Five-year results of the LEOPARD trial of commercially available

endografts
Christopher J. Kwolek, MD,a Kenneth Ouriel, MD,b Fred S. Stucky, MD,c Vikram K. Rao, MD,d
Peter J. Pons, MD,e Samuel E. Wilson, MD,f and Scott W. Kujath, MD,g Wellesley, MA; New York, NY; Huntsville, AL;
Florence, AL; Willoughby, OH; Orange, CA; and North Kansas City, MO

ABSTRACT
Objective: The LEOPARD (Looking at EVAR Outcomes by Primary Analysis of Randomized Data) trial is a randomized
controlled trial comparing the outcomes of endovascular aneurysm repair (EVAR) using commercially available devices
in a real-world population.
Methods: A prospective, randomized, multi-center trial was performed to compare the anatomically fixated (AF) AFX/
AFX2 endograft system (Endologix) with endografts with proximal fixation (PF) (Cook Medical Zenith Flex; Gore Excluder;
and Medtronic Endurant II) in patients with infrarenal abdominal aortic aneurysms. The primary endpoint was freedom
from aneurysm-related complications (ARCs), a composite endpoint consisting of perioperative death (#30 days),
aneurysm rupture, conversion to open surgical repair, postoperative endoleaks, endograft migration ($10 mm), aneurysm
enlargement ($5 mm), endograft limb occlusion, and device- or aneurysm-related reintervention.
Results: The study population was 455 patients enrolled at 56 United States centers: 235 patients were treated with AF
devices and 220 with PF devices. The primary endpoint supported noninferiority of the AF cohort at 1 year. The 5-year
freedom from ARC Kaplan-Meier estimates were 63.8% for AF patients and 55.5% for PF patients (P ¼ .10). Kaplan-
Meier estimates for freedom from aneurysm-related mortality were 98.7% and 97.0% in the AF group and 99.5% and
98.5% in the PF group at 1 and 5 years. There was no difference in aneurysm-related mortality, all-cause mortality, rupture,
secondary interventions, and type I and type III endoleak between the two cohorts. The type III endoleak rate at 5 years for
the AFX cohort was 1.5% and 0.0% for the comparator cohort (P ¼ .11). There was a lower type II endoleak rate in the AF
group at 5 years (78.8% vs 68.4%; P ¼ .037). There were zero open surgical conversions (0.0%) in the AF group and four
(2.0%) in the PF group.
Conclusions: The 5-year results from the LEOPARD study demonstrated that there was no clinically significant difference
in overall aneurysm-related outcomes between patients randomized to the AFX endograft system or commercially
available endografts with proximal fixation. (J Vasc Surg 2023;78:324-32.)
Keywords: AFX/AFX2 endografts; Anatomical fixation; Endovascular aneurysm repair (EVAR); proximal fixation;
Randomized controlled trials

Endovascular aneurysm repair (EVAR) is the predomi- States.1 The endografts utilized to exclude the aneurysm
nant method used to treat infrarenal abdominal aortic from the circulation in EVAR were originally conceived
aneurysms (AAAs) in up to 75% of patients in the United with differing design intents. Some endografts used

From The Vascular Care Group, Wellesleya; the NAMSA, New Yorkb; the Valley Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier:
Vascular Consultants, Huntsvillec; the Northeast Ohio Vascular Associates, NCT02407457.
Inc, Willoughbyd; the Alabama Heart and Vascular Center, Florencee; the Uni- Author conflict of interest: K.O. is an employee of NAMSA, a clinical research or-
versity of California Irvine Medical Center, Orangef; and the Midwest Aortic ganization that receives research support from Endologix, the sponsor of the
and Vascular Institute, North Kansas City.g LEOPARD study. S.K. is a consultant for Endologix and Medtronic
Funding: This study was sponsored by Endologix LLC (www.endologix.com). Additional material for this article may be found online at www.jvascsurg.org.
