1/10/2013. None to disclose

(1)

Helene

Maltz,

B.S.,

Pharm.D.

PGY

‐

2 Pharmacy

Resident

‐

Internal

Medicine

Kingsbrook Jewish

Medical

Center

Department

of

Pharmacy

Clinical

Assistant

Professor

of

Pharmacy

Practice

Arnold

&

Marie

Schwartz

College

of

Pharmacy

and

Health

Sciences

Long

Island

University

Brooklyn,

New

York

January

20,

2013



None

to

disclose

2



Explain

the

mechanism

of

action

of

select

antiplatelet

and

anticoagulant

agents



Outline

a

treatment

plan

for

bleeding

complications

associated

with

antiplatelet

agents

including

aspirin,

clopidogrel,

prasugrel,

and

ticagrelor



Describe

potential

reversal

options

for

anticoagulation

with

warfarin,

heparin,

low

molecular

weight

heparins,

fondaparinux,

dabigatran,

rivaroxaban,

and

apixaban

(2)



Explain

the

mechanism

of

action

of

select

antiplatelet

and

anticoagulant

agents



Outline

a

treatment

plan

for

bleeding

complications

associated

with

antiplatelet

and

anticoagulant

agents

4



Primary

hemostasis at

endothelial

damage

site



Platelet

adhesion



Thrombin

burst

via

extrinsic

pathway



Immediate

seal

formation

5



Secondary

hemostasis



Thrombin

activation

of

intrinsic

pathway



Fibrin

generation



Fully

developed

clot

INDICATIONS

AND

USAGE



Up

to

2%

of

developed

world

population



Uses



Atrial fibrillation



Venous

thromboembolism



Post

‐

MI



Post

‐

PCI



Ischemic

stroke

AVAILABLE

CLASSES



Vitamin

K

antagonists

(VKA)



Unfractionated heparin

(UFH)



Low

molecular

weight

heparins

(LMWH)



Pentasaccharides (FXa inhibitor)



Oral

direct

thrombin

inhibitors

(DTI)



Dabigatran



Factor

Xa inhibitors

(oral)



Rivaroxaban



Apixaban

6

Vigue B. Critical Care.2009;13:209 (doi:10.1186/cc7001 Levi MM, et al. Neth J Med. 2010;68:68‐76

(3)

7

Direct

thrombin

inhibitors

Vitamin

K

antagonists

Unfractionated

heparin

Factor

Xa

inhibitors

Low

molecular

weight

heparins

http://www.cancerthrombosis.org/content/modules/2/articleFigures/mod02NEW_fig02.jpg

INDICATIONS



Primary

CAD/CVA

prophylaxis



Secondary

CAD/CVA

prophylaxis



Peripheral

vascular

disease



Post

‐

stent

placement

AVAILABLE

AGENTS



Aspirin



ADP

‐

P2Y

12 inhibitors



Clopidogrel



Prasugrel



Ticagrelor



Ticlopidine



Phosphodiesterase

inhibitors



Cilostazol



Dipyridamole



GP

IIb/IIIa

antagonists

8



Normal

platelet

effects:



Seal

microscopic

gaps

in

endothelium



Activated

platelets

recruit

additional

platelets

through

secretion

of

ADP,

histamine,

serotonin,

thromboxane A

2

(TXA

2

)

and

growth

factor



Adherence

surface

for

coagulation

factors

9

(4)



Worse

than

non

‐

anticoagulant

associated

bleeds



Major

bleeding



Critical

locations:

intracranial,

retroperitoneal,

gastrointestinal,

genitourinary



Associated

with

intensity

of

anticoagulation

and

combination

with

antiplatelet agents



Predictor

of

mortality:

5 ‐

fold

increased

risk

of

death

within

30 days

of

bleed



Outcomes

improved

if

rapid

reversal

of

anticoagulation



Risk/benefit

balance

must

be

favorable

for

use

10

Vigue B. Critical Care.2009;13:209 (doi:10.1186/cc7001) Levi MM, et al. Neth J Med. 2010;68:68‐76 Levi M, et al. J Thromb Haemostas. 2011;9:1705‐12 Kalyanasundaram A, et al. Nat Rev Cardiol.2011;8:592‐600



