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Drug-Coated Balloon Treatment for Femoropopliteal Artery Disease
JACC: CARDIOVASCULAR INTERVENTIONS
VOL. 10, NO. 20, 2017
ª 2017 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER
ISSN 1936-8798 http://dx.doi.org/10.1016/j.jcin.2017.06.018
THE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Drug-Coated Balloon Treatment for Femoropopliteal Artery Disease The IN.PACT Global Study De Novo In-Stent Restenosis Imaging Cohort Marianne Brodmann, MD,a Koen Keirse, MD,b Dierk Scheinert, MD,c Lubomir Spak, MD, MPH,d Michael R. Jaff, DO,e,f Randy Schmahl, MSC,g Pei Li, PHD,h Thomas Zeller, MD,i on behalf of the IN.PACT Global Study Investigators
ABSTRACT OBJECTIVES This study sought to evaluate the safety and effectiveness of a paclitaxel-coated drug-coated balloon (DCB) for the treatment of patients with de novo in-stent restenosis (ISR). BACKGROUND Treatment of patients with ISR remains a challenge. Current strategies are plagued by high rates of recurrent restenosis and need for reintervention. The best intervention for ISR remains to be elucidated. METHODS The IN.PACT Global study is an independently adjudicated multicenter, prospective, single-arm study that enrolled 1,535 subjects with symptomatic atherosclerotic disease of the superficial femoral and/or popliteal arteries, including de novo ISR lesions. Patients enrolled in the pre-specified ISR imaging cohort were evaluated for vessel patency and reintervention within the 12-month follow-up period. RESULTS A total of 131 subjects with 149 ISR lesions were included for analysis. The mean age of the cohort was 67.8 years. Mean lesion length was 17.17 10.47 cm, including 34.0% total occlusions and 59.1% calcified lesions. The 12-month Kaplan-Meier estimate of primary patency was 88.7%. The rate of clinically driven target lesion revascularization (CD TLR) at 12 months was 7.3%. The primary safety outcome, a composite of freedom from device- and procedure-related mortality through 30 days and freedom from major target limb amputation and CD TLR within 12 months, was 92.7%. There were no major target limb amputations, no deaths, and a low (0.8%) thrombosis rate. CONCLUSIONS Results from the ISR imaging cohort demonstrate high patency and a low rate of CD TLR at 12 months. These data confirm the safety and effectiveness of the IN.PACT Admiral DCB (Medtronic, Dublin, Ireland) in complex femoropopliteal lesions, including this challenging subset. (J Am Coll Cardiol Intv 2017;10:2113–23) © 2017 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
From the aDepartment of Internal Medicine, Division of Angiology, Medical University, Graz, Austria; bDepartment of Vascular Surgery, Regional Hospital Heilig Hart Tienen, Tienen, Belgium; cDivision of Interventional Angiology, University Hospital Leipzig, Leipzig, Germany; dClinic of Angiology, Eastern Slovak Institute for Cardiovascular Diseases, Kosice, Slovak Republic; e
President, Newton-Wellesley Hospital, Newton, Massachusetts; fProfessor of Medicine, Harvard Medical School Boston, Mas-
sachusetts; gMedtronic, Bakken Research Center BV, Maastricht, the Netherlands; hMedtronic, Minneapolis, Minnesota; and i
Universitäts-Herzzentrum Freiburg-Bad Krozingen, Bad Krozingen, Germany. Funding support was provided by Medtronic. Dr.
Brodmann has received honoraria from Bard Peripheral Vascular, Biotronik, Medtronic, Spectranetics, and Viva Physicians; and has served as a consultant for Bard Peripheral Vascular, Biotronik, Medtronic, and Spectranetics. Dr. Keirse has reported that he has no relationships relevant to the contents of this paper to disclose. Dr. Scheinert has served as a consultant and on the scientific advisory board for Abbott Vascular, Biotronik, Boston Scientific Corporation, Cook Medical, Cordis, CR Bard, Gardia Medical, Hemoteq, Medtronic, Ostial Inc., TriReme Medical, Trivascular, Upstream Medical Technologies. Dr. Spak has served as a consultant for Medtronic. Dr. Jaff has served as a noncompensated advisor for Medtronic; a compensated board member of VIVA Physicians, a 501(c)(3) not-for-profit education and research organization; has served as an advisor for Micell; and has been an equity investor of PQ Bypass, Embolitech, and Vascular Therapies. Mr. Schmahl and Dr. Li are full-time employees of Medtronic. Dr. Zeller has received speaking honoraria from Abbott Vascular, Bard Peripheral Vascular, Biotronik, Boston Scientific Corporation, Cook Medical, Cordis Corp., GLG, Gore & Associates, Medtronic, Philips, Spectranetics, Straub Medical, TriReme, Veryan, and VIVA Physicians; and has served as a consultant for Abbott Vascular, Bard Peripheral Vascular, Boston Scientific Corporation, Cook Medical, Gore & Associates, Medtronic, and Spectranetics; and his clinic has received study funds or funds
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JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 20, 2017 OCTOBER 23, 2017:2113–23
Drug-Coated Balloons for De Novo In-Stent Restenosis
E
ABBREVIATIONS AND ACRONYMS ABI = ankle-brachial index CD = clinically driven DCB = drug-coated balloon
ndovascular interventions, including percutaneous
transluminal
METHODS
angio-
plasty with a traditional uncoated
IN.PACT GLOBAL STUDY: DESIGN, SUBJECTS, AND
balloon, implantation of bare-metal or drug-
TREATMENT. A prospective analysis of DCBs for the
eluting stents (DES), angioplasty with a
treatment of de novo ISR was incorporated into the
drug-coated balloon (DCB), and debulking
design of the IN.PACT Global study, a prospective,
DES = drug-eluting stent(s)
with mechanical or laser atherectomy, have
multicenter, international, single-arm clinical trial
DUS = duplex ultrasonography
become the primary mode of revasculariza-
assessing the safety and effectiveness of a paclitaxel-
ISR = in-stent restenosis
tion in patients with symptomatic peripheral
coated DCB for the treatment of patients with inter-
PAD = peripheral artery
artery disease (PAD). Balloon angioplasty of
mittent claudication or rest pain due to obstructive
disease
the femoropopliteal segment is associated
disease of the femoropopliteal artery, including the
SFA = superficial femoral
with a high incidence of restenosis, with
full native SFA and/or full popliteal artery (P1 to P3
the best results seen for very focal stenosis
segments).
artery
TLR = target lesion
and noncomplex lesions (1). Stents yield
Greater than 1,400 patients who satisfied the
better outcomes when compared with con-
inclusion or exclusion criteria for the IN.PACT Global
ventional angioplasty alone (2–5), but are
study were consecutively enrolled at participating
associated with the risk of post-procedural
centers into the clinical cohort (Figure 1). Patients
in-stent restenosis (ISR) and other stent-
enrolled at sited qualified by the VasCore Duplex Core
related complications that can negatively
Lab (Boston, Massachusetts) were screened to meet 1
affect the patient’s long-term clinical outlook (6,7).
or more of the imaging criteria based on an algorithm.
Treatment of ISR with conventional methods remains
The hierarchy for the imaging cohort subgroup
a clinical challenge (8), with no clear frontline
assignment was as follows: 1) de novo ISR; 2) long
strategy.
lesions $15 cm; and 3) chronic total occlusions $5 cm.
revascularization
TVR = target vessel revascularization
WIQ = Walking Impairment Questionnaire
SEE PAGE 2124
Enrollment in the respective imaging cohorts was only open to subjects that had a de novo ISR, long
Technical improvements with DESs, DCBs, cutting
lesion, or chronic total occlusion at pre-procedure
balloons, and directional and laser atherectomy have
baseline. The only subjects who were included in
been aimed at reducing the occurrence of ISR (9–15).
the respective imaging cohort analyses, however,
DCBs and DESs deposit a long lasting antiproliferative
were those who had the primary target lesions that
therapeutic on the inner wall of the artery that sup-
met the criteria of the respective cohort during the
ports the sustained inhibition of restenosis, but DCBs
index procedure (i.e., no other types of lesions could
have the additional advantage of treating the lesion
have been treated during the index procedure).
without leaving a permanent device at the target site
Subjects with symptoms of intermittent claudica-
(16). The safety and effectiveness of DCBs for the
tion or ischemic rest pain (Rutherford clinical cate-
treatment of symptomatic PAD patients has been
gory 2 to 4) and angiographic evidence of occlusion or
demonstrated in randomized controlled clinical trials
stenosis (length $2 cm) in the SFA or popliteal artery
(17–20). Although few, studies have reported positive
(including P1 to P3 segments) were eligible for
outcomes with DCBs for the treatment of complex
enrollment in the IN.PACT Global study. Subjects
PAD lesions, including those that are formed by de
with multiple lesions were allowed. Subjects with
novo ISR (10,15,21,22).
tissue loss were excluded.
The IN.PACT Global Study was designed to eval-
Independent core laboratories analyzed all images,
uate the safety and effectiveness of a paclitaxel-
including duplex ultrasonography (DUS) (VasCore,
coated DCB (IN.PACT Admiral, Medtronic, Dublin,
Massachusetts General Hospital, Boston, Massachu-
Ireland) in the treatment of subjects with athero-
setts) and angiography (SynvaCor Angiographic Core
sclerotic femoropopliteal disease, including de novo
Lab, Springfield, Illinois). In cases where both angi-
ISR in the superficial femoral artery (SFA) or the
ography and duplex ultrasonography were available
entire length of the popliteal artery. Herein we report
at the same assessment, then angiography was pref-
12-month results from the ISR cohort.
erentially used. An independent Clinical Events
for research or clinical trials from 480 Biomedical, Abbott Vascular, B. Braun, Bard Peripheral Vascular, Bayer Pharma, Biotronik, Caveo Med, Contego Medical, Cook Medical, CSI, Gore & Associates, Innora, Intact Vascular, Medtronic, Mercator, Philips, Pluristem, Shockwave, Spectranetics, Terumo, TriReme, and Veryan. Manuscript received December 8, 2016; revised manuscript received April 20, 2017, accepted June 13, 2017.
