Outcomes of Thoracic Endovascular Aneurysm Repair (TEVAR) in Patients With Connective Tissue Disorders

Introduction

Connective tissue disorders such as Marfan syndrome (MFS), Ehlers-Danlos syndrome (EDS), and Loeys-Dietz syndrome (LDS) are associated with an increased risk of thoracic aortic aneurysm formation and dissection. ¹ Marfan syndrome is an autosomal dominant disorder with mutation of the fibrillin-1 gene and occurs relatively commonly in about 2 to 3 of 10 000 individuals. ² The most concerning manifestations in these patients remain the cardiovascular complications. Aortic dissection and aneurysm is age-dependent, with severe cases of dilatation at the sinuses of Valsalva occurring in utero. ²

There are 6 subtypes of EDS, with subtype IV being primarily responsible for vascular complications and arterial rupture. ¹ Type IV EDS is caused by an autosomal dominant defect in the COL3A1 gene, which results in ineffective collagen synthesis and vascular fragility. ^3,4 Loeys-Dietz syndrome is caused by an autosomal dominant mutation in the transforming growth factor beta receptor genes 1 and 2. The upregulation of TGF-B in blood vessels leads to aggressive aortic aneurysm formation and arterial tortuosity. ¹

Over the past 20 years, thoracic endovascular aortic repair (TEVAR) has gradually become the treatment of choice for thoracic aortic disease. ^5,6,7 When compared with open surgical repair, TEVAR is associated with a shorter length of hospital stay, lower rates of postoperative paraplegia, and fewer cardiac complications. ^{8 -11} However, for patients with connective tissue disorders, open repair is still generally preferred due to concerns of vessel fragility and weakness of the arterial wall. ^12,13 A weak arterial wall could potentially make endograft placement, which relies on adequate seal in “normal” aortic tissue, a less durable option due to concerns of subsequent proximal or distal aortic degeneration. This degeneration is likely a result of outward force of the endograft on a fragile vessel intima. Therefore, the traditional approach of an open repair with suturing graft material directly to the aorta has better durability.

Despite this, some physicians may still elect to perform a TEVAR in patients who are too high risk for surgery, young, or as a bridge to subsequent open repair. Our objective was to utilize the national Vascular Quality Initiative (VQI) database to analyze the outcomes of endovascular treatment of patients with connective tissue disorders and thoracic aortic pathology.

Methods

Utilizing the VQI national registry, a retrospective cohort study was performed. This study was approved by the Society for Vascular Surgery Vascular quality initiative (SVS VQI) Research Advisory Committee and the institutional review board of Northwell Health (15-378). The need for patient consent was waived. The VQI registry identified 12 207 patients who were treated with TEVAR from January 2010 to December 2018, including 102 with diagnoses of MFS, EDS, or LDS. These diagnoses are not based off of genetic testing, but rather on patient-reported history and clinical characteristics.

Data were collected regarding patient demographics, indications for treatment, anatomic characteristics, and perioperative details. Patients were categorized by the treating center as aneurysmal, acute, or chronic dissections. Zone of disease was also determined by the treating center and we collected data on proximal zone of the disease process and the proximal and distal landing zones of the TEVAR endograft. Perioperatively, we analyzed technical success as well as presence and type of endoleak, spinal cord ischemia, visceral ischemia, stroke, myocardial infarction, and lower limb ischemia. Perioperative mortality was defined as mortality within 30 days of operation. Follow-up data were utilized to assess 1-year mortality as well as reintervention rates and endoleaks.

Results

The VQI registry included 12 207 patients treated with TEVAR during the selected time period, with 102 patients with a history of a connective tissue disorder. Median age was 50.6 years (interquartile range: 57.0-75.0), and 62 (60.7%) were male. Eighty-eight (86.3%) patients had MFS, 9 (8.8%) had EDS, and 5 (4.9%) had LDS (Table 1).

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Table 1.

Demographics.

Demographics	N = 102
Male	62 (60.7%)
Age, years	50.6 (IQR: 39-62)
African American	17 (16.7%)
Height (inches)	71.9 (IQR: 69-75.9)
COPD	18.60%
CVD	7.80%
CHF	12.70%
CAD	14.70%
DM	7.80%
HD	2%
HTN	78%
Smoking	44.50%
Genetic history
Marfans	88
Ehlers-Danlos	9
Loeys-Dietz	5
Prior open surgical aortic intervention
Ascending thoracic	38
Descending thoracic	13
Suprarenal aorta	3
Infrarenal aorta	4
Prior endovascular aortic intervention
Ascending thoracic	2
Descending thoracic	7
Suprarenal aorta	2
Infrarenal aorta	4

Abbreviations: CAD, coronary artery disease; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular disease; DM, diabetes mellitus; IQR, interquartile range; HD, hemodialysis; HTN, hypertension.

