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Round table: Intravenous antithrombotics
Saturday, January 19th, 2013
The clinical utility of intravenous
direct thrombin inhibitors in ACS / PCI
George Hahalis
Associate Professor,
University of Patras, Greece
Basics on bivalirudin mode of action…
Θξ
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βίλ
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Ελεξγή ζέζε
Εμσηεξηθή ζέζε 2 ζύλδεζεο
κε ηελ Ηπαξίλε
Εμσηεξηθή ζέζε 1 ζύλδεζεο
κε ηελ Μπηβαιηξνπδίλε
Τν κόξην ηεο ζξνκβίλεο & νη ζέζεηο ζύλδεζεο
2
1
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Αληη-
Θξνκβίλε
2
1
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βίλ
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Αληη-
Θξνκβίλε
2
1
Θξ
νκ
βίλ
ε
Μπηβαιηξνπδίλε
2
1
Τκήκα ζπλδεόκελν
κε ηελ ελεξγό ζέζε
2
1
Τν ζύκπιεγκα
επαρίλες-αληηζροκβίλες δελ είλαη
αποηειεζκαηηθό έλαληη ζξνκβίλεο
δεζκεπκέλεο ζε ζξόκβν
Απηή ε δεμακελή ηεο ελεξγνύ ζροκβίλες
ζσλετίδεη λα ελεργοποηεί ηα
αηκοπεηάιηα γηα δεκηνπξγία πεξαηηέξσ
ζξόκβνπ
Η κπηβαιηροσδίλε, έρεη πςειή ζπγγέλεηα
γηα ηελ ζξνκβίλε
& ηελ απνκαθξύλεη από ην ηλώδεο
Η κπηβαιηξνπδίλε αλαζηέιιεη
απνηειεζκαηηθά ηελ ζροκβίλε πιάζκαηος
θαη ηοσ ζρόκβοσ
Hirsh J et al. Chest. 2001;119(1 suppl):64S Weitz JI et al. Thromb Res. 2002;106:V275
Η Μπηβαιηροσδίλε Αλαζηέιιεη ηελ Θροκβίλε ηες
Σσλδεδεκέλες κε ηολ Θρόκβο
Η Μπηβαιηροσδίλε ζηης Μειέηες Φάζεως ΙΙΙ
1. Lincoff AM et al. JAMA. 2004;292(6):696-703. 2. Kastrati A et al. NEJM. 2008;359(7):688-96. 3. Stone GW et al. JAMA.
2007;298(21):2497-506. 4. Stone GW et al. Lancet. 2011;377(9784):2193-204. 5. Kastrati A et al. NEJM. 2011;365(21):1980
Η Μπηβαιηξνπδίλε ζηηο Μειέηεο Φάζεσο ΙΙΙ…
NSTEMI
ISAR-REACT 4
1721 patients
Similar ischemia
Bleeding 46%
Koutousis M, et al. Heart 2011 Sep;97(18):1484 Dangas GD, et al. JACC. 2011;57:2309
Bivalirudin
+UFH(n=1 178)
7.6%
UFH +
GP IIb/IIIa-Inh
(n=1 179)
12.3%
P=0.0001
Major bleeding @ 30 dHORIZONS-AMI
Bivalirudin
+UFH(n=1 068)
6.5%
Bivalirudin(n=1 928)
11.3%
Adj. OR 0.55, 95% CI 0.41 to 0.72,
P<0.001
Death or definite stent thrombosis @ 30dSCAAR Registry
Bivalirudin/UFH Switch Therapy in Primary PCI
HORIZONS-AMI patientsHORIZONS-AMI patientsHORIZONS-AMI patients
Bivalirudin & Clopidogrel Pretreatment in Primary PCI
HORIZONS-AMI patients
Dangas GD, et al.
Circulation 2011;123:1745
Death, MI, urgent target vessel revascularization @ 30 days
UFH+Abciximab (n=290)Bivalirudin (n=274)
No-HPR HPR
6.7%
P=NS
5%
OR:5.4
P<0.0001
9.4%
Bivalirudin vs. Abciximab & High On-clopidogrel Treatment Platelet
Reactivity (HPR) in NSTEMI Patients: ISAR-REACT 4
Sibbing D, et al.JACC 2012;60:369
22%
Back to the meta analyses…
Bivalirudin versus Heparin+ΙΙβ/ΙΙΙα GP Receptor Inhibitors
Bivalirudin vs. UFH Monotherapy
BLEEDINGMIDEATHMACE
-45% P<0.001
+12% P=0.07
+7% P=NS
-7% P=NS
Bivalirudin versus Heparin+ΙΙβ/ΙΙΙα GP Receptor InhibitorsMeta analysis on 19 772 patients undergoing PCI in 5 clinical trials
Lee MS, et al. Int J Cardiol 2011;152:369
No bleeding difference if CrCl
<60 ml/min in primary PCI
(HORIZONS-AMI trial) (Saltzman AJ, JACC CV Interv 2011;4:1011)
Η Μπηβαιηροσδίλε ζηελ πρωηογελή αγγεηοπιαζηηθήΚαηαγραθή Ottawa 2004-2010
Μπηβαιη- Αλαζηνιείο Γι/Πξση
-ξνπδίλε ππνδνρέσλ ΙΙβ/ΙΙΙα Ηπαξίλε(n = 748) ( n = 699) (n = 676)
Μείδνλεο αηκνξξαγίεο θαηά ΤΙΜΙ 2.7% 7.3% 3.3%
Θάλαηνο,
Μείδσλ αηκνξξαγία,
ΑΕΕ,
Επαλέκθξαγκα 7.6% 11.4% 9.5%
Hibbert B, et al. Circ Cardiovasc Interv. 2012;Epub ahead of print.
