Comment optimiser l'environnement pharmacologique du STEMI?

Comment optimiser l'environnement pharmacologique du STEMI?

Guillaume Cayla, Institut de Cardiologie

Unité INSERM 937 La Pitié SalpetrièreService de Cardiologie CHU Nîmes

Agents antiplaquettaires exclus

Conflits d’intérêt: Lilly -Daishi, Abbott, Astra Zeneca, Servier, CLS Behring

Objectif: Diminution complications ischémiques

Diminution TS avec AAP

mortalité élevée

Incidence thrombose de TS < 30 jours IDM: 2%

Décès et infarctus

22.4% à 1 an*

Circulation 2010; 122: 52-61

Objectifs n°2: Diminution complications Hémorragiques

Augmentation de la mortalité cardiovasculaire

Majoration Hémorragie par les tt AAP

STEMI: Contexte 2010 en France?

• Association agents antiplaquettaires puissants:AntiGPIIb/IIIa

nouveaux AAP oraux

• Angioplastie voie radiale

Intérêt voie radiale

Jolly et al AHJ 2009

Analyse 23 essaies randomisés, n=7020 patients

1) Evaluation du risque hémorragique individuel

2) Eviter cross over HBPM/ HNF

4) Utiliser voie radiale chez les patients à haut risque

3) Ajuster le traitement antithrombotique au poids et à l’I Rénale

5) Arrêt traitement anticoagulant après angioplastie

6) Utilisation sélective d’antiGPIIb/IIIa

ESC guidelines

Période hospitalière: sites de ponction

Antithrombotique idéal

1. Rapidité d’action

2. Rapidité de disparition de l’effet (ou disponibilité d’un antidote)

3. Effet pharmacodynamique attendu homogène, sans nécessité de monitoring

4. Absence d’interaction avec médicaments couramment utilisés

7.Faible cout

5. Faible surcout hémorragique

6.Administration aisée

8.Possibilité d’administration en cas d’Insuffisance Rénale sévère?

9. Pas d’augmentation de Thrombose de stent

Quelles sont les molécules disponibles?

HNF

HBPM

Fondaparinux

Bivalirudine

Clopidogrel

Prasugrel

Ticagrelor

Abciximab

Tirofiban/Eptifibatide

Rien

Traitement antithrombotique

Traitement AAP PO

Traitement AAP IV

Up stream In the Cath Lab

72 possibilités!!!!

Un traitement pour tous? Traitement individualisé ?

HNF

• Haut niveau de recommandation (I)* (ESC )• Niveau de preuve (B)• Reste le tt antithrombotique le plus utilisé• Souvent utilisée comme comparateur en association

aux antiGPIIb/IIIa

360 US Hospital

JACC interv 2010; 3: 1166-77

ATHeparine

2

1

Thrombine

HNF





7.Faible cout

5. Surcout hémorragique




HNF





7.Faible cout

5. Faible Surcout hémorragique




+ Thrombopénie + Origine animale

Fondaparinux

IIaIIaIIII

FibrinogenFibrinogen Fibrin clotFibrin clot

Extrinsic Extrinsic pathwaypathway

IntrinsicIntrinsicpathwaypathway

AT XaXaAT AT

Fondaparinux Fondaparinux

XaXa

Antithrombin

Fondaparinux: A Synthetic Factor Xa Inhibitor

Adapted with permission from Adapted with permission from TurpieTurpie AGG AGG et al. et al. NN EnEnglgl J Med.J Med. 2001;3442001;344:619.:619.

THROMBIN

Fondaparinux





7.Faible cout





Fondaparinux< UHF Primary PCI

OASIS 6 JAMA 2006; 295; 1519-1530

Antithrombinique : bivalirudine

Analogue hirudine

Inhibiteur direct de synthèse de la thrombine

Pharmacodynamie : demi vie 25 minutes

Pas d’antidote

2

1

Thrombine

Bivalirudine


2. Rapidité de disparition de l’effet (demie vie 30 minutes)



7.Faible cout

5. Faible Surcout hémorragique




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

*MACE or major bleeding (non CABG)

12.2%

9.3%HR [95%CI] =0.75 [0.62, 0.92]

P=0.006

Number at riskBivalirudin 1800 1660 1633 1626 1620 1607 1544Heparin + GPIIb/IIIa 1802 1635 1591 1578 1569 1552 1482

Prim

ary

End

poin

tN

et a

dver

se c

linic

al e

vent

s (%

)*

Time in Days

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

HORIZON MI (NACE: 30 Jours)

Series10

5

10

15

12.1

8.3

5.5

9.2

4.9 5.4

Heparin + GP IIb/IIIa Inhibitor (n=1,802)Bivalirudin alone (n=1,800)*

30-d

ay e

vent

rate

s (%

)

NACE Major Bleeding† MACE‡

P=0.005

P<0.001

P=0.95

*In HORIZONS AMI, 93% of bivalirudin patients received monotherapy, without provisional GP IIb/IIIa.†Not related to CABG.‡MACE=all-cause death, reinfarction, ischaemic TVR, or stroke.