Twenty-six (25.5%) patients were treated for degenerative aneurysmal disease with mean maximum aortic diameter of 53.2 mm (±0.9). Seventy-six (74.5%) patients were treated for type B dissections. Of the patients categorized as type B dissections, 33 (43.4%) were acute, and 31 (40.8%) were chronic, while 12 (15.7%) did not have information regarding chronicity. Most common indications for interventions in patients with type B dissection were pain (n = 41), aneurysmal degeneration (n = 16), and malperfusion (n = 8), with 3 patients who presented with a rupture of their aorta.

In terms of procedural details, percutaneous access was utilized in 61.7% of patients, with a 2.9% rate of arterial injury requiring reintervention. Spinal drains were placed preoperatively in 50 (49%) patients. Technical success was 95.2% with one conversion to open repair in a patient who presented with a ruptured thoracic aortic aneurysm. The majority of stent grafts proximal landing zone was zone 2 (n = 31) followed by zone 3 (n = 25) and zone 4 (n = 12). Distal landing zones were primarily zone 4 (n = 34) and zone 5 (n = 25). There was no significant correlation between zone of coverage and endoleak or retrograde dissection.

In the postoperative period, rate of return to operating room for aortic intervention was low (2.9%, n = 2). One patient had persistent type 1 endoleak, and another patient had persistent false lumen perfusion requiring reintervention. The rate of arterial access injury requiring return to OR was 2.9%.

In terms of perioperative morbidity, the rates of myocardial infarction (1%), CVA (1%), and spinal cord ischemia (1.96%) were low. Perioperative mortality was 1.96%. Two patients died in the postoperative period, 1 ruptured postoperatively and 1 had visceral ischemic embolization requiring multiple returns to the operating with bowel resection but ultimately died.

When comparing the different subgroups (acute/chronic dissection and aneurysm) there was no significant difference in terms of rates of overall perioperative complications, summarized in Table 2 (P = .14). Endoleak rates were more common in patients with aneurysmal disease (Table 2).

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Table 2.

Perioperative Complications.

Perioperative complicationsa	Overall	Dissection		Aneurysm
		Acute	Chronic
	N = 102	N = 33	N = 31	N = 26
Mortality	2 (1.96%)	1 (3.0%)	1 (3.2%)	0 (0%)
Endoleak	13 (12.7%)	0 (0%)	4 (12.9%)	7 (26.9%)
Type I	4	0	2	2
Type II	4	0	1	3
Type III	1	0	0	1
Type IV	1	0	0	1
Indeterminate	3	0	1	1
Spinal cord ischemia	2 (2.0%)	2 (6.1%)	0 (0%)	0 (0%)
Limb ischemia	4 (3.9%)	3 (9.1%)	0 (0%)	0 (0%)
RTOR for aortic intervention	3 (2.9%)	2 (6.1%)	1 (3.2%)	0 (0%)
Arterial injury	3 (2.9%)	1 (3.0%)	1 (3.2%)	0 (0%)

Abbreviation: RTOR, Return to Operating Room.

^a P = .14 − comparison of overall perioperative complication rate between each group.

Follow-up data were available for 75 (73.3%) patients at a mean follow-up of 15.6 months. Overall mortality was 5.3%, mortality cause was not listed in the VQI database for these patients. There were 30 patients with follow-up endoleak data, and 8 (26.7%) endoleaks were identified. All endoleaks were in patients treated for acute type B dissection, and all resolved after a mean of 2.1 reinterventions. Two (1.96%) patients treated for acute TBAD had retrograde dissections requiring intervention. There were zero late ruptures identified.

Discussion

Our study identified 102 patients with connective tissue disorders treated with TEVAR. While it accounts for a small percentage of total TEVARs (0.8%), we found operative outcomes had high rates of technical success (95.2%) and low open conversion rates, with low rates of perioperative morbidity (spinal cord ischemia [2%], limb ischemia [3.9%], and arterial injury [2.9%]) and perioperative mortality (1.96%).

