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1Oct 2003 LACI 2

Circulatory System Devices Circulatory System Devices Advisory PanelAdvisory Panel

LACI ReviewLACI Review

IntroductionsIntroductions Outline of presentationsOutline of presentations PresentationsPresentations

Introductions & History

2Oct 2003 LACI 2

IntroductionsIntroductions Chris Reiser PhDChris Reiser PhD

– VP Technology & Clinical Research, SpectraneticsVP Technology & Clinical Research, Spectranetics

John Laird MDJohn Laird MD, Washington Hospital Center, Washington Hospital Center– LACI Principal InvestigatorLACI Principal Investigator

Bruce Gray DO, Bruce Gray DO, Greenville Memorial Hosp,Greenville Memorial Hosp, SC SC

– LACI Steering Committee, InvestigatorLACI Steering Committee, Investigator

Venkatesh Ramaiah MD FACS, Venkatesh Ramaiah MD FACS, Arizona HeartArizona Heart

– staff surgeon and LACI PIstaff surgeon and LACI PI


3Oct 2003 LACI 2

Outline of PresentationsOutline of Presentations Background and historyBackground and history LACI Phase 2 resultsLACI Phase 2 results Benefits of LACIBenefits of LACI Why limb salvage is better than limb lossWhy limb salvage is better than limb loss Alternative treatment strategiesAlternative treatment strategies

1 : medication1 : medication 2 : primary amputation2 : primary amputation

3 : PTA3 : PTA 4 : bypass surgery4 : bypass surgery

Summary of alternativesSummary of alternatives


4Oct 2003 LACI 2

Basic TechnologyBasic Technology

Excimer laser atherectomy (ELA):Excimer laser atherectomy (ELA):– XeCl excimer laser, 308 nm, pulsed at XeCl excimer laser, 308 nm, pulsed at

40 pulses/second maximum40 pulses/second maximum Delivered via a fiberoptic catheterDelivered via a fiberoptic catheter First approved by FDA in 1993 for First approved by FDA in 1993 for

use in coronary arteriesuse in coronary arteries Similar but slightly different than Similar but slightly different than

LASIKLASIK


5Oct 2003 LACI 2

Quick ComparisonQuick Comparison

ELAELA 308 nm308 nm fiber deliveryfiber delivery catheterscatheters arteries & veinsarteries & veins ““cool” UV ablationcool” UV ablation

LASIKLASIK 193 nm193 nm free-air free-air

propagationpropagation work stationwork station corneascorneas ““cool” UV ablationcool” UV ablation


6Oct 2003 LACI 2

CVX-300 Laser SystemCVX-300 Laser System

Gen 4 approved 1994?Gen 4 approved 1994? Same system used for Same system used for

all our applications:all our applications:– coronary atherectomycoronary atherectomy– pacing lead removalpacing lead removal– peripheral atherectomy peripheral atherectomy

(EU only)(EU only) A few facts...A few facts...


7Oct 2003 LACI 2

Excimer Laser CathetersExcimer Laser Catheters

4th generation 4th generation since first FDA since first FDA approvalapproval

Latest models are Latest models are “legs-only” devices“legs-only” devices

All have same All have same basic features and basic features and work the same work the same wayway


8Oct 2003 LACI 2

How ELA Works...How ELA Works...


9Oct 2003 LACI 2



10Oct 2003 LACI 2



11Oct 2003 LACI 2

Coronary IndicationsCoronary Indications

Long, diffuse lesionsLong, diffuse lesions Total occlusions crossable with a wireTotal occlusions crossable with a wire Moderately calcified lesionsModerately calcified lesions Ostial lesionsOstial lesions Balloon angioplasty failuresBalloon angioplasty failures Vein graftsVein grafts In-stent restenosis prior to In-stent restenosis prior to

brachytherapybrachytherapy


12Oct 2003 LACI 2

ELA Experience in the LegsELA Experience in the Legs

Initial IDE work in the USA - early Initial IDE work in the USA - early ‘90s‘90s

Commercial experience in EU since Commercial experience in EU since ‘95?‘95?

Anecdotal single-site experiencesAnecdotal single-site experiences

LACI Phase 1LACI Phase 1 LACI Phase 2LACI Phase 2


13Oct 2003 LACI 2

LLaser aser AAngioplasty for ngioplasty for CCritical ritical Limb Limb IIschemiaschemia

Results of the LACI Phase 2 RegistryResults of the LACI Phase 2 Registry

LACI 2 Results

14Oct 2003 LACI 2

Study DesignStudy Design• Prospective, multi-center studyProspective, multi-center study• Patients with CLIPatients with CLI

– Rutherford Category 4-6Rutherford Category 4-6– poor surgical candidatespoor surgical candidates

• Treatment: ELA of SFA, popliteal and/or infrapopliteal Treatment: ELA of SFA, popliteal and/or infrapopliteal arteries, with adjunctive PTA and optional stentingarteries, with adjunctive PTA and optional stenting

• Primary Efficacy Endpoint: limb salvage at 6 mo.Primary Efficacy Endpoint: limb salvage at 6 mo.– freedom from amputation at or above the anklefreedom from amputation at or above the ankle

• Primary Safety Endpoint: death at 6 mo.Primary Safety Endpoint: death at 6 mo.

