The clinical utility of intravenous direct thrombin inhibitors in ACS / PCI

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1 Round table: Intravenous antithrombotics Saturday, January 19 th, 2013 The clinical utility of intravenous direct thrombin inhibitors in ACS / PCI George Hahalis Associate Professor, University of Patras, Greece

2 Basics on bivalirudin mode of action

3 Θξνκβίλε Τν κόξην ηεο ζξνκβίλεο & νη ζέζεηο ζύλδεζεο Εμσηεξηθή ζέζε 2 ζύλδεζεο κε ηελ Ηπαξίλε 2 Ελεξγή ζέζε 1 Εμσηεξηθή ζέζε 1 ζύλδεζεο κε ηελ Μπηβαιηξνπδίλε

4 Θξνκβίλε 2 Αληη- Θξνκβίλε 1

5 Θξνκβίλε 2 Αληη- Θξνκβίλε 1

6 Θξνκβίλε Μπηβαιηξνπδίλε 2 Τκήκα ζπλδεόκελν κε ηελ ελεξγό ζέζε 1

7 Η Μπηβαιηροσδίλε Αλαζηέιιεη ηελ Θροκβίλε ηες Σσλδεδεκέλες κε ηολ Θρόκβο 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

8 Η Μπηβαιηροσδίλε ζηης Μειέηες Φάζεως ΙΙΙ 1. Lincoff AM et al. JAMA. 2004;292(6): Kastrati A et al. NEJM. 2008;359(7): Stone GW et al. JAMA. 2007;298(21): Stone GW et al. Lancet. 2011;377(9784): Kastrati A et al. NEJM. 2011;365(21):1980

9 Η Μπηβαιηξνπδίλε ζηηο Μειέηεο Φάζεσο ΙΙΙ

10 NSTEMI ISAR-REACT patients Similar ischemia Bleeding 46%

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16 Bivalirudin/UFH Switch Therapy in Primary PCI Death or definite stent 30d SCAAR Registry HORIZONS-AMI patients Adj. OR 0.55, 95% CI 0.41 to 0.72, P<0.001 Major 30 d HORIZONS-AMI P= Bivalirudin (n=1 928) 11.3% Bivalirudin +UFH (n=1 068) 6.5% UFH + GP IIb/IIIa-Inh (n=1 179) 12.3% Bivalirudin +UFH (n=1 178) 7.6% Koutousis M, et al. Heart 2011 Sep;97(18):1484 Dangas GD, et al. JACC. 2011;57:2309

17 Bivalirudin & Clopidogrel Pretreatment in Primary PCI HORIZONS-AMI patients Dangas GD, et al. Circulation 2011;123:1745

18 Bivalirudin vs. Abciximab & High On-clopidogrel Treatment Platelet Reactivity (HPR) in NSTEMI Patients: ISAR-REACT 4 Death, MI, urgent target vessel 30 days Bivalirudin (n=274) UFH+Abciximab (n=290) OR:5.4 P< P=NS 22% 5% 6.7% 9.4% No-HPR HPR Sibbing D, et al.jacc 2012;60:369

19 Back to the meta analyses Bivalirudin versus Heparin+ΙΙβ/ΙΙΙα GP Receptor Inhibitors Bivalirudin vs. UFH Monotherapy

20 Bivalirudin versus Heparin+ΙΙβ/ΙΙΙα GP Receptor Inhibitors Meta analysis on patients undergoing PCI in 5 clinical trials MACE DEATH MI BLEEDING +12% P= % P=NS -7% P=NS No bleeding difference if CrCl <60 ml/min in primary PCI (HORIZONS-AMI trial) (Saltzman AJ, JACC CV Interv 2011;4:1011) Lee MS, et al. Int J Cardiol 2011;152:369-45% P<0.001

21 Η Μπηβαιηροσδίλε ζηελ πρωηογελή αγγεηοπιαζηηθή Καηαγραθή Ottawa Μπηβαιη- Αλαζηνιείο Γι/Πξση -ξνπδίλε ππνδνρέσλ ΙΙβ/ΙΙΙα Ηπαξίλε (n = 748) ( n = 699) (n = 676) Ρ<0.05 Μείδνλεο αηκνξξαγίεο θαηά ΤΙΜΙ 2.7% 7.3% 3.3% Ρ=ΜΣ Θάλαηνο, Μείδσλ αηκνξξαγία, ΑΕΕ, Επαλέκθξαγκα 7.6% 11.4% 9.5% «Σσμπέραζμα: Η Bivalirudin μείωζε ηον κίνδσνο μεγάλης αιμορραγίας ζε ζύγκριζη με GPIs, αλλά ότι ζε ζύγκριζη με μόνον ηην ηπαρίνη» Hibbert B, et al. Circ Cardiovasc Interv. 2012;Epub ahead of print.

22 Bivalirudin vs. UFH Monotherapy in Stable or Unstable Angina: ISAR-REACT patients undergoing PCI Pre-treatment with a 600-mg of clopidogrel > 2 hours before PCI 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], ; P = 0.57) Incidence of major bleeding: 3.1% vs. 4.6% (RR, 0.66; 95% CI, ; P = 0.008) Kastrati A et al. NEJM. 2008;359(7):688

23 Bivalirudin versus Heparin Monotherapy Meta analysis on patients undergoing PCI in 16 studies (RCT s=3) MACE DEATH MI BLEEDING -8% P=NS RCT s -3% P=NS -37% P=NS -45% P<0.001 MACE DEATH MI BLEEDING Bertrand OF, et al. Am J Cardiol 2012;110:599

24 Details on the hemorrhagic risk reduction

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26 UFH versus newer Anticoagulants in primary PCI 40% 20% 0-20% - 40% OASIS 6 Fondaparinux Mortality HORIZONS-AMI Bivalirudin ATOLL Enoxaparin Major bleedings

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30 Εηήζηα Μείωζε Αηκορραγηώλ κεηά από Αγγεηοπιαζηηθή National Cardiovascular Data CathPCI registry Εηήζηα Μείωζε OR (95% CI) Elective PCI (n = ) 1.4% 1.1% ( ) Unstable Angina/NSTEMI (n = ) 2.3% 1.8% ( ) STEMI (n = ) 4.9% 4.5% ( ) P=NS 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 < 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

31 The Patras (vs.ncdcathpci registry) Experience in Patients with ACSs Subherwal S, et al. J Am Coll Cardiol. 2012;59:1861 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

32 Is Bivalirudin the Ultimate Antithrombotic Answer in Primary PCI? 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)

33 The radial approach may obviate the need of bivalirudin Pro:

34 Bivalirudin vs. Heparin after Transradial & Transfemoral PCI 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) Machaalany J, et al. AJC 2012;110:1742

35 Bivalirudin vs. Heparin after Transradial (n=200) & Transfemoral (n=3 134) primary PCI (HORIZONS-AMI) Incidence of major hemorrhages P for trend: < % 2.9% TR+ Bival 4.1% TR+ IIb/IIIa 5.6% TF+ Bival TF+ IIb/IIIa Transradial Transfemoral Genereux P, et al. Eurointervention 2012;7:

36 The radial approach may obviate the need of bivalirudin Contra:

37 Combined dataset from the REPLACE-2, ACUITY, & HORIZONS-AMI trials in 17,393 PCI patients Randomization to bivalirudin vs. heparin + GPI resulted in 43% relative reductions TIMI major bleeding,(p < ), with significant reductions in both access and nonaccess site bleeding Verheugt FW,...Mehran R, Stone GW. JACC Cardiovasc Interv Feb;4(2):191.

38 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