Scholarly article on topic 'Lower Extremity Revascularization Using Directional Atherectomy'

Lower Extremity Revascularization Using Directional Atherectomy Academic research paper on "Clinical medicine"

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{angioplasty / atherectomy / claudication / "critical limb ischemia" / "peripheral artery disease"}

Abstract of research paper on Clinical medicine, author of scientific article — James F. McKinsey, Thomas Zeller, Krishna J. Rocha-Singh, Michael R. Jaff, Lawrence A. Garcia

Abstract Objectives The aim of this study was to assess the safety and effectiveness of directional atherectomy (DA) for endovascular treatment of peripheral arterial disease (PAD) in infrainguinal arteries in patients with claudication or critical limb ischemia. Background To date, no prospective, multicenter, independently-adjudicated study has evaluated the effectiveness and durability of DA in the treatment of PAD. Previous DA studies have not been prospectively powered to evaluate any differences in outcomes in patients with and without diabetes. Methods DEFINITIVE LE ( D etermination of EF fectiveness of the SilverHawk® Per I pheral Plaque Excisio N System (S I lverHawk Device) for the T reatment of I nfrainguinal VE ssels / L ower E xtremities) prospectively enrolled subjects at 47 multinational centers with an infrainguinal lesion length up to 20 cm. Primary endpoints were defined as primary patency at 12 months for claudicants and freedom from major unplanned amputation for critical limb ischemia (CLI) subjects. A pre-specified statistical hypothesis evaluated noninferiority of primary patency in diabetic versus nondiabetic claudicants. Independent angiographic and sonographic core laboratories assessed outcomes, and events were adjudicated by a clinical events committee. Results A total of 800 subjects were enrolled. The 12-month primary patency was 78% (95% confidence interval: 74.0% to 80.6%) in claudicants, with a 77% rate in the diabetic subgroup versus 78% in the nondiabetic subgroup (noninferior, p < 0.001). The rate of freedom from major unplanned amputation of the target limb at 12 months in CLI subjects was 95% (95% confidence interval: 90.7% to 97.4%). Periprocedural adverse events included embolization (3.8%), perforation (5.3%), and abrupt closure (2.0%). The bail-out stent rate was 3.2%. Conclusions The DEFINITIVE LE study demonstrated that DA is a safe and effective treatment modality at 12 months for a diverse patient population with either claudication or CLI. Furthermore, DA was shown to be noninferior for treating PAD in patients with diabetes compared with those without diabetes. (Study of SilverHawk/TurboHawk in Lower Extremity Vessels [DEFINITIVE LE]; NCT00883246).

Academic research paper on topic "Lower Extremity Revascularization Using Directional Atherectomy"

© 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER INC.

VOL. 7, NO. 8, 2014 ISSN 1936-8798/$36.00 http://dx.doi. org/10.1016/j. j c i n . 2014. 05. 006

Lower Extremity Revascularization Using Directional Atherectomy

12-Month Prospective Results of the DEFINITIVE LE Study

James F. McKinsey, MD,* Thomas Zeller, MD,y Krishna J. Rocha-Singh, MD,Z Michael R. Jaff, DO,§ Lawrence A. Garcia, MD,|| on behalf of the DEFINITIVE LE Investigators

ABSTRACT

OBJECTIVES The aim of this study was to assess the safety and effectiveness of directional atherectomy (DA) for endovascular treatment of peripheral arterial disease (PAD) in infrainguinal arteries in patients with claudication or critical limb ischemia.

BACKGROUND To date, no prospective, multicenter, independently-adjudicated study has evaluated the effectiveness and durability of DA in the treatment of PAD. Previous DA studies have not been prospectively powered to evaluate any differences in outcomes in patients with and without diabetes.

METHODS DEFINITIVE LE (Determination of Effectiveness of the SilverHawk® Peripheral Plaque ExcisioN System (Silver-Hawk Device) for the Treatment of Infrainguinal VEssels/Lower Extremities) prospectively enrolled subjects at 47 multinational centers with an infrainguinal lesion length up to 20 cm. Primary endpoints were defined as primary patency at 12 months for claudicants and freedom from major unplanned amputation for critical limb ischemia (CLI) subjects. A pre-specified statistical hypothesis evaluated noninferiority of primary patency in diabetic versus nondiabetic claudicants. Independent angiographic and sonographic core laboratories assessed outcomes, and events were adjudicated by a clinical events committee.

RESULTS A total of 800 subjects were enrolled. The 12-month primary patency was 78% (95% confidence interval: 74.0% to 80.6%) in claudicants, with a 77% rate in the diabetic subgroup versus 78% in the nondiabetic subgroup (noninferior, p < 0.001). The rate of freedom from major unplanned amputation of the target limb at 12 months in CLI subjects was 95% (95% confidence interval: 90.7% to 97.4%). Periprocedural adverse events included embolization (3.8%), perforation (5.3%), and abrupt closure (2.0%). The bail-out stent rate was 3.2%.

CONCLUSIONS The DEFINITIVE LE study demonstrated that DA is a safe and effective treatment modality at 12 months for a diverse patient population with either claudication or CLI. Furthermore, DA was shown to be noninferior for treating PAD in patients with diabetes compared with those without diabetes. (Study of SilverHawk/TurboHawk in Lower Extremity Vessels [DEFINITIVE LE]; NCT00883246). (J Am Coll Cardiol Intv 2014;7:923-33) © 2014 by the American College of Cardiology Foundation.