Brodmann et al.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 20, 2017 OCTOBER 23, 2017:2113–23
Drug-Coated Balloons for De Novo In-Stent Restenosis
F I G U R E 1 Subject Flow in the IN.PACT Global Study and ISR Imaging Cohort
The imaging cohort was part of the clinical cohort and contained 3 prospectively defined subcohorts, including de novo in-stent restenosis (ISR). Subjects with at least 1 de novo ISR could be enrolled in the ISR imaging cohort (n ¼ 166), but analysis was restricted to subjects who had only de novo ISR lesions treated during the index procedure (n ¼ 131). CTO ¼ chronic total occlusion; DCB ¼ drug-coated balloon.
Committee (Syntactx Clinical Events Committee, New
before enrollment. The trial was conducted in accor-
York, New York) was established to assess the
dance with the Declaration of Helsinki, good clinical
primary and select secondary endpoints and to
practice guidelines, and applicable laws as specified
determine
by all relevant governmental bodies. The trial is
criteria.
whether The
each
Clinical
met
Events
protocol-specified Committee
was
composed of interventional and noninterventional
registered with the U.S. National Institutes of Health as NCT01609296.
clinicians with pertinent expertise who were not participants in the study and did not have any con-
DE NOVO ISR IMAGING COHORT STUDY ENDPOINTS.
flicts of interest.
The primary safety composite endpoint was freedom
The study protocol was approved by the institu-
from
device-
and
procedure-related
mortality
tional review board or ethics committee at each trial
through 30 days, and freedom from major target
site. Informed consent was obtained from all subjects
limb amputation and target lesion revascularization
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Drug-Coated Balloons for De Novo In-Stent Restenosis
T A B L E 1 Baseline Demographics and Clinical Characteristics of
endpoints included the incidence of major adverse
Subjects in the IN.PACT Global Study ISR Imaging Cohort
events (all-cause mortality, CD TVR, major target
(N ¼ 131)*
limb amputation, thrombosis at the target lesion site), CD TLR, any TLR, and any TVR at 12 months.
Age, yrs Mean Median Minimum, maximum Male
67.8 10.1 (130)
Other secondary endpoints included change in
68.0
Rutherford clinical category, change in ABI, and
39, 90
level of walking impairment as assessed by the
69.5 (91/131)
Body mass index, kg/m2
26.1 4.3 (131)
Walking
Impairment
Questionnaire
(WIQ)
at
12 months.
Obesity (body mass index $30 kg/m )
17.6 (23/131)
Diabetes
35.1 (46/131)
Insulin-dependent diabetes
15.3 (20/131)
or categories of stent coverage, see the Online
Hypertension
81.5 (106/131)
Appendix.
Hyperlipidemia
72.1 (93/129)
Current smoker
35.9 (47/131)
Coronary heart disease
36.5 (46/126)
ANALYSIS. All analyses were based on the intention-
Carotid artery disease
19.8 (23/116)
to-treat principle and all summaries were based on
9.9 (11/111)
subjects or lesions with evaluable data. Subjects or
100.0 (131/131)
lesions with missing data were excluded from the
43.3 (55/127)
analyses. Unless otherwise specified, all baseline
2
Renal insufficiency† Previous peripheral revascularization Below-the-knee disease of target leg Run-off vessel(s) occluded
For definitions of acute periprocedural outcomes
DE
NOVO
ISR
demographics
0
38.6 (49/127)
1
33.9 (43/127)
2
25.2 (32/127)
3
2.4 (3/127)
IMAGING
and
COHORT
clinical
STATISTICAL
characteristics
were
summarized on a subject basis; lesion characteristics were summarized on a lesion basis. For baseline characteristics, continuous variables were described as mean SD; dichotomous and categorical variables
Rutherford clinical category 0–1
0.0 (0/130)
were described as counts and proportions. The
2
33.1 (43/130)
Kaplan-Meier method was used to evaluate time-to-
3
57.7 (75/130)
event data for primary patency and CD TLR over the
4
7.7 (10/130)
5
1.5 (2/130)‡
12-month follow-up period. The outcome analysis
6 ABI, per target limb, mm Hg§ Bilateral disease
0.0 (0/130) 0.667 0.187 (124) 2.3 (3/131)
was performed at a subject level. For event rates that were expressed as a proportion, the number of subjects with an event was the numerator and the total number of subjects with either at least 330 days
Values are mean SD (N) or % (n/n), unless otherwise indicated. *Summaries are based on nonmissing assessments. In some cases, baseline demographic or clinical data were not available and therefore the total number of subjects for that variable was <131. †Defined as baseline serum creatinine $1.5 mg/dl. ‡Due to protocol violations, 2 subjects classified as Rutherford clinical category 5 were enrolled and included in the analysis. §For subjects with bilateral disease, ankle-brachial index (ABI) is included for each target limb. ISR ¼ in-stent restenosis.
of clinical follow-up was the denominator. For assessment of clinical characteristics at 12 months, subjects were required to have data at both baseline and 12 months, but were not required to have a full 330 days of clinical follow-up. Statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, North Carolina).
(TLR) within 12 months post-index procedure. For
RESULTS
the primary safety composite endpoint, TLR was assessed at the subject level and defined as the first
BASELINE SUBJECT AND LESION CHARACTERISTICS.
event that required TLR in the subject. The Clinical
The IN.PACT Global Study enrolled 1535 subjects
Events Committee reviewed all TLR and target
across 64 sites in more than 25 countries from
vessel revascularization (TVR) events to determine
Europe, the Middle East, Asia, Australia, Canada, and
which were clinically driven (CD), defined as any
Latin America. Subjects with at least 1 de novo ISR
reintervention within the target lesion(s) due to
were prospectively enrolled in the ISR imaging
symptoms or ankle-brachial index (ABI) decrease
cohort (n ¼ 166). Analysis was limited to subjects in
of $20% or >0.15 when compared with post–index
which de novo ISR lesions were the only targets
procedure baseline ABI. The primary effectiveness
treated during the index procedure (n ¼ 131). Due to
endpoint was 12-month primary patency, defined as
protocol violations, 2 subjects classified as Ruth-
freedom from CD TLR and freedom from restenosis
erford category 5 were enrolled and included in the
(DUS peak systolic velocity ratio #2.4). Secondary
analysis.
Brodmann et al.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 20, 2017 OCTOBER 23, 2017:2113–23
Drug-Coated Balloons for De Novo In-Stent Restenosis
In this study, site-reported data were independently evaluated and adjudicated by an imaging core laboratory. Differences in technique between sitereported and core laboratory evaluated data resulted
T A B L E 2 Lesion Characteristics From Subjects in the IN.PACT
Global Study ISR Imaging Cohort (N ¼ 131, 148 Lesions)*†
Pre-procedure Lesion type‡
in a disparate number of target lesions. Per site
ISR
assessment, there were 149 target lesions among 131
Vessel§
100.0 (149/149)
subjects. Per core lab evaluation, there were 144
Superficial femoral artery
92.4 (133/144)
target lesions among 131 subjects. For this analysis of
Proximal popliteal artery
29.2 (42/144)
ISR lesions, lesions characteristics per the core lab are
Lesion length§ Mean, cm
based on a total of 144 lesions. Baseline demographics and characteristics of the
Minimum, maximum
17.17 10.47 (138) 2.5, 50.0
Occluded§
34.0 (48/141)
ISR imaging cohort are reported in Tables 1 and 2. Six
With calcification¶§
59.1 (78/132)
subjects did not complete the study through the
With severe calcification†§
13-month follow-up window: 4 withdrew consent and
Reference vessel diameter, mm‡
2 were lost to follow-up. Several subjects had lesions
Diameter stenosis, %§
in both limbs (n ¼ 3 of 131, 2.3%). Mean lesion length
TASC lesion type§
was 17.17 10.47 cm (range 2.5 to 50.0 cm). Thirtyfour percent (n ¼ 48 of 141) were total occlusions and 8.3% (n ¼ 11 of 132) were severely calcified.
A
8.3 (11/132) 5.222 0.601 (149) 84.8 14.9 (141) 26.0 (34/131)
B
32.1 (42/131)
C
32.1 (42/131)
D
9.9 (13/131)
Mehran classification method pattern of ISR#
EFFECTIVENESS OUTCOMES. Acute periprocedural
Focal type**
45
success was 98.5% or higher by all measures. Device
Diffuse ISR pattern**
88
success was achieved with 99.6% (n ¼ 282 of 283) of
Procedure 1.9 1.1 (149)
devices used. Procedural success was achieved in
No. treatment balloons per lesion‡
99.3% (n ¼ 148 of 149) of lesions and clinical success
Pre-dilatation‡
64.1 (84/131)
Post-dilatation‡
26.0 (34/131)
Provisional stenting‡
13.4 (20/149)
was achieved in 98.5% (n ¼ 129 of 131) of subjects. Provisional stents were implanted in 13.4% (n ¼ 20 of
Post-procedure
149) of lesions. For additional procedural details, see
Device success††
99.6 (282/283)
Online Table 1.
Procedural success‡‡
99.3 (148/149)
Clinical success§§
98.5 (129/131)
Primary patency by Kaplan-Meier estimate was 88.7% in the ISR imaging cohort at 12 months (Figure 2, top) and 80.7% through the 13-month follow-up
window.
Freedom
from
CD
TLR
by
Kaplan-Meier estimate was 92.9% at 12 months (Figure 2, bottom). Primary patency was compared between nonstented and stented subjects in the ISR imaging cohort
(Figure
3).
