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Reversing Medications That

Cause Bleeding

Diane M. Birnbaumer, M.D., FACEP Professor of Medicine

University of California, Los Angeles Senior Faculty

Department of Emergency Medicine Harbor-UCLA Medical Center

The Agony and The Ecstasy of

Platelets and Clotting

The Ecstasy

We can change how people clot We can prevent strokes We can prevent DVT and PE

We can improve cardiac outcomes in ACS

The Agony and The Ecstasy of

Platelets and Clotting

The Agony

Variable efficacy Narrow therapeutic index Potential drug / food interactions Need for monitoring

Bleed risk

Antidotes and reversibility

The Agony and The Ecstasy of

Platelets and Clotting

We need better drugs… and guess what!

We have them!

But better HOW????

Newer is Better… Right?

Depends on what color glasses you are

looking through…

As a cardiologist? As a neurologist?

As an emergency physician?

Issues with the New Agents

For emergency practitioners

Can we measure their activity if we need

to?

(2)

Will NOT cover

Daltaparin (Fragmin)

Fondaparinux (Arixtra)

Aspirin

Tried and true

Poisons platelet for life of the platelet

5-10 days

Can reverse with (and/or)

Platelet concentrate DDAVP (0.3-0.4 µg/kg) Reversal in 15-30 minutes

Antiplatelet Agents

Clopidigrel and Prasugrel

Thienopyridine derivatives

Block ADP receptor on platelet

Can be effectively combined with aspirin

in some cases

Increases bleeding risk signficantly

Therefore, in some cases the combination

overall is not worth the risk

Antiplatelet Agents

Clopidigrel and Prasugrel

Clopidigrel (Plavix

®

) vs. Prasugrel

(Effient®) Prasugrel has stronger antiplatelet effect In general

More effective than clopidigrel

More major bleeding events than clopidigrel

Antiplatelet Agents

Clopidigrel and Prasugrel

Can reverse with (and/or)

Platelet concentrate (15-30 minutes) Maybe add DDAVP (0.3-0.4 µg/kg) Reversal in 15-30 minutes

Anticoagulants

Heparin

(3)

EXTRINSIC PATHWAY Rivaroxaban Apixaban Dabigatran Prothrombin a INTRINSIC PATHWAY X Warfarin X Heparin Anti-thrombin III

Anticoagulants

Heparin

Binds to antithrombin

Potentiates inhibition of thrombin and

factor Xa (by 1000-fold)

Half-life of 60-90 minutes

Anticoagulants

Heparin

If stopped, hemostasis restored in 3-4 hr

Reversed with protamine sulfate

Dosing is 1 mg protamine per 100 units heparin given in last 2-3 hours

Usually 25-30 mg effective

Maximum dose 50 mg

Half-life 10 minutes

Reversal is immediate May cause allergic reaction

Anticoagulants

Low Molecular Weight Heparin

Low dose vs. high dose have differing

half-lives

Both, however, last longer than regular

unfractionated IV heparin

Anticoagulants

Low Molecular Weight Heparin

If stopped, hemostasis restored in 12-24

hours

Partially reversed by protamine sulfate

1 mg protamine per 100 units LMWH given in

the last 8 hours

Anticoagulants

(4)

PATHWAY Rivaroxaban Apixaban Dabigatran Prothrombin a PATHWAY X Warfarin X Heparin Anti-thrombin III

Vit K Antagonists: Warfarin

Long experience with its use

Blocks production of vitamin K dependent

coagulation factors (II, VII, IX, X)

Induces a factor deficiency state Means we may be able to replace these

factors to reverse it

Risk of major bleeding 0.5% per year

Risk of ICH is 0.2% per year

Anticoagulants

Vit K Antagonists: Warfarin

Risk of bleeding directly related to height

of INR

Over 3.0, incidence doubles when compared to INR of 2.0-3.0

Risk of bleeding increases with

co-administration of antiplatelet agents

Elderly have two-fold increased risk of ICH

Anticoagulants

Vit K Antagonists: Warfarin

Hemostasis after cessation: 60-80 hours

Reversal

Vitamin K (dose depends on INR and body wgt)

IV: Reversal in 12-16 hours

PO: Reversal in 24 hours

FFP – large amounts needed may be prohibitory

PCCs – reversal is immediate

What is a PCC?