Scheduled

versus

urgent



Antiplatelet/anticoagulant

indication



Cardiovascular

events:

low

versus

high

risk



Time

since

stent

placement

and

stent

type



Thromboembolic

complications

(mechanical

valves,

atrial

fibrillation,

VTE):

low

versus

high

risk



Procedure

type/location



Minor

dental

or

dermatologic

versus

cataract



Cardiac



Gastrointestinal,

genitourinary



Weigh

thrombosis

risk

(ex.

antithrombotic

indication,

CHADS

2 )

versus

bleeding

risk

(ex.

HAS

‐

BLED)

11

Levi MM, et al. Neth J Med. 2010;68:68‐76

Ortel TL. Hematology Am Soc Hematol Educ Program. 2012;529‐35. doi: 10.1182/asheducation‐2012.1.529



Assess

whole

patient



Consider

drug

half

life



Determine

goal



Complete

reversal



Return

to

“therapeutic

anticoagulation”



Create

protocols

for

institution



Remain

vigilant

with

new

agents

(5)

Supportive

Care

Discontinue

drug

Fluid

resuscitation

Blood

Identification

and

control

of

bleeding

source

Hemostasis agents: •Aminocaproic acid •Tranexamic acid

Removal

of

Drug

Activated

charcoal

Hemodialysis

Hemoperfusion

with

charcoal

Antidotes

Protamine

sulfate

Vitamin

K

Investigational:

•Factor

Xa

antidote

•Monoclonal

antibodies

•Avidin

neutralization

Replacement

Therapy

Platelet

infusions

Fresh

frozen

plasma

(FFP)

Prothrombin complex concentrates (PCC) Recombinant factor VIIa (rFVIIa)

Desmopressin

13

1 unit

single

donor

platelets

(5

– 6

units

multiple

donor)

30 x

10

9 _/L

_platelet

count

increase

Immediate

restoration

of

platelet

activity



Blood

bank

product



22ºC

incubator,

agitator



Blood

typing

required



Administration



Filter



Infuse

over

30 minutes



Use

within

4 hours



Potential

risks



Infection



ABO

‐

mismatch



Alloimmunization



Refractoriness

14

Nishijima DK, et al. J Trauma Acute Care Surg. 2012;72:1658‐63



Replaces

all

coagulation

factors

at

1 unit/ml



Dose:

10 – 15

ml/kg



Blood

bank

product



Requires

blood

typing



Requires

thawing

time



Administration



Blood

giving

set

(filter)



Use

within

4 hours

of

thaw



Infuse

each

unit

over

30 minutes



Limitations



Fluid

overload



Cannot

fully

replete

factors

at

tolerable

volume



Freezing

reduces

factor

concentration



Delays

in

procurement



Allergic

reactions



Transfusion

acute

lung

injury



Cost



~$60

per

unit

(200

ml)



~$360

per

treatment

(80

kg)

15

Peacock WF, et al. Clin Cardiol. 2012;doi:10.1002/clc.22037 Beshay JE, et al. J Neurosug. 2010;112:307‐18 Lexi‐Comp OnlineTMLexi‐Comp, Inc.; Accessed January 4, 2013.

(6)



MOA:

Replaces

factors

II,

IX,

X

resulting

in

thrombin

formation

and

hemostasis



Indications



Labeled:

Factor

IX

deficiency



Unlabeled:

warfarin coagulopathy



Dosed

by

FIX

activity

Profilnine (25%

greater

activity):

1 unit/kg

raises

plasma

factor

IX

level

by

1%



Pharmacy

product



Refrigerated;

bring

to

room

temp,

reconstitute,

and

use

within

3 hours



No

thawing

required



Lower

volume

than

FFP



Administration



IV

infusion



Bebulin:

< 2

ml/minute



Profilnine:

< 10

ml/minute



24 hour

intervals



Half

life:

~24

hours



Limitations



No

FVII



Adverse

reactions

▪ Flushing,

rash

▪ Nausea,

vomiting

▪ Thrombosis



Cost



~$0.97

per

unit



~$1,940

per

treatment

(warfarin

reversal:

25 U/kg

for

80 kg)

16

Peacock WF, et al. Clin Cardiol. 2012;doi:10.1002/clc.22037 Bauer KA. Am J Hematol. 2012;87:S119‐S126 Lexi‐Comp OnlineTM; Accessed January 4, 2013.



