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Bioresorbable Everolimus-Eluting Vascular Scaffold for Patients With Peripheral Artery Disease (ESPRIT I)
JACC: CARDIOVASCULAR INTERVENTIONS
VOL. 9, NO. 11, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 1936-8798/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jcin.2016.02.051
PERIPHERAL
Bioresorbable Everolimus-Eluting Vascular Scaffold for Patients With Peripheral Artery Disease (ESPRIT I) 2-Year Clinical and Imaging Results Johannes Lammer, MD,a Marc Bosiers, MD,b Koen Deloose, MD,c Andrej Schmidt, MD,d Thomas Zeller, MD,d Florian Wolf, MD,a Wouter Lansink, MD,e Antoine Sauguet, MD,f Frank Vermassen, MD, PHD,g Geert Lauwers, MD,e Dierk Scheinert, MD,c Jeffrey J. Popma, MD,h Robert McGreevy, PHD,i Richard Rapoza, PHD,i Lewis B. Schwartz, MD,i Michael R. Jaff, DOj
JACC: CARDIOVASCULAR INTERVENTIONS CME This article has been selected as this issue’s CME activity, available online
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clinical endpoints among patients implanted with bioresorbable scaffolds in peripheral arteries as opposed to coronaries.
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Author Disclosures: The study was supported and monitored by Abbott
credit commensurate with the extent of their participation in the
Vascular. Drs. Lammer, Bosiers, Zeller, Scheinert, and Vermassen are
activity.
members of Abbott Vascular scientific advisory board. Dr. Lammer received honorarium as principal investigator of the ESPRIT I study. Dr.
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Schmidt consults for Abbott Vascular. Dr. Popma has received grants from Abbott Vascular. Drs. McGreevy and Rapoza are employees of
To obtain credit for this CME activity, you must:
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CME Objective for This Article: 1) evaluate the benefits of using bio-
Issue Date: June 13, 2016
resorbable vascular scaffolds in the treatment of peripheral atrial disease;
Expiration Date: June 12, 2017
From the aCardiovascular and Interventional Radiology Department, Medical University Vienna, Vienna, Austria; bDepartment of Vascular Surgery, Sint-Blasius Hospital, Dendermonde, Belgium; cDepartment of Interventional Angiology, University Leipzig, Leipzig, Germany; dDepartment of Angiology, Universitaets-Herzzentrum Freiburg-Bad Krozingen, Bad Krozingen, Germany; e
Vaatcentrum, Oost Limburg Ziekenhuis, Genk, Belgium; fDepartment of General Interventional Cardiology, Clinique Pasteur,
Toulouse, France; gDepartment of Vascular Surgery, Ghent University Hospital, Gent, Belgium; hBeth Israel Deaconess Medical Center, Boston, Massachusetts; iAbbott Vascular, Santa Clara, California; and the jVascular Ultrasound Core Laboratory, Massachusetts General Hospital, Boston, Massachusetts. The study was supported and monitored by Abbott Vascular. Drs. Lammer, Bosiers, Zeller, Scheinert, and Vermassen are members of Abbott Vascular scientific advisory board. Dr. Lammer received honorarium
Lammer et al.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 9, NO. 11, 2016 JUNE 13, 2016:1178–87
2-Year Results for Everolimus-Eluting BVS for PAD
Bioresorbable Everolimus-Eluting Vascular Scaffold for Patients With Peripheral Artery Disease (ESPRIT I) 2-Year Clinical and Imaging Results Johannes Lammer, MD,a Marc Bosiers, MD,b Koen Deloose, MD,c Andrej Schmidt, MD,d Thomas Zeller, MD,d Florian Wolf, MD,a Wouter Lansink, MD,e Antoine Sauguet, MD,f Frank Vermassen, MD, PHD,g Geert Lauwers, MD,e Dierk Scheinert, MD,c Jeffrey J. Popma, MD,h Robert McGreevy, PHD,i Richard Rapoza, PHD,i Lewis B. Schwartz, MD,i Michael R. Jaff, DOj
ABSTRACT OBJECTIVES This is the first-in-human study of a drug-eluting bioresorbable vascular scaffold (BVS) for treatment of peripheral artery disease (PAD) involving the external iliac artery (EIA) and superficial femoral artery (SFA). BACKGROUND Drug-eluting BVS has shown promise in coronary arteries. METHODS The ESPRIT BVS system is a device-drug combination consisting of an everolimus-eluting poly-L-lactide scaffold. Safety and performance were evaluated in 35 subjects with symptomatic claudication. RESULTS Lesions were located in the SFA (88.6%) and EIA (11.4%). Mean lesion length was 35.7 16.0 mm. The study device was successfully deployed in 100% of cases, without recoil. Procedure-related minor complications were observed in 3 patients (groin hematoma, dissection). Within 2 years there was 1 unrelated death, but no patients in this cohort had an amputation. At 1 and 2 years, the binary restenosis rates were 12.1% and 16.1%, respectively, and target lesion revascularization was performed in 3 of 34 patients (8.8%) and 4 of 32 patients (11.8%), respectively. The ankle brachial index 0.75 0.14 improved from pre-procedure to 0.96 0.16 at 2 years’ follow-up. At 2 years, 71.0% of the patients were Rutherford-Becker 0, and 93.5% achieved a maximum walking distance of 1,500 feet. CONCLUSIONS The safety of the ESPRIT BVS was demonstrated with no procedure or device-related deaths or amputations within 2 years. The low occurrence of revascularizations was consistent with duplex-ultrasonography showing sustained patency at 2-years. (A Clinical Evaluation of the Abbott Vascular ESPRIT BVS [Bioresorbable Vascular Scaffold] System [ESPRIT I]; NCT01468974) (J Am Coll Cardiol Intv 2016;9:1178–87) © 2016 by the American College of Cardiology Foundation.
A
bioresorbable vascular scaffold (BVS) theo-
irritation of the vessel wall, device fracture, limita-
retically provides radial support in the
tion of future options for endovascular or surgical
acute procedural setting and during the
revascularization, and artifact on noninvasive imag-
healing phase to treat flow-limiting dissection,
ing such as those seen on computed tomography
vascular recoil, and constrictive remodeling (1,2).
angiography (CTA) and on magnetic resonance angi-
The device should be resorbed once the acute pro-
ography (MRA).
cesses have subsided. Due to its temporary nature, BVS
will
not
incur
the
long-term
Various types of bioresorbable metallic or poly-
limitations
meric stents are currently under investigation (1–11).
of metal stents such as continuous mechanical
Today, those based on lactide–derived polymers are
as principal investigator of the ESPRIT I study. Dr. Schmidt consults for Abbott Vascular. Dr. Popma has received grants from Abbott Vascular. Drs. McGreevy and Rapoza are employees of Abbott Vascular. Dr. Schwartz is a former employee of Abbott Vascular. Dr. Jaff is a uncompensated advisor to Abbott Vascular; a board member of VIVA Physicians; and an equity shareholder in PQ Bypass. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received January 5, 2016; revised manuscript received February 16, 2016, accepted February 25, 2016.
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2-Year Results for Everolimus-Eluting BVS for PAD
ABBREVIATIONS
the most advanced because of their biocom-
AND ACRONYMS
patibility and their hydrolytic degradability.
scaffold
The drug-eluting coronary version of the
(Figure 1). The ESPRIT BVS has crush recovery
fully
properties which help withstand the mechanical
ABI = ankle brachial index BVS = bioresorbable vascular scaffold
CAD = coronary artery disease CDUS = color duplex
resorbable,
Absorb
BVS
(Abbott
MLD = minimal lumen diameter PAD = peripheral arterial
PSVR = peak systolic velocity ratio
RB = Rutherford-Becker clinical
fluoroscopy
forces inherent in the superficial femoral artery
cohort A, which demonstrated excellent
nal expanded diameter is 6 mm.
of 101 patients, demonstrated a sustained long-term patency to 3 years, comparable to that seen in metallic drug-eluting stents
disease
under
(SFA). The nominal length is 58 mm, and the nomi-
3.4% (12). Absorb cohort B, a single-arm trial
EIA = external iliac artery
visibility
initially tested in humans in the Absorb trial
a major adverse cardiac event rate of only
DS = diameter stenosis
provide
Vascular, Santa Clara, California), has been
long-term clinical results up to 5 years, with
ultrasonography
markers on the proximal and distal ends of the
(DES), confirmed by angiography, intravascular ultrasonography (IVUS), and optical coherence tomography (OCT). It should be
category
noted that drug elution is a critical compo-
SFA = superficial femoral
nent required to control neointimal prolif-
artery
erative reaction to procedural injury and
TLR = target lesion
scaffold implantation (7–11). The first studies
revascularization
of non–drug-eluting BVS in peripheral arteries showed high restenosis rates of up to 68% at 12 months (13,14).