The steering committee consisted of Drs Benjamin Starnes, Christopher Kwo- Correspondence: Christopher J. Kwolek, MD, The Vascular Care Group, 981
lek, Daneil Clair, Jason Lee, Thomas Maldonado, Timothy Sullivan, Kenneth Worcester St, Ste 2A, Wellesley, MA 02482 (e-mail: ckwolek@
Ouriel, and Frank Veith. An outside analytics vendor, Core Lab, reviewed vascularcaregrp.com).
and assessed the imaging data and analyzed the database. An independent The editors and reviewers of this article have no relevant financial relationships to
physician reviewer, Dr Zack Arthurs, was paid for his services to evaluate avail- disclose per the JVS policy that requires reviewers to decline review of any
able data for all device-related events/major adverse events in the study and manuscript for which they may have a conflict of interest.
provided final adjudication inclusive of Core Lab assessments. The sponsor 0741-5214
played a role in the study design; collection, analysis, and interpretation of Copyright Ó 2023 The Authors. Published by Elsevier Inc. on behalf of the So-
data; and manuscript writing. Statistical analysis was provided by Dr Erik Zen- ciety for Vascular Surgery. This is an open access article under the CC BY-NC-
dejas. Dr Zendejas is the Director, Clinical Analysis and Scientific Communica- ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
tions of Endologix LLC and receives a salary from Endologix LLC. https://doi.org/10.1016/j.jvs.2023.04.011

324
Journal of Vascular Surgery
Volume 78, Number 2
active fixation, either suprarenal or infrarenal, to secure
the endograft in position in the proximal aorta (proxi-
mally fixated endografts [PF]), whereas others used the
aortic bifurcation as an anatomical point of fixation
(anatomically fixated endografts [AF]).
The AFX family of endografts (Endologix LLC) was intro-
duced into commercial practice in the United States in
2011, and the earliest version of this endograft (AFX
Strata) had a failure mode of type III endoleaks.2 Since
commercialization, the AFX endograft has undergone
design changes, manufacturing changes, and labeling
updates changes that have culminated in the currently
commercialized AFX2 endograft with Duraply fabric.3
To date, there is limited published data on the perfor-
mance of AFX/AFX2 with Duraply. Further, although
EVAR has been in widespread clinical practice for several
decades, there are no prospective randomized trials eval-
uating the results of EVAR with devices using different
design principles, namely PF vs distal AF.
The LEOPARD trial was designed to prospectively eval-
uate the outcomes of elective infrarenal AAA repair when
using the AFX/AFX2 endograft system with AF compared
with a cohort of commercially available EVAR devices
with PF (Cook Medical Zenith Flex; Gore Excluder; and
Medtronic Endurant II). All aneurysm-related complica-
tions were considered, including all endoleak types.
Type II endoleaks were included as they may be associ-
ated with negative outcomes. Here, we present the pri-
mary clinical endpoint, a composite of aneurysm-
related complications (ARCs), through 5 years.
METHODS
Study design. The LEOPARD (Looking at EVAR Out-
comes by Primary Analysis of Randomized Data) study
was a prospective, randomized, multi-center study,
designed to evaluate EVAR outcomes with contemporary
endografts as used in a real-world population. The AF
cohort was treated with the AFX/AFX2 system with Dura-
ply fabric,4 whereas the PF group was treated with the
individual investigator’s choice of commercially available
endograft (Zenith Flex, Excluder, and Endurant II).
LEOPARD evaluated freedom from ARCs through
5 years. The study was designed to test the hypothesis
that AF is noninferior to PF for ARC at 1 year, followed
by a test for superiority. Endologix LLC sponsored this
study and provided statistical analysis of the data. Prior
to the initiation of the trial, a steering committee was
formed comprising of physicians experienced in EVAR
and considered global thought leaders in the field (see
acknowledgements). The steering committee designed
and conducted the trial and interpreted the results.
The study is registered (ClinicalTrials.gov number,
NCT02407457) and was conducted according to the clin-
ical study protocol.5 The protocol and informed consent
were approved by the Institutional Review Board,
informed consent was obtained from all patients, and
Kwolek et al 325
ARTICLE HIGHLIGHTS
d
Type of Research: Multi-center prospective random-
ized study
d
Key Findings: The 5-year results of the LEOPARD ran-
domized clinical trial demonstrated that anatomi-
cally fixated (n ¼ 235) and proximally fixated (n ¼
220) endografts had comparable freedom from
aneurysm-related complications, reinterventions,
all-cause mortality, and type I/III endoleaks, and a
reduced type II endoleak rate in the anatomically
fixated endograft.
d
Take Home Message: Overall performance after 5
years of follow-up was comparable between
anatomically fixated and proximally fixated devices.
the study was conducted in accordance with the Decla-
ration of Helsinki and the current International Confer-
ence on Harmonization Good Clinical Practice
guidelines.