Replaces

factors

II,

VII,

IX,

X,

proteins

C

and

S

resulting

in

thrombin

formation

and

hemostasis



Labeled

indication:

VKA

coagulopathy



Not

available

in

US



Dose

by

initial

INR:

max

120 ml



Pharmacy

product



Refrigerated;

bring

to

room

temp,

reconstitute,

and

use

immediately



No

thawing

required



Product

is

light

blue



Lower

volume

than

FFP



Administration



IV

infusion



Initial:

1 ml/minute



If

no

significant

tachycardia,

can

increase

to

2 – 3

ml/minute



Onset:

within

10 minutes



Half

life

Duration



FII:

48 – 72

hour



FVII:

1.5 – 6

hour



FIX:

20 – 24

hour



FX:

24 – 48

hour



Adverse

reactions



Hypertension



Headache



Elevated

LFTs



Hypersensitivity

reactions

17

Peacock WF, et al. Clin Cardiol. 2012;doi:10.1002/clc.22037 Bauer KA. Am J Hematol. 2012;87:S119‐S126 Lexi‐Comp OnlineTM. Lexi‐Comp, Inc.; Accessed January 4, 2013.

6 – 8

hours



Replaces

activated

factors

II,

VII,

IX,

X

(and

protein

C)

resulting

in

thrombin

formation

and

hemostasis



Indications



Labeled:

bleeding

or

surgery

in

hemophilia

A/B



Unlabeled:

rivaroxaban reversal



BOXED

WARNING:

thromboembolic events



Dose:

50 – 100

unit/kg;

based

on

FVIII

bypassing

activity



Pharmacy

product



Room

temp

storage,

reconstitute,

and

use

within

3 hours



Administration



IV

infusion



2 units/kg/minute



Onset:

within

15 – 30

minutes



Half

life

Duration



FII:

48 – 72

hour



FVII:

1.5 – 6

hour



FIX:

20 – 24

hour



FX:

24 – 48

hour



Adverse

reactions



Hypotension



Thrombosis



Rash

and

allergic

reactions



Cost



~$1.70

per

unit



$10,227

per

treatment

(75

unit/kg

for

80 kg)

18

Peacock WF, et al. Clin Cardiol. 2012;doi:10.1002/clc.22037 Bauer KA. Am J Hematol. 2012;87:S119‐S126 Lexi‐Comp OnlineTMLexi‐Comp, Inc.; Accessed January 4, 2013.

(7)



Replaces

FVIIa



Binds

to

tissue

factor

(TF)

on

subendothelial cells



TF

‐

VIIa

complex

activates

FIX

and

FX



Thrombin

generated

(small

amount)



Thrombin

activates

platelets,

FV

and

FVIII



“Thrombin

burst”

and

fibrin

clot

formation



Indications



Labeled:

bleeding

due

to

hemophilia

A/B,

acquired

hemophilia,

factor

VII

deficiency



Unlabeled:

warfarin

‐

ICH



BOXED

WARNING:

off

‐

label

use,

monitor

for

thrombosis



Pharmacy

product



Refrigerated;

bring

to

room

temp,

reconstitute,

and

use

within

3 hours



Dosage:

10 – 100

mcg/kg



Administration



IV

bolus

over

2 – 5

minutes



Redose at

2 – 6

hour

intervals



Limitations



Half

life:

~2.3

hours



Only

contains

FVIIa



Adverse

reactions

▪ Thrombosis

risk

(hemophilia

dosing)

