PROSPECTIVE RANDOMIZED PROSPECTIVE RANDOMIZED

COMPARATIVE STUDY BETWEEN COMPARATIVE STUDY BETWEEN

FEMORO-DISTAL BYPASS WITHFEMORO-DISTAL BYPASS WITH

PTFE AND HEPARIN-BONDED PTFE. PTFE AND HEPARIN-BONDED PTFE.

IntroductionIntroduction

The long term-results in femoro-popliteal reconstructions The long term-results in femoro-popliteal reconstructions with synthetic grafts are less good than with autologous with synthetic grafts are less good than with autologous veinsveinsReasons for that difference are the higher Reasons for that difference are the higher thrombogenicity of the inner surface of these grafts thrombogenicity of the inner surface of these grafts compared to the endothelium at the inner surface of compared to the endothelium at the inner surface of autologous veins and the more pronounced formation of autologous veins and the more pronounced formation of intimal hyperplasia. intimal hyperplasia. Heparin-bonding could theoretically reduce Heparin-bonding could theoretically reduce thrombogenicity and diminish intimal hyperplasiathrombogenicity and diminish intimal hyperplasia

Results with heparin-bondingResults with heparin-bonding

Clinical dataClinical data– 1 randomized study in dacron grafts:1 randomized study in dacron grafts:

In 209 patients a significant improvement in results could be shown In 209 patients a significant improvement in results could be shown between a heparin-bonded Dacron prosthesis and uncoated PTFE between a heparin-bonded Dacron prosthesis and uncoated PTFE (Devine, et al; Journal of vascular surgery, 33(3):533-539).(Devine, et al; Journal of vascular surgery, 33(3):533-539).

– No randomized studies in PTFE graftsNo randomized studies in PTFE grafts

Animal experimentsAnimal experiments– Heparin-bonded PTFE-grafts caused Heparin-bonded PTFE-grafts caused less distal micro-embolisationless distal micro-embolisation than than

PTFE-grafts irrigated with heparin (Ritter, et al; Surgery, 122(5):888- PTFE-grafts irrigated with heparin (Ritter, et al; Surgery, 122(5):888-892). 892).

– The The patency was higher and thrombus deposition lesspatency was higher and thrombus deposition less in an in an interposition experiment in dogs (Begovac, et al; European journal of interposition experiment in dogs (Begovac, et al; European journal of vascular and endovascular surgery, 25(5):432-437).vascular and endovascular surgery, 25(5):432-437).

– Heparin coated PTFE-grafts had a Heparin coated PTFE-grafts had a better patencybetter patency than uncoated grafts than uncoated grafts in a rat experiment (Walpoth, et al; Circulation, 98(19):II319-II323, suppl in a rat experiment (Walpoth, et al; Circulation, 98(19):II319-II323, suppl S, nov 10,1998).S, nov 10,1998).

Jotec heparin-bonded PTFE graftJotec heparin-bonded PTFE graft

Bonding of heparin to PTFE by means of a covalent binding Bonding of heparin to PTFE by means of a covalent binding and ionic interactions. In-vitrotests could show less and ionic interactions. In-vitrotests could show less platelet adhesion to the surface, also resulting in a platelet adhesion to the surface, also resulting in a thinner neo-intimal layer. thinner neo-intimal layer.

Studies on results in vivo or on the influence on patency Studies on results in vivo or on the influence on patency are not available. Randomised studies between PTFE-are not available. Randomised studies between PTFE-grafts with and without heparin bonding are totally grafts with and without heparin bonding are totally lacking.lacking.

Results with heparin-bonded graftsResults with heparin-bonded grafts

Evidence based medicineEvidence based medicine

PROSPECTIVE RANDOMIZED PROSPECTIVE RANDOMIZED

COMPARATIVE STUDY BETWEEN COMPARATIVE STUDY BETWEEN

FEMORO-DISTAL BYPASS WITHFEMORO-DISTAL BYPASS WITH

PTFE AND HEPARIN-BONDED PTFE. PTFE AND HEPARIN-BONDED PTFE.