LACI 2 Results

15Oct 2003 LACI 2

Study DesignStudy Design• Included catheters:Included catheters:

– 2.2 - 2.5mm Spectranetics peripheral laser catheters 2.2 - 2.5mm Spectranetics peripheral laser catheters – any Spectranetics coronary laser catheterany Spectranetics coronary laser catheter

• Poor surgical candidates because:Poor surgical candidates because:– poor or absent vessel for outflow anastamosis, orpoor or absent vessel for outflow anastamosis, or– absence of venous conduit, orabsence of venous conduit, or– significant co-morbiditysignificant co-morbidity

• Enrollment period: April ‘01 - April ’02Enrollment period: April ‘01 - April ’02• Enrollment: 145 patients, 155 limbsEnrollment: 145 patients, 155 limbs

LACI 2 Results

16Oct 2003 LACI 2

Historical Control GroupHistorical Control Group Italian multicenter randomized study of Italian multicenter randomized study of

Prostaglandin E1 in CLI patientsProstaglandin E1 in CLI patients– 771 in alprostadil group771 in alprostadil group– 789 in control group789 in control group

Control group received variety of therapies Control group received variety of therapies (bypass, endarterectomy, medication, and a (bypass, endarterectomy, medication, and a few PTAs)few PTAs)– ““the best you can do” for these patientsthe best you can do” for these patients

Ann Intern Med 1999; 130:412-421Ann Intern Med 1999; 130:412-421 Conforms to TASC definitions and GCPConforms to TASC definitions and GCP

17Oct 2003 LACI 2

Enrollment by Site

Arizona HeartArizona Heart 2323Hertzentrum LeipzigHertzentrum Leipzig 2424Hertzentrum Bad Kroz.Hertzentrum Bad Kroz. 2222Greenville MemorialGreenville Memorial 1919Manatee HospitalManatee Hospital 1010Lankanau MemorialLankanau Memorial 8 8Riverside MethodistRiverside Methodist 7 7

Glendale MemorialGlendale Memorial 7 7St. Joseph’s PatersonSt. Joseph’s Paterson 7 7Univ. FrankfurtUniv. Frankfurt 6 6Springhill MemorialSpringhill Memorial 5 5Washington HCWashington HC 5 5Ochsner ClinicOchsner Clinic 1 1St. Luke’s MilwaukeeSt. Luke’s Milwaukee 1 1

total patientstotal patients 145145total legstotal legs 155155

• 36% of sites enrolled 68% of patients

• 145 patients at 14 sites145 patients at 14 sites

LACI 2 Results

18Oct 2003 LACI 2

Patient Descriptors

LACILACI ControlControl ppMean age, yearsMean age, years 72 72 ±± 10 10 72 72 ±± 10 10 nsnsMenMen 53% 53% 72%72% * *Risk factorsRisk factors

Smoking currentSmoking current 14% 14% 25%25% * *Prior MIPrior MI 23%23% 15% 15% * *Prior strokePrior stroke 21%21% 12% 12% * *Diabetes mellitusDiabetes mellitus 66%66% 39% 39% * *HypertensionHypertension 83%83% 49% 49% * *DyslipidemiaDyslipidemia 56%56% 16% 16% * *ObesityObesity 35%35% 7% 7% * *

*significant*significant

LACI 2 Results

19Oct 2003 LACI 2

Leg Descriptors

LACILACI ControlControl ppRutherford CategoryRutherford Category

44 27%27% 30% 30% nsns5 or 65 or 6 72%72% 70% 70% nsns

Reasons for poor surgical candidacyReasons for poor surgical candidacy Absence of venous graftAbsence of venous graft 32%32% Poor/no distal vesselPoor/no distal vessel 68%68% High surgical riskHigh surgical risk 46%46% 11% 11% ** Only one reasonOnly one reason 61%61% Any two reasonsAny two reasons 33%33% All three reasonsAll three reasons 6% 6%

LACI 2 Results

20Oct 2003 LACI 2

Case ProfileCase Profile

• 61 year old Hispanic woman61 year old Hispanic woman• Diabetic for > 20 yearsDiabetic for > 20 years• ESRD; hemodialysis for 1 yearESRD; hemodialysis for 1 year• Non-smokerNon-smoker• Multiple ischemic ulcers on both feetMultiple ischemic ulcers on both feet• Bilateral ELA on 14 Aug 01Bilateral ELA on 14 Aug 01• Skin grafts during follow-up periodSkin grafts during follow-up period• Investigator: Dr. Mitar Vranic at Arizona HeartInvestigator: Dr. Mitar Vranic at Arizona Heart

LACI 2 Results

21Oct 2003 LACI 2

Case Profile : Right FootCase Profile : Right Foot 1/41/4

Prior to treatmentPrior to treatment

LACI 2 Results

22Oct 2003 LACI 2


• 2.2 mm laser2.2 mm laser• 3.0 mm balloon3.0 mm balloon• no stentno stent

• popliteal also treatedpopliteal also treated

LACI 2 Results

23Oct 2003 LACI 2


3 months post treatment3 months post treatment

LACI 2 Results

24Oct 2003 LACI 2


6 months post treatment6 months post treatment

LACI 2 Results

25Oct 2003 LACI 2

Case Profile : Left FootCase Profile : Left Foot

baselinebaseline3 months3 months

6 months6 monthslaserlaser

balloonballoon

no stentno stent

LACI 2 Results

26Oct 2003 LACI 2LACI 2 Results

27Oct 2003 LACI 2LACI 2 Results

28Oct 2003 LACI 2

Case ProfileCase Profile

• 45 year old 45 year old femalefemale

• Diabetes mellitus, Diabetes mellitus, morbid obesitymorbid obesity

• Distal popliteal Distal popliteal occlusion, tibial occlusion, tibial diseasedisease

• Painful, ischemic Painful, ischemic 22ndnd toe toe

LACI 2 Results

29Oct 2003 LACI 2

SITE 009-WHCPAT 0056 MOS

LACI 2 Results

30Oct 2003 LACI 2

Vascular Lesion LocationsVascular Lesion Locations

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

SFA popliteal infrapopliteal other

% o

f Id

entif

ied

Lesi

ons

LACI 2 Results

31Oct 2003 LACI 2

Lesion TypesLesion Types

Mean # of treated lesions/pt: 2.7 1.4 (1-7)