From the *Division of Vascular Surgery, New York Presbyterian Hospital, University Hospital of Columbia and Cornell, New York, New York; fUniversitats-Herzzentrum Freiburg-Bad Krozingen, Bad Krozingen, Germany; ^Prairie Heart Institute at St. John's Hospital, Springfield, Illinois; gInstitute for Heart, Vascular, and Stroke Care, Massachusetts General Hospital, Boston, Massachusetts; and the ^Sections of Interventional Cardiology and Vascular Medicine, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts. This study was funded by ev3/Covidien. Dr. McKinsey has received consulting fees/ speaker honoraria from ev3/Covidien and Bayer; has received educational grants from ev3/Covidien, Bayer, Boston Scientific, and Medtronic; and is a conational principal investigator for Atheromed. Dr. Zeller has received consulting fees/honoraria from Sanofi-Aventis, C.R. Bard, Johnson & Johnson Cordis, ev3/Covidien, Boston Scientific, Straub Medical, Invatec, Biotronik, Pathway Medical, W.L. Gore, and IDEV; is on the Advisory Boards of Medtronic-Invatec, W.L. Gore, Angioslide, Medtronic-Ardian, and ev3/ Covidien; and has received research grants from Cook, Krauth Medical, Pathway Medical, Abbott Vascular, Johnson & Johnson Cordis, Angioslide, Ardian, Biotronik, Invatec, InnoRa, W.L. Gore, Veryan, ev3/Covidien, Medtronic-Ardian, Medtronic-Invatec, and 480 Biomedical. Dr. Rocha-Singh is a paid consultant for ev3/Covidien and Cardiovascular Systems, Inc.; and is a board member of VIVA Physicians, a 501c3 not-for-profit education and research organization. Dr. Jaff is an advisor to Cardinal Health and a noncompensated advisor for ev3/Covidien, Abbott Vascular, Cordis Corporation, Boston Scientific and Medtronic Vascular; is an equity shareholder in PQ Bypass; and is a board member of VIVA Physicians. Dr. Garcia is a paid consultant for ev3/Covidien

AUGUST 2014:923 - 33

ABBREVIATIONS AND ACRONYMS

ABI = ankle-brachial index

CEC = clinical events committee

CI = confidence interval

CLI = critical limb ischemia

CTO = chronic total occlusion

DA = directional atherectomy

DCB = drug-coated balloon

DEP = distal embolic protection

FDA = U.S. Food and Drug Administration

PAD = peripheral arterial disease

PSVR = peak systolic velocity ratio

PTA = percutaneous transluminal angioplasty

RC = Rutherford classification

SFA = superficial femoral artery

he incidence of peripheral arterial disease (PAD) is continuing to grow worldwide, resulting in increasing requirements for treatment and increasing healthcare costs (1,2). In 2010, 202 million people were living with PAD globally, an estimated 23.5% increase over the previous decade (1). In 2001, the estimated cost of PAD in the United States was $4.37 billion (3). Diabetes mellitus, the most prevalent risk factor for PAD, currently affects 371

SEE PAGE 934

million people worldwide, and the incidence is predicted to reach 552 million by2030 (4,5). PAD now affects 1 in 3 patients with diabetes (6). Diabetic patients with PAD remain a challenge to treat. Previous studies have shown a decrease in primary and secondary patency following surgical bypass and endovascular interventions in patients with diabetes compared with those without diabetes (7-10). Results of treatment with directional atherectomy (DA), a modality designed to precisely remove the obstructing arterial atheroma, have been reported in multiple single-center and retrospective studies (11-18). Patency rates at 12 months varied widely from 54% to 84% depending on patient and lesion characteristics, including recurrent stenosis, method of follow-up, study definitions, and use of a core laboratory for independent evaluation. Previous PAD studies have shown a 10% to 15% decrease in the patency rate when independently adjudicated by a core laboratory compared with investigator-reported patencies (19). DEFINITIVE LE (Determination of Effectiveness of the SilverHawk® Peripheral Plaque ExcisioN System (SilverHawk Device) for the Treatment of infrainguinal VEssels / Lower Extremities) was a prospective study with core laboratory-adjudicated data gathered in patients with claudication and CLI and with lesions up to 20 cm.

METHODS

DEFINITIVE LE was a prospective, multinational, single-arm study designed to evaluate the acute and 12-month safety and effectiveness of DA for endo-vascular treatment of 800 subjects with PAD. In the DEFINITIVE LE study, there were no anatomic

restrictions as to location of disease or the number of inflow or outflow lesions in subjects with claudication or critical limb ischemia (CLI). The study was conducted in accordance with Good Clinical Practices and applicable laws of all relevant governing bodies. Each site's institutional review board/ethics committee reviewed and approved the study protocol. Before enrollment, signed informed consent was required for all subjects. A clinical events committee (CEC) composed of independent physicians adjudicated adverse events. Independent core laboratories conducted analyses of and adjudicated angiographic images (SynvaCor, Springfield, Illinois) and duplex ultrasound images (VasCore, Massachusetts General Hospital, Boston, Massachusetts). Regular monitoring visits were conducted at all investigational sites.

The primary endpoint for subjects with claudication (Rutherford classification [RC] of 1 to 3) was primary patency at 12 months defined in the protocol as duplex ultrasonography measurement of the peak systolic velocity ratio (PSVR) #3.5 at the target le-sion(s) with no clinically-driven reintervention within the target segment. The primary endpoint of a PSVR #3.5 was defined at the creation of the study and must be reported. The secondary endpoint for primary patency was defined as a PSVR #2.4, which has since been clinically established as the more appropriate value to detect restenosis. Therefore, a PSVR #2.4 was used as the indicator of all other patency rates reported in this paper. Clinically-driven revascularization was defined and monitored by the CEC as reintervention due to $50% diameter stenosis in the presence of recurrent symptoms or an asymptomatic $70% stenosis in the treated segment.

A pre-specified hypothesis postulated that DA treatment of claudicants with diabetes would have noninferior primary patency at 12 months compared with subjects without diabetes. Previous single-center data evaluated the effectiveness of DA and revealed a primary patency of 67% at 12 months in subjects with claudication. In this study, diabetic subjects had a 12-month primary patency of 60% and nondiabetic subjects had a 12-month primary patency of 68% (14). In the DEFINITIVE LE study, the sample size required to evaluate the hypothesis of noninferior patency in diabetic versus nondiabetic claudicants with 80% power was statistically derived with a 1-sided alpha of 0.05 and a noninferiority margin of 12%. The postulated rate of primary patency at 1 year as per previous

and iDEV/Abbott. He is a noncompensated consultant for Boston Scientific, AngioSculpt/Spectranetics, and Pathway/Volcano; and is an equity shareholder in Spirox, Primacea, TissueGen, CV Ingenuity, and Scion Cardiovascular.

