Comparative outcomes of open, hybrid, and fenestrated branched endovascular repair of extent II and III thoracoabdominal aortic aneurysms

Comparative outcomes of open, hybrid, and fenestrated branched endovascular repair of extent II and III thoracoabdominal aortic aneurysms Dean J. Arnaoutakis, MD, MBA,a Salvatore T. Scali, MD,a Adam W. Beck, MD,b Paul Kubilis, MS,a Thomas S. Huber, MD, PhD,a Andrew J. Martin, MD,a Liza Laquian, MD,a Martin Back, MD,a Kristina A. Giles, MD,a Javairiah Fatima, MD,a Thomas M. Beaver, MD, MPH,c and Gilbert R. Upchurch Jr, MD,a Gainesville, Fla; and Birmingham, Ala

ABSTRACT Objective: Open repair of extent II and III thoracoabdominal aortic aneurysms (TAAA) is associated with substantial morbidity. Alternative strategies, such as hybrid operations combining proximal thoracic endovascular aortic repair with either staged open distal TAAA repair or visceral debranching (hybrid), as well as fenestrated/branched endografts (FEVAR), have been increasingly reported; however, benefits of these approaches compared with direct open surgery remain unclear. The purpose of this study was to compare outcomes of these three different strategies in the management of extent II/III TAAA. Methods: All extent II/III TAAA repairs (2002-2018) for nonmycotic, degenerative aneurysm or chronic dissection at a single institution were reviewed. The primary end point was 30-day mortality. Secondary end points included incidence of spinal cord ischemia (SCI), complications, unplanned re-operation, 90-day readmission, and out-of-hospital survival. To mitigate impact of covariate imbalance and selection bias, intergroup comparisons were made using inverse probability weighted-propensity analysis. Cox regression was used to estimate survival while cumulative incidence was used to determine reoperation risk. Results: One hundred ninety-eight patients (FEVAR, 92; hybrid, 40; open, 66) underwent repair. In unadjusted analysis, compared with hybrid/open patients, FEVAR patients were significantly older with more cardiovascular risk factors, but less likely to have a connective tissue disorder or dissection-related indication. Unadjusted 30-day mortality and complication rates were: 30-day mortality, FEVAR 4%, hybrid 13%, open 12% (P ¼ .01); and complications, FEVAR 36%, hybrid 33%, open 50% (P ¼ .11). Permanent SCI was not different among groups (FEVAR 3%, hybrid 3%, open 6%; P ¼ .64). In adjusted analysis, 30-day mortality risk was greater for open vs FEVAR (hazard ratio, 3.6; 95% confidence interval, 1.4-9.2; P ¼ .01) with no difference for hybrid vs open/FEVAR. There was significantly lower risk of any SCI for open vs FEVAR (hazard ratio, 0.3; 95% confidence interval, 0.09-0.96; P ¼ .04); however, no difference in risk of permanent SCI was detected among the three groups. There was no difference in complications or unplanned reoperation, but open patients had the greatest risk of unplanned 90-day readmission. There was a time-varying effect on survival probability, with open repair having a significant survival disadvantage in the first 1 to 6 months after the procedure compared with hybrid/FEVAR patients (Cox model P ¼ .03), but no difference in survival at 1 and 5 years (1- and 5-year survival: FEVAR, 86 6 3%, 55 6 8%; hybrid, 86 6 5%, 60 6 11%; open 69 6 7%, 59 6 8%; Cox-model P ¼ .10). Conclusions: Extent II/III TAAA repair, regardless of operative strategy, is associated with significant morbidity risk. FEVAR is associated with the lowest 30-day mortality risk compared with hybrid and open repair when estimates are adjusted for preoperative risk factors. These data support greater adoption of FEVAR as first-line therapy to treat complex TAAA disease in anatomically suitable patients who present electively. (J Vasc Surg 2019;-:1-12.) Keywords: Thoracoabdominal aortic aneurysm repair; FEVAR; EVAR; TEVAR; hybrid repair

From the Division of Vascular Surgery and Endovascular Therapy,a and Division

Correspondence: Dean J. Arnaoutakis, MD, MBA, Assistant Professor of Surgery,

of Thoracic and Cardiac Surgery,c University of Florida College of Medicine,

Division of Vascular Surgery and Endovascular Therapy, University of Florida

Gainesville; and the Division of Vascular Surgery and Endovascular Therapy,

College of Medicine, 1600 SW Archer Rd NG-45, PO Box 100128, Gainesville,

University of Alabama at Birmingham School of Medicine, Birmingham.b

FL 32610-0128 (e-mail: [email protected]fl.edu).

Supported in part by funding from the National Institutes of Health (NIH-NHLBI

The editors and reviewers of this article have no relevant financial relationships to

5K23HL115673-02) and the Society for Vascular Surgery Foundation Mentored

disclose per the JVS policy that requires reviewers to decline review of any

Patient- Oriented Research Award. Author conflict of interest: none. Presented at the Forty-third Annual Meeting of the Southern Association of Vascular Surgery, Boca Raton, Fla, January 24, 2019.

manuscript for which they may have a conflict of interest. 0741-5214 Copyright Ó 2019 by the Society for Vascular Surgery. Published by Elsevier Inc. https://doi.org/10.1016/j.jvs.2019.08.236

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Open repair of thoracoabdominal aortic aneurysm (TAAA) disease remains one of the most technically and physiologically demanding operations with morbidity and mortality rates of 30% to 50% and 4% to 20%, respectively.1-3 Notably, aneurysm extent4 is predictive of postoperative neurologic outcomes and survival.4,5 For the most extensive disease (extent II/III), different strategies have evolved in an attempt to mitigate the significant risk of open repair. Most commonly, alternative approaches include either a hybrid procedure (staged or unstaged proximal thoracic endovascular aortic repair [TEVAR] with either retrograde aortoiliac visceral/renal debranching or open paravisceral aortic repair) or a total endovascular solution via fenestrated/branched endovascular aortic repair (FEVAR). These strategies were originally proposed to extend treatment options to patients deemed poor open surgical candidates; however, many centers now use them preferentially in anatomically suitable patients.6-10 A variety of factors influence surgical decision making for repair type, including age, comorbidities (especially cardiac, pulmonary and renal disease), functional capacity, aortic/branch vessel morphology, access vessel anatomy, patient preference, and institution/surgeon experience. Owing to marked heterogeneity in patient and institution treatment philosophy, a randomized trial examining which approach is most optimal is unlikely to occur. However, for centers that continue to offer therapy for extent II/III TAAA, there is a paucity of literature providing information on comparative outcomes after open, hybrid and FEVAR extent II/III TAAA repair to facilitate decision making. The purpose of this study was to compare outcomes of these three different strategies in the management of extent II/III TAAA while controlling for patient- and procedure-related variables known to influence risk of postoperative outcomes.