Prothrombin Complex Concentrate

Briplex, Octaplex – 4 factors Profilnine, Bebulin – 3 factors Contain multiple factors, including

prothrombin

Have more prothrombin than FFP

Anticoagulants

Factor Xa Inhibitors

(5)

EXTRINSIC PATHWAY Rivaroxaban Apixaban Dabigatran Prothrombin a INTRINSIC PATHWAY X Warfarin X Heparin Anti-thrombin III

Anticoagulants

Factor Xa Inhibitors

The “xabans”

Oral Factor Xa inhibitors

Rivaroxaban – Xarelto®(approved 7/11/11)

Apixaban – Eliquis®(approved 12/30/12)

Cannot measure anticoagulant effect

Anticoagulants

Factor Xa Inhibitors

The “xabans”

Rivaroxaban – Xarelto®(approved 7/11/11)

Surgical DVT prophylaxis

Stroke prevention in nonvalvular AF

DVT/PE treatment

ACS coming down the pike?

Apixaban – Eliquis®(approved 12/30/12)

Stroke prevention in nonvalvular AF

Edoxaban - Lixiana®

Anticoagulants

Factor Xa Inhibitors

The “xabans”

Rivaroxaban – Xarelto® Half-life 5-13 hours Apixaban – Eliquis® Half-life 9-14 hours Edoxaban - Lixiana® Half-life 9-10 hours

Anticoagulants

Factor Xa Inhibitors

The “xabans”

General efficacy / safety data (so far) Compared with LMWH (DVT prophylaxis)

Lower bleeding risk

Similar efficacy

Anticoagulants

Factor Xa Inhibitors

Reversal in bleeding

Cessation of medication will reverse anticoagulant effect

How long it takes depends on half-life

(6)

Anticoagulants

Direct Thrombin Inhibitors

Rivaroxaban Apixaban Dabigatran Prothrombin a X Warfarin X Heparin Anti-thrombin III

Anticoagulants

Direct Thrombin (IIa) Inhibitors

Hirudin was prototype (leech spit)

Dabigatran – Pradaxa

®

(appr. Oct 2010)

Competitive, direct thrombin inhibitor

Approved for

Stroke prevention in A Fib (2010) DVT prophylaxis after surgery (ACS coming soon?)

Half-life 12-17 hours

Anticoagulants

Direct Thrombin (IIa) Inhibitors

Dabigatran – Pradaxa

®

Benefits over warfarin

Anticoagulation immediate No transient hypercoagulable state Does not require blood testing to monitor Minimal interactions with food/drugs

Not recommended in renal failure or in

patients with impaired hepatic function

Anticoagulants

Direct Thrombin (IIa) Inhibitors

Dabigatran – Pradaxa

®

For stroke prevention

As effective as warfarin

Risk of major bleeding same or less than warfarin (around 3%)

Older patients had higher risk of bleeding

(Note: These rates were in trials; we’ll see what happens in the “real world”)

Anticoagulants

Direct Thrombin (IIa) Inhibitors

Issues for emergencies

Cannot follow blood testing for anticoagulation effect (non-linear effect) Coagulation studies are elevated, but do not

(7)

Anticoagulants

Direct Thrombin (IIa) Inhibitors

Issues for emergencies

Treatment of bleeding

Supportive care

pRBCs, IV fluids, stopping bleeding by direct means

Activating thrombin

Removing dabigatran

Not highly protein bound

4 hours of dialysis removes 68% of dabigatran

Anticoagulants

Direct Thrombin (IIa)Inhibitors

Issues for emergencies

Treatment of bleeding

Activating thrombin

May be impossible

FFP has minimal prothrombin – not likely useful PCCs may be useful but poorly studied to date

rVIIa not adequately studied and unlikely useful Not useful: Cryoprecipitate, protamine, DDAVP,

tranexamic acid, aminocaproic acid

Time to hemostasis after stopping taking medication

Antidote Time to reversal

Heparin 3-4 hr Protamine sulfate Immediate

LMW Heparin 12-24 hr Protamine (partial) Immediate

Pentasaccharides Fonda: 24-30 hr

Idrapar: 5-15k Recomb VIIa Immediate thrombin

generation

Vit K Antag Warfarin: 60-80 hr Vit K IV

Vit K oral PCCs

12-16 hr 24 hr Immediate Oral thrombin and

factor Xa inhibitors Usually within 12 hr Recomb fact XaThrombin???? Unknown

Aspirin 5-10 days DDAVP, platelets 15-30 minutes

Clopidogrel

Prasugrel 1-2 days Platelets, maybe DDAVP 15-30 minutes

Thank You For

Your Attention!

Any

Questions?

References

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