“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 InterestDisclosure 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 efficacyDES efficacy

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

Angio efficacy = LL Clinical efficacy = TLR

DES safetyDES safety

Events at 360 daysSirolimus

(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

SIRIUS @ 1 Yr

The available clinical results on the first The available clinical results on the first DES studies led the medical community DES studies led the medical community

to conclude the following:to conclude the following:

DES efficacy > BMS efficacy

DES safety = BMS safety

But…But……First concerns on long term DES …First concerns on long term DES

safety started to come…safety started to come…

ESC06: DES safety dataESC06: DES safety data

ROTTERDAM & BERN experienceOverall 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 days 1,2%

1 year 1,7%

2 years 2,3%

3 years 2,9% (152/8146)

*: Presentation at ESC06

ESC06: DES safety data (II)ESC06: DES safety data (II)

Stent Thrombosis timingStent Thrombosis timingD

ESD

ESBM

SBM

S

Days after PCI

6

4

2

00 30 50 300

N

Early61%

(N=33)

Late20%

(N=11)

Very late19%

(N=10)

100 1000Days after PCI

6

4

2

00 30 50 300

N

Early61%

(N=33)

Late20%

(N=11)

Very late19%

(N=10)

100 1000

Days after PCI

10

8

6

4

2

0 0 30 100 1000

N

Early75%

(N=71)

Late23%

(N=22)

50 300

Very late2%

(N=2)

Days after PCI

10

8

6

4

2

0 0 30 100 1000

N

Early75%

(N=71)

Late23%

(N=22)

50 300

Very late2%

(N=2)

Days after PCI

10

8

6

4

2

0 0 30 100 1000

N

Early75%

(N=71)

Late23%

(N=22)

50 300

Very late2%

(N=2)

Overall incidence of stent thrombosisOverall incidence of stent thrombosis95 of 6058 patients (1.6%)95 of 6058 patients (1.6%)Overall incidence of stent thrombosisOverall incidence of stent thrombosis95 of 6058 patients (1.6%)95 of 6058 patients (1.6%)

Overall incidence of stent thrombosisOverall incidence of stent thrombosis54 of 3376 patients (1.5%)54 of 3376 patients (1.5%)Overall incidence of stent thrombosisOverall incidence of stent thrombosis54 of 3376 patients (1.5%)54 of 3376 patients (1.5%)

EARLY 61%

(n=33)

EARLY 61%

(n=33)

LATE20%

(n=11)

LATE20%

(n=11)

VERY LATE 19%

(n=10)

VERY LATE 19%

(n=10)

VERY LATE 2%(n=2)

VERY LATE 2%(n=2)

LATE23%

(n=22)

LATE23%

(n=22)

EARLY 75% (n=71)

EARLY 75% (n=71)

Wenaweser P et al. Eur Heart J 2005 Wenaweser P et al. Eur Heart J 2005

Wenaweser P et al. ACC/i2, 2006, Poster Session 2902-74Wenaweser P et al. ACC/i2, 2006, Poster Session 2902-74

DES benchmark & REAL DAT duration in DES benchmark & REAL DAT duration in clinical studiesclinical 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 TCT2009 - *: Leader trial results presented at TCT10 - **: Endeavor IV – Presented TCT2009

Latest available DES > 6 months 1 year 2 years 3 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 implantationBad 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*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 1614-1617 (15 December 2008)

85,7%

13,6%

0,7%0%

10%20%30%40%50%60%70%80%90%

Nuisancebleeding

Internalbleeding

Alarmingbleeding

Type of reported bleeding

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.

0

20

40

60

80

100

11.2%

58.7%

100%

Ab

solu

te C

lop

ido

gre

l

dis

co

nti

nu

atio

n (

%)

0

10

20

30

40

50

60 52.2%

43.7%

3.9%

Att

rib

uta

ble

Clo

pid

og

rel

dis

co

nti

nu

atio

n (

%)

Patients non-responders to Clopidogrel: Patients non-responders to Clopidogrel: The Re-Close study results*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?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)

Expenses for DAT therapy with current & newer DES

0

0,5

1

1,5

2

2,5

3

3,5

4

4,5

5

First year Second year Third year Forth year Fifth year

Bill

ion

US$

- Newer DES

Current DES

Which is the economic impact of DAT Which is the economic impact of DAT duration extension?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 – OptimaCID DES – OptimaPolymer-freePolymer-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 CarbofilmTM 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 JetCID DES - Optima JetAbluminal Reservoir TechnologyAbluminal Reservoir Technology

