Life-Btk Nejmoa2305637

new england
The
journal of medicine
established in 1812 January 4, 2024 vol. 390 no. 1
Drug-Eluting Resorbable Scaffold versus Angioplasty

for Infrapopliteal Artery Disease
Ramon L. Varcoe, M.B., B.S., Ph.D., M.Med. (Clin.Epi.), Brian G. DeRubertis, M.D., Raghu Kolluri, M.D.,
Prakash Krishnan, M.D., David C. Metzger, M.D., Marc P. Bonaca, M.D., M.P.H.,
Mehdi H. Shishehbor, D.O., M.P.H., Ph.D., Andrew H. Holden, M.B., Ch.B., Danielle R. Bajakian, M.D.,
Lawrence A. Garcia, M.D., Steven W.C. Kum, M.B., B.S., M.Med., John Rundback, M.D., Ehrin Armstrong, M.D.,
Jen‑Kuang Lee, M.D., Yazan Khatib, M.D., Ido Weinberg, M.D., Hector M. Garcia‑Garcia, M.D., Ph.D.,
Karine Ruster, Ph.D., Nutte T. Teraphongphom, Ph.D., Yan Zheng, M.S., Jin Wang, Ph.D.,
Jennifer M. Jones‑McMeans, Ph.D., and Sahil A. Parikh, M.D., for the LIFE-BTK Investigators*
a bs t r ac t
BACKGROUND
Among patients with chronic limb-threatening ischemia (CLTI) and infrapopliteal The authors’ affiliations are listed in the
Appendix. Dr. Parikh can be contacted at
artery disease, angioplasty has been associated with frequent reintervention and sap2196@cumc.columbia.edu or at Co-
adverse limb outcomes from restenosis. The effect of the use of drug-eluting re- lumbia University Irving Medical Center,
sorbable scaffolds on these outcomes remains unknown. 161 Fort Washington Ave., 6th Fl., New
York, NY 10032.
METHODS *A complete list of the LIFE-BTK Inves-
In this multicenter, randomized, controlled trial, 261 patients with CLTI and infra tigators is provided in the Supplemen-
popliteal artery disease were randomly assigned in a 2:1 ratio to receive treatment tary Appendix, available at NEJM.org.
with an everolimus-eluting resorbable scaffold or angioplasty. The primary effi- Drs. Varcoe, DeRubertis, and Parikh con-
cacy end point was freedom from the following events at 1 year: amputation above tributed equally to this article.
the ankle of the target limb, occlusion of the target vessel, clinically driven revas- This article was published on October
cularization of the target lesion, and binary restenosis of the target lesion. The 25, 2023, at NEJM.org.
primary safety end point was freedom from major adverse limb events at 6 months N Engl J Med 2024;390:9-19.
and from perioperative death. DOI: 10.1056/NEJMoa2305637
Copyright © 2023 Massachusetts Medical Society.
RESULTS
CME
The primary efficacy end point was observed (i.e., no events occurred) in 135 of at NEJM.org
173 patients in the scaffold group and 48 of 88 patients in the angioplasty group
(Kaplan–Meier estimate, 74% vs. 44%; absolute difference, 30 percentage points;
95% confidence interval [CI], 15 to 46; one-sided P<0.001 for superiority). The
primary safety end point was observed in 165 of 170 patients in the scaffold group
and 90 of 90 patients in the angioplasty group (absolute difference, −3 percentage
points; 95% CI, −6 to 0; one-sided P<0.001 for noninferiority). Serious adverse
events related to the index procedure occurred in 2% of the patients in the scaffold
group and 3% of those in the angioplasty group.
CONCLUSIONS
Among patients with CLTI due to infrapopliteal artery disease, the use of an
everolimus-eluting resorbable scaffold was superior to angioplasty with respect to
the primary efficacy end point. (Funded by Abbott; LIFE-BTK ClinicalTrials.gov
number, NCT04227899.)
n engl j med 390;1 nejm.org January 4, 2024 9