«Σσμπέραζμα: Η Bivalirudin μείωζε ηον κίνδσνο μεγάλης αιμορραγίας ζε
ζύγκριζη με GPIs, αλλά ότι ζε ζύγκριζη με μόνον ηην ηπαρίνη»
Ρ<0.05
Ρ=ΜΣ
•4570 patients undergoing PCI
•Pre-treatment with a 600-mg of clopidogrel > 2 hours before PCI
Bivalirudin vs. UFH Monotherapy in
Stable or Unstable Angina: ISAR-REACT 3
•Incidence of the primary end point (death, MI, urgent target-vessel
revascularization due to myocardial ischemia <30 days, or major
bleeding during the index hospitalization)::
8.3% vs. 8.7% (RR, 0.94; 95% CIs [CI], 0.77 -1.15; P = 0.57)
•Incidence of major bleeding:
3.1% vs. 4.6% (RR, 0.66; 95% CI, 0.49 - 0.90; P = 0.008)
Kastrati A et al. NEJM. 2008;359(7):688
Bivalirudin versus Heparin MonotherapyMeta analysis on 32 492 patients undergoing PCI in 16 studies (RCT’s=3)
Bertrand OF, et al. Am J Cardiol 2012;110:599
BLEEDINGMIDEATHMACE
-37% P=NS
-3% P=NS
BLEEDINGDEATHMACE
RCT’s
-8% P=NS
-45%P<0.001
MI
Details on the hemorrhagic risk reduction…
OASIS 6
Fondaparinux
ATOLL
Enoxaparin
HORIZONS-AMI
Bivalirudin
UFH versus newer Anticoagulants in primary PCI
40
% 2
0%
0 -
20
% -
40
%
Major bleedingsMortality
40
% 2
0%
0 -
20
% -
40
%
Major bleedingsMortality
40
% 2
0%
0 -
20
% -
40
%
Major bleedingsMortality
40
% 2
0%
0 -
20
% -
40
%
Major bleedingsMortality
0.975 (0.948-1.004)
P=NS4.5%4.9%
STEMI(n = 267 632)
0.939 (0.918-0.961)1.8%2.3%
Unstable
Angina/NSTEMI(n = 836 103)
0.920 (0.896-0.945)1.1%1.4%Elective PCI(n = 599 524)
Εηήζηα Μείωζε
OR (95% CI)20092005
National Cardiovascular
Data CathPCI registry
Εηήζηα Μείωζε Αηκορραγηώλ κεηά από Αγγεηοπιαζηηθή
•Μείσζε αηκνξξαγηώλ ζηο ζεκείο πρόζβαζες θαη ζηηο 3 νκάδεο†
•Αύμεζε αηκνξξαγηώλ εθηός ζεκείοσ πρόζβαζες ζηελ νκάδα
STEMI κόλνλ, από 2.6% ζε 3.1%† †P < 0.001
•Χξήζε ηεο θερθηδηθής αρηερίας: ρακειή (< 3%)
•Χξήζε ζσζθεσής θιεηζίκαηος: αύμεζε από 44% ζε 49% Subherwal S, et al. J Am Coll Cardiol. 2012;59:1861
The Patras (vs.NCDCathPCI registry) Experience in Patients with ACSs
N=516 consecutive patients received
•IIb/IIIa GP receptor Inhibitors: 6.2%
National Cardiovascular Data CathPCI registry: 28 % (from 41%)
•Bivalirudin: 33.7%
National Cardiovascular Data CathPCI registry: 30% (from 17%)
•Pre-treatment with Prasugrel / Ticagrelor: ~80%
•Transradial approach: <10%
•Stent thrombosis, in-hospital: 1 patient (0.2%), subacute
Subherwal S, et al. J Am Coll Cardiol. 2012;59:1861
•“Bivalirudin Is the Gold Standard for Primary PCI in STEMI!”(Mehran R)
•“Anticoagulant for primary PCI - the last dance for unfractionated heparin”?
(Silvain J, Montalescot G)
•“In the bivalirudin era are we still looking for a potent antiplatelet agent?”(Cortese B, et al)
Is Bivalirudin the Ultimate Antithrombotic Answer in Primary PCI?
The radial approach may obviate the need of bivalirudin…
Pro:
•A radial approach was used in 71% of both groups
•Bivalirudin reduced bleeding events in femoral-treated
patients (n = 125), but no such clinical benefit was observed in
the radial-treated patients (n = 125)
Bivalirudin vs. Heparin after Transradial & Transfemoral PCI
Machaalany J, et al. AJC 2012;110:1742
Transradial Transfemoral
9.7%
TF+
IIb/IIIa
5.6%
TF+
Bival
4.1%
TR+
IIb/IIIa
2.9%
TR+
Bival
P for trend: <0.0001
Incidence of major hemorrhages
Bivalirudin vs. Heparin after Transradial (n=200)
& Transfemoral (n=3 134) primary PCI (HORIZONS-AMI)
Genereux P, et al. Eurointervention 2012;7:
The radial approach may obviate the need of bivalirudin…
Contra:
Randomization to bivalirudin vs.
heparin + GPI resulted in 43% relative reductions
TIMI major bleeding,(p < 0.0001), with
significant reductions
in both access and nonaccess site bleeding
Verheugt FW, ...Mehran R, Stone GW. JACC Cardiovasc Interv. 2011 Feb;4(2):191.
Combined dataset from the REPLACE-2, ACUITY, &
HORIZONS-AMI trials in 17,393 PCI patients
Conclusions
•Bivalirudin almost halves incident bleeding
even compared with UFH
•May be useful even in the new era of rare use of
GP IIb/IIIa inhibitors
•Antiplatelet pre-treatment is advised
•Switch from UFH does not harm; it may be beneficial
•RCT’s with UFH in transradial PCIs are warranted