Gestion péri-interventionnelle des antiplaquettaires Charles Marc SAMAMA Pôle Anesthésie Réanimations Thorax Explorations Hôpitaux Universitaires Paris-Centre

Conflits d’intérêt - Diapos 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)

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 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

PLATO study 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.

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 STRATAGEM Essai 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 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.

% of Bleeding Patients/Total CABG-related TIMI Major and Minor Bleeding: Days from Last Dose to CABG % of Bleeding Patients/Total

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

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

Cardiovascular events 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 1.30 3.53 [0.78 ; 2.18] [1.54 ; 8.08] 0.312 Delay between PCI and surgery 0-3 months 4-6- months 7-12 months more than 12 months 1.01 1.16 0.74 [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

Arrêt des AAP et complications cardiaques Registre RECO

Solutions ?

Platelet Inhibition: VerifyNow, P2Y12 assay device (Accumetrics) 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 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 If acetylsalicylic acid therapy is maintained, short-term discontinuation of a thienopyridine may be relatively safe in patients with drug-eluting stents

Onset-Offset Jours de non-prise : Ticagrelor (Brilique®) 5 jours (RCP 7j) Clopidogrel (Plavix®) 5 jours Prasugrel (Efient®) 7 jours Prasugrel Background—Ticagrelor is the first reversibly binding oral P2Y12 receptor antagonist. This is the first study to compare the onset and offset of platelet inhibition (IPA) with ticagrelor using the PLATO (PLATelet inhibition and patient Outcomes) trial loading dose (180 mg) with a high loading dose (600 mg) of clopidogrel. Methods and Results—In a multicenter, randomized, double-blind study, 123 patients with stable coronary artery disease who were taking aspirin therapy (75 to 100 mg/d) received ticagrelor (180-mg load, 90-mg BID maintenance dose [n57]), clopidogrel (600-mg load, 75-mg/d maintenance dose [n54]), or placebo (n12) for 6 weeks. Greater IPA (20 mol/L ADP, final extent) occurred with ticagrelor than with clopidogrel at 0.5, 1, 2, 4, 8, and 24 hours after loading and at 6 weeks (P0.0001 for all); by 2 hours after loading, a greater proportion of patients achieved 50% IPA (98% versus 31%, P0.0001) and 70% IPA (90% versus 16%, P0.0001) in the ticagrelor group than in the clopidogrel roup, respectively. A faster offset occurred with ticagrelor than with clopidogrel (4-to-72– hour slope [% IPA/h] 1.04 versus 0.48, P0.0001). At 24 hours after the last dose, mean IPA was 58% for ticagrelor versus 52% for clopidogrel (PNS). IPA for ticagrelor on day 3 after the last dose was comparable to clopidogrel at day 5; IPA on day 5 for ticagrelor was similar to clopidogrel on day 7 and did not differ from placebo (PNS). Conclusions—Ticagrelor achieved more rapid and greater platelet inhibition than high-loading-dose clopidogrel; this was sustained during the maintenance phase and was faster in offset after drug discontinuation. Gurbel et al. Circulation 2009; 120

Angiolillo DJ et al. 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…)

En cas de saignement…

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. 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)

mars 2011

Antiplaquettaires : les règles Les nouveaux antiplaquettaires (prasugrel, ticagrelor, …) vont changer notre pratique Poursuite l’aspirine possible pour presque toutes les interventions Le clopidogrel, le prasugrel et le ticagrelor majorent le saignement périopératoire… L’interruption du traitement augmente le risque thrombotique : non-prise maxi aspirine 3j, clopidogrel 5j, ticagrelor 5j, prasugrel 7j Stents non actifs : retarder l’intervention (6 semaines jusqu’à 3 mois) 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. Reprise sans dose de charge