Assessment of the Effectiveness of Zone 1-Landing Hybrid TEVAR by Comparing Its Outcomes with Those of Zone 2-Landing Hybrid TEVAR

Abstract Background: Hybrid thoracic endovascular aortic repair (TEVAR) without median sternotomy is increasingly being performed in high-risk patients with aortic arch disease. The outcomes of hybrid TEVAR were reported to be worse with a more proximal landing zone. This study aims to clarify the effectiveness of zone 1-landing hybrid TEVAR by comparing the outcomes of zone 2-landing hybrid TEVAR. Methods: From April 2008 to October 2020, 213 patients (zone 1: zone 1-landing hybrid TEVAR, n = 82, 38.5%; zone 2: zone 2-landing hybrid TEVAR, n = 131, 61.5%) were enrolled (median age, 72 years; interquartile range [IQR], 65–78 years), with a median follow-up period of 6.0 years (IQR, 2.8–9.7 years). Results: The mean logistic EuroSCORE was 20.9 ± 14.8%: the logistic EuroSCORE of the zone 1 group (23.3 ± 16.1) was significantly higher than that of the zone 2 group (19.3 ± 12.4%, p = 0.045). The operative time and hospital stay of the zone 1 group were significantly longer than those of the zone 2 group. On the other hand, the in-hospital and late outcomes did not differ significantly between the two groups. There were no significant differences in cumulative survival (66.8% vs. 78.0% at 10 years, Log-rank p = 0.074), aorta-related death-free rates (97.6% vs. 99.2% at 10 years, Log-rank p = 0.312), and aortic event-free rates (81.4% vs. 87.9% at 10 years, Log-rank p = 0.257). Conclusions: Zone 1- and 2-landing hybrid TEVAR outcomes were satisfactory. Despite the high procedural difficulty and surgical risk, the outcomes of zone 1-landing hybrid TEVAR were equal to those of zone 2-landing hybrid TEVAR. If the surgical risk is high, zone 1-landing hybrid TEVAR should not be avoided.


Introduction
The outcomes of hybrid thoracic endovascular aortic repair (TEVAR) have been reported to be worse when performed in more proximal landing zones [1,2].There are many reports of zone 0-and zone 2-landing hybrid TEVAR for aortic arch diseases, but few reports of zone 1-landing hybrid TEVAR [2][3][4][5][6][7].This is because an extra-anatomical bypass (right axillary artery [AxA]-left common carotid artery [LCCA]-left AxA bypass) and intracranial blood flow from the brachiocephalic artery (BCA) are required for zone 1-landing hybrid TEVAR.In our previous study, zone 1-landing hybrid TEVAR with extra-anatomical bypass did not influence the total intracranial flow [8].This study aims to clarify the effectiveness of zone 1-landing hybrid TEVAR by comparing its outcomes with those of zone 2-landing hybrid TEVAR.

Ethics Statement and Study Design
This single-center, retrospective, observational cohort study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of Osaka University School of Medicine.Informed consent was obtained from all patients before the procedures.

Study Population
Of the 752 patients who had undergone TEVAR for aortic arch pathologies between April 2008 and October 2020, 213 who had undergone zone 1-(Figure 1A) and zone 2-(Figure 1B) landing hybrid TEVARs were enrolled.The mean follow-up period was 6.0 years (interquartile range [IQR], 2.8-9.7 years).None of the patients were lost to followup, and all patient data were available.

Indications
The indications for surgical intervention for zone 1 and zone 2 hybrid TEVARs were as follows: aneurysm; aortic diameter expansion by ≥5 mm in 6 months; a maximum aortic diameter > 55 mm; aortic rupture; saccular aneurysm of any size; dissection; malperfusion syndrome; and an initial aortic diameter > 40 mm in TBAD, in addition to the indications for an aneurysm.

Treatment Strategy
The following anatomy of aorta conditions were satisfied before performing zone 1and zone 2-landing TEVARs: proximal LZ; diameter: ≤42 mm and length > 15 mm, and proximal stent graft; size ≤ 46 mm and oversizing rate: 10-20%.We selected a stent graft with the same oversizing for aneurysm and dissection.
Debranching procedures were as follows: zone 1-landing hybrid TEVAR; the patients underwent an extra-anatomical bypass from the right AxA to the LCCA and left AxA using a T-shaped, ringed, 8-mm expanded polytetrafluoroethylene graft, and zone 2-landing hybrid TEVAR; the patients underwent intentional covering of the left subclavian artery (LSA) without revascularization or extra-anatomical bypass (right AxA to left AxA and LCCA to left AxA).TEVAR was performed after the bypass within the same surgery.Since 2011, we have blocked the native forward flow of the blood vessel through which the device passes before TEVAR to prevent stroke due to thromboembolism.From 2012 onward, to prevent type 2 endoleak, we embolized the blood vessels using coils or ligated directly.Cerebrospinal fluid drainage was performed on patients with stent graft distal edge Th ≤ 10.The patients with atheroma grade ≥ 3 at the proximal LZ underwent TEVAR using a filter device from 2015, as previously described.

