Gestion péri-interventionnelle des antiplaquettaires

Charles Marc SAMAMA

Pôle Anesthésie Réanimations Thorax Explorations

Hôpitaux Universitaires Paris-Centre

Firmes et produits (DCI):

AstraZeneca (ximelagatran - ticagrelor) – Bayer (rivaroxaban) – BMS (apixaban)

Boehringer-Ingelheim (dabigatran) – Daïchi Sankyo (edoxaban) - GSK (fondaparinux – nadroparine)

Lilly+Daichii Sankyo (prasugrel) - Mitsubishi (argatroban) - Pfizer (daltéparine, apixaban)

Rovi (bémiparine) - Sanofi-Aventis (énoxaparine, idrabiotaparinux, aspirine, clopidogrel)

Agences, sociétés savantes et EPST :

AFSSaPS : groupe cardio-thrombose de la Commission d’AMM (expert titulaire)

ACCP : membre du panel pour les 9è Guidelines – SFAR : recos 2011

EMA : efficacy working party (expert consultant)

INSERM : laboratoire de thrombose expérimentale (U765)

Diapositives – remerciements : Jean-Philippe Collet (Paris), Pierre Sié (Toulouse) et Michel Meyer Samama (Paris)

Conflits d’intérêt - Diapos

• Homme de 67 ans, fumeur (100 PA), hypertendu traité par Irbésartan-hydrochlorothiazide (CoAprovel® ) et lercanodipine (Lercan®). Pose de deux stents actifs (sirolimus) il y a 7 mois après un syndrome coronaire aigu. Traitement par prasugrel (Efient®) et aspirine.

• Prévu pour pneumonectomie gauche sur adénocarcinome. Il est peu compliant et son fils est cardiologue.

• Il est sujet depuis peu à des épisodes hypotensifs.

• Lors de la visite pré-anesthésique la veille au soir, il est constaté

que le patient n'a pas interrompu son CoAprovel®, contrairement à

ce qui avait été demandé.

• Faut-il différer l'intervention, compte tenu de la gestion des

antiplaquettaires ?

J’étais pas là hier..

C’est pas dans mon équipe…

C’est Nathalie qui s’en occupe, mais elle est en RTT…

C’est commandé mais c’est pas arrivé

C’est dans le placard mais j’ai pas la clé…

Marchez pas dans le mouillé…

Ne quittez pas , je vais essayer de vous le passer…

Il est pas là, on n’a pas vu sa voiture…

Comment gérez-vous le traitement antiplaquettaire en pré-op

(une seule bonne réponse)

• Arrêt du prasugrel (Efient®) et de l’aspirine 5 jours avant

• Arrêt du prasugrel et de l’aspirine 7 jours avant

• Relais de l’aspirine par du Cébutid®

• Pas d’interruption de l’aspirine et arrêt du prasugrel au moins 7 jours avant

• Arrêt de l’aspirine 10 jours avant et poursuite du prasugrel

Comment reprenez-vous les antiplaquettaires(une bonne réponse)

• Reprise de l’aspirine et du prasugrel en dose de charge (pour les deux traitements) le soir même

• Reprise de l’aspirine et du prasugrel en dose de charge (pour les deux antiplaquettaires) le lendemain

• Prise de l’aspirine le soir même, et du prasugrel le lendemain ou le surlendemain, sans aucune dose de charge

• Reprise des deux traitements quand le chirurgien est d’accord…

Et l’héparine de bas poids moléculaire, vous la reprenez quand ? Quel est le traitement le plus important :

anticoagulant ou antiplaquettaire ?(trois bonnes réponses)

• Reprise de l’HBPM à dose préventive

• Bas anti-thrombose en attendant et mobilisation active du patient

• L’héparine doit être reprise tout de suite

• Les antiplaquettaires sont prioritaires

• Reprenons l’HBPM et le prasugrel en SSPI et prions !

Prasugrel (Efient®)

Irreversible inhibitor more active on ADP induced

platelet agregation ( x 10 to 100)

Faster metabolization to R-138727 active metabolite

Reduced inter individual variability of response

Irreversible inhibitor more active on ADP induced

platelet agregation ( x 10 to 100)

Faster metabolization to R-138727 active metabolite

Reduced inter individual variability of response

Multicenter, double-blind, randomized trial, ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter) - 18,624 patients admitted to the hospital with an ACS, with or without ST-segment elevation.