0%

10%

20%

30%

40%

50%

60%

70%

80%

stenoses occlusions stenoses andocclusions

% o

f L

imb

s

LACI 2 Results

32Oct 2003 LACI 2

TASC TypesTASC Types

LACI 2 Results

33Oct 2003 LACI 2

LACI Procedure ResultsLACI Procedure Results

Guidewire crossing successGuidewire crossing success92%92%

Laser treatment deliveredLaser treatment delivered 99%99%Adjunctive balloonAdjunctive balloon 96%96%Stent PlacementStent Placement

45%45%

Procedure SuccessProcedure Success 85%85%<50% residual stenosis at final<50% residual stenosis at final

Straight line flow to foot established Straight line flow to foot established 89%89%Hospital stay (days):Hospital stay (days): meanmean 3.03.0

medianmedian1.01.0 LACI 2 Results

34Oct 2003 LACI 2

Angiographic ResultsAngiographic ResultsVisual assessmentVisual assessment

%DS %DS LocationLocation BaselineBaseline Post-laserPost-laser FinalFinalSFASFA 91% 91% 56% 56% 16% 16% PoplitealPopliteal 94% 94% 53% 53% 14% 14% InfrapoplitealInfrapopliteal 92% 92% 53% 53% 24% 24%

• Laser provided about half of the net luminal gainLaser provided about half of the net luminal gain• Stenting was performed preferentially in larger Stenting was performed preferentially in larger vesselsvessels• Below the knee, final %DS was slightly higherBelow the knee, final %DS was slightly higher

LACI 2 Results

35Oct 2003 LACI 2

Control TreatmentsControl Treatments

Bypass or endarterectomyBypass or endarterectomy 35%35%

AngioplastyAngioplasty 5% 5%

ThrombectomyThrombectomy 3%3%

Conservative therapiesConservative therapies 57% 57%– analgesics, vasoactive, analgesics, vasoactive,

antithrombotic, oxygen therapy, etc.antithrombotic, oxygen therapy, etc.

LACI 2 Results

36Oct 2003 LACI 2

Adjudicated SAEsAdjudicated SAEs

LACILACI ControlControl ppDeathDeath 10% 10% 14% 14% nsns Major amputationMajor amputation 6% 6% 10% 10% nsnsNonfatal MI or StrokeNonfatal MI or Stroke .7% .7% 1.1% 1.1% nsnsReinterventionReintervention 17%17% 4% 4% * *Hematoma w/ surgeryHematoma w/ surgery .7% .7% .8% .8% nsnsAcute limb ischemiaAcute limb ischemia .7% .7% n/a n/aPerforation w/ surgeryPerforation w/ surgery 0 0 n/a n/aBypassBypass 2.1% 2.1% n/a n/aEndarterectomyEndarterectomy .7% .7% n/a n/a

Total SAEsTotal SAEs 38% 38% 30% 30% nsns

LACI 2 Results

37Oct 2003 LACI 2

6-Month Results: Patients6-Month Results: Patients

Total enrollmentTotal enrollment 145 patients 145 patients deathdeath 15 15 lost to follow-uplost to follow-up 11 11Reached 6-month follow-upReached 6-month follow-up 119119Major amputation in survivorsMajor amputation in survivors 99Patients with limb salvagePatients with limb salvage 110110

Intent-to-treat analysisIntent-to-treat analysis 110/145 = 76%110/145 = 76%Survival analysisSurvival analysis 110/119 = 92%110/119 = 92%

LACI 2 Results

38Oct 2003 LACI 2

6-Month Results: Limbs6-Month Results: Limbs

Total enrollmentTotal enrollment 155 limbs 155 limbs deathdeath 17 17 lost to follow-uplost to follow-up 11 11Reached 6-month follow-upReached 6-month follow-up 127127Major amputation in survivorsMajor amputation in survivors 99Limbs salvagedLimbs salvaged 118118

Intent-to-treat analysisIntent-to-treat analysis 118/155 = 76%118/155 = 76%Survival analysisSurvival analysis 118/118 = 93%118/118 = 93%

LACI 2 Results

39Oct 2003 LACI 2

Main Endpoints at 6 MonthsMain Endpoints at 6 Months

LACILACI ControlControl pp

nn 145 145 673 673

DiedDied 10% 10% 14% 14% nsns

Survived with:Survived with:

Limb salvageLimb salvage 76% 76% 73% 73% nsns

Persistent CLIPersistent CLI 30% 30% 31% 31% nsns

Any SAE*Any SAE* 38% 38% 30% 30% nsns

* Including reinterventions not originally termed SAE’s under protocol* Including reinterventions not originally termed SAE’s under protocol

LACI 2 Results

41Oct 2003 LACI 2

Ulcer Sizes Ulcer Sizes per-ulcer basisper-ulcer basis

Most healing occurred in the first 3 monthsMost healing occurred in the first 3 months

0%

20%

40%

60%

80%

100%

0 5 10 15 20

Ulcer size, cm2

Cu

mu

lati

ve

Fre

qu

en

cy

Baseline

3 months

6 months

LACI 2 Results

42Oct 2003 LACI 2

Functional OutcomesFunctional Outcomes

Of surviving legs:Of surviving legs:

69% Improved69% Improved

27% Stable27% Stable

4% Declined4% Declined

0-34

56

6

5

4

0-3

0

10

20

30

40

Category at Baseline

Category at6 months

Registry Legs

LACI 2 Results

43Oct 2003 LACI 2

Predictors of EventsPredictors of Events

Major AmputationMajor Amputation pp Category 6Category 6 .03.03 Previous minor amputationPrevious minor amputation .05.05

DeathDeath AgeAge .03.03

• by Cox proportional hazards modelingby Cox proportional hazards modeling

LACI 2 Results

44Oct 2003 LACI 2

StentingStenting

Stented Not StentedStented Not Stented n=70n=70 n=85n=85 pp

Procedure Success 93%Procedure Success 93% 79% 79% .01 .01

Straight-line flowStraight-line flow 96% 96% 84% 84% .02 .02

Limb SalvageLimb Salvage 83% 83% 71% 71% .09 .09p-values by Fisher’s Exactp-values by Fisher’s Exact

