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Jun 8, 2012

Reversing Anticoagulation - A how to guide (adapted from podcast interview with Tom Deloughery)

WARFARIN

If your patient IS NOT Bleeding: Goal is INR in 2-3 range

INR                             Action

3-4.5                           Hold dose until INR decreased

4.5-10                         1.25 mg Vitamin K PO and hold dose until INR decreased

>10                              2.5 - 5 mg Vitamin K PO hold dose until INR decreased OR

                   If high bleeding risk, Give 1mg IV Vitamin K and consider FFP

If your patient IS bleeding but not about to die: Goal is INR under 2

Should see INR back in therapeutic range in 24 hours

INR                             Action

2-4.5                           2.5 mg Vitamin K ± FFP (15 ml/kg)

4.5-10                         5 mg Vitamin K ± FFP (15 ml/kg)

>10                              5-10 mg Vitamin K ±FFP (15 ml/kg)

Whether to give FFP or PCC in this scenario is based on clinician judgment. There is no hard data to show superiority or inferiority of either product. PCC will reverse faster and with less volume.

FFP=fresh frozen plasma        PCC=Prothrombin complex concentrate

If your patient has LIFE THREATENING OR BRAIN BLEEDING
There are several choices in this scenario

1. Prothrombin complex concentrate 4,000 units IV + rVIIa 1mg IV

2. Prothrombin complex concentrate 4,000 units IV + 1 unit of FFP

3. 4 units of FFP if PCC is not available

Q: What's in Prothrombin Complex Concentrate?

A:  There are 2 basic types of PCC: Four factor,  which has 2,7,9,10 and  3 factor, which lacks factor 7. As of the date of this publication, the United States only has three factor PCC.  Three factor PCC will probably correct hemostasis but does not improve INR because it has no factor 7. So to replace all of the vitamin K factors, we need to add factor 7. This can be done either by giving a unit of recombinant factor VIIa (rVIIa) or a unit of FFP. Factor VII is faster to give but expensive and may carry thrombotic risk. Does adding rVIIa or a unit of FFP make a difference in clinical outcome? Unknown.
Q: Has there been a definitive trial to say PCC is better than FFP?

A: There have been no outcome trials. We know that PCC will reverse anticoagulation faster, and have taken this to mean that it will make bleeding stop sooner and improve patient outcome. But whether faster reversal actually translates to an improved outcome is unknown.

Q: Who should get PCC and who should get FFP? 

A: Any answer is going to be arbitrary and it’s mostly a matter of, “Do you have a few hours or do you need anticoagulation now?” It’s based on clinical judgement. PCC will make reversal happen much more quickly but may have a  higher thromboembolic (TE) risk. There isn’t much data on the safety profile of PCC, but there is a small yet quantifiable  TE risk. A recent meta-analysis found 1.8% risk of TE for 4 factor PCC and 0.7% for 3 factor PCC.

Q: Say you have someone who is having a life threatening bleed. What’s going to be the difference between giving 1mg and 10mg of vitamin K?

The response to vitamin K is as variable as response to warfarin - meaning it’s not an exact science. Why 10mg rather than 1 mg? One mg of vitamin K will get patients back to therapeutic INR, but that’s not what we want in a life threatening bleed. Full reversal probably happens around 2-2.5 mg of vitamin K. Humans are variable in their response to vitamin K and the 10 mg dose is somewhat arbitrary.  Some places give 5mg, others give 10mg. If you are in a situation where you do not want want to skimp on reversal,  10mg will fully reverse warfarin anticoagulation. But could you be faulted for giving 5mg? No. It is more a matter of making absolutely sure there is going to be full reversal, no questions asked. My recommendation, in life threatening bleeding, which more often than not is an intracranial bleed, give 10mg IV over 1 hour.

