Peter VerhammeBloedings- en Vaatziekten

UZ Leuven

WVTV 30 November 2018

Perioperatief Beleid Antitrombotica

1938Heparin

1942Dicoumarol Warfarin

1954

1986LMWH

2008NOACs

1899Aspirin

1996Clopidogrel

1960Aspirin

2008

TicagrelorPrasugrel

COUMARIN OF MARC

Prof. Marc Verstraete1925-2018

PERIOPERATIVE BRIDGING: BRIDGE trial

Douketis J, et al. N Engl J Med 2015;373:823

Primary Study Outcomes

Outcome%

No Bridging(N = 918)

Bridging(N = 895)

P- value

Arterial Thrombosis 0.4% 0.3% 0.01 (non-infer.)

- stroke 0.2% 0.3%- TIA 0.2% 0- systemic embolism 0 0

Major bleeding 1.3% 3.2% 0.005 (super.)

• Median time to TE event = 19.0 days (IQR, 6.0-23.0)• Median time to major bleed = 7.0 days (IQR, 4.0-18.0)

BRUISE CONTROL Trial

Patients on warfarin who need a pacemaker/ICDRandomized to:

- continue warfarin (INR <3.0 at procedure)or- interrupt warfarin + bridge

enoxaparin 1 mg/kg BIDstarting within 24 hours post-procedure

Birnie DH, Healey JS, Wells GA, et al. Pacemaker or defibrillator surgery without interruption of anticoagulation. N Engl J Med 2013;368:2084-93.

BRUISE CONTROL Trial

pacemaker hematomacontinued warfarin 3.5% interrupt warfarin + bridging 16.0%

surgical and thromboembolic complicationsrare and not different

Birnie DH, Healey JS, Wells GA, et al. Pacemaker or defibrillator surgery without interruption of anticoagulation. N Engl J Med 2013;368:2084-93.

Vitamin K Antagonists

• DON’T bridge most patients with Atrial Fibrillation & Venous Thromboembolism

• DO bridge patients with mechanical mitral valves orolder aortic valves

Perioperative management of NOACs

Dabigatran Apixaban - Edoxaban -Rivaroxaban

Low risk High risk Low risk High riskCrCl ≥80 ml/min ≥ 24 h ≥ 48 h

≥ 24 h≥ 48 h

CrCl 50-79 ml/min ≥ 36 h ≥ 72 h

CrCl 30-49 ml/min ≥ 48 h ≥ 96 h

CrCl 15-29 ml/min Not indicated Not indicated ≥ 36 h

CrCl <15 ml/min No official indication for useNo bridging with LMWH/UFH

Resume full dose of NOAC ≥ 24h post low bleeding risk interventions and 48 (-72) h post high-bleeding risk interventions

Steffel et al., EHRA Practical Guide, European Heart Journal 2018

Meta-analysis ARISTOTLE, ENGAGE-AF, RE-LY and ROCKET AF

DOACs vs VKA: Different bleeding pattern

Vanassche et al, Thrombosis and Haemostasis, 2014

Relative risk difference (%) (95% CI)

Intracranial bleeding

Other major bleeding

Gastrointestinal bleeding

Favours DOAC Favours warfarin–100 –50 0 50 100

84,540 patients and 4781 bleeding events

How do (a)PCCs support coagulation?

Tissue factor

Xa

Thrombin

Contact

Clot formation

Dabigatran

RivaroxabanApixabanEdoxaban

PCC or aPCC

IX

X

II

VII VIIaIXa rVIIa

What do the guidelines recommend?

• In case of life-threatening bleeding:

– PCC (50 U/kg)

– aPCC (50–200 U/kg)No strong data about additional benefit over PCC

– rFVIIa (90 µg/kg)No data about additional benefit

Heidbuchel et al, 2015

What is Idarucizumab?

Schiele F et al. Blood 2013;121:3554–62; Stangier J et al. ISTH 2015; OR320

Humanized Fab fragment

Binding affinity ~350� higher than dabigatran to thrombin

No procoagulant or anticoagulant effects expected

IV administration,immediate onset of action

Short half-life

Idarucizumab

Dabigatran

Idarucizumab to reverse dabigatran in patients with

bleeding

Pollack CV et al. N Engl J Med 2015;373:511–20

dTT

(s)

1 hr 2 hrs 4 hrs 12 hrs 24 hrsBaseline 10–30

min

Uncontrolled bleeding(n=51)

130

110

70

60

50

40

30

20

120

100

90

80

0

Time post-idarucizumab

Assay upper limit of normal

Between

vials

Idarucizumab 2 × 2.5 g

Reversal sustained over 12 hours in 90% of patients

Andexanet: Reversal of Anticoagulation by Factor Xa Inhibitors

Recombinant engineered factor Xa• No catalytic activity• Binds and neutralizes Xa-inhibitors both direct FXai and heparins

