Combining the advantages of the classical elephant trunk with modern stent technology, the frozen elephant trunk (FET) procedure has been instrumental in treating complex multi-segmental aortic pathologies in a single operation. The secured expansile stent-graft is able to facilitate downstream aortic remodelling by inducing false lumen thrombosis and depressurization of the false lumen, stabilize the dissecting membrane, and limit stent-graft migration and proximal type Ia endoleaks (1,2). While multiple meta-analyses have reaffirmed the relatively safe short-term profiles of these devices, much less is known regarding long-term outcomes, particularly in terms of overall survival and freedom from reintervention (3-7). The present meta-analysis aimed to determine long-term outcomes following the FET procedure.
Literature search strategy
Electronic searches were performed using Ovid Medline, Embase, Scopus, and PubMed, from their date of inception to October 2019. To achieve maximum sensitivity of the search strategy, the terms ‘elephant trunk’, ‘Thoraflex’, ‘E-vita’, ‘Gianturco Z’, ‘Chavan-Haverich’, or ‘Cronus’ were used as either keywords or MeSH terms. Determination of whether the descending endoprosthesis was stented (i.e., ‘frozen’) or not (i.e., conventional elephant trunk) was made upon full article review. The reference lists of all included studies were reviewed for further identification of other potentially relevant studies. All identified articles were systematically assessed using the inclusion and exclusion criteria.
Eligible studies for the present systematic review included those which (I) examined the use of FETs, (II) had clinical follow-up data of at least 12 months, and (III) had at least 10 patients. The FET is required to be deployed via open surgery in an antegrade fashion into the proximal descending aorta, and secured at the proximal aspect by sutures. No distinction was made regarding the management of head and neck vessels. All publications were limited to those involving human subjects and in the English language. Abstracts, case reports, conference presentations, editorials, and expert opinions were excluded. Review articles were omitted because of potential publication bias and duplication of results. Primary endpoint was overall survival. Secondary outcomes included freedom from reintervention, freedom from aortic events, 30 day/in-hospital mortality, stroke/permanent neurological damage, spinal cord damage, temporary neurological deficit, acute kidney injury, and hospital and intensive care unit (ICU) length of stay.
Data extraction and critical appraisal
All data were extracted from article texts, tables and figures. Two investigators (Y.J., H.H.) independently reviewed each retrieved article. Discrepancies between the two reviewers were resolved by the senior investigator (D.H.T.). Quality assessment was assessed using a modified schema used for assessing case series, developed by the Institute of Health Economics (Alberta, Canada) (8) (Table S1). This schema examines the suitability of study objective, design, population, intervention, outcome measure, statistical analysis, appropriateness of results and conclusions, and competing interests (Table S1). Each study was scored out of 15 points, with 13–15 representing high-quality, 10–12 as medium-quality, and less than 10 as low-quality.
Descriptive statistics were calculated for all collected variables. Categorical or continuous variables were aggregated using meta-analysis of proportions or means, as appropriate. Data is presented as N (%) or mean ± standard deviation (SD). Where continuous values are presented in median with range or interquartile ranges they were converted to mean and SD using methods published by Wan and colleagues (9). Guyot’s iterative algorithm was applied to digitized Kaplan-Meier curves to reconstruct individual patient data (10,11). This approach assumed a constant, non-informative censoring mechanism. The reconstructed patient data were then aggregated to form the combined survival curve. The estimated survival for a 57-year-old male in 2010, representing the median age, sex, and study period of all studies, is also plotted to represent general population survival curve. The American life tables were selected arbitrarily (Center for Disease Control, United States). All p-values were two-sided, and p-values less than 0.05 were considered statistically significant. All statistics were performed with R (version 3.3.5, R Core Team, Vienna, Austria).
Overall 2,084 records were identified from the literature search (Figure S1). Following review (1,2,12-29), 37 were included in the quantitative analysis with a total of 4,178 patients (Table S2) (30-46). No further studies were identified from review of references. Three studies were multi-center studies (12,14,42), including an international registry (14). The median size of included studies was 58 patients (interquartile range, 34–120). Most studies were published by Chinese centers (12 studies), followed by German (8 studies) and Japanese centers (7 studies). Median duration of study was 7 years, with average follow-up of 3.2 years.
FETs were used exclusively for acute dissections in 23 studies involving 1,801 patients. In 10 studies the patient cohorts were chronic dissections or elective surgeries (698 patients). In the remaining studies there was a mixture of emergent and elective indications. A variety of stent-grafts were used, including E-Vita Open/E-Vita Open Plus (13 studies), Cronus (10 studies), Thoraflex (6 studies), GORE TAG (3 studies), Valiant (2 studies), Medtronic TX2 (2 studies), JSOG (2 studies), as well as Frozenix (1 study), Gianturco stent/Hemashield Gold graft (1 study), and Chavan-Haverich (1 study).
