LA TERAPIA ANTIAGGREGANTE PRIMA E DOPO STENT Francesco Bellandi U.O. Cardiologia - Ospedale di Prato...

LA TERAPIA ANTIAGGREGANTE

PRIMA E DOPO STENT

Francesco BellandiU.O. Cardiologia - Ospedale di Prato

IL DIVENIRE CLINICOIN CARDIOLOGIA

Firenze 31 Ottobre 2008

RIDUZIONE DEL RISCHIO DI EVENTI ISCHEMICI

POSTPROCEDURALI

RIDUZIONE DEL RISCHIO DI TROMBOSI DELLO STENT

RISCHIO EMORRAGICO

Antiplatelet TherapyAntiplatelet Therapy

0

1 08

Placebo APTC CURE TRITON-TIMI 38

Single Antiplatelet Rx

Dual Antiplatelet Rx

Higher IPA

ASAASA +

Clopidogrel ASA + Prasugrel

- 22%

- 20%

- 19%

+ 60% + 38% + 32%

Reduction in

IschemicEvents

Increase in

Major Bleeds

ISCHEMIC EVENTS

ISCHEMIC EVENTS

BLEEDINGSBLEEDINGS

Ndrepepa G et al; JACC 2008: 690-697

Periprocedural Bleeding and 1-Year Periprocedural Bleeding and 1-Year Outcome Outcome

After Percutaneous Coronary After Percutaneous Coronary InterventionsInterventions

OR: 3.7; P < 0.001OR: 3.7; P < 0.001 OR: 4.7; P < 0.001OR: 4.7; P < 0.001

ASA

TIENOPIRIDINE

INIBITORI GLICOPROTEINE

DOPPIA DOPPIA ANTIAGGREGAZIONEANTIAGGREGAZIONE

DOPPIA DOPPIA ANTIAGGREGAZIONEANTIAGGREGAZIONE

Antiplatelets treatment

Main open issues:

Need of pretreatment

Loading Dose

Length and Dose of long term therapy

Clopidogrel low responsiveness

Perioperative Management in patients with stents

Dual antiplatelet therapy and Chronic oral Anticoagulation


Main open issues:

Need of pretreatmentLoading Dose





SABATINE MS et al, Am Heart J 2008: 910-917

MACE a 30 giorni (morte, infarto e stroke)MACE a 30 giorni (morte, infarto e stroke)

TOTALE 6336 pzTOTALE 6336 pz

Riduzione Riduzione 29%29%

Dal 5.8% al 4.1%Dal 5.8% al 4.1%

P = 0.004P = 0.004

SABATINE MS et al, Am Heart J 2008: 910-917

TIMI major or minor bleedingTIMI major or minor bleeding

TOTALE 6336 pzTOTALE 6336 pz

Dal 1.9% al 2.3%Dal 1.9% al 2.3%

OR: 1,21OR: 1,21

P = 0.29P = 0.29

Steinhubl S, J Am Coll Cardiol 2006; 47:939-43

CREDO Study: Optimal timing for the initiation of pre-treatment with 300mg clopidogrel before PCI.

PCI – ESC 2005Pretrattamento in caso di PCI Dose 300 mg almeno 6 ore prima della PCIprogrammata per CAD stabile e idealmente il giorno primaPretrattamento in caso di PCI Dose 300 mg almeno 6 ore prima della PCIprogrammata per CAD stabile e idealmente il giorno prima


Main open issues:


Loading Dose





Faster Onset of Action and Higher Level of Platelet Inhibition (Dose-Effect): ALBION Trial

40

35

30

25

20

15

10

5

0

Inh

ibit

ion

(%

)

1 2 3 4 5 6 24

Shortened time to reach the highestLevel of inhibition of the 300 mg LD

P < 0.05 vs. 300 mg LD

Time (Hours)

Maximum Inhibition of Platelet Aggregation (ADP 5 mol/L)