STUDY OBJECTIVE. The purpose of the ESPRIT I
clinical study was to evaluate the safety and performance of the ESPRIT BVS in patients with intermittent claudication due to PAD of the SFA and external iliac artery (EIA).
ENDPOINTS Key study endpoints included acute procedural success, death, and amputation of the ipsilateral extremity, scaffold thrombosis, binary restenosis rate, target lesion revascularization (TLR), ankle brachial index (ABI), and Rutherford-Becker (RB) clinical category. A core laboratory evaluated color duplex ultrasonography (CDUS) examinations. A peak systolic velocity ratio (PSVR) of $2.4 was regarded as
SEE PAGE 1188
a stenosis of $50%. An angiographic core laboratory evaluated the 1-year angiographic follow-up.
The evaluation of safety and performance of the ESPRIT BVS system for treatment of subjects with symptomatic peripheral artery disease (PAD) is the focus of this first-in-human clinical investigation.
METHODS The ESPRIT I clinical investigation was a prospective, single-arm, open-label, multicenter trial in which 35 subjects were registered to receive the study device at 7 clinical sites. The protocol was developed and
INCLUSION AND EXCLUSION CRITERIA. Key inclu-
sion criteria were patients with symptomatic claudication (RB 1 to 3) having a single de novo lesion of the SFA or iliac arteries, lesion length #50 mm, and vessel diameter from $5.0 mm to #6.5 mm. Key exclusion criteria were inability to walk, presence of ulcers on either foot, previous minor or major amputation of either lower extremity, occluded ipsilateral inflow artery, and a target lesion with severe calcification.
conducted in accordance with the International
TREATMENT. All procedures were performed using
Conference on Harmonisation/Good Clinical Practice
percutaneous techniques under local anesthesia, with
Guideline and the Declaration of Helsinki (ISO 14155-1
ipsilateral or contralateral access. Following manda-
and ISO 14155-2). It was approved by the local ethics
tory pre-dilation of the target lesion, the ESPRIT BVS
committees, and written informed consent was ob-
was deployed by balloon inflation up to 8 atm. A
tained from all patients. The study was registered at
maximum of one 6.0mm 58mm ESPRIT BVS study
the ISRCTN Register (NCT01468974).
device was used to treat the target lesion. Acute
INVESTIGATIONAL DEVICE. The ESPRIT BVS system
(Abbott Vascular, Santa Clara, California) consists of a polymer backbone of poly-L lactide coated with a
success was defined as the achievement of successful delivery and deployment of the study device at the intended target lesion.
thin layer of a 1:1 mixture of poly-D, L -lactide poly-
ADJUVANT MEDICAL THERAPY. Unless the patient
mer, and the anti-proliferative drug everolimus to
was
form an amorphous drug-eluting coating matrix
the patient was treated with a loading dose of
containing 100 m g of everolimus/cm 2 of scaffold.
clopidogrel bisulfate, 300 mg or prasugrel 60 mg,
The design consists of serpentine rings that open
and aspirin, 300 mg. Unfractionated heparin or biva-
during balloon expansion. Each ring is connected
lirudin was used for procedural anticoagulation.
to neighboring rings by connector links. Platinum
Subjects
receiving
who
chronic
received
antiplatelet
the
study
medication,
device
were
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2-Year Results for Everolimus-Eluting BVS for PAD
F I G U R E 1 ESPRIT Bioresorbable Everolimus-Eluting
T A B L E 1 Patient Demographics, Risk Factors, and
Poly- L -lactide Vascular Scaffold
Concomitant Vascular Diseases
Age, yrs
65.3 8.8 (35)
Males
77.1% (27 of 35)
Body mass index, kg/m2
27.1 4.7 (35)
Risk factor profile Dyslipidemia
85.7% (30 of 35)
Hypertension
71.4% (25 of 35)
History of premature CAD
24.1% (7 of 29)
Tobacco use
82.9% (29 of 35)
Diabetes Type 1
25.7% (9 of 35) 22.2% (2 of 9)
Type 2
77.8% (7 of 9)
With treatment
88.9% (8 of 9)
Cerebral vascular disease
8.6% (3 of 35)
CAD
28.6% (10 of 35)
Congestive heart failure
2.9% (1 of 35)
Chronic obstructive pulmonary disease
11.4% (4 of 35)
Renal insufficiency
8.6% (3 of 35)
Values are mean SD (N) or % (n of N). CAD ¼ coronary artery disease.
oversight of the study. Independent core laboratory analysis of CDUS (VasCore, Massachusetts General Hospital, Boston, Massachusetts), for angiography (Beth Israel Deaconess Medical Center, Boston, Massachusetts) and for the PK substudy (Cardialysis BV, Rotterdam, the Netherlands) was included. STATISTICAL ANALYSIS. Due to the small size of this
feasibility study, there was no formal hypothesis testing. The sample size requirement was determined by assessing the minimal number of subjects required to provide reliable and nontrivial results and to achieve in the Kaplan-Meier estimates results with a standard error of <10%. Baseline demographics, clinical characteristics, and angiographic endpoints were analyzed in this intention-to-treat population, using descriptive statistics. For binary variables such
T A B L E 2 Baseline Lesion Characteristics (Core Laboratory)
maintained on a thienopyridine agent (e.g., 75 mg of clopidogrel bisulfate or 10 mg of prasugrel daily) for a minimum of 6 months following the procedure. SUBSTUDIES. A pharmacokinetic (PK) substudy was
performed with assessments of everolimus plasma levels before scaffold placement at 1, 4, and 8 hours
Type of lesion, de novo
100% (35)
Target lesion location SFA
88.6% (31 of 35)
EIA
11.4% (4 of 35) 35.7 16.0
Lesion length, mm Occlusion
22.9% (8 of 35)
Calcification
following device deployment, prior to discharge and
Mild
40.0% (14 of 35)
at 1 month following the procedure. In addition an
Moderate
40.0% (14 of 35)
imaging substudy was performed to demonstrate the
Severe
20.0% (7 of 35)
visibility during CTA and MRA. A Data Safety Monitoring Board, a Clinical Events Committee, and a Trial Steering Committee provided
Values are % (N), % (n of N), or mean SD. EIA ¼ external iliac artery; SFA ¼ superficial femoral artery.
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2-Year Results for Everolimus-Eluting BVS for PAD
F I G U R E 2 A 56-Year-Old Male With Intermittent Claudication Rutherford-Becker Clinical Category 3 and Mildly Calcified Stenosis of Right SFA
(A) Angiography pre-procedure. (B) Balloon with ESPRIT BVS during deployment. (C) Control angiogram after index procedure. (D) Gadolinium-enhanced MR angiography at 6 months; note there is no signal loss within the device. (E) CT angiography at 12 months; note the proximal and distal platinum markers but no contrast of the ESPRIT BVS device. (F) Control angiography at 12 months; the device was located between the 2 white lines. BVS ¼ bioresorbable vascular scaffold; CT ¼ computed tomography; MR ¼ magnetic resonance; SFA ¼ superficial femoral artery.
as binary restenosis, TLR counts, percentages, and
Acute procedural success was achieved in 100%
standard error using the Clopper-Pearson method was
of cases (Figure 2). One patient withdrew in the
calculated. For continuous variables such as percent
first month the study was begun. There was 1 death
diameter stenosis, means, and standard deviations
due to an unrelated stroke in year 2, 1 myocardial
using the Gaussian approximation was calculated. If
infarction in a patient with known CAD in year 1, and
the assumption of normality seemed untenable,
no amputations. Procedure-related adverse events
nonparametric summary statistics was presented
included 1 flow-limiting dissection (treated by bare
instead. For time-to-event variables such as primary
metal stent implantation during the index procedure)
patency rate and freedom from TLR, survival curves
and 2 groin hematomas, which resolved without
were constructed using Kaplan-Meier estimates.
intervention. A total of 34 patients were available for follow-up at 1 year (35 enrolled, 1 withdrew); a total
RESULTS
of 32 patients were available for follow-up at 2 years (35 enrolled, 1 withdrew, 1 died, and 1 was lost
Baseline demographics and risk factors are summarized
in
Table
1.