METHODS The University of Florida Institutional Review Board approved this study (#978-2018). A waiver of informed consent was granted, as all collected data pre-existed in medical records and no patient contact or studyrelated interventions occurred. Study design and database. This was a single-center, retrospective, multicohort study of open, hybrid, and FEVAR patients undergoing extent II/III TAAA repair from 2002 to 2018. A prospectively collected database and institutional clinical data repository were queried to identify all patients treated for TAAA disease. Chart review was completed to verify study cohorts, as well as collect patient and procedure specific data with concomitant catalogue of outcomes. Indications analyzed included nonmycotic, degenerative aneurysm and chronic dissection with false lumen

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ARTICLE HIGHLIGHTS d

d

d

Type of Research: Single-center retrospective cohort study Key Findings: Outcomes of 198 patients who underwent extent II/III thoracoabdominal aortic aneurysm repair (fenestrated aneurysm repair [FEVAR], 92; hybrid, 40; open, 66) were compared. Complications were frequent among all groups. With risk adjustment, FEVAR and hybrid had significantly better survival within the first 6 months compared with open, but this survival advantage is lost over time. Take Home Message: The current data from this comparative outcomes analysis suggest that in anatomically eligible patients, elective extent II/III TAAA repairs should increasingly be managed with FEVAR.

aneurysm that were managed by the Division of Vascular Surgery and/or comanaged with the division of thoracic and cardiovascular surgery. Patients with Crawford extent4 I, IV, and V disease were excluded (Fig 1). Both elective and nonelective presentations were included. Patients undergoing chimney/periscope repair11 of TAAA disease were not reviewed. A proportion of the patients included in the analysis were treated before the establishment of an institutional review board and US Food and Drug Administration-approved, physiciansponsored investigational device exemption trial of physician-modified endovascular grafts (PMEG) and custom-made devices (Cook Zenith, Cooke Medical, Bloomington, Ind). All PMEG devices were based upon either a Cook Zenith or TX2 platform.12 Patients undergoing industry sponsored clinical trial devices were excluded. Clinical practice. The description of the practice environment, as well as the treatment philosophy and postoperative management surrounding complex open and endovascular aortic disease cases, has been previously published.12-14 Similarly, spinal drain use, subclavian revascularization for zone 2 coverage, and management of spinal cord ischemia (SCI) has been reported.15,16 FEVAR began being offered at our institution after January 2010 and the details of the principles governing device construction, deployment, and surveillance have been described.12-14 In general, a TEVAR was placed in the thoracic aorta and then a fenestrated/branched stent graft was extended across the paravisceral aorta with bridging stents placed into the visceral-renal vessels to achieve seal. These procedures could be staged such that the proximal TEVAR was completed before treating the pararenal aorta. A hybrid repair was defined as a planned staged (within 1 year) or nonstaged (simultaneous) TEVAR combined

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All TAAA Repairs (n=714)

Included 198 paents

Anatomy • Extent II and III Eology • Degenerave Aneurysm • Chronic Dissecon with Aneurysm

Open Repair (n=66)

Hybrid Repair (n=40)

Excluded 516 paents

Anatomy • Extent I, IV, and V Eology • Mycoc • Pseudoaneurysm • Penetrang Aorc Ulcer

FEVAR Repair (n=92)

Fig 1. The inclusion and exclusion criteria are depicted in the figure. Only elective and nonelective degenerativeand dissection-related Crawford extent II and III thoracoabdominal aortic disease was considered for analysis. After excluded mycotic, as well as nondegenerative aneurysm/dissection-related indications, as well as other anatomic extents, a study cohort of 198 patients was identified. These patients were managed with either direct, single-staged open aortic repair (n ¼ 66), a hybrid approach (n ¼ 40; single or multistaged proximal thoracic endovascular stent graft repair with distal aortic visceral/renal debranching or open pararenal aortic repair with anastomosis to the distal boundary of the stent) or total endovascular (either single or multistaged) fenestrated/ branched endovascular aortic stent graft repair (n ¼ 92). FEVAR, Fenestrated/branched endovascular aortic aneurysm repair.

with either distal aortoiliac retrograde visceral-renal debranching or open paravisceral aortic repair with proximal anastomosis to the distal boundary of the thoracic stent graft, as previously described.17,18 For retrograde debranching procedures, the patient underwent visceral-renal bypasses typically based off the iliac arteries followed by deployment of a TEVAR graft in either zone 2 or 3 proximally extending into the infrarenal aorta. The endograft could be deployed at the time of debranching (nonstaged) or at a separate date (staged). Additionally, endografting itself could be staged such that the thoracic aorta was treated before debranching and then the abdominal aorta covered after debranching. An alternative hybrid approach consisted of a proximal TEVAR deployed in zone 2 or 3 extending to zone 5, proximal to the celiac artery. Subsequently, these patients underwent direct pararenal aortic repair with anastomosis to the distal edge of the previously placed thoracic endograft. No prespecified treatment protocol existed for determining which operation was selected for a given clinical presentation. Instead, as a large, multidisciplinary group practice, each case was discussed and the optimal strategy for repair was determined. Generally, patients with connective tissue disease were predominantly offered open repair, while patients with advanced comorbidities (eg, congestive heart failure, stage 3 or higher chronic renal disease, oxygendependent pulmonary disease) were typically selected

to undergo either hybrid or FEVAR based on anatomic suitability, operating surgeon expertise and/or device availability. End points and definitions. The primary end point was 30-day mortality. Secondary end points included SCI incidence, complications, unplanned reoperation, 90day readmission, and out-of-hospital survival. Mortality outcomes were verified through query of the Social Security Death Masterfile. An unplanned reoperation included any event requiring a return trip to the operating room during the index hospitalization and/or follow-up related to TAAA management (eg, bleeding, graft thrombosis with end-organ ischemia, endoleak). Readmission within 90 days was captured only if it was related to the index operation (censored to only include readmission after the second stage operation for the hybrid patients unless these patients were readmitted for a complication related to the first-stage procedure). End point comparisons for staged FEVAR and hybrid patients were tabulated on an intention-to-treat basis, so complications, unplanned operations, and mortality rates were a composite from both stages of repair. However, owing to the significant operative heterogeneity for the staged vs unstaged approaches, comparisons for only the most complex aspect of repair (eg, stage that included the visceral-renal revascularization) are provided. Complications were defined based on reporting guidelines.19-22 SCI was clinically defined as any new

