Critical Bleeding Reversal Protocol
Coagulopathy, either drug related or multifactorial, is a major contributing factor to bleeding related mortality in a variety of clinical settings. Standard therapy for control of coagulopathy related bleeding has traditionally been limited to the utilization of available blood products, reversal of drug-induced anticoagulation, and recombinant activated factor VII (rFVIIa). With the implementation of the difficult to reverse new oral anticoagulants, dabigatran (Pradaxa®),
apixaban (Eliquis®) and rivaroxaban (Xarelto®), the need for a standardized reversal protocol
within UKHealthCare is warranted.
UKHealthcare has developed the following guideline to standardize the utilization, dosing, monitoring, and dispensing of agents used in traumatic, life-threatening, or drug induced coagulopathies.
Indication
Obtain history of possible oral anticoagulant use from patient, family, EMS, or referring facility when possible. If history is unknown consider the possibility of their use in patient based on their known past medical history (i.e. history of atrial fibrillation or deep venous thrombosis). This protocol is intended to be used for bleeding in the case of:
• Anticoagulant use (see below) • Antiplatelet use (see below) • Trauma
• Intracranial hemorrhage • Emergent surgery • Stroke
Laboratory Evaluation
The following labs should be drawn STAT and repeated as clinically indicated. While these labs may help to identify the presence or absence of oral anticoagulants the results of these studies should not delay the anticoagulation reversal treatment if a history of oral anticoagulant use is present or known.
CBC PT/INR BMP
Critical Bleeding Management Protocol
Bleeding Reversal Treatment Protocol
Anticoagulant Reversal Agents
Indication Drug Dose Max Dose
Known Drug Exposure Direct Thrombin Inhibitors
Dabigatran (Pradaxa®)
FEIBA (aPCC) 12.5-25 units/kg 100 units/kg
Bivalirudin Argatroban Factor Xa Inhibitors
Rivaroxaban (Xarelto®)
Kcentra (4PCC) 25 units/kg 2500 units/kg
Apixaban (Eliquis®) Fondaparinux Vitamin K Antagonist
Warfarin (Coumadin®) Kcentra (4PCC)€
INR Dose INR Dose
2-4 25 units/kg 2-4 2500 units/kg 4-6 35 units/kg 4-6 3500 units/kg > 6 50 units/kg > 6 5000 units/kg
Anticoagulant Exposure Suspected
Specific agent unknown FEIBA (aPCC) 12.5-25 units/kg 100 units/kg
No Anticoagulant Exposure Suspected
No Cause for Drug Contribution rFVIIa 30 mcg/kg 90 mcg/kg € assuming FFP/vitamin K have already been administered
Reversal Agent Review
If a drug-induced coagulopathy is suspected and reversal is indicated activated prothrombin complex concentrate (aPCC) or rFVIIa can be used. For the newer agents, Dabigatran, apixaban, and rivaroxaban, more complete reversal has been seen with the use of aPCC’s when compared to PCC’s. The UKHealthcare aPCC on formulary is FEIBA (factor eight inhibitor bypassing
activity). While aPCC’s have also been shown to reverse Warfarin, at this time the literature does not support its use over the current treatments of choice (FFP, and rFVIIa). The risk of thrombotic events with FEIBA when compared to rFVIIa has not been shown to be superior in the reversal of INR. If any of these therapies are warranted please contact the pharmD on call for indication, dosing, and administration assistance (pager # 7400).
Comparison of aPCC and rFVIIa Products
Activated PCC 4PCC rFVIIa
Brand Name Feiba® Kcentra® NovoSeven®
Factors Provided II, IX, X, VIIa II, IX, X, VII VIIa
Activated Yes No Yes
Drug Induced Coagulopathy Reversal
Warfarin Yes Yes Yes
Dabigatran Yes No No€
Rivaroxaban Yes No No€
Apixaban NA£ No NA£
€ literature is divided between in vitro and clinical studies
£ newest agent with smallest amount of data, initial reports put its reversal similar to Rivaroxaban the other Factor Xa inhibitor
* may repeat dosing up to 3 times if clinically indicated
Agent Review and Coagulation Evaluation
Drug Mechanism of Action Half Life PT/INR aPTT
Dabigatran (Pradaxa®)
Direct Thrombin
Inhibitor 12-28 hours
Not elevated at therapeutic levels, mod elevated at supra-therapeutic
levels
Elevation indicative of presence but not degree of anticoagulation
Rivaroxaban
(Xarelto®) Factor Xa Inhibitor 5-19 hours Elevated levels consistent with ingestion at higher doses No significant effect
Apixaban
(Eliquis®) Factor Xa Inhibitor 9-14 hours Elevated levels consistent with ingestion at higher doses No significant effect
Warfarin
(Coumadin®) Antagonist Vitamin K
INR reversal 6-24 hours w/ vit K
7-24 hours w/ FFP Minutes w/ FEIBA
Elevation in relation to dose No significant effect
Procedure For Ordering and Dispensing
When a patient presents with bleeding and it is determined by the attending physician that the patient would benefit from either rFVII or FEIBA a page/call to the PharmD on call will be placed.
• This will alert the PharmD to come and assess the patient for their potential risk, assist with laboratory interpretation and help to decide the appropriateness of reversal. • PharmD will discuss with appropriate physician the appropriateness and which reversal
agent would be indicated in this particular patient.
• If the decision is made to give a particular reversal agent, the PharmD will further assist by bringing the drug to the patient bedside, prepare the dose for administration, while also prompting discussions on potential alternative/adjunctive therapies that might impact the efficacy of the agent selected.
Non-Drug Induced Coagulopathy Reversal
Not all coagulopathies will be drug induced. After the optimization of supportive care measures have been done and drug induced causes have been ruled out it is appropriate to follow
previously established protocols (i.e. massive transfusion protocol).
Antiplatelet Reversal
If ingestion of one of the following oral antiplatelet agents is present during coagulopathy consider platelet transfusion.
• Clopidogrel (Plavix®)
• Ticagrelor (Brilinta®)
• Prasugrel (Effient®) • Ticlopidine (Ticlid®)
