A systematic review and meta-analysis of thoracic endovascular aortic repair with the proximal landing zone 0

Background Thoracic endovascular aortic repair, initially intended for thoracic aortic disease treatment, has extended its application to the proximal zone of the aorta. However, the safety and surgical outcomes of extending the proximal landing zone into the ascending aorta (zone 0) in selected cases remain unknown. Thus, we performed a systematic review and meta-analysis of zone 0 thoracic endovascular aortic repair (TEVAR) to obtain a deeper understanding of its safety, outcomes, and trends over time. Methods A literature search was performed using PubMed, EMBASE, and Web of Science databases in accordance with the preferred reporting items for systematic reviews and meta-analyses guidelines, from January, 1997 to January, 2022. Only studies involving zone 0 TEVAR were included. The retrieved data from the eligible studies included basic study characteristics, 30-day/in-hospital mortality rate, indications, comorbidities, stent grafts, techniques, and complications. Summary effect measures of the primary outcomes were obtained by logarithmically pooling the data with an inverse variance-weighted fixed-effects model. Results Fifty-three studies with 1,013 patients were eligible for analysis. The pooled 30-day/in-hospital mortality rate of zone 0 TEVAR was 7.49%. The rates of post-operative stroke, type Ia endoleak, retrograde type A aortic dissection, and spinal cord ischemia were 8.95, 9.01, 5.72, and 4.12%, respectively. Conclusions Although many novel stent grafts and techniques targeting zone 0 TEVAR are being investigated, a consensus on technique and device selection in zone 0 TEVAR is yet to be established in current practice. Furthermore, the post-operative stroke rate is relatively high, while other complication rates and perioperative death rate are comparable to those of TEVAR for other aortic zones.


. Introduction
Thoracic endovascular aortic repair (TEVAR) has become a viable treatment option for thoracic aortic pathologies over the past years (1,2). The proximal landing zone (PLZ) of the stent graft has been extended from the descending to the ascending aorta (zone 0) to ensure a sufficient and healthy PLZ. Following the development of surgical devices and improvement in supra-aortic vessels revascularization techniques, studies investigating the feasibility and safety of TEVAR with zone 0 landing have been conducted.

. . Inclusion and exclusion criteria
The studies included were published in English, containing zone 0 TEVAR, and clinical studies or cohort case reports. Studies containing only zone 0 TEVAR with prosthetic ascending aorta as the PLZ and studies, in which the reported number of cases of zone 0 TEVAR were <5, were excluded from the analysis.   N/A, not available, which means the specific information was not available or could not be extracted from manuscripts; TEVAR, thoracic endovascular aortic repair.

. . Statistical analysis
Data on stent graft, procedure and complications were summarized. Excel software (Microsoft Corp, Redmond, WA, USA) and Review Management 5.4 (The Cochrane. Collaboration, Oxford, UK) were used to record, analyze, conduct the metaanalysis, and tabulate clinical data. A meta-analysis was performed for perioperative mortality of zone 0 TEVAR and post-operative stroke, type Ia endoleak, spinal cord ischemia (SCI), and  . Results

. . Study selection
A total of 1,812 studies were retrieved from PubMed, EMBASE, and Web of Science between January, 1997 and January, 2022. A total of 133 studies were considered eligible according to the inclusion criteria, of which 74 were excluded according to the exclusion criteria ( Figure 1). Six studies were excluded because they were duplicates. Fifty-three studies, with a total number of 1,013 cases, were included in the final analysis ( Table 1). The present study included 48 retrospective and 5 prospective studies.

. . Pathology and comorbidities
The type of aortic pathologies and comorbidities are summarized in Tables 2, 3, respectively. Indications for zone 0 TEVAR of 636 cases from 32 studies were disclosed, and included aneurysm (n = 347, 54.56%), aortic dissection