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Table I. Unadjusted analysis of preoperative demographics and comorbidities FEVAR (n ¼ 92)

Hybrid (n ¼ 40)

Open (n ¼ 66)

P valuea

72 6 8

71 6 8

59 6 12

<.0001

Male

57 (62)

27 (68)

48 (73)

Body mass index

28 6 6

24 6 4

27 6 6

.009

ASA score $ 3

86 (93)

29 (73)

32 (48)

<.0001

Hypertension

90 (98)

35 (88)

60 (91)

.03

Dyslipidemia

77 (84)

22 (55)

35 (53)

<.0001

Tobacco use

76 (83)

34 (85)

35 (53)

<.0001

Chronic pulmonary disease

52 (57)

12 (30)

16 (24)

<.0001

Coronary disease

39 (42)

16 (40)

24 (36)

Diabetes mellitus

17 (18)

3 (8)

5 (8)

.06

Cerebrovascular disease

5 (5)

6 (15)

11 (17)

.05

Peripheral vascular disease

11 (12)

7 (18)

5 (8)

.3

35 (38)

14 (35)

2 (2)

1 (3)

Preoperative aspirin

80 (87)

23 (58)

40 (61)

<.0001

Preoperative statin

66 (72)

18 (45)

32 (48)

.002

Feature Age

Chronic renal disease Mixed connective tissue disease

.4

.7

2 (50)b

.8

9 (14)

.01

FEVAR, Fenestrated/branched endovascular aneurysm repair. Values are number (%) or mean 6 standard deviation. a Kruskal-Wallis for comparison of continuous variable distributions; c2 or Fischer exact test for categorical variable. b There were 62 missing values for preoperative creatinine; chronic renal insufficiency is defined as creatinine of >1.5 and/or and estimated glomerular filtration rate of <60.

postoperative lower extremity neurologic deficit not attributable to intracranial pathology and/or epidural hematoma.23 Neurology consultation and/or magnetic resonance imaging was only obtained in equivocal cases. Statistical analysis. Univariate analysis was used to evaluate baseline characteristics and short-term outcomes. The Wilcoxon rank-sum, likelihood ratio c2 (or Fisher exact), and log-rank tests were used for univariate comparison of continuous, categorical and time-to-event variables, respectively. Multipredictor Cox proportional hazards regression was used to assess differences in relative risk of end points among the three surgical approaches. A competing risks form of the Cox model was used to assess risk of reoperation, with reoperation and mortality considered as the competing risks. To mitigate the impact of covariate imbalance and selection bias, intergroup comparisons were adjusted for confounding using inverse propensity score weighting (IPW).24 Propensity scores were estimated as probabilities of treatment assignment to one of the three treatment groups using a logistic regression model that included age, gender, body mass index, comorbidities (cardiac, pulmonary, renal disease), pathologic indication, procedure urgency, as well as American Society of Anesthesia score. IPW was then applied to the Cox regression model fits to obtain adjusted hazard ratios with 95% confidence intervals (CIs). Kaplan-Meier methods were used to estimate cumulative survival and cumulative re-operation incidence. All analyses

were performed with SAS Version 9.4 (SAS Institute, Cary, NC) and significance was defined as a P value of less than .05.

RESULTS Study population. A total of 198 patients (FEVAR, 92; hybrid, 40; open, 66) who met inclusion criteria underwent extent II/III TAAA repair with a median follow-up in months of: FEVAR, 36 (interquartile range [IQR], 1548), hybrid, 19 (IQR, 4-69), and open, 16 (5-44). In unadjusted analysis, compared with hybrid and open patients, FEVAR patients were significantly older and had greater frequency of multiple cardiovascular risk factors (Table I). Presentation and operative characteristics. Details surrounding the preoperative presentation and common operative features shared among the three cohorts are highlighted in Table II. There was no difference among groups with respect to the distribution of extent II or III disease (P ¼ .1). Patients undergoing both open and FEVAR procedures were more likely than the hybrid patients to have a nonelective indication (P ¼ .002). Chronic dissection with false lumen aneurysm was much more likely to be managed with hybrid and open strategies compared with FEVAR (P < .0001). Significant variation in spinal drain use, procedure time, and estimated blood loss was evident among the groups. Specific to FEVAR, 51% (n ¼ 41) had prior history of either open or endovascular aortic repair. Twenty cases (22%) were completed in two stages (median, 49 days;

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Table II. Unadjusted analysis of perioperative presentation and intraoperative variables Feature

FEVAR (n ¼ 92)

Hybrid (n ¼ 40)

Open (n ¼ 66)

P valuea

Extent II

24 (33)

12 (31)

26 (39)

e

Extent III Preoperative max diameter

48 (67)

28 (69)

40 (61)

.1

66 [61-75]

67 [62-78]

65 [60-76]

.8

Nonelective

20 (22)

2 (5)

21 (33)

.002

Degenerative aneurysm

85 (92)

36 (90)

32 (48)

<.0001

Chronic dissection

7 (8)

4 (10)

34 (52)

e

Prior type A repair

4 (4)

1 (3)

18 (27)

<.0001

Prior type B dissection

7 (8)

5 (13)

19 (29)

.002

68 (74)

9 (23)b

62 (94)

<.0001

Procedure time, minutes

220 [170-290]

180 [115-400]

470 [375-530]

<.0001

Estimated blood loss, mL

200 [150-300]

100 [400-2000]

2000 [1000-4000]

<.0001

Spinal drain

FEVAR, Fenestrated/branched endovascular aneurysm repair. Values are number (%) or median [interquartile range]. a Kruskal-Wallis for comparison of continuous variable distributions; c2 or Fisher exact test for categorical variable. b Spinal drain comparison is for the second stage, open aortic reconstruction.