Botta et al studied 12 patients with MFS who underwent stent graft repair of descending aortic dissection. They reported no instances of surgical conversion, in-hospital deaths, perioperative paraplegia, or stroke. On follow-up, there were 2 cases of type II endoleak that resolved spontaneously within 12 months and 1 case of type I endoleak that required surgical reintervention. ¹⁴ Geisbüsch et al published a series on 8 patients with MFS and EDS who underwent TEVAR and also found no perioperative deaths, neurological complications, or conversions to open surgery. ¹⁵

Similarly, we also found low rates of endoleak (0%) in acute dissection perioperatively, but similar rates on follow-up (26.7%) ¹⁶ . All of the patients in Botta’s study had prior open aortic surgery, so it is possible that this contributed to their incidence of endoleak (25%). Regardless, they concluded that endovascular repair of descending aortic dissection can be safely performed in patients with MFS and our study advances this by showing similarly encouraging results in patients with connective tissue disorders. Of note, utilizing the VQI database, we are able to identify patients with prior open aortic surgery; however, there is no definitive way of determining whether proximal or distal seal of TEVAR was in that prior open graft. This is an important limitation as landing in a graft may be better than native aorta as it would be less vulnerable to potential degeneration.

Despite the operative feasibility of TEVAR in patients with connective tissue disorders, follow-up data are limited, and outcomes are controversial. Nordon et al reported 33% of reintervention in patients with MFS who underwent TEVAR for descending chronic dissection. ¹⁷ Eid-Lidt et al reported rates of 33% reintervention and 44% endoleak in Marfan patients with acute dissection who were treated with TEVAR. ¹⁸ These alarmingly high rates of complications on follow-up lead some to oppose endovascular intervention in patients with connective tissue disorders. In our study, we found 8 (26.7%) cases of endoleak in 30 patients with follow-up data at 15.6 months. These occurred solely in patients treated for acute dissection with no instances of endoleak occurring in chronic dissection or aneurysm.

These results suggest that acute type B dissections represent a higher risk subgroup with increased rates of endoleak and may require closer follow-up. The low risk of endoleak in chronic dissection and aneurysm suggests that endovascular interventions may have better long-term outcomes in these subgroups. Interestingly, Pacini et al noted that early endoleak occurs more often with chronic dissection (31%) as opposed to acute dissection (9%) in patients with MFS. However, the average age in the group with acute dissection was 31.9 years, which is significantly lower than that of the group with chronic dissection at 44.2 years. ¹⁹ Since connective tissue disorders are progressive and worsen with age, the integrity of the vessels more than 10 years later may be considerably worse and contribute to increased risk of postoperative endoleaks.

There are no large studies on TEVAR outcomes in EDS or LDS, but case reports have shown some success. Khalique et al reported a case of a patient with EDS type IV who presented with acute type B dissection was subsequently treated with endovascular stent graft and remained free of complications at 4-year follow-up. ²⁰ Kalra et al studied 2 patients with LDS who were managed with TEVAR for dissected descending aorta and found no evidence of endoleak or complications at 23-month and 4-year follow-up. ²¹ Similarly to the case reports, our study does not have long-term follow-up data, so it is difficult to speculate outcomes of endovascular procedures in these patients past this time period.

Retrograde dissection after endovascular treatment for type B dissection is a serious and life-threatening complication. Dong et al found that it occurred in 11 (2.5%) of 443 patients treated with stent graft for descending dissection and 3 of these patients had MFS. ²² Chen et al showed a similar incidence of 2.5% with a high associated mortality of 37.1%, more frequently occurring in aortic dissection as opposed to aneurysm. ²³ Of the 30 patients in our study who have data available, 2 of them were found to have retrograde dissection requiring intervention. All of these patients were treated for acute type B dissection, which is supported by the findings seen in Chen et al. This rate of 10% is significantly higher than the 2.5% seen in the normal population of patients and indicates the need for careful consideration prior to undergoing TEVAR in patients with connective tissue disorders who present with acute aortic dissection. This is also limited by the lack of available data for all patients regarding retrograde dissection.

Limitations of this study include its lack of long-term follow-up. Outcomes using the VQI registry have follow-up data available for 15.6 months. However, it is possible that the timeline for endovascular treatment failure could have been years after the initial presentation. Without this information, it is difficult to conclude the viability of TEVAR long-term. However, the promising perioperative outcomes and follow-up results until this time indicate that it can be used as a bridging procedure or as part of a staged treatment plan. In addition, there are many more patients with Marfan than Ehler-Danlos or Loey-Dietz in this study. These are genetic syndromes with distinct pathophysiologies and manifestations that do not necessarily have the same incidence of vascular complications and risks. However, cases of TEVAR in patients with Loeys-Dietz and Ehlers-Danlos are relatively rare and our study advances the limited literature on this topic.

In conclusion, TEVAR for patients with connective tissue disorders and thoracic aortic pathology can be performed with low perioperative mortality, spinal cord ischemia, or CVA. On follow-up, acute type B aortic dissections represent a higher risk subgroup with increased rates of endoleak and retrograde dissection. Closer follow-up for these patients and early reintervention may be beneficial.