▪ Hypertension,

bradycardia

▪ Fever,

headache

▪ Rash,

allergic

reactions



Cost



~$1,400

per

1 mg



~$4,480

– $10,000

per

treatment

(40

mcg/kg

for

warfarin reversal

and

90 mcg/kg

for

fondaparinux reversal

per

80 kg)

19



Increases

plasma

levels

of

von

Willebrand (VW)

factor,

factor

VIII,

and

tPA to

correct

platelet

dysfunction



Indications



Labeled:

diabetes

insipidus,

hemophilia

A

bleeding

(FVIII

activity

>5%),

VW’s

disease

(type

I),

primary

nocturnal

enuresis



Unlabeled:

uremic

bleeding

(in

renal

failure),

prevention

of

surgical

bleeding

in

uremia



Dosage

and

administration



VW’s

disease,

pre

‐

surgery:

0.3 mcg/kg

IVPB

over

15 – 30

minutes



Uremic

bleeding:

0.4 mcg/kg

IVPB

over

10 minutes



Pharmacy

product



Refrigerated



Dilute

in

10 – 50

ml

NS



Onset:

0.5 hr;

Peak:

1.5 – 2

hr



Half

life:

3 hr;

Duration:

6 – 14

hr



Adverse

reactions



Vasoconstriction,

hypertension



Headache,

GI

upset



Hyponatremia



Allergic

reactions



Thrombosis



Cost



~$59.30

per

4 mcg

vial



~$355.80

per

treatment

(at

0.3 mcg/kg

for

80 kg

for

aspirin

reversal)

20



Irreversible

inhibition

of

thromboxane A

2 (TXA

2 )

production

causes

platelet

inactivation



Half

life:

10 – 20

minutes



Duration

of

effect:

5 – 10

days



Recovery

of

TXA

2 production

takes

~4

days



Platelet

turnover:

10%

per

day



Requires

production

of

40%

non

‐

ASA

platelets



TXA

2

from

non

‐

ASA

platelets

can

activate

ASA

‐

platelets



Longer

if

used

with

clopidogrel



Platelet

transfusion

for

intracranial

hemorrhage



1 unit

single

donor

or

5 pooled

concentrates



Properly

‐

timed

platelet

transfusions

prior

to

procedures



Desmopressin

(0.3

mcg/kg)



May

correct

platelet

dysfunction



No

large

studies

done



rFVIIa



Reversal

of

ASA

antiaggregation

effect



Studied

in

healthy

individuals

21

Li C, et al. J Thromb Haemost. 2012;10:521‐8

(8)

CLOPIDOGREL/PRASUGREL



Irreversible

inhibition

of

ADP

‐

induced

platelet

aggregation



Recovery

takes

> 7

– 10

days



90%

platelet

turnover

required



Inhibited

platelets

cannot

aggregate

in

response

to

ADP



Platelet

transfusions*



10 – 12

pooled

concentrates



Up

to

4 – 5

days

after

last

dose

because

of

active

metabolites



Desmopressin



rFVIIa

(possibly)

TICAGRELOR



Reversible

ADP

inhibition



Shorter

acting

than

clopidogrel or

prasugrel



Requires

3 – 5

days

for

reversal

due

to

strong

antiplatelet effect



Platelet

transfusions

may

be

required

for

severe

bleeding

22

Li C, et al. J Thromb Haemost. 2012;10:521‐8 Campbell PG, et al. World Neurosurg. 2010;74:279‐85

Clopidogrel

Prasugrel

Ticagrelor

Half

life

6 hours

7 hours

Duration

7 – 10

days

5 – 9

days

3 – 5

days

*

PI

suggestion



TRUE

or

FALSE:

The

reversibility

and

short

half

life

of

ticagrelor

allow

for

its

discontinuation

the

evening

before

major

surgical

procedures.

