Chronic Limb Threatening Ischemia And The BEST-CLI Trial
Chronic Limb Threatening Ischemiaand the BEST-CLI TrialCaitlin W. Hicks MD, MSAssistant Professor of SurgeryDirector of Research, Multi-D Diabetic Foot & Wound ClinicSite PI, BEST-CLI TrialJohns Hopkins University School of Medicine
Disclosures None BEST-CLI trial Site PI for JHUSOM Trial supported by NHLBI: 1U01HL107407-01A1
Outline Chronic limb-threatening ischemia Definitions Epidemiology Natural History Treatment Algorithms Impediments to Optimal Management BEST-CLI trial Multidisciplinary approach to limb preservation
Definitions Peripheral Arterial Disease (PAD) a disorder causing lower extremity arterial obliterationthat limits blood flow to the limbs and may lead toarterial insufficiency
Definitions Peripheral Arterial Disease (PAD) a disorder causing lower extremity arterial obliterationthat limits blood flow to the limbs and may lead toarterial insufficiency Chronic Limb Threatening Ischemia (CLI) a state of arterial insufficiency manifested by chronic,inadequate tissue perfusion at rest characterized by ischemic rest pain, ulcers or gangrene presence of objective hemodynamic evidence ofarterial insufficiency
Etiology of PAD Atherosclerosis Embolization Thrombosis Buerger’s Disease Vasculitis Arterial Trauma Popliteal Entrapment Popliteal Adventitial Cystic Disease
Etiology of PAD Atherosclerosis Embolization Thrombosis Buerger’s Disease Vasculitis Arterial Trauma Popliteal Entrapment Popliteal Adventitial Cystic Disease
Epidemiology of PAD and CLI Peripheral Arterial Disease Prevalence: 25-30% patients 80 years old in the USo 200 million people worldwideHirsch AT. Circulation 2012;125 (110);1449-1472Norgren L. Int Angiol 2007;6(2):81-157Biancari F. J Cardiovasc Surg (Torino) 2013;54:663-9.Fowkes FG et al. Lancet 2013;382:1329-40.Nehler MR. J Vasc Surg 2014;60(3):686-695
Epidemiology of PAD and CLI Peripheral Arterial Disease Prevalence: 25-30% patients 80 years old in The USo 200 million people worldwide Chronic Limb Threatening Ischemia (CLI) Prevalence: 11% of patients with PAD Incidence:Acute500– 3,500 cases/million/yearLim bChronic Lim bCLIIschem iaALIIschem iaStableClaudicationAsym ptom aticPADHirsch AT. Circulation 2012;125 (110);1449-1472Norgren L. Int Angiol 2007;6(2):81-157Biancari F. J Cardiovasc Surg (Torino) 2013;54:663-9.Fowkes FG et al. Lancet 2013;382:1329-40.Nehler MR. J Vasc Surg 2014;60(3):686-695
Demographic FactorsNorgren L et al. TASC II. J Vasc Surg 2007;45:S5-67.