IQR, 29-69 days), one of whom died before the second stage operation. Of the 20 staged procedures, 5 (25%) were completed during the first half of the series, whereas the remaining 15 (75%) were completed during the second half of the series. A total of 250 branch vessels were revascularized with the most common configuration being either a three- or four-vessel fenestrated-branched graft (36%; n ¼ 33). A variety of other combinations of both fenestrated and/or branched stent grafts were used to complete repair in the remaining patients and the majority of cases were PMEG procedures (78%; n ¼ 72). One patient underwent intraoperative open conversion via a hybrid debranching owing to an inability to revascularize target vessels from severe aortic tortuosity in a symptomatic extent III TAAA procedure. Hybrid patients frequently had a prior history of endovascular or open aortic repair (45%; n ¼ 17). Patients undergoing a hybrid procedure had a median time to their second stage operation of 28 days (IQR, 790 days). On an intention-to-treat basis, 85% (n ¼ 34) were planned staged procedures; however, 21% (n ¼ 7) never underwent their second stage operation. Five died before the second stage, four of which were due to complications related to their first-stage operation. The remaining two patients were lost to follow-up. A majority of the second-stage procedures were retrograde visceral/renal debranching operations, whereas 14 (35%) involved direct repair of the abdominal aorta with the proximal anastomosis sewn to the distal boundary of the previously placed TEVAR. Conduct of the open TAAA operations incorporated a variety of adjunctive spinal cord and visceral-renal protective strategies, including deep hypothermic circulatory arrest (6%; n ¼ 4), cardiopulmonary bypass without circulatory arrest (50%; n ¼ 33), partial left heart bypass

via left pulmonary vein cannulation (2%; n ¼ 1), and axillofemoral bypass (5%; n ¼ 3). The remaining patients (38%; n ¼ 25), the majority of which had extent III disease, underwent a clamp-and-sew technique. Intercostal artery reimplantation occurred in 30% (n ¼ 22) and the visceral segment was reconstructed using a Carrel patch in 42% (n ¼ 28). In-hospital outcomes. The unadjusted 30-day mortality rate was different among groups: FEVAR-4%, hybrid-13%, open-12% (P ¼ .01). This finding was driven by differences in elective 30-day mortality (FEVAR, 1 of 72 [1%]; hybrid, 5 of 38 [13%]; open, 2 of 45 [4%]; P ¼ .03), whereas there was no difference in nonelective 30-day mortality (FEVAR, 3 of 20 [15%]; hybrid, 0 of 2 [0%]; open, 6 of 21 [29%]; P ¼ .7). Of note, a time-dependent association with improved mortality outcomes (hazard ratio, 0.9/year; 95% CI, 0.8-0.9; P ¼ .04) was detected for hybrid repair, but was not evident after FEVAR or open cases. Major complications were frequent among all groups (FEVAR, 36%; hybrid, 33%; open, 50%; P ¼ .1). FEVAR (1%) had a significantly lower rate of new hemodialysis requirement compared with hybrid (20%) and open repair (12%) (P ¼ .0003). Notably, the rate of permanent SCI was not different among groups: FEVAR, 3%; hybrid, 3%; and open, 6% (P ¼ .6) (Table III). In risk-adjusted IPW analysis, there was significantly lower risk of any SCI occurring after open repair compared with FEVAR (open vs FEVAR: odds ratio, 0.3; 95% CI, 0.09-0.96; P ¼ .04); however, there was no difference in the risk of permanent SCI among all three cohorts. Similarly, there was no difference in risk of developing postoperative major complications among the operative strategies (Table IV). With covariate adjustment, the 30-day mortality risk was significantly greater

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Table III. Unadjusted analysis of postoperative complications Outcome Any major complication

FEVAR (n ¼ 92)

Hybrid (n ¼ 40)

Open (n ¼ 66)

33 (36)

13 (33)

33 (50)

P valuea .1

Bleeding

7 (8)

7 (18)

11 (17)

.1

Wound complication

2 (2)

4 (10)

5 (8)

.08 <.0001

Pulmonary

5 (5)

11 (28)

16 (24)

Cardiac

4 (4)

3 (8)

4 (6)

Arrythmia

1 (1)

2 (5)

19 (29)

<.0001

Acute kidney injury

5 (5)

8 (20)

16 (24)

.002

Hemodialysis

1 (1)

8 (20)

8 (12)

.0003

Bowel ischemia

2 (2)

4 (10)

6 (9)

.07

Leg ischemia

2 (2)

0 (0)

4 (6)

.3

Stroke Any SCI Permanent SCI

.7

4 (4)

1 (3)

4 (6)

.7

14 (15)

3 (8)

6 (9)

.3

3 (3)

1 (3)

4 (6)

.6

FEVAR, Fenestrated/branched endovascular aneurysm repair; SCI, spinal cord ischemia. Values are number (%). a Kruskal-Wallis for comparison of continuous variable distributions; c2 or Fisher exact test for categorical variable.