Indications
The indications for surgical intervention for zone 1 and zone 2 hybrid TEVARs were as follows: aneurysm; aortic diameter expansion by ≥5 mm in 6 months; a maximum aortic diameter > 55 mm; aortic rupture; saccular aneurysm of any size; dissection; malperfusion syndrome; and an initial aortic diameter > 40 mm in TBAD, in addition to the indications for an aneurysm.

Treatment Strategy
The following anatomy of aorta conditions were satisfied before performing zone 1and zone 2-landing TEVARs: proximal LZ; diameter: ≤42 mm and length > 15 mm, and proximal stent graft; size ≤ 46 mm and oversizing rate: 10-20%.We selected a stent graft with the same oversizing for aneurysm and dissection.
Debranching procedures were as follows: zone 1-landing hybrid TEVAR; the patients underwent an extra-anatomical bypass from the right AxA to the LCCA and left AxA using a T-shaped, ringed, 8-mm expanded polytetrafluoroethylene graft, and zone 2-landing hybrid TEVAR; the patients underwent intentional covering of the left subclavian artery (LSA) without revascularization or extra-anatomical bypass (right AxA to left AxA and LCCA to left AxA).TEVAR was performed after the bypass within the same surgery.Since 2011, we have blocked the native forward flow of the blood vessel through which the device passes before TEVAR to prevent stroke due to thromboembolism.From 2012 onward, to prevent type 2 endoleak, we embolized the blood vessels using coils or ligated directly.Cerebrospinal fluid drainage was performed on patients with stent graft distal edge Th ≤ 10.The patients with atheroma grade ≥ 3 at the proximal LZ underwent TEVAR using a filter device from 2015, as previously described.

Follow-Up
Follow-ups were performed during regular patient visits.The patients were followed up with at least once every 3 months for the first year and every 6 months or 1 year there-after at our hospital for MDCT examination.Patient death was confirmed via telephone interviews with the patients' families.

Outcome Criteria
The primary outcomes of interest were (1) aortic events; known or suspected events, such as stroke, aneurysm enlargement ≥ 5 mm in diameter, or any cases of endoleak; stent graft migration; aortic rupture; aortic dissection; and prosthetic infection; and (2) aorta-related death (defined as death due to adverse events secondary to aortic pathologies).False lumen (FL) reperfusion was defined as persistent FL flow from a proximal entry tear at dissecting aortic aneurysm.We defined a stroke as having neurologic symptoms.

Statistical Analyses
Results are expressed as mean ± standard deviation and median (IQR) according to the normality of the distribution, assessed using the Shapiro-Wilk test, and compared using the Mann-Whitney U test.Categorical variables are presented as counts and percentages using the chi-square test or Fisher's exact test.The curves for overall survival and freedom from aorta-related death and aortic events were estimated using the Kaplan-Meier productlimiting method and compared using the log-rank test.Estimates are provided with 95% CIs.All p values were 2-sided, and statistical significance was set at p < 0.05.All statistical analyses were performed using JMP statistical software, version 16.0.0for MacOS X (SAS Institute Inc., Cary, NC, USA).

In-Hospital Outcomes
The in-hospital outcomes are presented in Table 3.The median postoperative hospital stay was 10 days (IQR, 8-16 days).The 30-day mortality rate was 0.5% (n = 1).The hospital mortality rate was 0.9% (n = 2); one (0.5%) patient in the zone 1 group had an abdominal embolic event and one (0.5%) had an aneurysm rupture due to a type 1a endoleak.Two (1.0%; one [1.2%] in the zone 1 group and one [0.8%] in the zone 2 group) patients experienced a stroke, and two (1.0%; one [1.2%] in the zone 1 group and one [0.8%] in the zone 2 group) had spinal cord injury.Endoleaks were reported in 11 (5.2%) patients, including type 1a (n = 3; 1.4%), type 1b (n = 1; 0.5%), and type 1c endoleaks (n = 7; 3.3%).Aortic events and endoleaks did not differ significantly between the groups.Of the two patients with type 1a endoleaks, one was treated successfully with conventional arch repair and the other experienced an aneurysm rupture.One patient with a type 1b endoleak underwent TEVAR.All type 1c endoleaks were detected based on LSA.We embolized the LSA using the coils, and the type 1c endoleak disappeared.

Comparison of the Outcomes in Aortic Pathologies
Comparisons of the outcomes for aneurysms and dissections between the two groups are presented in Supplementary Table S1.For both aneurysms and dissections, the preoperative patient characteristics did not differ significantly between the two groups.The operative time and hospital stay in the zone 1 group were significantly longer than those in the zone 2 group.In contrast, in-hospital and late outcomes did not differ significantly between the two groups.In addition, the aorta-related death and aortic-event-free rates in aneurysms and dissections did not differ significantly between the two groups (Supplementary Figure S1A-D).