2013;382:1329-40From 2000 to 2010 worldwideprevalence of PAD increased by23.5%
Diagnosis CLI is suspected in patients with atherosclerotic riskfactors who: Burning, gnawing pain in distal foot at rest made worseby elevation and improved with dependency Tissue loss usually affecting the distal extremityOn Physical Exam Ulceration or gangrene; dependent rubor; thin, shinyskin; absence of hair No palpable pulses
Confirmation of CLIVascular Laboratory Physiological Studies– Ankle Brachial Index (ABI)– Toe pressures– Doppler waveforms– Pulse Volume Recordings (PVR)– Transcutaneous oximetry (TcPO2)
Hemodynamic Definitions of CLI ABIs 0.4 Anyone with ABI 0.9deserves furtherinvestigationPatel MR et al. PARC. J Am Coll Cardiol. 2015;65:931-41
Natural History of CLI 1,500 patients in 13 studies at 1 year f/u----22% major amputation rate
Risk of Amputation is affected by Degree of ischemia
Risk of Amputation is affected by Degree of ischemia Extent and depth of tissue loss
Risk of Amputation is affected by Degree of ischemia Extent and depth of tissue loss Presence and extent of infection
Limb Issues Often OverlapTissue LossDominantIschemiaDominantInfectionDominantD.G. Armstrong, J.L. Mills / Wound Medicine 1 (2013) 13–14
Society for Vascular SurgeryWIfI Index Wound: extent and depth Ischemia: perfusion/flow Foot Infection: presence and extent
WIfI Classification Designed to be analogous to the TNM staging system for cancer Based upon existing validated systems or best available data with 4point scales
Risk of Amputation vs WIfI StageStudy (year): # limbs at riskStage 1Stage 2Stage 3Stage 4Cull (2014): 15137 (3%)63 (10%)43 (23%)8 (40%)Zhan (2015): 20139 (0%)50 (0%)53 (8%)59 (37%)Darling (2015): 5515 (0%)111 (10%)222 (11%)213 (24%)Causey (2016): 16021 (0%)48 (25%)42 (21%)49 (31%)Beropoulis (2016): 12629 (13%)42 (19%)29 (19%)26 (38%)Ward (2016): 985 (0%)21 (14%)14 (21%)58 (34%)Darling (2016): 99212 (0%)293 (4%)249 (4%)438 (21%)N 2279 (weighted mean)148 (3.4% )628 (8.3%)652 (10.3%)851 (25%)Median (% 1 yr amputation)0%10%19%34%Number of limbs at risk in each WIfI Stage with % amputation at 1 year in parenthesesCourtesy of J Mills
Relative 5-Year Mortality Rates1008680Patients 60(%)40203218392380Prostate Hodgkin'sCancer* Disease*BreastCancer*PAD †ColorectalLungCancer* Cancer**American Cancer Society. Cancer Facts and Figures, 2000.†Criqui MH et al. N Engl J Med. 1992;326:381-6.
Goals Of Treatment Medical therapy to optimize cardiovascularrisk Wound management Revascularization (measures to improve limbperfusion)Hirsch AT et al. J Am Coll Cardiol 2006;47:1239-131Conte MS and Farber A. BJS 2015;102:1007-1009
Medical Therapy Antiplatelet agents (ASA or clopidogrel) Tobacco cessation Statins Diabetes control Blood Pressure Reduction 130/85 mm Hg preferably with ACE-IJ Am Coll Cardiol. 2016 Mar 22;67(11):1338Circ Res. 2015 Apr 24;116(9):1509
Wound Management Antibiotics Debridement / Minoramputation Wound management &offloading
Revascularization Relieve pain Heal wounds Preserve a functional limb Avoid major amputation Maintain ambulatory status
Revascularization Options in CLI
Surgical Bypass1906- Technique of vascular anastomosisdescribed(Carrel A, Guthrie CC. Surg Gynecol Obstet 2:266,1906)
Surgical Bypass1906- Technique of vascular anastomosisdescribed(Carrel A, Guthrie CC. Surg Gynecol Obstet 2:266,1906)1948- 1st successful femoral popliteal bypassusing rGSV in a patient with PAD(Kunlin J. Rev Chir Paris 70:206-236, 1951)
Infrainguinal BypassPrimarySecondaryLimbGraft Patency Graft Patency Salvage@ 5 years@ 5 years@ 5 yearsTaylor L. et alN 30080%84%90%Shah D. et alN 2,04872%81%95%Pomposelli FB. et al.N 1,03257%63%78%Perioperative mortality: 1-6%
Infrainguinal Bypass Traditional treatmentDurable outcomesLong follow up periods available InvasiveIs associated with blood lossmorbiditymortalitywound complications
1964Charles Dotter
Novel Technology
Trends in PAD TherapyGoodney et al. JAMA Surg 2015;150(1):84-86
Endovascular Treatment Options Plain Balloon Angioplasty (PTA)StentingAtherectomyLaser assisted PTABrachytherapyStent graftsDrug eluting stentsDrug coated balloonsBioabsorbable stents
There is a lot of literature Publications reporting 1-yr patency following SFA stenting or stent-grafting from 2000-2009courtesy L. Schwartz
Endovascular Therapy for CLI Minimally invasive No need for general anesthesia incisions hospitalization Lower morbidity and mortality Decreased durability Low patency rates in some vascular beds Expensive Driven by business interests
We have tools that work . but which tool works best for whomand when?