Participants and interventions. Investigators deter-
mined eligibility for trial devices using standard practice
for EVAR. Each investigator was required to choose one
single PF device that they were most comfortable with
that they would use throughout the entire trial. The
physician needed to be confident that the patient could
be equally well-treated by either the AF or PF device.
Inclusion criteria included the presence of infrarenal AAA
assessed by the investigator to be eligible for EVAR, age
$18 years, minimum of 2-year life expectancy, and signed
informed consent. Exclusion criteria included participa-
tion in another study, allergy to any of the device com-
ponents, pregnancy, or prior EVAR. Investigators
performed EVAR according to the institutional standard
of care.
Patients were randomized to either an AF or PF device;
455 devices were subsequently implanted. All EVAR pa-
tients were followed procedurally to discharge, and
were scheduled for 1-, 6-, and 12-month visits with
follow-up annually through 5 years. Data were collected
and recorded under the supervision of each site’s prin-
cipal investigator. Data collection, data management,
secure authentication, and monitoring utilized an elec-
tronic case report form (eCRF). Imaging data were
reviewed and assessed by an independent Core Lab
(Cleveland Clinic). Analysis was based upon evaluations
by the independent Core Lab, and site-reported events
in the absence of Core Lab data. All device-related events
and major adverse events (MAEs) identified in the study
were reviewed and adjudicated by an independent
physician adjudicator (see acknowledgments). The inde-
pendent physician reviewer evaluated available clinical
data for events and provided final adjudication inclusive
326 Kwolek et al
Fig 1. Consolidated Standards of Reporting Trials (CONSORT) diagram for Looking at EVAR Outcomes by Primary
Analysis of Randomized Data (LEOPARD) enrollment. AT, As treated; mITT, modified intent to treat; PI, principal
investigator.
of Core Lab assessments. Source data verification was
performed according to the study’s monitoring plan.
Definitions and outcomes. The LEOPARD study’s pri-
mary clinical endpoint was a composite endpoint of 1-
year freedom from ARCs, consisting of perioperative
death (#30 days), aneurysm rupture, conversion to open
surgical repair, postoperative endoleaks, endograft
migration ($10 mm compared with 1-month computed
tomography[CT] imaging), aneurysm enlargement
($5 mm compared with 1 month CT imaging), endograft
limb occlusion, and any reinterventions for the device- or
aneurysm-related complications. This is a binary
endpoint at 1 year. All patients with evaluable informa-
tion for the 1-year endpoint were included in the hy-
pothesis testing. For Kaplan-Meier analyses through
5 years, the time to the first event is considered.
Secondary endpoints included ARC (>12 months to
#5 years), aneurysm-related mortality (ARM), all-cause
mortality (ACM), endoleaks, AAA-related secondary pro-
cedures, loss of device integrity, and any adjunctive pro-
cedures necessitated during the index procedure.
Comorbidities and aneurysm-related outcomes are pre-
sented according to the Society of Vascular Surgery
reporting standards.
Secondary endovascular procedures were defined as
any non-diagnostic intervention after the index
Journal of Vascular Surgery
August 2023
procedure intended to correct or repair an endoleak, de-
vice stenosis or occlusion, migration, aneurysm sac
expansion, and/or a device deficiency including graft
infection. These were generated at the physician’s discre-
tion without a formal prospective protocol.
Randomization. Block randomization was performed
(1:1) using with the equal allocation of patients to each
treatment, and the randomization schedule was gener-
ated with a random number generator in the SAS statis-
tical software. Investigators were blinded to the block
size, and no stratification based on risk factors was per-
formed. Each investigator selected one comparator de-
vice prior to enrollment of the first patient, and all
investigators were certified in both the AFX system and
their choice of comparator device.
