TRIAL UPDATE 1 ISAR – TRIPLE SECURITY Trial Dr Deven Patel Royal Free Hospital
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TRIALUPDATE1ISAR– TRIPLESECURITYTrial
Dr DevenPatelRoyalFreeHospital
NOCONFLICTOFINTERESTTODECLARE
ISAR– TRIPLEComparisonof6weeksvs 6monthsTripleTherapyinpatientsonoralanticoagulationafterDEStenting
ISAR- TRIPLE• Prospective,RandomisedattimeofPCI• Inclusion– DESinpts requiringOralAntiCoag• Exclusion– StentThrombosis/LMSStent
PrimaryEndpoints• Death,MI,StentThrombosis,Stroke,TIMIMajorbleeds
SecondaryEndpoints• Ischaemic – CardiacDeath,MI,StentThrombosis,Stroke• Bleeding- TIMIMajorbleeds
ISAR– TRIPLEStudyDesignISAR-TRIPLE: Study Organization614 patients with DES implantation
3 European centers
(September 2008 – December 2013)
6-week Clopidogrel
(n=307)
6-month Clopidogrel
(n=307)
Clinical follow up at 9 months in 606 patients (98.7%)
Aspirin and VKA
TEST HYPOTHESES:6-week superior to 6-month therapy;
Primary Endpoint 10%, Risk reduction
60% with 6-week therapy; Power = 80%,
alpha = 0.05; 283 patients per group
PRIMARY ENDPOINT: • Death, myocardial infarction, definite
stent thrombosis, stroke or TIMI
major bleeding at 9 months
SECONDARY ENDPOINTS:• Ischemic complications: Cardiac
death, myocardial infarction, definite
stent thrombosis or ischemic stroke
• Bleeding complications (TIMI major)
VKA: Vitamin K Antagonist
ISAR- TRIPLERandomization
PCIRandomi-
zation
Aspirin and oral anticoagulation
Stopclopidogrel
Group A
Aspirin and oral anticoagulationClopidogrel
0 6-weekFollow-up
6-monthFollow-up
9-monthFollow-up
Time(months)
Stopclopidogrel
Group B
A: 6-weekgroup
Fiedler et al. Am Heart J. 2014; 167(4):459-465
B: 6-monthgroup
Clopidogrel
ISARTRIPLE- ClinicalCharacteristics6WeeksGp (n=307) 6Monthsgp (n=307)
Age/ Female 74y/25% 73y/21%Diabetes 28% 23%ACS 33% 31%
Prev MI 29% 25%OAC- AF 83% 85%
OAC - MechanicalValve 5% 9%Clopidogrel usageat6mths* 26% 87%Clopidogrel usageat9mths* 23% 35%
DES 2nd Generation 49% 50%DESBiodeg Polymer 31% 33%DES1st GenPolymer 7% 4%
ISAR- TRIPLE
Months After Randomization
Cum
ulat
ive
Inci
denc
e(%
)
0
5
10
15
20
0 1 2 3 4 5 6 7 8 9
6-month group6-week group
Death, myocardial infarction, stent thrombosis, stroke or TIMI major bleeding
HR 1.14 (95%, CI 0.68 – 1.91), p=0.63
Primary Endpoint
9.8 %
8.8 %
ISAR- TRIPLEResults
6-week group(n=307)
6-month group(n=307)
Hazard ratio(95% CI)
p value
Death 12 (4.0) 16 (5.2) 0.75 (0.35 -1.59) 0.45Cardiac death 5 (1.7) 9 (3.0) 0.56 (0.19 - 1.66) 0.29Myocardial infarction 6 (2.0) 0 - 0.03
Definite stent thrombosis 2 (0.7) 0 - 0.50
Stroke 4 (1.3) 6 (2.0) 0.67 (0.14 - 2.78) 0.75
Ischemic stroke 3 (1.0) 4 (1.3) 0.75 (0.11 - 4.40) 0.99
Temporal distribution of MIs in 6-week group:4 within 24h of PCI1 at 2.5 weeks1 at 7 months
} Both groups on triple therapy
} Both groups on aspirin and OAC
ISAR- TRIPLEAny BARC Bleeding (type 1-5)
Any BARC Bleeding
Months After Randomization
Cum
ulat
ive
Inci
denc
e(%
)
10
30
50
0 1 2 3 4 5 6 7 8 9
HR 0.94 (0.73 - 1.21), p=0.63
40
0
20
6w
Months After Randomization
10
30
50
0 1 2 3 4 5 6 7 8 9
HR 0.68 (0.47 – 0.98), p=0.04
40
0
20
Post-hoc landmark analysis of any BARC Bleeding before and after 6 weeks (6w)
40.2 %
37.6 %27.9 %
20.5 %
6-month group
6-week group
ISAR– TRIPLEConclusions• Largeststudytodate.• LogicofClopidogrel withdrawalweredueconcernsfornon-responders.
• 6weeksTripletherapynotsuperiorto6mths• Shortenedtripletherapyassociatedwithreduceminorbleedingonly,butnotherewasnoincreaseinischaemic events
TripleTherapy
• 5-8%PCIforpatientonOralAnticoagulants• DESpreferredifbleedingriskislow.• WOESt – OmissionofAspirinreducedbleeding.