Lesion
characteristics
to follow-up).
are
summarized in Table 2. The majority of lesions were located in the SFA (88.6% [n ¼ 31 of 35]), followed by the EIA (11.4% [n ¼ 4 of 35]). The lesion length as assessed by the angiographic core laboratory was 35.7 16.0 mm. Prior to any treatment, the in-
T A B L E 3 Summary of Duplex Ultrasonography Results
(Core Laboratory) Follow-Up
In-Scaffold PSV, cm/s
Post-procedure
150.3 43.3
In-Scaffold PSVR
1.27 0.29
1 month
154.6 46.8
1.26 0.30
segment diameter stenosis (DS) in the vessel was
6 month
151.5 37.7
1.35 0.39
80.0 15.1%. As assessed by the core laboratory,
12 months
161.5 72.6
1.66 1.16
lesion calcification was absent or mild in 40% (n ¼ 14
24 months
162.7 47.9
1.56 0.49
of 35), moderate in 40% (n ¼ 14 of 35), and severe in 20% (n ¼ 7 of 35). However, investigators did not report severe calcifications in any case.
Values are mean SD. PSV ¼ peak systolic velocity; PSVR ¼ peak systolic velocity ratio.
Lammer et al.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 9, NO. 11, 2016 JUNE 13, 2016:1178–87
2-Year Results for Everolimus-Eluting BVS for PAD
F I G U R E 3 ESPRIT BVS Duplex Peak Systolic Velocity Ratio Distribution at 1- and 6-Month and 1- and 2-Year Follow-Up Examinations
Abbreviations as in Figure 2.
Duplex ultrasonography results are shown in
respectively (Figure 4). CDUS demonstrated begin-
Table 3. Mean PSVR was 1.27 0.29 post-procedure,
ning degradation of the ESPRIT device at 2 years’
rose to 1.66 1.16 at 1-year follow-up, and reached
follow-up. Investigators have not reported emboli-
1.56 0.49 at 2-year follow-up. Cumulative distribu-
zation of BVS fragments during the 2-year follow-up.
tion of evaluable PSVR at follow-up at 1 (n ¼ 29)
The scaffold was radiolucent on CTA as expected;
and 6 months (n ¼ 30), then at 1 (n ¼ 29) and 2 years
however, the platinum markers were clearly visible.
(n ¼ 24) can be found in Figure 3. At 1 and 6 months,
The ESPRIT BVS did not cause any signal loss of the
all subjects had an evaluable PSVR <2.4, which as
contrast-enhanced vessel lumen when imaged with
indicated on the plot, represents the transition point
MRI (Figure 2).
to binary restenosis. At 1 year there were 2 subjects
ANGIOGRAPHIC
with PSVR >2.4, while at 2-year there was 1 additional
assessment, the pre-procedure minimum lumen
subject with PSVR >2.4. The distributions are similar
diameter (MLD) was mean 1.01 0.78 mm, and the
across follow-up times and do not show separation
in-segment percent diameter stenosis (%DS) was
over time that would suggest disease progression in
mean 80.0 15.1%. After implantation, in-scaffold
the treated segments.
MLD was mean 4.46 0.72 mm and in-scaffold %
Four patients had TLR due to occlusion (n ¼ 2) and
RESULTS. By
core
laboratory
DS was mean 9.2 7.2%. Follow-up angiography at
stenosis (n ¼ 2) within the study device, none at 6
1-year was obtained in 28 subjects (Figure 2). Core
months, 3 at 1 year and another 1 within the 2-year
laboratory analysis of the images revealed 1 throm-
follow-up. Three TLR were clinically driven, 1 was
botic device occlusion, and in-scaffold MLD was
performed during the 1-year required control angio-
mean 3.24 1.22 mm and in-scaffold %DS was mean
gram in an asymptomatic patient. Freedom from TLR
31.8 26.1%. Further details of the angiographic
was 91.2% (SE 4.9% [n ¼ 3 of 34]) and 88.2% (SE
results are shown in Table 4. The impact of vessel
5.5% [n ¼ 4 of 31]) at 1 and 2 years of follow-up,
size on angiographic outcomes was explored in a
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2-Year Results for Everolimus-Eluting BVS for PAD
F I G U R E 4 Freedom From Any Target Lesion Revascularization Through 24 Months
post hoc subgroup analysis of the in-scaffold %DS
in-scaffold %DS was 8.7% in all subjects. At 1 year,
post-procedure and at 1 year follow-up. For those
the in-scaffold %DS was 31.8% in all subjects (a
patients who received 1 year angiographic follow-up
change of þ23.1%). In patients with a D max equal to
with an evaluable segment maximum diameter
or less than the median, the in-scaffold %DS was
(D max), in subjects with a D max less than median
20.1% (a change of þ11.2%), but in patients with a
(n ¼ 14) the post-procedure in-scaffold %DS was
D max greater than the median, the in-scaffold %DS was
8.9%, and in subjects with a D max greater than
44.4% (a change of þ35.9%) (p ¼ 0.023). Thus, the
the median (n ¼ 13), it was 8.5%. Post-procedure
vessel narrowing at 1 year was substantially lower in smaller vessels where the scaffold was oversized by 1 mm and imbedded deeply in the vessel wall.
T A B L E 4 Arteriographic Quantitative Analysis (Core Lab)*
RVD, mm
Pre-procedure
4.88 0.84
In-scaffold post-procedure 12 months
4.94 0.91
Consistent with the higher progression of angio-
MLD, mm
In-Segment %DS
graphic restenosis in larger vessels, all 3 subjects hav-
1.01 0.78
80.04 15.14
ing TLR at 1-year had Dmax values above the median.
4.46 0.72
9.21 7.18
3.24 1.22
31.88 26.06
Values are mean SD. *Analysis per lesion, n ¼ 35 at procedure, and n ¼ 28 at 12 months. %DS ¼ percent diameter stenosis; MLD ¼ minimal luminal diameter; RVD ¼ reference vessel diameter.
The mean ABI was 0.75 014 pre-procedure, 0.99 0.13 at post-procedure, 0.99 0.13 at 6 months, 0.98 0.15 at 12 months, and 0.96 0.16 at 24-months follow-up. RB clinical category assessment pre-procedure, post-procedure and during follow-up is found in Figure 5. At pre-procedure, 57.1% (n ¼ 20 of 35) of subjects were RB 3 and
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JACC: CARDIOVASCULAR INTERVENTIONS VOL. 9, NO. 11, 2016 JUNE 13, 2016:1178–87
100 90
62.9% (n ¼ 22 of 35) of subjects at 1-month, in 88.2%
80 RB B0
(n ¼ 30 of 34) at 12-month and in 93.5% (n ¼ 29 of 31) at
At 30 days, everolimus blood concentrations were
RB B1
50
RB B2
40
RB B3
30
0
The key findings of this first-in-humans clinical
pre-procedure re-procedure
RB B1
RB B2
DISCUSSION
RB B5
RB B2
10
RB B1
20
RB B1 RB B2 RB B3
below the lower limit of quantification (LLOQ) for all 3 subjects.
RB B4
RB B1
and 2.78 to 3.99 ng/ml at 1 day post-procedure.
RB B0
RB B2
11.6 ng/ml at 4 h, 5.56 to 5.59 ng/ml at 8 hours,
percent ercent
15.6 ng/ml at 1-h post scaffold placement, 7.5 to
60
RB B0
For the 3 subjects enrolled in the PK substudy, the everolimus blood concentrations were 14.6 to
RB B3
70
24-month.
RB B0
walking distance of 1,500 feet or more was possible in
post-procedure ost-procedure
Att 1-month
Att 6-month
Att 12-month
evaluation of ESPRIT BVS were: 1) the BVS was implanted successfully in all 35 patients, with residual %DS of <10% and no indication of acute recoil; 2)
(paclitaxel-eluting ZILVER stent) trial lesions with
the ESPRIT BVS is safe as demonstrated by an absence
a mean lesion length of 54 mm were treated. The
of related deaths or amputations to 2 years; 3) sus-
1-year primary patency rate for the DES cohort was
tained patency at 2 years with freedom from binary
83.1%, and improvement in the RB clinical category
restenosis at 12-month and 24-month in 87.9%
was observed in 65.6%. Freedom from TLR in the
and 83.9%, respectively; 4) low occurrence of
randomized versus single arm study was 90.8%
revascularizations (4 of 35 patients) and freedom
versus 89.3% at 1 year and 86.6% versus 80.5% at
from TLR at 12 and 24 months in 91.2% and
2 years (19,20). Recently a number of randomized
88.2%, respectively; 5) sustained improvement in
trials evaluating drug-eluting balloons were pub-
Rutherford-Becker clinical category and walking
lished. In the FemPac (Femoral Paclitaxel Random-
distance
follow-up.
ized Pilot) trial, TASC A-B lesions (median length of
This demonstrated that, in symptomatic, short,
40 mm) were treated. At 6 months the binary
mild-to-moderately calcified TASC (TransAtlantic In-
restenosis rate was 19% (21). In the THUNDER
ter-Society Consensus) A lesions (15), the ESPRIT drug-
(Local Taxane with Short Exposure for Reduction of
eluting BVS did not cause safety concerns and 2-year
Restenosis in Distal Arteries) and LEVANT (Lutonix
patency rates were encouraging.