Statistical analysis. The study utilized an “as-good-as-
or-better” design that sequentially evaluated noninferior-
ity and then superiority hypotheses.6 This approach used
a closed testing procedure to investigate the two hy-
potheses while protecting the overall type I error rate,
eliminating the need to adjust the a. The absolute dif-
ference in ARC at 1 year was evaluated and a 1-sided
exact 95% confidence interval (CI) (with 2.5% in the
lower direction) was constructed for the difference of the
two groups and the lower boundary compared with
Journal of Vascular Surgery Kwolek et al 327
Volume 78, Number 2

Table I. Baseline demographics, risk factors, and baseline vascular characteristics (as-treated [AT] population)
Characteristics AF (n ¼ 235) PF (n ¼ 220)
Age, years 72 6 8 72 6 8
Gender: male 212 (90) 192 (87)
Race: caucasian 225 (96) 199 (90)
ASA class: 3/4/5 164 (70) 158 (72)
History of smoking 123/235 (52) 142/220 (65)
Hypertension 195/235 (83) 184/220 (84)
Coronary artery disease 97/235 (41) 86/220 (39)
Myocardial infarction 46/235 (20) 32/220 (15)
Hyperlipidemia 167/235 (71) 159/220 (72)
Chronic obstructive pulmonary 71/235 (30) 67/220 (30)
disease
Peripheral vascular disease 39/235 (17) 42/220(19)
Diabetes mellitus 45/235 (19) 43/220 (20)
Family history of AAA 33/235 (14) 28/220 (13)
Maximum sac diameter, mm; N 56.1 6 8.0 (28.2-86.1); n ¼ 203 55.8 6 9.3 (33.4-88.0); n ¼ 194
Non-aneurysmal neck length, mm; N 24.3 6 14.2 (2.0-81.0); n ¼ 202 23.2 6 13.2 (2.0-76.0); n ¼ 193
Proximal diameter at the lowest 24.6 6 3.2 (17.0-35.0); n ¼ 203 24.8 6 3.6 (15.0-37.0); n ¼ 193
renal, mm; N
Aortic neck angulation, degrees 15.1 6 10.0 (1.0-84.0); n ¼ 199 14.8 6 9.0 (0.0-51.0); n ¼ 193
Common iliac artery diameter, mm 18.5 6 5.0 (6.0-46.0); n ¼ 405 18.3 6 5.7 (7.0-55.0); n ¼ 384
External iliac diameter, mm; n 7.3 6 1.8 (3.0-12.0); n ¼ 386 7.2 6 1.8 (3.0-15.0); n ¼ 376
Native aortic bifurcation 9 13
diameter <20 mm
Reverse taper 33 (16) 26 (13)
Off anatomic IFU 58 (25) 52 (24)
AAA, Abdominal aortic aneurysm; AF, anatomic fixation; ASA, American Society of Anesthesiologists; IFU, instructions for use; PF, proximal fixation.
Data are presented as number (%) or mean 6 standard deviation (interquartile range).

both the clinically defined noninferiority margin and a
difference of zero. The delta in ARC is determined by
subtracting the ARC-free rate of the comparator from
the ARC-free rate from AFX. The clinical steering com-
mittee considered an 8% noninferiority margin to be a
clinically meaningful difference.
The hypothesis testing was conducted on the modified
intent-to-treat (mITT) population, consisting of all ran-
domized patients treated with EVAR. An as-treated (AT)
population was also defined to evaluate outcomes based
on the actual device implanted. Multiple imputation
analysis was performed to address missing data for the
endpoint. Values were assigned by randomly sampling
patients (with replacement) with the same baseline
American Society of Anesthesiologists classification
scores, an approach known as “Hot Deck Imputation
within classes.”7 This was performed 10 times with
different seeds. The results were pooled using PROC MIA-
NALYZE in SAS. Missing data occurred in the case of pa-
tients exiting the study due to death, loss to follow-up, or
inadequate imaging for the endpoint.
Continuous variables were described with means
(6 standard deviation) together with medians and
interquartile ranges. Frequencies and percentages were
calculated for categorical variables. For components of
ARC that required imaging, the protocol defined the 1-year
imaging window as 365 6 60 days. Components of ARC
that did not require imaging for evaluation were consid-
ered until postoperative day 365. For the noninferiority
test, a 95% 1-sided exact CI (with 2.5% alpha on the lower
end) was constructed to evaluate the difference in ARC at
1 year. When the Kaplan-Meier approach was used for
ARC and the components of ARC, patients were censored
at the last informative timepoint. In the case of non-
imaging-driven outcomes where the precise day of the
event onset were known (eg, intervention), this was at their
current time in the study. For imaging-driven variables,
censoring was performed at the last image adequate to
evaluate that component. In the cases where the Kaplan-
Meier curves of the components of ARC did not overlap,
post-hoc comparisons were performed on using the
log-rank test. These post-hoc tests were performed without
controlling for alpha and are provided for informational
purposes. Statistical analysis was performed using SAS
software version 9.4. Power calculations were performed
using PASS 12.0.11.