Table IV. Risk-adjusted intergroup comparison of outcomes after Crawford extent II/III thoracoabdominal aortic aneurysm (TAAA) repaira Outcome Any SCI

Permanent SCI

Any major complication

90-Day readmission

Any unplanned reoperationb

Group

OR

95% CI

P value

Open:FEVAR

0.3

0.09-0.96

.04

Open:hybrid

0.9

0.1-5.6

.9

FEVAR:hybrid

2.9

0.5-17.1

.2

Open:FEVAR

1.4

0.3-7.1

.7

Open:hybrid

1.2

0.1-13.8

.9

FEVAR:hybrid

0.8

0.1-10.2

.9

Open:FEVAR

1.9

0.8-4.7

.2

Open:hybrid

3.3

0.7-16.5

.1

FEVAR:hybrid

1.7

0.4-7.9

.5

Open:FEVAR

1.3

0.4-4.2

.6

Open:hybrid

7.9

1.6-39.8

.01

FEVAR:hybrid

6.0

1.3-28.9

.03

Open:FEVAR

2.1

0.7-6.5

Open:hybrid

1.8

0.6-5.0

.3

FEVAR:hybrid

0.9

0.5-1.8

.8

.2

CI, Confidence interval; FEVAR, fenestrated/branched endovascular aneurysm repair; OR, odds ratio; SCI, spinal cord ischemia. a ORs adjusted using inverse probability weighted propensity analysis. The treatment assignment propensity score model included age, body mass index, gender, procedure urgency, pathologic indication, American Society of Anesthesia score, and all other cardiopulmonary risk factors. b Relative risk estimates are hazard ratios for any unplanned reoperation.

after open vs FEVAR (hazard ratio, 3.6; 95% CI, 1.4-9.2; P ¼ .01) with no difference for hybrid vs open or hybrid vs FEVAR (Table V). Reoperation, readmission, and survival. There was no difference in unplanned reoperation among the three different treatment strategies (Fig 2). However, both open and FEVAR patients had greater risk of an unplanned 90-day readmission compared with hybrid

patients (Table IV). When comparing all-cause mortality without intraprocedural risk adjustment, no significant difference in survival was noted between the subgroups (Fig 3). However, with risk adjustment, there was a timevarying effect of the procedure type on survival probability with open repair having greater overall mortality risk in the first 1 to 6 months after the procedure compared with the other two approaches (Table V) (Fig 4; Cox model P ¼ .03). The 1-year and 5-year survivals

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Table V. Risk-adjusted analysis for intergroup comparison of mortality after Crawford extent II/III thoracoabdominal aortic aneurysm (TAAA) repaira Outcome 30-Day mortality

90-Day mortality

180-Day mortality

365-Day mortality

Group

HR

95% CI

P value .01

Open:FEVAR

3.6

1.4-9.2

Open:hybrid

2.2

0.9-5.4

.1

FEVAR:hybrid

0.6

0.2-1.8

.4

Open:FEVAR

2.7

1.2-5.8

.01 .03

Open:hybrid

2.4

1.1-5.4

FEVAR:hybrid

0.9

0.4-2.2

.8

Open:FEVAR

1.8

0.8-3.9

.1

Open:hybrid

2.8

1.0-7.6

.05

FEVAR:hybrid

1.6

0.6-4.0

0.4

Open:FEVAR

0.9

0.3-2.8

.9

Open:hybrid

3.1

0.6-15.7

.2

FEVAR:hybrid

3.4

0.8-14.1

.1

CI, Confidence interval; FEVAR, fenestrated/branched endovascular aneurysm repair; HR, hazard ratio; OR, odds ratio; SCI, spinal cord ischemia. a Hazard ratios adjusted using inverse propensity score weighting. The treatment assignment propensity score included age, body mass index, gender, procedure urgency, pathologic indication, American Society of Anesthesia score, and all other cardiopulmonary risk factors.

Fig 2. This cumulative incidence risk analysis of any unplanned reoperation either during the index admission or during follow-up demonstrates no significant difference amongst the three different operative strategies used to treat extent II/III thoracoabdominal aortic disease. FEVAR, Fenestrated/branched endovascular aortic aneurysm repair.

did not differ significantly for open repair compared with hybrid and FEVAR (1- and 5-year survival: FEVAR, 86 6 3%, 55 6 8%; hybrid, 86 6 5%, 60 6 11%; open 69 6 7%, 59 6 8%; Cox model P ¼ .10).

DISCUSSION Extent II/III TAAAs pose one of the greatest challenges to cardiovascular surgeons owing to the technical

Fig 3. Estimated all-cause survival without risk adjustment between groups. No significant survival benefit is identified, however covariate adjustment for factors known to impact short and long-term survival are not factored into this Kaplan-Meier curve. FEVAR, Fenestrated/branched endovascular aortic aneurysm repair.

complexity of open repair, high prevalence of significant comorbidities, and relatively dismal perioperative outcomes. In early series reporting on open TAAA repair, SCI and renal failure rates approached 16% and 18%, respectively, with 30-day mortality rates of 8%.1 National datasets, which perhaps provide a more accurate representation of real-world outcomes, revealed much more

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Fig 4. The survival curve identifies a survival benefit for FEVAR compared with open repair (Cox model P ¼ .03); however, this is only present within the first 180 days postoperatively. After 180 days, there is no difference in survival among the three different operative approaches to extent II/III thoracoabdominal aortic disease. The Cox model hazard ratios were generated after accounting for patient age, indication, procedure urgency, anatomic extent, and multiple cardiovascular risk factors. FEVAR, Fenestrated/branched endovascular aortic aneurysm repair; SE, survival estimate.

sobering results with mortality rates approaching 20%.2,3 These rates have improved over time with the implementation of adjunctive measures to provide spinal cord and renal protection, like cerebrospinal fluid drainage,25 intercostal artery reimplantation,26 systemic hypothermia,27 assisted-circulation techniques,28 and cold renal perfusion.29 However, even modern series from centers of excellence, rates of SCI (6%-13%), renal failure (8%), and 30-day mortality (6%-9%)30-32 after open extent II/III TAAA repair remain significant. Given these results, it is not surprising that other treatment strategies have been increasingly adopted. For example, there is evidence that a hybrid strategy, using retrograde visceral debranching with TEVAR, has favorable outcomes. Specifically, Patel et al18 reported a 3.4% rate of both permanent SCI and 30-day mortality. An alternative hybrid option, TEVAR followed by direct open distal paravisceral aortic repair, has also been shown to decrease major complications by more than 50% compared with literature-based open TAAA results, especially SCI incidence.6 Although the total costs of a hybrid strategy can be high owing to the frequency of staged reconstruction and implant costs, Hawkins et al6 contend that the reduction in postoperative

