“Current DAT duration following DES implantation and CID polymer-free DES technology” Federico Piscione, MD, PhD Federico II University, Naples Italy “Edge Technologies: CID Drug Release & Stent Surface developments”

Disclosure Statement of Financial Interest I, Federico Piscione, DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation.

DES efficacy Reduced neo-intima growth → lower late loss (LL) as well as target lesion revascularization (TLR) rates vs. BMS Angio efficacy = LLClinical efficacy = TLR

DES safety Events at 360 days Sirolimus (533) Control (525) p Death 1.3 (7)0.8 (4)0.547 MI (all) 3.0 (16)3.4 (18)0.730 Q-wave 0.8 (4)0.4 (2)0.687 Non–Q-wave 2.3 (12)3.0 (16)0.449 First available clinical data on DES Death, MI & MACE rates (1-2 years) were satisfactory 1 Yr

The available clinical results on the first DES studies led the medical community to conclude the following: DES efficacy > BMS efficacy DES safety = BMS safety

But… …First concerns on long term DES safety started to come…

ESC06: DES safety data

ROTTERDAM & BERN experience Overall thrombosis rate in 8146 patients enrolled in Bern (SIRTAX and POST- SIRTAX studies) and Rotterdam (RESEARCH and T-SEARCH) treated with either Cypher (47%) or Taxus (53%) stents* Documented stent thrombosis 30 days1,2% 1 year1,7% 2 years2,3% 3 years2,9% (152/8146) *: Presentation at ESC06 ESC06: DES safety data (II)

Stent Thrombosis timing DES BMS Overall incidence of stent thrombosis 95 of 6058 patients (1.6%) Overall incidence of stent thrombosis 95 of 6058 patients (1.6%) Overall incidence of stent thrombosis 54 of 3376 patients (1.5%) Overall incidence of stent thrombosis 54 of 3376 patients (1.5%) EARLY 61% (n=33) LATE 20% (n=11) LATE 20% (n=11) VERY LATE 19% (n=10) VERY LATE 19% (n=10) VERY LATE 2% (n=2) VERY LATE 2% (n=2) LATE 23% (n=22) LATE 23% (n=22) EARLY 75% (n=71) Wenaweser P et al. Eur Heart J 2005 Wenaweser P et al. ACC/i2, 2006, Poster Session

DES benchmark & REAL DAT duration in clinical studies Following ESC06, DAT duration in DES clinical studies has been extended more and more. In some cases it’s been extended beyond 3years (much longer than the suggested DAT duration in product IFUs) ***: Spirit III study results presented at TCT *: Leader trial results presented at TCT10 - **: Endeavor IV – Presented TCT2009 Latest available DES> 6 months1 year2 years3 years Xience V***94.4%71.9%57.3%52.4% Taxus***94.2%70.8%60.5%52.0% Endeavor **92.1%57.6%65.4%48.2% Biomatrix * (Nobori)>95%68.1%23.4%19.6% Knowing that DAT extension may mask late stent thrombosis events, this should be taken into account when a DES has to be selected.

Bad news assessed after DES implantation We are treating an ageing patient population… Hidden comorbidities may show themselves with dual antiplatelet therapy!

Patient non-compliant to DAT* Among 2360 unselected patients undergoing successful DES implantation, 837 reported bleeding events (32,4% of the overall population). The type of bleeding has been assessed during the routine clinical follow-up. *: The American Journal of Cardiology, Volume 102, Issue 12, Pages (15 December 2008) Knowing the high risk of stent thrombosis consequent to a premature DAT termination, the impact of “Nuisance bleeding” on attributable Clopidogrel discontinuation resulted much higher than expected. 11.2% 58.7% 100% Absolute Clopidogrel discontinuation (%) 52.2% 43.7% 3.9% Attributable Clopidogrel discontinuation (%)

Patients non-responders to Clopidogrel: The Re-Close study results* Definite/Probable stent thrombosis for Responders & Non-Responders to Clopidogrel Primary endpoint: definite/probable DES thrombosis during the first 6 months follow-up Long-term event-free survival for primary endpoint * : Re-Close study results presented by Dr Antoniucci during TCT08

What about new anti-platelet compounds? Is stronger/ longer/ infinite DAT regimen the solution? Trials data on new drugs have been recently disclosed, but the benefits (less ST, MI, CVA…) remain mainly focused on short term vs. the potential long-term risks (bleeding)

Which is the economic impact of DAT duration extension? In this simulated case, DAT treatment with a current DES is compared to a foreseen DES which can allow for a DAT treatment of max 6-month (the number of procedures and the cost of Clopidogrel remain the same for 5 years) Assumptions: 2M pts per year receive DES “ON-label” use (=6 months DAT) = 30%* “OFF-label” use (≥12 months DAT) = 70%* Cost of Clopidogrel = 100 US$/month *: data presented at EuroPCR07 (70% Off-label DES use, 40% of which requires the longest possible DAT duration) 42% = 12 months 28% > 12 months

CID DES – Optima Polymer-free vs Stent+ Drug CID Carbostent™ Technology Polymer coated DES Stent+ Drug+ Polymer Lack of inflammatory polymers No thrombogenic surface towards the bloodstream and the vessel wall NO polymer drawbacks