328 Kwolek et al Journal of Vascular Surgery
August 2023

Fig 2. Kaplan-Meier curve demonstrating estimates of freedom from aneurysm-related complications (ARCs) (A);
and ARCs excluding type II endoleaks, using the as-treated (AT) population (B).

Table II. Kaplan-Meier estimates (standard error) at all patients. The analysis revealed that the AF group was
5 years trending towards a small advantage; however, the
AFX Comparator magnitude of this difference was too small to support
ARM 97.0 (1.2) 98.5 (0.9) clinically significant superiority with the planned sample
Aneurysm rupture 98.9 (0.8) 99.3 (0.7)
size. Based on this observation, an informed recom-
mendation was made by the steering committee to
Conversion to OSR 100 (0) 98.0 (1.0)
discontinue enrollment. The noninferiority test remained
Type I endoleak 92.8 (2.3) 95.1 (1.8)
sufficiently powered (>90%) with the previously enrolled
Type II endoleak 78.8 (2.9) 68.4 (3.7)
patients as it has a lower threshold to reach statistical
Type III endoleak 98.5 (1.1) 100 (0) significance. No change in protocol hypothesis or testing
Migration >10 mm 96.8 (1.7) 97.8 (1.3) plans were made. The original endpoint analysis pro-
Aneurysm expansion >5 mm 83.1 (3.4) 88.1 (2.9) ceeded but with a reduced study sample size. LEOPARD
Device occlusion 97.2 (1.3) 94.2 (1.7) was not powered to test the individual components of
Reintervention 84.4 (2.7) 85.5 (2.7) ARC.
ARC 63.8 (3.6) 55.5 (3.8)
ARC, Aneurysm-related complication; ARM, aneurysm-related
RESULTS
mortality. Demographics and baseline characteristics. Between
March 2015 and September 2017, 455 eligible patients
were enrolled at 56 United States centers. A CONSORT
Sample size. A sample size was chosen that supported flow diagram is illustrated in Fig 1. Of the 455 patients
the comparison of ARC endpoint results between co- randomly assigned to EVAR treatment, 234 patients
horts at 1 year. The evaluation consisted of testing both (51.4%) were allocated to the AF endograft and 221 pa-
noninferiority and superiority hypotheses in sequential tients (48.6%) to the PF endografts. One site inadvertently
fashion. The lower boundary of a one-sided 95% CI is implanted an AFX device despite the randomization to
sequentially compared against the noninferiority margin the comparator; thus, the number of actual devices
and zero difference to test these hypotheses. To provide implanted was 235 in the AF group and 220 in the PF
at least 80% power to test the superiority hypothesis, group. Additionally, one patient randomized to the AF
800 patients needed to be randomized at a 1:1 ratio after group withdrew from the study. Within the PF group,
an expected drop-out rate of 10%. Freedom from ARC at 41% (91 cases) were treated with Endurant, 33% (72 cases)
1 year was assumed to be 86% for the AF cohort and 79% with Excluder, and 26% (57 cases) with the Zenith Flex
for the PF cohort. A 7% to 8% delta in absolute difference endograft, consistent with the distribution observed in a
was assumed during study development. Given the real-world surveillance study.8
larger sample size required for the superiority test, the Patients’ baseline demographics, vascular characteris-
power of the noninferiority test approached 99%. The tics, and preoperative comorbidities are presented in
sample size was subsequently reduced after a descrip- Table I. Thirty-four percent in both the AF and PF groups
tive analysis was conducted. This descriptive analysis was were treated outside the instructions for use with
prompted by a regulatory request prior to enrollment of respect to proximal neck and iliac anatomy. Baseline
Journal of Vascular Surgery
Volume 78, Number 2
Fig 3. Kaplan-Meier curve demonstrating estimates of freedom from type I endoleak (A); type II endoleak (B); type
III endoleak (C), using the as-treated (AT) population.
characteristics between the treatment groups were
similar.9 Procedural details are displayed in the
Supplementary Table (online only).
A total of 214 patients in the AF group, and 188 patients
in the comparator cohort, had sufficient follow-up infor-
mation at 1 year to evaluate the endpoint. Five-year
follow-up was completed for 102 patients in the AF
group and 111 patients in the PF group. A total of 4187 im-
ages were obtained across all patients in the LEOPARD
study. Four hundred twenty-two patients (92.7%) had a
CT performed at any time.
Freedom from aneurysm-related complications.