Manuscript received March 17, 2014; revised manuscript received May 2, 2014, accepted May 8, 2014.

work was 60% in each subgroup, resulting in a minimal sample size of 424 claudicant subjects. The overall study was planned to evaluate both claudicants and subjects with CLI with anticipated enrollment of 600 claudicants and 200 subjects with CLI. This sample size ensured that there would be adequate enrollment for the diabetic versus nondiabetic subset analysis.

The primary endpoint for subjects with CLI (RC 4 to 6) was freedom from major unplanned amputation of the target limb through 12 months. Major amputation was defined as amputation above the metatarsal region that was unanticipated before the index procedure.

Pre-specified secondary endpoints included: 1) device success, defined as #30% residual angio-graphic stenosis after DA without adjunctive interventions; 2) procedural success, defined as #30% angiographic residual stenosis after DA and adjunc-tive interventions; 3) primary patency rate at 12 months, PSVR #2.4; 4) secondary 12-month patency; 5) primary duplex core laboratory-confirmed patency in CLI subjects at 12 months; 6) major adverse event rate at 30 days and 12 months, defined as a composite of clinically-driven target vessel revascularization, major unplanned amputation of the treated limb, or

all-cause mortality; 7) improvement in RC at 12 months; 8) improvement in ankle-brachial index (ABI) at 12 months; 9) amputation-free survival in subjects with claudication (baseline RC of 1 to 3) at 12 months; 10) wound healing at 3, 6, and 12 months in subjects with a baseline RC of 5 to 6; and 11) quality-of-life measurement Walking Impairment Questionnaire at 30 days and 12 months.

Patients with infrainguinal arterial lesions meeting inclusion criteria were enrolled; selection criteria are listed in Table 1. Significant stenoses or occlusions of inflow vessels (iliac or common femoral artery) required successful revascularization before enrollment. Multiple target lesions up to 20 cm regardless of location (above the knee, involving the popliteal, or below the knee) were allowed. A lesion was defined as single if the distance between stenoses was no longer than 3 cm in the superficial femoral artery (SFA) and popliteal segments or 2 cm in the infrapo-pliteal segments. If multiple diseased outflow vessels were present, the treatment of any outflow vessel nontarget lesion was left to the discretion of the operator. However, if only a single outflow vessel was present, then DA was required to treat that outflow.

TABLE 1 Inclusion and Exclusion Criteria

Inclusion criteria Rutherford classification 1-6.

Is willing and capable of complying with all follow-up evaluations 18 years of age of older Provides written informed consent

Has evidence of $50% stenosis or occlusion in the superficial femoral, popliteal, anterior tibial, posterior tibial, and/or peroneal arteries, confirmed by angiography

Has identifiable distal target vessel, which upon completion of the intervention, is anticipated to provide reconstitution of blood flow to the foot Exchangeable guidewire must cross lesion(s) with catheter able to cross lesion Each discrete target lesion's length is #20 cm Reference vessel diameter is 1.5-7 mm Exclusion criteria

Has $1 of the contraindications listed in the SilverHawk instructions for use

Has a contraindication to antiplatelet therapy, anticoagulants, thrombolytic drugs, or any other drug anticipated to be used Has a hypersensitivity to contrast material that cannot be adequately pre-treated Has known hypersensitivity to treatment device material

Has known uncontrollable hypercoagulable condition or refuses blood transfusion Has life expectancy <12 months

Has surgical endovascular procedure of the target vessel within 14 days before the index procedure

Has planned surgical intervention or endovascular procedure within 30 days after the index procedure

Is currently participating in an investigational drug or device study

Has other comorbid condition(s) that precludes safe percutaneous intervention

Has had a previous bypass affecting the target limb

Has end-stage renal disease

Has had a previous amputation above the metatarsal line on the target limb Has severe calcification in target lesion(s) Has in-stent restenosis of the target lesion. Has an aneurysmal target vessel

Has significant stenosis or occlusion of inflow tract that has not been revascularized before treatment of the target vessel

Has perforation, dissection, or other injury of the access or target vessel requiring additional stenting or surgical intervention before enrollment

926 McKinsey et al. JACC: CARDIOVASCULAR INTERVENTIONS VOL. 7, NO. 8, 2014

DEFINITIVE LE Trial: Final Results august 2014:923-33

TABLE 2 Baseline Subject Characteristics

Claudicants (n = 598) CLI (n = 201) All (N = 799) p Value, CLD vs. CLI

Age, yrs 69.5 ± 10.4 (598) 72.1 ± 11.4 (201) 70.1 ± 10.7 (799) 0.002

Female 43.8 (262/598) 50.2 (101/201) 45.4 (363/799) 0.120

Caucasian 71.7 (429/598) 64.7 (130/201) 70.0 (559/799) 0.062

History and risk factors

Diabetes mellitus 46.8 (280/598) 68.7 (138/201) 52.3 (418/799) <0.001

Angina pectoris 22.9 (137/598) 18.4 (37/201) 21.8 (174/799) 0.199

Cardiac arrhythmia 15.6 (93/598) 22.9 (46/201) 17.4 (139/799) 0.023

Congestive heart failure 13.2 (79/598) 17.9 (36/201) 14.4 (115/799) 0.104

Stroke 9.0 (54/598) 11.9 (24/201) 9.8 (78/799) 0.271

Myocardial infarction 18.6 (111/597) 18.9 (38/201) 18.7 (149/798) 0.916

CABG or PCI 39.5 (236/598) 32.3 (65/201) 37.7 (301/799) 0.077

Hypertension 92.0 (550/598) 92.0 (185/201) 92.0 (735/799) 1.000

Hyperlipidemia 86.1 (515/598) 76.1 (153/201) 83.6 (668/799) 0.001

Renal insufficiency 16.7 (100/598) 23.4 (47/201) 18.4 (147/799) 0.045

Nonhealing ischemic ulcers 2.0 (12/598) 56.2 (113/201) 15.6 (125/799) <0.001

Current or former smoker 53.5 (320/598) 35.8 (72/201) 49.1 (392/799) <0.001

Values are mean ± SD (N) or % (n/N). CABG = coronary artery bypass graft; CLD = claudicants; CLI = critical limb ischemia; PCI = percutaneous coronary intervention.

