Bleeding Management in the NOAC era

Bleeding Management in the NOAC era

Eddy LangSenior Researcher

Alberta Health ServicesAssociate Professor University of Calgary

http://www.ucalgary.ca/


Disclosures

• Member of Thrombosis Interest Group of Canada

• Sponsored presentations Boeringher Ingleheim / Bayer

• Research support BI – studentship grant• Failed heme exam in med school


Objectives (Q’s you will be able to answer)

1. What should my approach be to NOAC related bleeding?

2. How can I tell if the drug’s on board?

3. What do I do when the patient is spiralling?


Key PointsNOACs demand different

approaches

PTT / Thrombin time will point you the presence of dabigitran

PT/INR will tell you if rivaroxaban is at play


Key Points

Half-lives are a consideration

There are no full reversal agents

Dialysis is an option for one of the agents


Pharmacological advantages of the new OAC compared with warfarin include:

1.More rapid onset & offset of action

2.Easily reversible anticoagulant effect

3.No need for routine laboratory monitoring

4.All of the above

5.1 and 3


Case Scenario• 82 year old female• Rivaroxaban 20 mg OD• Started 3 mos ago for AF, CHADs 2• Syncope, melena this am• No liver disease• BP 90/60; HR 115• OB +ve; BUN 16; Hgb 95 (145)• GI: Stabilize first



New OACs: Advantages vs. VKAs

Feature Warfarin New OACs

Onset Slow Rapid

Dosing Variable Fixed

Food effect Yes No

Interactions Many Few

Monitoring Yes No

Offset Long Shorter


New OACs: Disadvantages vs. VKAsFeatures Warfarin New Agents

Frequency once-daily twice-daily*

Monitoring INR uncertain

Clearance non-renal renal 25-80%

Antidote vitamin K none

Familiarity extensive minimal

*dabigatran and apixaban


Pharmacology of New OACs Feature IIa Inhibitors Xa Inhibitors

Target factor IIa factor Xa

Prodrug Yes No

Bioavailability 6% 50-80%

Half-life 12-18 hrs 7-13 hrs

Renal 80% 25-35%

Monitoring No No

Interactions P-gp 3A4/P-gp


Three new drugs have been studied in AF (dabigatran, rivaroxaban,

apixaban)…1.All 3 are as efficacious as warfarin to

reduce stroke/SE

2.All 3 are associated with less overall bleeding

3.All 3 are associated with less intracranial bleeding

4.All of above

5.1 and 3 are correct


Feature Dabigatran (150 bid)

Rivaroxaban (20 mg od)

Apixaban (5mg bid)

Stroke -36% -12% -21%

Ischemic stroke -24% -1% -8%

ICH -60% -33% -58%

Death -12% -8% -11%

Bleeding -7% +3% -31%

GI Bleeding +36% +40% -11%

MI +27% -9% -12%

Other dyspepsia - -


PharmacokineticsProperty Conventional Anticoagulants New Anticoagulants

warfarin UFH LMWH fonda-parinux

dabigatran riva-roxaban

apixaban

Mode of action

vitamin K antagonist

indirect fIIa + Xa

inhibitor

indirect fXa (minor IIa) inhibitor

indirect fXa inhibitor

direct factor IIa inhibitor

direct factor Xa inhibitor

direct factor Xa inhibitor

Bioavailability (Frel)

100% 100% 100% 100% 6-7% 80% 80%

Peak action (tmax)

4-5 days immediate (IV); 0.5 hrs (SC)

2-4 hrs 2-4 hrs 1-3 hrs 1-3 hrs 1-3 hrs

Elimination half-life (t 1/2)