1. TRUE

2. FALSE

23



Risk

of

intracranial

hemorrhage

doubles

for

every

0.5 INR

increase

over

4.5 

Reversal

involves

de

novo

synthesis

of

affected

factors



Watch

for

long

duration

of

warfarin effect

▪ Half

life:

~40

hours

▪ Duration

of

effect:

2 – 5

days



FVII

replenished

before

FII

24

Vigue B. Critical Care.2009;13:209 (doi:10.1186/cc7001) Rolfe S, et al. J Pharm Practice.2010;23:217‐25 Leissinger CA, et al. Am J Hematol.2008;83:137‐43 Chapman SA, et al. Ann Pharmacother. 2011;45:869‐75 Beshay JE, et al. J Neurosug. 2010;112:307‐18

(9)



Vitamin

K*



Route

‐

dependent

(PO,

SQ,

IVPB)

timing

of

INR

decrease



Artificial:

reflects

primarily

FVII

increase,

requires

factor

supplementation

until

FII

recovery



FFP*

: historically used but significant limitations



PCC*

(with

rFVIIa*

20 – 60

mcg/kg

if

3 ‐

factor)



Provides

all

factors

for

rapid

INR

reversal



Doses

used:

20 – 50

U/kg



Concern

over

hypercoagulable state

25

Vigue B. Critical Care.2009;13:209 (doi:10.1186/cc7001) Rolfe S, et al. J Pharm Practice.2010;23:217‐25 Leissinger CA, et al. Am J Hematol.2008;83:137‐43 Chapman SA, et al. Ann Pharmacother. 2011;45:869‐75 Beshay JE, et al. J Neurosug. 2010;112:307‐18 Guyatt GH, et al.Chest; 2012;141:7S‐47

*

PI

suggestion



Chest

Guidelines,

2012



INR

as

surrogate

for

clinical

outcome

26

INR/bleeding

status

Treatment

4.5 – 10

AND

no

bleeding

No

vitamin

K

>

10 AND

no

bleeding

Oral

vitamin

K

Any INR

AND

major

bleeding

Vitamin K

5 – 10

mg

IVPB

+

4 ‐

factor

PCC

Levi M, et al. J Thromb Haemost. 2011;9:1705‐12. Guyatt GH, et al.Chest; 2012;141:7S‐47



What would you recommend for a 45 year old

male (80 kg) on warfarin 2 mg daily for MVR and

INR of 2.7 who requires emergency exploratory

laparotomy following a motor vehicle accident

with crushing injuries and internal bleeding?

1. Vitamin K 5 mg PO, 2 units FFP, and rFVIIa

2,400 mg

2. Vitamin K 10 mg IM and Octaplex 120 ml

3. Vitamin K 10 mg IVPB and Octaplex 120 ml

4. Vitamin K 10 mg IVPB, Profilnine SD 2,000 U,

and rFVIIa 2.4 mg

27

(10)



Stop

infusion

(heparin)



Protamine sulfate*

(partial

antidote

for

LMWH)



Consider

half

life



Err

towards

lower

dosage



e



Consider

FFP

(but

may

potentiate

antithrombin)

,

PCC,

rFVIIa

28

Time

since

bolus

Time

since

infusion

stopped

Protamine dose

(cumulative)

Heparin

<30 minutes

1 hour

1 mg/100

units

UFH

30 minutes

– 1

hour

1 – 2

hours

0.5 mg/100 units

UFH

>2

hours

2 hours

0.25 – 0.375 mg/100

units

UFH

LMWH

<

8 hours

n/a

1 mg/unit;

redose as

needed

Rolfe S, et al. J Pharm Practice.2010;23:217‐25.

Beshay JE, et al. J Neurosug. 2010;112:307‐18

*

PI

suggestion



Major

bleeding

1 – 2.2%



Long

half

‐

life:

17 – 21

hr



No

antidote



Protamine sulfate

ineffective



Avidin

‐

biotin

complex?