Paclitaxel-Coated Balloon for the Prevention of
up
to
24
months
of
If we compare these results with those of other
Femoropopliteal
Restenosis)
I
trials,
TASC
A-B
studies of patients with similar patterns of PAD
lesions (mean length of 75 to 81 mm) were treated.
(TASC A SFA lesion), the results of this study look
The 1-year TLR rate was 10% in the THUNDER trial
promising. In the FAST (femoral artery stent) trial,
and 30% at 2 years in the LEVANT I trial (22,23).
lesions of similar length were treated by bare metal
In the IN.PACT SFA (IN.PACT drug-eluting balloon
stents. The 1-year CDUS assessed freedom from
in superficial femoral artery) trial (mean lesion
binary restenosis rate was 68.3%, and the freedom
length of 89 mm) the 1-year primary patency rate
from TLR rate was 85.1% (16). In the RESILIENT
was 82.2%, in the LEVANT II trial (mean lesion
(A Randomized Study Comparing the Edwards Self-
length 62mm) the 1-year primary patency rate was
Expanding LifeStent vs. Angioplasty-alone In Lesions
65.2% (24,25).
INvolving The SFA &/or Proximal Popliteal Artery)
A late catch-up phenomenon after the first year
trial, TASC A and B SFA lesions were treated. The
that was observed with the everolimus eluting
primary patency rate for the stent group was 81.3%
nitinol stent in the STRIDES (Superficial Femoral Ar-
at 1-year follow-up. Freedom from TLR was 87.3% at
tery Treatment with Drug-Eluting Stent) trial has not
1 year and 78.8% at 2 years (17,18). In the ZILVER PTX
been observed in this trial (26,27). The maximum
RB B1 RB B2
(n ¼ 22 of 31) at 24-month (Figure 5). The maximum
RB B3
at 6-month, 73.5% (n ¼ 25 of 34) at 12-month, and 71.0%
Procedure and at 1-, 6-, 12-, and 24-Month Follow-Up Examinations
RB B0
84.8% (n ¼ 28 of 33) at 1-month, 67.6% (n ¼ 23 of 34)
F I G U R E 5 Rutherford-Becker Clinical Category for All Patients Before and After
RB B1 RB B2 RB B3
patients having symptom-free RB 0 classification were
RB B0
34.3% (n ¼ 12 of 35) were RB 2. The percentage of
was
1185
2-Year Results for Everolimus-Eluting BVS for PAD
Att 24-month
RB B6
1186
Lammer et al.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 9, NO. 11, 2016 JUNE 13, 2016:1178–87
2-Year Results for Everolimus-Eluting BVS for PAD
everolimus plasma concentration in ESPRIT-treated patients (14.6 to 15.6 ng/ml) was slightly higher than
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
that achieved in patients treated with the slower-
Johannes Lammer, Medical University of Vienna,
eluting STRIDES stent (4.66 ng/ml), similar to pa-
A-1090 Vienna, Waehringer Guertel 18, Austria.
tients treated with chronic oral everolimus for
E-mail:
immunosuppression (22 ng/ml) and far less than
meduniwien.ac.at.
[email protected]
OR
johannes.lammer@
levels achieved through high-dose oncologic chemoPERSPECTIVES
therapy (174 ng/ml). STUDY LIMITATIONS. Limitations of the study are
the small number of patients treated and that only
WHAT IS KNOWN? Bioresorbable drug-eluting
patients with short not-severely calcified lesions were
scaffolds have demonstrated excellent clinical results
included. The scaffold needs to be tested in TASC B
in coronary artery disease, comparable to those seen
and C lesions as well and should be compared to other
in metallic drug-eluting stents.
drug-eluting technologies.
WHAT IS NEW? This is the first-in-human study of an everolimus-eluting BVS for treatment of symp-
CONCLUSIONS This
preliminary
everolimus-eluting
tomatic claudication. In comparison to non–drug-
first-in-human BVS
in
trial
patients
of
with
an PAD
demonstrated no safety concerns in this small sample and efficacy during 2 years of follow-up were encouraging. The 1-year and 2-year freedom from TLR seems comparable to results of drug-eluting balloons and drug-eluting metal stents for periph-
eluting BVS, a high 2-year patency rate and low 2-year TLR rate have been demonstrated. WHAT IS NEXT? The BVS needs to be tested in TASC B-C lesions and should be compared to other drugeluting technologies such as DES and DEB in patients with PAD.
eral arteries.
REFERENCES 1. Serruys PW, Ormiston JA, Onuma Y, et al. A bioabsorbable everolimus-eluting coronary stent system (ABSORB): 2-year outcomes and results from multiple imaging methods. Lancet 2009;373:897–910. 2. Serruys PW, Onuma Y, Ormiston JA, et al. Evaluation of the second generation of a bioresorbable everolimus drug-eluting vascular scaffold for treatment of de novo coronary artery stenosis: six-month clinical and imaging outcomes. Circulation 2010;122:2301–12.
treatment of de novo coronary artery stenosis: 12month clinical and imaging outcomes. J Am Coll Cardiol 2011;58:1578–88. 7. Diletti R, Farooq V, Girasis C, et al. Clinical and intravascular imaging outcomes at 1 and 2 years after implantation of absorb everolimus eluting bioresorbable vascular scaffolds in small vessels. Late lumen enlargement: does bioresorption matter with small vessel size? Insight from the ABSORB cohort B trial. Heart 2013;99:98–105.
scaffold (DREAMS) in patients with de-novo coronary lesions: 12 month results of the prospective, multicentre, first-in-man BIOSOLVE-I trial. Lancet 2013;381:836–44. 12. Onuma Y, Dudek D, Thuesen L, et al. Fiveyear clinical and functional multislice computed tomography angiographic results after coronary implantation of the fully resorbable polymeric everolimus-eluting scaffold in patients with de novo coronary artery disease: the ABSORB cohort A trial. J Am Coll Cardiol Intv 2013;6:
3. Tamai H, Igaki K, Kyo E, et al. Initial and 6month results of biodegradable poly-l-lactic acid
8. Verheye S, Ormiston JA, Stewart J, et al. A next-generation bioresorbable coronary scaffold system: from bench to first clinical evaluation: 6-
coronary stents in humans. Circulation 2000;102: 399–404.
and 12-month clinical and multimodality imaging results. J Am Coll Cardiol Intv 2014;7:89–99.
4. Strandberg E, Zeltinger J, Schulz DG, Kaluza GL. Late positive remodeling and late lumen gain contribute to vascular restoration by a non-drug eluting bioresorbable scaffold: a four-year intravascular ultrasound study in normal porcine coronary arteries. Circ Cardiovasc Interv 2012;5:
9. Ormiston J, Webster M, Stewart J, et al. First-in-human evaluation of a bioabsorbable polymer-coated sirolimus-eluting stent: imaging and clinical results of the DESSOLVE I Trial (DES with sirolimus and a bioabsorbable polymer for the treatment of patients with de novo lesion
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in the native coronary arteries). J Am Coll Cardiol Intv 2013;6:1026–34.
Cardiol Intv 2014;7:305–12.
10. Erbel R, Di Mario C, Bartunek J, et al., PROGRESS-AMS Investigators. Temporary scaffolding of coronary arteries with bioabsorbable magnesium stents: a prospective, non-randomised multicentre trial. Lancet 2007;369:1869–75.
society consensus for the management of peripheral arterial disease (TASC II). Eur J Vasc Endovasc Surg 2007;33 Suppl 1:S1–75.
