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.