Study-designStudy-design

This study was set up as a prospective, open label, This study was set up as a prospective, open label, randomised, multi-centre study comparing heparin-randomised, multi-centre study comparing heparin-bonded PTFE-grafts with the same PTFE-grafts without bonded PTFE-grafts with the same PTFE-grafts without heparin-bonding. The goal was to randomize 520 heparin-bonding. The goal was to randomize 520 patients in 20 centres over a 3 years inclusion period, patients in 20 centres over a 3 years inclusion period, with 2 years of follow-up. with 2 years of follow-up.

The primary endpoint is primary patency; secundary The primary endpoint is primary patency; secundary endpoints are secundary patency, limb salvage and endpoints are secundary patency, limb salvage and mortality. mortality.

Study started may 2004 in 24 centresStudy started may 2004 in 24 centres

Study-designStudy-design

Randomisation is performed for each centre on a 1/1 basis Randomisation is performed for each centre on a 1/1 basis between both grafts. For randomisation no difference is between both grafts. For randomisation no difference is made between above and below knee interventions, nor made between above and below knee interventions, nor for other risk factors. Stratification, separate analysis and for other risk factors. Stratification, separate analysis and multi-variate analysis will allow to compensate for multi-variate analysis will allow to compensate for differences between both groups if these risk factors differences between both groups if these risk factors would prove to be significant or unevenly distributed would prove to be significant or unevenly distributed between both groups.between both groups.

StatisticsStatistics

Patency-results will be analysed according to an actuarial Patency-results will be analysed according to an actuarial life-table analysis. Differences will be analysed with the life-table analysis. Differences will be analysed with the logrank test. A p<0.05 value will be considered as logrank test. A p<0.05 value will be considered as significant. A multi-variate analysis will be performed for significant. A multi-variate analysis will be performed for potential risk-factors. potential risk-factors.

The study has a power of 0,8 to detect a relative difference The study has a power of 0,8 to detect a relative difference of 1.3, assuming a patency of 50% after 3 years with a of 1.3, assuming a patency of 50% after 3 years with a two-sided alpha error of 0.05.two-sided alpha error of 0.05.

Interim analyses are foreseen every 6 months.Interim analyses are foreseen every 6 months.Subanalyses will be performed for above and below knee Subanalyses will be performed for above and below knee

reconstructions separately.reconstructions separately.

Inclusion criteriaInclusion criteria

Symptomatic peripheral vascular disease Symptomatic peripheral vascular disease (Fontaine IIB-IV)(Fontaine IIB-IV)

Occlusion or significant stenosis of SFA Occlusion or significant stenosis of SFA and/or popliteal artery > 6 cmsand/or popliteal artery > 6 cms

Adequate outflow arteryAdequate outflow artery

Informed consentInformed consent

Follow-up possibleFollow-up possible

Exclusion criteriaExclusion criteria

Acute limb ischemiaAcute limb ischemiaPatient planned for amputationPatient planned for amputationIpsilateral, not corrected > 70% inflow stenosisIpsilateral, not corrected > 70% inflow stenosisAge < 18 yrsAge < 18 yrsPatient possibly pregnantPatient possibly pregnantAge expectancy < 1 yrAge expectancy < 1 yrRecent AMI (< 1 mth)Recent AMI (< 1 mth)Allergy for contrast or heparinAllergy for contrast or heparinImportant bleeding or coagulation disorderImportant bleeding or coagulation disorder

Follow-upFollow-up

Follow-up visits at 1, 3, 6, 12, 24 monthsFollow-up visits at 1, 3, 6, 12, 24 months

Evaluation of patency by clinical Evaluation of patency by clinical examination and ABI at each visitexamination and ABI at each visit

Duplex at 1, 12 and 24 months and when Duplex at 1, 12 and 24 months and when graft occlusion is suspectedgraft occlusion is suspected

InclusionsInclusions

OverallOverall– 467 patients in 29 centres467 patients in 29 centres– Mean FU = 636 days (sd 335 days)Mean FU = 636 days (sd 335 days)– Median FU = 703 daysMedian FU = 703 days

