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…

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κε ηελ Μπηβαιηξνπδίλε

Τν κόξην ηεο ζξνκβίλεο & νη ζέζεηο ζύλδεζεο

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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

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Major bleedingsMortality

40

% 2

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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