By
Kaplan-Meier
estimate,
12-month primary patency was 89.6% for the nonstented group and 83.3% for the stented group. At the end of the 13-month follow-up window, primary patency was 84.5% in the nonstented group and 57.7% in the stented group (p ¼ 0.0132). At baseline, 9.2% (n ¼ 12 of 130) of subjects in the overall ISR imagining cohort were Rutherford category 4 to 5 and 90.8% (n ¼ 118 of 130) were category 2 to 3 (Figure 4). At 12 months, 3.3% (n ¼ 4 of 120) of subjects were category 4 to 5, 20.0% (n ¼ 24 of 120) were category 2 to 3, and 76.7% (n ¼ 92 of 120) were category 0 to 1. The changes in Rutherford clinical category between baseline and 12 months were statistically significant (p < 0.001). Of the 12 subjects categorized as Rutherford category 4 to 5, 75% (n ¼ 9 of 12) showed improvements by 1 or more category,
Dissections‡ 0
69.1 (103/149)
A–C
26.2 (39/149)
D–F
4.7 (7/149)
Values are % (n/N), mean SD (N), or n, unless otherwise indicated. *Independent core imaging labs determined that there were 144 target lesions among 129 subjects in the in-stent restenosis; in-stent restenosis (ISR) imaging cohort. Lesion characteristics that were assessed by imaging core laboratories were based on this total number of target lesions. The investigators, using individual site techniques, determined that there were 149 target lesions among 131 subjects. Lesion characteristics that were assessed by the investigators were therefore based on this total number of lesions. †Summaries are based on nonmissing assessments. In some cases, baseline data were not available and therefore the total number of lesions for that variable was <144 for data reported by independent core imaging labs or <149 for data reported by investigators. ‡Data reported by investigators. §Data reported by independent core imaging labs. ¶Severe calcification defined as calcification with circumference $180 (both sides of vessel at the same location) and length greater than or equal to half of the total lesion length. #Number of subjects. **Focal types include type IA (body), IB (proximal margin), IC (distal margin), and ID (multifocal). Diffuse ISR patterns include pattern II (in-stent), pattern III (proliferative), and pattern IV (occlusive). ††Device success defined as successful delivery, inflation, deflation, and retrieval of the intact study balloon device without burst below the rated burst pressure. This analysis is device (balloon) based. ‡‡Procedural success defined as residual stenosis of #50% for nonstented subjects or #30% for stented subjects by core lab assessment (site-reported estimate was used if core lab assessment was not available). This analysis is lesion based. §§Clinical success defined as procedural success without procedural complications (death, major target limb amputation, thrombosis of the target lesion, or target vessel revascularization) before discharge. This analysis is subject based. TASC ¼ The TransAtlantic Inter-Society Consensus.
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F I G U R E 2 Kaplan-Meier Curves of Primary Patency and Freedom From CD TLR in the In-Stent Restenosis Imaging Cohort
(Top) Primary patency. (Bottom) Freedom from clinically driven target lesion revascularization (CD TLR). Number at risk represents the number at the beginning of the 30-day window before each follow-up interval.
8.3% (n ¼ 1 of 12) showed no change, and 8.3% (n ¼ 1
WIQ score from baseline was 40.7 35.9% (n ¼ 113,
of 12) showed worsening outcome. One subject did
p < 0.001).
not have 12-month data available. Mean ABI was 0.667 0.187 mm Hg at baseline
SAFETY OUTCOMES. The 12-month primary safety
(n ¼ 124 target limbs) and 0.909 0.193 mm Hg
composite endpoint was achieved in 92.7% (n ¼ 115 of
(n ¼ 112 target limbs) at 12 months. Mean change in
124) of subjects (Table 3). There were no acute adverse
ABI from baseline was 0.241 0.246 mm Hg (n ¼
events. The cumulative major adverse event rate at
104 target limbs; p < 0.001). The mean WIQ score
30 days was 0.0%. Major adverse events were re-
was 36.8 25.5% (n ¼ 125) at baseline and
ported in 8.9% (n ¼ 11 of 124) of subjects at 12 months.
76.7 30.9% (n ¼ 116) at 12 months. Mean change in
There was 1 case of thrombosis at the target lesion
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JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 20, 2017 OCTOBER 23, 2017:2113–23
Drug-Coated Balloons for De Novo In-Stent Restenosis
F I G U R E 3 Kaplan-Meier Curve of Primary Patency in the In-Stent Restenosis Imaging Cohort, by Stenting
Number at risk represents the number at the beginning of the 30-day window before each follow-up interval.
(0.8%, n ¼ 1 of 124) at 12 months. There were no deaths
(all
cause)
and
no
major
target
limb
F I G U R E 4 Rutherford Clinical Category at Baseline and 12 Months Among Subjects
in the ISR Imaging Cohort
amputations.
DISCUSSION The IN.PACT Global study was a prospective, multicenter, international, single-arm clinical trial that evaluated
the
safety
and
effectiveness
of
a
paclitaxel-coated DCB in a large population of subjects with intermittent claudication or rest pain due to obstructive disease of the femoropopliteal artery. One of the core strengths of the IN.PACT Global study ISR imaging cohort analysis was that it combined the rigor of a clinical trial, including independent
adjudication
of
adverse
events
and
independent analysis of angiography and duplex ultrasonography, with a subject population that represented the broad range of clinical variability seen in everyday practice. Results from the ISR imaging cohort analysis showed that the IN.PACT Admiral DCB is highly
IN.PACT Global study enrollment was open to subjects of Rutherford clinical categories 2 to 4. Due to protocol violations, 2 subjects classified as category 5 were enrolled and included in the analysis. This graph shows the distribution of subjects among Rutherford clinical categories at baseline and 12 months after index treatment. The change in
effective up to 12 months after treatment in real-
distribution among categories was statistically significant (p < 0.001). ISR ¼ in-stent
world subjects with long de novo ISR (mean lesion
restenosis.
length 17.17 10.47 cm) in the full length of the SFA
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Drug-Coated Balloons for De Novo In-Stent Restenosis
T A B L E 3 12-Month Safety Outcomes* for Subjects in the
IN.PACT Global Study ISR Imaging Cohort (N ¼ 124)†‡
Clinically driven TLR§
9 (7.3)
Primary safety endpoint¶
(mean length range 8.2 to 13.2 cm), except for in the PACUBA trial of a paclitaxel DCB where mean lesion length was 17.3 cm (Table 4) (10,15,21,23). The 12-month primary patency and freedom from
115 (92.7)
Major adverse events#
11 (8.9)
CD TLR in the ISR imaging cohort was higher than
Death (all-cause)
0 (0.0)
what has been reported for other endovascular
Major target limb amputation
0 (0.0)
modalities evaluated for de novo ISR (Table 5)
Thrombosis
1 (0.8)
(9,12–14,24–30), but direct comparisons cannot be
Any TLR
10 (8.1)
made because the ISR imagining cohort analysis was a
Any TVR
12 (9.7)
Values are n (%). *An independent Clinical Events Committee adjudicated all major adverse events. †Event rates expressed as a proportion: number of subjects with an event ¼ numerator, number of subjects with at least 330 days of clinical followup ¼ denominator. ‡Six subjects did not complete the study through the follow-up period. §Clinically driven target lesion revascularization (TLR) defined as any reintervention within the target lesion(s) due to symptoms or drop of anklebrachial index of $20% or >0.15 when compared with post–index procedure baseline ankle-brachial index. ¶The primary safety composite endpoint was freedom from device- and procedure-related mortality through 30 days, and freedom from major target limb amputation and TLR within 12 months post-index procedure. #Major adverse event defined as all-cause mortality, clinically driven target vessel revascularization, major target limb amputation, thrombosis at the target lesion site. ISR ¼ in-stent restenosis; TVR ¼ target vessel revascularization.
single-arm study that did not include an active comparator group. Treatment with the IN.PACT Admiral DCB had a sustained midterm clinical impact in the ISR imaging cohort analysis. Before the index procedure, all subjects were classified as Rutherford category 2 or higher. Twelve months after the index procedure with DCB treatment, 77% of subjects were Rutherford clinical category 0 to 1. The difference in distribution of subjects among Rutherford clinical categories between baseline and 12 months was statistically significant. Other functional outcome measures, such as change in ABI or WIQ, were also significantly improved at 12
or popliteal artery. Primary patency at 12 months by
months after intervention with the IN.PACT Admiral.
Kaplan-Meier estimate was high (88.7%) and consis-
Paclitaxel-coated DCBs were safe for the treatment
tent with the 12-month freedom from CD TLR by
of subjects in the ISR imaging cohort. There were no
Kaplan-Meir estimate (92.9%). These findings are
deaths and no major target limb amputations. The
similar to what has been reported for the use of
12-month incidence of thrombosis was low (0.8%),
paclitaxel-coated DCBs in the SFA or popliteal artery,
similar to what has been reported for DCBs in short
though in de novo ISR lesions of shorter mean length
lesions (18,19).
T A B L E 4 12-Month Effectiveness Findings From Clinical Studies Evaluating DCBs for De Novo ISR the Femoropopliteal Artery
Effectiveness at 12 Months Trial (Ref. #)
Study Design
Treatment Arms
Lesion Length (cm)*
Primary Patency†
Freedom From CD-TLR†
IN.PACT Global study de novo ISR imaging cohort
Multicenter Prospective Single arm Adjudicated
DCB‡ (n ¼ 131)
17.17 10.47
88.7%
92.9%
FAIR (10)
Multicenter Randomized Nonblinded Controlled
DCB‡ (n ¼ 62) PBA (n ¼ 57)
8.22 6.84
NR
90.8%
DEBATE-ISR (21)
Single site Prospective All-comers registry
DCB‡ (n ¼ 44) Historical PBA control group (n ¼ 42)
13.2 8.6§
NR
86%
Mercogliano registry (23)
Single site Prospective All-comers registry
DCB‡ (n ¼ 39)
8.29 7.89
92.1%
92.1%
PACUBA trial (15)
Dual center Prospective Randomized Controlled
DCB‡ (n ¼ 35) PBA (n ¼ 39)
17.3 11.3§
40.7%
49.0%
Values are mean SD or %. *Mean lesion length of total subject population unless otherwise specified. †By Kaplan-Meier estimate. ‡IN.PACT Admiral (Medtronic, Dublin, Ireland) used in the IN.PACT Global study, FAIR (Femoral Artery In-stent Restenosis), and DEBATE-ISR trials. IN.PACT (class unspecified) used in the Mercogliano Registry. FREEWAY 035 paclitaxel drug-coated balloon (DCB) (Eurocor GmbH, Bonn, Germany) used in the PACUBA trial. §Mean lesion length of DCB group only. DEBATE ISR ¼ Drug-Eluting Balloon in Peripheral Intervention for In-Stent Restenosis; ISR ¼ in-stent restenosis; NR ¼ not reported; PACUBA ¼ Paclitaxel Balloon Versus Standard Balloon in In-stent Restenoses of the Superficial Femoral Artery; PBA ¼ plain uncoated balloon angioplasty; TLR ¼ target lesion revascularization.