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The n e w e ng l a n d j o u r na l of m e dic i n e
P
eripheral artery disease is a global tical analysis plan (available with the full text of
health epidemic estimated to affect more this article at NEJM.org) was designed by the
than 230 million people, including 7 to 12 sponsor (Abbott) with input from the principal
million people in the United States alone.1,2 The investigators (the first two authors and the last
A Quick Take
most severe manifestation is chronic limb- author). The protocol was then approved by the
is available at threatening ischemia (CLTI), which is character- Food and Drug Administration (FDA) and the
NEJM.org ized by ischemic rest pain and nonhealing ulcer- institutional review board at each site. An inves-
ation or gangrene and is associated with a high tigational device exemption was approved by the
risk of amputation. The adverse limb outcomes FDA. All the patients provided written informed
associated with CLTI affect quality of life and consent. The trial was conducted at 50 sites in
life expectancy; the prognosis is worse than that six countries. The list of clinical trial commit-
for most cancers.3 tees is provided in the Supplementary Appendix
Open surgical revascularization with saphe- (available at NEJM.org), and the full list of inves-
nous-vein bypass has been shown to increase tigators is provided in Table S1 in the Supple-
the likelihood of limb salvage in highly selected mentary Appendix.
patients with CLTI.4 However, for the treatment Data were managed by the sponsor and ana-
of patients with CLTI and infrapopliteal artery lyzed by the principal investigators and the
disease (i.e., arterial disease below the knee), sponsor. An independent data and safety moni-
angioplasty has recently been shown to be supe- toring board oversaw the conduct of the trial,
rior to surgery.5 Infrapopliteal angioplasty has and an independent committee adjudicated all
limitations, such as elastic recoil, dissection, the clinical events. The results of angiography,
and restenosis, that reduce the durability of the intravascular ultrasonography, optical coherence
procedure. Such limitations may be avoided with tomography, duplex ultrasonography, and quan-
mechanical scaffolding. titative wound assessment were adjudicated at
The use of coronary drug-eluting stents has core laboratories by assessors who were unaware
shown promise in below-the-knee interventions,6-9 of the trial-group assignments. The principal
but stents can interfere with future reinterven- investigators wrote the first draft of the manu-
tion. Drug-eluting resorbable scaffolds have po- script, and all the authors reviewed and edited
tential advantages that may make them suitable the manuscript and approved the submitted ver-
for the treatment of infrapopliteal artery disease, sion. The principal investigators vouch for the
and observational studies have shown promising accuracy and completeness of the data and for
results.10-16 Drug-eluting resorbable scaffolds have the fidelity of the trial to the protocol.
unique scaffolding properties that allow them to
overcome mechanical failure while acting as a Patients
delivery platform for an antiproliferative drug Patients 18 years of age or older were eligible for
during the restenotic phase after intervention. inclusion in the trial if they presented with CLTI
These scaffolds also undergo resorption over associated with either ischemic rest pain (Ruther-
time, which facilitates vessel remodeling and ford–Becker class 4) or minor tissue loss (Ruth-
potentially reduces the late complications asso- erford–Becker class 5) and had infrapopliteal
ciated with permanent metal stents. artery stenosis or occlusion. A complete list of
We conducted a single-blind, randomized, clinical and anatomical inclusion and exclusion
controlled trial (LIFE-BTK) to evaluate the safety criteria is provided in Table S2. Randomization
and efficacy of a new everolimus-eluting resorb- was performed after all eligibility criteria had
able scaffold (Esprit BTK, Abbott Vascular) for been met, inf low and nontarget lesions had
the treatment of infrapopliteal artery disease in been treated successfully, and the guidewire
patients with CLTI. had crossed the target lesion.
Trial Procedures
Me thods
Patients who met the eligibility criteria were
Trial Design randomly assigned in a 2:1 ratio to receive treat-
The design of the LIFE-BTK trial has been de- ment with either the everolimus-eluting resorb-
scribed previously.17 The protocol with the statis- able scaffold (Fig. S1) or angioplasty. As many as
10 n engl j med 390;1 nejm.org January 4, 2024

