The titanium nitride oxide stent an alternative to DES. Adam de Belder MD FRCP Sussex Cardiac Centre BSUH on behalf of Hexacath

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1 The titanium nitride oxide stent an alternative to DES Adam de Belder MD FRCP Sussex Cardiac Centre BSUH on behalf of Hexacath

2 Advanced Angioplasty 2008 Declaration of interest I have received an honorarium for this talk from Hexacath

3 Are DES the answer to all coronary problems? n Late stent thrombosis n Polymer issue and re-endothelialisation n Negative late loss n Prolonged antiplatelet therapy n Evidence for life prolongation

4 Etc

5 Late stent thrombosis

6 DES IMPEDE RE-ENDOTHELIALIZATION Incomplete DES endothelialization BMS fully endothelialized CYPHER 16 months post implantation with uncomplete endothelialization

7 DES IMPEDES RE-ENDOTHELIALIZATION 40 MONTHS AFTER IMPLANTATION BMS 100% RE-ENDOTHELIALIZED DES <50% RE-ENDOTHELIALIZED

8 50% OF THE CYPHER TREATED PATIENTS HAVE A NEGATIVE LATE LOSS NEGATIVE LATE LOSS Circulation 2007 Negative Late Loss territory Negative Late Loss territory

9 DES INDUCE NEGATIVE LATE LOSS 30% of patients treated with XienceV have a negative Late Loss

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11 DES?ADVANTAGE OVER TIME SCAAR STUDY

12 GI complications of Dual Antiplatelet Therapy n Aspirin suppresses gastroduodenal mucosal PG synthesis leading to mucosal damage n Aspirin life threatening bleeding and perforation 3% n Aspirin risk is dose related OR for 75mgs is 2.3 OR for 300mg is 3.9 n Enteric coating makes little difference Vallurupalli NG, Goldhaber SZ Circulation 2006;113:e655-e658

13 GI complications of Dual Antiplatelet Therapy n n n No data that clopidogrel causes mucosal damage, but in 1 study, clopidogrel used in a cohort of patients with previous peptic ulceration lead to significant GI bleeding in 12% Combination of aspirin and clopidogrel leads to overt GI bleeding in first 30 days in 1.3% In CURE, risk of bleeding was higher in the high dose aspirin(200mg)/placebo arm (3.7%), than the clopidogrel/aspirin (75mg) combination (3%) Vallurupalli NG, Goldhaber SZ Circulation 2006;113:e655-e658

14 Ideal stent n Would reduce restenosis without the need for toxic drugs n No negative late loss n Be thrombosis free short and long-term n Avoid the need for long-term antiplatelet therapy n Superior biomechanical properties, with very low profile and flexibility

15 Non-DES coated stents n Metallic implants are passive with high corrosion resistance, and are protected by the continued presence of a stable oxide break down the oxide and corrosion will start n Titanium alloys have the highest degree of corrosion resistance of all metal alloys used in human medicine n Thrombogenicity of metals/alloys relates to the electrode potential Ti alloys are very thromboresistant.

16 TITAN-2 BAS Stent n Laser cut slotted tube 316LSS n Coated with thin atomic layer of titanium-no n Helicoidal design flexibility with excellent radial force n NO particles n Titanium coating extremely strong n Fatigue tests no fracturing TITAN - stent by Hexacath (France) Stent geometry Material Strut thickness Crimped profile HELICOIDAL DESIGN 316L+TITANOX COATING 90 MICRONS ~1mm TITANOX Coating (Titanium- Nitride-Oxide) Nitrogen, Oxygen and Titanium atoms are bounded with electronic and atomic links. (L.Pauling classification)

17 FUNDAMENTAL EVIDENCE 1-TITANIUM-NO MINIMIZES RBC DAMAGES FACT :Red blood cells adherent to titanium appear to be almost normal

18 FUNDAMENTAL EVIDENCE 1-TITANIUM-NO MINIMIZES RBC DAMAGES FACT :In comparison red blood cells adherent to LTI carbon appear to be damaged

19 FUNDAMENTAL EVIDENCE 2- TITANIUM-NO MINIMIZES P. AGGREGATION On the Titanium no platelet aggregation was found

20 FUNDAMENTAL EVIDENCE 2-TITANIUM-NO MINIMIZES P. AGGREGATION FACT : No platelet adherence were found on the surface of titanium

21 FUNDAMENTAL EVIDENCE 2-TITANIUM-NO MINIMIZES P. AGGREGATION FACT : In comparison platelet aggregation is found on the surface of LTI carbon

22 FUNDAMENTAL EVIDENCE 3-TITANIUM-NO MINIMIZES FIBRIN GROWTH Almost no fibrin was found on the Titanium oxide films

23 FUNDAMENTAL EVIDENCE 3-TITANIUM-NO MINIMIZES FIBRIN GROWTH FACT :No fibrin was found on the surface of titanium

24 FUNDAMENTAL EVIDENCE 3-TITANIUM-NO MINIMIZES FIBRIN GROWTH FACT : In comparison there is a large amount of fibrin on the surface of LTI carbon

25 FUNDAMENTAL EVIDENCE 4-TITANIUM-NO MINIMIZES INFLAMMATION Titanium-NO offers a most biocompatible arterial interface and acts as an unbreakable barrier against the release of toxic ions.