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complications yields better financial value for the health care system than traditional open repair.6 Total endovascular repair of extent II/III TAAAs using FEVAR, has emerged as another option at select centers. Results, albeit limited in their number and follow-up, demonstrate favorable mortality rates ranging from 0% to 5% and permanent SCI rates of 1% to 4%.7-10 These outcomes are consistent with the current series, even when combining elective and nonelective cases. Notably, these procedures demand a very steep learning curve and are associated with reintervention rates of nearly 50% within 2 years.10 Moreover, device availability and provider expertise are limited to high-volume centers, which presents a challenge to patient access and ability to train new surgeons in these cutting edge techniques. Prior reports have explored differences between open and either FEVAR or hybrid repair, but none have examined all three techniques simultaneously, which defines a unique distinction and contribution of this work. Additionally, unlike the current analysis, many other series include heterogeneous cohorts of extent IV TAAA and pararenal abdominal aneurysm patients, which have a lower risk profile than extent II/III TAAAs. In this series, FEVAR and hybrid patients were typically older and had more comorbidities compared with open repair patients. This finding is not unexpected, given our institutional preference to use these strategies in high-risk patients deemed poor candidates for open repair. This underscores the significance of the findings that even after risk adjustment, these two alternative strategies were associated with similar or better outcomes compared with open reconstruction. Notably, despite efforts to mitigate selection bias and covariate imbalance between groups, important anatomic differences persisted. For example, FEVAR was rarely used in patients with chronic dissection (n ¼ 8), whereas approximately 50% of the open cohort had a history of chronic dissection, a proportion that is higher than other TAAA series.31 Our perioperative FEVAR mortality rate (4%) is similar to other reports.7-10 The 30-day mortality after open repair (12%) is slightly higher than modern series but reflects an outcome derived from a composite of elective and nonelective presentations. Importantly, elective open repair had a 30-day mortality of 4% (2 of 45 patients), which is consistent with other centers and well below results reported from national datasets.2,3,30-32 After controlling for baseline differences, open repair had more than a three-fold increased risk of 30-day mortality compared with FEVAR. The open cohort did have more patients with urgent need for surgery, as well as a prior history of chronic dissection, both of which have been associated with worse outcomes.4,29 However, our IPW propensity model accounted for both elective vs nonelective status and dissection-related indication in the risk adjustment.

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A majority of open extent III repairs (n ¼ 18 of 32 [56%]) were performed using a clamp-and-sew technique, but the combined elective/nonelective mortality rate (17%) for this subgroup was similar to operations completed using assisted circulation techniques (14%; P ¼ .6). When comparing FEVAR with hybrid patients, the unadjusted 30-day mortality benefit of FEVAR (4% vs 13%) did not translate into statistical significance after risk adjustment, which may be explained by a relatively low number of hybrid patients. Of note, the hybrid mortality rate, which was calculated on an intention-to-treat basis with four patients dying before completion of their second stage procedure, was higher than other reports. These other series, however, do not specify whether patients were excluded if they did not complete the second stage and our analysis included both elective and nonelective presentations. Major complications were prevalent with no difference among groups on adjusted analysis. The permanent SCI rate (FEVAR, 3%; hybrid, 3%; open, 6%) was excellent for all groups and comparable with other series.10,18,31 When adjusting for preoperative variables, FEVAR did have a three-fold greater risk of developing any SCI (eg, transient and/or permanent) compared with open repair. Adjuncts during open reconstruction such as intercostal reimplantation and deep hypothermia may account for some of this difference as well as that in our earlier experience we were less likely to stage our FEVARs. Spinal drainage with permissive hypertension was aggressively used for all extent II/III repairs at our institution over the study period. Notably, a more comprehensive, bundled SCI protection protocol was implemented at our institution in May 2015 and applied uniformly to all complex TAAAs and we previously reported on its benefits within the FEVAR subgroup.15 After risk adjustment, both FEVAR and hybrid procedures had significantly better survival in the first 1 to 6 months after the procedure compared with open repair. One-year survival was also better in FEVAR and hybrid patients, although statistical significance was no longer evident by this time point. The explanation for this finding is multifactorial, but likely related to the elevated rates of postoperative hemodialysis, readmission, and unplanned reoperation in the open group. Similar to findings from randomized trials comparing open infrarenal AAA repair to EVAR, the early survival advantage detected in the FEVAR and hybrid groups is lost over time with all the curves converging by 5 years. This study was not designed to explain this convergence, but we suspect it is related to the greater age and higher prevalence of comorbidities in the endovascular patients who likely succumb to nonaortic-related disease over time. The implications of this study are evident, especially when centers treating extent II/III TAAA want to understand relative risks of important outcomes that influence

selection of these three techniques. The current data and contemporary literature suggest that, in anatomically eligible patients, elective extent II/III TAAA repairs should increasingly be managed with total endovascular solutions.9,10 However, when counseling patients, surgeons must acknowledge that endovascular repair mandates indefinite imaging surveillance, often requires reintervention, and ultimately there is no clear long-term survival benefit compared with open or hybrid repair. A major issue surrounding treatment of extent II/III TAAA with FEVAR is the limited device availability in the United States. The dissemination and adoption of the necessary skillset has been hindered by variable exposure to these procedures during fellowship training.33 Gaining expertise in FEVAR of extent II/III disease is challenging, often requiring additional training outside the United States. It would be naïve to think that this issue is unique to complex endovascular aortic surgery; similar problems exist for trainees with respect to open TAAA repair because these procedures are increasingly uncommon as fewer centers offer open aortic surgery.34,35 Perhaps most important, the US Food and Drug Administration and Centers for Medicare and Medicaid Services have only granted a select few physicians with investigational device exemption access to custom-made devices to manage extent II/III TAAA. At centers without IDEs, PMEGs are frequently used, which further raises controversy about the appropriate use of these techniques, especially in elective patients.36 Unfortunately, this issue continues to be a challenge for institutions offering complex TAAA repair since the planned expansion of this technology by the US Food and Drug Administration and Centers for Medicare and Medicaid Services remains poorly defined. If FEVAR is not an option, selecting between hybrid and open repair is somewhat equivocal based on our results, which is in contrast to reports by Hawkins et al6 and Patel.18 Given results from multiple prior series, we consider age and comorbidities, particularly chronic renal insufficiency, as the main factors dictating our surgical approach. Regardless, all patients with complex TAAA disease should be referred to high-volume centers because this has been shown to decrease mortality by nearly 50%.3 Some high-volume centers, including the University of Florida (https://ufhealth.org/uf-healthaortic-disease-center/overview), have formally created aorta disease centers to expedite hospital transfers, review complex cases in a multidisciplinary fashion, increase clinical trial enrollment, and promote crosscollaboration among basic and translational researchers with the ultimate goal of improving patient outcomes and advancing the treatment of aortic disease.37,38 There are several limitations to this analysis. No prespecified treatment protocol was in place when determining which surgical approach to pursue. Instead, patients were selected based on available surgeon