Drug-Eluting Resorbable Scaffold vs. Angioplasty
two target lesions could be treated. Tandem le- nually for 5 years. Details regarding follow-up
sions that were less than 3 cm apart were con- are provided in Table S3.
sidered to be a single target lesion. The lesions
could be de novo (previously untreated) or reste- End Points
notic (previously treated). The lesions had to be The primary efficacy end point was freedom
located in separate arteries in the proximal two from the following events at 1 year: amputation
thirds of the lower leg and to have a runoff vessel above the ankle of the target limb, total (100%)
to the ankle that was free of clinically significant occlusion of the target vessel, clinically driven
disease. revascularization of the target lesion, and binary
Patients received aspirin (at a loading dose of restenosis of the target lesion. The original pri-
≥300 mg) and a P2Y12 receptor inhibitor (clopid mary efficacy end point did not include freedom
ogrel, prasugrel, or ticagrelor) between 24 hours from binary restenosis of the target lesion. Be-
before the index procedure and 1 hour after the fore the completion of enrollment, this compo-
procedure, if they were not already receiving nent was added, and the duration of observation
these medications. Dual antiplatelet therapy was was extended from 6 months to 1 year. This
continued for at least 1 year in the scaffold decision was made after consideration of the
group and for 1 month in the angioplasty group, results of a prespecified interim analysis (de-
and single-agent therapy was provided thereafter. scribed below), as well as consideration of the
Planned minor amputation, such as toe or end points that had been used in recently com-
transmetatarsal amputation, was allowed at the pleted randomized trials that had insufficient
time of the index procedure or within the first power to discern clinically relevant treatment
month after the procedure. In the scaffold effects of the test device as compared with the
group, predilation was a mandatory step; the use standard of care.
of a noncompliant balloon with a 1:1 ratio of Binary restenosis was defined as the presence
balloon size to vessel size was preferred.18 Suc- of restenosis of more than 50% of the vessel
cessful predilation was defined as residual ste- diameter on angiography or a peak systolic veloc-
nosis of less than 30% of the vessel diameter. ity ratio (PSVR) of 2.0 or more on duplex ultra-
The length of the scaffold was selected to cover sonography.19 Each target lesion was interrogated.
a minimum of 2 mm of reference vessel at both If the patient underwent both angiography and
the proximal edge and the distal edge. The duplex ultrasonography at the same time point,
maximum total length of the scaffold allowed the results of angiography were used as the pri-
over all target lesions was 170 mm. In the angio- mary determinant. The following secondary
plasty group, the procedure was performed in criteria were used at the duplex-ultrasonography
accordance with the standard of care and at the core laboratories to confirm any target-lesion
discretion of the proceduralist. stenosis detected: visible stenosis on B-mode
The success of target-lesion treatment was imaging, a focal increase in the absolute peak
assessed by means of angiography performed in velocity, poststenotic turbulence, a change in
magnified orthogonal views. Successful treat- waveform shape, or a reduction in velocity distal
ment immediately after the index procedure was to the stenosis. If the PSVR could not be calcu-
defined as follows: residual stenosis of less than lated, these secondary criteria were used to de-
30% of the vessel diameter, a final number of termine whether stenosis was present. When the
runoff vessels that was equal to or greater than results were indeterminate (discordant), the pa-
the number on initial angiography, the absence tient was excluded from the analysis.
of residual dissection (defined as the absence of The primary safety end point was freedom
a persistent or increased amount of contrast from major adverse limb events at 6 months and
material outside the vessel lumen), and the ab- from perioperative death. Major adverse limb
sence of complications, such as distal emboliza- events were amputation above the ankle of the
tion, perforation, or thrombosis. target limb and major reintervention, which was
Follow-up visits were performed at 30 days, defined as new surgical bypass grafting, interpo-
3 months, 6 months, and 1 year; data from these sition grafting, thrombectomy, or thrombolysis.20
assessments are reported in this article. Addi- Perioperative death was defined as death from any
tional follow-up is planned to be performed an- cause within 30 days after the index procedure.

The trial was powered to assess two second- The primary efficacy end point was evaluated
ary end points, both of which were adjudicated in a superiority analysis performed with the use
at 1 year. The first was the original primary ef- of Pearson’s chi-square test at a one-sided trial-
ficacy end point (freedom from amputation wise alpha level of 0.0249. The primary safety
above the ankle of the target limb, occlusion of end point was evaluated in a noninferiority
the target vessel, and clinically driven revascu- analysis (noninferiority margin, −10 percentage
larization of the target lesion), and the second points) performed with the use of the Farrington–
was binary restenosis of the target lesion. A com- Manning method at a one-sided alpha level of
plete list of end points and their definitions is 0.025. It was assumed that the primary safety
provided in Tables S4 and S5. end point would be observed in 95% of the pa-
tients in each trial group. The two powered
Statistical Analysis secondary end points were evaluated in superior-
A prespecified interim analysis was performed ity analyses performed at a one-sided alpha level
during the enrollment period by an independent of 0.025. Assumptions were based on published
statistician on May 12, 2022. On September 7, data.6,8,9,21,23 For the superiority analyses, a between-
2022, the following components of the adaptive group difference of approximately 15 percentage
trial design were implemented by the principal points was required to show superiority.
investigators and the sponsor, in consultation The primary efficacy end point and the two
with the FDA: the sample size was increased, the powered secondary end points were assessed in
primary efficacy end point was modified to in- the intention-to-treat population, which includ-
clude freedom from binary restenosis of the ed all the patients who underwent randomiza-
target lesion, and the duration of observation tion. The primary safety end point was assessed
was extended from 6 months to 1 year. The in- in the as-treated population, which included all
vestigators and trial statisticians remained un- the patients who received the randomly assigned
aware of the trial-group assignments. For the treatment. For these end points, Kaplan–Meier
analysis of the primary efficacy end point, the estimates are reported. Kaplan–Meier time-to-
alpha level was adjusted by 0.0001 (from 0.025 event analyses for efficacy and safety from base-
to 0.0249). The original primary efficacy end line through the prespecified follow-up time
point was preserved as a powered secondary end point were performed as sensitivity analyses.
point, and binary restenosis of the target lesion Treatment effects were estimated with the use
at 1 year was also added as a powered secondary of Cox proportional-hazards regression and are
end point. The analyses of these powered sec- presented as hazard ratios with 95% confidence
ondary end points were conducted at a one-sided intervals. If the proportional-hazards assump-
alpha level of 0.025 because they were performed tion was violated, the Com–Nougue method was
only after the threshold for significance for the used; this method involves the use of estimates
primary efficacy and safety end points had been from the Kaplan–Meier analyses together with
met. Data were unblinded on July 7, 2023. variance estimated with the Greenwood method.
We estimated that a sample of 261 patients Missing data were handled with multiple im-
would provide the trial with more than 80% putation. The Markov chain Monte Carlo meth-
power to show the superiority of the use of the od was used to impute missing values for the
scaffold to angioplasty with respect to the pri- end points and prespecified baseline variables
mary efficacy end point. The sample size was with an arbitrary missing pattern from data un-
estimated on the basis of a difference between der the assumption of multivariate normal dis-
the scaffold group and the angioplasty group (i.e., tribution. A final assessment of the treatment ef-
treatment effect) of approximately 20 percentage fect was performed by combining the results for
points that was seen in previous data.6,9,21,22 We the treatment assessments across the five im-
initially estimated that a sample of 222 patients puted data sets with Rubin’s combination rules.
(148 in the scaffold group and 74 in the angio- If the threshold for significance for the pri-
plasty group) would provide the trial with more mary efficacy and safety end points was met, the
than 80% power to show a treatment effect of two powered secondary end points were to be
the scaffold; we then adjusted the sample size to tested in a hierarchical fashion until the thresh-
account for 15% attrition at 1 year. old for significance was not met; if an end point

