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