (BMT and surveillance) had aortic dilatation compared to 37% in the TEVAR and BMT group, but the study did not go on to examine long term clinical outcomes. There has been one RCT, examining clinical outcomes, allocating 140 patients to BMT and surveillance or TEVAR and BMT. This trial again showed remodelling of the aorta. The trial was extended to 5-years and using a landmark analysis strategy (designating a time point during follow-up (known as the landmark time) and analysing only those participants who have survived until this point) there was a significant advantage to stenting. This trial included patients 2-52 weeks after TBAD and so many received a stent once the aortic dissection flap between the true and false lumen lost its plasticity, so the expected remodelling of the aorta and closure of the false lumen would be less effective. Neither RCT reported cost-effectiveness.

Several registry-based publications have demonstrated an advantage to early TEVAR. A propensity matched analysis recorded that although the adverse event rate at 30-days after TEVAR was greater than in the BMT group, all-cause mortality in the TEVAR group was significantly lower at 5 years than that of the BMT group (8.1% vs. 17.8%), and aortic-related mortality was also lower in the TEVAR group compared to the BMT group (5.9% vs. 13.9%).[12] These 2 original RCTs and 4 observational studies were incorporated into one meta-analysis, involving 14,706 patients in total, of which 1,066 had TEVAR.[13] The aim was to compare peri-operative and late outcomes of patients with acute and subacute uTBAD treated by TEVAR or BMT. For the BMT group there was a lower early risk of stroke but the risk of late all-cause mortality (HR 1.54, 95% CI 1.27-1.86, p < .001) and aorta related mortality (HR 2.71, 95% CI 1.49-4.94, p = .001) was significantly higher than with TEVAR. Clearly the observational nature of the included studies means that the study suffers from inherent bias.

 INCLUSION CRITERIA 

• Patients with uTBAD, 10 days-3 months after the day of admission with acute uTBAD to hospital (the date of the index event). Note: patients are allowed left subclavian artery coverage/bypass and/or adjunctive procedures on/to the iliac vessels to permit safe introduction of the delivery device.
• Age ≥18.
• Life expectancy ≥2 years.
• Willing and able to provide written informed consent: voluntary agreement to participate in the trial following full disclosure of risks and procedures required

EXCLUSION CRITERIA

• Complicated TBAD (ruptured aorta, aortic dilatation >5cm or visceral/limb/spinal malperfusion, persistent pain or uncontrolled BP)
• Known connective tissue disorder
• Previous TBAD
• Type A dissection with distal residual dissection
• Intramural haematoma alone
• Traumatic dissection
• Aorto-iliac aneurysms
• Requiring carotid/innominate artery revascularisation to create a TEVAR landing zone or planned visceral artery intervention
• Unable to attend follow-up appointments
• Pregnancy during the period where stenting of the aorta would be necessary.

Participant Information Sheet: EARNEST PIS

Protocol: EARNEST Protocol

TBC

The aorta is the main blood vessel in the body; it carries blood full of oxygen from the heart to all the arteries that supply individual organs. It runs from the heart, in the chest, initially supplying blood to the head and arms and then it arches around and goes down to supply blood to all the other organs. An aortic dissection is a painful life-threatening condition caused by a tear in the lining of the aorta. Blood flows through this tear and forces the layers of the aortic wall apart creating an unintended false channel, often referred to as a false lumen. The true lumen is where the blood normally flows. A dissection involving the descending thoracic aorta at the back of the chest is called a type-B aortic dissection (TBAD) and occurs in both sexes and at all ages.
 
In some patients this can lead to immediate life-threatening complications such as a burst aorta with bleeding, or a significant restriction in blood flow to vital organs that requires emergency surgical treatment. However, more than eight in every ten patients with TBAD do not have an immediate life-threatening complication, these are uncomplicated TBAD (uTBAD) and are currently treated medically. This involves treatment with blood pressure (BP) tablets and regular surveillance each year with CT scans of the aorta to monitor for long-term problems.
 
Around three in ten of these patients will go on to develop an aortic aneurysm, as illustrated in diagram 2—a condition characterized by the ballooning of the body's main blood vessels—despite receiving optimal medical treatment for their dissection. If an aneurysm forms, there is a risk of bursting or rupture, with life-threatening internal bleeding. Repair is offered if the aorta reaches 5.5-6cm in size. These procedures are often complex, extensive operations with significant risk of death and major complication such as heart attack, stroke, kidney failure and paraplegia (paralysis of the legs).
 
It has been proposed that an early operation may be effective in allowing the aorta to remodel (heal) and avoid long-term expansion. The aorta is relined within 3 months to close the aortic tear with a stent graft. This is known as thoracic endovascular aortic repair (TEVAR). Surgeons use a small incision in the groin to insert a stent, which is a fabric tube with a metal scaffold, into the aorta under X-ray guidance. TEVAR relines the aorta and closes the tear, obliterating the false channel and leads to healing (remodeling) of the aorta in many cases. This operation reduces the risk of expansion and rupture and the need for complex operations in the years to come.
 
The TEVAR procedure is a well-established vascular surgery procedure which is minimally invasive – in other words surgeons use a keyhole approach, but with all operations there are some risks that may occur and of course some patients will get an operation who wouldn’t have gone in to form an aneurysm in the long term. Currently, there is no evidence that early TEVAR is better than medical treatment alone after aortic dissection. This study, which is explained in detail below, is a “randomised trial” to assess the clinical and cost-effectiveness of thoracic endovascular aortic repair (TEVAR) in patients with dissection.

• The Aortic Dissection Charitable Trust
• Aortic Dissection Awareness UK & Ireland Patient Charity
• British Heart Foundation
• Circulation Foundation