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expertise, anatomic constraints, and overall fitness for repair. We tried to account for this inherent selection bias through the use of inverse treatment assignment propensity score weighting, a rigorous statistical methodology which balances covariates to provide an unbiased intergroup comparison. In addition, the overall size of each cohort, especially the hybrid group, is modest with limited follow-up, which increases the risk of a type II error. We cannot determine the impact that selection bias and patient loss to follow-up had on outof-hospital unplanned reoperations. The purpose of this study was not to delineate the best solution for extent II/III TAAA disease, but rather to provide comparative outcomes for three different strategies that are used to treat a complex clinical problem. We concede that some end points such as endoleak or changes in residual aneurysm sac morphology over time are important considerations in FEVAR and hybrid strategies; however, the complexity of the current analysis, modest sample sizes, and lack of exposure risk for open TAAA patients limits ability to provide meaningful comparisons for these other surrogates of clinical success.

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CONCLUSIONS In the current analysis, management of extent II/III TAAA disease using multiple strategies can result in acceptable and comparable results for most outcomes when occurring at a center with experience managing complex aortic disease in a collaborative, multidisciplinary manner. However, significant early survival advantages of FEVAR support greater adoption as first-line therapy to treat complex TAAA disease in anatomically suitable patients who present electively. Ultimately, the open, hybrid and FEVAR strategies should be viewed as complementary techniques and all three will likely continue to have a role in selected patients in the future.

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AUTHOR CONTRIBUTIONS Conception and design: DA, SS, GU Analysis and interpretation: DA, SS, AB, PK, TH, MB, KG, JF, TB, GU Data collection: DA, SS, AM, LL Writing the article: DA, SS Critical revision of the article: DA, SS, AB, PK, TH, AM, LL, MB, KG, JF, TB, GU Final approval of the article: DA, SS, AB, PK, TH, AM, LL, MB, KG, JF, TB, GU Statistical analysis: SS, PK Obtained funding: Not applicable Overall responsibility: DA DA and SS contributed equally to this article and share co-first authorship.

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aortic operations. J Vasc Surg 1993;17:357-68; discussion: 368-70. Derrow AE, Seeger JM, Dame DA, Carter RL, Ozaki CK, Flynn TC, et al. The outcome in the United States after thoracoabdominal aortic aneurysm repair, renal artery bypass, and mesenteric revascularization. J Vasc Surg 2001;34:54-61. Cowan JA Jr, Dimick JB, Henke PK, Huber TS, Stanley JC, Upchurch GR Jr. Surgical treatment of intact thoracoabdominal aortic aneurysms in the United States: hospital and surgeon volume-related outcomes. J Vasc Surg 2003;37:1169-74. Crawford ES, Crawford JL, Safi HJ, Coselli JS, Hess KR, Brooks B, et al. Thoracoabdominal aortic aneurysms: preoperative and intraoperative factors determining immediate and long-term results of operations in 605 patients. J Vasc Surg 1986;3:389-404. Coselli JS, LeMaire SA, Preventza O, de la Cruz KI, Cooley DA, Price MD, et al. Outcomes of 3309 thoracoabdominal aortic aneurysm repairs. J Thorac Cardiovasc Surg 2016;151:1323-37. Hawkins RB, Mehaffey JH, Narahari AK, Jain A, Ghanta RK, Kron IL, et al. Improved outcomes and value in staged hybrid extent ii thoracoabdominal aortic aneurysm repair. J Vasc Surg 2017;66:1357-63. Spear R, Hertault A, Van Calster K, Settembre N, Delloye M, Azzaoui R, et al. Complex endovascular repair of postdissection arch and thoracoabdominal aneurysms. J Vasc Surg 2018;67:685-93. Schanzer A, Simons JP, Flahive J, Durgin J, Aiello FA, Doucet D, et al. Outcomes of fenestrated and branched endovascular repair of complex abdominal and thoracoabdominal aortic aneurysms. J Vasc Surg 2017;66:687-94. Oderich GS, Ribeiro M, Hofer J, Wigham J, Cha S, Chini J, et al. Prospective, nonrandomized study to evaluate endovascular repair of pararenal and thoracoabdominal aortic aneurysms using fenestrated-branched endografts based on supraceliac sealing zones. J Vasc Surg 2017;65: 1249-59.e1210. Eagleton MJ, Follansbee M, Wolski K, Mastracci T, Kuramochi Y. Fenestrated and branched endovascular aneurysm repair outcomes for type II and III thoracoabdominal aortic aneurysms. J Vasc Surg 2016;63:930-42. Schwierz E, Kolvenbach RR, Yoshida R, Yoshida W, Alpaslan A, Karmeli R. Experience with the sandwich technique in endovascular thoracoabdominal aortic aneurysm repair. J Vasc Surg 2014;59:1562-9. Scali ST, Waterman A, Feezor RJ, Martin TD, Hess PJ Jr, Huber TS, et al. Treatment of acute visceral aortic pathology with fenestrated/branched endovascular repair in highsurgical-risk patients. J Vasc Surg 2013;58:56-65.e51. Scali ST, Neal D, Sollanek V, Martin T, Sablik J, Huber TS, et al. Outcomes of surgeon-modified fenestrated-branched endograft repair for acute aortic pathology. J Vasc Surg 2015;62:1148-59.e1142. Pearce BJ, Scali ST, Beck AW. The role of surgeon modified fenestrated stent grafts in the treatment of aneurysms involving the branched visceral aorta. J Cardiovasc Surg (Torino) 2017;58:861-9. Scali ST, Kim M, Kubilis P, Feezor RJ, Giles KA, Miller B, et al. Implementation of a bundled protocol significantly reduces risk of spinal cord ischemia after branched or fenestrated endovascular aortic repair. J Vasc Surg 2018;67:409-23.e404. Scali ST, Wang SK, Feezor RJ, Huber TS, Martin TD, Klodell CT, et al. Preoperative prediction of spinal cord ischemia after thoracic endovascular aortic repair. J Vasc Surg 2014;60: 1481-90.e1.