Freedom from ARC at 1 year was the primary endpoint of
LEOPARD, and was 73.8% in patients treated with AF vs
64.9% for the PF group. The AF cohort had an 8.9%
higher ARC-free rate, with a lower confidence boundary
of 0.04%. The boundary of the confidence interval is
higher than the noninferiority margin of 8.0%, leading
to the rejection of the null hypothesis that the AF group
is inferior to the PF group by a clinically significant
margin. The single patient that was randomized into the
Kwolek et al 329
PF group yet received the AF device accounts for the
difference between the mITT population and the AT
population. This patient was not evaluable for the
endpoint, and thus the AT and mITT evaluations for the 1-
year endpoint are identical. As no bias towards the AF
cohort is therefore possible for the primary endpoint, the
AT analysis is presented here for simplicity.
The estimated freedom from ARC at 5 years was 63.8%
(standard error [SE], 3.6%) in patients treated with AF vs
55.5% (SE, 3.8%) for the PF group (P ¼ .10) (Fig 2, A).
Further analysis demonstrated that the lower incidence
of type II endoleaks in the AF group (21.2% in the AF
group vs 31.6% in the PF group) was largely reponsible
for the difference seen between the two cohorts. When
type II endoleaks were removed from consideration,
the groups closely track with each other across 5 years
of follow-up (Fig 2, B). The individual components of
ARC through 5 years are shown in Table II and indicate
similar performance between AF and PF devices.
Although LEOPARD was designed to compare the AF
group against the combined PF cohort, an analysis
that stratifies the PF cohort by device for informational
330 Kwolek et al
Fig 4. Kaplan-Meier curve demonstrating estimates of freedom from aneurysm-related mortality (ARM) in
anatomical and proximal fixation groups, using the as-treated (AT) population.
purposes is shown in the Supplementary Fig (online
only).
Endoleaks. Kaplan-Meier curves for freedom from
endoleak type I, II, and III through 5 years are shown in
Fig 3, A-C. There were no significant differences be-
tween the AF and PF groups for type I or type III endo-
leaks (Fig 3, A and C, respectively). Freedom from type II
endoleaks was 83.5%, 79.5%, and 78.8% (SE, 2.9%) in the
AF group and 75.6%, 70.7%, and 68.4% (SE, 3.7%) in
the PF group at 1 year, 3 years, and 5 years, respectively
(P ¼ .0371) (Fig 3, B).
Freedom from ACM and ARM. Freedom from ACM was
95.7%, 84.1%, and 70.4% (SE, 3.2%) at 1 year, 3 years, and
5 years in the AF group vs 92.6%, 82.7%, and 74.7% (SE,
3.2%) in the PF group. Freedom from ARM was estimated
as 98.7% at 1 year, 98.2% at 3 years, and 97% (SE, 1.2%) at
5 years for the AF group vs 99.5% for the PF cohort at 1
year, and 98.5% (SE, 0.9%) from 3 years through 5 years
(P ¼ .39) (Fig 4).
DISCUSSION
The LEOPARD trial is a randomized controlled trial
providing Level 1 evidence comparing EVAR outcomes
using commercially available devices in a real-world pop-
ulation. Given the history of the AFX device family, the
LEOPARD trial was designed specifically to compare
the performance of the most recent version of AFX/
AFX2 with Duraply fabric with several commercially
Journal of Vascular Surgery
August 2023
available PF endografts. The earliest version of the AFX
device (AFX Strata) had a failure mode of type III endo-
leaks.2 Since commercialization, the AFX endograft has
undergone design changes, manufacturing changes,
and labeling updates to mitigate the type III endoleak
failure mode. These changes have culminated in the
currently commercialized AFX2 endograft.3
LEOPARD demonstrates that the AFX/AFX2 endograft
with Duraply is noninferior to the PF endografts with
respect to ARCs at 1 year. Furthermore, the 5-year results
demonstrate comparable performance between the two
groups with respect to freedom from ARCs. Post-hoc an-
alyses demonstrated that there were no significant dif-
ferences between the AF and PF groups for ACM, ARM,
type I endoleaks, and device-related reinterventions
through 5 years of follow-up.