All subjects underwent revascularization of target lesions of the femoropopliteal and/or tibial-peroneal arteries using a DA device. If the DA device could not initially pass through the lesion, pre-dilation was performed to facilitate DA device passage. Angio-graphic films, including run off, were obtained immediately before and after the atherectomy procedure to document pre- and post-treatment results. Adjunctive procedures including percutaneous transluminal angioplasty (PTA) were performed per

physician discretion; however, if residual stenosis was <30%, additional post-dilation was not recommended. Distal protection devices were used at the discretion of the attending physician, as was the type of periprocedural anticoagulation and anti-platelet therapy.

Follow-up assessments and target lesion duplex ultrasound examinations occurred at 30 days, 6 months, and 12 months. Each visit included assessment of RC, Walking Impairment Questionnaire (for

TABLE 3 Baseline Lesion Characteristics

Lesion Characteristics Claudicants (n = 743) CLI (n = 279) All (N = 1,022) p Value, CLD vs. CLI

Target artery

SFA 72.1 (536/743) 48.4 (135/279) 65.7 (671/1,022) <0.001

Popliteal 15.3 (114/743) 17.2 (48/279) 15.9 (162/1,022) 0.501

Infrapopliteal 12.5 (93/743) 34.4 (96/279) 18.5 (189/1,022) <0.001

Lesion length, cm 7.5 ± 5.3 (743) 7.2 ± 5.5 (278) 7.4 ± 5.3 (1,021) 0.381

Longest lesion per subject, cm 8.3 ± 5.4 (598) 8.3 ± 5.7 (201) 8.3 ± 5.5 (799) 0.926

Pre-procedure reference vessel diameter, mm 4.3 ± 1.1 (741) 3.7 ± 1.3 (278) 4.2 ± 1.2 (1,019) <0.001

Pre-procedure minimal lumen diameter, mm 1.2 ± 0.9 (741) 0.9 ± 0.9 (278) 1.1 ± 0.9 (1,019) <0.001

Baseline stenosis 72.7 ± 18.1 (741) 75.9 ± 20.0 (278) 73.6 ± 18.7(1,019) 0.015

Occlusions 17.4 (129/741) 29.9 (83/278) 20.8 (212/1,019) <0.001

Calcification 37.1 (275/742) 37.1 (103/278) 37.1 (378/1,020) 1.000

De novo (site assessed) 93.5 (695/743) 87.1 (243/279) 91.8 (938/1,022) 0.001

Target lesion length, cm

$10.0 28.9 (215/743) 24.8 (69/278) 27.8 (284/1,021) 0.209

5.0-9.9 33.0 (245/743) 32.0 (89/278) 32.7 (334/1,021) 0.822

<5 38.1 (283/743) 43.2 (120/278) 39.5 (403/1,021) 0.150

Values are % (n/N) or mean ± SD (N). SFA = superficial femoral artery; other abbreviations as in Table 2.

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 7, NO. 8, 2014 McKinsey et al. 927

AUGUST 2014:923-33 DEFINITIVE LE Trial: Final Results

TABLE 4 Procedural Characteristics

Claudicants CLI Total p Value, CLD vs. CLI

Procedure time, min 60.0 (43.0-89.0) [596] 77.0 (51.0-100.0) [201] 65.0 (45.0-92.0) [797] <0.001

Contrast administered, ml 140.0 (90.0-210.0) [593] 135.0 (95.0-200.0) [200] 140.0 (90.0-207.0) [793] 0.772

Fluoroscopy time, min: 16.0 (10.0-24.0) [592] 19.0 (13.0-29.0) [194] 16.0 (11.0-25.0) [786] <0.001

Embolic protection 20.6 (598) 27.9 (201) 22.4 (799) 0.039

SpiderFX only 20.2 (598) 27.4 (201) 22.0 (799) 0.038

Device success (core laboratory)* 75.9 (727) 72.1 (269) 74.9 (996) 0.218

Post-device stenosis, %* 23.9 ± 13.1 (727) 25.6 ± 13.8 (269) 24.3 ± 13.3 (996) 0.073

Procedure success (core laboratory)* 91.3 (738) 83.0 (277) 89.1 (1,015) <0.001

Post-adjunctive stenosis, %* 18.0 ± 11.0 (278) 20.9 ± 12.3 (81) 18.6 ± 11.4 (359) 0.045

Values are median (interquartile range) [n], % (n), or mean ± SD (n). *Lesion level characteristics. Abbreviations as in Table 2.

subjects without tissue loss [baseline RC 1 to 4]), EQ-5D questionnaire, ABI, and adverse event evaluations. In addition, subjects with a RC of 5 and 6 at baseline had wound assessments at each follow-up visit, including an additional visit at 3 months. Wounds were classified using the Wagner Classification System. All target lesions were analyzed as identified by the angiographic core laboratory.

All statistical analyses were performed using SAS for Windows version 9.1 or higher (SAS Institute Inc., Cary, North Carolina). Continuous variables presented as mean ± SD were evaluated with t tests, whereas continuous variables presented as median (interquartile range) were evaluated with the Wil-coxon rank sum test for independent samples or Wilcoxon signed rank test for pairwise comparisons.

