ChryssaPapageorgiou

Anesthetist- Intensivist,

PraticienHospitalier

Centre HospitalierUniversitaireTenon,

Paris

Antiplatelet agents

Inhibitors of

Arachidonate pathway

Aspirin

Indobufen

Flurbiprofen

Triflusal

Ridogrel

Picotamide

S 18886

Cilostasol

Antagonists of

ADP receptor

Ticlopidin

Clopidogrel

Prasugrel

Ticagrelor

Cangrelor

Antagonists of

GP IIb/IIIa

Abciximab

Tirofiban

Eptifibatide

Inhibition of platelet aggregation

Down-regulation of thrombin generation

Risk reduction of

stent thrombosis and restenosis

recurrent ACS and MACE

evolution of atherothrombosis

Balance of bleeding risk which increases mortality in the

1st year after PCI

Aims of antiplatelettreatment

Single treatment

ASA

125 mg – 325 mg/o.d.

Clopidogrel

75 mg o.d.

Dual treatment

Clopidogrel + ASA

ASA 125 mg - 325 mg o.d.

Clopidogrel

300 or 600 mg loading dose before PCI;

75 mg o.d. or

150 mg o.d.

Prasugrel + ASA

Ticagrelor + ASA

Dipyridamol + ASA TIA

Triple treatment

ASA + Clopidogrel + anti-GPIIb/IIIa

Major options for antiplatelettreatment in ACS

Aspirin Clopidogrel Ticagrelor Αnti-GPIIb/IIIa

Target -protein COX-1 P2Y12 aIIβ3

Reversibility of

action

no no yes yes

Half-time life min min 7-12 h hours

Dose titration noNo

Loading dose of 300 mg in high risk

patients

?

Orally active yes yes yes no (?)

Main characteristics of antiplatelet drugs

Nucleoside

analogue

Properties of P2Y12 receptor antagonists

Drug

Administration Activation

via CYP450

metabolism

ttPeak of

pltinhibition

Reversibility

(half-life)Route Frequency

Clopidogrel Oral Once dailyProdrug

(yes)

2-6h (after

600 mg

loading

dose)

No

Prasugrel OralOnce daily Prodrug

(yes)2h No

Cangrelor i.v. Continuous No 30 min Yes (3-5 min)

Ticagrelor Oral Twice daily No 2h Yes (12h

Prasugrel vs clopidogrel clinical pharmacology More efficient generation of active metabolite

10-fold higher potency

Greater inhibition of ADP-induced platelet

aggregation

More concistentresponse

Faster onset of action

Reduced rates of ischemic events including stent

thrombosis

Ticagrelor

Reversible orally active P2Y12

receptorantagonist

Non competitive inhibitor of ADP on P2Y12

receptor

Functional recovery of all circulating platelets

Not a prodrug; does not require metabolic

activation

Rapid onset of inhibitory effect on the P2Y12

receptor

Potent inhibitor of ADP induced platelet

aggregation

New pharmaclogical

class

cyclo-pentyl-triazolo-

pyrimidine (CPTP)

Ticagrelor

Reduced rates of death from vascular causes,

myocardial infraction and stroke without an increase

in the rate of overall major bleeding…..

Wallentin L et all, N Engl J Med 2009

Iakovou et al JAMA 2005; 293:2126-30

HR 95% CI P value

Antiplatelet discontinuation 89.8 30–269 < 0.001

Renal failure 6.49 2.6–16.1 < 0.001

Bifurcation lesions 6.42 1.74–7.89 < 0.001

Diabetes 3.71 1.74–7.89 < 0.001

Low EF 1.09 1.05–1.36 < 0.001

Cumulative proportion of late stenosis time cases among patients who discontinued antiplatelettherapy

Eisenberg M J et al. Circulation 2009;119:1634-1642

Cumulative proportion of late stenosis time cases among patients who discontinued antiplatelettherapy

Eisenberg M J et al. Circulation 2009;119:1634-1642

The effect of discontinuation of antiplatelet therapy on the timing of late stenosis time

Eisenberg M J et al. Circulation 2009;119:1634-1642

PES: paclitaxel-eluting stent

SES: sirolimus-eluting stent

Van Belle et al Circulation 2001; 103:1218-24

Bare Metal Stents• Reendothelialisationin 1 month• Prevent the risk of thrombosis• Riskof restenosis Curfman GD et al NEJM 2007

STENTs and VascularReactions

Drug ElutingStents• Retardedre-endothelialisation• Lowrisk of restenosis• High riskof thrombosis