300 mg LD 600 mg LD 900 mg LD

Montalescot G, et al. JACC 2006Montalescot G, et al. JACC 2006

P = 0.041

*Death, MI; TVR to 30 d

ISAR REACT II: ISAR REACT II: 2022 NSTE ACS pts2022 NSTE ACS pts

Kastrati A et at; JAMA 2005Kastrati A et at; JAMA 2005

ISAR-REACT II Study: Optimal timing for the initiation of pre-treatment with 600 mg clopidogrel before PCI

> 3 h

≤ 3 h

Clopidogrel interval (hours)

19.8%

26.4% 25.1%

30.4%

> 3 h

≤3 h

Abciximab Placebo

one - year Death/MI/TVR

Ndrepepa G, Eur Heart J 2007

0,0

5,0

10,0

15,0

20,0

600 mg 300 mg(n = 126) (n = 129)

Co

mp

osi

te 1

° E

nd

po

int

(%)*

P = 0.041

*Death, MI; TVR to 30 d

ARMYDA–2: Randomized Trial of Clopidogrel Loading Dose

4-8 Hours Before PCI

Patti G, et al. Circulation. 2005;111:2099-106.Patti G, et al. Circulation. 2005;111:2099-106.

PCI – ESC 2005

ARMYDA 2

PCI URGENTE o Dose carico 600 mg immediatamente dopo il primoPCI ad hoc per CAD stabile contatto medico, se clinicamente giustificabilePCI URGENTE o Dose carico 600 mg immediatamente dopo il primoPCI ad hoc per CAD stabile contatto medico, se clinicamente giustificabile

PCI – AHA 2007 updatePCI – AHA 2007 update

Classe IIaClasse IIa

If clopidogrel is given at the time of procedure, If clopidogrel is given at the time of procedure, supplementation with GP IIb/IIIa receptor supplementation with GP IIb/IIIa receptor antagonists can be beneficial. antagonists can be beneficial. (Level of Evidence: B).

Oasis – 7CURRENT study

..

Clopidogrel optimal loading dose Usage to Reduce Recurrent EveNTs

Randomized, multinational, double-blind, comparing a high loading dose regimen of Clopiodgrel versus standard dose in pts with NSTEMI managed with an early invasive strategy


Main open issues:


Loading Dose

Length and Dose of long term therapyClopidogrel low responsiveness



TROMBOSI DELLO STENTdefinizione e classificazione

acuta

PCI 24 ore 1 mese

subacuta

1 anno

tardiva (“late”) “very late”

Classificazione temporale

Definizione ARC (Academic Research ConsortiumDefinizione ARC (Academic Research Consortium))

•Trombosi definita = sindrome coronarica acuta con evidenza angiografica oTrombosi definita = sindrome coronarica acuta con evidenza angiografica o autoptica di trombosi o occlusione dello stentautoptica di trombosi o occlusione dello stent

•Trombosi probabile = 1) qualsiasi morte non altrimenti spiegabile entro 30 dallaTrombosi probabile = 1) qualsiasi morte non altrimenti spiegabile entro 30 dalla dalla procedura;dalla procedura; 2) infarto miocardico acuto nel territorio dell’arteria coronica2) infarto miocardico acuto nel territorio dell’arteria coronica trattata senza conferma angiograficatrattata senza conferma angiografica

•Trombosi possibile = qualsiasi morte non altrimenti inspiegabile oltre 30 giorni dalla procedura

• Stent metallici → endotelizzazione

completata in 9-12 giorni → terapia antitrombotica per 3-4 settimane dopo

impianto di stent

ASA ASA + Ticlopidina ASA + Warfarin

Stent thrombosis

STARS 2,9% 0,5% 2,7%ISAR - 0,8% 5,4%

PCI – AHA 2007 update

Classe IClasse I

For post-PCI patients receiving a For post-PCI patients receiving a BMSBMS, clopidogrel , clopidogrel should be given for a minimum of should be given for a minimum of 1 month 1 month (level of Evidence: A)

and and ideally up to 12 monthsideally up to 12 months (unless the patient is at (unless the patient is at increased risk of bleeding; then it should be given for a increased risk of bleeding; then it should be given for a minum of 2 weeks minum of 2 weeks (Level of Evidence: B)

• Stent medicati → azione antiproliferativa

→ endotelizzazione ritardata → durata durata terapia antitrombotica ?terapia antitrombotica ?