remained, it was to be tested in an exploratory regarding characteristics of the patients and

fashion. One-sided P values are reported. For target lesions at baseline and the procedures are
other analyses, 95% confidence intervals are provided in Tables S7 through S12. Results for
presented without adjustment for multiplicity. procedural end points are shown in Table S13.
Thus, the confidence intervals should not be
used to infer definitive treatment effects. Details Clinical Outcomes
regarding the statistical analysis are provided in At 1 year, follow-up data were available for 231
the Supplementary Appendix. All analyses were patients (89%, including 88% in the scaffold
conducted with the use of SAS software, version group and 89% in the angioplasty group). The
9.4 (SAS Institute). median follow-up was 390 days (range, 0 to
1012) in the scaffold group and 397 days (range,
35 to 884) in the angioplasty group. The use of
R e sult s
concomitant medical therapy is shown in Table
Patients and Procedures S14. The use of dual antiplatelet therapy at 30
From July 2020 through September 2022, a total days and at 1 year is shown in Table S15.
of 7837 patients were assessed for eligibility at For the primary efficacy end point (freedom
50 clinical sites with 66 unique operators, and from amputation above the ankle of the target
635 patients provided consent. Subsequently, 365 limb, occlusion of the target vessel, clinically
patients had a screening failure before or during driven revascularization of the target lesion, and
the index procedure, 8 withdrew consent before binary restenosis of the target lesion at 1 year),
randomization, and 1 provided consent but the the Kaplan–Meier estimate was 74% in the scaf-
site closed and the patient did not undergo fold group and 44% in the angioplasty group,
randomization; 261 patients underwent random- with an absolute difference of 30 percentage
ization. points (95% confidence interval [CI], 15 to 46;
A total of 173 patients (with 179 target le- one-sided P<0.001 for superiority) (Table 3). The
sions) were randomly assigned to receive the results for freedom from clinically driven revas-
scaffold, and 88 patients (with 92 target lesions) cularization of the target lesion at 1 year and
were randomly assigned to undergo angioplasty freedom from binary restenosis of the target le-
(Fig. S2). The characteristics of the patients at sion at 1 year appeared to be consistent with the
baseline are shown in Table 1. The representa- results for the primary efficacy end point. Re-
tiveness of the trial population is shown in Table sults for subgroup analyses of the primary effi-
S6. The mean (±SD) age of the patients was cacy end point are shown in Figure S7.
72.6±10.1 years, and 32% were female. Ruther- The primary safety end point (freedom from
ford–Becker class 4 disease (associated with major adverse limb events at 6 months and peri-
ischemic rest pain) was present in 135 patients operative death) was observed in 165 of 170 pa-
(52%), and Rutherford–Becker class 5 disease tients in the scaffold group and 90 of 90 patients
(associated with minor tissue loss) was present in the angioplasty group, with an absolute dif-
in 126 patients (48%). There was a wound on the ference of −3 percentage points (95% CI, −6 to
target limb in 130 patients (50%), and the mean 0; one-sided P<0.001 for noninferiority). Results
ankle–brachial index of the target limb was for the prespecified analysis of binary data are
0.88±0.32. shown in Table S16, and results for the imputa-
The characteristics of the target lesions are tion analysis are shown in Table S17.
shown in Table 2. The mean lesion length at The first powered secondary end point (free-
baseline was 43.8±31.8 mm in the scaffold group dom from amputation above the ankle of the
and 44.8±29.1 mm in the angioplasty group. On target limb, occlusion of the target vessel, and
the basis of angiography performed at the angi- clinically driven revascularization of the target
ography core laboratory, successful treatment lesion at 1 year) was observed in 148 of 173 pa-
immediately after the index procedure occurred tients in the scaffold group and 66 of 88 patients
in 91% of the patients in the scaffold group and in the angioplasty group. The second powered
in 70% of the patients in the angioplasty group. secondary end point (binary restenosis of the
Bailout stenting was performed in 5 patients target lesion at 1 year) was observed in 35 of 173
(6%) in the angioplasty group. Additional data patients in the scaffold group and 35 of 88 pa-