THROMBOTIC RISK Τhe 30% of patients with stent will be operated for non-

cardiac operations during the first 2 years after stent’s

placement

The risk of thrombosis exists for the bare metal stents as well

as for the DES

The risk of thrombosis is inversely correlated to the time from

the stent placement

The risk of thrombosis exists even after the first thrombogenic

period ( 6 weeksfor ΒΜSand 12 months for the DES)

THROMBOTIC RISK AND SYRGERY

Stopingaspirin in coronary patients augments the risk of

ACSFerrari et al, J AM CollCardiol 2005;45:456-9

The cancer and vasculaire surgeryis a thrombogenic

situation whichrises up the risk of stentthrombosis

The interruption of aspirincouldprovoke a

reboundeffectAlbaladejo et al, AnesthAnalg 2004;99:440-3

6-10 daysafteraspirin interruption thereis a highrisk

of AIS

THROMBOTIC RISK AND SYRGERY

Surgeryfurtherincreases the prothrombotic and

inflammatory state, which ,

combinedwithincompletelyendothelialiseddrugeluting

stentscanlead to stentthrombosis and

consequentlymyocardialinfarction and / or death

Newsome LT et al, AnesthAnalg 2008;107:570-590

In patientswith thrombosis

Platelet activation

Generalisedhypercoagulable state

Increase of inflammation markers

Inflammation

Platelet activation

Thrombingeneration

THROMBOTIC RISK AND SYRGERY RECO study, cohortstudy of 1134 consecutive patients

withcoronarystentswhounderwentsurgicalprocedures

Patients withcoronarystentsundergoing an invasive procedure are

athighrisk of

perioperativemyocardialinfarctionincludingstentthrombosisirrespectiv

e of the stent type and major bleeding.

Interruption of OAT more than 5 daysprior to an invasive procedure

and operation time < 3 months of stent’s implantation are the

keyplayers for major adverse cardiac and cerebrovascularevents

Albaladejo et al, Heart 2011;97:1566-72

Perioperative hemorrhagic risk

High hemorrhagic risk

• Procedures > 45min

• Τype of surgery

– Vasculair

– Cardiosurgery

– Μajor orthopedics

– Prostatectomy

– Cancer surgery

– Αmugdalectomy

Low hemorrhagic risk

Procedures< 45min

Diagnostic procedures

Endoscopies, biopsies ( except renal

and hepatic biopsies)

Dental procedures

Ophtalmological procedures

1.5-fold increase of bleedingrisk in aspirintreated

patients (interquartile range: 1.0-2.5)

iAspirintreatmentdid not lead to a higherlevel of the

severity of bleeding complications (exception:

intracranialsurgery, and

possiblytransurethralprostatectomy))

41trials

n=49 590,14981 pts treatedwith aspirin

12retrospectives 19prospectives10randomised

Burger et al,JIntern Med 2005; 257: 399–414

Aspirin and surgeryrelatedrisk of bleeding

•In patients atmoderate to highrisk for cardiovasculareventswho are receiving ASA therapy and requirenoncardiacsurgery, wesuggestcontinuing ASA around the time of sur-geryinstead of stopping ASA 7 to 10 daysbeforesurgery(Grade 2C).

• In patients atlowrisk for cardiovasculareventswho are receiving ASA therapy, wesuggeststopping ASA 7 to 10 daysbeforesurgeryinstead of continuation of ASA (Grade 2C).

ACCP Recommandations, Chest 2012;141;e326S-e350S

Perioperative management of antiplatelet treatment

In patients withcoronarystent and who are

receiving dual antiplatelettherapy and

requiredsurgerywerecommenddeferringsurgery

for at least 6 weeks for baremetalstents and for

at least 6 months for the DES instead for

undertakingsurgerywithinthis time periods(Grade

1C)

ACCP Recommandations, Chest 2012;141;e326S-e350S

Perioperative management of antiplatelet treatment

In patients whorequiresurgerywithin 6 weeks of

placement of a bare-metalstent or within 6

months of placement of a drug-elutingstent,

wesuggestcontinuing dual

antiplatelettherapyaround the time of

surgeryinstead of stopping dual antiplate- let

therapy 7 to 10 daysbeforesurgery(Grade 2C).

ACCP Recommendations, Chest 2012;141;e326S-e350S

Preoperativeevaluation of patients withstents: a checklist

Determine type of stent(s): Baremetal or drug –eluting

Determine how long agoeachstentwasimplanted

Determine location of eachstent in the coronary circulation

How complicatedwas the revascularisation?werethereany complications (

malapposition)?

Is there a priorhistory of stentthrombosis?

Whatantiplateletregimenwabeingused?

