Dipartimento di CardioScienzeUnità Operativa Complessa

Cardiologia Interventistica e UTIC

Marino Scherillo

LINEE GUIDA PER L’IMPIANTO

CORONARICO DI STENT E CORRETTA TERAPIA ANTIAGGREGANTE

Napoli 12-15 ottobre 2008 Mostra d’Oltremare

Cardiologia Interventistica ed UTIC – A.O. G.Rummo - BENEVENTO

G.F. , 52 y / male, Diabetes ,Tn I+NSTEMIStrategia Farmaco-Interventistica Precoce

ASA CLOPIDOGREL

LMWHSTATINA

PCI - STENT

Recommendations for Oral Antiplatelet Drugs

I IIaIIb • Aspirin• Loading dose (160 - 325 mg)

• Maintenance (75 - 100 mg)

• Clopidogrel• Loading dose 300 mg + 75 mg

• 12 months maintenance

• Contraindication for Aspirin

• 600 mg LD for PCI

• Postpone CABG 5 days after withdrawal

III

A

AA

BA

BC

ESC 2007

LG come Bussola per Medici e Pazienti

Linee Guida : Verso una Definizione Linee Guida : Verso una Definizione Operativa per la ComunitOperativa per la Comunitàà

“ Le LG indicano genericamente la Direzione e non lo

specifico Percorso per Migliorare la Quantitàe la Qualità della Vita

dei Pazienti ”

Le Linee Guida non sono il TomTom

La Conoscenza non èSapere Certo

“Episteme” ma Sapere Congetturale

“Doxa”e Noi tutti siamo

Ricercatori non Possessori della Verità

Karl Popper

La Grappa diLa Grappa di PopperPopperLinee Guida come Distillato della VeritLinee Guida come Distillato della Veritàà ScientificaScientifica

Osservazioni Trial

Ragionamenti Studi Fisiopatologici

Linee Guida

Trombosi Tardiva IntrastentSTEMI 9 mesi dopoPCI - DES 3.5x15 mm Durante ASA - CLO

PCI - BMS3.5x18 mmABCXMAB

….. e se fosse un paziente CLOPIDOGREL Non Responder

9

804Pazienti

PCI - DESASA – CLO 300 / 75

Responders 699 (87%)

No Responders 105 (13 %)

Inhibition of Platelet Aggregation10 µM ADP > 70%

RE-CLOSE Trial

Definizione di No Responders :

12 – 18 h dal carico di Clopidogrel 600 mg

10

STENT THROMBOSIS

Non - Responders Responders9 / 105 (8.6 %) 16 / 699 (2.3 %)

AMI 3 (33%) 7 (44%)

Bifurcation 5 (55%) 10 (62%)

Multivessel PCI 5 (55%) 10 (62%)

Stent length > 30mm 8 (89%) 8 (50%)

LVEF < 30% 5 (55%) 8 (55%)

11

Cox multivariate analysis:Predictors of Stent Thrombosis

HR (95% CI) pvalue

! Non-responsiveness to clopidogrel 3.08 (1.32-7.16) 0.009

! Acute myocardial infarction 2.41 (1.04-5.63) 0.041

! Total stent length (mm) 1.01 (1.00-1.02) 0.010

! LVEF per 1 % increase 0.95 (0.92-0.98) 0.001

12

Definite / Probable STENT THROMBOSISfor Responders and Non - Responders to

Clopidogrel (Kaplan-Meyer)

91 ± 3

98 ± 1

Prim

ary

end

poin

t–fr

ee s

urvi

val%

(def

inite

or p

roba

ble

sten

tthr

ombo

sis)

80

82

84

86

88

90

92

94

96

98

100

Time (days)0 30 60 90 120 150 180

Log rank p < 0.001

Non-RespondersResponders

13

Time (days)

80

85

90

95

100

0 60 120 180 240 300 360 420 480 540 600 660 720

Even

t-fre

e su

rviv

al%

(def

inite

orp

roba

ble

sten

t thr

ombo

sis) 97 ± 1

88 ± 3

Log rank p <.001

RespondersNon-responders

LONG - TERM SURVIVAL FOR PRIMARY END-POINT(DEFINITE OR PROBABLE STENT THROMBOSIS)

n=804 pts; median time follow-up 21 months - IQ 18-25

14

Non-responsiveness to CLOPIDOGREL is a strong

independent predictor of stent thrombosis and

mortality in patients receiving DES. Alternative

revascularization strategies (BMS or CABG), or

pharmacologic strategies using increasing dose of

clopidogrel or other antiplatelet agents should be

considered to reduce the risk of thrombotic

events.