5. Ormiston JA, Serruys PW, Regar E, et al. A bioabsorbable everolimus-eluting coronary stent system for patients with single de-novo coronary artery lesions (ABSORB): a prospective open-label trial. Lancet 2008;37:899–907. 6. Serruys PW, Onuma Y, Dudek D, et al. Evaluation of the second generation of a bioresorbable everolimus-eluting vascular scaffold for the
11. Haude M, Erbel R, Erne P, et al. Safety and performance of the drug-eluting absorbable metal
999–1009. 13. Bosiers M, Peeters P, Lammer J, et al., AMS INSIGHT Investigators. AMS INSIGHT—absorbable metal stent implantation for treatment of belowthe-knee critical limb ischemia: 6-month analysis. Cardiovasc Intervent Radiol 2009;32:424–35. 14. Werner M, Micari A, Cioppa A, et al. Evaluation of the biodegradable peripheral Igaki-Tamai stent in the treatment of de novo lesions in the superficial femoral artery: the GAIA study. J Am Coll 15. Norgren L, Hiatt WR, Dormandy JA, et al. Inter-
16. Krankenberg H, Schlüter M, Steinkamp HJ, et al. Nitinol stent implantation versus percutaneous transluminal angioplasty in superficial femoral artery lesions up to 10 cm in length: the
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JACC: CARDIOVASCULAR INTERVENTIONS VOL. 9, NO. 11, 2016 JUNE 13, 2016:1178–87
femoral artery stenting trial (FAST). Circulation 2007;116:285–92. 17. Laird JR, Katzen BT, Scheinert D, Lammer J, et al., RESILIENT Investigators. Nitinol stent implantation versus balloon angioplasty for lesions in the superficial femoral artery and proximal popliteal artery: twelve-month results from the RESILIENT randomized trial. Circ Cardiovasc Interv 2010;3:267–76. 18. Laird JR, Katzen BT, Scheinert D, et al., RESILIENT Investigators. Nitinol stent implantation vs. balloon angioplasty for lesions in the superficial femoral and proximal popliteal arteries of patients with claudication: three-year follow-up from the RESILIENT randomized trial. J Endovasc Ther 2012;19:1–9. 19. Dake MD, Ansel GM, Jaff MR, et al., Zilver PTX Investigators. Paclitaxel-eluting stents show superiority to balloon angioplasty and bare metal stents in femoropopliteal disease: twelve-month Zilver PTX randomized study results. Circ Cardiovasc Interv 2011;4:495–504.
2-Year Results for Everolimus-Eluting BVS for PAD
lesions: 2-year follow-up from the Zilver PTX randomized and single-arm clinical studies. J Am Coll Cardiol 2013;61:2417–27. 21. Werk M, Langner S, Reinkensmeier B, et al. Inhibition of restenosis in femoropopliteal arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial. Circulation 2008;118:1358–65. 22. Tepe G, Zeller T, Albrecht T, et al. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med 2008;358: 689–99. 23. Scheinert D, Duda S, Zeller T, et al. The LEVANT I (Lutonix Paclitaxel-Coated Balloon for the Prevention of Femoropopliteal Restenosis) trial for femoropopliteal revascularization: first-in-human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty. J Am Coll Cardiol Intv 2014;7:10–9.
20. Dake MD, Ansel GM, Jaff MR, et al., Zilver PTX
24. Tepe G, Laird J, Schneider P, Brodmann M, et al. Drug-coated balloon versus standard percutaneous transluminal angioplasty for the
Investigators. Sustained safety and effectiveness of paclitaxel-eluting stents for femoropopliteal
treatment of superficial femoral and popliteal peripheral artery disease: 12-month results from
the IN.PACT SFA randomized trial. Circulation 2015;131:495–502. 25. Rosenfield K, Jaff MR, White CJ, et al. Trial of a paclitaxel-coated balloon for femoropopliteal artery disease. N Engl J Med 2015;373:145–53. 26. Lammer J, Scheinert D, Vermassen F, et al. Pharmacokinetic analysis after implantation of everolimus-eluting self-expanding stents in the peripheral vasculature. J Vasc Surg 2012;55: 400–5. 27. Lammer J, Bosiers M, Zeller T, et al. First clinical trial of nitinol self-expanding everolimuseluting stent implantation for peripheral arterial occlusive disease. J Vasc Surg 2011;54:394–401.
KEY WORDS bioresorbable vascular scaffold, drug-eluting stent(s), femoropopliteal artery, peripheral artery disease, poly- L -lactide
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ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
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PERIPHERAL
Bioresorbable Everolimus-Eluting Vascular Scaffold for Patients With Peripheral Artery Disease (ESPRIT I) 2-Year Clinical and Imaging Results Johannes Lammer, MD,a Marc Bosiers, MD,b Koen Deloose, MD,c Andrej Schmidt, MD,d Thomas Zeller, MD,d Florian Wolf, MD,a Wouter Lansink, MD,e Antoine Sauguet, MD,f Frank Vermassen, MD, PHD,g Geert Lauwers, MD,e Dierk Scheinert, MD,c Jeffrey J. Popma, MD,h Robert McGreevy, PHD,i Richard Rapoza, PHD,i Lewis B. Schwartz, MD,i Michael R. Jaff, DOj
JACC: CARDIOVASCULAR INTERVENTIONS CME This article has been selected as this issue’s CME activity, available online
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metallic stents in peripheral arteries; and 3) consider the differences in
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clinical endpoints among patients implanted with bioresorbable scaffolds in peripheral arteries as opposed to coronaries.
Accreditation and Designation Statement The American College of Cardiology Foundation (ACCF) is accredited by
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Author Disclosures: The study was supported and monitored by Abbott
credit commensurate with the extent of their participation in the
Vascular. Drs. Lammer, Bosiers, Zeller, Scheinert, and Vermassen are
activity.
members of Abbott Vascular scientific advisory board. Dr. Lammer received honorarium as principal investigator of the ESPRIT I study. Dr.
Method of Participation and Receipt of CME Certificate
Schmidt consults for Abbott Vascular. Dr. Popma has received grants from Abbott Vascular. Drs. McGreevy and Rapoza are employees of
To obtain credit for this CME activity, you must:
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CME Objective for This Article: 1) evaluate the benefits of using bio-
Issue Date: June 13, 2016
resorbable vascular scaffolds in the treatment of peripheral atrial disease;
Expiration Date: June 12, 2017
From the aCardiovascular and Interventional Radiology Department, Medical University Vienna, Vienna, Austria; bDepartment of Vascular Surgery, Sint-Blasius Hospital, Dendermonde, Belgium; cDepartment of Interventional Angiology, University Leipzig, Leipzig, Germany; dDepartment of Angiology, Universitaets-Herzzentrum Freiburg-Bad Krozingen, Bad Krozingen, Germany; e
Vaatcentrum, Oost Limburg Ziekenhuis, Genk, Belgium; fDepartment of General Interventional Cardiology, Clinique Pasteur,
Toulouse, France; gDepartment of Vascular Surgery, Ghent University Hospital, Gent, Belgium; hBeth Israel Deaconess Medical Center, Boston, Massachusetts; iAbbott Vascular, Santa Clara, California; and the jVascular Ultrasound Core Laboratory, Massachusetts General Hospital, Boston, Massachusetts. The study was supported and monitored by Abbott Vascular. Drs. Lammer, Bosiers, Zeller, Scheinert, and Vermassen are members of Abbott Vascular scientific advisory board. Dr. Lammer received honorarium
Lammer et al.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 9, NO. 11, 2016 JUNE 13, 2016:1178–87
2-Year Results for Everolimus-Eluting BVS for PAD
Bioresorbable Everolimus-Eluting Vascular Scaffold for Patients With Peripheral Artery Disease (ESPRIT I) 2-Year Clinical and Imaging Results Johannes Lammer, MD,a Marc Bosiers, MD,b Koen Deloose, MD,c Andrej Schmidt, MD,d Thomas Zeller, MD,d Florian Wolf, MD,a Wouter Lansink, MD,e Antoine Sauguet, MD,f Frank Vermassen, MD, PHD,g Geert Lauwers, MD,e Dierk Scheinert, MD,c Jeffrey J. Popma, MD,h Robert McGreevy, PHD,i Richard Rapoza, PHD,i Lewis B. Schwartz, MD,i Michael R. Jaff, DOj
ABSTRACT OBJECTIVES This is the first-in-human study of a drug-eluting bioresorbable vascular scaffold (BVS) for treatment of peripheral artery disease (PAD) involving the external iliac artery (EIA) and superficial femoral artery (SFA). BACKGROUND Drug-eluting BVS has shown promise in coronary arteries. METHODS The ESPRIT BVS system is a device-drug combination consisting of an everolimus-eluting poly-L-lactide scaffold. Safety and performance were evaluated in 35 subjects with symptomatic claudication. RESULTS Lesions were located in the SFA (88.6%) and EIA (11.4%). Mean lesion length was 35.7 16.0 mm. The study device was successfully deployed in 100% of cases, without recoil. Procedure-related minor complications were observed in 3 patients (groin hematoma, dissection). Within 2 years there was 1 unrelated death, but no patients in this cohort had an amputation. At 1 and 2 years, the binary restenosis rates were 12.1% and 16.1%, respectively, and target lesion revascularization was performed in 3 of 34 patients (8.8%) and 4 of 32 patients (11.8%), respectively. The ankle brachial index 0.75 0.14 improved from pre-procedure to 0.96 0.16 at 2 years’ follow-up. At 2 years, 71.0% of the patients were Rutherford-Becker 0, and 93.5% achieved a maximum walking distance of 1,500 feet. CONCLUSIONS The safety of the ESPRIT BVS was demonstrated with no procedure or device-related deaths or amputations within 2 years. The low occurrence of revascularizations was consistent with duplex-ultrasonography showing sustained patency at 2-years. (A Clinical Evaluation of the Abbott Vascular ESPRIT BVS [Bioresorbable Vascular Scaffold] System [ESPRIT I]; NCT01468974) (J Am Coll Cardiol Intv 2016;9:1178–87) © 2016 by the American College of Cardiology Foundation.