36-42 hrs 1-1.5 hrs 3-4 hrs 17-21 hrs 14-17 hrs 9-15 hrs 9-14 hrs

Route of clearance

multiple reticulo-endotheial

>80% renal 100% renal 80% renal 35% renal 25% renal

Involvement of CYP

yes no no no minor minor minor

Douketis JD. Curr Pharm Des 2010;16:3436


Dabigatran and the aPTT- non-linear dose-response - median peak aPTT is approximately 2-fold of control- 12 hrs after the last dose (trough level), median aPTT 1.5-fold of control


Measuring Anticoagulant Effect of Dabigatran: INR?- dose-dependent and short-lived (1-4 hrs after dose) prolongation of INR


Thrombin Time

- linear dose-response over therapeutic concentrations of dabigatran

- directly measures plasma thrombin activity


Laboratory Monitoring of Dabigatran• PT (INR)

– Dabigatran has MINIMAL or NO EFFECT on effect on PT

– Apixiban and Rivaroxiban do effect PT– not reliable to measure anticoagulant effect

• aPTT– dabigatran HAS EFFECT on aPTT– Apix and Dabi no effect on aPTT– trough level (10-16 hrs post-ingestion) >80 sec = ABNORMAL– trough level >1.5-times control aPTT = EXPECTED

– prolongation reflects thrombin (factor II) inhibition NOT factor deficiency


Laboratory Monitoring of Dabigatran• Thrombin clotting time (TCT)

– normal TCT (<30 sec) likely reflects absence of significant anticoagulant effect

– too sensitive for routine monitoring (to distinguish different levels of anticoagulation) but determines if any dabigatran present

• Dilute thrombin clotting time (Hemoclot assay)– 1/16th dilution of TCT– peak (2 hr post-ingestion levels): 125-175 ng/mL– trough (10-16 hrs post-ingestion levels): 65-90

ng/mL


Laboratory Monitoring of Dabigatran: Use in Practice

• Step 1: aPTT– qualitative test (for screening)– if elevated aPTT (and no other cause), likely some dabigatran

effect– if normal aPTT, no clinically significant dabigatran effect– for extra reassurance that no residual anticoagulant effect…

• Step 2: TCT (or Hemoclot test)– quantitative test – if normal TCT (<30 sec) or if normal Hemoclot test, no

detectable dabigatran anticoagulant effect


Laboratory Monitoring of Rivaroxaban (and Apixaban)

• Step 1: PT– qualitative test (for screening)– if elevated PT (and no other cause), likely some

rivaroxaban effect BUT, highly assay-dependent– if normal PT, no clinically significant rivaroxaban

effect– for extra reassurance that no residual anticoagulant

effect…• Step 2: anti-factor Xa assay

– ‘LMWH-calibrated’ anti-factor Xa assay– can develop rivaroxaban (apixaban) – calibrated

assays


Laboratory Measurement of Anticoagulant Effect

aPTT or TTdilute TT (Hemoclot assay)

PTanti-factor Xa assay

PTanti-factor Xa assay

Dabigatran (Pradaxa®)

Rivaroxaban (Xarelto®)

Apixaban (Eliquis®)

Clinical Indications and Doses- atrial fibrillation (indefinite duration) - acute VTE treatment (3 to 6 months) - VTE prevention after hip or knee replacement surgery (14 to 35 days)

150 mg or 110 twice-daily 150 mg twice-daily† 110 mg or 220 mg once-daily

20 mg once-daily 20 mg once-daily (15 mg twice-daily for initial 7-10 d) 10 mg once-daily

5 mg twice-daily† 5 mg twice-daily† 2.5 mg twice-daily


General Management1. Stop offending drug + general supportive

measures

2. Baseline tests: CBC, aPTT, INR, TCT, creat

3. Investigate and treat bleeding: ulcer electrocautery, polyp clipping, embolization, etc.

4. Antidote- vitamin K for VKAs- others for new anticoagulants in development


General Management

5. Transfuse pRBCs as required- dilutional coagulopathy after 8 units pRBCs- consider cryoprecipitate (especially if low fibrinogen)