Average age of included patients was 57 years old (IQR, 54–60 years), with 72% males (Tables 1,S3). The majority of patients were hypertensive (76%), with a small proportion having diabetes (8%), and renal dysfunction (8%). Other comorbidities, such as respiratory dysfunction, Marfan’s syndrome, previous surgery, were insufficiently reported. Average cardiopulmonary bypass and cross-clamp times were 206 minutes and 118 minutes, respectively (Table S4). Average hypothermic circulatory arrest time was 46 minutes with antegrade cerebral perfusion time of 63 minutes (where reported). Circulatory arrest occurred at 23 °C on average.
Overall survival at 1-, 2-, 3-, 5-, and 10-year were 89.6%, 87.1%, 85.2%, 82.0%, and 68.0%, respectively (Figure 1). Survival at 1-, 2-, 3-, 5-, and 10-year for studies that reported only acute dissections were 90.7%, 88.3%, 86.1%, 83.9%, and 73.5%, compared to 90.0%, 87.4%, 85.2%, 79.1%, and 56.0% for studies that only included chronic dissections/elective aneurysmal patients. Freedom from reintervention at 1-, 2-, 3-, and 5-year were 93.9%, 91.6%, 89.3%, and 86.8%, respectively (Figure 2). Freedom from aortic events at 1-, 2-, 3-, and 5-year were 98.3%, 96.2%, 91.3%, and 86.6%, respectively (Figure 3).
Pooled in-hospital/30-day mortality was 10.2% (Tables 2,S5). Permanent neurological deficit and spinal cord injury were 7.7% and 6.5%, respectively. Acute kidney injury, with varying definitions, was 15.5%. There were insufficient data to evaluate temporary neurological deficit and hospital and ICU length of stay.
The majority of studies were assessed to be medium-quality, with one high-quality and seven low-quality studies. Almost all of the studies were retrospective, single center trials, with no predetermined definitions of clinical outcomes. Loss to follow-up and the consecutive nature of patient enrolment were also inconsistently reported.
The present systematic review examined long-term outcomes of the FET technique. Aggregation of Kaplan-Meier curves found overall survival at 1-, 3-, and 5-year were 89.6%, 85.2%, and 82.0%, respectively. In comparison, patients who received planned second-stage procedures after a classic elephant trunk had a 3-year survival rate of 75% (47). Indeed, the interval mortality between the first-stage and second-stage completion procedures ranges between 2–11% (48), with the latter operation greatly precluded by the use of the FET. Furthermore, it has been shown that a patent false lumen in the descending aorta is a predictor for late mortality and need for reintervention due to aortic expansion (49,50). In a meta-analysis of 11 cohort studies, residual patent false lumen was found to increase the risk of late mortality and aortic events in type A dissections by 71% and 179%, respectively (50). The FET’s ability to promote downstream remodelling and induce false lumen thrombosis has been well validated (2,6), therefore providing an attractive option for management of such pathologies.
The need for reintervention after the FET procedure is not negligible. The ideal length of FET remains controversial, requiring careful balance between sufficient length to achieve adequate distal false lumen occlusion and minimizing occlusion of vascular collaterals that supply the spinal cord. As such, it is often not possible to provide full distal coverage of the aortic pathology due to fear of spinal cord ischemia, thereby necessitating a second-stage procedure despite the use of FETs (43,51). However, it should be noted that the FET simplifies such reinterventions by providing a more appropriate landing zone for endovascular completion (52,53). In the present review, freedom from reintervention at 1-, 3-, and 5-year was 93.9%, 89.3%, and 86.8%, respectively, reaffirming the need for close serial follow-up after the FET procedure.
There are several limitations to the present review that must be considered when interpreting these results. First, in order to attain sufficient statistical power and increase overall representativeness of the findings, this analysis included a heterogeneous cohort of patients, with varying comorbidities, pathologies, and surgical techniques. While subgroup classifications have been made based on clinical urgency, the assortment of surgical approaches, such as the extent of surgery, management of supra-aortic vessels (e.g., debranching procedures), neuroprotection strategies, and type and length of FETs is likely to have confounded results. Secondly, the volume of practice varied between hospitals, and particularly amongst geographic regions. Finally, the average length of follow-up is only 3.2 years, with limited data available beyond this period.
The present review demonstrates that survival after the FET procedure is favorable, though the need for reintervention still remains. Larger robust multi-institutional registries are required to elucidate the precise role of the FET in managing complex multisegmental aortic pathologies.
Conflicts of Interest: The authors have no conflicts of interest to declare.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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