. . Stent graft
Stent grafts used in zone 0 TEVAR are summarized in Table 4. , and E-vita (Jotec, Hechingen, Germany) (n = 1, 0.18%). In 337 (60.83%) cases, stent grafts had a proximal bare-metal portion. Three novel stent grafts dedicated to zone 0 TEVAR had been introduced in the reviewed studies (25, 34, 48). Zenith ascending stent graft is aimed at the ascending aorta and has no branches or fenestrations for supra-aortic vessels. Najuta thoracic stent graft system is a fenestrated stent graft with one to three fenestrations, which can preserve all supraaortic vessels. NEXUS Aortic Arch Stent Graft System is a novel single branch, two stent graft system used for endovascular aortic arch repair.
The causes and outcomes of stroke in 26 studies are presented in Table 6. Causes were disclosed in 11 studies, and outcomes were disclosed in 16 studies. Atherosclerotic plaque was considered the principal cause of stroke in six studies (12,18,26,29,45,55). Other possible causes suggested by the authors included migration and compression of chimney stents, LSA dissection, debranching of LSA, and lower left ventricular ejection fraction (27,32,39,44). Based on available data, it appears that stroke was the cause of death in 12 of the 65 patients who suffered from this complication (6,14,18,26,37,44,45).
Causes and outcomes of type Ia endoleak in 11 studies are shown in Table 7. Causes were disclosed in seven studies, while outcomes were disclosed in eight studies. Migration of stent graft was considered the principal cause of type Ia endoleak in three studies (16,28,37). Other possible causes suggested by the . /fcvm. .  authors included aneurysmal evolution of aorta, unfavorable stent placement, gutter leakage between the main stent graft and chimney stent, short distance between the ostium of innominate artery and the aneurysm, lack of comfortability of Najuta stent prototype, and short proximal neck length (10, 20, 31, 37, 55). Based on available data, 17 of the 36 patients who presented with type Ia endoleak were treated conservatively, while in 5 patients type Ia endoleak lead to aneurysm enlargement, which ruptured and caused death in 1 patient (6,10,15,20,28,30,42). Tables 8, 9 show the causes and outcomes of SCI and RTAD in 11 and 9 studies, respectively. One study suggested that SCI might have been caused by LSA coverage and long extent of aortic coverage (20). Outcomes of SCI were disclosed in 10 studies. Three out of 15 SCI patient were left with long-term sequelae (20, 30). Causes of RTAD were disclosed in seven studies, and outcomes were disclosed in nine studies, with clamp injury in hybrid procedure being considered the principal cause in four manuscripts (9, 21, 27, 46). An acute angle formed by the ascending aorta and PLZ, lack of conformability of the COOK TX2 stent graft in zone 0, primary disease progression, >30% oversizing of the stent graft, angulation of the proximal aortic arch >120 • and stent graft diameter >42 mm have also been suggested as possible causes   of RTAD (21, 35,51). Four patients died of complications related to RTAD, and based on the available data eight out of 17 patients received reintervention (6,9,15,19,21,46).