26 FUNDAMENTAL EVIDENCE 5-TITANIUM-NO PROMOTES RE-ENDOTHELIALIZATION

27 FUNDAMENTAL EVIDENCE 5-TITANIUM-NO PROMOTES RE-ENDOTHELIALIZATION FACT : Titanium Oxides have proven to speed up the reendothelialization process in comparison to stainless steel or nitinol.

28 NO PRESENCE ON STENT SURFACE 6-NEW FINDINGS Recent in vitro tests have shown the presence of NO on the surface of the TITAN2 BAS stent while no NO presence was found on the surface of the BMS.

29 TITAN BAS unsputtered TITAN BAS sputtered BMS HELISTENT High NO concentration High NO concentration No NO concentration

30 ANIMAL EVIDENCE THE ANIMAL MODEL Titanium-NO coated stent Bare Stent Titanium Nitride Oxide Vs 316L in porcine model 47% reduction of neointimal hyperplasia

31 ANIMAL EVIDENCE THE ANIMAL MODEL REMINDER! Sirolimus (Cypher) in porcine model 50 % reduction of neointimal hyperplasia

32 That s all very well.what about the clinical evidence 1-THE TINOX RANDOMISED TRIAL

33 TINOX TRIAL

34 TINOX TRIAL LATE LOSS REDUCTION 0.90mm 39% (p=0.03) 0.55mm TITANIUM -NO BMS

35 TITAX Trial: Study Design Patients Baseline Presenting Patient Acute Characteristics Myocardial Infarction Requiring PCI TITANOX PES P value Baseline Patient (195) Characteristics (187) Written Informed Consent Age (Mean ± SD) Male sex, n (%) Randomization 1:1 Diabetes, TITAN n (%) Titanium-Nitride Nitride-Oxide Coated Stent NIDDM, (%) (TITANOX) 200 IDDM, Patientsn (%) Indication of PCI 64 ± ± (75) 138 TITANOX (74) NS PES (195) (187) 43 Taxus-Liberte (22) 26 (14) 0.05 Paclitaxel-eluting eluting Stent 39 (20) 24 (13) NS (PES) TITANOX 4 (2) 200 Patients 2 (1) NS ( 195) History of smoking, n (%) 101 (52) 88 (47) Primary Endpoint: Acute STEMI, MACE RVD, n at (mm) (%) 1 Year 75 (38) Defined Hyperlipidemia, as Composite, n of (%) Repeat Myocardial Infarction, 146 (75) Ischemia Driven 143 (76) Target Vessel (TVR) or Target Lesion Lesion (TLR) Revascularization, length, (mm) or Previous myocardial Cardiovascular infarction, Acute NSTEMI, n (%) Death n (%) 42 (22) 18 (10) 120 (62) Branch vessel involved,, n (%) Previous PCI, n (%) 20 (10) 10 (5) Previous CABG, n (%) Multivessel disease, Stent n diameter, (%) (range, mm) 13 (7) 13 (7) 90 (46) Stent length Death, used, (range,mm) n (%) NS P value Procedural and Lesion Characteristics 30 Days Follow-up Total stent length, Death, from (mm) cardiac causes, n (%) ± 6.49 No of stents per Myocardial lesion,, n infarction, (%) n (%) NS 3.19 ± (47) 3.11 NS ± 0.51 NS NS ± ± 6.43 NS TITANOX PES P 100 (53) NS 49 (25) (195) 43 (23) (187) NS value NS 3.24 ± NS (40) 3.06 NS ± up (at the end of Nov 2006) ± (0.5) ± NS (1.1) NS 1.09 ± 0.3 PES ( 187) 6 Months Follow-up P Value ± 7.90 TITANOX 2 NS (1.1) (117) 1 (0.5) 1.12 ± NS (4.8) NS PES (107) P value Multivessel PCI, TVR, n (%) n (%) 28 (14) 3 (1.5) 17 (9) Death, n (%) Direct stenting, n TLR, (%) n (%) 21 (11) 3 (1.5) 25 (13) Death from cardiac causes, n (%) Postdilatation,, n (%) 83 (43) 65 (35) TVR (non-tlr), n (%) 0 Myocardial infarction, n (%) 5 NS (2.7) 3 (2.6) 4 NS (2.1) 0 (0) NS 1 (0.5) 5 (4.3) NS 2 (1.8) NS 2 (1.8) NS 9 (8.4) NS NS NS MACE, n (%) TVR, n (%) 3 (1.5) 10 (5.3) 9 (7.7) 0,049 6 (5.6) NS Stent thrombosis, n (%) TLR, n (%) 1 (0.5) 5 (2.7) 8 (6.8) NS 4 (3.7) NS TVR (non-tlr), n (%) 1 (0.9) 2 (1.9) NS MACE, n (%) 9 (7.7) 11 (10.3) NS Stent thrombosis, n (%) 0 (0) 4 (3.7) 0.035

