Late Drug-Eluting Late Drug-Eluting Stent Thrombosis: Stent Thrombosis: Should we be worried? Should we be worried?
Jan 15, 2016
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withdrawn for colonscopyDay 335335: Anterior MI: Cypher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:
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