Table 1. Baseline Characteristics of the Patients.*
Scaffold Angioplasty Total

Characteristic (N = 173) (N = 88) (N = 261)
Age — yr 73.3±9.9 71.1±10.4 72.6±10.1
Sex — no. (%)
Male 117 (68) 61 (69) 178 (68)
Female 56 (32) 27 (31) 83 (32)
Race or ethnic group — no. (%)†
White 98 (57) 56 (64) 154 (59)
American Indian or Alaska Native 0 1 (1) 1 (<1)
Asian 36 (21) 11 (12) 47 (18)
Black 21 (12) 11 (12) 32 (12)
Native Hawaiian or Pacific Islander 1 (1) 2 (2) 3 (1)
Declined or unable to disclose 18 (10) 7 (8) 25 (10)
Hispanic ethnic group — no. (%)†
Hispanic or Latinx 31 (18) 12 (14) 43 (16)
Not Hispanic or Latinx 132 (76) 70 (80) 202 (77)
Declined or unable to disclose 10 (6) 6 (7) 16 (6)
Body-mass index‡ 27.85±5.47 28.94±5.77 28.21±5.58
Risk factors — no. (%)
Tobacco use 91 (53) 47 (53) 138 (53)
Hypertension 163 (94) 80 (91) 243 (93)
Hyperlipidemia 140 (81) 72 (82) 212 (81)
Diabetes mellitus 123 (71) 61 (69) 184 (70)
Previous minor amputation of target limb — no. (%) 16 (9) 7 (8) 23 (9)
Rutherford–Becker classification — no. (%)§
Class 4 90 (52) 45 (51) 135 (52)
Class 5 83 (48) 43 (49) 126 (48)
Wound on target limb — no. (%) 85 (49) 45 (51) 130 (50)
Ankle–brachial index of target limb¶ 0.87±0.32 0.91±0.33 0.88±0.32
Toe–brachial index of target limb‖ 0.51±0.31 0.46±0.24 0.49±0.29
* Plus–minus values are means ±SD. Percentages may not total 100 because of rounding.
† Race or ethnic group was reported by the patient.
‡ The body-mass index is the weight in kilograms divided by the square of the height in meters.
§ Rutherford–Becker class 4 disease is associated with ischemic rest pain, and Rutherford–Becker class 5 disease is associ-
ated with minor tissue loss.
¶ Data for the ankle–brachial index of the target limb are shown for 227 patients (87%). The ankle–brachial index is the
ratio of ankle pressure to arm pressure; a value of 0.9 to 1.4 is considered to be borderline or normal, a value lower
than 0.9 indicates peripheral artery disease, and a value higher than 1.4 suggests a noncompressible artery. When the
ankle–brachial index was higher than 1.4 or could not be measured reliably, a toe-pressure measurement was obtained
and the toe–brachial index was used.
‖ Data for the toe–brachial index of the target limb are shown for 79 patients (30%). The toe–brachial index is the ratio of
toe pressure to arm pressure; a value of 0.7 or higher is considered to be normal, and a value lower than 0.7 indicates
peripheral artery disease.

Table 2. Baseline, Procedural, and Postprocedural Characteristics of the Target Lesions.*
Scaffold Angioplasty Difference Total