TROMBOSI DELLO STENTQUAL’E’ LA DIMENSIONE DELPROBLEMA?

NEI VARI TRIALS RANDOMIZZATI L’INCIDENZACUMULATIVA AD UN FOLLOW-UP DI 9-12 MESI ERA: 0.7 – 1.2%

Ma nei vari registri, più rappresentativi della pratica clinica quotidiana, vengono riportate incidenza 2-3

volte superiori

Una differenza sostanziale rispetto agli stents metallici è il PATTERN TEMPORALE della trombosi che non

infrequentemente viene osservata oltre i 12 mesi dalla procedura (vey late)

Kaul S et al; JACC 2007

Wenaweser MS et al, Am Heart J 2008: 910-917

DES THROMBOSIS (follow-up 4 years)DES THROMBOSIS (follow-up 4 years)

Wenaweser P et al; JACC 2008: 1134-1140

0,4-0,6% year

Chechi T et al; JACC 2008: 2396-2402

6-month OUTCOMES6-month OUTCOMES

Ninety-two (80%) of these STs presented as STEMINinety-two (80%) of these STs presented as STEMI

20.9% vs 10.2%20.9% vs 10.2% 31.4% vs 17.3%31.4% vs 17.3%

MACCE: major adverse cardiovascular and cerebrovascular events

Riperfusione efficaceRiperfusione efficace

Chechi T et al; JACC 2008: 2396-2402

STEMI with ST STEMI without ST

INDICAZIONI ALL’USO DEI DESINDICAZIONI ALL’USO DEI DES

PCI 2005Classe I

In patients who have undergone PCI, clopidogrel 75 mg daily should be given for at least 3 months after sirolimus stent implantation, and 6 months

after paclitaxel stent implantation, and ideally up

to 12 months in

patients who are not at high risk of bleeding. (Level of

Evidence: B)

PCI UPDATE 2007Classe I

For all post-PCI stented patients receiving a DES, clopidogrel 75 mg daily

should be given for at least 12 months if patients are

not at high risk of

bleeding. (Level of Evidence: B)

For patients with clinical features associated with stent thrombosis, such as renal insufficiency, diabetes, or

procedural characteristics such as left main, bifurcating left main, single patent coronary vessel, multiple stents or treatment of a bifurcation lesion, extended DAT beyond 1 year may be reasonable.

PCI 2007 updateClasse IIb

Continuation of clopidogrel therapy beyond 1 year may be considered in patients undergoing DES placement

(Level of Evidence: C)

DES THROMBOSISOPEN ISSUES

Se l’interruzione della doppia antiaggregazione rappresenta il fattore predittivo indipendente di maggior peso per la trombosi dello stent, occorre ricordare che una percentuale variabile da un terzo alla metà dei casi avviene sotto doppia antiaggregazione

(Holmes DR et al; JACC 2007)


Main open issues:


Loading Dose


Clopidogrel low responsivenessPerioperative Management in patients with stents


Variability in platelet responsiveness to 300 mg loading dose of clopidogrel among 544 individuals.

Serebruany VL et al, JACC 2005;45:246-51.

0

20

40

60

80

100

120

Change in ADP-induced platelet aggregation

-20-100102030405060708090

Impact of Platelet Reactivity After Clopidogrel Impact of Platelet Reactivity After Clopidogrel Administration on Drug-Eluting Stent Administration on Drug-Eluting Stent

ThrombosisThrombosis

Buonamici P et al, JACC 2007Incidence ST: 8.6% NR vs 2.3% R, p=0,001

ISAR-CHOICE 2A double-blind, randomized study on platelet aggregation in pts treated with a daily dose of 150 or 75mg of clopidogrel for 30 days.

