1. Late Drug-Eluting Stent Thrombosis: Should we be worried?

2. DEATH TLR MACE MI Babapulle et al. Lancet 2004 “Early” Events

3. Moreno et al. JACC 2005 Late stent thrombosis: >1 month …but follow-up max only 1 year at the moment of the analysis…

4. “Official” DES vs. BMS RCTs…

5. …plus several independent RCTs SES (11 trials): TYPHOON,STRATEGY,SESAMI ( AMI ) SCANDSTENT ( complex lesions ) SES-SMART ( small vessels ) SIRS,ISAR-DESIRE ( ISR ) DIABETES ( diabetes ) BASKET ( all comers ) PRISON II ( CTO ) RRISC ( SVG ) PES (4 trials): BASKET ( all comers ) ISAR-DESIRE ( ISR ) TAXUS V-ISR ( ISR ) PASSION ( AMI )

6. Different DES Different RCT Different DEFINITIONS Different RESULTS?

7. 63 years, male Taxus stent Day 338: Aspirin withdrawal for bladder polyp excision 343 Day 343: Anterior MI 73 years, male Taxus stent Day 435: Aspirin withdrawal for colonic surgery 442 Day 442: Anterior MI 42 years, male Cypher stent, Vision stent Day 180: Clopidogrel withdrawn Day 361: Aspirin withdrawn 375 Day 375: Cypher occluded, Vision patent 62 years, male Cypher stent, Vision stent Day 331: Aspirin/clopidogrel withdrawn for colonscopy 335 Day 335: Anterior MI: Cypher occluded, Vision patent McFadden et al. Lancet 2004 VERY LATE STENT THROMBOSIS: >1 YEAR!

8. Angioscopy and pathology findings in DES vs. BMS Kotani J et al. JACC 2006Joner et al. JACC 2006

9. Camenzind et al. ESC 2006

11. Established metaanalytical techniques Appropriate statistical tests

12. 50% decline in DES use in Sweden after these data…

13. Wenaweser ESC 2006

14. Established metaanalytical methods Adequate search for pertinent articles (up to the end of 2005) Appropriate statistical tests

16. “All that glisters is not gold” Prince of Morocco The Merchant of Venice Act II, Scene VI.

17. -ONLY “SPONSORED” TRIALS… -DOUBTFUL STATISTICAL ANALYSIS Log rank test in pooled data?

18. Official SES trials stent thrombosis definition MI attributable to the target vessel, of thrombus or occlusion of the target site, MI attributable to the target vessel, with angiographic documentation of thrombus or occlusion of the target site, and freedom from an interim PCI of the target vessel Late ST > 30 days Thrombotic occlusion of the stented segment observed at the time of a clinically-driven angiographic restudy OR Q-wave MI in territory of stented vessel OR Any death not attributed to a non-cardiac cause Early Stent Thrombosis (Acute + Sub-acute)  30 Days

19. Official PES trials stent thrombosis definition MI attributable to the target vessel, of thrombus or occlusion of the target site, MI attributable to the target vessel, with or without angiographic documentation of thrombus or occlusion of the target site, and freedom from an interim PCI of the target vessel Late ST > 30 days Thrombotic occlusion of the stented segment observed at the time of a clinically-driven angiographic restudy OR Q-wave MI in territory of stented vessel OR Any death not attributed to a non-cardiac cause Early Stent Thrombosis (Acute + Sub-acute)  30 Days

21. Academic Research Consortium (ARC) ARC Co-Chairs Patrick Serruys, MD PhD, Thoraxcenter, Rotterdam and Cardialysis Patrick Serruys, MD PhD, Thoraxcenter, Rotterdam and Cardialysis Don Cutlip, MD, Harvard and HCRI Don Cutlip, MD, Harvard and HCRI Other Participants Interventional Cardiologists Interventional Cardiologists Representatives from FDA Representatives from FDA Academic CROs (Cardialysis, HCRI, DCRI, CRF) Academic CROs (Cardialysis, HCRI, DCRI, CRF) Representatives from major stent manufacturers Representatives from major stent manufacturers

22. Rationale for ARC Definitions for DES Endpoints Objectives Standardization of definitions Consensus on the new standard Consistency for reporting Transparency of data Concerns Variability in definitions of key clinical endpoints across DES TrialsVariability in definitions of key clinical endpoints across DES Trials Inappropriate comparisons and conclusions based on different definitionsInappropriate comparisons and conclusions based on different definitions Potential to bias results by choosing definitions most favorable to those conducting analysesPotential to bias results by choosing definitions most favorable to those conducting analyses

23. ARC Proposed Definitions Definite/Confirmed Definite/Confirmed  Acute coronary syndrome AND  Angiographic confirmation of thrombus or occlusion OR  Pathologic confirmation of acute thrombosis Probable Probable  Unexplained death within 30 days  Target vessel MI without angiographic confirmation of thrombosis or other identified culprit lesion Possible Possible  Unexplained death after 30 days NOTE: Patients who have a TLR prior to a thrombosis are included by this set of definitions, as opposed to the “Per Protocol” definition Every target vessel-MI and any unexplained death are considered stent thromboses

24. SES: Freedom From Thrombosis 0 – 1,440 Days Freedom from ANY Stent Thrombosis (%) LR p=0.89 SESBMS 96.7% 96.5% Freedom from Definite/Probable Stent Thrombosis (%) 98.3% 98.5% LR p=0.70 Pooled Data from RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS Trials. Data on File, Cordis Corporation

25. Impact of TLR on Stent Thrombosis Rate SES BMS BMS ARC Definite/Prob. Primary ST Post TLR ST Total ST PrimaryST Post TLR ST ST Total ST Total ST Early 404303 Late 101628 Very Late 808044 Total 130139615 SES BMS BMS ARC Any Primary ST Post TLR ST Total ST Primary ST Post TLR ST Total ST Total ST Early404303 Late2029211 Very Late 230236814 Total29029181028 Pooled Data from RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS Trials. Data on File, Cordis Corporation WHICH STENT HAS BEEN USED??

26. Baim D. On-label use of the Taxus drug-eluting stent system, Part I. FDA Circulatory Systems Devices Advisory Panel on drug-eluting stent safety. December 7, 2006; Washington, DC. ARC and per protocol stent thrombosis: Taxus data set Definition Taxus: 4-y cumulative (n=1400) Bare-metal stent: 4-y cumulative (n=1397) Log rank P-value Per protocol 1.3 % 0.8 % NS ARC probable or definite 1.8 % 1.1 % 1.1 %NS ARC all 3.5 % 3.6 % NS

28. Announcing…

29. For further slides on these topics please feel free to visit the metcardio.org website: http://www.metcardio.org/slides.html http://www.metcardio.org/slides.html