Current Status of LimbRevascularization?1. Variability in Treatment2. Absence of Value-driven Care3. Insufficient Comparative Effectiveness Data
Variability of Intensity of Vascular Care AcrossRegions of the United StatesGoodney et al, Circulation CV Q O 2012 (5) 94-102
Vascular Quality Initiative% of Patients with CLI and PAD treated withSurgical Bypass (vs. Endovascular Therapy)100% Bypass100%All VQI Centers Mean 31%90%80%Procedure Selection Variation70%60%50%40%30%20%10%0%0% BypassVQI Centers
CLI is
Americans pay much higherprices for healthcare services
Medicare expenditure on CLI 4 billion(CHF 3.9B, Cerebrovascular disease 3.7B) 90% inpatient care 1,700 per patient ( 2X avg beneficiary) 3% of total Medicare budget
At the end of the day we need toknow how to manage this patient 75 year old diabetic woman with right forefootgangrene PE: normal femoral but no distal pulses Rt ABI: 0.3
Which FIRST RevascularizationOption in CLI Has the BEST Value?VSBypass SurgeryEndovascularTherapy
Limitations of Published DataRetrospectivePoorly controlledSuboptimal endpointsSponsor and Operator biasPatients with claudication and CLI are“lumped together” Short or incomplete follow up
Is There any Level I Evidence?
BASIL Trial Aim: To compare outcomes of surgery-first strategy withangioplasty first strategy in patients with CLI Results:o No significant difference in amputation-free survival at 5year follow-upo Trend toward benefit for surgery noted in those patentsAFSwho survived more than 2 years Limitations:o Underpoweredo Endovascular therapy limited to angioplastyo Lack of lesion standardizationAdam DJ. Lancet. Dec 3 2005;366(9501):1925-1934Bradbury A. J Vasc Surg 2010; 51(5 Suppl)5S-17S
Vascular Quality Initiative% of Patients with CLI and PAD treated withSurgical Bypass (vs. Endovascular Therapy)100% Bypass100%All VQI Centers Mean 31%90%80%Procedure Selection Variation70%60%50%40%30%20%10%0%0% BypassVQI Centers
Sponsored by the National Heart Lung and Blood Institute
BEST-CLI Trial: Overview Prospective, randomized, multicenter, multispecialty,pragmatic, open-label superiority trial 2100 patients at 160 clinical sites Funded at level of 25 million Goal: to assess treatment efficacy, functionaloutcomes, cost and value in patients with CLI andinfrainguinal PAD who are candidates for both openvascular and endovascular surgery
BEST Trial OrganizationNational Heart, Lung, and Blood InstituteDSMBD. Bonds, D. Reid, X. TianCost-EffectivenessCoreBrigham and Women’sHospitalJ. Avorn, N. ChoudhryClinical Coordinating CenterTrial ChairsBrigham and Women’s HospitalA. Farber, Boston Medical CenterM. Menard, Brigham and Women’s Hospital*K. Rosenfield, Mass General Hospital* Awarded InstitutionSubcommitteesExecutive CommitteeNHLBI, CCC, DCC, C-E Core M. Conte, C. White (Co-Chairs)M. Creager, M. Dake, M. Jaff,J. Kaufman, R. PowellCertified Clinical CentersUS & CanadaClinicalEventsCommitteeData CoordinatingCenterNew England ResearchInstitutes, Inc.S. Assmann, S. Siami
BEST-CLI Global FootprintFinlandGermany (soon)Italy5 Active Sites OverseasNew Zealand Wellington Hospital Waikato Hospital Auckland City HospitalFinland Helsinki University HospitalItaly San Giovanni di Dio HospitalOnboardingGermany St. Franziskus Hospital – MuensterNew Zealand133 sites currently open for enrollment
BEST-CLI is a Pragmatic Trial Definition of “Best Treatment” is left to theinvestigator All commercially available endovasculartherapies allowed as long as accepted asstandard of care All surgical bypass techniques and conduitsallowed Trial approximates “real world”
BEST-CLI Trial Design: Two Cohorts Cohort #1 Patients with adequate single segment greatsaphenous vein (SSGSV) N 1620Open surgery vs. Endovascular treatment Cohort #2 Patients without adequate SSGSV (ifrandomized to OPEN conduit may include arm vein, shortsaphenous vein, composite vein, cryopreserved vein, andprosthetic conduit) N 480Open surgery vs. Endovascular treatment