TABLE 5 Periprocedural Events, Days 0 to 30

Event Type Claudicants (n = 598) CLI (n = 201) All (N = 799) p Value, CLD vs. CLI

Any periprocedural event 10.7 (64) 12.9 (26) 11.3 (90) 0.3703

Requiring treatment 7.7 (46) 7.5 (15) 7.6 (61)

Distal embolization 2.5 (15) 7.5 (15) 3.8 (30) 0.004

Requiring treatment 1.2 (7) 3.0 (6) 1.6 (13)

Surgical intervention 0 (0) 0.5 (1) 0.1 (1)

Stenting 0.2 (1) 0 (0) 0.1 (1)

PTA/lysis/embolectomy/aspiration 1.0 (6) 2.5 (5) 1.4 (11)

Abrupt closure 0.7 (4) 6.0 (12) 2.0 (16) <0.001

Requiring treatment 0.5 (3) 4.5 (9) 1.5 (12)

Surgical intervention 0.5 (3) 2.5 (5) 1.0 (8)

Stenting 0 (0) 0.5 (1) 0.1 (1)

PTA 0 (0) 1.5 (3) 0.4 (3)

Dissection (flow limiting) 2.2 (13) 2.5 (5) 2.3 (18) 0.786

Requiring treatment 1.3 (8) 2.0 (4) 1.5 (12)

Surgical intervention 0 (0) 0 (0) 0 (0)

Stenting 0.7 (4) 2.0 (4) 1.0 (8)

PTA 0.7 (4) 0 (0) 0.5 (4)

Perforation 6.2 (37) 2.5 (5) 5.3 (42) 0.044

Requiring treatment 5.0 (30) 1.5 (3) 4.1 (33)

Surgical intervention 0.2 (1) 0 (0) 0.1 (1)

Stenting 2.3 (14) 0.5 (1) 1.9 (15)

PTA 2.5 (15) 1.0 (2) 2.1 (17)

Aneurysm 0.5 (3) 0 (0) 0.4 (3) 0.576

Requiring treatment 0.3 (2) 0 (0) 0.3 (2)

Surgical intervention 0 (0) 0 (0) 0 (0)

Stenting 0.3 (2) 0 (0) 0.3 (2)

PTA 0 (0) 0 (0) 0 (0)

Values are % (n). PTA = percutaneous transluminal angioplasty; other abbreviations as in Table 2.

AUGUST 2014:923 - 33

FIGURE 2 Patency Outcomes: Diabetic Versus Nondiabetic Claudicants

Kaplan-Meier estimates of patency (peak systolic velocity ratio #2.4) by lesion. CI = confidence interval.

ordinal variables with Mantel-Haenszel chi-square. p values are 2 sided, with values <0.05 deemed statistically significant. No adjustments for multiple comparisons were performed. The primary endpoints are analyzed and presented using Kaplan-Meier time-to-event methods; estimates of incidence were taken at 12 months post-intervention. The study was pro-spectively powered to test the hypothesis that clau-dicants with diabetes would have noninferior primary patency at 12 months compared with nondiabetic claudicants when treated with DA. Noninferiority was tested using Blackwelder's method.

RESULTS

FIGURE 1 Patency Outcomes: Claudicant Cohort

Kaplan-Meier estimates of patency by lesion. The red line represents the primary patency rate defined as a peak systolic velocity ratio (PSVR) #3.5, and the blue line represents primary patency defined as a PSVR #2.4. CI = confidence interval.

For continuous variables collected at multiple time points, change scores from baseline were computed and used for the basis of analysis. Binary categorical variables are evaluated with the Fisher exact test and

From April 2009 to April 2011, 800 subjects at 47 multinational centers were treated with DA using the SilverHawk and/or TurboHawk Atherectomy Devices (Covidien, Plymouth, Minnesota). Mean age was 70.1 ± 10.7 years; 55% were male, and 52.3% had diabetes (Table 2). One subject's data were excluded from all analyses due to an invalid informed consent, yielding a cohort of 799 analyzable subjects.

A total of 1,022 target lesions were treated, the mean longest lesion per patient was 8.3 ± 5.5 cm, 28% had a lesion length >10 cm, and 21% were total occlusions (Table 3). Although the most proximal aspect of target lesions was used to identify lesion location, the lesion could extend up to 20 cm into more distal arterial segments. Because multiple target lesions were allowed per treated limb, each target lesion was classified separately.

The median procedure time (arterial access to catheter removal) was 65.0 min (45.0 to 92.0 min) (Table 4). Predictors of a longer procedure time included CLI, longer target lesions, greater baseline severity of stenosis, number of lesions, distal embolic protection utilization, and arterial calcification. Pre-dilation was performed with small PTA balloons to allow passage of the DA device, so as not to have a therapeutic angioplasty effect on the target lesion. Pre-dilation to allow DA passage was performed in 8.3% of lesions in claudicants and in 15.8% of lesions in CLI subjects; 75% of PTA balloons were #3 mm in diameter, and the mean inflation pressure was 6.5 atm. By multivariate analysis, predictors of need for pre-dilation of the target lesion included calcification, chronic total occlusion (CTO), small MLD, de novo, higher Rutherford Category, age, and diabetes (p # 0.05). Adjunctive therapy after DA treatment was performed in 35.3% (claudicants, 38.0%; CLI, 30.2%). At investigator discretion, 20% of lesions that had <30% residual stenosis after DA (per core laboratory assessment) still underwent adjunctive PTA.

TABLE 6 Primary Patency Rate (PSVR #2.4) in Claudicant Cohort by Lesion Length and Location

Primary Patency (PSVR #2.4) in Claudicant Cohort

Subgroup n Mean Lesion Length, cm 12-Month Patency Rate, %

All 743 7.5 78

SFA 536 8.1 75

<5 cm 183 2.7 79

5-9.9 cm 168 7.0 83

$10 cm 185 14.6 65

Popliteal 114 6.0 77

<5 cm 48 2.5 84

5-9.9 cm 48 6.8 74

$10 cm 18 13.1 65

Infrapoplitea 93 5.5 90

<5 cm 52 2.7 90

5-9.9 cm 29 7.2 88

$10 cm 12 13.4 91

Primary Patency (PSVR #2.4) in CLI Cohort

Subgroup n Mean Lesion Length, cm 12-Month Patency Rate, %

All 279 7.2 71

SFA 135 8.6 68

<5 cm 45 2.6 75

5-9.9 cm 41 7.2 65

$10 cm 48 15.5 63

Popliteal 48 5.4 67

<5 cm 27 3.0 78

5-9.9 cm 16 7.1 50

$10 cm 5 13.5 75

Infrapoplitea 96 6.0 78

<5 cm 48 2.5 79

5-9.9 cm 32 6.9 79

$10 cm 16 14.4 73

PSVR = peak systolic velocity ratio; other abbreviations as in Table 2.