Characteristic (N = 173) (N = 88) (95% CI)† (N = 261)
Baseline characteristics reported by trial sites
Target lesions treated
No. of target lesions 1.0±0.2 1.0±0.2 0.0 (−0.0 to 0.1) 1.0±0.2
One target lesion — no. (%) 165 (95) 85 (97) −1 (−5 to 6) 250 (96)
Two target lesions — no. (%) 7 (4) 3 (3) 1 (−6 to 5) 10 (4)
Calcification of target lesion — no./total no. of target lesions (%)
None or mild 124/179 (69) 64/92 (70) 0 (−11 to 12) 188/271 (69)
Moderate 49/179 (27) 26/92 (28) −1 (−12 to 10) 75/271 (28)
Severe 6/179 (3) 2/92 (2) 1 (−5 to 5) 8/271 (3)
Baseline characteristics reported by core laboratory‡
Diameter of reference vessel before treatment — mm 2.94±0.77 2.82±0.74 0.12 (−0.09 to 0.32) 2.90±0.76
Length of target lesion — mm 43.8±31.8 44.8±29.1 −1.0 (−8.7 to 6.8) 44.1±30.9
Absence of thrombus — no. (%) 172 (100) 89 (100) 0 (−2 to 4) 261 (100)
Location of target lesion — no. (%)
Anterior tibial artery 59 (34) 24 (27) 7 (−5 to 18) 83 (32)
Posterior tibial artery 26 (15) 16 (18) −3 (−13 to 6) 42 (16)
Peroneal artery 28 (16) 21 (24) −7 (−18 to 3) 49 (19)
Tibioperoneal trunk 26 (15) 15 (17) −2 (−12 to 7) 41 (16)
Tibioperoneal trunk to posterior tibial artery 15 (9) 8 (9) 0 (−9 to 6) 23 (9)
Tibioperoneal trunk to peroneal artery 18 (10) 5 (6) 5 (−3 to 11) 23 (9)
TASC II classification — no. (%)§
Class A 83 (48) 47 (53) −5 (−17 to 8) 130 (50)
Class B 61 (35) 23 (26) 10 (−2 to 20) 84 (32)
Class C 28 (16) 19 (22) −5 (−16 to 5) 47 (18)
Stenosis before treatment — % of vessel diameter 72.6±18.9 73.7±21.0 −1.1 (−6.3 to 4.1) 73.0±19.6
Procedural characteristics reported by trial sites
Predilation performed — no./total no. of target lesions (%) 179/179 (100) 92/92 (100) 0 (−2 to 4) 271/271 (100)
Postdilation performed without complications — no./total no. 176/179 (98) NA NA NA
of target lesions (%)
Bailout devices used — no. (%) 0 5 (6) −6 (−13 to 2) 5 (2)
Postprocedural characteristics reported by core laboratory¶
Residual stenosis after predilation — % of vessel diameter 30.0±12.6 25.0±8.7 5.0 (−14.8 to 24.8) 29.8±12.5
Residual stenosis after index procedure — % of vessel diameter 17.0±9.3 22.8±11.2 −5.8 (−8.6 to −3.0) 19.0±10.3
Residual stenosis after index procedure <30% of vessel diameter 163/170 (96) 61/84 (73) 23 (14 to 34) 224/254 (88)
— no./total no. (%)
* Plus–minus values are means ±SD. Percentages may not total 100 because of rounding. CI denotes confidence interval and NA not appli-
cable.
† Differences in percentages are shown in percentage points.
‡ No patients had ulceration or aneurysm of the target lesion at baseline.
§ The Trans-Atlantic Inter-Society Consensus (TASC) II classification indicates the anatomical pattern of atherosclerotic disease severity. No
patients had class D.
¶ No patients had residual flow-limiting dissection after the index procedure.

16
Table 3. Efficacy and Safety End Points.
Difference
End Point Scaffold Angioplasty (95% CI)* P Value†
no./total no. Kaplan–Meier % no./total no. Kaplan–Meier %

Primary efficacy end point‡
Freedom from amputation above ankle of target limb, occlusion of target vessel, 135/173 74 48/88 44 30 (15 to 46) <0.001
clinically driven revascularization of target lesion, and binary resteno-
sis of target lesion at 1 yr
The
Freedom from amputation above ankle of target limb at 1 yr 169/173 98 88/88 100 — —
Freedom from occlusion of target vessel at 1 yr 155/173 87 76/88 83 — —
Freedom from clinically driven revascularization of target lesion at 1 yr 162/173 93 77/88 87 — —
Freedom from binary restenosis of target lesion at 1 yr 138/173 76 53/88 50 — —
Powered secondary end points
n engl j med 390;1

Original primary efficacy end point: freedom from amputation above ankle of 148/173 83 66/88 70 0.56 0.03
target limb, occlusion of target vessel, and clinically driven revascular- (0.32 to 0.99)
ization of target lesion at 1 yr
Binary restenosis of target lesion at 1 yr 35/173 24 35/88 50 −26 (−41 to −11) <0.001
nejm.org
Primary safety end point§
n e w e ng l a n d j o u r na l

of
Freedom from major adverse limb events at 6 mo and perioperative death 165/170 97 90/90 100 −3 (−6 to 0) <0.001
Freedom from major adverse limb events at 6 mo 167/170 98 90/90 100 — —
Freedom from amputation above ankle of target limb 168/170 99 90/90 100 — —
January 4, 2024
Freedom from major reintervention of target limb 169/170 99 90/90 100 — —

m e dic i n e
Freedom from perioperative death 168/170 99 90/90 100 — —
* For the primary efficacy end point, the difference in percentages (shown in percentage points) and 95.02% confidence interval are provided. For the original primary efficacy end point
(the first powered secondary end point), the hazard ratio and 95% confidence interval are provided. For binary restenosis of the target lesion at 1 year (the second powered secondary
end point) and for the primary safety end point, differences in percentages (shown in percentage points) and 95% confidence intervals are provided.
† The one-sided P values were calculated on the basis of the Com–Nougue method against a one-sided alpha level of 0.025, except the P value for the primary efficacy end point, which
was calculated against a one-sided alpha level of 0.0249.
‡ Patients were included in the analysis of the primary efficacy end point if they had data from duplex ultrasonography (or data from angiography, if both angiographic and duplex ultraso-
nographic data were available) from a qualified core laboratory at 1 year or had had a clinical event. Clinical events were adjudicated by the clinical events committee through 365 days,
whereas angiographic data through 423 days and duplex ultrasonographic data through 453 days were used to evaluate patency.
§ Major reintervention was defined as new surgical bypass grafting, interposition grafting, thrombectomy, or thrombolysis. Perioperative death was defined as death from any cause
within 30 days after the index procedure.
tients in the angioplasty group. Additional re-

sults for primary and secondary end points, as 100
well as results of an analysis performed accord- 90
Scaffold
ing to lesion-length terciles, subgroup analyses, 80
Percentage of Patients
74
Free from All Events