Novel Primary EndpointMajor Adverse Limb Event (MALE) – free survivalMALE defined as: Above ankle amputation or Major re-intervention new bypass graft jump/interposition graft revision thrombectomy/thrombolysis
Key Secondary Endpoints Re-intervention and Amputation-free Survival Amputation-free Survival MALEAdditional Secondary Endpoints Freedom from hemodynamic failure Freedom from clinical failure Freedom from critical limb ischemia Number of re-interventions per limb salvaged Freedom from re-interventions (major and minor) inindex limb
Robust Cost-Effectiveness Analysis Functional status / quality of life measures EQ5D as main measure; also SF-12 All financial costs of care Hospital care (index admission and all f/u) Outpatient care Rehabilitation
Collaboration within BEST-CLIInclusive of everyone who performsrevascularization for CLI: Vascular Surgeons Interventional Cardiologists Interventional RadiologistsWhat about Podiatry?If our trial is going to define practice it has toinvolve everyone.
BEST-CLI Site Multidisciplinary Status 72 % sites are multidisciplinary VS aloneVS IRVS ICVS IR IC28%23%32%13%
BEST Investigator Data Investigators by Specialty (n 930) 690 Vascular Surgeons 114 Interventional Cardiologists 111 Interventional Radiologists 3 Vascular MedicineIC 12% 12 Other specialtiesIC 12%VS 74%VSICIRVMother
Enrollment Update As of March 26, 2019 - 1657 subjects randomized (79% complete)
Patient Characteristics (as of 4/9/2018 data freeze) Strata Rest pain, no tibial dz8% Rest pain and tibial dz 12% Tissue loss, no tibial dz 24% Tissue loss and tibial dz 56%
BEST-CLI is positioned Provide a treasure trove of relevant data about CLI and itsmanagement
What questions will BEST-CLI answer? How does infrainguinal bypass with optimal conduit (SSGSV) fareagainst endovascular therapy? How does bypass with non-optimal conduit fare againstendovascular therapy? Will assess Comparative effect of clinical presentation and anatomyDefinean evidence-based standard of care for comparative QOL and cost effectivenessrevascularizationofCLI outcomes of revascularization as it relates to presence of tibial disease,clinical presentation, gender, race, age, diabetes, heel ulcer, renaldysfunction Will prospectively validate the SVS WIfI classification Will relate comparative hemodynamic outcomes ofrevascularization to clinical outcomes
What about the wounds?
Case Example 69 year old female PMH: DM, HPL, CAD, obesity Underwent left partial ray amputation atOSH for wet gangrene Wound ischemia - dry gangrene Recommended LLE AKA because foot notsalvageable
Physical Exam
Randomized to Bypass Left common femoral endarterectomy withbovine pericardium patch angioplasty Left CFA to PTA bypass w Propaten and veinpatch
TMA with rotational plantar flap (Podiatry)
Post-Op Intra-op Cx: E. cloacae, Proteus, MSSA ID: Zosyn x6 weeks (PICC) Discharged to Rehab Fu in Multi-D clinic Sutures out/healed by 14 d post-op
A Multifactorial Problem Needs aMultidisciplinary Approach
The Johns Hopkins ExperienceMultidisciplinary Diabetic Foot & Wound Service Multidisciplinary team Vascular surgery, surgical podiatry,endocrinology Single clinic visit Robust home health nursing group Consultants Ortho foot & ankle, plastic surgery, ID, PMNR Inpatient/outpatient
The Johns Hopkins ExperienceMultidisciplinary Diabetic Foot & Wound Service July 2012 – Dec 2015290 Diabetic patients412 wounds 58% WIfI Stage 3 or 4352 Debridments & minoramputations118 revascularizations
The Johns Hopkins ExperienceMultidisciplinary Diabetic Foot & Wound Service Major amputation at 1 yearP 0.56
The Burden of Limb SalvageTime spent