Stone GW. NEJM 2008;358:2218-30: 19

HORIZON MI (30 Jours)

30 Day Mortality

Number at riskBivalirudin 1800 1758 1751 1746 1742 1729 1666Heparin + GPIIb/IIIa 1802 1764 1748 1736 1728 1707 1630

3.1%

2.1%

Time in Days

Dea

th (%

)

HR [95%CI] =0.66 [0.44, 1.00]

P=0.048


HORIZON Mortalité 30 J

Number at riskBivalirudin 1800 1697 1675 1668 1664 1653 1590 Heparin + GPIIb/IIIa 1802 1651 1617 1606 1598 1581 1511

Prim

ary

End

poin

tM

ajor

Ble

edin

g (%

)

Time in Days

8.4%

5.0%

HR [95%CI] =0.59 [0.45, 0.76]

P<0.0001


HORIZON Non CABG Major Bleeding

1800 1690 1658 1627 13591802 1669 1637 1579 1324

p= 0.005

HR [95% CI]=0.59 [0.41, 0.86]

2.5%

4.2%

Cardiac Mortality

0

1

2

3

4

5

Months

0 3 6 9 12 15 18 21 24

Number at riskBivalirudin aloneHeparin+GPIIb/IIIa

Mor

talit

y (%

)

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

1800 1690 1658 1627 13591802 1669 1637 1579 1324

p= 0.69

HR [95% CI]=1.10 [0.69, 1.76]

2.2% 2.0%

Non Cardiac Mortality

0

1

2

3

4

5

Months

0 3 6 9 12 15 18 21 24

HORIZON Mortalité

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

1066 1052 1051 1050 1049545 531 529 528 528

Number at riskP-R HeparinNo P-R Heparin

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 Hours0 6 12 18 24

Pre-Randomization HeparinNo Pre-Randomization Heparin

UFH+GPI

UFH+GPI

1211 1208 1207 1207 1207378 377 375 374 374

P-R HeparinNo P-R Heparin

Bivalirudin

Bivalirudin

0.1%

0.8%HR [95%CI] = 9.64 [1.00,92.70]

P = 0.02

0.9%

2.6%

HR [95%CI] = 3.07 [1.33,7.09]

P = 0.006

Pint antithrombin x pre-rand hep = 0.39

Thrombose de stent < 24 H: impact administration héparine

1.6%

3.4%

1.5%

1.2%

HR [95%CI] =1.30 [0.54-3.16]

P = 0.56

HR [95%CI] =2.11 [1.07,4.17]P = 0.03

1013519

1009 990 969 957 943 863514 497 486 480 474 430

Number at risk600 mg300 mg

Def

/Pro

b S

tent

Thr

ombo

sis

(%)

0

1

2

3

4

5

Time in Days

0 1 30 90 180 270 365

600mg Clopidogrel300mg Clopidogrel

Thrombose de stent < 24 H: LD clopidogrel

HORIZON MILes Points positifs Les Points négatifs

Réduction bleeding+++

Large population (3602 patients)

Bénéfice mortalité (30 J, 1an, 2 ans)

Augmentation TDS 24 H

Etude ouverte

Critère principal composite

Approche US (Fémorale , forte dose HNF )

Intérêt Etude Européenne : Euromax n=3680Bivalirudine préhospitalier

HBPM

1. Rapidité d’action (IV)




7.Faible cout





+ Thrombopénie (+ faible/HNF) + Origine animale

Enoxaparine: STEEPLE Non-CABG-Related Bleeding*

5,9

1,2

6,5

1,2

8,5

2,8

0123456789

10

Major and minor bleeding Major bleeding

Patie

nts

(%)

Enoxaparin 0.5 mg/kgEnoxaparin 0.75 mg/kgUFH

P = 0.01

P = 0.051

P = 0.004

P = 0.007

-57%

*1° endpoint

Montalescot G, et al. N Engl J Med. 2006;355:1006-1017.