• Stents improved acute resultsStents improved acute results• Stents did not significantly affect limb salvageStents did not significantly affect limb salvage• Sample size is small (low statistical power)Sample size is small (low statistical power)

LACI 2 Results

45Oct 2003 LACI 2

LACI Phase 2 SummaryLACI Phase 2 Summary

• Treatment of complex disease – multiple stenoses and Treatment of complex disease – multiple stenoses and occlusionsocclusions

• High risk patient population – poor candidates for High risk patient population – poor candidates for surgical revascularizationsurgical revascularization

• High procedural success with few in-hospital SAE’s and High procedural success with few in-hospital SAE’s and short hospital stayshort hospital stay

• Excellent limb salvage rate despite this high-risk patient Excellent limb salvage rate despite this high-risk patient cohortcohort

LACI 2 Results

46Oct 2003 LACI 2

LACI Phase 2 SummaryLACI Phase 2 Summary

• Outcomes met all hypotheses in the Outcomes met all hypotheses in the protocolprotocol

• Statistics meet the benchmarks of Statistics meet the benchmarks of safety and effectivenesssafety and effectiveness

LACI 2 Results

47Oct 2003 LACI 2

Clinical Benefit of LACIClinical Benefit of LACI The LACI treatment strategy salvaged The LACI treatment strategy salvaged

limbs...limbs...– Efficacy endpoint equaled “the best” benchmarks Efficacy endpoint equaled “the best” benchmarks

in the literaturein the literature

……without affecting patient’s chances of without affecting patient’s chances of survival...survival...– Safety endpoint equaled “the best”Safety endpoint equaled “the best”

… …or significantly increasing patients’ or significantly increasing patients’ risk of serious adverse events.risk of serious adverse events.

Benefits

48Oct 2003 LACI 2

Clinical Benefit of LACIClinical Benefit of LACI

LACI is an intravascular interventionLACI is an intravascular intervention– avoids perioperative risks of surgeryavoids perioperative risks of surgery– shortens initial hospital stayshortens initial hospital stay– does not jeopardize future surgical does not jeopardize future surgical

options and may create new surgical options and may create new surgical optionsoptions

LACI Phase 2 results were achieved LACI Phase 2 results were achieved with virtually no surgerywith virtually no surgery

Benefits

49Oct 2003 LACI 2

Clinical Benefit of LACIClinical Benefit of LACI The LACI strategy is applicable to a wide The LACI strategy is applicable to a wide

range of vascular disease statesrange of vascular disease states– not limited to lesions amenable to PTAnot limited to lesions amenable to PTA– LACI Phase 2 enrolled essentially “all LACI Phase 2 enrolled essentially “all

comers”comers”– useful in patients with no other options for useful in patients with no other options for

limb salvagelimb salvage LACI results are predictableLACI results are predictable

– high rate of procedure successhigh rate of procedure success

Benefits

50Oct 2003 LACI 2

Technical BenefitTechnical Benefit

ELA reduces a complex lesion ELA reduces a complex lesion pattern into something that balloons pattern into something that balloons and (optional) stents can handle...and (optional) stents can handle...

Benefits

51Oct 2003 LACI 2

Progressive SimplificationProgressive Simplification

Normal Baseline Post Laser 3mm Balloon Final

Benefits

52Oct 2003 LACI 2

Other AdvantagesOther Advantages

ELA technology is matureELA technology is mature ELA skills are based on standard ELA skills are based on standard

interventional techniqueinterventional technique ELA uses “cool” UV laser ablationELA uses “cool” UV laser ablation

Benefits

53Oct 2003 LACI 2

Limb Salvage vs. Limb LossLimb Salvage vs. Limb Loss

Is limb salvage always the best Is limb salvage always the best goal?goal?

Or, stated another way:Or, stated another way: What patient groups benefit from What patient groups benefit from

limb salvage?limb salvage? What patients are better served by What patients are better served by

primary amputation?primary amputation?

Benefits of Limb Salvage

54Oct 2003 LACI 2

Clinical OutcomesClinical OutcomesIn Class C patients*In Class C patients*

revascularizationrevascularization amputationamputation

operative mortalityoperative mortality 6%6% 16%16%

hospital stay, dayshospital stay, days 1414 3131

regained ambulationregained ambulation 72%72% 44%44%

3-year survival3-year survival 76%76% 29%29%* Goldman score >9 or ASA class IV or V. * Goldman score >9 or ASA class IV or V. Surgery 1988; 104:667-672Surgery 1988; 104:667-672

Promulgated “an aggressive approach to lower-Promulgated “an aggressive approach to lower-extremity vascular reconstruction, irrespective of extremity vascular reconstruction, irrespective of medical status” medical status”


55Oct 2003 LACI 2

Quality of LifeQuality of Life Comparing revascularized patients to Comparing revascularized patients to

primary amputees:primary amputees:– Revascularization had significantly lower Revascularization had significantly lower

depression, lower impairment of social function, depression, lower impairment of social function, greater mobilitygreater mobility

– QOL maintained after reinterventionQOL maintained after reintervention– QOL similar between primary amputation and QOL similar between primary amputation and

amputation after failed revascularizationamputation after failed revascularization QOL always higher in limb salvageQOL always higher in limb salvage

Eur J Vasc Surg 1995; 9:310-313Eur J Vasc Surg 1995; 9:310-313


56Oct 2003 LACI 2

Elderly PatientsElderly Patients

In patients >80 yearsIn patients >80 yearsrevascularizationrevascularization amputationamputation

survivalsurvival 44% @ 5 yrs 28% 44% @ 5 yrs 28% @ 4 yrs @ 4 yrs

maintainedmaintainedresidential statusresidential status 88%88% 65%65%

Elderly patients fare better with Elderly patients fare better with salvaged limbssalvaged limbs

J Vasc Surg 1998; 28:215-225J Vasc Surg 1998; 28:215-225


57Oct 2003 LACI 2

TASC Recommendation 103TASC Recommendation 103

Primary amputation for CLI is indicated:Primary amputation for CLI is indicated:– Unreconstructable occlusive arterial diseaseUnreconstructable occlusive arterial disease– Necrosis of significant areas of weight-Necrosis of significant areas of weight-

bearing portions of the footbearing portions of the foot– Fixed unremediable flexion contracture of Fixed unremediable flexion contracture of

the legthe leg– Terminal illness, limited life expectancyTerminal illness, limited life expectancy

In how many patients does this apply?In how many patients does this apply?