Because type III endoleaks were a demonstrated failure
mode in the first generation of the AFX family, we evalu-
ated this specific outcome across all devices. The present
study did not detect an elevated type III endoleak rate in
any device group, and there was no statistical difference
in type III endoleak rates between the AF and PF groups
through 5 years in a post-hoc analysis. The current study
supports the findings of Vetsch et al4 that demonstrated
the AFX2 endograft with Duraply did not have an
elevated risk of type III endoleaks at 4 years of follow-
up. Further, the recently published VQI-VISION data
demonstrated that although there was an increased
rate of reintervention and conversion in patients treated
Journal of Vascular Surgery
Volume 78, Number 2
with the early AFX Strata device (prior to January 1, 2015),
this was not observed in the late AFX group (after
January 1, 2015) through 3 years of follow-up.8
The inclusion of type II endoleaks within the primary
endpoint was chosen at the time of trial design by the
steering committee in consideration of potential clinical
sequelae associated with this finding. It has been re-
ported that persistent type II endoleaks are associated
with a variety of adverse outcomes including sac expan-
sion, an increased rate of reintervention, need for conver-
sion, and aneurysm rupture.10 At 5 years, the freedom
from type II endoleaks was 78.8% in AF and 68.4% in
the PF group.
Several limitations need be considered when interpret-
ing the results of this study. First, there are inherent lim-
itations with industry-sponsored studies compared with
independent RCTs.11,12 Although we recognize these, a
steering committee was assembled to provide unbiased
input into study design and execution. Further, an
external Core Lab (Cleveland Clinic) reviewed and
assessed the imaging data and analyzed the database,
and an independent physician reviewer evaluated avail-
able data for all device-related events/MAEs in the study
and provided final adjudication inclusive of Core Lab
assessments.
Second, there is the potential for enrollment bias
because there was no independent review committee
to evaluate eligibility for endovascular repair. Individual
physicians were required to assess the patient using their
clinical protocols, choose a single PF device, and be
comfortable randomizing between their chosen PF de-
vice and the AF device. This allowed physicians to treat
patients who they felt were anatomically appropriate.
One-third of the patients across each device had at least
one parameter that fell outside the corresponding in-
structions for use. We believe that LEOPARD better illus-
trates a real-world population than tightly restricted
pivotal studies. The impact of this deserves further inves-
tigation in the future, but it remains true in clinical prac-
tice, that a substantial proportion of patients are treated
with endografts outside of the manufacturer’s instruc-
tions for use.
Third, the decreased sample size from the original pro-
tocol resulting from an unplanned descriptive analysis is
a limitation. However, the study was sufficiently powered
to support the primary endpoints. Fourth, we accept that
the total number of patients for follow-up decreases over
time. Much of this is due to natural attrition in this older
population with multiple comorbidities. Over 90% of the
patients eligible for 5-year follow-up in both cohorts have
completed the study. The Kaplan-Meier method ac-
counts for this and provides robust estimates with
reasonable standard errors. Log-rank testing for signifi-
cant differences between Kaplan-Meier curves was
Kwolek et al 331
done in a post-hoc fashion and without control of the
alpha error. Finally, imaging was performed per each
site’s standard of care. Over one-fourth of imaging was
in the form of ultrasound, and 8% of CTs were without
contrast. The authors anticipate that this may lead to
decreased sensitivity of certain events, particularly type
II endoleaks and sac expansion rates.
CONCLUSIONS
This prospective, randomized, multi-center trial
demonstrated that AF and PF endografts performed
well and had comparable freedom from ARCs, reinter-
ventions, all-cause mortality, and type I/III endoleaks
through 5 years of follow-up. A lower type II endoleak
rate was observed in the anatomically fixated arm
through 5 years of follow-up. However, the clinical rele-
vance of this finding remains to be determined.
AUTHOR CONTRIBUTIONS
Conception and design: CK, KO, FS, VR, PP, SW, SK
Analysis and interpretation: CK, KO, FS, VR, PP, SW, SK
Data collection: CK, KO, FS, VR, PP, SW, SK
Writing the article: CK, KO, FS, VR, PP, SW, SK
Critical revision of the article: CK, KO, FS, VR, PP, SW, SK
Final approval of the article: CK, KO, FS, VR, PP, SW, SK
Statistical analysis: Not applicable
Obtained funding: Not applicable
Overall responsibility: CK
REFERENCES
1. Dua A, Kuy S, Lee CJ, Upchurch GR Jr, Desai SS. Epidemiology of
aortic aneurysm repair in the United States from 2000 to 2010.
J Vasc Surg 2014;59:1512-7.