Lu et al. Nature Medicine (2013),19(4): 446-51

Factor Xa

Catalytic Domain

Gla-domain S S

S419Factor Xa inhibitor

GlaS S

andexanet

A419Factor Xa inhibitor

Andexanet: Reversal of Rivaroxaban

Siegal, NEJM 2015

ANNEXA-4: preliminary analysis in patients with major bleeding

Connolly SJ, et al. NEJM 2016

Management of Bleeding

• DOACs cause less serious bleeding

• Implement protocols to prevent and manage bleeding

• Reversal strategies with non-specific procoagulants and specific agents: Work in progress

Weitz et al. Circulation, 2012; Majeed et al. Circulation, 2013

NEJM,2015

FXI Antisense

FXI mRNA Protein Synthesis Blocked

Ribosome

Hepatocyte

Plasma

FXI-ASO (ISIS 416858) is a second generation single-stranded 2ʹ-O-(2-methoxyethyl) (2ʹ-MOE) antisense oligonucleotideFXI-ASO antisense oligonucleotide

Effects of FXI-ASO and enoxaparin on factor XI activity before and after surgery

Surgery

Compounds that target factor XI/XIa and XII/XIIaTarget Inhibitor

Type Compound Mechanism of Action Reference

XI/XIa Monoclonal IgG

O1A6 (aXIMAb) Binds to Apple 3 domain of XI inhibiting activation. Binds to A3 domain of XIa inhibiting activation of factor IX.

Tucker et al. Blood 2009;113:936

14E11 Binds to Apple 2 domain of XI inhibiting its activation by XIIa (contact activation)

Cheng et al. Blood 2010;116:3981

ASO Anti-XI ASO ASOs are available for inhibiting production of XI in mice, rabbits, cynamolgus monkeys and olive baboons

Zhang et al. Blood 2010;116:4684 Yau et al. Blood 2014;123:2102 Younis et al. Blood 2012;119:2401 Crosby et al. ATVB 2013;33:1670

ISIS-FXIRx ASO to human XI mRNA has been tested in normal healthy volunteers and as prophylaxis in patients undergoing total knee replacement

Liu et al. Blood 2011;118:Abs209 Büller et al. NEJM 2015;372:232

Active site inhibitors

Aryl boronic acid derivative

Irreversible inhibitor of XIa active site Lazarova et al. Bioorgan Med Chem Lett 2006;16:5022

Ketoarginine Peptidomimetics

Irreversible inhibitor of XIa active site. Reduced thrombus size in a rat venous thrombosis model

Deng et al. Bioorgan Med Chem Lett 2006;16:3049

4-carboxy-2- azetidinone compound (BMS-262084)

Irreversible inhibitor of XIa active site produced a dose-dependent effect on arterial and venous thrombus formation in rabbits.

Wong et al. J Thromb Hameost 2011;32:129

Tetrahydroquinalone derivative

Reversible inhibitor of XIa produced an antithrombotic effect in a rabbit A-V shunt model without affecting hemostasis.

Quan et al. J Med Chem 2014;57;955

Allosteric inhibitors

Sulfated Pentagalloylglucoside

Binds to charged residues on the XI/XIa catalytic domain leading to changes in active site conformation.

Al-Horani et al. J Med Chem 2013;56:867

Natural Inhibitors

Protease Nexin 2 Kunitz-domain

The Kunitz-type inhibitory domain from protease nexin 2 inhibits XIa by binding to the protease active site.

Wu et al. Blood 2012;120:671

Clavatadine A Bromine containing compound from marine sponge Suberea clavata is probably an active site inhibitor of XIa

Buchanan et al. J Med Chem 2008;51:3583

Desmolaris Kunitz-type inhibitor of XIa active site from vampire bat saliva Ma et al. Blood 2013;122:4094

XII/XIIa Monoclonal Antibody

3F7 IgG targets the active site of XIIa and prevents thrombus formation in an extracorporeal circuit in rabbits

Larsson et al. Sci Transl Med 2014;6:222ra17

15H8 IgG binds to the heavy chain of XII, inhibiting its activation probably by preventing XII from binding to charged surfaces

Matafonov et al. Blood 2014;123:1739

ASO Anti-XII ASO ASOs are available for inhibiting XII production in mice and rabbits Zhang et al. Blood 2010;116:4684 Yau et al. Blood 2014;123:2102

Small Molecule

Bicyclic Peptide 3 Binds to XII and prevents activation Baeriswyl et al. J Med Chem 2013;56:3742

RNA aptamer

R4cXII-1 Binds XII inhibiting activation, and XIIa inhibiting XI activation. Woodruff et al. J Thromb Haemost 2013;11:1362

Natural Inhibitors

Infestin-4 Active site inhibitor of XIIa from Triatoma infestan attached to albumin. Inhibits thrombosis in rodents

Hagedorn et al. Circulation 2010;121:1510 Xu et al. Thromb Haemost 2013;111:694

!Gailani D, Hematology 2014

1938Heparin

1942Dicoumarol Warfarin

1954

1986LMWH

2008NOACs

1899Aspirin

1996Clopidogrel

1960Aspirin

2008

TicagrelorPrasugrel

Peter VerhammeBloedings- en Vaatziekten

UZ Leuven

Perioperatief Beleid Antitrombotica