DES endothelialization in DES endothelialization in complex settings: Animal studies resultscomplex settings: Animal studies results

*: study performed by Virmani. Presented at EuroPCR05 & EuroPCR06

Two DES in overlapping implantation (results at 28days)*

CarbostentDES

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:Randomized clinical trial:8-months results*8-months results*

0

2

4

6

8

10

12

14

16

Cardiac death MI TLR MACE

0 0

6 6

1 1

13

15

%

Carbostent DES BMS

p = 0.038

- 60%

*: Han et al. Chin Med J 2007; 120 (7): 552-556

p = 0.059

- 54%

Dual antiplatelet therapy duration Carbostent DES BMS

4 months 100% 100%

Stent thrombosis Carbostent DES BMS

Acute 0% 0%

Sub-acute 0% 0%

Late 0% 0%

MATRIX I REGISTRY - 553 patientsEvaluation 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 DATVs

MATRIX II REGISTRY – 392 patientsEvaluation 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**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*Matrix I Registry - 12 m results*

2 months pts 6 months pts

30 days 99,46% (96,25 – 99,92) 184 99,44% (97,81 – 99,86) 359

6 months 99,46% (96,25 - 99.92) 175 99,16% (97,44 – 99,73) 352

12 months 99,46% (96,25 – 99,92) 170 98,86% (97,00 – 99,57) 325

2 months pts 6 months pts

30 days 97,86% (94,41 – 99,19) 181 98,37% (96,41 – 99,27) 358

6 months 97,86% (94,41 – 99,19) 172 97,25% (94,96 – 98,52) 348

12 months 97,29% (93,63 – 98,87) 164 96,95% (94,57 – 98,30) 322

Months190 Pts 382 Pts

Total %2 months DAT 6 months DAT

Acute Thrombosis1

0 1 0,17%Sub - Acute Thrombosis 0 0 0%

Late Thrombosis (up to 6 months)

2

0 0%3

0456

Late Thrombosis (up to 12 months)

7

0 0 0%

89

101112

*: S.Cassese et al – Catheterization and Cardiovascular Intervention, IN PRESS

Matrix II RegistryMatrix II RegistryPrimary 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

Patients 392 pts

DiabetesDiabetes 25.0%

Unstable anginaUnstable angina 25.0%

NSTEMI + STEMI>48hNSTEMI + STEMI>48h 30.4%

Multivessel diseaseMultivessel disease 57.4%

Number of lesions 440

Bifurcations 24.8% (109)

Ostial lesions 4.3% (19)

CTOs 5.4% (24)

Intracoronary thrombus 13.4% (59)

Lesion length (mm) 16.4±6.6

Lesion classification ACC/AHA Vessel distribution

Presented during GISE2010 – Dr Cassese

Results at 12 months - Primary Endpoint

2 months DAT pts

30 days 99.74% (98.17 - 99.96) 387 pts

6 months 96.46% (93.99 - 97.93) 367 pts

12 months 95.11% (92.25 – 96.95) 291 pts

95,11 %

Cumulative incidence of TLR 4,89 %

2 months DAT pts

30 days 98.96% (97.28 - 99.61) 387 pts

6 months 95.70% (93.09 - 97.35) 367 pts

12 months 93.80% (90.07 - 95.52) 291 pts

93,80 %

Presented during GISE2010 – Dr Cassese

Matrix II Registry – Results (I)Matrix II Registry – Results (I)

Months392 Pts

Total %2 months DAT

Acute Thrombosis1

1 0,2%Sub - Acute Thrombosis 0

0%

Late Thrombosis (up to 6 months)

2

0%3

0456

Late Thrombosis (up to 12 months)

7

0 0%

89

101112

99,1 %

Presented during GISE2010 – Dr Cassese

Results at 12 months – Secondary Endpoint

Matrix II Registry – Results (II)Matrix II Registry – Results (II)

Thromb Haemost. 2010 Jan;103(1):13-28

ESC Guide lines for PCI in AF patientsESC 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”…

CONCLUSIONSCONCLUSIONS 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 CarbofilmTM, 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