Dialysis*

removes

20%



Potential

role

for

rFVIIa

at

30 – 90

mcg/kg



Case

series,

N=8,

2011



Major,

symptomatic

bleeding

with

detectable

anti

‐

Xa activity



5/8

with

ASA/clopidogrel



rFVIIa 90

mcg/kg

with

PRBC



Assessed

for

clinical

bleeding

control

(4/8)

and

thrombotic

complications

(0/8)



If

abnormal,

aPTT and

INR

normalized



Anti

‐

Xa gradually

decreased:

ineffective

with

high

baseline

anti

‐

Xa

activity

29

Rolfe S, et al. J Pharm Practice.2010;23:217‐25 Luporsi P, et al. Acute Card Care. 2011;13:93‐8

*

PI

suggestion



85 yo M

atrial fibrillation

(CHADS2

score:

5)

on

dabigatran 150

mg

BID;

also

ASA

325 mg



Hemorrhagic

shock

following

upper

GI

bleed



Treatment:

22 U/kg

3 ‐

factor

PCC

and

FFP

over

4 days



Result:

stabilization

of

hemoglobin,

aPTT;

however,

patient

died

from

multi

‐

organ

failure



Low

dose

PCC

used,

3 ‐

factor

PCC

used,

concomitant

ASA

not

addressed

30 Dumkow LE, et al. Am J Health‐Syst Pharm.2012;69:1646‐50

(11)



Oral

DTI



Appropriate

use:

no

increase

ICH

or

GI

bleed

compared

with

warfarin



Indication



Age



Renal

function



K



No

antidote:

investigational

monoclonal

antibody

(clone

22)



<

2 hours:

activated

charcoal



Major

bleeding



Supportive

care

:

PRBCs,

FFP

and

platelet

concentrates

if

thrombocytopenic

or

antiplatelet

drugs

used



Consider

hemodialysis*

▪ 60%

removal

in

2 – 3

hours

▪ Watch

for

rebound



aPCC

:

some

in

‐

vitro

effects

at

75 –

80 U/kg



PCC

:

Single

healthy

human

study

did

not

reverse

aPTT

elevation



rFVIIa

:

no

effect

31

http://www.fda.gov/drugs/drugsafety/ucm326580.htm Miyares MA, et al.Am J Health‐Syst Pharm. 2012;69:1473‐84 Siegal D, et al. Eur Heart J. 2012; DOI:10.1093/eurheartj/ehs‐408

Kaatz S, et al.Am JHematol . 2012;87:S141‐45

*

PI

suggestion

CrCl (ml/min)

T1/2

(hr)

> 80

13

50 – 80

15

30 – 50

18

15 – 30

27

12 healthy

males

Rivaroxaban

20 mg

BID

Dabigatran

150 mg

BID

Dabigatran

150 mg

BID

Rivaroxaban

20 mg

BID

••

4 ‐

factor

PCC

• placebo

with

Lab

monitoring

32

••

4 ‐

factor

PCC

• placebo

with

Lab

monitoring

2.5 days

11 day

washout

2.5 days

Dabigatran:

aPTT,

ecarin clotting

time,

thrombin

time,

endogenous

thrombin

potential

Rivaroxaban:

PT,

endogenous

thrombin

potential

RESULTS:

• Dabigatran:

NO

EFFECT

• Rivaroxaban:

normalized

PT

and

endogenous

thrombin

potential

Eerenberg ES, et al. Circulation. 2011;124:1573‐9

10 healthy

males

Rivaroxaban

20 mg

Dabigatran

150 mg

Dabigatran

150 mg

Rivaroxaban

20 mg

•4 factor

PCC

•4

‐

factor

PCC

• aPCC

• rFVIIa

Lab

monitoring

33

1 dose

Blood draw after 2 hr

Lab

monitoring

of

thrombin

generation:

endogenous

thrombin

potential,

peak

thrombin

generation,

lag

time,

time

to

peak

thrombin

Dabigatran:

•

4 ‐

factor

PCC

and

rVIIa:

inconsistent

effect

on

lab

values

• aPCC:

some

effect

Marlu R, et al. Thromb Hemost. 2012;108:217‐24

•4 factor

PCC

•4

‐

factor

PCC

• aPCC

• rFVIIa

Lab

monitoring

1 dose

Rivaroxaban:

•

4 ‐

factor

PCC

and

rVIIa:

inconsistent

effect

on

lab

values

• aPCC:

consistent

reversal

effect

(12)



Oral

FXa inhibitors



No

specific

antidote:

rFXa?