 

ANTIPLATELET AGENTS

Aspirin

Minor – desmopressin 0.3 mcg/kg x 1   Major - platelet transfusion (1 unit or 6pack)

Clopidogrel (Plavix®)

Minor – desmopressin 0.3 mcg/kg x 1  Major - platelet transfusion – consider two units if life or brain threatening bleeding

Prasugrel (Effient®)

Minor – desmopressin 0.3 mcg/kg x 1   Major - platelet transfusion – consider two units if life or brain threatening bleeding

Ticagrelor (Brilinta®)

Minor – desmopressin 0.3 mcg/kg x 1   Major - platelet transfusion – consider two units if life or brain threatening bleeding

Sustained Release Aspirin/Dipyridamole (Aggrenox®)

Minor – desmopressin 0.3 mcg/kg x 1   Major - platelet transfusion (1 unit or 6pack)

Abciximab (Reopro®)

Major - platelet transfusion

Eptifibatide (Integrilin®)

Minor – desmopressin 0.3 mcg/kg x 1   Major: platelet transfusions plus infusion of 10 units of cryoprecipitate

Tirofiban (Aggrastat®)

Minor – desmopressin 0.3 mcg/kg x 1   Major: platelet transfusions plus infusion of 10 units of cryoprecipitate

 

HEPARIN AND HEPARIN LIKE AGENTS

Reversal Agent = Protamine. Protamine infusion rate should not exceed 5 mg/min.  Maximum dose is 50 mg per dose.

Unfractionated (standard) Heparin

Time since last heparin dose    Dose of Protamine
< 30 minutes     1 unit/100 units of heparin
30-60 minutes     0.5 - 0.75 units/100 units of heparin
60-120 minutes     0.375 - 0.5 units/100 units of heparin
> 120 minutes     0.25 - 0.375 units/100 units of heparin

Low Molecular Weight Heparin

Reversal of Bleeding: Protamine will give partial reversal of LMWH (probably about 70%, which is less than protamine reverses unfractionated  heparin, but still better than nothing) . If protamine is given within 4 hours of LMWH dose, give 1 mg of protamine for each 1 mg of enoxaparin or 100 units of daltaparin and tinzaparin.  Repeat one-half dose of protamine in 4 hours.  If 4-8 hours after dose,  give 0.5 mg for each 1 mg of enoxaparin or 100 units of daltaparin and tinzaparin

Fondaparinux (Arixtra®)

Major Bleeding Reversal - Protamine ineffective - rVIIa (90 mcg/kg) may be of use

Dabigatran (Pradaxa®)

Reverse if patient shows signs of bleeding and had an elevated aPTT > 40 seconds

Profilnine (Factor IX complex) 4000 units (50 units/kg for patients under 80 kg)  plus 1 mg of rfVIIa

Rivaroxaban (Xarelto®)

Reverse if patient shows signs of bleeding and has an INR > 1.5

Profilnine (Factor IX complex) 4000 units (50 units/kg for patients under 80 kg) plus 1 mg of rfVIIa

 

THROMBOLYTICS

The goal is to rebuild the entire clotting system

1 unit of pheresis platelets

2 units of FFP

10 units of cryoprecipitate

 

Definition of Bleeding

Minor bleeding – Any clinically overt sign of hemorrhage (including imaging) that is associated with a <5 g/dl decrease in the hemoglobin concentration or < 15% decrease in the hematocrit felt by the clinician to be related to anticoagulation

Major bleeding – Intracranial hemorrhage or a ≥5 g/dl decrease in the hemoglobin concentration or a ≥15% absolute decrease in the hematocrit resulting in hemodynamic compromise or compression of a vital structure and felt by the clinician to be related to anticoagulation

References and Links

Anticoagulation reversal PDF for your pocket brain

Warfarin overdose management by Chris Nickson of Lifeinthefastlane.com

Tom Deloughery's guide to anticoagulation reversal

Journal of Family Practice warfarin reversal review

Warfarin reversal: Australasian Society of Thrombosis and Haemostasis

Safety of prothrombin complex concentrates- meta analysis