WIfI Stage Predicts CostsOverall costs of multidisciplinary careInpt & Outpt Stage 1Stage 2Stage 3Stage 4PTotal Revenue13,20516,40642,47058,374 .001Total Cost12,57714,69238,14152,733 .001Variable Direct5,6986,53416,84924,564 .001Variable Indirect1,5561,8144,2045,726 .001Fixed Direct1,5721,7524,6996,083 .001Fixed Indirect3,7514,59312,38916,359 .001Variable Net Margin6,1229,17622,62326,635 .001Overall Net Margin2,1763,2706,4667,980.008
Controlling CostsMajor vs. Minor amputationsMulti-D teams decreasemajor amps &save
Controlling CostsMajor vs. Minor amputationsSingle Center Study examining Outcomes Pre/Post DFSDecreased AmputationsDecreased SurgeriesConclusionEarly referral to DFS 1. Earlier presentation of disease2. Reduced delays to treatment3. Decreased costs of care
BEST-CLI, Podiatry, and CLIAn Important ascularizationManagement
BEST-CLI, Podiatry, and CLIOur Plea to You Continue to take excellent care of patients Be cognizant of CLI in patients who presentwith foot wounds Liason with BEST-CLI investigators tooptimize blood flow Aggressive and early debridement/minoramputation as needed Consider establishing/joining a multi-D limbpreservation team This is where CLI care is headed!
Thank I
Peripheral Arterial Disease (PAD) a disorder causing lower extremity arterial obliteration that limits blood flow to the limbs and may lead to arterial insufficiency Chronic Limb Threatening Ischemia (CLI) a state of arterial insufficiency m
Upper Limb sEMG Signal Abstract -In this paper, a lower limb exoskeleton robot based on upper limb sEMG signal controlledby designed for patients with lower limb functional injury in the middle and late stage of rehabilitation. It realized the patient's active and random control when wearing the lower limb exoskeleton for rehabilitation
The trial is designed to run seamlessly with the main trial but sites can opt out if they choose not to participate. See . section. 18 for more details. 2. CIAO -ISCHEMIA (Changes in Ischemia and Angina over One year among ISCHEMIA trial screen failures with no obstructive coronary .
Mar 05, 2021 · Index and tabular changes for critical limb ischemia were officially adopted as part of ICD-10-CM by HHS. The new index entries and tabular notes are mandated to appear in all versions of ICD-10-CM as of October 1, 2020. Use of ICD-10-CM is specifically mandated by HIPAA
Critical Limb Ischemia Course Focused on Diabetic Foot CLC Course Directors: M. Manzi, MD L.M. Palena, MD Scuola Grande
the activities of five lower limb muscles in 13 experienced yoga practitioners during single-limb (Tree and Warrior 3) and double-limb (Downward Facing Dog, Half-Moon, and Chair) yoga asanas [24]. The EMG results showed differences in frontal and sagittal plane muscle activation between the single-limb and double-limb poses. In another study .
Analysis of the Relative Motion Between the Socket and Residual Limb in Transtibial Amputees While Wearing a Transverse Rotation Adapter Corey A. Pew,1 Sarah A. Roelker,2 Glenn K. Klute,3,4 and Richard R. Neptune2 1Montana State University; 2The University of Texas at Austin; 3University of Washington; 4Center for Limb Loss and Mobility The coupling between the residual limb and the lower-limb .
exoskeleton limb attachment that is compliant to individual limb geometries fabricated using the Fused Deposition Modelling (FDM) process using a Zortrax M200 3D Printer. Limb are scanned using a low-cost 3D scanner and from this scanned geometry, a limb attachment is designed. A Finite Element Analysis is configured to simulate
Academic Phrasebank. Setting objectives –student tip “It is important that your chosen research question is clearly focused and well written; answering it must be achievable in the time available to you!” Your research question and the objectives to achieve it. Your research title Your dissertation title is important as it tells your reader what your dissertation is about ! Titles often .