• DurationofTripletherapyshouldbetailoredindividuallydependingonproceduraloutcome,thromboembolicrisk(CHA2DS2-Vasc)andbleedingrisk(HAS-Bled).
SECURITY
SixmonthsversusTwelvemonthsDAPTfollowingSecondGenerationDrug-ElutingStent
Implantation
SECURITY- Methods• Prospective non-inferioritydesign• Randomisation attimeofPCI• Second-generationDES - EndeavorResolute,Xience ,Promus,Nobori,Biomatrix
• StableAnginaorACS• NopriorDESimplantedbeforetargetprocedure• NoBMSin3monthsbeforetargetprocedure
Exclusions• Bypassgrafts/in-stentrestenosis/UnprotectedLeftMain• STeMI <48hourspriortoprocedure• NonSTeMI previoussixmonths• LVEF≤30%• Chronicrenalinsufficiency(creatinine>180µmol/l)
SECURITY – Objectives
• PrimaryEndpointat12months– Compositeofcardiacdeath,MI,stroke,definiteorprobablestentthrombosisorBARCtype3- 5bleeding.
• SecondaryEndpoints– Compositeofcardiacdeath,spontaneousMI,stroke,definiteorprobablestentthrombosisorBARCtype2-5bleeding12,24mths
– MI,UrgentTVR,All-bleedingeventsandAll-causemortalityat30days,6,12 and24 months.
SECURITY - ClinicalCharacteristicsCharacteristics 6-MonthDAPT(682) 12-MonthDAPT(717)
Age /Females 65 /22% 66 /23%
DiabetesMellitus 30% 31%
ACS 22% 20%
StableAngina 62% 62%
No ofVessels 1/2/3 56%/32% /11% 59%/29%/11%
AHA ClassB 65% 64%
DAPT6mthsASA+clopidogrel 97% 98%
DAPT12mthsASA+clopidogrel 34% 96%
ASAonly12mths 63% 2%
SECURITY- Primary andSecondary Endpoints
P=NSP=NS
P=NS
0.7%
0.9%
0.4%
0.8%
12Months 24Months
Cardiac Mortality6MonthsDAPT 12MonthsDAPT
SECURITY- Secondary Endpoints
0.6% 0.7%
1.1% 1.1%
12Months 24Months
BARC3or5Bleeding6MonthsDAPT 12MonthsDAPT
2.3%
3.1%
2.1% 2.6%
12Months 24Months
Myocardial Infarction6MonthsDAPT 12MonthsDAPT
0.9% 0.9%
0.3% 0.4%
12Months 24Months
Stroke6MonthsDAPT 12MonthsDAPT
Stent Thrombosis – Events Timeline
DAPT ASAOnly NoAPT ST
day 1
day4
day540
6-monthGroup
073090180360720 days
073090180360720
day1
day40
day78
12-monthGroup
days
All onDAPTat thetimeofST(Except 1very late)
0.3%
0.4% 0.4%
0.4%
SECURITY- Event Rateafter 6months
6-MonthDAPT(N=682)
12-MonthDAPT(N=717)
M12 M24 M12 M24
Cardiac death - 1(0.2%) 1(0.2%) 3 (0.5%)
MyocardialInfarction
2(0.3%) 5(0.9%) 2(0.3%) 4(0.7%)
Stroke 3 (0.5%) - - 1(0.2%)
Stent Thrombosis - 1(0.2%) - -
BARC3or5 1(0.2%) 1(0.2%) 2(0.3%) -
TimeLineofBleeding Risk
P=NS P=NS P=NS P=NS
SECURITY- Primary EndpointMultivariateAnalysis
VariablesintheModel HR 95%CI pvalue
Age≥75years 2.211 1.234– 3.962 0.007
StentType 0.019
EndeavorResolute Vs.Biomatrix /Xience /Promus 2.336 1.051– 5.190
MeanNumberofStents(foreachunitincrease) 1.410 1.128– 1.741 0.002
MeanStentsLength(foreach5unitsincrease) 1.383 1.135– 1.685 0.001
MeanStentSize(foreach2.5unitsincrease) 1.326 1.106– 1.590 0.002
DiabetesMellitus 0.069
NIDDMVs.None 0.895 0.464– 1.729
IDDMVs.None 2.349 1.080– 5.106
DAPT6- vs.12-month 1.272 0.754– 2.145 0.367
SECURITY- Conclusions
• SixmonthsDAPTappeared non-inferiorto12monthswith2nd-generationDES forprimaryandsecondaryendpoints
• 1/3ofpatientsinshortdurationcohortcontinuedDAPTto12months
• Stentthrombosis,bleedingrateslowaftersixmths.
• Age≥75years,Stenttype,numberofstents,lengthandsizepredictorsofadverseoutcome.
DurationofDualAntiplateletTherapypostDEStenting
• Shortdurationstudiesnotadequatelypowered.• DAPTstudyshowedbenefitinreducingstentthrombosisfor30mths comparedto12mths attheexpenseofincreasedbleedingrisk.
• PCIinACSshouldbeforminimum12months.• Selectedpatientscouldstopat6mths.
• Durationcouldbetailoredtono,typeofstents,complexityandriskofbleeding.
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