60 stable pts, < 12 h from PCI pretreated with 600mg CLO

Randomization

150mg for 30 d 75mg for 30 d

Platelet function testing 5 µM ADP-aggregation (%)

65±1245±20

P <0.001

Von Beckerath, E Heart J 2007; 28:1814-1819

High Clopidogrel maintaining dosage improves long-term clinical outcomes in Pts with ACS undergoing DES implantation

634 ACS pts, PCI + DES pretreated with 600mg CLORandomization

150mg for 30 d 75mg for 30 d

Clinical evaluation (mean 18mo)

20.2

13

Han Y, TCT 2007

75mg for 12 mo 75mg for 12 mo

8.13.7

14.79

4.22.7

All MI TVR death

ns

major bleed trasfusion

1.62.3 1.32

P <0.001P <0.001

P <0.001

ns ns

PCI – AHA 2005

Classe IIbClasse IIb

For patients in whom subacute thrombosis may For patients in whom subacute thrombosis may be catastrophic (unprotected left main, be catastrophic (unprotected left main, bifurcating left main, or single patent coronary bifurcating left main, or single patent coronary vessel), it is reasonable to perform platelet vessel), it is reasonable to perform platelet aggregation studies, and if < 50% platelet aggregation studies, and if < 50% platelet inhibition, consider 150 mg/day (clopidogrel).inhibition, consider 150 mg/day (clopidogrel).

Novel platelet receptor antagonist

Prasugrel

AZD6140Cangrelor

ADP P2Y12

BMS-180291 BS 13.177 GR 32191TERUTROBA

N(S188886)

TP (TXA2/PGH2)

SCH 30348

E5555

PAR1 (Trombina)

Comparison with Higher Dose Clopidogrel

P<0.0001 for each

IPA (%; 20 M ADP)

Hours 14 Days

IPA (%; 20 M ADP)

P<0.0001

Prasugrel 10 mg

Clopidogrel 150 mg

Wiviott et al Circ 2007

N=201

Prasugrel 60 mg

Clopidogrel 600 mg

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81(0.73-0.90)P=0.0004

Prasugrel

Clopidogrel

Days

En

dp

oin

t (%

)

12.1

9.9

HR 1.32(1.03-1.68)

P=0.03

Prasugrel

Clopidogrel1.82.4

138 events

35 events

Balance of Balance of Efficacy and SafetyEfficacy and Safety

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = 46

NNH = 167

TRITON-TIMI 38TRITON-TIMI 38N Engl J Med 2007N Engl J Med 2007

RR – 24%

RR + 32%

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81(0.73-0.90)P=0.0004

Prasugrel

Clopidogrel

Days

En

dp

oin

t (%

)

12.1

9.9

HR 1.32(1.03-1.68)

P=0.03

Prasugrel

Clopidogrel1.82.4

138 events

35 events

Balance of Balance of Efficacy and SafetyEfficacy and Safety

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = 46

NNH = 167

TRITON-TIMI 38TRITON-TIMI 38N Engl J Med 2007N Engl J Med 2007

RR – 24%

RR + 32%

NET CLINICAL BENEFIT favours PRASUGREL

P 12,2% vs C 13,9%P 12,2% vs C 13,9%

P = 0,004

Bleeding Risk SubgroupsBleeding Risk SubgroupsTherapeutic ConsiderationsTherapeutic Considerations

Significant Net Clinical Benefit

with Prasugrel80%

MD MD 10 mg10 mg

Reduced MD

Guided by PK

Age > 75 or

Wt < 60 kg

16%

Avo

id

Prasu

grel

Prio

r

CV

A/T

IA

4%4%

TIMI Major NonCABG Bleeding

Antman EM et al, JACC 2008


Main open issues:


Loading Dose



Perioperative Management in patients with stentsDual antiplatelet therapy and Chronic oral Anticoagulation

ACC/AHA 2007 Guidelines on Perioperative CardiovascularACC/AHA 2007 Guidelines on Perioperative CardiovascularEvaluation and Care for Noncardiac SurgeryEvaluation and Care for Noncardiac Surgery

Surgery Room

5 daybefore

Stopclopidogrel

2 dayafter

Restartclopidogrel

0

ASA 80 mg/dASA 80 mg/d

ACC/AHA 2007 Guidelines on Perioperative CardiovascularACC/AHA 2007 Guidelines on Perioperative CardiovascularEvaluation and Care for Noncardiac SurgeryEvaluation and Care for Noncardiac Surgery

