New oral anticoagulant: Relevant pharmacology and

management of bleeding

Dr Noel Chan

Haematology Department

Monash Medical Centre

Aims

To review:

1. Relevant pharmacology of TGA-approved

NOACs

2. Type and burden of bleeding with the NOACs

compared with warfarin

3. Current & emerging approaches for the reversal

of NOACs in emergency situation

NOAC: Terminology

DOAC1 – direct oral anticoagulants

TSOC2 – target-specific oral anticoagulants

NOAC3 – Non-Vitamin K antagonist (VKA) oral anticoagulants

1Thromb Res. 2014 Feb 13 2Siegal Blood. 2014 Feb 20;123(8):1152-8 3Lip GYH et al, Non-Vitamin K Antagonist Oral Anticoagulants: An Appeal for

Consensus on Terminology. Chest. 2014;145(5):1177-1178

Currently approved NOACs:

Drug

SPAF Treatment of

acute VTE

Prevention of VTE

recurrence

Prevention of VTE

after hip/knee

replacement

surgery

Dabigatran (BI)

Pradaxa

✔ ✔

Rivaroxaban (Bayer)

Xarelto

✔ ✔ ✔ ✔

Apixaban (BMS)

Eliquis

✔ ✔

SPAF = Stroke prevention in Atrial Fibrillation

VTE = Venous thromboembolism (Deep vein thrombosis or Pulmonary embolism)

NOACs in SPAF:

at least as effective and safe as warfarin

Chan NC et al. New oral anticoagulants for stroke prevention in atrial fibrillation: impact of study design, double counting and

unexpected findings on interpretation of study results and conclusions. Thromb Haemost. 2014 May 5;111(5):798-807.

NOACs in VTE treatment:

at least as effective and safe as warfarin

Yeh CH et al. Evolving use of new oral anticoagulants for treatment of venous thromboembolism. Blood. 2014 Aug 14;124(7):1020-8

Pharmacodynamics: Stoichiometric inhibitors of FIIa or FXa

1:1 stoichiometric inhibitor

One molecule of

dabigatran binds one

molecule of thrombin

One molecule of Xa

inhibitor binds one

molecule of Xa

In contrast to catalytic

inhibitors (e.g: heparin,

LMWH, fondaparinux)

Chan NC et al. Future Cardiol. 2014 Jan;10(1):43-52

Key pharmacokinetic characteristics

impacting on exposure:

Tran H, et al. New oral anticoagulants: a practical guide on prescription, laboratory testing and peri-procedural/bleeding

management. Australasian Society of Thrombosis and Haemostasis. Intern Med J. 2014 Jun;44(6):525-36. doi: 10.1111/imj.12448.

Dosing recommendations based on clinical

characteristics

Chan NC et al. Thromb Haemost. 2014 May 5;111(5):798-807.

Dosing recommendations based on clinical

characteristics: (Dabigatran)

Chan NC et al. Real-world variability in dabigatran levels in patients with atrial fibrillation. J Thromb Haemost. Dec 2014

Clinically relevant drug interactions:

(at least 50% change in the exposure)

Heidbuchel et al. Eur Heart J. 2013;34:2094–2106.

To review:

1. Relevant pharmacology of TGA-approved

NOACs

2. Bleeding with the NOACs compared with

warfarin

3. Emerging approaches for the reversal of

NOACs in emergency situation

Bleeding in anticoagulated patients

Is common

Major bleeding 1-5% per year in AF

Intracranial bleeding 0.5-1.2% per year in AF

Associated with adverse outcomes

3 to 5-fold increase in thrombotic events & death

Rapid and timely control of bleeding is likely

to improve clinical outcomes but the efficacy

of anticoagulant reversal is unproven

Bleeding in patients receiving NOACs

As a group, NOACs cause less major

bleeding than warfarin (23% reduction).

Organ specific pattern of bleeding

NOACs cause less intracranial and intracerebral bleed (haemorrhagic stroke) than warfarin (60% reduction)

GI bleeding is increased with selected NOACs, and dose (DE150, Rivaroxaban, Edoxaban 60mg)

Vanassche T et al, Organ-specific bleeding patterns of anticoagulant therapy: lessons from clinical trials. Thromb Haemost. 2014

Nov;112(5):918-23.

What about mortality after bleeding in

absence of an antidote?