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17. Johnston WF, Upchurch GR Jr, Tracci MC, Cherry KJ, Ailawadi G, Kern JA. Staged hybrid approach using proximal thoracic endovascular aneurysm repair and distal open repair for the treatment of extensive thoracoabdominal aortic aneurysms. J Vasc Surg 2012;56:1495-502. 18. Patel HJ, Upchurch GR Jr, Eliason JL, Criado E, Rectenwald J, Williams DM, et al. Hybrid debranching with endovascular repair for thoracoabdominal aneurysms: a comparison with open repair. Ann Thorac Surg 2010;89:1475-81. 19. Fillinger MF, Greenberg RK, McKinsey JF, Chaikof EL. Reporting standards for thoracic endovascular aortic repair (TEVAR). J Vasc Surg 2010;52:1022-33.e15. 20. Johnston KW, Rutherford RB, Tilson MD, Shah DM, Hollier L, Stanley JC. Suggested standards for reporting on arterial aneurysms. Subcommittee on reporting standards for arterial aneurysms, ad hoc committee on reporting standards, Society for Vascular Surgery and North American Chapter, International Society for Cardiovascular Surgery. J Vasc Surg 1991;13:452-8. 21. Chaikof EL, Dalman RL, Eskandari MK, Jackson BM, Lee WA, Mansour MA, et al. The Society for Vascular Surgery practice guidelines on the care of patients with an abdominal aortic aneurysm. J Vasc Surg 2018;67:2-77.e2. 22. Chaikof EL, Blankensteijn JD, Harris PL, White GH, Zarins CK, Bernhard VM, et al. Reporting standards for endovascular aortic aneurysm repair. J Vasc Surg 2002;35:1048-60. 23. DeSart K, Scali ST, Feezor RJ, Hong M, Hess PJ Jr, Beaver TM, et al. Fate of patients with spinal cord ischemia complicating thoracic endovascular aortic repair. J Vasc Surg 2013;58:635-42.e2. 24. Austin PC, Stuart EA. Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies. Stat Med 2015;34:3661-79. 25. Coselli JS, LeMaire SA, Koksoy C, Schmittling ZC, Curling PE. Cerebrospinal fluid drainage reduces paraplegia after thoracoabdominal aortic aneurysm repair: results of a randomized clinical trial. J Vasc Surg 2002;35:631-9. 26. Afifi RO, Sandhu HK, Zaidi ST, Trinh E, Tanaka A, Miller CC 3rd, et al. Intercostal artery management in thoracoabdominal aortic surgery: to reattach or not to reattach? J Thorac Cardiovasc Surg 2018;155:1372-8.e1. 27. Acher CW, Wynn M. A modern theory of paraplegia in the treatment of aneurysms of the thoracoabdominal aorta: an

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Submitted Apr 4, 2019; accepted Aug 2, 2019.

DISCUSSION Dr Hazim J. Safi (Houston, Tex). The weakness of the fenestrated/branched endovascular aneurysm repair (FEVAR) is that it arguably does not protect the spinal cord. The lower intercostal arteries are very important for delaying immediate paraplegia, yet, you have no endograft that will suit this. I challenge all those endovascular surgeons to suit the device to fit all patients and not the patient to fit the device. In contrast, with an open repair, everybody can do this regardless. I commend you on using mortality at 30, 60, 90 days, and at 1 year. That is wonderful. I have a few questions: (1) The selection criteria with which you selected, FEVAR, hybrid, or open, was this based on

surgeon experience, protocol or patient characteristics? (2) When staging procedures, what was the interval between operations and what was the mortality rate during this interval? In our experience with elephant trunk, 2.9% of our patients die while awaiting their second procedure. Furthermore, if the interval is beyond 6 weeks, there is a 45% mortality rate related to rupture. (3) In your series, almost 40% of the open repairs were performed in a clamp-and-sew fashion. However, clamp and sew is associated with higher mortality, renal failure, and spinal cord ischemia rates in

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extent II and III aneurysms which probably skewed your results against the open repair group. (4) In our experience, the glomerular filtration rate (GFR) is a better predictor of mortality and complication. Did you look into that? Dr Dean J. Arnaoutakis. Thank you, Dr Safi, for your comments and questions. With regards to our treatment protocol, we did not have a prespecified protocol in place, which is certainly one of the major limitations of our series. Rather, patients were selected to one of three treatment arms based on surgeon availability and expertise in addition to anatomical constraints such as branch vessel morphology, iliac access, degree of atheroma, and the underlying pathology (dissection vs aneurysm). Despite no current treatment protocol, members from both divisions, vascular surgery and cardiothoracic surgery, meet twice monthly to discuss all complicated aortic cases to generate a group consensus as to the best approach. With regard to staging, there was a change in our practice pattern over time in this series. Of the 40 hybrid patients, seven never underwent the second operation, five of whom died during that interval, which equates to a 13% mortality. The median interval for hybrid patients

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was 28 days. With regard to the 92 FEVAR patients, 20 of them were staged. We started doing FEVAR at the University of Florida in 2010. If dividing the study’s overall time period into two halves, we certainly noticed a change in our practice pattern over time as more patients were staged during the second half of the series. Of the 20 staged patients, only four or five were done in the first half with the remainder in the second half. I suspect this change was driven by our spinal cord ischemia rates observed earlier on, as well as more recent publications demonstrating the protective effects of staging on the spinal cord. In our FEVAR group, the median duration between procedures was 49 days with only one patient dying during that period, for a mortality rate of 5%. Regarding the various assisted circulation techniques used in the open group, we did have a relatively high percentage of clamp and sew at 38%. The majority of these were in extent III repairs. When comparing the mortality rate for clamp and sew vs assisted circulation, there was no statistical difference between these subgroups with mortality rates of 17% and 14%, respectively. Finally, we did not use the GFR, but rather used creatinine level in our logistic regression model. We could swap this out in the future.