Conclusion

Possible Causes / Mechanisms of Variability Platelet Response With

Antiplatelet Agents• Genetic1

– Receptors: P2Y12 H2 haplotype (clopidogrel), GPIIb/IIIa, collagen,thromboxane

– Enzymes: COX-1, COX-2, thromboxane A2 synthetase, etc. (aspirin)

• Pharmacokinetic / Bioavailability1

– Non-compliance– Underdosing– Poor absorption (e.g., enteric coated aspirin)– Interference: NSAIDs coadministration (aspirin); atorvastatin (clopidogrel)

• Pharmacodynamic1

– Incomplete suppression of thromboxane A2 generation (aspirin)– Accelerated platelet turnover, with introduction into the blood stream of newly

formed, drug-unaffected platelets– Stress-induced COX-2 in platelets (aspirin)– Increased platelet sensitivity to ADP and collagen

• Environment / Concomitant disease– Diabetes mellitus (aspirin)2

1 Michelson A. Circulation 2004;110:e489-932 Albert SG et al. Diabetes Res Clin Pract 2005;70:195-9

16

Follow-up Time (Months)N

Follow-up Time (Months)N

80859095

100

80859095

100

Polymorphism of the P2Y12 Receptor is a Possible Explanation for Clopidogrel

Failure, Though not Associated with All-cause Mortality• In PAD patients, clopidogrel

variability exists, which may results in increased risk forcerebrovascular events

• Sequence alterations of the target receptor gene represent one possible mechanism forclopidogrel failure

• Genotype frequencies for mutated, heterozygous, and wild-type alleles were– For polymorphism 34C>T = 9%,

44%, and 47% – For polymorphism 52G>T = 4%,

27%, and 70%• In clopidogrel patients, carriers of

at least one 34T allele had a 4.02-fold increased adjusted risk for neurological events compared with carriers of 34C allele

• Neither polymorphisms were i t d ith ll t lit

Ziegler S et al. Stroke 2005;36:1394-9

34C>T Polymorphism

Neu

rolo

gica

l Eve

nt –

Free

Sur

viva

l (%

)

0 3 6 9 12 15 18 21 24

34T non-carrierplus aspirin34T non-carrierplus clopidogrel

34T carrierplus clopidogrel

34T carrierplus aspirin

473 457 422 389 358 318 286 233 167

Log Rank p = 0.0095

0 3 6 9 12 15 18 21 24

52T non-carrierplus aspirin52T non-carrierplus clopidogrel

52T carrierplus clopidogrel

52T carrierplus aspirin

473 457 422 389 358 318 286 233 167

Log Rank p = 0.19

52G>T Polymorphism

Novel ADP P2YNovel ADP P2Y1212Receptor AntagonistReceptor Antagonist

PrasugrelPrasugrel

AZD 6140AZD 6140

CangrelorCangrelor

18

Healthy VolunteerHealthy VolunteerCrossover StudyCrossover Study

--2020

00

2020

4040

6060

8080

100100

IPA

at 2

4 ho

urs

(%)

IPA

at 2

4 ho

urs

(%)

Response toResponse toPrasugrelPrasugrel 60 mg60 mg

Response toResponse toClopidogrelClopidogrel 300 mg300 mg

ClopidogrelClopidogrel ResponderResponder

ClopidogrelClopidogrel NonNon--responderresponder

Inte

rpat

ient

Inte

rpat

ient

Varia

bilit

yVa

riabi

lity

InterpatientInterpatientVariabilityVariability

From Brandt JT AHJ 153: 66e9,2007

N=66

elevato non ènecessariamente migliore perché ècorrelato al Rischio Emorragico

20

Clopidogrel Responsiveness Shows a Normal Distribution in Patients

" Individuals receivingclopidogrel exhibit awide variability in response that follows a normal distribution curve

" In this study (retrospective analysis of a dataset of different type of patients)# Hypo-responsive

patients = 4.2%# Hyper-responsive

patients = 4.8%# Defined as to be 2

standard deviation lessthan and greater thanthe mean respectively

Serebruany V et al. J Am Coll Cardiol 2005;45:246-51

08

1624324048566472808896

104112

< = -20Delta 5µM ADP

[-10,0] [11,20] [31,40] [51,60] [71,80] [91,100]

Number of Patients

Distribution of the changes in 5 µmol of adenosinediphosphate (ADP)-induced platelet aggregation in 544 patients after receiving clopidogrel therapy. Negative changes in aggregation values represent aggregation values after the administration of clopidogrel that were higher than the baseline readings.

21

Change in Aggregation to 5µM ADP

What Are the Clinical Implications?

0

16

32

48

64

80

96

112

< = -20 [-10,0] [11,20] [31,40] [51,60] [71,80] [91,100]

Num

ber o

f Pat

ient

s

Adapted from: Serebrauny V et al. J Am Coll Cardiol 2005;45:246-51

Are hypo-responders at risk for thrombotic

events?

Are hyper-responders at risk for bleeding

events?