PLATO study

Cangrelor

• Voie IV

• Inhibition plaquettaire très rapide (> 90% en 4 min) et rapidement

réversible à l’arrêt (1h)

• 2 essais de phase III

• CHAMPION-PLATFORM : cangrelor vs pcb + TT habituel chez

patient non répondeur au clopidogrel avant ATL 4000 pts

• CHAMPION-PCI : cangrelor vs clopidogrel avant ATL 9000 pts

Antiplatelet agents should not be always withdrawn… (1)

• Aspirin alone may increase the bleeding risk, but usually not the transfusion rate.

• Many invasive procedures can be performed in aspirin-treated patients

Samama ChM et al. Can J Anesth 2002 ; 49 : S26-S35

Aspirin (75 mg) or placebo 7 days before surgery and continued until the 3rd postop day.

Follow-up 30 days after surgery.

220 patients: 109 patients received aspirin and 111 received placebo

Four patients (3.7%) in the aspirin group and 10 patients (9.0%) in the placebo group

had elevated troponin T levels in the postoperative period (P=0.10).

Twelve patients (5.4%) had an major adverse cardiac events (MACE) during the first 30 postoperative days. Two of these patients (1.8%) were in the aspirin group and 10 patients (9.0%) were in the placebo group (P=0.02).

Aspirin: 7.2% absolute risk reduction for postoperative MACE. The relative risk reduction was 80% (95% CI, 9.2–95%).

No significant differences in bleeding complications

PHRC STRATAGEMEssai randomisé, double aveugle

Aspirine vs placebo pdt 10 j pré-op

Etude de supériorité

Chir. non cardiaque

Critère composite : score événement thrombotique + hémorragique

Retrospective cohort analysis performed of randomly selected ACS patients requiring CABG in 14 hospitals across the U.S. Patients exposed to clopidogrel were compared with those not exposed to clopidogrel within 5 days prior to surgery

Single-center, retrospective study. 142 patients (375 polypectomies) taking clopidogrel (cases) and 1243 patients (3226 polypectomies) not taking clopidogrel (controls)

Ophthalmology. 2011;118:543–547.

61 patients (64 pars plana vitrectomy (PPV) procedures) in the warfarin group and 118 (125 eyes; 136 PPV procedures) in the clopidogrel group. A control group included 110 patients (110 eyes; 110 PPV procedures) who were not receiving warfarin or clopidogrel.

No patient experienced anesthesia-related hemorrhagic complications resulting from peribulbar or retrobulbar block.

Transient vitreous hemorrhage occurred in 1 (1.6%) of 64 PPV procedures in the warfarin group (P = 0.6531), 5 (3.7%) of 136 PPV in the clopidogrel group (P = 1.0), and 4 (3.6%) of 110 PPV in the control group. No choroidal or retrobulbar hemorrhages occurred in any patient.

CABG-related TIMI Major and Minor Bleeding: Days from Last Dose to CABG

% o

f B

leed

ing

Pat

ien

ts/T

ota

l

Ticagrelor – PLATO trial

Antiplatelet agents should not be withdrawn… (4)

Several case reports and some recent series have emphasized the risk to interrupt such treatments preoperatively

2229 consecutive patients: sirolimus-eluting (1062 patients, 1996 lesions, 2272 stents); paclitaxel-eluting (1167 patients, 1801 lesions,2223 stents) stents. At 9-month follow-up, 29 patients (1.3%) had stent thrombosis (9 [0.8%] with sirolimus and 20 [1.7%] with paclitaxel; P=.09).

Iakovou, I. et al. JAMA 2005;293:2126-2130.

Heart 2011 ;97:1566–1572

Prospective, multicentre, observational cohort study,1134 consecutive patients with coronary stents. Cardiovascular events

OR CI 95% P

Stopping all APA for more than 5 days

2.25 [1.32 ; 3.83] 0.003

Preoperative hemoglobin

>12 g/dl (or missing)

10-12 g/dl

<10 g/dl

Ref

1.15

2.95

[0.62 ; 2.10]

[1.21 ; 7.16]

0.66

0.017

Creatinin clearance

>60 ml/min (or missing)

30-60 ml/min

<30 ml/min

Ref

1.30

3.53

[0.78 ; 2.18]

[1.54 ; 8.08]

