Author + information
- Received December 8, 2016
- Revision received April 20, 2017
- Accepted June 13, 2017
- Published online October 16, 2017.
- Marianne Brodmann, MDa,∗ (, )
- Koen Keirse, MDb,
- Dierk Scheinert, MDc,
- Lubomir Spak, MD, MPHd,
- Michael R. Jaff, DOe,f,
- Randy Schmahl, MSCg,
- Pei Li, PhDh,
- Thomas Zeller, MDi,
- on behalf of the IN.PACT Global Study Investigators
- 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
- ePresident, Newton-Wellesley Hospital, Newton, Massachusetts
- fProfessor of Medicine, Harvard Medical School Boston, Massachusetts
- gMedtronic, Bakken Research Center BV, Maastricht, the Netherlands
- hMedtronic, Minneapolis, Minnesota
- iUniversitäts-Herzzentrum Freiburg-Bad Krozingen, Bad Krozingen, Germany
- ↵∗Address for correspondence:
Dr. Marianne Brodmann, Department of Internal Medicine, Division of Angiology, Medical University, Auenbruggerplatz 15, A-8036 Graz, Austria.
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.
Endovascular interventions, including percutaneous transluminal angioplasty with a traditional uncoated balloon, implantation of bare-metal or drug-eluting stents (DES), angioplasty with a drug-coated balloon (DCB), and debulking with mechanical or laser atherectomy, have become the primary mode of revascularization in patients with symptomatic peripheral artery disease (PAD). Balloon angioplasty of the femoropopliteal segment is associated with a high incidence of restenosis, with the best results seen for very focal stenosis and noncomplex lesions (1). Stents yield better outcomes when compared with conventional angioplasty alone (2–5), but are associated with the risk of post-procedural in-stent restenosis (ISR) and other stent-related complications that can negatively affect the patient’s long-term clinical outlook (6,7). Treatment of ISR with conventional methods remains a clinical challenge (8), with no clear frontline strategy.
Technical improvements with DESs, DCBs, cutting balloons, and directional and laser atherectomy have been aimed at reducing the occurrence of ISR (9–15). DCBs and DESs deposit a long lasting antiproliferative therapeutic on the inner wall of the artery that supports the sustained inhibition of restenosis, but DCBs have the additional advantage of treating the lesion without leaving a permanent device at the target site (16). The safety and effectiveness of DCBs for the treatment of symptomatic PAD patients has been demonstrated in randomized controlled clinical trials (17–20). Although few, studies have reported positive outcomes with DCBs for the treatment of complex PAD lesions, including those that are formed by de novo ISR (10,15,21,22).
The IN.PACT Global Study was designed to evaluate the safety and effectiveness of a paclitaxel-coated DCB (IN.PACT Admiral, Medtronic, Dublin, Ireland) in the treatment of subjects with atherosclerotic femoropopliteal disease, including de novo ISR in the superficial femoral artery (SFA) or the entire length of the popliteal artery. Herein we report 12-month results from the ISR cohort.
IN.PACT global study: Design, subjects, and treatment
A prospective analysis of DCBs for the treatment of de novo ISR was incorporated into the design of the IN.PACT Global study, a prospective, multicenter, international, single-arm clinical trial assessing the safety and effectiveness of a paclitaxel-coated DCB for the treatment of patients with intermittent claudication or rest pain due to obstructive disease of the femoropopliteal artery, including the full native SFA and/or full popliteal artery (P1 to P3 segments).
Greater than 1,400 patients who satisfied the inclusion or exclusion criteria for the IN.PACT Global study were consecutively enrolled at participating centers into the clinical cohort (Figure 1). Patients enrolled at sited qualified by the VasCore Duplex Core Lab (Boston, Massachusetts) were screened to meet 1 or more of the imaging criteria based on an algorithm. The hierarchy for the imaging cohort subgroup assignment was as follows: 1) de novo ISR; 2) long lesions ≥15 cm; and 3) chronic total occlusions ≥5 cm. Enrollment in the respective imaging cohorts was only open to subjects that had a de novo ISR, long lesion, or chronic total occlusion at pre-procedure baseline. The only subjects who were included in the respective imaging cohort analyses, however, were those who had the primary target lesions that met the criteria of the respective cohort during the index procedure (i.e., no other types of lesions could have been treated during the index procedure).
