Pourquoi la Bivaluridine et pourquoi pas les IIb-IIIa? Guillaume Cayla, Service de Cardiologie CHU Nîmes-Pr Messner Unité INSERM 937 La Pitié Salpetrière Pr Montalescot COI: AstraZeneca, Abbott Vascular, Biotronik, CLS Behring, Daiichi Sankyo, Eli Lilly, Iroko Cardio

Les Questions Bivalirudine: Forces et Faiblesses? HNF/IIbIIIa comparateur, quid Enoxaparine? IIb/IIIa molécules anciennes, nouvelles données? Conclusion: les questions en suspens….

Harmonizing Outcomes with Revascularization and Stents in AMI HORIZON MI Harmonizing Outcomes with Revascularization and Stents in AMI ≥3400* pts with STEMI with symptom onset ≤12 hours UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide) Bivalirudin monotherapy (± provisional GP IIb/IIIa) Aspirin, thienopyridine R 1:1 Emergent angiography, followed by triage to… Primary PCI CABG – Medical Rx 3000 pts eligible for stent randomization R 1:3 Bare metal stent TAXUS paclitaxel-eluting stent Clinical FU at 30 days, 6 months, 1 year, and then yearly through 5 years *To rand 3000 stent pts

@ 1 month PNI ≤ 0.0001 Psup ≤ 0.0001 Psup = 1.00 PNI ≤ 0.0001 Diff = -3.3% [-5.0, -1.6] RR = 0.60 [0.46, 0.77] PNI ≤ 0.0001 Psup ≤ 0.0001 Diff = 0.0% [-1.6, 1.5] RR = 0.99 [0.76, 1.30] Psup = 1.00 Diff = -2.9% [-4.9, -0.8] RR = 0.76 [0.63, 0.92] PNI ≤ 0.0001 Psup = 0.006 Stone et al, NEJM 2008

Cardiac mortality @ 3 years Heparin + GPIIb/IIIa (n=1802) Bivalirudin alone (n=1800) Cardiac Mortality (%) P=0.001 3-yr HR (95%CI) 0.56 (0.40, 0.80) 2.9% 12 15 18 21 24 27 30 33 36 Months 3 6 9 1 5 4 2 3.8% 2.1% 5.1% Stone et al, Lancet 2011

UFH + GP IIb/IIIa (N=1802) Bivalirudin (N=1800) UFH pre randomization 76.3% 65.8% Antithrombin in CCL - UFH 98.9% 2.6% - Bivalirudin 0.2% 96.9% - Peak ACT 264 [228, 320] 357 [300, 402] GP IIb/IIIa in CCL 94.5%* 7.2%* - Bail-out per protocol** - 4.4% - Abciximab 49.9% 4.0% - Eptifibatide 44.4% 3.1% - Tirofiban 0.1% * « Administration if No Reflow or Giant Thrombus post PCI » Stone et al, NEJM 2008

Thrombose aigue de stent? Impact de l’administration HNF Impact de la dose de charge de clopidogrel

HORIZON MI Les Points positifs Les Points négatifs Thrombose aigue stent? Pas de réduction événements ischémiques Impact de la coadministration héparine Dose de clopidogrel Bail out IIB/IIIA 7% Utilisation radiale: 6%.... Large population (3602 patients) Réduction hémorragies+++ Bénéfice mortalité court et long terme

Bivalirudine ESC STEMI 2010 AHA 2011

Les Questions Bivalirudine: Forces et Faiblesses? HNF(+IIbIIIa) comparateur, quid Enoxaparine? IIb/IIIa molécules anciennes, nouvelles données? Conclusion: les questions en suspens….

with or without GPIIbIIIa ATOLL Trial design Randomization as early as possible (MICU +++) Real life population (shock, cardiac arrest included) No anticoagulation and no lytic before Rx Similar antiplatelet therapy in both groups STEMI  Primary PCI ENOXAPARIN IV 0.5 mg/kg with or without GPIIbIIIa UFH IV 50-70 IU with GP IIbIIIa 70-100IU without GP IIbIIIa (Dose ACT-adjusted) IVRS 30-day results Primary PCI ENOXAPARIN SC UFH IV or SC Montalescot et al Lancet 2011; 378: 693-703

ATOLL study Death, Complication of MI, Procedure Failure or Major Bleeding RRR=17% P=0.063

Main Secondary Endpoint (ischemic) Death, Recur MI/ACS or Urgent Revasc Main Secondary Endpoint (ischemic)

Enoxaparine: ATOLL trial Death, MI, Major bleeding Montalescot G Lancet 2011; 378: 693-703

Les Questions Bivalirudine: forces et faiblesses? HNF/IIbIIIa comparateur, quid Enoxaparine? IIb/IIIa molécules anciennes, nouvelles données? Conclusion: les questions en suspens….