6. Use non-specific “blood thickeners” ??? - DDAVP

- Amicar/Tranexamic acid- platelet transfusion

7. Consider dialysis to remove drug (dabigatran)

8. By the time all this is done…most drugs will have been cleared

Crowther M, et al. Blood 2008


Apr 2012

Prothrombin complex concentrates

Contain all vitamin K-dependent coagulation factors

Non-activated:– ‘4-factor-concentrates’ contain Factors II, VII, IX, and X

(e.g. Beriplex, Octaplex, Proplex T, Cofact)– ‘3-factor-concentrates’ contain lower amounts of Factor

VII(e.g. Prothrombinex-HT, Profilnine and BEBULIN)

Activated: – FEIBA VH contains Factors II, IX, X and protein C mainly

in non-activated forms and Factor VII mainly in the activated form

Van Ryn J et al. Thromb Hemost 2010;103:1116–27• Boehringer-Ingelheim (Canada) Ltd cannot recommend the use of any product outside the Canadian approved Product

Monograph• The content of this slide may contain information not reviewed by Health Canada

Apr 201226

Studies evaluating reversal with new oral anticoagulants

ICH = intracranial haemorrhage; OAC = oral anticoagulant; PCC = prothrombin complex concentrate1. van Ryn J et al. Blood (ASH Annual Meeting Abstracts) 2009;114;Abs 1065; 2. Warkentin TE et al. Blood 2012;119:2172–4; 3. Zhou W et al. Stroke 2011;42:3594–9; 4. van Ryn J et al. Blood (ASH Annual Meeting Abstracts) 2011;118:Abs 2316; 5. van Ryn J et al. Pathophysiol Haemost Thromb 2010;37:A94–P486; 6. Eerenberg ES et al. Circulation 2011;124:1573–9; 7. Perzborn A et al. J Thromb Haemost 2009;7(suppl 2):Abs PP-MO-183; 8. Gruber A et al. Haematologica 2009;94(suppl 2):181 Abs 0449; 9. Godier A et al. Anesthesiology 2012;116:94–102. 10. Wang X et al. Clin Pharmacol Ther 2012;91(suppl 1):Abs PI-90; 11. Martin A-C et al. ACC 2012; 24-27 March, Chicago, IL, USA: Abs 904-8; 12. Fukuda T et al. Thromb Haemost 2012;107:253–9

Dabigatran Rivaroxaban Apixaban Edoxaban

Oral activated charcoal

Adsorbs and neutralizes, in vitro data1

Adsorbs and neutralizes

Adsorbs and neutralizes,

in vivo data10

No data

HaemodialysisHuman volunteers,

case report2 Not possible Not possible No data

Fresh frozen plasma Mouse ICH3 model No data No data No data

Activated FVIIa Mouse3, rat4 modelBaboon8, rabbit trauma9 models

Rabbit trauma11 model

Rat12 model

3-factor PCC No data No data No data No data

4-factor PCCMouse3, rat4, rabbit

trauma5 model, human volunteers6

Rat7, baboon8, rabbit trauma9,

human volunteers6

Rabbit trauma11 model

Rat12 model

• Boehringer-Ingelheim (Canada) Ltd cannot recommend the use of any product outside the Canadian approved Product Monograph

• The content of this slide may contain information not reviewed by Health Canada

Administer antidote…?• There are no “antidotes” for dabigatran or

rivaroxaban (apixaban)

• Hemodialysis (…and patience!) are the only methods to remove dabigatran

• Hemodialysis does NOT work for rivaroxaban (apixaban) since these are highly protein-bound (…can’t dialyse out)

• No blood product (FFP, PCC) has been shown to reverse the anticoagulant effect of the new agents in bleeding patients

27


Agent Dabigatran Rivaroxaban or Apixabanb

4-Factor Prothrombinase

Complex Concentrate (PCC;

Beriplex, Octaplex)

Possibly beneficial Probably beneficial

Activated 4-Factor

Prothrombinase Complex

Concentrate (FEIBA)

Probably beneficial Probably beneficial

Recombinant activated Factor VII

(Novoseven, Niastase)

Possibly beneficial Possibly beneficial

Fresh frozen plasma Probably ineffective Probably ineffective

Cryoprecipitate Probably ineffective Probably ineffective

3-Factor Prothrombinase

Complex Concentrate

No available evidence No available evidence

Antifibrinolytic agents

(Aminocaproic acid – Amicar;

Tranexamic acid – Cyklokapron)

No available evidence.