Subjects with symptoms of intermittent claudication or ischemic rest pain (Rutherford clinical category 2 to 4) and angiographic evidence of occlusion or stenosis (length ≥2 cm) in the SFA or popliteal artery (including P1 to P3 segments) were eligible for enrollment in the IN.PACT Global study. Subjects with multiple lesions were allowed. Subjects with tissue loss were excluded.
Independent core laboratories analyzed all images, including duplex ultrasonography (DUS) (VasCore, Massachusetts General Hospital, Boston, Massachusetts) and angiography (SynvaCor Angiographic Core Lab, Springfield, Illinois). In cases where both angiography and duplex ultrasonography were available at the same assessment, then angiography was preferentially used. An independent Clinical Events Committee (Syntactx Clinical Events Committee, New York, New York) was established to assess the primary and select secondary endpoints and to determine whether each met protocol-specified criteria. The Clinical Events Committee was composed of interventional and noninterventional clinicians with pertinent expertise who were not participants in the study and did not have any conflicts of interest.
The study protocol was approved by the institutional review board or ethics committee at each trial site. Informed consent was obtained from all subjects before enrollment. The trial was conducted in accordance with the Declaration of Helsinki, good clinical practice guidelines, and applicable laws as specified by all relevant governmental bodies. The trial is registered with the U.S. National Institutes of Health as NCT01609296.
De novo ISR imaging cohort study endpoints
The primary safety composite endpoint was freedom from device- and procedure-related mortality through 30 days, and freedom from major target limb amputation and target lesion revascularization (TLR) within 12 months post-index procedure. For the primary safety composite endpoint, TLR was assessed at the subject level and defined as the first event that required TLR in the subject. The Clinical Events Committee reviewed all TLR and target vessel revascularization (TVR) events to determine which were clinically driven (CD), defined as any reintervention within the target lesion(s) due to symptoms or ankle-brachial index (ABI) decrease of ≥20% or >0.15 when compared with post–index procedure baseline ABI. The primary effectiveness endpoint was 12-month primary patency, defined as freedom from CD TLR and freedom from restenosis (DUS peak systolic velocity ratio ≤2.4). Secondary endpoints included the incidence of major adverse events (all-cause mortality, CD TVR, major target limb amputation, thrombosis at the target lesion site), CD TLR, any TLR, and any TVR at 12 months. Other secondary endpoints included change in Rutherford clinical category, change in ABI, and level of walking impairment as assessed by the Walking Impairment Questionnaire (WIQ) at 12 months.
For definitions of acute periprocedural outcomes or categories of stent coverage, see the Online Appendix.
De novo ISR imaging cohort statistical analysis
All analyses were based on the intention-to-treat principle and all summaries were based on subjects or lesions with evaluable data. Subjects or lesions with missing data were excluded from the analyses. Unless otherwise specified, all baseline demographics and clinical 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 were described as counts and proportions. The Kaplan-Meier method was used to evaluate time-to-event data for primary patency and CD TLR over the 12-month follow-up period. The outcome analysis 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 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).
Baseline subject and lesion characteristics
The IN.PACT Global Study enrolled 1535 subjects across 64 sites in more than 25 countries from Europe, the Middle East, Asia, Australia, Canada, and Latin America. Subjects with at least 1 de novo ISR were prospectively enrolled in the ISR imaging cohort (n = 166). Analysis was limited to subjects in which de novo ISR lesions were the only targets treated during the index procedure (n = 131). Due to protocol violations, 2 subjects classified as Rutherford category 5 were enrolled and included in the analysis.
In this study, site-reported data were independently evaluated and adjudicated by an imaging core laboratory. Differences in technique between site-reported and core laboratory evaluated data resulted in a disparate number of target lesions. Per site assessment, there were 149 target lesions among 131 subjects. Per core lab evaluation, there were 144 target lesions among 131 subjects. For this analysis of ISR lesions, lesions characteristics per the core lab are based on a total of 144 lesions.
Baseline demographics and characteristics of the ISR imaging cohort are reported in Tables 1 and 2⇓⇓. Six subjects did not complete the study through the 13-month follow-up window: 4 withdrew consent and 2 were lost to follow-up. Several subjects had lesions in both limbs (n = 3 of 131, 2.3%). Mean lesion length was 17.17 ± 10.47 cm (range 2.5 to 50.0 cm). Thirty-four percent (n = 48 of 141) were total occlusions and 8.3% (n = 11 of 132) were severely calcified.