58Oct 2003 LACI 2

Delphi Consensus StudyDelphi Consensus Study Physicians were presented with 596 Physicians were presented with 596

hypothetical CLI patient scenarioshypothetical CLI patient scenarios Surgeons and radiologists indicated Surgeons and radiologists indicated

primary amputation in 9-10% primary amputation in 9-10%

General consensus:General consensus: Vast majority should be revascularizedVast majority should be revascularized Primary amputation should be reserved Primary amputation should be reserved

for the most hopeless casesfor the most hopeless casesEur J Vasc Surg 2002; 24:411-416Eur J Vasc Surg 2002; 24:411-416


59Oct 2003 LACI 2

Medication for CLIMedication for CLI In the absence of LACI, patients at high In the absence of LACI, patients at high

risk of surgical mortality would receive risk of surgical mortality would receive medication and bed restmedication and bed rest

TASC recommends only prostanoids, and TASC recommends only prostanoids, and then only whenthen only when– revascularization has failed or is impossiblerevascularization has failed or is impossible– alternative is amputationalternative is amputation

How would this subset of patients fare?How would this subset of patients fare?

Alternative Therapy: Medication

60Oct 2003 LACI 2

Recent ReportsRecent Reports Selected reports of medication for Selected reports of medication for

treatment of CLItreatment of CLI– published in last 10 yearspublished in last 10 years– at least 100 CLI patientsat least 100 CLI patients– poor surgical candidatespoor surgical candidates– follow-up to at least 6 monthsfollow-up to at least 6 months

Compared to a subset of LACI patients Compared to a subset of LACI patients who were at high risk of surgical who were at high risk of surgical mortality (ASA Class mortality (ASA Class 4)4)


61Oct 2003 LACI 2

Literature ComparisonsLiterature ComparisonsLACIASA Class4 or above

UK SLIGroup,1991

Norgren etal, 1990

Lepantaloet al, 1996

N, patients 71 (100%) 151 103 105Hospital stay, days 3.4 4.8 14-28 >14Perioperativemortality

0

Outcomes at 6-month Follow-UpLimb salvage 49 (69%) 52% 58%Persistent CLI 15 (21%) No CLI in

26%Death 10 (14%) 8% 13% 42%Major amputation 4 (6%) 37% 38%Surgical bypass 1 (1%) 11%Total SAEs 28 (39%) 48% 51% 42%


62Oct 2003 LACI 2

SummarySummary

Outlook for conservatively-treated Outlook for conservatively-treated CLI is dismalCLI is dismal– 37% amputation in 6 months37% amputation in 6 months– high incidence of adverse eventshigh incidence of adverse events

LACI provided greater limb LACI provided greater limb salvage, fewer SAEs, and shorter salvage, fewer SAEs, and shorter hospital stayshospital stays


63Oct 2003 LACI 2

Why not randomize vs. Meds?Why not randomize vs. Meds?

Randomizing against a treatment Randomizing against a treatment plan that promises 37% major plan that promises 37% major amputation at 6 months has amputation at 6 months has ethical issuesethical issues


64Oct 2003 LACI 2

Amputation for CLIAmputation for CLI It might be proposed that patients who It might be proposed that patients who

are not at a high risk of surgical mortality are not at a high risk of surgical mortality may better benefit from primary may better benefit from primary amputation.amputation.

Is this true for Is this true for allall CLI patients who are CLI patients who are not at a high risk of surgical mortality?not at a high risk of surgical mortality?

How would this subset of patients fare?How would this subset of patients fare?

Alternative Therapy: Amputation

65Oct 2003 LACI 2

Recent ReportsRecent Reports Selected reports of amputation for Selected reports of amputation for

treatment of CLItreatment of CLI– at least 100 CLI patientsat least 100 CLI patients– follow-up statistics for comparisonsfollow-up statistics for comparisons

Compared to a subset of LACI Compared to a subset of LACI patients who were not at high risk patients who were not at high risk of surgical mortality (not ASA Class of surgical mortality (not ASA Class 4)4)


66Oct 2003 LACI 2

Literature Comparisons Literature Comparisons 1/21/2

LACI -Not ASA Class4 or higher

Ouriel et al,1988

Bunt et al,1984

N, patients 84 (100%) 158 BKA 113 BKA140 AKA

Hospital stay, days 2.6 5.3 days 19Perioperativemortality

0% 7.6%¤ 1% BKA3% AKA

Outcomes at Follow-UpLimb salvage 69 (82%) 0% 0%Persistent CLI 28 (33%) - 0%Death 5 (6%) (within 6

months)8% -

Reintervention 13 (15%) - -Major amputation 7 (8%) - -Total SAEs 30 (36%) - -

¤30 days


67Oct 2003 LACI 2


LACI - NotASA Class 4or higher

Rush et al, 1981 Dormandy et al,1994

N, patients 84 (100%) 135 BKA121 AKA

713 BKA

Hospital stay,days

2.6 5.3 days 22 BKA36 AKA

33**

Perioperativemortality

0 6% BKA11% AKA

1%

Outcomes at Follow-Up

Limb salvage 69 (82%) 0% 0%Persistent CLI 28 (33%) 0% 11% unhealed

stumpsDeath 5 (6%) (within

6 months)21% BKA*34% AKA*

11%†

Reintervention 13 (15%) 19% BKA to AKA 19% BKA to AKA

Major amputation 7 (8%) 100% 100%Total SAEs 30 (36%) 34% 30%

*12 months **among thosepts dischargedby 3 months†3 months


68Oct 2003 LACI 2

SummarySummary Patients receiving primary amputation are Patients receiving primary amputation are

at risk for:at risk for:– perioperative mortalityperioperative mortality– long hospital staylong hospital stay– high incidence of secondary amputation, high incidence of secondary amputation,

BKA BKA AKA AKA LACI provided limb salvage with shorter LACI provided limb salvage with shorter

hospital stays and decreased hospital stays and decreased perioperative and post-operative mortalityperioperative and post-operative mortality


69Oct 2003 LACI 2

Why not randomize vs. Amp?Why not randomize vs. Amp?