Activated

charcoal*



Not

dialyzable



Major

bleeding



Supportive

care,

FFP



4 ‐

factor

PCC

(50

U/kg)

may

reverse

PT

elevation



FEIBA

:

some

in

‐

vitro

effects

at

75 – 80

U/kg



rFVIIa

:

no

effect

34

Miyares MA, et al.Am J Health‐Syst Pharm. 2012;69:1473‐84 Kaatz S, et al.Am J Hematol. 2012;87:S141‐45 Peacock WF, et al. Clin Cardiol.2012; DOI:10.1002/clc.22037

Siegal D, et al. Eur Heart J. 2012; DOI:10.1093/eurheartj/ehs‐408

*

PI

suggestion

Rivaroxaban

Apixaban

Half

life

5 – 9

hours

~12

hours

Duration

12 hours

No

data

Minor

Bleeding

• Local

hemostasis

• Weigh

risk/benefit

of

holding

anticoagulant

Moderate

Bleeding

• Hold

anticoagulant

• Compression

• Hemodynamic

monitoring

• Volume

replacement

• Surgical

intervention

Administer:

• PRBC

• FFP

• Platelets

if

concomitant

antiplatelet agents

Severe

Bleeding

As

per

moderate

plus

• ICU

• Vasopressor agents

• Prohemostatic agents

(PCC

‐

FXa inhibitors,

aPCC

‐

DTI)

Adjunctive

therapy:

• Activated

charcoal

• Hemodialysis

(dabigatran)

• Desmopressin

• Antifibrinolytic agents

35

Assess:

• hemodynamic

stability

• bleeding

source

• time

since

last

dose

• renal

function

Siegal D, et al. Eur Heart J. 2012; DOI:10.1093/eurheartj/ehs‐408

Half

life

Duration

of

effect

Pre

‐

procedure

management

Reversal

agent

Antiplatelets

Aspirin

20 min

5 – 10

days

7 – 10

days

• Platelets, DDAVP

Clopidogrel

6 hr

7 – 10

days

5 – 10

days

• Platelets, DDAVP

Prasugrel

7 hr

5 – 9

days 5 – 7

days

• Platelets, DDAVP

Ticagrelor

7 hr

3 – 5

days

>

5 days

• Aminocaproic

acid,

tranexamic acid,

rFVIIa

36

Levi MM, et al. Neth J Med. 2010;68:68‐76 Lexi‐Comp OnlineTM.; Accessed November 20, 2012.

(13)

Half

life

Duration

of

effect

Pre

‐

procedure

management

Reversal

agent

Anticoagulants

VKAs

(warfarin)

40 hr

60 – 80

hr 5

days

• Vitamin

K,

PCC

(+

rFVIIa),

FFP

Heparin

1.5 hr

3 – 4

hr

Discontinue

• Protamine

sulfate

LMWHs

~5

– 6

hr

12 – 24

hr 12

hours

• Protamine

sulfate

Fondaparinux

17 – 21

hr

24 – 30 hr

• Consider rFVIIa

Rivaroxaban

5 – 9

hr

~12

hr

> 1

day

• Consider

PCC,

rFVIIa

Apixaban

~12

hr

no information

• Consider

FFP,

rFVIIa

Dabigatran

12 – 17

hr

~12

hr

Clcr > 50:

1 ‐

2 days

Clcr <

50:

3 ‐

5 days

• Consider

PCC,

FFP,

rFVIIa

• Dialysis

37

Levi MM, et al. Neth J Med. 2010;68:68‐76

Lexi‐Comp OnlineTM. Lexi‐Drugs OnlineTM, Hudson, Ohio: Lexi‐Comp, Inc.; Accessed January 4, 2013.



Which

approach/agent

would

you

select

for

the

treatment

of

bleeding

to

factor

Xa

inhibitor

use?

(More

than

one

choice

may

be

selected)

1. Hemodialysis

2. FFP

3. FEIBA

4. rFVIIa

5.