The adjunctive stent rate was 3.2%, including a 1.9% stent rate to treat a perforation.

Device success (defined as #30% residual stenosis in target lesions after DA) was reported as 87% by the investigators. Independent angiographic core laboratory assessment reported a 74.9% (95% confidence interval [CI]: 72.0% to 77.6%) device success. Procedural success (DA plus post-DA adjunctive procedures) was investigator reported in 99% of lesions (claudicants, 100%; CLI, 98%). The angiographic core laboratory assessment revealed 89.1% (95% CI: 86.9% to 90.9%) procedural success (claudicants, 91.3% [95% CI: 89.0% to 93.3%]; CLI, 83.0% [95% CI: 78.0% to 87.3%]). On univariate analysis, predictors of greater procedural success included female gender, SFA lesions, smaller diameter stenosis, absence of calcification, and shorter lesion length.

The most common periprocedural adverse event was arterial perforation at 5.3% (Table 5). Perforations

100 so no

30 20 10

0 1 — PtWwv Pitoirc* - S Months -5«cwiiJaiy Patency - 1 Ltnb i-IVrj. SI

Monde 0 6 9 1!

Piinun At Bisk 279 ; 213 17S 1«

PltMCT Pltcoor CT) 100 (1M 0.1COO) 97(94 1.9S J) 87 (S2 6.90 9) 77(714.82 0) 71 (646.76.3)

S«oodn* At Risk 279 262 240 218 124

Plt*n<? Pitracy CT) 100 ci 00.0.100.0) 100(100 0.10)0) 98(93.6.994) 95 (913. 97.4) 83 (829. 92.1)

I™K At Risk 201 ISO 173 162 100

Sihngc Lint SiKig«(95»»CT) 100 (1W.0.100.0) 97(93.3.98.6) 97(933.986) 96 (92J. 98.3) 95 (90.7.97.4)

FIGURE 3 Endpoint Outcomes: CLI Cohort

Kaplan-Meier estimates of outcomes in the critical limb ischemia (CLI) cohort. CI = confidence interval.

from any source were included, whether from DA, wire passage, or adjunctive therapy. Distal embolization was noted in 30 of 799 (3.8%) subjects as reported by the investigator or angiographic core laboratory, or adjudicated by the CEC. In total, 13 subjects (1.6%) were noted to have distal embolizations and underwent additional intervention during the primary procedure (endovascular therapy in 12 and surgical intervention in 1).

Occluded lesions were present in 127 claudicants and 81 CLI subjects. The rate of periprocedural complications requiring treatment was higher in subjects with occluded lesions: 11.5% (24 of 208) versus 6.3% (37 of 591) (p = 0.022) through 30 days. The most frequent complication was perforation requiring treatment with a rate of 4.8% (10 of 208) in the occlusion subgroup versus 3.9% (23 of 591) (p = 0.548) in the nonoccluded group. The frequency of abrupt closures requiring treatment was 3.8% (8 of 208) in the CTO subgroup compared with 0.7% (4 of 591) (p = 0.003) in the non-CTO subgroup.

A total of 22.4% of subjects had procedures performed with distal embolic protection (DEP) via a filter device (98.3% of those with the SpiderFX Embolic Protection System [Covidien]. DEP was used more frequently in CLI subjects than in claudicants (27.9% vs. 20.6%). The material captured in the DEP device was not pathologically analyzed. Embolization

AUGUST 2014:923 - 33

TABLE 7 Functional Outcomes Through 12 Months

30-Day 12-Month

Baseline Follow-Up Follow-Up

RC clinical category

All 3.0 (2.0-4.0) 1.0 (0.0-2.0) 1.0 (0.0-2.0)

Claudicant 3.0 (2.0-3.0) 1.0 (0.0-2.0) 1.0 (0.0-2.0)

CLI 5.0 (4.0-5.0) 4.0 (1.0-5.0) 1.0 (0.0-3.0)

Ankle-brachial index

All 0.65 ± 0.16 0.90 ± 0.18 0.83 ± 0.21

Claudicant 0.67 ± 0.15 0.91 ± 0.17 0.84 ± 0.20

CLI 0.59 ± 0.18 0.87 ± 0.23 0.77 ± 0.26

Walking Impairment Questionnaire (baseline RC 1-3 only)

Pain 50.0 (37.5-75.0) 75.0 (62.5-100.0) 87.5 (62.5-100.0)

Walking distance 9.3 (2.3-27.6) 34.7 (7.3-89.3) 44.6 (12.6-89.3)

Walking speed 14.1 (3.3-30.4) 30.4 (10.9-50.0) 35.9 (17.4-56.5)

Stair climbing 20.8 (4.2-54.2) 45.8 (8.3-87.5) 54.2 (16.7-87.5)

EQ-5D Index

All 0.78 (0.68-0.81) 0.81 (0.76-1.00) 0.82 (0.77-1.00)

Claudicant 0.78 (0.71-0.82) 0.83 (0.78-1.00) 0.83 (0.78-1.00)

CLI 0.75 (0.45-0.78) 0.78 (0.68-0.84) 0.78 (0.71-0.84)

EQ-5D Visual Analog Scale

All 65.0 ± 19.2 71.0 ± 20.1 71.8 ± 18.8

Claudicant 66.6 ± 18.3 72.8 ± 19.2 72.3 ± 19.0

CLI 60.2 ± 20.8 65.3 ± 21.7 70.2 ± 18.0

Wound healing (baseline RC 5-6 only)

Wagnar score 1.0 (1.0-2.0) 1.0 (1.0-2.0) 0.0 (0.0-1.0)

Data presented as median (interquartile range) or mean ± SD. All changes from baseline to 30 days and 12 months are statistically significant (p < 0.05).