Randomizing against a treatment Randomizing against a treatment plan that promises 100% major plan that promises 100% major amputation with a high death rate, amputation with a high death rate, both perioperative and long term, both perioperative and long term, has ethical issueshas ethical issues


70Oct 2003 LACI 2

Bypass for CLIBypass for CLI

Bypass surgery is the “gold standard” for Bypass surgery is the “gold standard” for treatment of CLI.treatment of CLI.– Outcomes after bypass could be used as a Outcomes after bypass could be used as a

possible benchmark for safety and efficacypossible benchmark for safety and efficacy LACI patients were poor surgical LACI patients were poor surgical

candidatescandidates– Bypass was not a treatment optionBypass was not a treatment option

How do LACI outcomes compare with the How do LACI outcomes compare with the “gold standard”?“gold standard”?

Alternative Therapy: Bypass

71Oct 2003 LACI 2

Recent ReportsRecent Reports Selected reports of bypass for Selected reports of bypass for

treatment of CLItreatment of CLI– patients treated with current bypass patients treated with current bypass

standards (treatment period 1987 - standards (treatment period 1987 - 2000)2000)

– autogenous vein graftsautogenous vein grafts– infrainguinal revascularizationinfrainguinal revascularization

Compared to all LACI patientsCompared to all LACI patients


72Oct 2003 LACI 2


LACI 2 Pomposelli,2003

Toursarkissian,2002

Treated during 2000-01 1990-2000 -Pts/limbs 145/155 865/ 1032 64/ 68CLI 100% 100% 100%Pt selection All poor surgical

candidates, 66%diabetic

92% diabetic 100% diabetic

Graft type;placement

99.8%autogenous;DP

94.1%autogenous;infrainguinal

Follow-uptimeframe

6 months 23.6 months(1 – 120)

12 6 months(1-26)

Reintervention/graft revisionw/in 30 days

2 (1.3%) 71 (7.9%):13 (1.3%)revisions plus 68(6.6%) underwentunexpected earlyreoperation

-

Reintervention/graft revisionduring follow-up

22 (14.2%) - 13 (19.1%), at amean of 4 3months

Bypass 2% 100% 100%Death 0%*

10%‡1.0%*51.4% at 5 yrs

-

Majoramputation

7%‡ 78.2% LS at 5 yrs 11.8%

*30 day ‡6 months †1 year LS = Limb Salvage, DP = Dorsalis Pedis, GSV = Greater Saphenous Vein


73Oct 2003 LACI 2


LACI 2 Curi, 2002 (GSVarm of study)

Kalra, 2001

Treated during 2000-01 1995-2000 1987-1998Pts/limbs 145/155 239 bypasses 256/ 280CLI 100% LS attempt in 91% 100%Pt selection All poor surgical

candidates, 66%diabetic

62% diabetic 74.6% diabetic

Graft type;placement

100%autogenous;infrageniculate

100%autogenous;DP

Follow-uptimeframe

6 months 18 months(0.1-79)

2.7 yrs(0.1-10.1)

Reintervention/graft revisionw/in 30 days

2 (1.3%) - 9 (3.2%)

Reintervention/graft revisionduring follow-up

22 (14.2%) - 23 (8.2%)

Bypass 2% 100% 100%Death 0%*

10%‡2.1%*~25% at 4 yrs

1.6%*30.2% during f-up

Majoramputation

7%‡ 4.6%* 18.2%

*30 day ‡6 months †1 year LS = Limb Salvage, DP = Dorsalis Pedis, GSV = Greater Saphenous Vein


74Oct 2003 LACI 2

SummarySummary Patients receiving bypass are at risk for Patients receiving bypass are at risk for

early in-hospital complications early in-hospital complications including:including:– reintervention (graft revision or early re-reintervention (graft revision or early re-

operation)operation)– death at 30 daysdeath at 30 days

LACI provided limb salvage with very LACI provided limb salvage with very little need of bypass for patients who little need of bypass for patients who were poor surgical candidateswere poor surgical candidates


75Oct 2003 LACI 2

Why not randomize vs. Bypass?Why not randomize vs. Bypass?

LACI patients were poor surgical LACI patients were poor surgical candidatescandidates– high risk of surgical mortality, and/orhigh risk of surgical mortality, and/or– lack of distal anastomosis site, and/orlack of distal anastomosis site, and/or– lack of venous conduit for bypasslack of venous conduit for bypass


76Oct 2003 LACI 2

PTA for CLIPTA for CLI Literature reports several single-center Literature reports several single-center

experiences since early ‘80sexperiences since early ‘80s Results were variableResults were variable

– patient selection criteria differed site-to-sitepatient selection criteria differed site-to-site– pre-selected disease patternspre-selected disease patterns– adjunctive use or other treatments (atherectomy, adjunctive use or other treatments (atherectomy,

thrombectomy, stents, etc) often not reportedthrombectomy, stents, etc) often not reported– follow-up intervals varied widelyfollow-up intervals varied widely

No trials of PTA vs. anything in the past 15 No trials of PTA vs. anything in the past 15 yearsyears