0.312

0.003

Delay between PCI and surgery

0-3 months

4-6- months

7-12 months

more than 12 months

1.01

1.16

0.74

Ref

[0.47 ; 2.15]

[0.50 ; 2.68]

[0.30 ; 1.81]

0.979

0.736

0.506

Urgent surgery

High risk surgery

3.12

3.55

[1.76 ; 5.53]

[2.32 ; 5.44]

<0.001

<0.001

0

5

10

15

20

25

30

0-5 days 6-10 days more than 10 days no antiplatelet treatment

Cardiovascular events (%)

Arrêt des AAP et complications cardiaques

Registre RECO

Solutions ?

Price MJ et al: Onset and Offset of Platelet Inhibition After High-Dose Clopidogrel Loading and Standard Daily Therapy Measured by a Point-of-Care Assay in Healthy Volunteers. Am J Cardiol 2006;98: 681– 684

Healthy volunteers (n=45) randomized

to 3 loading doses of clopidogrel (300,

600, and 900 mg) and continued at 75

mg/day for 6 to 18 days

Platelet Inhibition: VerifyNow, P2Y12

assay device (Accumetrics)

Medline search for reported cases of late stent thrombosis and very late stent thrombosis published between January 2001 and July 2008 (n = 161)

Among the 48 patients who stopped both agents, 36 cases (75%) occurred within 10 days

Among the 94 patients who discontinued a thienopyridine but continued acetylsalicylic acid, only 6 cases (6%) occurred within 10 days.

If acetylsalicylic acid therapy is maintained, short-term discontinuation of a thienopyridine may be relatively safe in patients with drug-eluting stents

If patients stopped both antiplatelet agents simultaneously, median time to event: 7 days

If the thienopyridine was stopped but acetylsalicylic acid was maintained, median time to event: 122 days

Onset-Offset

Gurbel et al. Circulation 2009; 120

Prasugrel

Jours de non-prise :

Ticagrelor (Brilique®) 5 jours (RCP 7j)

Clopidogrel (Plavix®) 5 jours

Prasugrel (Efient®) 7 jours

Jours de non-prise :

Ticagrelor (Brilique®) 5 jours (RCP 7j)

Clopidogrel (Plavix®) 5 jours

Prasugrel (Efient®) 7 jours

Prospective, randomized, double-blind, placebo-controlled, multicenter trial, 210 patients with an acute coronary syndrome or treated with a coronary stent and receiving a thienopyridine awaiting CABG surgery.

Thienopyridines were stopped (2 days up to 7days). Cangrelor 0.75 μg/kg or placebo for at least 48 hours, which was discontinued 1 to 6 hours before CABG surgery.

Excessive CABG surgery–related bleeding occurred in 11.8%vs 10.4%) in the cangrelor and placebo groups, respectively (NS).

There were no significant differences in major bleeding prior to CABG surgery (TIMI) , although minor bleeding episodes were numerically higher with cangrelor.

Ischemic end points:2.8% vs 4.0% in cangrelor and placebo, respectively, prior to surgery (not powered for…)

Angiolillo DJ et al.

En cas de saignement…

Dose: 0.7 • 1011, i.e., the standard concentrate, per 7 kg of body weight in adults.

(Previous dose: 0.5.1011 platelets for 10 kg BW)

Platelet transfusions to reduce or stop postoperative blood loss in patients treated with antiplatelets are effective (grade E) despite the absence of level I or II evidence.

mars 2011

Antiplaquettaires : les règles

1. Les nouveaux antiplaquettaires (prasugrel, ticagrelor, …) vont changer notre pratique

2. Poursuite l’aspirine possible pour presque toutes les interventions

3. Le clopidogrel, le prasugrel et le ticagrelor majorent le saignement périopératoire…

4. L’interruption du traitement augmente le risque thrombotique : non-prise

maxi aspirine 3j, clopidogrel 5j, ticagrelor 5j, prasugrel 7j

5. Stents non actifs : retarder l’intervention (6 semaines jusqu’à 3 mois)

6. Stents actifs : pas d’interruption…ou 5 jours (7 j prasu) , retarder si possible de 6 mois à 1 an.

Chirurgie après information du patient, et staff avec le cardiologue, l’hémostasien et le chirurgien.

Approche multidisciplinaire écrite.

7. Reprise sans dose de charge