Amélioration flux TIMI-3 Study or Sub-category EARLY (n/N) LATE (n/N) RELAx-MI 25/105 11/105 ERAMI 7/40 5/40 REOMOBILE 11/48 8/52 Rakowski et al. 8/25 3/30 ReoPro-BRIDGING 8/28 2/27 Zorman et al. 9/56 1/56 Subtotal (95% CI) 68/302 30/310 Weight (%) Peto OR (IPD) (95% CI) 12.48 2.55 (1.24, 5.21) 2.67 1.45 (0.31, 6.81) 6.47 1.62 (0.60, 4.39) 3.70 3.86 (1.04, 14.39) 3.47 4.05 (1.04, 15.77) 3.83 5.69 (1.56, 20.73) 32.62 2.69 (1.73, 4.19) Abciximab Test for heterogeneity: Chi² = 3.56, df = 5 (P = 0.61), I² = 0% Test for overall effect: Z = 4.38 (P < 0.0001) Emre et al. 10/32 4/35 Cutlip et al. 7/23 6/30 ON-TIME 46/243 36/244 Subtotal (95% CI) 63/298 46/309 4.67 3.15 (0.98, 10.15) 4.72 1.86 (0.58, 5.97) 28.47 1.35 (0.84, 2.16) 37.85 1.56 (1.03, 2.35) Tirofiban Test for heterogeneity: Chi² = 1.84, df = 2 (P = 0.40), I² = 0% Test for overall effect: Z = 2.11 (P=0.03) INTAMI 18/53 5/49 TITAN TIMI-34 41/171 27/142 Subtotal (95% CI) 59/224 32/191 7.48 3.85 (1.53, 9.70) 22.05 1.34 (0.78, 2.29) 29.53 1.75 (1.10, 2.79) Eptifibatide Test for heterogeneity: Chi² = 3.74, df = 1 (P = 0.05), I² = 73.3% Test for overall effect: Z = 2.35 (P=0.02) Total (95% CI) 190/824 108/810 100 1.93 (1.50, 2.48) Test for heterogeneity: Chi² = 12.53, df = 10 (P = 0.25), I² = 20.2% Test for overall effect: Z = 5.08 (P < 0.00001) Favours Late GP IIb-IIIa inhibitors 0.1 0.2 0.5 1 2 5 10 Favours Early GP IIb-IIIa inhibitors Adapted from De Luca et al. Heart 2008; Epub ahead of print

IIb/IIIa Données Récentes: Impact du temps et du risque du patient High Risk and short delay EUROTRANSFER RELAX-AMI On Time-2 FINESSE substudy Risk Profile High Intermediate Low High Risk and long delay FINESSE BRAVE-3 Low Risk and long delay Low Risk and short delay MISTRAL 60 120 180 240 300 360 Ischemic Time (min) (Symptom Onset - TTT) Studies with benefit of IIbIIIa inhibitors Studies without benefit of IIbIIIa inhibitors

Les questions en 2012 ? Voie intracoronaire?→ AIDA STEMI Nouveaux P2Y12 inhibiteurs?

Guidelines 2010 Utilisation plus sélective

Les Questions Bivalirudine: forces et faiblesses? HNF/IIbIIIa comparateur, quid Enoxaparine? IIb/IIIa molécules anciennes, nouvelles données? Conclusion: les questions en suspens….

Ischemic complications : ATOLL Study Bleeding complications: HORIZON Conclusion Radiale? (RIVAL/RIFLE) UFH Enoxaparine Bivalirudine Prasugrel/Ticagrelor? Utilisation + selective IIb/IIIa? Ischemic complications : ATOLL Study Enoxaparine? UFH/IIbIIIa Enoxaparine/IIb/IIIa Bivalirudine Bleeding complications: HORIZON

BACK UP SLIDE

Euromax

RIVAL S Jolly et al Lancet 2011; 377:1409-20

RIFLE STEAACS 30-day NACE rate p = 0.003 N=1001 21.0% p = 0.029 13.6% 12.2% 11.4% 7.2% 7.8% Net Adverse Clinical Event (NACE) = MACCE + bleeding Major Adverse Cardiac and Cerebrovascular event (MACCE) = composite of cardiac death, myocardial infarction, target lesion revascularization, stroke 30-day NACE rate 25

RIFLE STEAACS 30-day bleeding rate N=1001 p = 0.026 p = 1.000 12.2% 7.8% 6.8% 5.4% 5.2% 2.6% 30-day bleeding rate 26

HORIZON MI Transradial:n=200!!!

2-Year Stent Thrombosis (ARC Definite/Probable) 6 Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 5 4.6% 4.3% 4 Stent Thrombosis (%) 3 HR [95%CI]= 2 0.94 [0.67, 1.32] p= 0.73 1 3 6 9 12 15 18 21 24 Months Number at risk Bivalirudin alone 1611 1509 1475 1444 1206 Heparin+GPIIb/IIIa 1591 1482 1449 1386 1153

Thrombose de stent 3.0% 2.2% P = 0.06 HR [95%CI] = 1.73 [0.47-1.13] Bivalirudin monotherapy Heparin + GPIIb/IIIa inhibitor 3.5 HR [95%CI] = 5.93 [2.06-17.04] P = 0.0002 3.0% 3.0 2.5 2.2% 2.0 Def/Prob Stent Thrombosis (%) 1.5% 1.5 HR [95%CI] = 1.73 [0.47-1.13] P = 0.06 1.0 0.5 0.3% 0.0 1 30 90 180 270 365 Time in Days Number at risk Bivalirudin 1611 1600 1562 1525 1506 1485 1355 UFH+GPIIb/IIIa 1591 1587 1521 1495 1476 1457 1315