36 RANDOMIZED STUDIES VS DES THE TITAX TRIAL (Titan2 Vs Taxus) (n=400pts) Primary Endpoint: 6 months, 1 year, 2 years Results: 6 months 7.7% Titan2 vs 10.3% Taxus

37 CLINICAL STUDIES TITAN Vs PES/SES IN SV Clinical Comparative study Titan/PES/SES 173 Pts (Titan2) Vs 88 Pts (Taxus) Vs 207 Pts (Cypher) in small vessels Titan2 19 months : 7.3% Taxus 12 months : 8.1% Cypher 14 months : 6.1%

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40 Use of the Titanium- Nitride- Oxide Coated Stent in Clinical Practice The Titan PORI Registry P.Karjalainen MD Satakunta Central Hospital Pori Finland Sweden Finland Russia *Pori Helsinki Washington DC Oct

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42 THE FINNISH REGISTRY 9 - M o n th M a c e C o m p o s itio n Titan R e g is tr y (n = / lesio n s / sten ts ) Taxus R e g is t r y (n = / lesio n s / sten ts ) % p= ,5 C V d e a t h p= ,5 O th e r death p= ,1 10,2 N S 5,1 4,1 3,1 N S A M I TLR non-tl R TVR 3 10,3 M p=0.238 N S 13,7 A C E T it a n T a x u s

43 A 12-Months Clinical Outcome after Implantation of Titanium Nitride Oxide Coated Stents, Paclitaxel Eluting Stents or Bare-Metal Stents in an Unselected Population P Karjalainen, MD, Department of Cardiology, Satakunta Central Hospital, PORI, Finland

44 12- MONTHS FOLLOW-UP TITANOX (201) PES (204) BMS (184) P value* Death, n (%) 5 (2.5) 8 (3.9) 8 (4.3) 0.58 Death from cardiac causes, n (%) 1 (0.5) 5 (2.5) 6 (3.3) 0.14 Myocardial infarction, n (%) 9 (4.5) 21 (10.3) 17 (9.2) TVR, n (%) 16 (8.0) 14 (6.9) 16 (8.7) 0.80 TLR, n (%) 10 (5.0) 10 (4.9) 13 (7.1) 0.58 TVR (non-tlr), n (%) 6 (3.0) 4 (2.0) 3 (1.6) 0.64 MACE, n (%) 22 (10.9) 28 (13.7) 33 (17.9) 0.14 Stent thrombosis, n (%) 0 (0) e 7 (3.4) 3 (1.6) * ANOVA. e Bonferroni correction for multiple comparison. e: TITANOX vs. PES, p = 0.023

45 12-MONTHS MACE COMPOSITION TITANOX (n=201) PES (n=204) % ,5 Control Angiography 3,3 2,5 Cardiac Death TITANOX 20% PES 19% BMS 22% 3,9 4,3 2,5 Overall Death 4,5 10,3 9,2 5 4,9 7, ,6 AMI TLR non-tlr TVR BMS 17,9 13,7 10,9 MACE (n=184) TITANOX PES BMS

46 THE TIBET STUDY

47 CLINICAL STUDIES TIBET STUDY VS SIRIUS DIABETICS (QCA/IVUS) Late loss (mm) in-segment Sirolimus (n=131) SIRIUS Vs TIBET 100% Diabetics 0.40 Titan NO (n=156) 0.50 IVUS 0.56 QCA (n=45) TLR (%) MACE (%)

48 Publication: EuroIntervention 2006

49 THE ISRAELI REGISTRY

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53 TITAN-2 BIO ACTIVE STENT SAFETY 1-LOWEST ACUTE & SUB ACUTE LEVELS OF THROMBOSIS WITH NO LATE OR VERY LATE THROMBOSIS

54 TITAN-2 BIO ACTIVE STENT SAFETY 2-ABSENCE OF POLYMER

55 BIO ACTIVE STENT DURABILITY

56 TITAN-2 BAS STENT n No polymer 0.93mm n No drug n Biocompatible coating n No negative late loss n No late or very late stent thrombosis n Superior results to BMS.worth a look