CLI = critical limb ischemia; RC = Rutherford classification.

occurring at any time during the procedure, including crossing the lesion pre-atherectomy, were included in the analysis. Positive evidence of distal embolization associated with DEP was defined as an embolus distal to the DEP device or remaining after the removal of the DEP device. No significant difference in the rate of distal embolization was noted (3.6% [22 of 620] without DEP vs. 4.5% [8 of 179] with DEP, p = 0.512). However, direct comparison is confounded by the use

of DEP with longer, more stenotic, and heavily calcified lesions. Of the 8 subjects with embolic events despite DEP use, 3 were associated with treatment of isolated SFA lesions, 1 with an isolated infrapopliteal lesion, and 4 with multivessel treatment. Of these 8 emboli-zations, 3 subjects required no further treatment and 5 subjects underwent aspiration or PTA with clearing of the embolus.

The 30-day major adverse event rate was 1.6% (95% CI: 0.8% to 2.8%) including 4 deaths (0.5%) (3 myocardial infarctions, 1 cardiogenic shock) and 6 clinically-driven target lesion revascularizations (0.9%). There were 3 major unplanned amputations (0.4%; 1 above knee, 1 below knee, 1 Syme's), all in CLI subjects. Major adverse events were more common among CLI subjects (3.5% vs. 1.0% in claudi-cants, p = 0.024). None of the deaths within 30 days were adjudicated by the CEC as related to either the study device or the index procedure.

Primary patency reported across all anatomic vascular beds in the claudicant cohort (598 subjects with 743 lesions) at 12 months was 81.5% (PSVR #3.5 and no reintervention for target lesions). Primary patency at 12 months, using the now more accepted endpoint of PSVR #2.4, was 78% (95% CI: 74.0% to 80.6%) (Fig. 1). The pre-specified noninferiority hypothesis of DA patency in diabetic versus nondia-betic subjects with claudication was met (77% [95% CI: 71.7% to 81.4%] diabetic vs. 78% [95% CI: 72.9% to 82.1%] nondiabetic) (noninferiority, p < 0.001; superiority, p = 0.98, using a PSVR #2.4) (Fig. 2). In moderate-length lesions (5.0 to 9.9 cm), patency rates were 83% in the SFA, 74% in the pop-litealartery, and 88% in the infrapopliteal artery. The patency rates in longer lesions ($10 cm) were 65% in the SFA and popliteal arteries. Patency was 88% to 91% for infrapopliteal lesions irrespective of length (Table 6). Secondary 12-month patency among clau-dicants was 89% overall.

The primary endpoint of CLI subjects at 12 months (freedom from target limb major amputation) was

TABLE 8 SFA Patency Comparison

Study Device Mean Length, cm Patency, % Patency Definition, PSVR

DEFINITIVE LE* DA 8.1 75 #2.4

RESILIENT (20) Bare-metal stent 6.2 81.3 <2.5

DURABILITY II (22) Bare-metal stent 8.9 77.2 <2.0

STRIDES (33) Drug-eluting stent 9.0 68 <2.5

Zilver RCT (21) Drug-eluting stent 5.4 83.1 <2.0

Italian Registry (25) Drug-coated balloon 7.6 83.7 <2.5

LEVANT I (34) Drug-coated balloon 8.1 67 <2.5

*Data from superficial femoral artery (SFA) lesions in claudicant cohort. DA = directional atherectomy; PSVR = peak systolic velocity ratio; RCT = randomized controlled trial.

95% (95% CI: 90.7% to 97.4%). Duplex-determined primary patency in all CLI lesions, a pre-specified secondary endpoint, was 71% (95% CI: 64.6% to 76.5%) and secondary patency was 88% (95% CI: 82.9% to 92.1%) (Fig. 3, Table 6). Target lesion location patency at 12 months in CLI subjects was as follows: SFA, 68%; popliteal artery, 67%; and infrapopliteal artery, 78%. The patency rate in the CTO lesions was 63.3% in the claudicants (mean lesion length, 11.2 cm) and 65.5% in the CLI cohort, with a mean length of 10.3 cm. Lesion patency at 12 months in pre-dilation versus non-pre-dilation was 87.5% versus 76.6% (p = 0.2) in claudication subjects and 56.4% versus 73.7% (p = 0.021) in CLI subjects, respectively.

Functional clinical outcomes for ABI, RC, and quality-of-life measurements for both claudicant and CLI subjects revealed statistically significant (p < 0.05) improvement in all categories at 30 days and 12 months (Table 7).

DISCUSSION

The DEFINITIVE LE study objectively evaluated, with independent core laboratory and CEC adjudication, the acute safety and 12-month durability of DA in the treatment of infrainguinal PAD in claudicants and CLI subjects. This study demonstrated effective debulking to #30% diameter stenosis in lesions up to 20 cm in length using DA with selective adjunctive PTA. Stent placement rate was a very low 3.2%, dramatically lower than the 40% to 50% bail-out rates reported in the PTA arms of recent stent studies (20,21). Critically, the patency rates observed in DEFINITIVE LE are similar to the rates published in SFA studies of second-generation nitinol stents (Table 8). Although direct comparisons cannot be made given the heterogeneity of the subjects studied across all protocols, the DEFINITIVE LE study demonstrates that DA has results comparable to those of other contemporary technologies treating infrain-guinal PAD but with the distinct advantage of rarely leaving a permanent implant in place. The DEFINITIVE LE study was not limited to a specific lesion or subset of lesions, and, as such, it is able to provide scientific information across many anatomic locations and subject subsets.

Lesion length is a predictor of long-term patency for most endovascular therapies (20-22). In the DEFINITIVE LE study, the mean lesion length was 7.5 cm, the longest mean lesion was 8.3 cm, and 28% of lesions were >10 cm in length. The RESILIENT (Randomized Study Comparing the Edwards Self-ExpandIng Lifestent versus Angioplasty Alone In LEsions INvolving The SFA and/or Proximal Popliteal

Artery) randomized study allowed treatment of multiple lesions. The mean per-subject lesion length was

7.1 cm (20), but the individual mean lesion length was

6.2 cm, as noted in device labelling. The observed patency rate was 81.3%. DURABILITY II (StuDy for EvalUating EndovasculaR TreAtments of Lesions in the Superficial Femoral Artery and Proximal Popliteal By usIng the Protege EverfLex NitInol STent SYstem II) (22) reported a 77.2% primary patency rate (8.9-cm mean lesion length) and the Zilver PTX drug-eluting stent (Cook Medical, Bloomington, Indiana) achieved a primary patency rate of 83.1% in lesions with a mean length of 5.4 cm (21). The DEFINITIVE LE data, although not randomized, compare favorably with outcomes of these trials (Table 8). Further, across multiple anatomic segments, DA provided a similar primary patency with selective adjunctive PTA.

