Late Drug-Eluting Late Drug-Eluting

Stent Thrombosis:Stent Thrombosis:

Should we be worried?Should we be worried?

DEATHDEATH

TLRTLRMACEMACE

MIMI

Babapulle et al. Lancet 2004

“Early” Events

“Early” Events

Moreno et al. JACC 2005

Late stent thrombosis: >1 month

…but follow-up max only 1 year at the moment of

the analysis…

“Official” DES vs. BMS RCTs…

…plus several independent RCTs

SES SES (11 trials):(11 trials):

TYPHOON,STRATEGY,SESAMI (TYPHOON,STRATEGY,SESAMI (AMIAMI))

SCANDSTENT (SCANDSTENT (complexcomplex lesionslesions))

SES-SMART (SES-SMART (smallsmall vesselsvessels))

SIRS,ISAR-DESIRE (SIRS,ISAR-DESIRE (ISRISR))

DIABETES (DIABETES (diabetesdiabetes))

BASKET (BASKET (allall comerscomers))

PRISON II (PRISON II (CTOCTO))

RRISC (RRISC (SVGSVG))

PES PES (4 trials):(4 trials):

BASKET (BASKET (allall comerscomers))

ISAR-DESIRE (ISAR-DESIRE (ISRISR))

TAXUS V-ISR (TAXUS V-ISR (ISRISR))

PASSION (PASSION (AMIAMI))

Different DES

Different RCT

Different DEFINITIONS

Different RESULTS?

63 years, maleTaxus stentDay 338: Aspirin withdrawal for

bladder polyp excisionDay 343343: Anterior MI

73 years, maleTaxus stentDay 435: Aspirin withdrawal for

colonic surgeryDay 442442: Anterior MI

42 years, maleCypher stent, Vision stentDay 180: Clopidogrel withdrawnDay 361: Aspirin withdrawnDay 375375: Cypher occluded,

Vision patent

62 years, maleCypher stent, Vision stentDay 331: Aspirin/clopidogrel

withdrawn for colonscopyDay 335335: Anterior MI: Cypher

occluded, Vision patent

McFadden et al. Lancet 2004VERY LATE STENT THROMBOSIS:

>1 YEAR!

Angioscopy and pathology findings in DES vs. BMS

Angioscopy and pathology findings in DES vs. BMS

Kotani J et al. JACC 2006 Joner et al. JACC 2006

Camenzind et al. ESC 2006

Established metaanalytical

techniquesAppropriate statistical

tests

50% decline in DES use in Sweden

after these data…

Wenaweser ESC 2006

Established metaanalytical

methodsAdequate search for pertinent articles (up to the end of 2005)

Appropriate statistical tests

““All that glisters is not gold”All that glisters is not gold”

Prince of MoroccoPrince of MoroccoThe Merchant of Venice Act II, Scene VI.The Merchant of Venice Act II, Scene VI.

-ONLY “SPONSORED” TRIALS…ONLY “SPONSORED” TRIALS…

-DOUBTFUL STATISTICAL ANALYSISLog rank test in pooled data?

Official SES trialsstent thrombosis definition

Official SES trialsstent thrombosis definition

MI attributable to the target vessel, MI attributable to the target vessel, with angiographic documentation of thrombus or occlusion of the target site, of thrombus or occlusion of the target site,

and freedom from an interim PCI of the target vessel

Late Late ST > 30 days ST > 30 days

Thrombotic occlusion of the stented segment observed at the time Thrombotic occlusion of the stented segment observed at the time of a clinically-driven angiographic restudy of a clinically-driven angiographic restudy

ORQ-wave MI in territory of stented vesselQ-wave MI in territory of stented vessel

ORAny death not attributed to a non-cardiac causeAny death not attributed to a non-cardiac cause

EarlyEarly Stent Thrombosis (Acute + Sub-acute) Stent Thrombosis (Acute + Sub-acute) 30 Days 30 Days

Official PES trialsstent thrombosis definition

Official PES trialsstent thrombosis definition

MI attributable to the target vessel, MI attributable to the target vessel, with or without angiographic documentation of thrombus or occlusion of the target site, of thrombus or occlusion of the target site,

and freedom from an interim PCI of the target vessel

Late Late ST > 30 days ST > 30 days

Thrombotic occlusion of the stented segment observed at the time Thrombotic occlusion of the stented segment observed at the time of a clinically-driven angiographic restudy of a clinically-driven angiographic restudy

ORQ-wave MI in territory of stented vesselQ-wave MI in territory of stented vessel

ORAny death not attributed to a non-cardiac causeAny death not attributed to a non-cardiac cause

EarlyEarly Stent Thrombosis (Acute + Sub-acute) Stent Thrombosis (Acute + Sub-acute) 30 Days 30 Days

Academic Research Consortium (ARC)

Academic Research Consortium (ARC)

ARC Co-ChairsARC Co-Chairs Patrick Serruys, MD PhD, Thoraxcenter, Patrick Serruys, MD PhD, Thoraxcenter,

Rotterdam and CardialysisRotterdam and Cardialysis Don Cutlip, MD, Harvard and HCRIDon Cutlip, MD, Harvard and HCRI

