Guillaume Cayla, Service de Cardiologie CHU Nîmes-Pr Messner

Unité INSERM 937 La Pitié Salpetrière Pr Montalescot

Pourquoi la Bivaluridine et pourquoi pas les IIb-IIIa?

COI: AstraZeneca, Abbott Vascular, Biotronik, CLS Behring, Daiichi Sankyo, Eli Lilly, Iroko Cardio

Les Questions

1) Bivalirudine: Forces et Faiblesses?2) HNF/IIbIIIa comparateur, quid Enoxaparine?3) IIb/IIIa molécules anciennes, nouvelles

données?4) Conclusion: les questions en suspens….

HORIZON MIHarmonizing Outcomes with Revascularization and Stents in AMI

≥3400* pts with STEMI with symptom onset ≤12 hours

Emergent angiography, followed by triage to…

Primary PCICABG – Medical Rx–

UFH + GP IIb/IIIa inhibitor(abciximab or eptifibatide)

Bivalirudin monotherapy(± provisional GP IIb/IIIa)

Aspirin, thienopyridine R 1:1

3000 pts eligible for stent randomization R 1:3

Bare metal stent TAXUS paclitaxel-eluting stent

*To rand 3000 stent pts

Clinical FU at 30 days, 6 months,1 year, and then yearly through 5 years

Diff = 0.0% [-1.6, 1.5]RR = 0.99 [0.76, 1.30]

Psup = 1.00

Diff = -3.3% [-5.0, -1.6]RR = 0.60 [0.46, 0.77]

PNI ≤ 0.0001Psup ≤ 0.0001

Diff = -2.9% [-4.9, -0.8]RR = 0.76 [0.63, 0.92]

PNI ≤ 0.0001Psup = 0.006

Stone et al, NEJM 2008

@ 1 month

Cardiac mortality @ 3 yearsC

ardi

ac M

orta

lity

(%)

P=0.001

3-yr HR (95%CI) 0.56 (0.40, 0.80)

2.9%

0 12 15 18 21 24 27 30 33 36

Months3 6 9

0

1

6

5

4

3

2

3.8%

2.1%

5.1%

Bivalirudin alone (n=1800)Heparin + GPIIb/IIIa (n=1802)

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 0.2% 0.1%

Stone et al, NEJM 2008* « Administration if No Reflow or Giant Thrombus post PCI »

Thrombose aigue de stent?

Impact de l’administration HNF

Impact de la dose de charge de clopidogrel

HORIZON MILes Points positifs

Réduction hémorragies+++

Large population (3602 patients)

Bénéfice mortalité court et long terme

Les Points négatifs

Thrombose aigue stent?

Pas de réduction événements ischémiques

Impact de la coadministration héparineDose de clopidogrel

Bail out IIB/IIIA 7%

Utilisation radiale: 6%....

Bivalirudine

ESC STEMI 2010

AHA 2011

Les Questions

1) Bivalirudine: Forces et Faiblesses?2) HNF(+IIbIIIa) comparateur, quid Enoxaparine?3) IIb/IIIa molécules anciennes, nouvelles

données?4) Conclusion: les questions en suspens….

ATOLL Trial design

STEMI Primary PCI

30-day results

Randomization as early as possible (MICU +++)Real life population (shock, cardiac arrest included) No anticoagulation and no lytic before RxSimilar antiplatelet therapy in both groups

ENOXAPARIN IV0.5 mg/kg

with or without GPIIbIIIa

UFH IV 50-70 IU with GP IIbIIIa

70-100IU without GP IIbIIIa(Dose ACT-adjusted)

IVRS

Primary PCI ENOXAPARIN SC UFH IV or SC

Montalescot et al Lancet 2011; 378: 693-703

33.7

28

0

5

10

15

20

25

30

35

40

UFHENOX

RRR = 17% P = 0.07

% o

f pat

ient

s

ATOLL studyDeath, Complication of MI, Procedure Failure or Major Bleeding

RRR=17%P=0.063

0 5 10 15 20 25 30

0.00

0.05

0.10

0.15

Days

Mai

n se

cond

ary

EP

rate UFH

ENOXLog-Rank Test

p=0.01 11.3%

6.7%

30d rate (%)

i 41%

Death, Recur MI/ACS or Urgent Revasc

Main Secondary Endpoint (ischemic)

Enoxaparine: ATOLL trialDeath, MI, Major bleeding

Montalescot G Lancet 2011; 378: 693-703

Les Questions

1) Bivalirudine: forces et faiblesses?2) HNF/IIbIIIa comparateur, quid Enoxaparine?3) IIb/IIIa molécules anciennes, nouvelles

données?4) Conclusion: les questions en suspens….