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

Time (hours)

Ant

i-Xa

IU/m

L

0 2 4 6 8 10 12 14 16 18 200

0.4

0.8

1.20.5 mg/kg IV

1 mg/kg SC

• Choussat et al (elective PCI)• Miller et al (ACS-PCI)• Carnendran et al (elective PCI)• STEEPLE (elective PCI)• PROTECT –TIMI30 (ACS-PCI)• Silvain et al (elective PCI)• FINESSE (primary PCI)• Brieger et al. (Primary PCI)

PD experience Clinical experience

Choussat et al. JACC. 2002;40:1943-50.Miller L. J Invasive Cardiol. 2002;14:247-50Carnendran et al. J Invasive Cardiol. 2003;15:235-8.Montalescot et al. N Engl J Med. 2006;355:1006-17.Gibson et al. JACC. 2006;47:2364-2373Silvain et al. JACC. 2010;55:617-25Montalescot et al. JACC Cardiovasc Interv. 2010;3:203-12Brieger et al. Catheter Cardiovasc Interv. 2010 [in press]

Sanchez-Pena P. Br J Clin Pharmacol. 2005;60:364-73.

Enoxaparine (0,5 mg/kg)

Baseline characteristics

UFH (n=460)

ENOXAPARIN (n=450)

Male sex 78% (359) 78% (353) Age, median (Q1;Q3) Age > 75

60 (52; 70)17% (80)

59 (52; 71)19% (85)

Pre-hospital randomization 71% (325) 70% (318)Current smoker, % (n) 47% (218) 44% (199) Diabetes, % (n) 15% (69) 14% (63)Hypertension, % (n) 45% (207) 46% (205)Hyperlipidemia, % (n) 40% (184) 40%(180)Prior myocardial infarction, % (n) 10% (44) 6% (28) Prior stroke, % (n) 2% (10) 3% (12)

Shock and/or cardiac arrest before sheath, % (n) 5% (24) 4% (17)

Time from symptom onset to randomization—hr, median (Q1;Q3)

2h19(1h26; 4h37)

2h33(1h29; 4h50)

Baseline

Procedure and study medications

UFH (n=460)

ENOXAPARIN (n=450)

Radial artery access, % (n) Other artery access, % (n)

66% (305)34% (155)

69% (309) 31% (141)

Stent implanted (among PCI patients) , % (n) Thrombectomy (among PCI patients) , % (n)

94% (366)44% (173)

96% (364)48% (184)

Glycoprotein IIb/IIIa before start of PCI,% (n) Abciximab Eptifibatide Tirofiban

77% (357) 64% (295) 11% (54)

2% (8)

71% (313)62% (277)

8% (34)0.4% (2)

Medications before/during hospitalization — % (n) Aspirin Clopidogrel < 300mg > 300 and < 600mg > 600 and < 900mg > 900mg Beta-blockers ACE-inhibitors Statins

94% (434)93% (427)37% (171) 37% (172) 25% (113)

1% (4)84% (385)72% (333)83% (382)

96% (431)94% (422)37% (168)39% (174) 22% (101)

2% (7)88% (398)75% (336)87% (392)

Procedure and medication

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

Main Secondary Endpoint (ischemic)

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

0 5 10 15 20 25 30

0.00

0.02

0.04

0.06

0.08

0.10

DaysDea

thor

resu

scita

ted

card

iac

arre

stra

te

UFHENOX Log-Rank Test

p=0.049 7.0%

4.0%

30d rate (%)

0 5 10 15 20 25 30

0.00

0.02

0.04

0.06

0.08

0.10

Days

Dea

thra

te

UFHENOX Log-Rank Test

p=0.08 6.3%

3.8%

30d rate (%)

i 40%i 42%

6.3%

3.8%

7.0%

4.0%

Death (any) Death or

resuscitated cardiac arrest

Mortality?

)

P = NS%

of p

atie

nts

Non-CABG Major Bleeding (STEEPLE definition)

?

REGISTRIES RANDOMIZED

Dea

thra

te %

Zeymer et al. Eurointervention 2009;4:524-8. Li et al. Am Heart J 2010;159:684-90. Montalescot et al. JACC CI 2010;3:203-12. Brieger et al. CCI 2010 (DOI:10.1002/ccd.22674)

Death finding Chance finding

Conclusion

Optimisation du tt antithrombotique

Diminution complications ischémiquesAide des nouveaux AAP Diminution complications

hémorragiques

Optimisation environnement antithrombotique

ESC Guideline 2010Enoxaparine?

Comment optimiser l'environnement pharmacologique du STEMI?

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