Brodmann et al.
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Drug-Coated Balloons for De Novo In-Stent Restenosis
T A B L E 5 Effectiveness Findings From Clinical Studies Evaluating Treatment Options Other Than DCBs for De Novo ISR in the
Femoropopliteal Artery Effectiveness
Trial (Ref. #)
Lesion Length (cm)*
Primary Patency†
Freedom From TLR†
Rate of Restenosis†
Study Design
Active intervention
Multicenter Prospective Single arm
Zilver-PTX DES (n ¼ 108)
13.3 9.2
78.8%
81.0%
NR
Multicenter Prospective Randomized PBA controlled
Vascular stent graft (n ¼ 39)
17.3 7.8§
74.8%
NR
NR
Single center Prospective Randomized PBA controlled
Cutting balloon angioplasty (n ¼ 17)
8.0 6.8
NR
NR
65%‡
Single center Prospective Single arm
PBA þ brachytherapy (n ¼ 90)
24.6
79.8%
NR
NR
EXCITE ISR trial (14)
Multicenter Prospective Randomized PBA controlled
Excimer laser atherectomy þ PBA (n ¼ 169)
19.6 12.0§
NR
73.5%‡
NR
PATENT registry (26)
Multicenter Prospective Registry
Excimer laser atherectomy þ PBA (n ¼ 90)
12.3 9.6
37.8%
64.4%
NR
JETSTREAM-ISR trial (27)
Multicenter Prospective Registry
Rotational and aspiration atherectomy þ PBA (n ¼ 29)
19.5 12.9
72%‡
NR
NR
Rotarex study (28)
Single center Prospective Single arm
Rotational thrombectomy þ PBA (n ¼ 32)
16.0
58.1%
NR
NR
Silver Hawk registry (29)
Single center Prospective Registry
Directional atherectomy (n ¼ 43 ISR lesions) þ PBA (n ¼ 28 of 43)
13.1 11.1
54%
NR
NR
Silver Hawk single-arm trial (30)
Single center Prospective Single arm
Directional atherectomy (n ¼ 33)
10.8 10.2
25%
NR
NR
Multicenter Prospective Registry
Excimer laser atherectomy þ vascular stent graft (n ¼ 27)
20.7 10.3
48%
NR
NR
Drug-eluting stents Zilver-PTX single-arm ISR subgroup (9) Vascular stent grafts RELINE trial (24)
Cutting balloon angioplasty Vienna General Hospital trial (12)
Brachytherapy Rhenium-188 (25)
Debulking procedures
Combination procedures SALVAGE registry (13)
Values are mean SD or %. *Mean lesion length of total subject population unless otherwise specified. †All effectiveness findings for 12 months unless otherwise specified. ‡Six months after index treatment. §Mean lesion length of active intervention group only. EXCITE ISR ¼ EXCImer Laser Randomized Controlled Study for Treatment of FemoropopliTEal In-Stent Restenosis; JETSTREAM ISR ¼ JetStream (JS) Atherectomy in Femoropopliteal In-Stent Restenotic Lesions; PATENT ¼ Photoablation using the turbo-booster and excimer laser for in-stent restenosis treatment; RELINE ¼ GORE VIABAHN Versus Plain Old Balloon Angioplasty (POBA) for Superficial Femoral Artery (SFA) In-Stent Restenosis; SALVAGE ¼ Excimer laser with adjunctive balloon angioplasty and heparin-coated self-expanding stent grafts for the treatment of femoropopliteal artery in-stent restenosis; other abbreviations as in Table 4.
The IN.PACT Global study ISR imaging cohort
unilateral or bilateral disease; any lesion 2 cm or
analysis is unique in that it combined the all-comer
longer), the ISR imaging cohort results are generaliz-
approach of an observational registry with the
able to patients that are encountered in clinical
rigor of a clinical trial, including the independent
practice. The combination of these design strengths
adjudication of adverse events by a Clinical Events
serve to bolster the findings of DCB safety and
Committee and the independent analysis of angiog-
effectiveness in the ISR imaging cohort, which is the
raphy and DUS by core laboratories. By evaluating a
largest group of subjects with de novo ISR in the SFA
heterogeneous population (single or multiple lesions;
or popliteal artery that has been evaluated to date.
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Drug-Coated Balloons for De Novo In-Stent Restenosis
STUDY
LIMITATIONS. The
IN.PACT Global study
ISR imaging cohort analysis was a single-arm, nonrandomized study. The study did not include a control group or an active comparator, and the results of the ISR imaging cohort analysis cannot support the superiority of one modality versus another.
CONCLUSIONS
PERSPECTIVES WHAT IS KNOWN? Endovascular intervention is an accepted method for the treatment of patients with symptomatic PAD, but complex lesions such as de novo ISR can be especially difficult to manage and are often associated with high rates of restenosis and reintervention.
The IN.PACT Admiral DCB was safe and highly effective up to 12 months after treatment in a rigorous
WHAT IS NEW? Patients with complex femoropo-
independently adjudicated analysis of subjects with
pliteal lesions, such as de novo ISR, should be made
de novo ISR (mean lesion length 17.17 10.47 cm) in
aware that the use of DCBs may have the potential to
the full native SFA and/or full popliteal artery.
improve the outcomes of an angioplasty procedure.
ACKNOWLEDGMENTS The authors thank Despina
Voulgaraki, PhD, Eric Fernandez, MD, and Azah Tabah, PhD, for technical review of the manuscript, and Paula Soto, PhD, and Zachary Harrelson, PhD, of Meridius Health Communications Inc. (San Diego, California) for providing medical writing support, which was funded by Medtronic Inc. (Minneapolis, Minnesota) in accordance with Good Publication Practice guidelines (http://www.ismpp.org/gpp3). ADDRESS FOR CORRESPONDENCE: Dr. Marianne
Brodmann, Department of Internal Medicine, Division of Angiology, Medical University, Auenbruggerplatz 15, A-8036 Graz, Austria. E-mail: marianne.brodmann@
The 12-month results of the ISR imaging cohort analysis demonstrate the safety and effectiveness of treatment with paclitaxel-coated IN.PACT Admiral DCB in patients with de novo ISR in the full native SFA or full popliteal artery, a traditionally difficult-to-treat patient population. WHAT IS NEXT? Although 12-month primary patency and freedom from CD TLR is higher in the ISR imaging cohort compared with what has been reported for other treatment modalities, future investigations should focus on head-to-head comparisons of DCBs with alternative approaches such as DES, atherectomy, and surgical reconstruction.
medunigraz.at.
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6. Iida O, Uematsu M, Soga Y, et al. Timing of the restenosis following nitinol stenting in the superficial femoral artery and the factors associated with early and late restenoses. Catheter Cardiovasc Interv 2011;78:611–7.
12. Dick P, Sabeti S, Mlekusch W, et al. Conventional balloon angioplasty versus peripheral cutting balloon angioplasty for treatment of femoropopliteal artery in-stent restenosis: initial experience. Radiology 2008;248:297–302.
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J Endovasc Ther 2014;21:463–71. 8. Tosaka A, Soga Y, Iida O, et al. Classification and clinical impact of restenosis after femoropopliteal stenting. J Am Coll Cardiol 2012;59:16–23. 9. Zeller T, Dake MD, Tepe G, et al. Treatment of femoropopliteal in-stent restenosis with paclitaxel-eluting stents. J Am Coll Cardiol Intv 2013;6:274–81. 10. Krankenberg H, Tubler T, Ingwersen M, et al. Drug-coated balloon versus standard balloon for superficial femoral artery in-stent restenosis: the randomized Femoral Artery In-stent Restenosis (FAIR) trial. Circulation 2015;132:2230–6. 11. Jaff MR, Rosenfield K, Scheinert D, et al. Drugcoated balloons to improve femoropopliteal artery patency: rationale and design of the LEVANT 2 trial. Am Heart J 2015;169:479–85.