*Data on Carbofilm TM thromboresistance available in published clinical studies (SAFE, ANTARES, HURRICANE, SIMPLE)  Drug release only towards the vessel wall  100% drug release  Deep reservoir maintains the drug concentration gradient vs. vessel wall drug release maintained for 2-3 months  The clinically proven* bio & haemo-compatible CarbofilmTM coating* is the only contact surface with the blood and the vessel wall. CID DES - Optima Jet Abluminal Reservoir Technology

DES endothelialization in complex settings: Animal studies results *: study performed by Virmani. Presented at EuroPCR05 & EuroPCR06 Two DES in overlapping implantation (results at 28days)* Carbostent DES Other DES Endothelialization of Carbostent DES located over the ostium of a side branch** **: Presented during TCT07 (Courtesy of dr. Perez De Prado, Leon – Spain)

Randomized clinical trial: 8-months results* p = % *: Han et al. Chin Med J 2007; 120 (7): p = % Dual antiplatelet therapy durationCarbostent DESBMS 4 months100% Stent thrombosisCarbostent DESBMS Acute0% Sub-acute0% Late0%

MATRIX I REGISTRY patients Evaluation of safety and efficacy of Tacrolimus Eluting Carbostent in real world patients who underwent PCI, with two period of dual anti-platelet therapy (DAT) 2 months DAT 6 months DAT Vs MATRIX II REGISTRY – 392 patients Evaluation of safety and efficacy of OPTIMA Tacrolimus-Eluting Carbostent in real world patients undergoing PCI, followed by only two months of dual anti-platelet therapy (DAT) 2 months DAT Matrix Registries I* & II** *: S.Cassese et al – Catheterization and Cardiovascular Intervention, IN PRESS **: Presented during GISE2010 – Dr S.Cassese

Matrix I Registry - 12 m results* 2 months pts 6 months pts 30 days99,46% (96,25 – 99,92)18499,44% (97,81 – 99,86)359 6 months99,46% (96, )17599,16% (97,44 – 99,73) months99,46% (96,25 – 99,92)17098,86% (97,00 – 99,57)325 2 months pts 6 months pts 30 days97,86% (94,41 – 99,19)18198,37% (96,41 – 99,27)358 6 months97,86% (94,41 – 99,19)17297,25% (94,96 – 98,52) months97,29% (93,63 – 98,87)16496,95% (94,57 – 98,30)322 Months 190 Pts382 Pts Total % 2 months DAT6 months DAT Acute Thrombosis ,17% Sub - Acute Thrombosis 0 0 0% Late Thrombosis (up to 6 months) 2 00% Late Thrombosis (up to 12 months) 7 000% *: S.Cassese et al – Catheterization and Cardiovascular Intervention, IN PRESS

Matrix II Registry Primary Endpoint - Incidence of Major Adverse Cardiac Events (MACE) within 12 and 24 months after implant procedure. Secondary Endpoint - Thrombosis rate within 30 days, 6, 12 and 24 months after implant procedure Patients392 pts Diabetes 25.0% Unstable angina 25.0% NSTEMI + STEMI>48h 30.4% Multivessel disease 57.4% Number of lesions440 Bifurcations24.8% (109) Ostial lesions4.3% (19) CTOs5.4% (24) Intracoronary thrombus13.4% (59) Lesion length (mm)16.4±6.6 Lesion classification ACC/AHAVessel distribution Presented during GISE2010 – Dr Cassese

Results at 12 months - Primary Endpoint 2 months DAT pts 30 days99.74% ( )387 pts 6 months96.46% ( )367 pts 12 months95.11% (92.25 – 96.95)291 pts 95,11 % Cumulative incidence of TLR 4,89 % 2 months DAT pts 30 days 98.96% ( ) 387 pts 6 months 95.70% ( ) 367 pts 12 months 93.80% ( ) 291 pts 93,80 % Presented during GISE2010 – Dr Cassese Matrix II Registry – Results (I)

Months 392 Pts Total % 2 months DAT Acute Thrombosis 1 10,2% Sub - Acute Thrombosis 0 0% Late Thrombosis (up to 6 months) 2 0% Late Thrombosis (up to 12 months) 7 00% ,1 % Presented during GISE2010 – Dr Cassese Results at 12 months – Secondary Endpoint Matrix II Registry – Results (II)

Thromb Haemost Jan;103(1):13-28 ESC Guide lines for PCI in AF patients AF patients who would benefit from DES efficacy? …..”The use of DES of first and second generation, due to the prolonged need of dual antiplatelet therapy, should be avoided in patients with an indication for long-term OAC”…....”the new third generation DES seem to have accelerated re- endothelialisation and might become of interest. Retrospective registries (e.g.Italian Matrix registry) and trail to test their usefulness are currently performed”…

CONCLUSIONS  Following ESC06, DAT duration in real-world PCI with DES has been extended much beyond 1 year heavily impacting on countries’ health budget.  Clopidogrel hypo-responsiveness, DAT compliance or bleeding may expose patient to higher risk of DES thrombosis with a consequent increased risk of cardiac death or MI.  The OPTIMA DES (polymer-free, abluminal reservoir, integral Carbofilm TM, Tacrolimus drug elution and the new delivery system) has been specifically developed to optimize DES efficacy and safety.  All the clinical data collected up to today confirm excellent CID DES technology safety & very positive outcomes in “real world” population, including high risk patients. These results have been achieved with short dual antiplatelet therapy duration.  OPTIMA is the only DES to allow 2 months DAT - Specific patients’ populations such as AF and high risk of bleeding today can benefit from the DES efficacy thanks to CID DES