Alternative Therapy: PTA

77Oct 2003 LACI 2

Current ConsensusCurrent Consensus

TASC document recommends PTA for CLI TASC document recommends PTA for CLI only in simple lesions:only in simple lesions:– Type A: single stenoses <1 cmType A: single stenoses <1 cm

TASC does not recommend PTA in:TASC does not recommend PTA in:– Type B: multiple short stenosesType B: multiple short stenoses– Type C: long stenoses; short occlusionsType C: long stenoses; short occlusions– Type D: occlusions >2cm; diffuse diseaseType D: occlusions >2cm; diffuse disease

surgery is recommended for Type Dsurgery is recommended for Type D


78Oct 2003 LACI 2

TASC Types in LACITASC Types in LACI

TASC Lesion TypeTASC Lesion Type LACI legs LACI legs n=155n=155

A : short stenosesA : short stenoses 3 (2%) 3 (2%)

B : multiple short lesionsB : multiple short lesions 13 (8%)13 (8%)

C : complex patternsC : complex patterns 44 (28%)44 (28%)

D : long diffuse diseaseD : long diffuse disease 93 (60%)93 (60%)

insufficient data in 2/155 casesinsufficient data in 2/155 cases


79Oct 2003 LACI 2

Recent Reports of PTA in CLIRecent Reports of PTA in CLI

Selected recent articles Selected recent articles 8 years old 8 years old 50 patients 50 patients – follow-up follow-up 6 months 6 months – CLI in CLI in 90% of patients90% of patients

Inclusive of modern balloons, Inclusive of modern balloons, stents, anticoagulants, closure stents, anticoagulants, closure devicesdevices


80Oct 2003 LACI 2


LACI 2 Soder2000

Lofberg1996

Matsi1994

Treated during 2000-01 1996-7 1989-93 1989-92Pts/limbs 145/155 60/72 82/86 103/117CLI 100% 100% 100% 100%Pt selection All poor

surgicalcandidates

Selectedfor PTA

Selectedfor PTA

Selectedfor PTA

Total treated length 16.2 cm 3.8 cm - 10.6 cmLesions/limb 2.7 2.6 2.3 1.8Reintervention 15%‡ 11%‡ 12%† 9%†

Bypass 2%‡ - 15%† 7%Death 10%‡ 25%† 17%† 9%*Major amputation 7%‡ 17%† 19%‡ 21%*

*30 day ‡6 months †1 year


81Oct 2003 LACI 2


‡6 months †1 year ª5 year, initial successes only

LACI 2 Danielsson2001

Dorros 2001

Treated during 2000-01 1990-97 1983-96Pts/limbs 145/155 140/155 235/284CLI 100% 90% 100%Pt selection All poor

surgicalcandidates

Selected forPTA

Selected forPTA; resultson successfulPTA only

Total treated length 16.2 cm -Lesions/limb 2.7 1.5 2.3Reintervention 15%‡ 10%†

Bypass 2%‡ 6%† 8%ªDeath 10%‡ 15%† 10%†

Major amputation 7%‡ 10%† 9%ª


82Oct 2003 LACI 2

SummarySummary

Literature reports patients pre-Literature reports patients pre-selected for PTA, not “all comers”selected for PTA, not “all comers”

Some articles report on initial Some articles report on initial successes onlysuccesses only

If the index procedure is If the index procedure is successful, results may be successful, results may be comparable to LACIcomparable to LACI


83Oct 2003 LACI 2

SummarySummary Compared to these articles, LACI hadCompared to these articles, LACI had

– lower incidence of bypasslower incidence of bypass– fewer major amputationsfewer major amputations– similar rate of reinterventionsimilar rate of reintervention– similar rate of deathsimilar rate of death– more complex diseasemore complex disease– more fragile patient setmore fragile patient set

LACI outcomes equaled “the best” despite LACI outcomes equaled “the best” despite possible bias in the LACI populationpossible bias in the LACI population


84Oct 2003 LACI 2

Why not randomize vs. PTA?Why not randomize vs. PTA?

PTA is not recommended for all PTA is not recommended for all disease patterns in CLI (see TASC)disease patterns in CLI (see TASC)

Evidence that PTA can be Evidence that PTA can be successful in CLI/poor surgical successful in CLI/poor surgical candidates is lacking; question of candidates is lacking; question of ethics in the control groupethics in the control group

No study has made PTA the “gold No study has made PTA the “gold standard”standard”


85Oct 2003 LACI 2

Study DesignStudy Design Randomized studies are easier to Randomized studies are easier to

interpret than other controlled designsinterpret than other controlled designs

Could LACI have been randomized?Could LACI have been randomized? Is there one control-group therapy thatIs there one control-group therapy that

– is the standard of care,is the standard of care,– is indicated for LACI patients, andis indicated for LACI patients, and– avoids the ethical issue of substandard care avoids the ethical issue of substandard care

in the control group?in the control group?

Why not randomize?

86Oct 2003 LACI 2

Candidate Control TherapiesCandidate Control Therapies

Medication (conservative therapy)Medication (conservative therapy) Primary amputationPrimary amputation PTA + optional stentsPTA + optional stents Bypass surgeryBypass surgery

Why not randomize?

87Oct 2003 LACI 2

Why not randomize vs. Bypass?Why not randomize vs. Bypass?

LACI patients were poor surgical LACI patients were poor surgical candidatescandidates

Perioperative death is 1-10% Perioperative death is 1-10% higher for bypass than for LACIhigher for bypass than for LACI

Why not randomize?

88Oct 2003 LACI 2

Why not randomize vs. Amp?Why not randomize vs. Amp? Patients receiving primary amputation are Patients receiving primary amputation are

at risk for:at risk for:– perioperative mortalityperioperative mortality– long hospital staylong hospital stay– high incidence of secondary amputation, high incidence of secondary amputation,

BKA BKA AKA AKA Randomizing against a treatment plan that Randomizing against a treatment plan that

promises 100% major amputation with a promises 100% major amputation with a high death rate, both perioperative and long high death rate, both perioperative and long term, has ethical issuesterm, has ethical issues

Why not randomize?