A
bioresorbable vascular scaffold (BVS) theo-
irritation of the vessel wall, device fracture, limita-
retically provides radial support in the
tion of future options for endovascular or surgical
acute procedural setting and during the
revascularization, and artifact on noninvasive imag-
healing phase to treat flow-limiting dissection,
ing such as those seen on computed tomography
vascular recoil, and constrictive remodeling (1,2).
angiography (CTA) and on magnetic resonance angi-
The device should be resorbed once the acute pro-
ography (MRA).
cesses have subsided. Due to its temporary nature, BVS
will
not
incur
the
long-term
Various types of bioresorbable metallic or poly-
limitations
meric stents are currently under investigation (1–11).
of metal stents such as continuous mechanical
Today, those based on lactide–derived polymers are
as principal investigator of the ESPRIT I study. Dr. Schmidt consults for Abbott Vascular. Dr. Popma has received grants from Abbott Vascular. Drs. McGreevy and Rapoza are employees of Abbott Vascular. Dr. Schwartz is a former employee of Abbott Vascular. Dr. Jaff is a uncompensated advisor to Abbott Vascular; a board member of VIVA Physicians; and an equity shareholder in PQ Bypass. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received January 5, 2016; revised manuscript received February 16, 2016, accepted February 25, 2016.
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2-Year Results for Everolimus-Eluting BVS for PAD
ABBREVIATIONS
the most advanced because of their biocom-
AND ACRONYMS
patibility and their hydrolytic degradability.
scaffold
The drug-eluting coronary version of the
(Figure 1). The ESPRIT BVS has crush recovery
fully
properties which help withstand the mechanical
ABI = ankle brachial index BVS = bioresorbable vascular scaffold
CAD = coronary artery disease CDUS = color duplex
resorbable,
Absorb
BVS
(Abbott
MLD = minimal lumen diameter PAD = peripheral arterial
PSVR = peak systolic velocity ratio
RB = Rutherford-Becker clinical
fluoroscopy
forces inherent in the superficial femoral artery
cohort A, which demonstrated excellent
nal expanded diameter is 6 mm.
of 101 patients, demonstrated a sustained long-term patency to 3 years, comparable to that seen in metallic drug-eluting stents
disease
under
(SFA). The nominal length is 58 mm, and the nomi-
3.4% (12). Absorb cohort B, a single-arm trial
EIA = external iliac artery
visibility
initially tested in humans in the Absorb trial
a major adverse cardiac event rate of only
DS = diameter stenosis
provide
Vascular, Santa Clara, California), has been
long-term clinical results up to 5 years, with
ultrasonography
markers on the proximal and distal ends of the
(DES), confirmed by angiography, intravascular ultrasonography (IVUS), and optical coherence tomography (OCT). It should be
category
noted that drug elution is a critical compo-
SFA = superficial femoral
nent required to control neointimal prolif-
artery
erative reaction to procedural injury and
TLR = target lesion
scaffold implantation (7–11). The first studies
revascularization
of non–drug-eluting BVS in peripheral arteries showed high restenosis rates of up to 68% at 12 months (13,14).
STUDY OBJECTIVE. The purpose of the ESPRIT I
clinical study was to evaluate the safety and performance of the ESPRIT BVS in patients with intermittent claudication due to PAD of the SFA and external iliac artery (EIA).
ENDPOINTS Key study endpoints included acute procedural success, death, and amputation of the ipsilateral extremity, scaffold thrombosis, binary restenosis rate, target lesion revascularization (TLR), ankle brachial index (ABI), and Rutherford-Becker (RB) clinical category. A core laboratory evaluated color duplex ultrasonography (CDUS) examinations. A peak systolic velocity ratio (PSVR) of $2.4 was regarded as
SEE PAGE 1188
a stenosis of $50%. An angiographic core laboratory evaluated the 1-year angiographic follow-up.
The evaluation of safety and performance of the ESPRIT BVS system for treatment of subjects with symptomatic peripheral artery disease (PAD) is the focus of this first-in-human clinical investigation.
METHODS The ESPRIT I clinical investigation was a prospective, single-arm, open-label, multicenter trial in which 35 subjects were registered to receive the study device at 7 clinical sites. The protocol was developed and
INCLUSION AND EXCLUSION CRITERIA. Key inclu-
sion criteria were patients with symptomatic claudication (RB 1 to 3) having a single de novo lesion of the SFA or iliac arteries, lesion length #50 mm, and vessel diameter from $5.0 mm to #6.5 mm. Key exclusion criteria were inability to walk, presence of ulcers on either foot, previous minor or major amputation of either lower extremity, occluded ipsilateral inflow artery, and a target lesion with severe calcification.
conducted in accordance with the International
TREATMENT. All procedures were performed using
Conference on Harmonisation/Good Clinical Practice
percutaneous techniques under local anesthesia, with
Guideline and the Declaration of Helsinki (ISO 14155-1
ipsilateral or contralateral access. Following manda-
and ISO 14155-2). It was approved by the local ethics
tory pre-dilation of the target lesion, the ESPRIT BVS
committees, and written informed consent was ob-
was deployed by balloon inflation up to 8 atm. A
tained from all patients. The study was registered at
maximum of one 6.0mm 58mm ESPRIT BVS study
the ISRCTN Register (NCT01468974).
device was used to treat the target lesion. Acute
INVESTIGATIONAL DEVICE. The ESPRIT BVS system
(Abbott Vascular, Santa Clara, California) consists of a polymer backbone of poly-L lactide coated with a
success was defined as the achievement of successful delivery and deployment of the study device at the intended target lesion.
thin layer of a 1:1 mixture of poly-D, L -lactide poly-
ADJUVANT MEDICAL THERAPY. Unless the patient
mer, and the anti-proliferative drug everolimus to
was
form an amorphous drug-eluting coating matrix
the patient was treated with a loading dose of
containing 100 m g of everolimus/cm 2 of scaffold.
clopidogrel bisulfate, 300 mg or prasugrel 60 mg,
The design consists of serpentine rings that open
and aspirin, 300 mg. Unfractionated heparin or biva-
during balloon expansion. Each ring is connected
lirudin was used for procedural anticoagulation.
to neighboring rings by connector links. Platinum
Subjects
receiving
who
chronic
received
antiplatelet
the
study
medication,
device
were
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2-Year Results for Everolimus-Eluting BVS for PAD
F I G U R E 1 ESPRIT Bioresorbable Everolimus-Eluting
T A B L E 1 Patient Demographics, Risk Factors, and
Poly- L -lactide Vascular Scaffold
Concomitant Vascular Diseases
Age, yrs
65.3 8.8 (35)
Males
77.1% (27 of 35)
Body mass index, kg/m2
27.1 4.7 (35)
Risk factor profile Dyslipidemia
85.7% (30 of 35)
Hypertension
71.4% (25 of 35)
History of premature CAD
24.1% (7 of 29)
Tobacco use
82.9% (29 of 35)
Diabetes Type 1
25.7% (9 of 35) 22.2% (2 of 9)
Type 2
77.8% (7 of 9)
With treatment
88.9% (8 of 9)
Cerebral vascular disease
8.6% (3 of 35)
CAD
28.6% (10 of 35)
Congestive heart failure
2.9% (1 of 35)
Chronic obstructive pulmonary disease
11.4% (4 of 35)
Renal insufficiency
8.6% (3 of 35)
Values are mean SD (N) or % (n of N). CAD ¼ coronary artery disease.