2. Lemmon GW, Motaganahalli RL, Chang T, Slaven J, Aumiller B,
Kim BJ, et al. Failure mode analysis of the Endologix endograft.
J Vasc Surg 2016;64:571-6.
3. Endologix. 2016-2019 Clinical update, https://endologix.com/
wp-content/uploads/2019/10/MM2165-Rev-01-Endologix-2016-2019-
AFXClinical-Update.pdf. Accessed March 31, 2023.
4. Vetsch R, Garrett HE Jr, Stout CL, Wladis AR, Thompson M,
Lombardi JV. Midterm outcomes of 455 patients receiving the AFX2
endovascular graft for the treatment of abdominal aortic aneurysm:
a retrospective multi-center analysis. PLoS One 2021;16:e0261623.
5. Endologix I. Post-market study to assess outcomes of patients treated
with AFX system compared to other EVAR devices (LEOPARD). Clin-
icalTrials.gov identifier: NCT02407457 2021, https://www.clinicaltrials.
gov/ct2/show/NCT02407457. Accessed November 7, 2022.
6. Julious SA. Sample sizes for clinical trials. Boca Raton, Florida:
Chapman and Hall/CRC; 2010. p. 18-9.
7. Little RJA, Rubin DB. In: Statistical analysis with missing data. 2nd ed.
Hoboken, New Jersey: John Wiley and Sons; 2002. p. 66-74.
8. Goodney P, Mao J, Columbo J, Suckow B, Schermerhorn M, Malas M,
et al. Use of linked registry claims data for long term surveillance of
devices after endovascular abdominal aortic aneurysm repair:
observational surveillance study. BMJ 2022;379:e071452.
9. Knol MJ, Groenwold RH, Grobbee DE. P-values in baseline tables of
randomised controlled trials are inappropriate but still common in
high impact journals. Eur J Prev Cardiol 2012;19:231-2.
10. Jones JE, Atkins MD, Brewster DC, Chung TK, Kwolek CJ,
LaMuraglia GM, et al. Persistent type 2 endoleak after endovascular
repair of abdominal aortic aneurysm is associated with adverse late
outcomes. J Vasc Surg 2007;46:1-8.
332 Kwolek et al Journal of Vascular Surgery
August 2023

11. Montaner JS, O’Shaughnessy MV, Schechter MT. Industry-sponsored Submitted Nov 11, 2022; accepted Apr 10, 2023.
clinical research: a double-edged sword. Lancet 2001;358:1893-5.
12. Laterre PF, Francois B. Strengths and limitations of industry vs. aca-
Additional material for this article may be found online
demic randomized controlled trials. Clin Microbiol Infect 2015;21:
906-9. at www.jvascsurg.org.
Journal of Vascular Surgery Kwolek et al 332.e1
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APPENDIX (online only).

Supplemental Table (online only). Procedural characteristics (as-treated [AT] population)

Procedural Data AF PF
Characteristic No. Result No. Result P valuea
Total procedure time, minutes 230 79.5 (30-374) 218 90.5 (34-303) < .0001
Catheter time, minutes 200 57.5 (14-351) 178 68 (4-265) .0017
Fluoroscopy time, minutes 216 16 (3-116) 194 18.5 (5-84) .0424
Total anesthesia time, minutes 212 152.5 (57-490) 201 166 (65-390) .0142
Contrast volume, mL 223 68 (15-220) 214 84 (15-345) < .0001
Access type:
Main body percutaneous, contralateral percutaneous 163 69.4 146 66.4 .5467
Anesthesia type: local 15 6.4 10 4.5 .8527
General 193 82.1 187 85.0
Requiring blood transfusion: yes 1 0.4 2 0.9 .6122
No 234 99.6 218 99.1
Time in ICU, days 235 0 (0-7.3) 220 0 (0-11.2) .6295
Time to hospital discharge, days 234 1.3 (0.7-16) 220 1.3 (0.7-31.0) .2155
AF, Anatomic fixation; ICU, intensive care unit; PF, proximal fixation.
Data are presented as number (%) or median (interquartile range).
a
Results from the Wilcoxon rank sum test (non-parametric) using two-sided normal approximation, or the Fisher exact test depending on variable
type.
332.e2 Kwolek et al Journal of Vascular Surgery
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Supplementary Fig (online only). Kaplan-Meier curve demonstrating estimates of freedom from aneurysm-
related complications (ARCs) across different comparator devices, using the as-treated (AT) population.