Potentially harmful

No available evidence.

Potentially harmful


Administer coagulation factor replacement…?

• Replacement of clotting factors– does NOT reverse effect of dabigatran or rivaroxaban– existing drug will simply inhibit ADDED clotting factors…

BUT– adding factor II (or X) may ‘overwhelm’ this inhibitory effect

• No agent has been shown to reverse the anticoagulant effect of the new agents in bleeding patients– ? 4-factor PCC (contains: II, VII, IX, X) – Octaplex, Beriplex– ? activated 4-factor PCC – Feiba– ? recombinant (activated) factor VII – Novoseven


Apr 2012

Reversal of dabigatran activity by coagulation factor concentrates: van Ryn et al.

n=4van Ryn J et al. Blood (ASH Annual Meeting Abstracts) 2011;118:Abs 2316

31

Prolonged bleeding time induced by dabigatran was rapidly reversed within 5 min of concentrate administration– Effect maintained during study period (120 min)

Control

Bleeding time prolonged with dabigatran (vs control)

Effect of dabigatran reversed by concentrate administration

500

0

Mean (

standard

err

or)

ble

edin

g t

ime, se

conds

400

5 15 30 120

300

200

Dabigatran etexilate 30 mg/kg+ Beriplex 35 U/kg+ Octaplex 40 U/kg+ FEIBA 100 U/kg+ NovoSeven 500 µg/kg

Time post concentrate addition (min)



Apr 2012

Reversal of rivaroxaban and dabigatran activity by PCC in healthy subjects: Eerenberg et al.

Effects of a single dose of concentrate were assessed in a randomized, double-blind, placebo-controlled, crossover trial– Healthy male volunteers (n=12)– Single dose of PCC (Cofact* 50 U/kg)

Assessments were coagulation parameters only*Non-activated PCC derived from human plasma containing a high concentration of the procoagulation Factors II, VII, IX, and X, as well as the natural anticoagulants protein C and S and antithrombinBID = twice daily; PCC = prothrombin complex concentrateEerenberg ES et al. Circulation 2011;124:1573–9

32

Rivaroxaban 20 mg BID

(n=6)

Dabigatran150 mg BID

(n=6)

2.5 days

PCC or

placebo

Rivaroxaban 20 mg BID

(n=6)

Dabigatran150 mg BID

(n=6)

2.5 daysWashout period(11 days)

PCC or

placebo



Apr 2012


Rivaroxaban significantly prolonged PT and significantly decreased ETPEffects were normalized by subsequent PCC infusion

Data are mean ± standard deviationETP = endogenous thrombin potential; PCC = prothrombin complex concentrate; PT = prothrombin timeEerenberg ES et al. Circulation 2011;124:1573–9

33

1 h 4 h

12

14

16

18

0

10

PT (

seco

nds)

2 h 24 h6 h

Time

1 h 4 h

100

150

200

0

50ETP (

%)

2 h 24 h6 h

TimeBaselin

eT=

0

15 m

in

30 m

in

Effect of rivaroxaban

Baselin

eT=

0

15 m

in

30 m

in

PlaceboPCC

Effect of subsequent PCC or placebo infusion

Effect of rivaroxaban


PlaceboPCC



Apr 2012


Dabigatran significantly prolonged aPTT, TT, and ECTEffects not reversed by subsequent infusion of PCC