oversight of the study. Independent core laboratory analysis of CDUS (VasCore, Massachusetts General Hospital, Boston, Massachusetts), for angiography (Beth Israel Deaconess Medical Center, Boston, Massachusetts) and for the PK substudy (Cardialysis BV, Rotterdam, the Netherlands) was included. STATISTICAL ANALYSIS. Due to the small size of this
feasibility study, there was no formal hypothesis testing. The sample size requirement was determined by assessing the minimal number of subjects required to provide reliable and nontrivial results and to achieve in the Kaplan-Meier estimates results with a standard error of <10%. Baseline demographics, clinical characteristics, and angiographic endpoints were analyzed in this intention-to-treat population, using descriptive statistics. For binary variables such
T A B L E 2 Baseline Lesion Characteristics (Core Laboratory)
maintained on a thienopyridine agent (e.g., 75 mg of clopidogrel bisulfate or 10 mg of prasugrel daily) for a minimum of 6 months following the procedure. SUBSTUDIES. A pharmacokinetic (PK) substudy was
performed with assessments of everolimus plasma levels before scaffold placement at 1, 4, and 8 hours
Type of lesion, de novo
100% (35)
Target lesion location SFA
88.6% (31 of 35)
EIA
11.4% (4 of 35) 35.7 16.0
Lesion length, mm Occlusion
22.9% (8 of 35)
Calcification
following device deployment, prior to discharge and
Mild
40.0% (14 of 35)
at 1 month following the procedure. In addition an
Moderate
40.0% (14 of 35)
imaging substudy was performed to demonstrate the
Severe
20.0% (7 of 35)
visibility during CTA and MRA. A Data Safety Monitoring Board, a Clinical Events Committee, and a Trial Steering Committee provided
Values are % (N), % (n of N), or mean SD. EIA ¼ external iliac artery; SFA ¼ superficial femoral artery.
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2-Year Results for Everolimus-Eluting BVS for PAD
F I G U R E 2 A 56-Year-Old Male With Intermittent Claudication Rutherford-Becker Clinical Category 3 and Mildly Calcified Stenosis of Right SFA
(A) Angiography pre-procedure. (B) Balloon with ESPRIT BVS during deployment. (C) Control angiogram after index procedure. (D) Gadolinium-enhanced MR angiography at 6 months; note there is no signal loss within the device. (E) CT angiography at 12 months; note the proximal and distal platinum markers but no contrast of the ESPRIT BVS device. (F) Control angiography at 12 months; the device was located between the 2 white lines. BVS ¼ bioresorbable vascular scaffold; CT ¼ computed tomography; MR ¼ magnetic resonance; SFA ¼ superficial femoral artery.
as binary restenosis, TLR counts, percentages, and
Acute procedural success was achieved in 100%
standard error using the Clopper-Pearson method was
of cases (Figure 2). One patient withdrew in the
calculated. For continuous variables such as percent
first month the study was begun. There was 1 death
diameter stenosis, means, and standard deviations
due to an unrelated stroke in year 2, 1 myocardial
using the Gaussian approximation was calculated. If
infarction in a patient with known CAD in year 1, and
the assumption of normality seemed untenable,
no amputations. Procedure-related adverse events
nonparametric summary statistics was presented
included 1 flow-limiting dissection (treated by bare
instead. For time-to-event variables such as primary
metal stent implantation during the index procedure)
patency rate and freedom from TLR, survival curves
and 2 groin hematomas, which resolved without
were constructed using Kaplan-Meier estimates.
intervention. A total of 34 patients were available for follow-up at 1 year (35 enrolled, 1 withdrew); a total
RESULTS
of 32 patients were available for follow-up at 2 years (35 enrolled, 1 withdrew, 1 died, and 1 was lost
Baseline demographics and risk factors are summarized
in
Table
1.
Lesion
characteristics
to follow-up).
are
summarized in Table 2. The majority of lesions were located in the SFA (88.6% [n ¼ 31 of 35]), followed by the EIA (11.4% [n ¼ 4 of 35]). The lesion length as assessed by the angiographic core laboratory was 35.7 16.0 mm. Prior to any treatment, the in-
T A B L E 3 Summary of Duplex Ultrasonography Results
(Core Laboratory) Follow-Up
In-Scaffold PSV, cm/s
Post-procedure
150.3 43.3
In-Scaffold PSVR
1.27 0.29
1 month
154.6 46.8
1.26 0.30
segment diameter stenosis (DS) in the vessel was
6 month
151.5 37.7
1.35 0.39
80.0 15.1%. As assessed by the core laboratory,
12 months
161.5 72.6
1.66 1.16
lesion calcification was absent or mild in 40% (n ¼ 14
24 months
162.7 47.9
1.56 0.49
of 35), moderate in 40% (n ¼ 14 of 35), and severe in 20% (n ¼ 7 of 35). However, investigators did not report severe calcifications in any case.
Values are mean SD. PSV ¼ peak systolic velocity; PSVR ¼ peak systolic velocity ratio.
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2-Year Results for Everolimus-Eluting BVS for PAD
F I G U R E 3 ESPRIT BVS Duplex Peak Systolic Velocity Ratio Distribution at 1- and 6-Month and 1- and 2-Year Follow-Up Examinations
Abbreviations as in Figure 2.
Duplex ultrasonography results are shown in
respectively (Figure 4). CDUS demonstrated begin-
Table 3. Mean PSVR was 1.27 0.29 post-procedure,
ning degradation of the ESPRIT device at 2 years’
rose to 1.66 1.16 at 1-year follow-up, and reached
follow-up. Investigators have not reported emboli-
1.56 0.49 at 2-year follow-up. Cumulative distribu-
zation of BVS fragments during the 2-year follow-up.
tion of evaluable PSVR at follow-up at 1 (n ¼ 29)
The scaffold was radiolucent on CTA as expected;
and 6 months (n ¼ 30), then at 1 (n ¼ 29) and 2 years
however, the platinum markers were clearly visible.
(n ¼ 24) can be found in Figure 3. At 1 and 6 months,
The ESPRIT BVS did not cause any signal loss of the
all subjects had an evaluable PSVR <2.4, which as
contrast-enhanced vessel lumen when imaged with
indicated on the plot, represents the transition point
MRI (Figure 2).
to binary restenosis. At 1 year there were 2 subjects
ANGIOGRAPHIC
with PSVR >2.4, while at 2-year there was 1 additional
assessment, the pre-procedure minimum lumen
subject with PSVR >2.4. The distributions are similar
diameter (MLD) was mean 1.01 0.78 mm, and the
across follow-up times and do not show separation
in-segment percent diameter stenosis (%DS) was
over time that would suggest disease progression in
mean 80.0 15.1%. After implantation, in-scaffold
the treated segments.
MLD was mean 4.46 0.72 mm and in-scaffold %
Four patients had TLR due to occlusion (n ¼ 2) and
RESULTS. By
core
laboratory
DS was mean 9.2 7.2%. Follow-up angiography at
stenosis (n ¼ 2) within the study device, none at 6
1-year was obtained in 28 subjects (Figure 2). Core
months, 3 at 1 year and another 1 within the 2-year
laboratory analysis of the images revealed 1 throm-
follow-up. Three TLR were clinically driven, 1 was
botic device occlusion, and in-scaffold MLD was
performed during the 1-year required control angio-
mean 3.24 1.22 mm and in-scaffold %DS was mean
gram in an asymptomatic patient. Freedom from TLR
31.8 26.1%. Further details of the angiographic
was 91.2% (SE 4.9% [n ¼ 3 of 34]) and 88.2% (SE
results are shown in Table 4. The impact of vessel
5.5% [n ¼ 4 of 31]) at 1 and 2 years of follow-up,
size on angiographic outcomes was explored in a
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2-Year Results for Everolimus-Eluting BVS for PAD
F I G U R E 4 Freedom From Any Target Lesion Revascularization Through 24 Months
post hoc subgroup analysis of the in-scaffold %DS
in-scaffold %DS was 8.7% in all subjects. At 1 year,
post-procedure and at 1 year follow-up. For those
the in-scaffold %DS was 31.8% in all subjects (a
patients who received 1 year angiographic follow-up
change of þ23.1%). In patients with a D max equal to
with an evaluable segment maximum diameter
or less than the median, the in-scaffold %DS was
(D max), in subjects with a D max less than median
20.1% (a change of þ11.2%), but in patients with a
(n ¼ 14) the post-procedure in-scaffold %DS was
D max greater than the median, the in-scaffold %DS was
8.9%, and in subjects with a D max greater than
44.4% (a change of þ35.9%) (p ¼ 0.023). Thus, the
the median (n ¼ 13), it was 8.5%. Post-procedure
vessel narrowing at 1 year was substantially lower in smaller vessels where the scaffold was oversized by 1 mm and imbedded deeply in the vessel wall.