0

20

40

60

80

Inclusions

Aantal 66 57 51 40 30 22 21 18 13 13 12 10 10 9 7 6 4 4 4 4 4 2

SJUG

LM

KU

ZL

WI

SL

VU

JYBO

AS

KO

SZ

MM

MS

NL

HS

GZ

GI IXCT

UA

450

ABOVE KNEE325

BELOW KNEE125

HEPARIN154

NON HEPARIN171

HEPARIN74

NON HEPARIN51

AFS : 16 P1 : 309

P3 : 91ATA : 15

FA : 6ATP : 13

INCLUSIONS

Results – Interim analysisResults – Interim analysis

OcclusionsOcclusions– Primary graft occlusions 90/476 (19 %)Primary graft occlusions 90/476 (19 %)– Mean FU = 219 days (sd 194 days)Mean FU = 219 days (sd 194 days)– Median FU = 167 daysMedian FU = 167 days

Occlusions

90

164

primary

secundary

tertiary

OCCLUSIONSOCCLUSIONS

110

ABOVE KNEE72

BELOW KNEE38

90 primary16 secondary

4 tertiary

HEPARIN25

HEPARIN23

NON HEPARIN47

NON HEPARIN15

BELOW01

Overall Patency

0 200 400 600 800 1000 1200

Timeheparine + nonheparine

100

90

80

70

60

50

40

30

20

10

0

Sur

viva

l pro

babi

lity

(%)

ABOVE KNEE

BELOW KNEE

p=0,0298

Results – Interim analysisResults – Interim analysis

Primary patency

0 200 400 600 800 1000 1200

TimeAll bypasses

100

90

80

70

60

50

40

30

20

10

0

Sur

viva

l pro

babi

lity

(%)

HEPARIN

NON HEPARINp=0,0525

Results – Interim analysisResults – Interim analysis

Management after occlusionManagement after occlusion110 occlusion in 90 patients110 occlusion in 90 patients90 primary occlusion90 primary occlusion16 reocclusions16 reocclusions4 third occlusion4 third occlusion

21 treated conservatively21 treated conservatively40 received thrombolysis40 received thrombolysis27 received thrombectomy27 received thrombectomy23 received a new bypass23 received a new bypass4 had an amputation4 had an amputation

Occlusions

90

16 4

primary

secundary

tertiary

Treatment

18%

36%23%

20%3%

conservativethrombolysisthrombectomynew bypassamputation

Management after occlusionsManagement after occlusions

ABOVEABOVE BELOWBELOW

7272 3838

2525 4747 2323 1515

hephep nonhepnonhep hephep nonhepnonhepconservativeconservative 33 1111   

    not not

signsign..    

55 22

thrombolysisthrombolysis 1212 1616 77 55

thrombectomiethrombectomie 77 1111 55 44

new bypassnew bypass 77 88 44 44

amputationamputation 00 11 33 00

European studyEuropean study

Randomized study in GermanyRandomized study in GermanyRegistries in The Netherlands, Italy, …Registries in The Netherlands, Italy, …Increases the power of the studyIncreases the power of the studyEnables to test for a lesser differenceEnables to test for a lesser differenceLarge European database of patients with PAD Large European database of patients with PAD undergoing femoropopliteal bypassundergoing femoropopliteal bypass– Analysis of results in function of risk-factorsAnalysis of results in function of risk-factors– Influence of drug-treatment (statins, ACEI, etc)Influence of drug-treatment (statins, ACEI, etc)– Fate after occlusionFate after occlusion– Etc..Etc..

ConclusionsConclusions

Heparin-bonding on PTFE-grafts can Heparin-bonding on PTFE-grafts can theoreticaly improve patencytheoreticaly improve patencyRandomized trials are needed to prove this with Randomized trials are needed to prove this with level 1 evidencelevel 1 evidenceIt is feasible to set up a randomized trial It is feasible to set up a randomized trial between PTFE and heparin bonded PTFE graftsbetween PTFE and heparin bonded PTFE graftsThe results with the Jotec-prostheses in the The results with the Jotec-prostheses in the femoro-politeal area are promisingfemoro-politeal area are promisingFinal results of the Belgian study are expected in Final results of the Belgian study are expected in one year from nowone year from nowA large European database will enable us to A large European database will enable us to answer a lot of collateral questionsanswer a lot of collateral questions