and heparin-coated self-expanding stent grafts for the treatment of femoropopliteal artery in-stent restenosis: twelve-month results from the SALVAGE study. Catheter Cardiovasc Interv 2012; 80:852–9. 14. Dippel EJ, Makam P, Kovach R, et al. Randomized controlled study of excimer laser atherectomy for treatment of femoropopliteal instent restenosis: initial results from the EXCITE ISR trial (EXCImer Laser Randomized Controlled Study for Treatment of FemoropopliTEal In-Stent Restenosis). J Am Coll Cardiol Intv 2015;8:92–101. 15. Kinstner CM, Lammer J, Willfort-Ehringer A, et al. Paclitaxel-eluting balloon versus standard balloon angioplasty in in-stent restenosis of the superficial femoral and proximal popliteal artery: 1-year results of the PACUBA trial. J Am Coll Cardiol Intv 2016;9:1386–92. 16. Byrne RA, Joner M, Alfonso F, Kastrati A. Drug-coated balloon therapy in coronary and
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18. 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. 19. Tepe G, Laird J, Schneider P, et al. Drug-coated balloon versus standard percutaneous transluminal angioplasty for the treatment of superficial femoral and popliteal peripheral artery disease: 12-month results from the IN.PACT SFA randomized trial. Circulation 2015;131:495–502. 20. Laird JR, Schneider PA, Tepe G, et al. Durability of treatment effect using a drug-coated balloon for femoropopliteal lesions: 24-month results of IN.PACT SFA. J Am Coll Cardiol 2015; 66:2329–38. 21. Liistro F, Angioli P, Porto I, et al. Paclitaxeleluting balloon vs. standard angioplasty to reduce recurrent restenosis in diabetic patients with in-stent restenosis of the superficial femoral and
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23. Stabile E, Virga V, Salemme L, et al. Drugeluting balloon for treatment of superficial femoral artery in-stent restenosis. J Am Coll Cardiol 2012;60:1739–42. 24. Bosiers M, Deloose K, Callaert J, et al. Superiority of stent-grafts for in-stent restenosis in the superficial femoral artery: twelve-month results from a multicenter randomized trial. J Endovasc Ther 2015;22:1–10. 25. Werner M, Scheinert D, Henn M, et al. Endovascular brachytherapy using liquid beta-emitting rhenium-188 for the treatment of long-segment femoropopliteal in-stent stenosis. J Endovasc Ther 2012;19:467–75. 26. Schmidt A, Zeller T, Sievert H, et al. Photoablation using the turbo-booster and excimer laser for in-stent restenosis treatment: twelve-month results from the PATENT study. J Endovasc Ther 2014;21:52–60. 27. Shammas NW, Shammas GA, Banerjee S, Popma JJ, Mohammad A, Jerin M. JetStream
rotational and aspiration atherectomy in treating in-stent restenosis of the femoropopliteal arteries: results of the JETSTREAM-ISR feasibility study. J Endovasc Ther 2016;23:339–46. 28. Silingardi R, Cataldi V, Moratto R, Azzoni I, Veronesi J, Coppi G. Mechanical thrombectomy in in-stent restenosis: preliminary experience at the iliac and femoropopliteal arteries with the Rotarex System. J Cardiovasc Surg (Torino) 2010;51: 543–50. 29. Zeller T, Rastan A, Sixt S, et al. Long-term results after directional atherectomy of femoropopliteal lesions. J Am Coll Cardiol 2006;48: 1573–8. 30. Trentmann J, Charalambous N, Djawanscher M, Schafer J, Jahnke T. Safety and efficacy of directional atherectomy for the treatment of in-stent restenosis of the femoropopliteal artery. J Cardiovasc Surg (Torino) 2010;51:551–60.
KEY WORDS drug-coated balloon, femoropopliteal artery, in-stent restenosis, paclitaxel, peripheral artery disease A PP END IX For an expanded Methods section and supplemental table, please see the online version of this article.
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VOL. 10, NO. 20, 2017
ª 2017 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER
ISSN 1936-8798 http://dx.doi.org/10.1016/j.jcin.2017.06.018
THE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Drug-Coated Balloon Treatment for Femoropopliteal Artery Disease The IN.PACT Global Study De Novo In-Stent Restenosis Imaging Cohort Marianne Brodmann, MD,a Koen Keirse, MD,b Dierk Scheinert, MD,c Lubomir Spak, MD, MPH,d Michael R. Jaff, DO,e,f Randy Schmahl, MSC,g Pei Li, PHD,h Thomas Zeller, MD,i on behalf of the IN.PACT Global Study Investigators
ABSTRACT OBJECTIVES This study sought to evaluate the safety and effectiveness of a paclitaxel-coated drug-coated balloon (DCB) for the treatment of patients with de novo in-stent restenosis (ISR). BACKGROUND Treatment of patients with ISR remains a challenge. Current strategies are plagued by high rates of recurrent restenosis and need for reintervention. The best intervention for ISR remains to be elucidated. METHODS The IN.PACT Global study is an independently adjudicated multicenter, prospective, single-arm study that enrolled 1,535 subjects with symptomatic atherosclerotic disease of the superficial femoral and/or popliteal arteries, including de novo ISR lesions. Patients enrolled in the pre-specified ISR imaging cohort were evaluated for vessel patency and reintervention within the 12-month follow-up period. RESULTS A total of 131 subjects with 149 ISR lesions were included for analysis. The mean age of the cohort was 67.8 years. Mean lesion length was 17.17 10.47 cm, including 34.0% total occlusions and 59.1% calcified lesions. The 12-month Kaplan-Meier estimate of primary patency was 88.7%. The rate of clinically driven target lesion revascularization (CD TLR) at 12 months was 7.3%. The primary safety outcome, a composite of freedom from device- and procedure-related mortality through 30 days and freedom from major target limb amputation and CD TLR within 12 months, was 92.7%. There were no major target limb amputations, no deaths, and a low (0.8%) thrombosis rate. CONCLUSIONS Results from the ISR imaging cohort demonstrate high patency and a low rate of CD TLR at 12 months. These data confirm the safety and effectiveness of the IN.PACT Admiral DCB (Medtronic, Dublin, Ireland) in complex femoropopliteal lesions, including this challenging subset. (J Am Coll Cardiol Intv 2017;10:2113–23) © 2017 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
From the aDepartment of Internal Medicine, Division of Angiology, Medical University, Graz, Austria; bDepartment of Vascular Surgery, Regional Hospital Heilig Hart Tienen, Tienen, Belgium; cDivision of Interventional Angiology, University Hospital Leipzig, Leipzig, Germany; dClinic of Angiology, Eastern Slovak Institute for Cardiovascular Diseases, Kosice, Slovak Republic; e
President, Newton-Wellesley Hospital, Newton, Massachusetts; fProfessor of Medicine, Harvard Medical School Boston, Mas-
sachusetts; gMedtronic, Bakken Research Center BV, Maastricht, the Netherlands; hMedtronic, Minneapolis, Minnesota; and i
Universitäts-Herzzentrum Freiburg-Bad Krozingen, Bad Krozingen, Germany. Funding support was provided by Medtronic. Dr.
Brodmann has received honoraria from Bard Peripheral Vascular, Biotronik, Medtronic, Spectranetics, and Viva Physicians; and has served as a consultant for Bard Peripheral Vascular, Biotronik, Medtronic, and Spectranetics. Dr. Keirse has reported that he has no relationships relevant to the contents of this paper to disclose. Dr. Scheinert has served as a consultant and on the scientific advisory board for Abbott Vascular, Biotronik, Boston Scientific Corporation, Cook Medical, Cordis, CR Bard, Gardia Medical, Hemoteq, Medtronic, Ostial Inc., TriReme Medical, Trivascular, Upstream Medical Technologies. Dr. Spak has served as a consultant for Medtronic. Dr. Jaff has served as a noncompensated advisor for Medtronic; a compensated board member of VIVA Physicians, a 501(c)(3) not-for-profit education and research organization; has served as an advisor for Micell; and has been an equity investor of PQ Bypass, Embolitech, and Vascular Therapies. Mr. Schmahl and Dr. Li are full-time employees of Medtronic. Dr. Zeller has received speaking honoraria from Abbott Vascular, Bard Peripheral Vascular, Biotronik, Boston Scientific Corporation, Cook Medical, Cordis Corp., GLG, Gore & Associates, Medtronic, Philips, Spectranetics, Straub Medical, TriReme, Veryan, and VIVA Physicians; and has served as a consultant for Abbott Vascular, Bard Peripheral Vascular, Boston Scientific Corporation, Cook Medical, Gore & Associates, Medtronic, and Spectranetics; and his clinic has received study funds or funds
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E
ABBREVIATIONS AND ACRONYMS ABI = ankle-brachial index CD = clinically driven DCB = drug-coated balloon
ndovascular interventions, including percutaneous
transluminal
METHODS
angio-
plasty with a traditional uncoated
IN.PACT GLOBAL STUDY: DESIGN, SUBJECTS, AND
balloon, implantation of bare-metal or drug-
TREATMENT. A prospective analysis of DCBs for the
eluting stents (DES), angioplasty with a
treatment of de novo ISR was incorporated into the
drug-coated balloon (DCB), and debulking
design of the IN.PACT Global study, a prospective,
DES = drug-eluting stent(s)
with mechanical or laser atherectomy, have
multicenter, international, single-arm clinical trial
DUS = duplex ultrasonography
become the primary mode of revasculariza-
assessing the safety and effectiveness of a paclitaxel-
ISR = in-stent restenosis
tion in patients with symptomatic peripheral
coated DCB for the treatment of patients with inter-
PAD = peripheral artery
artery disease (PAD). Balloon angioplasty of
mittent claudication or rest pain due to obstructive
disease
the femoropopliteal segment is associated
disease of the femoropopliteal artery, including the
SFA = superficial femoral
with a high incidence of restenosis, with
full native SFA and/or full popliteal artery (P1 to P3
the best results seen for very focal stenosis
segments).
artery
TLR = target lesion
and noncomplex lesions (1). Stents yield
Greater than 1,400 patients who satisfied the
better outcomes when compared with con-
inclusion or exclusion criteria for the IN.PACT Global
ventional angioplasty alone (2–5), but are
study were consecutively enrolled at participating
associated with the risk of post-procedural
centers into the clinical cohort (Figure 1). Patients
in-stent restenosis (ISR) and other stent-
enrolled at sited qualified by the VasCore Duplex Core
related complications that can negatively
Lab (Boston, Massachusetts) were screened to meet 1
affect the patient’s long-term clinical outlook (6,7).
or more of the imaging criteria based on an algorithm.