Holmes DR et al; JACC 2007

Class IIaClass IIa; level of evidence: C

Surgery Room

5 daybefore

Stopclopidogrel

1 dayafter

Restartclopidogrel

0

Interventi chirurgici a maggior rischio di sanguinamentoInterventi chirurgici a maggior rischio di sanguinamento

LMWHLMWH7 day beforestart STOP

GISE 2008

3 daybefore

StopASA

RestartASA

3 dayafter

Surgery Room

3 daybefore

Stopclopidogrel

1 dayafter

Restartclopidogrel

0

ASA 80 mg/dASA 80 mg/d

Interventi chirurgici a basso rischio di sanguinamentoInterventi chirurgici a basso rischio di sanguinamento

LMWHLMWH7 day before

start STOP

GISE 2008

ACCP 2008ACCP 2008

In patients with a bare metal coronary stent (BMS) who require surgery within 6 weeks of stent placement, we recommend

continuingcontinuing aspirin and clopidogrel in the perioperative period (Grade 1C).

In patients with a drug-eluting coronary stent (DES) who require surgery within 12 months of stent placement, we

recommend continuingcontinuing aspirin and clopidogrel in the perioperative period (Grade 1C).

In patients with a coronary stent who have interruption of

antiplatelet therapy before surgery, we suggest againstagainst the routine use of bridging therapy with UFH, LMWH, direct thrombin inhibitors, or glycoprotein IIb/IIIa inhibitors (Grade 2C).


Main open issues:


Loading Dose





ASA ASA + Ticlopidina ASA + Warfarin

Stent thrombosis

STARS 2,9% 0,5% 2,7%ISAR - 0,8% 5,4%

Combination therapy with aspirin, clopidogrel and warfarin following coronary stenting is associated with a significant risk of bleeding

2,3%/year

3,9%/year

7%/year

0

5

10

1

Maj

or

ble

edin

g (

%/y

ear)

A

A + W

A + W + C

A = ASA; W = WARFARIN; C = CLOPIDOGREL

Khurram Z et al J Invasive Cardiol 2006

TROMBOSI DELLO STENTDES ed anticoagulazione (LG FA 2006)

STENTS e WARFARIN

1)1)AD ELEVATO RISCHIO EMBOLICO + BMSAD ELEVATO RISCHIO EMBOLICO + BMSACCP 2008 (Grado 2 C)ACCP 2008 (Grado 2 C)

• Clopidogrel + ASA + warfarin per 4 settimane

• Warfarin + ASA successivamente (con INR target 2-2,5)

2) A RISCHIO EMBOLICO BASSO o MODERATO + 2) A RISCHIO EMBOLICO BASSO o MODERATO + BMS (+ DES)BMS (+ DES)

• ASA + Clopidogrel per 4 settimane (1 anno ASA + Clopidogrel per 4 settimane (1 anno se DES)se DES)

• ASA successivamenteASA successivamente

3)3) ELEVATO RISCHIO EMBOLICO + DES ACCP 2008 (Grado 2C)

• ASA + CLOPIDOGREL + WARFARIN (9-12 ASA + CLOPIDOGREL + WARFARIN (9-12 mesi)mesi)

TROMBOSI DELLO STENTDES ed anticoagulazione (LG FA 2006)

1.1. Gli autori ritengono che il clopidogrel sia il farmaco più importante per ilGli autori ritengono che il clopidogrel sia il farmaco più importante per il mantenimento della pervietà dello stent.mantenimento della pervietà dello stent.

2. l’aggiunta di aspirina alla terapia anticoagulante comporta più rischi che benefici.

3. La terapia di mantenimento dovrebbe consistere nell’associazione tra3. La terapia di mantenimento dovrebbe consistere nell’associazione tra clopidogrel (75 mg/die) + warfarin (con INR tra 2 e 3) per 9-12 mesi clopidogrel (75 mg/die) + warfarin (con INR tra 2 e 3) per 9-12 mesi

4. Dopo 9-12 mesi, sospensione del clopidogrel e proseguimento del warfarin4. Dopo 9-12 mesi, sospensione del clopidogrel e proseguimento del warfarin come monoterapiacome monoterapia

CLASSE IIb; livelllo di evidenza: C

VI RINGRAZIOVI RINGRAZIO

PER LA BONTA’PER LA BONTA’

PCI – AHA 2007 update (ASA)PCI – AHA 2007 update (ASA)

Classe IClasse I

Patients already taking daily long-term aspirin therapy Patients already taking daily long-term aspirin therapy should take 75 mg to 325 mg of aspirin before PCI is should take 75 mg to 325 mg of aspirin before PCI is performed. performed. (Level of Evidence: A).