Data are mean ± standard deviationaPTT = activated partial thromboplastin time; ECT = ecarin clotting time; PCC = prothrombin complex concentrate; TT = thrombin timeEerenberg ES et al. Circulation 2011;124:1573–9

34

Baselin

e

TimeT=

0

15 m

in

30 m

in 1 h 4 h

60

80

100

0

40

aPTT (

seco

nd

s)

2 h 24 h6 h

20

Baselin

e

TimeT=

0

15 m

in

30 m

in 1 h 4 h

80

100

>120

0

TT (

seco

nd

s)

2 h 24 h6 h

Baselin

e

TimeT=

0

15 m

in

30 m

in 1 h 4 h

50

100

150

0

EC

T (

seco

nd

s)

2 h 24 h6 h

60

40

20

Effect of dabigatran








Apr 201235

Reversing the effects of dabigatran by coagulation factor concentrates: summary

There is some experimental evidence to support the role of coagulation factor concentrates in reversing the anticoagulant effect of dabigatranHowever, limited clinical evidence is available– Guidance regarding reversal of dabigatran activity (e.g. in cases of overdose or

major bleeding) highlights that the usefulness of CFCs in clinical settings has not yet been demonstrated

*Recommendation based only on limited non-clinical data; there is no experience in volunteers or patientsCFCs = coagulation factor concentrates; PCC = prothrombin complex concentrate;rFVIIa = recombinant activated Factor VIIa

Patient with bleeding on dabigatran therapy

Mild bleeding Moderate to severe bleeding Life-threatening bleeding

Delay next dose or discontinue treatment

as appropriate

• Symptomatic treatment• Mechanical compression• Surgical intervention• Fluid replacement and haemodynamic

support• Blood product transfusion• Oral charcoal application*

(if dabigatran etexilate ingested <2 hrs before)

• Haemodialysis

• Consideration of rFVlla or PCC*

• Charcoal filtration*

van Ryn J et al. Thromb Haemost 2010;103:1116-1127.• Boehringer-Ingelheim (Canada) Ltd cannot recommend the use of any product outside the Canadian approved Product

Monograph• The content of this slide may contain information not reviewed by Health Canada

Apr 2012

Reversal of rivaroxaban activity by coagulation factor concentrates: Perzborn et al.

Rivaroxaban significantly increased bleeding time vs baselinePCC reversed rivaroxaban-induced bleeding (dose-dependent)

*P<0.01 vs baselinePCC = prothrombin complex concentrate; PT = prothrombin timePerzborn E et al. ISTH XXII Congress, July 11–16 2009, Boston, MA, USA: PP-MO-183

36

U/kg

Rivaroxaban2 mg/kg+ vehicle

Ble

edin

g t

ime (

seco

nds) 1400

1000

600

200

0Rivaroxaban

2 mg/kg+ PCC 25 U/kg

Rivaroxaban2 mg/kg

+ PCC 50 U/kg

400

800

1200

BaselineAfter treatment

**

Take-home Messages

• New OACs use increasing but warfarin will remain

– warfarin in users with good results and INR monitoring

– patients with impaired renal function


…more Take-home Messages • Laboratory monitoring

– rivaroxaban/apixaban: PT (screen), anti-Xa (quantitative)

– dabigatran: aPTT (screen), TT (more sensitive)

• Bleeding in patients receiving new OACs– supportive care (fluids, pRBCs) is most relevant– FFP and PCC do NOT eliminate anticoagulant effect– no full antidotes yet BUT short drug half-lives– HD for dabigatran but NOT rivaroxaban/apixaban– Fab for Dabigitran


Case Scenario

• 82 year old female• Rivaroxaban 20 mg QD• Started 3 mos ago for AF, CHADs 2• Syncope, melena this am• No liver disease• BP 90/60; HR 115• OB +ve; BUN 16; Hgb 95 (145)• GI: Stabilize first


Q and A…


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Bleeding Management in the NOAC era