Dabigatran vs. warfarin

The Kaplan–Meier analysis suggest a reduced risk for death with dabigatran vs warfarin during 30 days after the bleeding (P=0.052)

Mort

alit

y r

ate

(%

)

Time (days)

0

0.1

0.2

0.3

5 10 15 20 25 30 35

Warfarin

Dabigatran

Majeed A, et al. Circulation 2013

Apixaban vs. warfarin is associated with

better outcomes after bleeding

0

10

20

30

40

50

60

70

80

Apixaban Warfarin

Nu

mb

er

of

pa

tie

nts

ex

pe

rie

nc

ing

ma

jor

ble

ed

ing

fo

llo

we

d b

y d

ea

th i

n 3

0 d

ays

Major bleeding followed by death within 30 days

35 patients

(n=9,088)

69 patients (n=9,052)

HR=0.50 (95% CI 0.33-0.75; p<0.001)

Hylek EM et al. Presented at: American Heart Association.

November 2012. Los Angeles, CA. Abstract 15115.

Specific Questions

What is the general approach to

management of anticoagulant-related

bleeding?

When should I consider reversing

anticoagulation in a bleeding patient?

How should I reverse NOAC therapy?

Approaches to minimize the burden of

bleeding

Prevention of bleeding

Anticoagulant selection

Patient and dose selection

Appropriate management of interruption

Treatment of bleeding

General measures

Reversal of anticoagulation

General measures to control bleeding

Hold antithrombotic drug (note: short half

lives of NOACs)

Identify source of bleeding

Local / surgical haemostasis

Volume replacement / blood transfusion

Evaluation of anticoagulant effect

Determine timing of last dose of drug

Measure anticoagulant activity (repeat after

2-4 hours in patients with recent drug

ingestion)

Measure creatinine (NOACs)

Consider reversal agent

Measurement of anticoagulant

effects of NOACs

Test Dabigatran Rivaroxaban Apixaban

Specific

Assay*

Drug

specific Hemoclot Anti-Xa Anti-Xa

Non-specific

assays

aPTT ↑↑↑ ↑ ↑

PT ↑ ↑↑ ↑

TT ↑↑↑↑ No effect No effect

Questions

What is the general approach to

management of anticoagulant related

bleeding?

When should I consider reversing

anticoagulation in a bleeding patient?

How should I reverse NOAC therapy?

When should I consider reversing

anticoagulation in a bleeding patient?

Life-threatening (e.g., intracranial)

Critical organ (e.g., pericardial,

retroperitoneal)

Ongoing (despite measures to control

bleeding)

Expected long delay in restoration of normal

haemostasis (over-anticoagulation, long drug

half-life)

Questions

What is the general approach to

management of anticoagulant related

bleeding

When should I consider reversing

anticoagulation in a bleeding patient?

How should I reverse NOAC therapy?

Reversal of NOACs

Activate coagulation to overcome the effect

of the drug

Remove drug

Neutralize drug

Lauw M, et al. Can J Cardiol 2014

Activate coagulation to overcome the

effects of the drug

Tissue factor

Xa

Thrombin

Contact (e.g., stents, valves

catheters)

(e.g., plaque

rupture)

Clot formation

Dabigatran

Rivaroxaban

Apixaban PCC

IX

X

II

VII VIa IXa

Activate coagulation to overcome the

effects of the drug

Tissue factor

Xa

Thrombin

Contact (e.g., stents, valves

catheters)

(e.g., plaque

rupture)

Clot formation

Dabigatran

Rivaroxaban

Apixaban

aPCC VIIa, IXa, Xa, IIa

rVIIa VIa IXa

Overwhelm or bypass the agent

The basis for rVIIa, PCC,

aPCC or FFP based

strategies

May be effective but

raises spectre of

thrombosis

Lack of specificity makes

control difficult

Slide courtesy of Huyen Tran

Remove drug

Haemofiltration or haemodialysis

Limited availability, expensive, burdensome

Slow drug clearance (hours)

Only partially effective

Restricted to non-protein bound drug

(dabigatran and edoxaban are partly

unbound)

Neutralize the effects of the drug

Specific antidotes (in phase II trials)

Idarucizumab Andexanet

alpha

Aripazine

PER977

Structure Humanized

Fab fragment

Human

rXa variant

Synthetic small

molecule

Target Dabigatran FXa inhibitors Universal

Binding Non-competit.

High affinity Competitive ?

Clinical

studies

Rapid

complete

reversal

Rapid, near

complete

reversal

Rapid reversal

of edoxaban

Lauw M, et al. Can J Cardiol 2014)

Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013;121(18):3554-3562.

Lu G, DeGuzman FR, Hollenbach SJ, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med.