89Oct 2003 LACI 2

Why not randomize vs. Meds?Why not randomize vs. Meds?

Outlook for conservatively-treated CLI is Outlook for conservatively-treated CLI is dismaldismal– 37% amputation in 6 months37% amputation in 6 months– high incidence of adverse eventshigh incidence of adverse events

LACI provided greater limb salvage, fewer LACI provided greater limb salvage, fewer SAEs, and shorter hospital stays SAEs, and shorter hospital stays

Randomizing against a treatment plan Randomizing against a treatment plan that promises 37% major amputation at 6 that promises 37% major amputation at 6 months has ethical issuesmonths has ethical issues

Why not randomize?

90Oct 2003 LACI 2

PTA SummaryPTA Summary Literature reports patients pre-selected Literature reports patients pre-selected

for PTA, not “all comers”for PTA, not “all comers” Some articles report on initial successes Some articles report on initial successes

onlyonly There is no definitive study making PTA There is no definitive study making PTA

the standard in CLIthe standard in CLI– We lack statistics needed to design a study We lack statistics needed to design a study

using PTA as controlusing PTA as control– Would an IRB allow a non-standard control?Would an IRB allow a non-standard control?

Why not randomize?

91Oct 2003 LACI 2

TASC Types in LACITASC Types in LACI

TASC Lesion TypeTASC Lesion Type LACI LACI legslegs

A : short stenosesA : short stenoses 2% 2%

B : multiple short lesionsB : multiple short lesions 8% 8%

C : complex patternsC : complex patterns 28%28%

D : long diffuse diseaseD : long diffuse disease 60%60%

TASC says: PTA

Surgery

Why not randomize?

92Oct 2003 LACI 2

Why not randomize vs. PTA?Why not randomize vs. PTA?

PTA is not recommended for all PTA is not recommended for all disease patterns in CLI (see TASC)disease patterns in CLI (see TASC)

Evidence that PTA can be Evidence that PTA can be successful in CLI/poor surgical successful in CLI/poor surgical candidates is lackingcandidates is lacking

Question of ethics in a PTA control Question of ethics in a PTA control groupgroup

Why not randomize?

93Oct 2003 LACI 2

Randomization SummaryRandomization Summary

No one therapy is appropriate, ethical, No one therapy is appropriate, ethical, and standard-of-care for this and standard-of-care for this populationpopulation

Randomization would be unworkableRandomization would be unworkable

What does that leave?What does that leave? Self-controlled study designsSelf-controlled study designs Historical controlsHistorical controls

Why not randomize?

94Oct 2003 LACI 2

Best-Case Historical ControlBest-Case Historical Control Exact match in patient characteristicsExact match in patient characteristics Huge enrollmentHuge enrollment Full statistics, excellent follow-upFull statistics, excellent follow-up Treatment plan defines “standard”Treatment plan defines “standard”

– in this case, a mixed set of modalities in this case, a mixed set of modalities that uses best-case therapy for each that uses best-case therapy for each patientpatient

Conforms to TASC definitionsConforms to TASC definitions

Why not randomize?

95Oct 2003 LACI 2

ICAI StudyICAI Study Italian multicenter randomized study of Italian multicenter randomized study of

Prostaglandin E1 in CLI patientsProstaglandin E1 in CLI patients– 771 in alprostadil group771 in alprostadil group– 789 in control group789 in control group

Control group received variety of therapies Control group received variety of therapies (bypass, endarterectomy, medication, and (bypass, endarterectomy, medication, and a few PTAs)a few PTAs)– ““the best you can do” for these patientsthe best you can do” for these patients

Ann Intern Med 1999; 130:412-421Ann Intern Med 1999; 130:412-421 Conforms to TASC definitions and GCPConforms to TASC definitions and GCP

Why not randomize?

96Oct 2003 LACI 2

ICAI Study: DifferencesICAI Study: Differences ICAI differs from LACI slightlyICAI differs from LACI slightly ICAI enrolled CLI patients regardless of ICAI enrolled CLI patients regardless of

candidacy for surgerycandidacy for surgery– 35% of ICAI patients received surgery as 35% of ICAI patients received surgery as

their primary treatment optiontheir primary treatment option– LACI enrolled only poor surgical candidatesLACI enrolled only poor surgical candidates

ICAI treatment plan is ICAI treatment plan is notnot an alternative an alternative for LACI patientsfor LACI patients

Why not randomize?

97Oct 2003 LACI 2

ICAI Study: ImplicationsICAI Study: Implications ICAI treatment plan is not a fall-back plan ICAI treatment plan is not a fall-back plan

for LACI patientsfor LACI patients– LACI population is not eligible for the same LACI population is not eligible for the same

treatments, and hence may not enjoy the treatments, and hence may not enjoy the same outcomes as ICAI patientssame outcomes as ICAI patients

ICAI statistics represent the benchmark ICAI statistics represent the benchmark for “the best you can do”for “the best you can do”

If ICAI statistics are safe and effective, If ICAI statistics are safe and effective, then a treatment plan with equal then a treatment plan with equal statistics must also be safe and effectivestatistics must also be safe and effective

Why not randomize?

98Oct 2003 LACI 2

Implications for LACIImplications for LACI ICAI sets the benchmark as high as ICAI sets the benchmark as high as

possiblepossible– ““the best you can do”the best you can do”– including surgery in 35% of patientsincluding surgery in 35% of patients

We chose the highest benchmark we We chose the highest benchmark we could find against which to measure LACIcould find against which to measure LACI

The control statistics are The control statistics are benchmarksbenchmarks, , not a true measure of alternatives not a true measure of alternatives available to the LACI populationavailable to the LACI population

Why not randomize?

ppt

Documents

stent laci

history laci phase

results benefits of

significant laci

sites laci

laci pi introductions

registry laci

limbs laci