4 ‐

factor

PCC

38



Due to their mechanisms of action, the major

risk of antiplatelet and anticoagulant agents is

bleeding



Reversal agents and procedures include vitamin

K, protamine sulfate, FFP, PCCs, rFVIIa, and

dialysis



Some older agents, including warfarin and

heparin, have antidotes



Many newer agents, including dabigatran,

rivaroxaban and apixaban, do not have clear

reversal agents or protocols at this time

39

(14)

40

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 Beshay JE, MorganH, Madden C, Yu W, Sarode R. Emergency reversal of anticoagulation and antiplatelet therapies in neurosurgical patients. J Neurosurg. 2010;112:307‐18.

 Campbell PG, Sen A, Yadla S, Jabbour P, Jallo J. Emergency reversal of antiplatelet agents in patients presenting with an intracranial hemorrhage: a clinical review. World Neurosurg. 2010;74:279‐85.

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doi: 10.1093/eurheartj/ehr424. Epub 2011 Nov 17.

 Dumkow LE, Voss Jr, Peters M, Jennings DL. Reversal of dabigatran‐induced bleeding with a prothrombin complex concentrate and fresh frozen plasma. Am J Health‐Syst Pharm. 2012;69:1646‐50.

 Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo‐controlled, crossover study in healthy subjects. Circulation. 2011;124:1573‐9.

 FDA Drug Safety Communication: Safety review of post‐market reports of serious bleeding events with the anticoagulant Pradaxa (dabigatran etexilate mesylate), U.S. Food and Drug Administration. Available at:

http://www.fda.gov/drugs/drugsafety/ucm326580.htm Accessed January 3, 2013.

 Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schunemann HJ. Executive summary: antithrombotic therapy and prevention of thrombosis, 9thed: American College of Chest Physicians evidence‐based clinical practice guidelines. Chest. 2012;141:7S‐47S.

 Kalyanasundaram A, Lincoff AM. Managing adverse effects and drug‐drug interactions of antiplatelet agents. Nat Rev Cardiol.2011;8:592‐600.

 Kaatz S, Kouides PA, Garcia, et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol. 2012;87:S141‐45.

 Leissinger CA, Blatt PM, Hoots WK, Ewenstein B. Role of prothrombin complex concentrates in reversing warfarin anticoagulation: a review of the literature. Am J Hematol.2008;83:137‐43.

41

 Levi M, Eerenberg E, Kamphuisen PW. Bleeding risk and reversal strategies for old and new anticoagulants and antiplatelet agents. J Thromb Haemost. 2011;9:1705‐12.

 Levi MM, Eerenberg E, Lowenberg E, Kamphuisen PW. Bleeding in patients using new anticoagulants or antiplatelet agents: risk factors and management. Neth J Med. 2010;68:68‐76.

 Li C, Hirsh J, Xie C, Johnston MA, Eikelboom JW. Reversal of the anti‐platelet effects of aspirin and clopidogrel. J Thromb Haemost. 2012;10:521‐8.

 Luporsi P, Chopard R, Janin S, et al. Use of recombinant factor VIIa (NovoSeven) in 8 patients with ongoing life‐threatening bleeding treated with fondaparinux. Acute Cardiac Care. 2011;13:93‐8.

 Marietta M, Pedrazzi, Luppi M. Three‐or four‐factor prothrombin complex concentrate for emergency anticoagulation reversal: what are we really looking for? Blood Transfus. 2011;9:469.

 Marlu R, Hodaj E, Paris A, Albaladejo P, Crackowski JL, Pernod G. Effect of non‐specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost. 2012;108:217‐24.

 Miyares MA, Davis K. Newer oral anticoagulants: a review of laboratory monitoring options and reversal agents in the hemorrhagic patient. Am J Health‐Syst Pharm. 2012;69:1473‐84.

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 Siegal D, Crowther MA. Acute management of bleeding in patients on novel oral anticoagulants. Eur Heart J. 2012; DOI:10.1093/eurheartj/ehs‐408.

 Vigue B. Bench‐to‐bedside review: optimizing emergency reversal of vitamin K antagonists in severe haemorrhage – from theory to practice. Critical Care.2009;13:209 (doi:10.1186/cc7001).