Determinepatient’scomorbidities to furtherascertainrisklevel (ejection

fraction, diabetes,renalinsufficiency)

Whatis the recommendedduration of dual antiplatelettherapy for the specific

patient in hand?

Consultwithpatient’scardiologist to reviewcurrentantiplatelet management

and discuss optimal management strategy

Perioperativeantiplatelet treatment in patients with stents

Μqjor Moderate Minor

Μajor •Deferring operation 6-

12months after stents’

implantation

•If it isn’t possible,

discontinuation of

anpiplatelet therapy 5

days preoperatively

•Re-initiation of

treatment as soon as

adequate hemostasis

is confirmed

•Deferring operation 6-

12months after stents’

Implantation

•If it isn’t possible,

discontinuation of

clopidogrel 5 days

before surgery and

continuation of ASA

•Deferring surgery

•Continuation of dual

antiplatelet treatment

Μoderate •Continuation of ONE

antiplatelet agent

•Substitution of

clopidogrel or

prasugrel or ticagrenol

with ASA

Discontinuation of

clopidogrel 5 days

before surgery and

continuation of ASA

Continuation of dual

antiplatelet treatmentTh

rom

bo

tic

ris

k

Hemorrhagic risk

Recommendations de la SocieteFrancaises

d’Anesthésie et Réanimation SFAR 2010

Re-initiation of antiplatelettreatment

In patients who had interrupted the aspirin or

clopidogrel before surgery we

recommenendantiplatelets initiation in the first

24 hours after operation or in the next morning if

there is adequate post-operative

hemostasis(Grade 2C).

ACC/AHA 2007 guidelines,AnesthAnalg 2008

Re-initiation of antiplatelettreatment

In patients with DES < 12 μήνες, in whom

clopidogrel was interrupted before operation, the

charge dose of clopidogrel (300mg) is

recommended when there is adequate

hemostasis post-operative.

ACC/AHA 2007 guidelines,AnesthAnalg 2008

Risk of epiduralhaematoma

1/150.000 patients who had neuraxial regional anesthesia

68% of epidural hematomas in patients under antithrombotic treatment

15 –fold greater risk in patients with antithrombotic treatment in whom the management of this treatment isn’t correctly done before RA

60% of epidural hematomas during the removal of epidural catheter

Antiplatelet drugs

Time before and

afterneuraxialpuncture/

catheter manipulation

or removal

Time before and

afterneuraxialpuncture/

catheter manipulation

or removal

Acetylsalicylicacid none none

Clopidogrel 7 days After catheter removal

Ticlodipine 10days After catheter removal

Prasugrel 7 -10 days 6h after catheter removal

Ticagrelor 5days 6 h after catheter removal

Recommenced time intervals before and after neuraxial puncture or catheter removal 1

1 Recommendations of the European Society of Anaesthesiology, EJA 2010;27:999-1016

Conclusions

Ιindividualized assessment of hemorrhagic and

thrombotic risk preoperatively in patients with stent

Continuation of at least one antiplatelet agent

preoperatively

Surgeon’s, anesthetist’s and cardiologist’s

collaboration

Death and AMI following discontinuation of clopidogrel at 6 moths after stent implantation: Duke Registry

12 18 24

0

2

4

6

8

% c

um

ula

tive incid

ence r

ate

months

4666 patients with BMS (n=3165) or DES (n=1501)

Eisenstein et al JAMA 2007;297:159-68

7,2% DES - Clop

6% BMS - Clop

5,5% BMS + Clop

3,1% DES +Clop

Single treatment

ASA

125 mg – 325 mg/o.d.

Clopidogrel

75 mg o.d.

Dual treatment

Clopidogrel + ASA

ASA 125 mg - 325 mg o.d.

Clopidogrel

300 - 600 mg loading dose before PCI; 75 mg o.d.

Dipyridamol + ASA TIA

Prasugrel + ASA

Triple treatment

ASA + Clopidogrel + anti-GPIIb/IIIa

Options for antiplatelet treatment

Minimal efficacy dose of aspirin

DisorderMinimum effective daily

dose (mg)

Men at high cardiovascular risk 75

Hypertension 75

Stable angina 75

Unstable angina 75

Acute mycardial infarction 160

TIA and Ischemic Stroke 50

Severe carotide artery disease 75

Acute Ischemic Stroke 160

Patrono et al CHEST 2004; 126:234S–264S

.

Maximal inhibition of platelets

>8h

2h

4 – 7days

Dose(p.o.)

300 mg

600 mg

75 mg

Duration of platelets’ inhibiton is 5 days

Dose of clopidogrel