22

Change in Aggregation to 5µM ADP

What Could be the Clinical Implications with Higher IPA and

Less Variable Response?

< = -20 [-10,0] [11,20] [31,40] [51,60] [71,80] [91,100]

Num

ber o

f Pat

ient

s

Adapted from: Serebrauny V et al. J Am Coll Cardiol 2005;45:246-51

Are hyper-responders at risk for bleeding

events?

Are hypo-responders at risk for thrombotic

events?

Il Bravo Cardiologo Tra Scilla e Cariddi

ScillaTrombosi

CariddiEmorragia

24

TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel

TRITONTRITON--TIMI 38TIMI 38AHA 2007AHA 2007

Orlando, FloridaOrlando, Florida

Disclosure StatementDisclosure Statement: : The TRITONThe TRITON--TIMI 38 trial was supported by a research grant to the TIMI 38 trial was supported by a research grant to the

Brigham and WomenBrigham and Women’’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.

25

Study Design

Double-blind

ACS (STEMI or UA/NSTEMI) & Planned PCIASA

PRASUGREL60 mg LD/ 10 mg MD

CLOPIDOGREL300 mg LD/ 75 mg MD

1o endpoint: CV death, MI, Stroke2o endpoints: CV death, MI, Stroke, Rehosp-Rec Isch

CV death, MI, UTVRStent Thrombosis (ARC definite/prob.)

Safety endpoints: TIMI major bleeds, Life-threatening bleedsKey Substudies: Pharmacokinetic, Genomic

Median duration of therapy - 12 months

N= 13,600

26

StentStent ThrombosisThrombosis(ARC Definite + Probable)(ARC Definite + Probable)

0

1

2

3

0 30 60 90 180 270 360 450

RRR – 52 %P <0.0001

Prasugrel

Clopidogrel2.4

(142)

NNT= 77

1.1 (68)

Days

Endp

oint

(%)

AnyAny StentStent at Index PCIat Index PCIN= 12,844N= 12,844

270

5

10

15

0 30 60 90 180 270 360 450

RRR – 19 % (0.73-0.90)P=0.0004

Prasugrel

Clopidogrel

Days

Endp

oint

(%)

12.1

9.9

HR 1.32(1.03-1.68)

P=0.03

Prasugrel

Clopidogrel1.82.4

138events

+ 32 %events

Balance of Balance of Efficacy and SafetyEfficacy and Safety

CV Death / MI / Stroke

TIMI MajorNonCABG Bleeds

NNT = 46

NNH = 167

28

Diabetic SubgroupDiabetic Subgroup

0

2

4

6

8

10

12

14

16

18

0 30 60 90 180 270 360 450

RRR – 30%P<0.001

Days

Endp

oint

(%)

CV Death / MI / Stroke

TIMI MajorNonCABG Bleeds

NNT = 46

N=3146N=3146

17.0

12.2

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel 2.62.5

29

Net Clinical BenefitNet Clinical BenefitBleeding Risk SubgroupsBleeding Risk Subgroups

OVERALL

>=60 kg

< 60 kg

< 75

>=75

No

Yes

0.5 1 2

PriorStroke / TIA

Age

Wgt

Risk (%)+ 37

-16

-1

-16

+3

-14

-13

Prasugrel Better Clopidogrel BetterHR

Pint = 0.006

Pint = 0.18

Pint = 0.36

PostPost--hoc analysishoc analysis

……. e se utilizzoClopidogrel ad alte dosi (600 / 150 mg) aumento IPA senza incrementare il rischio emorragico ?

31

Comparison with Higher Dose Clopidogrel

P<0.0001 for each

IPA (%; 20 µM ADP)

Hours 14 Days

IPA (%; 20 µM ADP)P<0.0001

Prasugrel10 mg

Clopidogrel150 mg

Wiviott et al Circ 2007 (In Press)

N=201

Prasugrel 60 mg

Clopidogrel 600 mg

32

CURRENT Study Flow Chart

All patientsrandomized to ASA low dose (75 -100 mg o.d ) or high dose (300-325 mg o.d)

RPatients with UA and NSTEMI

Planned for early invasive strategy (i.e., intent for PCI as soon as possible within 24 hours)

Day 1 Hospital Discharge or Day 8 (whichever comes first) Day 30 (+7 days)

Day 1 = 600 mg LDDay 2 –Day 7 = 150 mg dailyDay 8-30 = 75 mg

Day 1 = 300 mg LD + placeboDay 2 –Day 7 = 75 mg daily + placebo Day 8-30 75 mg daily

Day

8

Day 8 to 30 = clopidogrel75 mg

High dose group

Standard dose group~ 7000 Pts

~ 7000 Pts

Scienziato non é colui che sa

dare le vere Risposte,

ma colui che sa porre le giuste

Domande

Claude Levi Strauss