Other ParticipantsOther Participants Interventional CardiologistsInterventional Cardiologists Representatives from FDA Representatives from FDA Academic CROs (Cardialysis, HCRI, DCRI, CRF)Academic CROs (Cardialysis, HCRI, DCRI, CRF) Representatives from major stent manufacturersRepresentatives from major stent manufacturers

Rationale for ARC Definitions for DES Endpoints

Rationale for ARC Definitions for DES Endpoints

ObjectivesObjectives Standardization of

definitions Consensus on the new

standard Consistency for reporting Transparency of data

ConcernsConcerns

• Variability in definitions of Variability in definitions of key clinical endpoints across key clinical endpoints across DES TrialsDES Trials

• Inappropriate comparisons Inappropriate comparisons and conclusions based on and conclusions based on different definitionsdifferent definitions

• Potential to bias results by Potential to bias results by choosing definitions most choosing definitions most favorable to those favorable to those conducting analysesconducting analyses

ARC Proposed DefinitionsARC Proposed Definitions

Definite/ConfirmedDefinite/Confirmed Acute coronary syndrome Acute coronary syndrome ANDAND

Angiographic confirmation of thrombus or occlusion Angiographic confirmation of thrombus or occlusion OROR

Pathologic confirmation of acute thrombosisPathologic confirmation of acute thrombosis

ProbableProbable Unexplained death within 30 daysUnexplained death within 30 days Target vessel MI without angiographic confirmation of Target vessel MI without angiographic confirmation of

thrombosis or other identified culprit lesionthrombosis or other identified culprit lesion

PossiblePossible Unexplained death after 30 daysUnexplained death after 30 days

NOTE: Patients who have a TLR prior to a thrombosis are included by NOTE: Patients who have a TLR prior to a thrombosis are included by this set of definitions, as opposed to the “Per Protocol” definition this set of definitions, as opposed to the “Per Protocol” definition

Every Every target vessel-MItarget vessel-MI and and any any unexplained deathunexplained death are are

considered stent thrombosesconsidered stent thromboses

SES: Freedom From Thrombosis0 – 1,440 Days

SES: Freedom From Thrombosis0 – 1,440 Days

Freedom from Freedom from ANYANY Stent Stent

Thrombosis (%)Thrombosis (%)

94%

95%

96%

97%

98%

99%

100%

0 180 360 540 720 900 1080 1260 1440

94%

95%

96%

97%

98%

99%

100%

0 180 360 540 720 900 1080 1260 1440

LR p=0.89LR p=0.89SESSES BMSBMS

96.7%96.7%

96.5%96.5%

Freedom from Freedom from Definite/ProbableDefinite/Probable Stent Thrombosis Stent Thrombosis

(%)(%)

98.3%98.3%

94%

95%

96%

97%

98%

99%

100%

0 180 360 540 720 900 1080 1260 1440

94%

95%

96%

97%

98%

99%

100%

0 180 360 540 720 900 1080 1260 1440

98.5%98.5%

LR p=0.70LR p=0.70

Pooled Data from RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS Trials. Data on File, Cordis CorporationPooled Data from RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS Trials. Data on File, Cordis Corporation

Impact of TLR on Stent Thrombosis Rate

Impact of TLR on Stent Thrombosis Rate

SESSES BMSBMS

ARCARCDefinite/ProbDefinite/Prob..

Primary Primary STST

Post TLR Post TLR STST

Total Total STST

Primary Primary STST

Post TLRPost TLR STST

  Total Total STST

EarlyEarly 44 00 44 33 00 33

LateLate 11 00 11 66 22 88

Very Late Very Late 88 00 88 00 44 44

TotalTotal 1313 00 1313 99 66 1515

SESSES BMSBMS

ARC AnyARC AnyPrimary Primary 

STSTPost TLR Post TLR

STSTTotal Total

STSTPrimary Primary

STST Post TLR STPost TLR ST  Total Total

STST

EarlyEarly 44 00 44 33 00 33

LateLate 22 00 22 99 22 1111

Very Late Very Late 2323 00 2323 66 88 1414

TotalTotal 2929 00 2929 1818 1010 2828

Pooled Data from RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS Trials. Data on File, Cordis CorporationPooled Data from RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS Trials. Data on File, Cordis Corporation

WHICH STENT HAS WHICH STENT HAS BEEN USED??BEEN USED??

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

DefinitionDefinition Taxus:Taxus:4-y cumulative 4-y cumulative

(n=1400)(n=1400)

Bare-metal stent:Bare-metal stent:4-y cumulative 4-y cumulative

(n=1397)(n=1397)

Log Log rank rank

P-valueP-value

Per protocolPer protocol 1.3 %1.3 % 0.8 %0.8 % NSNS

ARC probable or ARC probable or definitedefinite

1.8 %1.8 % 1.1 %1.1 % NSNS

ARC allARC all 3.5 %3.5 % 3.6 %3.6 % NSNS

Announcing…Announcing…

For further slides on these topics please feel For further slides on these topics please feel free to visit the metcardio.org website:free to visit the metcardio.org website:

http://www.http://www.metcardiometcardio..orgorg//slidesslides..htmlhtml