T A B L E 4 Arteriographic Quantitative Analysis (Core Lab)*
RVD, mm
Pre-procedure
4.88 0.84
In-scaffold post-procedure 12 months
4.94 0.91
Consistent with the higher progression of angio-
MLD, mm
In-Segment %DS
graphic restenosis in larger vessels, all 3 subjects hav-
1.01 0.78
80.04 15.14
ing TLR at 1-year had Dmax values above the median.
4.46 0.72
9.21 7.18
3.24 1.22
31.88 26.06
Values are mean SD. *Analysis per lesion, n ¼ 35 at procedure, and n ¼ 28 at 12 months. %DS ¼ percent diameter stenosis; MLD ¼ minimal luminal diameter; RVD ¼ reference vessel diameter.
The mean ABI was 0.75 014 pre-procedure, 0.99 0.13 at post-procedure, 0.99 0.13 at 6 months, 0.98 0.15 at 12 months, and 0.96 0.16 at 24-months follow-up. RB clinical category assessment pre-procedure, post-procedure and during follow-up is found in Figure 5. At pre-procedure, 57.1% (n ¼ 20 of 35) of subjects were RB 3 and
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JACC: CARDIOVASCULAR INTERVENTIONS VOL. 9, NO. 11, 2016 JUNE 13, 2016:1178–87
100 90
62.9% (n ¼ 22 of 35) of subjects at 1-month, in 88.2%
80 RB B0
(n ¼ 30 of 34) at 12-month and in 93.5% (n ¼ 29 of 31) at
At 30 days, everolimus blood concentrations were
RB B1
50
RB B2
40
RB B3
30
0
The key findings of this first-in-humans clinical
pre-procedure re-procedure
RB B1
RB B2
DISCUSSION
RB B5
RB B2
10
RB B1
20
RB B1 RB B2 RB B3
below the lower limit of quantification (LLOQ) for all 3 subjects.
RB B4
RB B1
and 2.78 to 3.99 ng/ml at 1 day post-procedure.
RB B0
RB B2
11.6 ng/ml at 4 h, 5.56 to 5.59 ng/ml at 8 hours,
percent ercent
15.6 ng/ml at 1-h post scaffold placement, 7.5 to
60
RB B0
For the 3 subjects enrolled in the PK substudy, the everolimus blood concentrations were 14.6 to
RB B3
70
24-month.
RB B0
walking distance of 1,500 feet or more was possible in
post-procedure ost-procedure
Att 1-month
Att 6-month
Att 12-month
evaluation of ESPRIT BVS were: 1) the BVS was implanted successfully in all 35 patients, with residual %DS of <10% and no indication of acute recoil; 2)
(paclitaxel-eluting ZILVER stent) trial lesions with
the ESPRIT BVS is safe as demonstrated by an absence
a mean lesion length of 54 mm were treated. The
of related deaths or amputations to 2 years; 3) sus-
1-year primary patency rate for the DES cohort was
tained patency at 2 years with freedom from binary
83.1%, and improvement in the RB clinical category
restenosis at 12-month and 24-month in 87.9%
was observed in 65.6%. Freedom from TLR in the
and 83.9%, respectively; 4) low occurrence of
randomized versus single arm study was 90.8%
revascularizations (4 of 35 patients) and freedom
versus 89.3% at 1 year and 86.6% versus 80.5% at
from TLR at 12 and 24 months in 91.2% and
2 years (19,20). Recently a number of randomized
88.2%, respectively; 5) sustained improvement in
trials evaluating drug-eluting balloons were pub-
Rutherford-Becker clinical category and walking
lished. In the FemPac (Femoral Paclitaxel Random-
distance
follow-up.
ized Pilot) trial, TASC A-B lesions (median length of
This demonstrated that, in symptomatic, short,
40 mm) were treated. At 6 months the binary
mild-to-moderately calcified TASC (TransAtlantic In-
restenosis rate was 19% (21). In the THUNDER
ter-Society Consensus) A lesions (15), the ESPRIT drug-
(Local Taxane with Short Exposure for Reduction of
eluting BVS did not cause safety concerns and 2-year
Restenosis in Distal Arteries) and LEVANT (Lutonix
patency rates were encouraging.
Paclitaxel-Coated Balloon for the Prevention of
up
to
24
months
of
If we compare these results with those of other
Femoropopliteal
Restenosis)
I
trials,
TASC
A-B
studies of patients with similar patterns of PAD
lesions (mean length of 75 to 81 mm) were treated.
(TASC A SFA lesion), the results of this study look
The 1-year TLR rate was 10% in the THUNDER trial
promising. In the FAST (femoral artery stent) trial,
and 30% at 2 years in the LEVANT I trial (22,23).
lesions of similar length were treated by bare metal
In the IN.PACT SFA (IN.PACT drug-eluting balloon
stents. The 1-year CDUS assessed freedom from
in superficial femoral artery) trial (mean lesion
binary restenosis rate was 68.3%, and the freedom
length of 89 mm) the 1-year primary patency rate
from TLR rate was 85.1% (16). In the RESILIENT
was 82.2%, in the LEVANT II trial (mean lesion
(A Randomized Study Comparing the Edwards Self-
length 62mm) the 1-year primary patency rate was
Expanding LifeStent vs. Angioplasty-alone In Lesions
65.2% (24,25).
INvolving The SFA &/or Proximal Popliteal Artery)
A late catch-up phenomenon after the first year
trial, TASC A and B SFA lesions were treated. The
that was observed with the everolimus eluting
primary patency rate for the stent group was 81.3%
nitinol stent in the STRIDES (Superficial Femoral Ar-
at 1-year follow-up. Freedom from TLR was 87.3% at
tery Treatment with Drug-Eluting Stent) trial has not
1 year and 78.8% at 2 years (17,18). In the ZILVER PTX
been observed in this trial (26,27). The maximum
RB B1 RB B2
(n ¼ 22 of 31) at 24-month (Figure 5). The maximum
RB B3
at 6-month, 73.5% (n ¼ 25 of 34) at 12-month, and 71.0%
Procedure and at 1-, 6-, 12-, and 24-Month Follow-Up Examinations
RB B0
84.8% (n ¼ 28 of 33) at 1-month, 67.6% (n ¼ 23 of 34)
F I G U R E 5 Rutherford-Becker Clinical Category for All Patients Before and After
RB B1 RB B2 RB B3
patients having symptom-free RB 0 classification were
RB B0
34.3% (n ¼ 12 of 35) were RB 2. The percentage of
was
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2-Year Results for Everolimus-Eluting BVS for PAD
Att 24-month
RB B6
1186
Lammer et al.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 9, NO. 11, 2016 JUNE 13, 2016:1178–87
2-Year Results for Everolimus-Eluting BVS for PAD
everolimus plasma concentration in ESPRIT-treated patients (14.6 to 15.6 ng/ml) was slightly higher than
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
that achieved in patients treated with the slower-
Johannes Lammer, Medical University of Vienna,
eluting STRIDES stent (4.66 ng/ml), similar to pa-
A-1090 Vienna, Waehringer Guertel 18, Austria.
tients treated with chronic oral everolimus for
E-mail:
immunosuppression (22 ng/ml) and far less than
meduniwien.ac.at.
[email protected]
OR
johannes.lammer@
levels achieved through high-dose oncologic chemoPERSPECTIVES
therapy (174 ng/ml). STUDY LIMITATIONS. Limitations of the study are
the small number of patients treated and that only
WHAT IS KNOWN? Bioresorbable drug-eluting
patients with short not-severely calcified lesions were
scaffolds have demonstrated excellent clinical results
included. The scaffold needs to be tested in TASC B
in coronary artery disease, comparable to those seen
and C lesions as well and should be compared to other
in metallic drug-eluting stents.
drug-eluting technologies.
WHAT IS NEW? This is the first-in-human study of an everolimus-eluting BVS for treatment of symp-
CONCLUSIONS This
preliminary
everolimus-eluting
tomatic claudication. In comparison to non–drug-
first-in-human BVS
in
trial
patients
of
with
an PAD
demonstrated no safety concerns in this small sample and efficacy during 2 years of follow-up were encouraging. The 1-year and 2-year freedom from TLR seems comparable to results of drug-eluting balloons and drug-eluting metal stents for periph-
eluting BVS, a high 2-year patency rate and low 2-year TLR rate have been demonstrated. WHAT IS NEXT? The BVS needs to be tested in TASC B-C lesions and should be compared to other drugeluting technologies such as DES and DEB in patients with PAD.
eral arteries.
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KEY WORDS bioresorbable vascular scaffold, drug-eluting stent(s), femoropopliteal artery, peripheral artery disease, poly- L -lactide
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