70
sensitivity analyses, and a center-effects analy-
60
sis, are provided in Tables S16 through S21. The
50
Kaplan–Meier curve for efficacy is shown in 48
Angioplasty
40
Figure 1.
30
Four patients in the scaffold group had un- 20
dergone amputation above the ankle by 1 year. 10 P<0.001 for superiority
Three of these patients had patent scaffolds. The 0
other patient had evidence suggestive of scaffold 0 30 90 180 270 360 450 540
occlusion on duplex ultrasonography reported by Days since Index Procedure
the trial site, but the scaffold was found to be Days 0 30 90 180 365 453
patent on follow-up angiography. Of those four No. at Risk
Scaffold 173 163 152 142 95 42
patients, two had undergone clinically driven Angioplasty 88 82 78 67 33 15
revascularization of the target lesion by 1 year,
Patients Free from
including the aforementioned patient and a pa- All Events (%)
tient with 57% stenosis of the vessel diameter as Scaffold 100 96 91 89 80 74
Angioplasty 94 93 91 81 54 48
adjudicated by the core laboratory.
Wound healing was observed in 37 of 83 pa-
Figure 1. Kaplan–Meier Curve for Efficacy.
tients (45%) in the scaffold group by 1 year, with
The primary efficacy end point was freedom from the following events at
a mean time to healing of 196.7±130.1 days.
1 year: amputation above the ankle of the target limb, occlusion of the tar-
Wound healing was observed in 25 of 45 pa- get vessel, clinically driven revascularization of the target lesion, and binary
tients (56%) in the angioplasty group by 1 year, restenosis of the target lesion. The Kaplan–Meier curve shows the percent-
with a mean time to healing of 187.6±122.7 age of patients free from all events from baseline through day 453. Patients
days. The mean ankle–brachial index at 1 year is were included in the analysis of the primary efficacy end point if they had
data from duplex ultrasonography (or data from angiography, if both angio-
shown in Table S22; the percentage of patients
graphic and duplex ultrasonographic data were available) from a qualified
with an abnormal ankle–brachial index and with core laboratory at 1 year or had had a clinical event. Clinical events were
an abnormal toe–brachial index at various time adjudicated by the clinical events committee through 365 days, whereas
points between baseline and 1 year is shown in angiographic data through 423 days and duplex ultrasonographic data
Tables S23 and S24, respectively. Serious adverse through 453 days were used to evaluate patency. One event in the angio-
plasty group that was based on duplex ultrasonographic data obtained af-
events related to the index procedure occurred in
ter 453 days was excluded from the Kaplan–Meier analysis but was includ-
2% of the patients in the scaffold group and 3% ed in the analysis of the primary efficacy end point. The one-sided P value
of those in the angioplasty group. A summary of for the primary efficacy end point was calculated on the basis of the Com–
serious and nonserious adverse events reported Nougue method against a one-sided alpha level of 0.0249.
by the trial sites is shown in Tables S25, S26,
and S27.
when freedom from binary restenosis of the
target lesion was included in the end point
Discussion
(the primary efficacy end point). With respect
The results of this randomized, controlled trial to freedom from major adverse limb events at
showed that among patients with CLTI and infra 6 months and perioperative death (the primary
popliteal artery disease, the incidence of free- safety end point), the use of the scaffold was
dom from amputation above the ankle of the noninferior to angioplasty.
target limb, occlusion of the target vessel, and Several trials have evaluated methods for re-
clinically driven revascularization of the target vascularization in the infrapopliteal circulation
lesion (the original primary efficacy end point) in an attempt to avoid the poor patency out-
at 1 year was higher among patients who re- comes seen with angioplasty. However, most of
ceived an everolimus-eluting resorbable scaffold these methods have failed because of the com-
than among those who received angioplasty — plex nature of the atherosclerotic disease and
and the magnitude of the effect was increased the difficulty of maintaining patency in both the