Treatment of ISR with conventional methods remains
The hierarchy for the imaging cohort subgroup
a clinical challenge (8), with no clear frontline
assignment was as follows: 1) de novo ISR; 2) long
strategy.
lesions $15 cm; and 3) chronic total occlusions $5 cm.
revascularization
TVR = target vessel revascularization
WIQ = Walking Impairment Questionnaire
SEE PAGE 2124
Enrollment in the respective imaging cohorts was only open to subjects that had a de novo ISR, long
Technical improvements with DESs, DCBs, cutting
lesion, or chronic total occlusion at pre-procedure
balloons, and directional and laser atherectomy have
baseline. The only subjects who were included in
been aimed at reducing the occurrence of ISR (9–15).
the respective imaging cohort analyses, however,
DCBs and DESs deposit a long lasting antiproliferative
were those who had the primary target lesions that
therapeutic on the inner wall of the artery that sup-
met the criteria of the respective cohort during the
ports the sustained inhibition of restenosis, but DCBs
index procedure (i.e., no other types of lesions could
have the additional advantage of treating the lesion
have been treated during the index procedure).
without leaving a permanent device at the target site
Subjects with symptoms of intermittent claudica-
(16). The safety and effectiveness of DCBs for the
tion or ischemic rest pain (Rutherford clinical cate-
treatment of symptomatic PAD patients has been
gory 2 to 4) and angiographic evidence of occlusion or
demonstrated in randomized controlled clinical trials
stenosis (length $2 cm) in the SFA or popliteal artery
(17–20). Although few, studies have reported positive
(including P1 to P3 segments) were eligible for
outcomes with DCBs for the treatment of complex
enrollment in the IN.PACT Global study. Subjects
PAD lesions, including those that are formed by de
with multiple lesions were allowed. Subjects with
novo ISR (10,15,21,22).
tissue loss were excluded.
The IN.PACT Global Study was designed to eval-
Independent core laboratories analyzed all images,
uate the safety and effectiveness of a paclitaxel-
including duplex ultrasonography (DUS) (VasCore,
coated DCB (IN.PACT Admiral, Medtronic, Dublin,
Massachusetts General Hospital, Boston, Massachu-
Ireland) in the treatment of subjects with athero-
setts) and angiography (SynvaCor Angiographic Core
sclerotic femoropopliteal disease, including de novo
Lab, Springfield, Illinois). In cases where both angi-
ISR in the superficial femoral artery (SFA) or the
ography and duplex ultrasonography were available
entire length of the popliteal artery. Herein we report
at the same assessment, then angiography was pref-
12-month results from the ISR cohort.
erentially used. An independent Clinical Events
for research or clinical trials from 480 Biomedical, Abbott Vascular, B. Braun, Bard Peripheral Vascular, Bayer Pharma, Biotronik, Caveo Med, Contego Medical, Cook Medical, CSI, Gore & Associates, Innora, Intact Vascular, Medtronic, Mercator, Philips, Pluristem, Shockwave, Spectranetics, Terumo, TriReme, and Veryan. Manuscript received December 8, 2016; revised manuscript received April 20, 2017, accepted June 13, 2017.
Brodmann et al.
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Drug-Coated Balloons for De Novo In-Stent Restenosis
F I G U R E 1 Subject Flow in the IN.PACT Global Study and ISR Imaging Cohort
The imaging cohort was part of the clinical cohort and contained 3 prospectively defined subcohorts, including de novo in-stent restenosis (ISR). Subjects with at least 1 de novo ISR could be enrolled in the ISR imaging cohort (n ¼ 166), but analysis was restricted to subjects who had only de novo ISR lesions treated during the index procedure (n ¼ 131). CTO ¼ chronic total occlusion; DCB ¼ drug-coated balloon.
Committee (Syntactx Clinical Events Committee, New
before enrollment. The trial was conducted in accor-
York, New York) was established to assess the
dance with the Declaration of Helsinki, good clinical
primary and select secondary endpoints and to
practice guidelines, and applicable laws as specified
determine
by all relevant governmental bodies. The trial is
criteria.
whether The
each
Clinical
met
Events
protocol-specified Committee
was
composed of interventional and noninterventional
registered with the U.S. National Institutes of Health as NCT01609296.
clinicians with pertinent expertise who were not participants in the study and did not have any con-
DE NOVO ISR IMAGING COHORT STUDY ENDPOINTS.
flicts of interest.
The primary safety composite endpoint was freedom
The study protocol was approved by the institu-
from
device-
and
procedure-related
mortality
tional review board or ethics committee at each trial
through 30 days, and freedom from major target
site. Informed consent was obtained from all subjects
limb amputation and target lesion revascularization
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Drug-Coated Balloons for De Novo In-Stent Restenosis
T A B L E 1 Baseline Demographics and Clinical Characteristics of
endpoints included the incidence of major adverse
Subjects in the IN.PACT Global Study ISR Imaging Cohort
events (all-cause mortality, CD TVR, major target
(N ¼ 131)*
limb amputation, thrombosis at the target lesion site), CD TLR, any TLR, and any TVR at 12 months.
Age, yrs Mean Median Minimum, maximum Male
67.8 10.1 (130)
Other secondary endpoints included change in
68.0
Rutherford clinical category, change in ABI, and
39, 90
level of walking impairment as assessed by the
69.5 (91/131)
Body mass index, kg/m2
26.1 4.3 (131)
Walking
Impairment
Questionnaire
(WIQ)
at
12 months.
Obesity (body mass index $30 kg/m )
17.6 (23/131)
Diabetes
35.1 (46/131)
Insulin-dependent diabetes
15.3 (20/131)
or categories of stent coverage, see the Online
Hypertension
81.5 (106/131)
Appendix.
Hyperlipidemia
72.1 (93/129)
Current smoker
35.9 (47/131)
Coronary heart disease
36.5 (46/126)
ANALYSIS. All analyses were based on the intention-
Carotid artery disease
19.8 (23/116)
to-treat principle and all summaries were based on
9.9 (11/111)
subjects or lesions with evaluable data. Subjects or
100.0 (131/131)
lesions with missing data were excluded from the
43.3 (55/127)
analyses. Unless otherwise specified, all baseline
2
Renal insufficiency† Previous peripheral revascularization Below-the-knee disease of target leg Run-off vessel(s) occluded
For definitions of acute periprocedural outcomes
DE
NOVO
ISR
demographics
0
38.6 (49/127)
1
33.9 (43/127)
2
25.2 (32/127)
3
2.4 (3/127)
IMAGING
and
COHORT
clinical
STATISTICAL
characteristics
were
summarized on a subject basis; lesion characteristics were summarized on a lesion basis. For baseline characteristics, continuous variables were described as mean SD; dichotomous and categorical variables
Rutherford clinical category 0–1
0.0 (0/130)
were described as counts and proportions. The
2
33.1 (43/130)
Kaplan-Meier method was used to evaluate time-to-
3
57.7 (75/130)
event data for primary patency and CD TLR over the
4
7.7 (10/130)
5
1.5 (2/130)‡
12-month follow-up period. The outcome analysis
6 ABI, per target limb, mm Hg§ Bilateral disease
0.0 (0/130) 0.667 0.187 (124) 2.3 (3/131)
was performed at a subject level. For event rates that were expressed as a proportion, the number of subjects with an event was the numerator and the total number of subjects with either at least 330 days
Values are mean SD (N) or % (n/n), unless otherwise indicated. *Summaries are based on nonmissing assessments. In some cases, baseline demographic or clinical data were not available and therefore the total number of subjects for that variable was <131. †Defined as baseline serum creatinine $1.5 mg/dl. ‡Due to protocol violations, 2 subjects classified as Rutherford clinical category 5 were enrolled and included in the analysis. §For subjects with bilateral disease, ankle-brachial index (ABI) is included for each target limb. ISR ¼ in-stent restenosis.
of clinical follow-up was the denominator. For assessment of clinical characteristics at 12 months, subjects were required to have data at both baseline and 12 months, but were not required to have a full 330 days of clinical follow-up. Statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, North Carolina).
(TLR) within 12 months post-index procedure. For
RESULTS
the primary safety composite endpoint, TLR was assessed at the subject level and defined as the first
BASELINE SUBJECT AND LESION CHARACTERISTICS.
event that required TLR in the subject. The Clinical
The IN.PACT Global Study enrolled 1535 subjects
Events Committee reviewed all TLR and target
across 64 sites in more than 25 countries from
vessel revascularization (TVR) events to determine
Europe, the Middle East, Asia, Australia, Canada, and
which were clinically driven (CD), defined as any
Latin America. Subjects with at least 1 de novo ISR
reintervention within the target lesion(s) due to
were prospectively enrolled in the ISR imaging
symptoms or ankle-brachial index (ABI) decrease
cohort (n ¼ 166). Analysis was limited to subjects in
of $20% or >0.15 when compared with post–index
which de novo ISR lesions were the only targets
procedure baseline ABI. The primary effectiveness
treated during the index procedure (n ¼ 131). Due to
endpoint was 12-month primary patency, defined as
protocol violations, 2 subjects classified as Ruth-
freedom from CD TLR and freedom from restenosis
erford category 5 were enrolled and included in the
(DUS peak systolic velocity ratio #2.4). Secondary
analysis.
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Drug-Coated Balloons for De Novo In-Stent Restenosis
In this study, site-reported data were independently evaluated and adjudicated by an imaging core laboratory. Differences in technique between sitereported and core laboratory evaluated data resulted
T A B L E 2 Lesion Characteristics From Subjects in the IN.PACT
Global Study ISR Imaging Cohort (N ¼ 131, 148 Lesions)*†
Pre-procedure Lesion type‡
in a disparate number of target lesions. Per site
ISR
assessment, there were 149 target lesions among 131
Vessel§
100.0 (149/149)
subjects. Per core lab evaluation, there were 144
Superficial femoral artery
92.4 (133/144)
target lesions among 131 subjects. For this analysis of
Proximal popliteal artery
29.2 (42/144)
ISR lesions, lesions characteristics per the core lab are
Lesion length§ Mean, cm
based on a total of 144 lesions. Baseline demographics and characteristics of the
Minimum, maximum
17.17 10.47 (138) 2.5, 50.0
Occluded§
34.0 (48/141)
ISR imaging cohort are reported in Tables 1 and 2. Six
With calcification¶§
59.1 (78/132)
subjects did not complete the study through the
With severe calcification†§
13-month follow-up window: 4 withdrew consent and
Reference vessel diameter, mm‡
2 were lost to follow-up. Several subjects had lesions
Diameter stenosis, %§
in both limbs (n ¼ 3 of 131, 2.3%). Mean lesion length
TASC lesion type§
was 17.17 10.47 cm (range 2.5 to 50.0 cm). Thirtyfour percent (n ¼ 48 of 141) were total occlusions and 8.3% (n ¼ 11 of 132) were severely calcified.
