1. PROSPECTIVE RANDOMIZED COMPARATIVE STUDY BETWEEN FEMORO-DISTAL BYPASS WITH PTFE AND HEPARIN-BONDED PTFE.

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

3. Results with heparin-bonding Clinical data –1 randomized study in dacron grafts: In 209 patients a significant improvement in results could be shown between a heparin-bonded Dacron prosthesis and uncoated PTFE (Devine, et al; Journal of vascular surgery, 33(3):533-539). –No randomized studies in PTFE grafts Animal experiments –Heparin-bonded PTFE-grafts caused less distal micro-embolisation than PTFE-grafts irrigated with heparin (Ritter, et al; Surgery, 122(5):888- 892). –The patency was higher and thrombus deposition less in an interposition experiment in dogs (Begovac, et al; European journal of vascular and endovascular surgery, 25(5):432-437). –Heparin coated PTFE-grafts had a better patency than uncoated grafts in a rat experiment (Walpoth, et al; Circulation, 98(19):II319-II323, suppl S, nov 10,1998).

4. Jotec heparin-bonded PTFE graft Bonding of heparin to PTFE by means of a covalent binding and ionic interactions. In-vitrotests could show less platelet adhesion to the surface, also resulting in a thinner neo-intimal layer. Studies on results in vivo or on the influence on patency are not available. Randomised studies between PTFE- grafts with and without heparin bonding are totally lacking.

5. Results with heparin-bonded grafts

6. Evidence based medicine

7. PROSPECTIVE RANDOMIZED COMPARATIVE STUDY BETWEEN FEMORO-DISTAL BYPASS WITH PTFE AND HEPARIN-BONDED PTFE.

8. Study-design This study was set up as a prospective, open label, randomised, multi-centre study comparing heparin- bonded PTFE-grafts with the same PTFE-grafts without heparin-bonding. The goal was to randomize 520 patients in 20 centres over a 3 years inclusion period, with 2 years of follow-up. The primary endpoint is primary patency; secundary endpoints are secundary patency, limb salvage and mortality. Study started may 2004 in 24 centres

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

10. Statistics Patency-results will be analysed according to an actuarial life-table analysis. Differences will be analysed with the logrank test. A p<0.05 value will be considered as significant. A multi-variate analysis will be performed for potential risk-factors. 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 two-sided alpha error of 0.05. Interim analyses are foreseen every 6 months. Subanalyses will be performed for above and below knee reconstructions separately.

11. Inclusion criteria Symptomatic peripheral vascular disease (Fontaine IIB-IV) Occlusion or significant stenosis of SFA and/or popliteal artery > 6 cms Adequate outflow artery Informed consent Follow-up possible

12. Exclusion criteria Acute limb ischemia Patient planned for amputation Ipsilateral, not corrected > 70% inflow stenosis Age < 18 yrs Patient possibly pregnant Age expectancy < 1 yr Recent AMI (< 1 mth) Allergy for contrast or heparin Important bleeding or coagulation disorder

13. Follow-up Follow-up visits at 1, 3, 6, 12, 24 months Evaluation of patency by clinical examination and ABI at each visit Duplex at 1, 12 and 24 months and when graft occlusion is suspected

14. Inclusions Overall –467 patients in 29 centres –Mean FU = 636 days (sd 335 days) –Median FU = 703 days

15. INCLUSIONS

16. Results – Interim analysis Occlusions –Primary graft occlusions 90/476 (19 %) –Mean FU = 219 days (sd 194 days) –Median FU = 167 days

17. OCCLUSIONS

18. ABOVE KNEE BELOW KNEE p=0,0298 Results – Interim analysis

19. HEPARIN NON HEPARIN p=0,0525 Results – Interim analysis

20. Management after occlusion 110 occlusion in 90 patients 90 primary occlusion 16 reocclusions 4 third occlusion 21 treated conservatively 40 received thrombolysis 27 received thrombectomy 23 received a new bypass 4 had an amputation

21. Management after occlusions ABOVEBELOW 7238 25472315 hepnonhephepnonhep conservative311 not sign. not sign. 52 thrombolysis121675 thrombectomie71154 new bypass 7844 amputation0130

22. European study Randomized study in Germany Registries in The Netherlands, Italy, … Increases the power of the study Enables to test for a lesser difference Large European database of patients with PAD undergoing femoropopliteal bypass –Analysis of results in function of risk-factors –Influence of drug-treatment (statins, ACEI, etc) –Fate after occlusion –Etc..

23. Conclusions Heparin-bonding on PTFE-grafts can theoreticaly improve patency Randomized trials are needed to prove this with level 1 evidence It is feasible to set up a randomized trial between PTFE and heparin bonded PTFE grafts The results with the Jotec-prostheses in the femoro-politeal area are promising Final results of the Belgian study are expected in one year from now A large European database will enable us to answer a lot of collateral questions