short term and the long term.22-26 The challenges a powered secondary end point, and the results
associated with infrapopliteal artery revascular- for that end point were significant, although the
ization include extensive medial calcinosis, long magnitude of the effect was smaller than that
lesion lengths, acute lesion recoil, and a predi- for the primary efficacy end point. Second, the
lection for flow-limiting dissection after angio- trial population was highly selected, with patients
plasty. Various methods have not shown efficacy having shorter lesions than those commonly
with respect to the maintenance of long-term encountered in clinical practice. Nevertheless,
patency and the reduction of undesirable long- patients in the two trial groups had coexisting
term clinical events, such as reintervention and conditions that were evenly matched and were
amputation. The findings suggest that device consistent with those of the population of pa-
success may require both the mechanical prop- tients with CLTI in clinical practice.
erties of a stent and an antiproliferative coating. Third, the prescribed predilation in the scaf-
Drug-eluting devices that inhibit neointimal fold group may have influenced the results to
hyperplasia have not been used routinely for some extent, but this technique is known to be
the treatment of infrapopliteal artery disease. an important consideration in attaining the best
In numerous trials of drug-coated balloons and results with these scaffolds. Fourth, as with most
drug-eluting scaffolds and stents, the treatment clinical trials, participation in the trial conferred
has not resulted in greater patency than angio- close supervision of the patients, and the ex-
plasty or has had practical limitations.22-24,26,27 Of pected incidences of amputation and clinically
all the available approaches, the use of coronary driven revascularization of the target lesion were
drug-eluting stents with sirolimus analogues substantially lower than the incidences that might
in below-the-knee interventions has shown be expected in clinical practice. Fifth, the use of
the most promise for maintaining primary the scaffolds in the trial was restricted to the
patency.6-9,28 However, the permanent nature of proximal two thirds of the infrapopliteal arter-
these metal implants has made some clinicians ies. Caution must be used in extrapolating these
wary of their routine use. findings to other anatomical locations.
This trial had several limitations that should Among patients with CLTI due to infrapop
be considered during the interpretation of the liteal artery disease, the use of an everolimus-
data. First, after the interim analysis was con- eluting resorbable scaffold was superior to an-
ducted, the primary efficacy end point of the gioplasty with respect to the primary efficacy
trial was changed to include freedom from bi- end point. With respect to the primary safety
nary restenosis of the target lesion. However, end point, the use of the scaffold was noninfe-
this change was made during the enrollment rior to angioplasty.
period, and the investigators and other person- Supported by Abbott.
nel conducting the trial remained unaware of Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
the trial-group assignments. In addition, the origi- A data sharing statement provided by the authors is available
nal primary efficacy end point was preserved as with the full text of this article at NEJM.org.
Appendix
The authors’ affiliations are as follows: the Prince of Wales Hospital and University of New South Wales, Randwick, Australia (R.L.V.);
New York Presbyterian–Weill Cornell Medical Center (B.G.D.), Mount Sinai Hospital (P.K.), and Columbia University Irving Medical
Center and Columbia Vagelos College of Physicians and Surgeons (D.R.B., S.A.P.), New York, and Catholic Health Services, St. Francis
Hospital and Heart Center, Roslyn (L.A.G.) — all in New York; Syntropic Core Lab and OhioHealth Heart and Vascular, Columbus
(R.K.), and University Hospitals Harrington Heart and Vascular Institute, Cleveland (M.H.S.) — both in Ohio; Ballad Health, Kingsport,
TN (D.C.M.); CPC Clinical Research, Cardiovascular Division, University of Colorado School of Medicine, Aurora (M.P.B.), and Ad-
vanced Heart and Vein Center, Denver (E.A.) — both in Colorado; Auckland Hospital and Auckland University, Grafton, Auckland, New
Zealand (A.H.H.); the Department of Surgery, Changi General Hospital, Singapore (S.W.C.K.); Advanced Interventional and Vascular
Services, Teaneck, NJ (J.R.); National Taiwan University Hospital, Taipei City, Taiwan (J.-K.L.); First Coast Cardiovascular Institute,
Jacksonville, FL (Y.K.); VasCore, Boston (I.W.); MedStar Washington Hospital Center, Washington, DC (H.M.G.-G.); and Abbott Vas-
cular, Santa Clara, CA (K.R., N.T.T., Y.Z., J.W., J.M.J.-M.).

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new england

Drug-Eluting Resorbable Scaffold versus Angioplasty

n engl j med 390;1 nejm.org January 4, 2024 9

10 n engl j med 390;1 nejm.org January 4, 2024

The New England Journal of Medicine

n engl j med 390;1 nejm.org January 4, 2024 11

12 n engl j med 390;1 nejm.org January 4, 2024

The New England Journal of Medicine

remained, it was to be tested in an exploratory regarding characteristics of the patients and

n engl j med 390;1 nejm.org January 4, 2024 13

Table 1. Baseline Characteristics of the Patients.*

Scaffold Angioplasty Total

14 n engl j med 390;1 nejm.org January 4, 2024

The New England Journal of Medicine

Table 2. Baseline, Procedural, and Postprocedural Characteristics of the Target Lesions.*

Scaffold Angioplasty Difference Total

n engl j med 390;1 nejm.org January 4, 2024 15

no./total no. Kaplan–Meier % no./total no. Kaplan–Meier %

n engl j med 390;1

The New England Journal of Medicine

Copyright © 2024 Massachusetts Medical Society. All rights reserved.

Freedom from perioperative death 168/170 99 90/90 100 — —

tients in the angioplasty group. Additional re-

Free from All Events

n engl j med 390;1 nejm.org January 4, 2024 17

18 n engl j med 390;1 nejm.org January 4, 2024

The New England Journal of Medicine

n engl j med 390;1 nejm.org January 4, 2024 19

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