. Discussion
To meet the challenges posed by the lack of dedicated stent grafts for zone 0 TEVAR, numerous procedures and novel devices have been developed. Techniques range from hybrid surgery to fenestrated, chimney, and branched TEVAR, while newer devices try to provide simpler and safer procedures. According to the reviewed studies, no clear protocol was shown regarding the selection technique or device for zone 0 TEVAR.
Stroke is the most common post-operative complication after zone 0 TEVAR (8.95%). Two meta-analyses of TEVAR for descending thoracic aortic diseases performed by Karaolanis et al. and Allmen et al. suggested that stroke rates in TEVAR for descending aortic aneurysm and type B dissection were 4.1 and 4.4%, respectively, lower than those in zone 0 TEVAR (58, 59).
A meta-analysis from 2019 involving 989 patients undergoing total arch replacement with frozen elephant trunk also showed a lower stroke rate (8.95 vs. 2.38%) (60). Six authors suggested detachment of atherosclerotic plaque debris in the aortic arch, induced by manipulation of the guide-wire or stent graft delivery system was the cause of stroke (12,18,26,29,45,55). Three authors suggested that the occlusion of supra-aortic vessels owing to migration or compression of stents, and the dissection of supra-aortic vessels could be a further cause (24, 32, 44). Other possible causes included prolonged procedural time, lower left ventricular ejection fraction, and increased blood loss (27, 39). While no author in reviewed studies attributed stroke to planned LSA coverage without revascularization, the meta-analysis made by Chen et al. and Karaolanis et al. reported a significant reduction in stroke rate when the covered LSA had been revascularized (59,61). However, the stroke rate in the planned LSA coverage without revascularization remains unknown in reviewed studies. To prevent stroke, some authors introduced procedures such as mini-cardiopulmonary bypass support and temporary inflow blockage of branch vessels (39, 50). The principal goal of these  interventions is to prevent atheromatous debris from accessing the cerebral blood supply. Given 8.95% stroke rate and 18.46% (12/65) stroke-related death in the review, post-operative stroke prevention must be considered more when planning zone 0 TEVAR (6,14,18,26,37,44,45). The incidence of type Ia endoleak in zone 0 TEVAR is 9.01% in the review. That is slightly lower than that (10.07%) reported in the multicenter study, involving 1, 18, 43, 55, and 22 cases of zone 0, 1, 2, 3, 4 TEVAR, conducted by Hammo et al. (62) in 2019. In the aortic arch, the varied lengths of the outer and inner curves pose a barrier to the stent graft's stability. This leads a bird-beak configuration after TEVAR increasing the risk of type Ia endoleak. However, Kudo et al. (63) proposed that bird-beak configuration did not occur during the early or late periods after zone 0 TEVAR. Causes suggested by the authors include migration, unfavorable deployment, and lack of flexibility of the stent graft (10, 16,20,28,37   León et al. (42) classified type Ia endoleak as "fast" and "slow" based on the time needed to visualize the aneurysmal sac during arteriogram. Based on their observation, they postulated that slow endoleak tends to resolve naturally within 1 year after TEVAR. Of 36 patients with type Ia endoleak, one died of aneurysm rupture and 7 resolved spontaneously indicating that active surveillance and timely treatment can lead to favorable results in selected cases (6,9,42). The incidence of SCI is 4.12% in zone 0 TEVAR, near to that (4.5%) reported by Uchida, which included 7,309 patients treated by TEVAR in 2014 (64). There were no concrete explanations for SCI or risk factors in the reviewed studies. In theory, sacrifice of  LSA inflow is a risk factor for SCI; however, absence of detailed information impeded analysis in this review. In this review, only one SCI patient had their LSA covered without revascularization (20). Nonetheless, previous studies have suggested that LSA revascularization in selected patients might prevent SCI (34). Authors also provided other preventive procedures including prophylactic cerebrospinal fluid drainage and maintenance of higher mean arterial pressure (18,34). In this review, 8 cases of SCI were successfully treated with cerebrospinal fluid drainage. Only one case of permanent paraplegia was recorded, in a patient implanted with a long aortic stent, with LSA coverage (20). The rate of post-operative RTAD in the present review is 5.72%, lower than that reported by Chen et al. in their metaanalysis. Their study, conducted in 2018, highlighted the higher risk of RTAD in zone 0 TEVAR compared to zones 1, 2, 3, and 4 (8.12 vs. 2.57, 2.66, 0.67,% and 0.67%, respectively) (65). The anatomy of the arch and lack of comfort with newer stent grafts might contribute to the high rate of RTAD in zone 0 TEVAR. In four reviewed studies, RTAD patients had undergone hybrid procedures, and the leading cause suggested by the authors was clamp injury while debranching or bypassing branch vessels (9, 21, 27, 46). Oversizing of the stent graft, a large diameter of the stent graft, and an acute angle formed by the ascending aorta and PLZ contribute to RTAD according to some authors (21, 51). Although previous studies suggested proximal bare-metal configuration as a risk factor for RTAD, this configuration was present in 60.56% of cases in the reviewed studies and did not correlate with the rate of RTAD (65,66). Prevention of RTAD mainly focuses on pre-operative planning and stent graft design. Chassin-Trubert et al. (46) suggested that, in selected hybrid procedures, rapid right ventricular pacing might decrease the risk of RTAD following zone 0 TEVAR. Given the 4/17 (23.5%) relateddeath rate and 8/17 (47.0%) reintervention rate, surgeons should consider reintervention as soon as RTAD is discovered (6,9,15,19,21,46).
In the present review, the overall 30-day/in-hospital death rate of zone 0 TEVAR is 7.49%, close to that reported for all zone TEVAR (8.07%) in a systematic review by Ramdass in 2015 (67). But it exceeds the rates after TEVAR for descending thoracic aortic disease, as shown by Naazie in 2022 and Harris in 2020 (4.2% in 2,141 patients and 4.0% in 1,784 patients, respectively) (68,69). If arch disease is taken into account, the 30-day rate of death in this review is lower than that reported for frozen elephant trunk in a multicenter study by Leone (437 patients, 14.9%), and higher than that reported for open total arch replacement in a meta-analysis performed in 2016 (2,880 patients, 5.3%) (70,71).
The present meta-analysis and systemic review shows some limitations. First, most studies were conducted in a single center and lacked specific clinical data on individual patients. Second, most of the reviewed studies focused on one or two techniques, leading significant reporting biases. Finally, the recruitment time in reviewed studies with high heterogeneity inhibited further analysis of yearly trends. Consequently, to obtain a complete picture of zone 0 TEVAR, more exhaustive investigations on zone 0 TEVAR are required in the future.

. Conclusion
Despite the absence of stent grafts dedicated for zone 0 TEVAR, novel stent grafts and various techniques targeting zone 0 TEVAR are currently being investigated and developed. However, there is still no consensus on technique and device selection for zone 0 TEVAR in current practice. Furthermore, the post-operative stroke rate is relatively high, while other complications and perioperative death rate are comparable to those of TEVAR for other aortic zones.
The small number of studies aimed at zone 0 TEVAR calls for more comprehensive and detailed clinical studies to improve the informed decision-making in patients who may benefit from zone 0 TEVAR.

Data availability statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.