A
8.3 (11/132) 5.222 0.601 (149) 84.8 14.9 (141) 26.0 (34/131)
B
32.1 (42/131)
C
32.1 (42/131)
D
9.9 (13/131)
Mehran classification method pattern of ISR#
EFFECTIVENESS OUTCOMES. Acute periprocedural
Focal type**
45
success was 98.5% or higher by all measures. Device
Diffuse ISR pattern**
88
success was achieved with 99.6% (n ¼ 282 of 283) of
Procedure 1.9 1.1 (149)
devices used. Procedural success was achieved in
No. treatment balloons per lesion‡
99.3% (n ¼ 148 of 149) of lesions and clinical success
Pre-dilatation‡
64.1 (84/131)
Post-dilatation‡
26.0 (34/131)
Provisional stenting‡
13.4 (20/149)
was achieved in 98.5% (n ¼ 129 of 131) of subjects. Provisional stents were implanted in 13.4% (n ¼ 20 of
Post-procedure
149) of lesions. For additional procedural details, see
Device success††
99.6 (282/283)
Online Table 1.
Procedural success‡‡
99.3 (148/149)
Clinical success§§
98.5 (129/131)
Primary patency by Kaplan-Meier estimate was 88.7% in the ISR imaging cohort at 12 months (Figure 2, top) and 80.7% through the 13-month follow-up
window.
Freedom
from
CD
TLR
by
Kaplan-Meier estimate was 92.9% at 12 months (Figure 2, bottom). Primary patency was compared between nonstented and stented subjects in the ISR imaging cohort
(Figure
3).
By
Kaplan-Meier
estimate,
12-month primary patency was 89.6% for the nonstented group and 83.3% for the stented group. At the end of the 13-month follow-up window, primary patency was 84.5% in the nonstented group and 57.7% in the stented group (p ¼ 0.0132). At baseline, 9.2% (n ¼ 12 of 130) of subjects in the overall ISR imagining cohort were Rutherford category 4 to 5 and 90.8% (n ¼ 118 of 130) were category 2 to 3 (Figure 4). At 12 months, 3.3% (n ¼ 4 of 120) of subjects were category 4 to 5, 20.0% (n ¼ 24 of 120) were category 2 to 3, and 76.7% (n ¼ 92 of 120) were category 0 to 1. The changes in Rutherford clinical category between baseline and 12 months were statistically significant (p < 0.001). Of the 12 subjects categorized as Rutherford category 4 to 5, 75% (n ¼ 9 of 12) showed improvements by 1 or more category,
Dissections‡ 0
69.1 (103/149)
A–C
26.2 (39/149)
D–F
4.7 (7/149)
Values are % (n/N), mean SD (N), or n, unless otherwise indicated. *Independent core imaging labs determined that there were 144 target lesions among 129 subjects in the in-stent restenosis; in-stent restenosis (ISR) imaging cohort. Lesion characteristics that were assessed by imaging core laboratories were based on this total number of target lesions. The investigators, using individual site techniques, determined that there were 149 target lesions among 131 subjects. Lesion characteristics that were assessed by the investigators were therefore based on this total number of lesions. †Summaries are based on nonmissing assessments. In some cases, baseline data were not available and therefore the total number of lesions for that variable was <144 for data reported by independent core imaging labs or <149 for data reported by investigators. ‡Data reported by investigators. §Data reported by independent core imaging labs. ¶Severe calcification defined as calcification with circumference $180 (both sides of vessel at the same location) and length greater than or equal to half of the total lesion length. #Number of subjects. **Focal types include type IA (body), IB (proximal margin), IC (distal margin), and ID (multifocal). Diffuse ISR patterns include pattern II (in-stent), pattern III (proliferative), and pattern IV (occlusive). ††Device success defined as successful delivery, inflation, deflation, and retrieval of the intact study balloon device without burst below the rated burst pressure. This analysis is device (balloon) based. ‡‡Procedural success defined as residual stenosis of #50% for nonstented subjects or #30% for stented subjects by core lab assessment (site-reported estimate was used if core lab assessment was not available). This analysis is lesion based. §§Clinical success defined as procedural success without procedural complications (death, major target limb amputation, thrombosis of the target lesion, or target vessel revascularization) before discharge. This analysis is subject based. TASC ¼ The TransAtlantic Inter-Society Consensus.
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F I G U R E 2 Kaplan-Meier Curves of Primary Patency and Freedom From CD TLR in the In-Stent Restenosis Imaging Cohort
(Top) Primary patency. (Bottom) Freedom from clinically driven target lesion revascularization (CD TLR). Number at risk represents the number at the beginning of the 30-day window before each follow-up interval.
8.3% (n ¼ 1 of 12) showed no change, and 8.3% (n ¼ 1
WIQ score from baseline was 40.7 35.9% (n ¼ 113,
of 12) showed worsening outcome. One subject did
p < 0.001).
not have 12-month data available. Mean ABI was 0.667 0.187 mm Hg at baseline
SAFETY OUTCOMES. The 12-month primary safety
(n ¼ 124 target limbs) and 0.909 0.193 mm Hg
composite endpoint was achieved in 92.7% (n ¼ 115 of
(n ¼ 112 target limbs) at 12 months. Mean change in
124) of subjects (Table 3). There were no acute adverse
ABI from baseline was 0.241 0.246 mm Hg (n ¼
events. The cumulative major adverse event rate at
104 target limbs; p < 0.001). The mean WIQ score
30 days was 0.0%. Major adverse events were re-
was 36.8 25.5% (n ¼ 125) at baseline and
ported in 8.9% (n ¼ 11 of 124) of subjects at 12 months.
76.7 30.9% (n ¼ 116) at 12 months. Mean change in
There was 1 case of thrombosis at the target lesion
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F I G U R E 3 Kaplan-Meier Curve of Primary Patency in the In-Stent Restenosis Imaging Cohort, by Stenting
Number at risk represents the number at the beginning of the 30-day window before each follow-up interval.
(0.8%, n ¼ 1 of 124) at 12 months. There were no deaths
(all
cause)
and
no
major
target
limb
F I G U R E 4 Rutherford Clinical Category at Baseline and 12 Months Among Subjects
in the ISR Imaging Cohort
amputations.
DISCUSSION The IN.PACT Global study was a prospective, multicenter, international, single-arm clinical trial that evaluated
the
safety
and
effectiveness
of
a
paclitaxel-coated DCB in a large population of subjects with intermittent claudication or rest pain due to obstructive disease of the femoropopliteal artery. One of the core strengths of the IN.PACT Global study ISR imaging cohort analysis was that it combined the rigor of a clinical trial, including independent
adjudication
of
adverse
events
and
independent analysis of angiography and duplex ultrasonography, with a subject population that represented the broad range of clinical variability seen in everyday practice. Results from the ISR imaging cohort analysis showed that the IN.PACT Admiral DCB is highly
IN.PACT Global study enrollment was open to subjects of Rutherford clinical categories 2 to 4. Due to protocol violations, 2 subjects classified as category 5 were enrolled and included in the analysis. This graph shows the distribution of subjects among Rutherford clinical categories at baseline and 12 months after index treatment. The change in
effective up to 12 months after treatment in real-
distribution among categories was statistically significant (p < 0.001). ISR ¼ in-stent
world subjects with long de novo ISR (mean lesion
restenosis.
length 17.17 10.47 cm) in the full length of the SFA
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T A B L E 3 12-Month Safety Outcomes* for Subjects in the
IN.PACT Global Study ISR Imaging Cohort (N ¼ 124)†‡
Clinically driven TLR§
9 (7.3)
Primary safety endpoint¶
(mean length range 8.2 to 13.2 cm), except for in the PACUBA trial of a paclitaxel DCB where mean lesion length was 17.3 cm (Table 4) (10,15,21,23). The 12-month primary patency and freedom from
115 (92.7)
Major adverse events#
11 (8.9)
CD TLR in the ISR imaging cohort was higher than
Death (all-cause)
0 (0.0)
what has been reported for other endovascular
Major target limb amputation
0 (0.0)
modalities evaluated for de novo ISR (Table 5)
Thrombosis
1 (0.8)
(9,12–14,24–30), but direct comparisons cannot be
Any TLR
10 (8.1)
made because the ISR imagining cohort analysis was a
Any TVR
12 (9.7)
Values are n (%). *An independent Clinical Events Committee adjudicated all major adverse events. †Event rates expressed as a proportion: number of subjects with an event ¼ numerator, number of subjects with at least 330 days of clinical followup ¼ denominator. ‡Six subjects did not complete the study through the follow-up period. §Clinically driven target lesion revascularization (TLR) defined as any reintervention within the target lesion(s) due to symptoms or drop of anklebrachial index of $20% or >0.15 when compared with post–index procedure baseline ankle-brachial index. ¶The primary safety composite endpoint was freedom from device- and procedure-related mortality through 30 days, and freedom from major target limb amputation and TLR within 12 months post-index procedure. #Major adverse event defined as all-cause mortality, clinically driven target vessel revascularization, major target limb amputation, thrombosis at the target lesion site. ISR ¼ in-stent restenosis; TVR ¼ target vessel revascularization.
single-arm study that did not include an active comparator group. Treatment with the IN.PACT Admiral DCB had a sustained midterm clinical impact in the ISR imaging cohort analysis. Before the index procedure, all subjects were classified as Rutherford category 2 or higher. Twelve months after the index procedure with DCB treatment, 77% of subjects were Rutherford clinical category 0 to 1. The difference in distribution of subjects among Rutherford clinical categories between baseline and 12 months was statistically significant. Other functional outcome measures, such as change in ABI or WIQ, were also significantly improved at 12
or popliteal artery. Primary patency at 12 months by
months after intervention with the IN.PACT Admiral.