Amélioration flux TIMI-3Study 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

0.1 0.2 0.5 1 2 5 10 Favours Early GP IIb-IIIa inhibitors Favours Late GP IIb-IIIa inhibitors

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 4/35Cutlip et al. 7/23 6/30ON-TIME 46/243 36/244Subtotal (95% CI) 63/298 46/309

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)

INTAMI 18/53 5/49TITAN TIMI-34 41/171 27/142Subtotal (95% CI) 59/224 32/191

Test for heterogeneity: Chi² = 1.84, df = 2 (P = 0.40), I² = 0% Test for overall effect: Z = 2.11 (P=0.03)

Test for heterogeneity: Chi² = 3.74, df = 1 (P = 0.05), I² = 73.3% Test for overall effect: Z = 2.35 (P=0.02)

Test for heterogeneity: Chi² = 12.53, df = 10 (P = 0.25), I² = 20.2% Test for overall effect: Z = 5.08 (P < 0.00001)

Total (95% CI) 190/824 108/810

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)

7.48 3.85 (1.53, 9.70)22.05 1.34 (0.78, 2.29)29.53 1.75 (1.10, 2.79)

100 1.93 (1.50, 2.48)

Abc

ixim

abTi

rofib

anEp

tifib

atid

e

Adapted from De Luca et al. Heart 2008; Epub ahead of print

Risk Profile

Ischemic Time (min)(Symptom Onset - TTT)

60 120 180 240 300 360

High

Intermediate

Low

High Risk and long

delay

FINESSE

Low Risk and short delay

MISTRAL

High Risk and short delay

EUROTRANSFER

RELAX-AMIOn Time-2

FINESSE substudy

Studies with benefit of IIbIIIa inhibitors

Studies without benefit of IIbIIIa inhibitors

BRAVE-3Low Risk and long delay

IIb/IIIa Données Récentes: Impact du temps et du risque du patient

Les questions en 2012 ?

Voie intracoronaire?→ AIDA STEMINouveaux P2Y12 inhibiteurs?

Guidelines 2010

Utilisation plus sélective

Les Questions

1) Bivalirudine: forces et faiblesses?2) HNF/IIbIIIa comparateur, quid Enoxaparine?3) IIb/IIIa molécules anciennes, nouvelles

données?4) Conclusion: les questions en suspens….

Conclusion

UFH Enoxaparine Bivalirudine

Bleeding complications: HORIZON

Ischemic complications : ATOLL Study

UFH/IIbIIIa Enoxaparine/IIb/IIIa Bivalirudine

Radiale? (RIVAL/RIFLE)Prasugrel/Ticagrelor?Utilisation + selective IIb/IIIa?Enoxaparine?

BACK UP SLIDE

Euromax

RIVAL

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

NACE MACCE Bleedings

femoral arm radial armp = 0.003

• 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

p = 0.029 p = 0.02621.0%

11.4%

7.2%

12.2%

7.8%

13.6%

RIFLE STEAACS

N=1001

30-day bleeding rate

p = 1.000

12.2%

6.8%

2.6%5.4% 5.2%

p = 0.026

Bleedings Access site related Non access site related

femoral arm radial arm

7.8%

p = 0.002

RIFLE STEAACSN=1001

HORIZON MI

Transradial:n=200!!!

2-Year Stent Thrombosis(ARC Definite/Probable)

1611 1509 1475 1444 12061591 1482 1449 1386 1153

p= 0.73

HR [95%CI]=0.94 [0.67, 1.32]

4.3% 4.6%

Ste

nt T

hrom

bosi

s (%

)

0

1

2

3

4

5

6

0 3 6 9 12 15 18 21 24

Number at riskBivalirudin aloneHeparin+GPIIb/IIIa

Bivalirudin alone (n=1800)Heparin + GPIIb/IIIa (n=1802)

Months

2.2%

3.0%

1.5%

0.3%

HR [95%CI] = 1.73 [0.47-1.13]

P = 0.06

HR [95%CI] =5.93 [2.06-17.04]

P = 0.0002

16111591

1600 1562 1525 1506 1485 13551587 1521 1495 1476 1457 1315

Number at riskBivalirudinUFH+GPIIb/IIIa

Def

/Pro

b S

tent

Thr

ombo

sis

(%)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Time in Days

0 1 30 90 180 270 365

Thrombose de stent

Bivalirudin monotherapyHeparin + GPIIb/IIIa inhibitor