Treatment of infrapopliteal lesions includes athe-rectomy, PTA alone, or PTA with stenting, generally with a coronary drug-eluting stent in very short lesions. The ACHILLES study evaluated the effectiveness of infrapopliteal treatment of PAD (RC 3 to 5) with DES versus PTA alone in 200 subjects (23). The mean lesion length was 2.69 ± 2.09 cm, and the 1-year patency rate was 75% for drug-eluting stents and 57.1% for PTA alone. The limb salvage rate at 1 year was 86% and 80%, in the DES and PTA groups respectively. This core laboratory-controlled trial revealed lower patency and limb salvage rates with use of PTA and drug-eluting stents compared with the DA infrapopliteal data reported in this study. DEFINITIVE LE claudicants with infrapopliteal lesions had a 5.5-cm mean lesion length and a 90% primary patency rate; CLI subjects had a 6.0-cm mean lesion length, a 78% primary patency rate, and a 95% limb salvage rate. Interestingly, the longer lesions in the infrapopliteal arteries, regardless of diabetic status, showed better patency outcomes than similar length lesions in the SFA and popliteal arteries.

Drug-coated balloons (DCBs) are proving to be an effective treatment option that does not require a permanent endoprosthesis. However, rates of bailout stenting in the treatment arms of DCB studies range from 4% in the THUNDER (Local Taxane with Short Exposure for Reduction of Restenosis in Distal Arteries) study (24), to 12.3% in the Italian Registry (25), and 21% in the PACIFIER study (26). Combining upfront atherectomy with DCB angioplasty may overcome the current limitations of DCB angioplasty such as lesion calcification, as reported by Cioppa et al. (12). This group treated 30 subjects with severe calcification with DA followed by a DCB. Bail-out stents were necessary in only 2 subjects (6.5%), and the primary patency rate at 1 year was 90%.

AUGUST 2014:923 - 33

A unique attribute of the DEFINITIVE LE study design was the pre-specified noninferiority hypothesis for 12-month patency of diabetic to nondiabetic subjects, which was met (77% vs. 78%; noninferiority, p < 0.001; superiority, p = 0.98). With increased scrutiny regarding healthcare cost, effectiveness and durability of treatment modalities are required. Most studies do not stratify outcomes by diabetic status, but previous work has demonstrated worse outcomes with open and endovascular therapy in diabetic patients compared with nondiabetic patients (7,8). An exception to this statement is the retrospective, nonpowered, ad-hoc analysis of the Zilver PTX registry, which found similar rates of patency as reported by sites regardless of diabetes status (27).

The limb salvage rate of 95% observed in the DEFINITIVE LE CLI cohort is higher than the CLI surgical bypass studies that reported rates between 81% and 87% (28-30) and the PTA arm of the BASIL (Bypass versus Angioplasty in Severe Ischaemia of the Leg) study that reported a rate of 71% (31). Complete wound healing in DEFINITIVE LE subjects with an RC 5 or 6 at baseline was 72% at 12 months. This is comparable to the rates seen in bypass studies of CLI subjects (74% to 75%) (28-30).

The DEFINITIVE LE study has confirmed the safety in treatment of subjects with single-level to multilevel lower extremity disease and confirmed the durability of DA across a broad spectrum of subjects. Indeed, the ability to treat multilevel disease with a single device and to have an adjunctive stent rate just over 3% and a patency rate consistent with rates of previous primary stent trials indicates that DA is a very effective therapy for patients with PAD who present with either claudication or CLI.

STUDY LIMITATIONS. The study's principal limitations include a lack of randomization and follow-up beyond 12 months. At the time of the creation of the DEFINITIVE LE study protocol, there were no self-expanding stents with U.S. Food and Drug Administration (FDA) approval for PAD treatment. Therefore, randomization to a control group would have been

limited to PTA alone, which would have had an expected primary 12-month patency rate of 33%, per the VIVA Performance Goal (32). However, the large group of subjects enrolled and the adjudication through core laboratory analyses overcame many of these limitations. Another limitation is the use of a PSVR >3.5 as the primary endpoint for restenosis in the claudication group. After the finalization of the study protocol, it became more accepted to use a PSVR >2.4 as an indicator of restenosis. Fortunately, that endpoint was used as a secondary endpoint, and all data points and patencies have been expressed in this paper using the secondary endpoint definition rather than the primary endpoint definition. Additionally, these data should not be extrapolated to other FDA-approved atherectomy devices because their mechanisms of action differ from those of DA. Studies with randomization of all FDA-approved treatment modalities such as the recent National Institutes of Health-funded BEST (Best Endovascular vs. Best Surgical Therapy in Patients With Critical Limb Ischemia) trial will be required to further clarify the role of each of the treatment modalities.

CONCLUSIONS

The DEFINITIVE LE study confirmed that DA is a safe and effective treatment modality through 12 months for patients with claudication and CLI. Furthermore, DA was shown to be noninferior for treating PAD in patients with diabetes compared with nondiabetic patients.

ACKNOWLEDGMENTS The authors thank Scott Brown, PhD, and Sarah Verdoliva, MS, from Covidien for statistical analysis and Meghan Schadow, MS, from Covidien for assistance with technical aspects of the manuscript.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

James F. McKinsey, Mount Sinai Systems Chief for Complex Aortic Interventions, 1000 10th Avenue, Suite 5G 67, New York, New York 10019. E-mail: jmckinsey@chpnet.org.

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KEYWORDS angioplasty, atherectomy, claudication, critical limb ischemia, peripheral artery disease

APPENDIX For a listing of the investigators involved in the DEFINITIVE LE Study, please see the online version of this article.