Patients not already taking daily longterm aspirin Patients not already taking daily longterm aspirin therapy should be given 300 mg to 325 mg of aspirin at therapy should be given 300 mg to 325 mg of aspirin at least 2 hours and preferably 24 hours before PCI is least 2 hours and preferably 24 hours before PCI is performed. performed. (Level of Evidence: C)

PCI – AHA 2007 updatePCI – AHA 2007 update


For patients with an absolute contraindication to For patients with an absolute contraindication to aspirin, it is reasonable to give a 300-mg to 600-mg aspirin, it is reasonable to give a 300-mg to 600-mg loading dose of clopidogrel, administered at least 6 loading dose of clopidogrel, administered at least 6 hours before PCI, and/or GP IIb/IIIa antagonists, hours before PCI, and/or GP IIb/IIIa antagonists, administered at the time of PCI. administered at the time of PCI. (Level of Evidence: C)

ACCP 2008ACCP 2008

For patients undergoing PCI with a DES, we recommend aspirin (75–100 mg/d) plus clopidogrel (75 mg/d for at least 12 months) [Grade 1A for 3 to 4 months; Grade 1B for 4 to 12 months].

PCI – AHA 2007 update (ASA)PCI – AHA 2007 update (ASA)Classe IClasse I

(Level of Evidence: B).(Level of Evidence: B).

After PCI, in patients without allergy or increased risk of bleeding, After PCI, in patients without allergy or increased risk of bleeding, aspirin 162 mg to 325 mg daily should be given for at least:aspirin 162 mg to 325 mg daily should be given for at least:• 1 month after BMS implantation, 1 month after BMS implantation, • 3 months after sirolimus-eluting stent implantation, and 3 months after sirolimus-eluting stent implantation, and • 6 months after paclitaxel-eluting stent implantation, 6 months after paclitaxel-eluting stent implantation, • after which daily long-term aspirin use should be continued after which daily long-term aspirin use should be continued indefinitely at a dose of 75 mg to 162 mg. indefinitely at a dose of 75 mg to 162 mg.


In patients for whom the physician is concerned about In patients for whom the physician is concerned about risk of bleeding, a lower dose of 75 mg to 162 mg of risk of bleeding, a lower dose of 75 mg to 162 mg of aspirin is reasonable during the initial period after stent aspirin is reasonable during the initial period after stent implantation. implantation. (Level of Evidence: C)

Ticlopidina

• Azione ritardata (fino a 3 giorni)• Duplice somministrazione

giornaliera• Effetti collaterali (10.6% CLASSICS):

a) Rush cutanei, disturbi gastrointestinali b) Depressione midollare con

trombocitopenia e neutropenia (2%) → nei primi 3 mesi (controllo emocromo ogni 2 settimane)

c) Porpora trombotica trombocitopenica (raro)

Clopidogrel

• CLASSICS (2000):

1) Ticlopidina e clopidogrel hanno efficacia antitrombotica simile

1) Clopidogrel con più bassa frequenza di effetti collaterali (5.3% vs. 10.6% ticlopidina)

Clopidogrel - vantaggi

• Rapido ed elevato livello di antiaggregazione dopo carico

orale• Bassa incidenza di depressione

midollare• Bassa incidenza di effetti

collaterali cutanei e gastrointestinali

• Monosomministrazione giornaliera

LA TERAPIA ANTIAGGREGANTE PRIMA E DOPO STENT Francesco Bellandi U.O. Cardiologia - Ospedale di Prato...

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Transcript of LA TERAPIA ANTIAGGREGANTE PRIMA E DOPO STENT Francesco Bellandi U.O. Cardiologia - Ospedale di Prato...