Acute periprocedural success was 98.5% or higher by all measures. Device success was achieved with 99.6% (n = 282 of 283) of devices used. Procedural success was achieved in 99.3% (n = 148 of 149) of lesions and clinical success was achieved in 98.5% (n = 129 of 131) of subjects. Provisional stents were implanted in 13.4% (n = 20 of 149) of lesions. For additional procedural details, see Online Table 1.
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 = 0.0132).
At baseline, 9.2% (n = 12 of 130) of subjects in the overall ISR imagining cohort were Rutherford category 4 to 5 and 90.8% (n = 118 of 130) were category 2 to 3 (Figure 4). At 12 months, 3.3% (n = 4 of 120) of subjects were category 4 to 5, 20.0% (n = 24 of 120) were category 2 to 3, and 76.7% (n = 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 = 9 of 12) showed improvements by 1 or more category, 8.3% (n = 1 of 12) showed no change, and 8.3% (n = 1 of 12) showed worsening outcome. One subject did not have 12-month data available.
Mean ABI was 0.667 ± 0.187 mm Hg at baseline (n = 124 target limbs) and 0.909 ± 0.193 mm Hg (n = 112 target limbs) at 12 months. Mean change in ABI from baseline was 0.241 ± 0.246 mm Hg (n = 104 target limbs; p < 0.001). The mean WIQ score was 36.8 ± 25.5% (n = 125) at baseline and 76.7 ± 30.9% (n = 116) at 12 months. Mean change in WIQ score from baseline was 40.7 ± 35.9% (n = 113, p < 0.001).
The 12-month primary safety composite endpoint was achieved in 92.7% (n = 115 of 124) of subjects (Table 3). There were no acute adverse events. The cumulative major adverse event rate at 30 days was 0.0%. Major adverse events were reported in 8.9% (n = 11 of 124) of subjects at 12 months. There was 1 case of thrombosis at the target lesion (0.8%, n = 1 of 124) at 12 months. There were no deaths (all cause) and no major target limb amputations.
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 effective up to 12 months after treatment in real-world subjects with long de novo ISR (mean lesion length 17.17 ± 10.47 cm) in the full length of the SFA or popliteal artery. Primary patency at 12 months by Kaplan-Meier estimate was high (88.7%) and consistent with the 12-month freedom from CD TLR by Kaplan-Meir estimate (92.9%). These findings are similar to what has been reported for the use of paclitaxel-coated DCBs in the SFA or popliteal artery, though in de novo ISR lesions of shorter mean length (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 CD TLR in the ISR imaging cohort was higher than what has been reported for other endovascular modalities evaluated for de novo ISR (Table 5) (9,12–14,24–30), but direct comparisons cannot be made because the ISR imagining cohort analysis was a 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 months after intervention with the IN.PACT Admiral.
Paclitaxel-coated DCBs were safe for the treatment of subjects in the ISR imaging cohort. There were no deaths and no major target limb amputations. The 12-month incidence of thrombosis was low (0.8%), similar to what has been reported for DCBs in short lesions (18,19).
The IN.PACT Global study ISR imaging cohort analysis is unique in that it combined the all-comer approach of an observational registry with the rigor of a clinical trial, including the independent adjudication of adverse events by a Clinical Events Committee and the independent analysis of angiography and DUS by core laboratories. By evaluating a heterogeneous population (single or multiple lesions; unilateral or bilateral disease; any lesion 2 cm or longer), the ISR imaging cohort results are generalizable to patients that are encountered in clinical practice. The combination of these design strengths serve to bolster the findings of DCB safety and effectiveness in the ISR imaging cohort, which is the largest group of subjects with de novo ISR in the SFA or popliteal artery that has been evaluated to date.
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.
The IN.PACT Admiral DCB was safe and highly effective up to 12 months after treatment in a rigorous independently adjudicated analysis of subjects with de novo ISR (mean lesion length 17.17 ± 10.47 cm) in the full native SFA and/or full popliteal artery.
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.
WHAT IS NEW? Patients with complex femoropopliteal lesions, such as de novo ISR, should be made aware that the use of DCBs may have the potential to improve the outcomes of an angioplasty procedure. 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.
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).
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 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.
- Abbreviations and Acronyms
- ankle-brachial index
- clinically driven
- drug-coated balloon
- drug-eluting stent(s)
- duplex ultrasonography
- in-stent restenosis
- peripheral artery disease
- superficial femoral artery
- target lesion revascularization
- target vessel revascularization
- Walking Impairment Questionnaire
- Received December 8, 2016.
- Revision received April 20, 2017.
- Accepted June 13, 2017.
- 2017 The Authors
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