Comparison of the Outcomes in Aortic Pathologies
Comparisons of the outcomes for aneurysms and dissections between the two groups are presented in Supplementary Table S1.For both aneurysms and dissections, the preoperative patient characteristics did not differ significantly between the two groups.The operative time and hospital stay in the zone 1 group were significantly longer than those in the zone 2 group.In contrast, in-hospital and late outcomes did not differ significantly between the two groups.In addition, the aorta-related death and aortic-event-free rates in aneurysms and dissections did not differ significantly between the two groups (Supplementary Figure S1A-D).

Discussion
It is a well-known fact that total arch replacement (TAR) is the first-choice treatment method for aortic arch diseases [9][10][11][12][13].However, despite recent developments in surgical techniques and the perioperative management of aortic arch diseases, TAR, which requires sternotomy, hypothermic circulatory arrest, selective cervical arterial perfusion, and cardiopulmonary bypass, remains a high-risk procedure, particularly in older adults with significant comorbidities [14][15][16][17].Some previous studies have reported that high-risk patients aged > 75 years have significantly lower in-hospital mortality, and hybrid TEVAR improves short-and mid-term outcomes, particularly in high-risk patients [18,19].Some recent studies reported that the long-term results of hybrid TEVAR are equivalent to those of TAR [20][21][22][23].However, the outcome of TAR is better than that of hybrid TEVAR in terms of aortic event-free and aortic reintervention-free rates [21,23].Hybrid TEVAR has been established as the minimally invasive first-line treatment for aortic arch diseases at our institution since 2008 [24][25][26].
Zone 0-landing hybrid TEVAR requires a median sternotomy; therefore, zone 1-and zone 2-landing hybrid TEVARs should be recommended from the viewpoint of surgical invasiveness.In our previous study, zone 0-landing hybrid TEVAR performed relatively well.The stroke (1.5%), 30-day mortality (0.5%), 10-year aortic event-free (94.9%), and 10-year aorta-related death-free (82.3%) rates of zone 0-landing hybrid TEVAR were equal to those of zone 1-and zone 2-landing hybrid TEVARs.However, some studies have reported that the outcomes of hybrid TEVAR were worse in the more proximal landing zone.Zone 0 had an increased 30-day mortality rate compared to zone 1 (9.3% in zone 0 vs. 3.7% in zone 1), and zone 1 had an increased rate of ischemic stroke compared to zone 2 (7.7% in zone 1 vs. 6.6% in zone 2) [1,2].However, as previously reported, zone 0 landing hybrid TEVAR is undoubtedly advantageous for avoiding the bird-beak configuration [25,27].There is also a zone 0-landing hybrid TEVAR with the chimney technique, but as previously reported, a type 1a endoleak may occur; therefore, it is not recommended except in severe cases [28][29][30].
In the present study, both groups achieved satisfactory in-hospital and late outcomes.In-hospital mortality was 0.5% (1.2% in zone 1 vs. 0% in zone 2), and over 95% of the patients were discharged.The stroke rate was not significantly different between the groups (0.9%, 1.2% in zone 1 vs. 0.8% in zone 2, p = 1.00) and is superior to that reported in other studies.Regarding cerebral blood flow, our previous study showed that zone 1 and zone 2-landing hybrid TEVARs do not affect the total intracranial blood flow.In addition, this study revealed that the 10-year aortic event-free and aorta-related death-free rates were 98.6% (97.6% in zone 1 vs. 99.2% in zone 2, Log-rank p = 0.312) and 85.5% (81.4% in zone 1 vs. 87.9% in zone 2, Log-rank p = 0.257), respectively, which were superior to those reported in other papers on hybrid TEVAR.
It is an undeniable fact that anatomical consideration is important in stent graft therapy.In this study, zone 1-landing hybrid TEVAR had similar outcomes to zone 2-landing hybrid TEVAR, despite the high procedure difficulty and surgical risk.Therefore, zone 1-landing hybrid TEVAR has more outstanding merit in older adults, who cannot be treated with zone 2-landing hybrid TEVAR, than zone 0 landing hybrid TEVAR.

Limitation
This study has some limitations.First, this was a retrospective study, and some patients had relatively short follow-up periods.Second, the sample size was small for both groups, and more cases are required for further analysis.Therefore, a prospective multicenter study with long-term follow-up is required to confirm our findings.

Conclusions
The outcomes of zone 1-and zone 2-landing hybrid TEVAR were satisfactory.Zone 0-landing hybrid TEVAR is higher invasive.The high-risk patient with an unsuitable landing zone at zone 2 should not be discouraged from zone 1-landing hybrid TEVAR.

Supplementary Materials:
The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/jcm12165326/s1,Supplementary Table S1: Comparison of the outcomes in aortic pathologies.Supplementary Figure S1: Kaplan-Meier curve of the each aortic pathologies.

Table 1 .
Preoperative patient characteristics and measurements.