Kaplan-Meier estimate was high (88.7%) and consis-
Paclitaxel-coated DCBs were safe for the treatment
tent with the 12-month freedom from CD TLR by
of subjects in the ISR imaging cohort. There were no
Kaplan-Meir estimate (92.9%). These findings are
deaths and no major target limb amputations. The
similar to what has been reported for the use of
12-month incidence of thrombosis was low (0.8%),
paclitaxel-coated DCBs in the SFA or popliteal artery,
similar to what has been reported for DCBs in short
though in de novo ISR lesions of shorter mean length
lesions (18,19).
T A B L E 4 12-Month Effectiveness Findings From Clinical Studies Evaluating DCBs for De Novo ISR the Femoropopliteal Artery
Effectiveness at 12 Months Trial (Ref. #)
Study Design
Treatment Arms
Lesion Length (cm)*
Primary Patency†
Freedom From CD-TLR†
IN.PACT Global study de novo ISR imaging cohort
Multicenter Prospective Single arm Adjudicated
DCB‡ (n ¼ 131)
17.17 10.47
88.7%
92.9%
FAIR (10)
Multicenter Randomized Nonblinded Controlled
DCB‡ (n ¼ 62) PBA (n ¼ 57)
8.22 6.84
NR
90.8%
DEBATE-ISR (21)
Single site Prospective All-comers registry
DCB‡ (n ¼ 44) Historical PBA control group (n ¼ 42)
13.2 8.6§
NR
86%
Mercogliano registry (23)
Single site Prospective All-comers registry
DCB‡ (n ¼ 39)
8.29 7.89
92.1%
92.1%
PACUBA trial (15)
Dual center Prospective Randomized Controlled
DCB‡ (n ¼ 35) PBA (n ¼ 39)
17.3 11.3§
40.7%
49.0%
Values are mean SD or %. *Mean lesion length of total subject population unless otherwise specified. †By Kaplan-Meier estimate. ‡IN.PACT Admiral (Medtronic, Dublin, Ireland) used in the IN.PACT Global study, FAIR (Femoral Artery In-stent Restenosis), and DEBATE-ISR trials. IN.PACT (class unspecified) used in the Mercogliano Registry. FREEWAY 035 paclitaxel drug-coated balloon (DCB) (Eurocor GmbH, Bonn, Germany) used in the PACUBA trial. §Mean lesion length of DCB group only. DEBATE ISR ¼ Drug-Eluting Balloon in Peripheral Intervention for In-Stent Restenosis; ISR ¼ in-stent restenosis; NR ¼ not reported; PACUBA ¼ Paclitaxel Balloon Versus Standard Balloon in In-stent Restenoses of the Superficial Femoral Artery; PBA ¼ plain uncoated balloon angioplasty; TLR ¼ target lesion revascularization.
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T A B L E 5 Effectiveness Findings From Clinical Studies Evaluating Treatment Options Other Than DCBs for De Novo ISR in the
Femoropopliteal Artery Effectiveness
Trial (Ref. #)
Lesion Length (cm)*
Primary Patency†
Freedom From TLR†
Rate of Restenosis†
Study Design
Active intervention
Multicenter Prospective Single arm
Zilver-PTX DES (n ¼ 108)
13.3 9.2
78.8%
81.0%
NR
Multicenter Prospective Randomized PBA controlled
Vascular stent graft (n ¼ 39)
17.3 7.8§
74.8%
NR
NR
Single center Prospective Randomized PBA controlled
Cutting balloon angioplasty (n ¼ 17)
8.0 6.8
NR
NR
65%‡
Single center Prospective Single arm
PBA þ brachytherapy (n ¼ 90)
24.6
79.8%
NR
NR
EXCITE ISR trial (14)
Multicenter Prospective Randomized PBA controlled
Excimer laser atherectomy þ PBA (n ¼ 169)
19.6 12.0§
NR
73.5%‡
NR
PATENT registry (26)
Multicenter Prospective Registry
Excimer laser atherectomy þ PBA (n ¼ 90)
12.3 9.6
37.8%
64.4%
NR
JETSTREAM-ISR trial (27)
Multicenter Prospective Registry
Rotational and aspiration atherectomy þ PBA (n ¼ 29)
19.5 12.9
72%‡
NR
NR
Rotarex study (28)
Single center Prospective Single arm
Rotational thrombectomy þ PBA (n ¼ 32)
16.0
58.1%
NR
NR
Silver Hawk registry (29)
Single center Prospective Registry
Directional atherectomy (n ¼ 43 ISR lesions) þ PBA (n ¼ 28 of 43)
13.1 11.1
54%
NR
NR
Silver Hawk single-arm trial (30)
Single center Prospective Single arm
Directional atherectomy (n ¼ 33)
10.8 10.2
25%
NR
NR
Multicenter Prospective Registry
Excimer laser atherectomy þ vascular stent graft (n ¼ 27)
20.7 10.3
48%
NR
NR
Drug-eluting stents Zilver-PTX single-arm ISR subgroup (9) Vascular stent grafts RELINE trial (24)
Cutting balloon angioplasty Vienna General Hospital trial (12)
Brachytherapy Rhenium-188 (25)
Debulking procedures
Combination procedures SALVAGE registry (13)
Values are mean SD or %. *Mean lesion length of total subject population unless otherwise specified. †All effectiveness findings for 12 months unless otherwise specified. ‡Six months after index treatment. §Mean lesion length of active intervention group only. EXCITE ISR ¼ EXCImer Laser Randomized Controlled Study for Treatment of FemoropopliTEal In-Stent Restenosis; JETSTREAM ISR ¼ JetStream (JS) Atherectomy in Femoropopliteal In-Stent Restenotic Lesions; PATENT ¼ Photoablation using the turbo-booster and excimer laser for in-stent restenosis treatment; RELINE ¼ GORE VIABAHN Versus Plain Old Balloon Angioplasty (POBA) for Superficial Femoral Artery (SFA) In-Stent Restenosis; SALVAGE ¼ Excimer laser with adjunctive balloon angioplasty and heparin-coated self-expanding stent grafts for the treatment of femoropopliteal artery in-stent restenosis; other abbreviations as in Table 4.
The IN.PACT Global study ISR imaging cohort
unilateral or bilateral disease; any lesion 2 cm or
analysis is unique in that it combined the all-comer
longer), the ISR imaging cohort results are generaliz-
approach of an observational registry with the
able to patients that are encountered in clinical
rigor of a clinical trial, including the independent
practice. The combination of these design strengths
adjudication of adverse events by a Clinical Events
serve to bolster the findings of DCB safety and
Committee and the independent analysis of angiog-
effectiveness in the ISR imaging cohort, which is the
raphy and DUS by core laboratories. By evaluating a
largest group of subjects with de novo ISR in the SFA
heterogeneous population (single or multiple lesions;
or popliteal artery that has been evaluated to date.
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STUDY
LIMITATIONS. The
IN.PACT Global study
ISR imaging cohort analysis was a single-arm, nonrandomized study. The study did not include a control group or an active comparator, and the results of the ISR imaging cohort analysis cannot support the superiority of one modality versus another.
CONCLUSIONS
PERSPECTIVES WHAT IS KNOWN? Endovascular intervention is an accepted method for the treatment of patients with symptomatic PAD, but complex lesions such as de novo ISR can be especially difficult to manage and are often associated with high rates of restenosis and reintervention.
The IN.PACT Admiral DCB was safe and highly effective up to 12 months after treatment in a rigorous
WHAT IS NEW? Patients with complex femoropo-
independently adjudicated analysis of subjects with
pliteal lesions, such as de novo ISR, should be made
de novo ISR (mean lesion length 17.17 10.47 cm) in
aware that the use of DCBs may have the potential to
the full native SFA and/or full popliteal artery.
improve the outcomes of an angioplasty procedure.
ACKNOWLEDGMENTS The authors thank Despina
Voulgaraki, PhD, Eric Fernandez, MD, and Azah Tabah, PhD, for technical review of the manuscript, and Paula Soto, PhD, and Zachary Harrelson, PhD, of Meridius Health Communications Inc. (San Diego, California) for providing medical writing support, which was funded by Medtronic Inc. (Minneapolis, Minnesota) in accordance with Good Publication Practice guidelines (http://www.ismpp.org/gpp3). ADDRESS FOR CORRESPONDENCE: Dr. Marianne
Brodmann, Department of Internal Medicine, Division of Angiology, Medical University, Auenbruggerplatz 15, A-8036 Graz, Austria. E-mail: marianne.brodmann@
The 12-month results of the ISR imaging cohort analysis demonstrate the safety and effectiveness of treatment with paclitaxel-coated IN.PACT Admiral DCB in patients with de novo ISR in the full native SFA or full popliteal artery, a traditionally difficult-to-treat patient population. WHAT IS NEXT? Although 12-month primary patency and freedom from CD TLR is higher in the ISR imaging cohort compared with what has been reported for other treatment modalities, future investigations should focus on head-to-head comparisons of DCBs with alternative approaches such as DES, atherectomy, and surgical reconstruction.
medunigraz.at.
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KEY WORDS drug-coated balloon, femoropopliteal artery, in-stent restenosis, paclitaxel, peripheral artery disease A PP END IX For an expanded Methods section and supplemental table, please see the online version of this article.
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