2013;19(4):446-451.

Ansell J, Bakhru SH, Laulicht SS, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban [published online ahead of print November 5, 2014]. N

Engl J Med.

.

Summary of NOAC reversal

in the bleeding patient

General haemostatic agent

PCC 25-50 IU/kg

FEIBA 25-50 IU/kg

rFVIIa 90 ug/kg

Drug removal (dabigatran)

Haemodialysis or haemofiltration

Activated charcoal if <2 hr since administration

Key points:

1. NOACs provide opportunity to minimize growing burden of potentially preventable thromboembolism (especially AF).

2. Patient, dose, and anticoagulant selection are important to prevent bleeding complication.

3. For bleeding patients receiving NOACs, the management consists of:

General measures

Consideration given to reversing the anticoagulant effect

Tran H, et al. New oral anticoagulants: a practical guide on prescription, laboratory testing and peri-procedural/bleeding management.

Australasian Society of Thrombosis and Haemostasis. Intern Med J. 2014 Jun;44(6):525-36. doi: 10.1111/imj.12448.

ASTH Practical Guide:

Acknowledgments:

(for use of their slides)

Dr Huyen Tran

Dr J Eikelboom

Any questions?

Timing of last dose before surgery and first

dose after surgery of therapeutic DOAC

96 h 48-72h 24h Resumption

Xa inhibitors High risk*

and/or

renal**

Low risk* When

hemostasis

is secured

(48-72h) Dabigatran High risk*

and renal**

High risk*

or renal**

Low risk* and

no renal**

SURGERY

*Low vs. High risk for bleeding

** creatinine clearance 30–49 mL/min ASTH recommendations

Tran IMJ 2014;44:525-36

NOAC & Urgent Surgery

STOP NOAC

DABIGATRAN APTT & TT PROLONGED

RIVAROXABAN PT PROLONGED

APIXABAN - Anti-Xa level therapeutic (when available)

Anticoagulant effect

Consider Charcoal if surgical team agrees

Maintain BP & Urine Output

Control bleeding

Transfusion support

DISCUSS FEASIBILITY OF DELAYING SURGERY

DABIGATRAN

NORMAL APTT & TT

NORMAL APTT & PROLONGED TT

RIVAROXABAN

NORMAL PT

IMMEDIATE SURGERY

DISCUSS WITH HAEMATOLOGY

IF CONSIDERING HAEMOSTATIC

AGENT

3F-PCC/aPCC

DELAY 4-12 SURGERY

CONSIDER HAEMODIALYSIS

FOR DABIGATRAN

DELAY >12H SURGERY

REFER TO ELECTIVE

SURGERY STRATEGY

DOAC level low/absent

PROCEED TO SURGERY

*Routine coagulation tests are insensitive to apixaban. Anti-Xa testing for apixaban is not currently available.

aPCC=activated prothrombin complex concentrate; 3F-PCC=3-factor prothrombin complex concentrate Huyen Tran

Haemostatic agents & NOAC

Reversal Agent Rivaroxaban Dabigatran

Prothrombin

complex

concentrate -4F*

Data in healthy volunteers

suggest a dose of 50 U/kg

Data in healthy volunteers do

not demonstrate efficacy

based on coagulation

parameters

Activated

prothrombin

complex

concentrate (FEIBA)

Animal data available for the use

of FEIBA for the reversal of

rivaroxaban.

Observational reports

No data in human patients or

volunteers, but reversed

bleeding in rat tail.

Case reports1,2

Recombinant FVIIa Not studied No data in human patients or

volunteers, but reversed

bleeding in rat tail & rabbit

models. Case reports

Fresh Frozen

Plasma

Not recommended Not recommended

*3F-PCC available in ANZ Huyen Tran 1Schulman BrJH 2014;164:308-10 2Wong BrJH 2014;164

Removal of NOACs

1. van Ryn J et al. Blood (ASH Annual Meeting Abstracts) 2009;114;Abs 1065; 2. Stangier Clin Pharmacokinet 2010; 49 (4): 259-268

3. Warkentin TE et al. Blood 2012;119:2172–4; 4. Wang X et al. Clin Pharmacol Ther 2012;91(suppl 1):Abs PI-90;

Dabigatran Rivaroxaban Apixaban Edoxaban

Oral activated

charcoal

Adsorbs &

neutralizes,

in vitro data1

Adsorbs &

neutralizes

Adsorbs &

neutralizes, in

vivo data4

No data

Haemodialysis

Human

volunteers2,

case report3

Not possible Not possible No data