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Management of Emergent Warfarin CoagulopathyZach JarouMichigan State University

+Warfarin

used to prevent thromboembolism for >50 years atrial fibrillation prosthetic heart values venous thromboembolism

narrow therapeutic window requires regular INR checks 3-7% patients are at risk of major, life-threatening bleeding

mechanism of action = vitamin K antagonist

+Coagulation Cascade

+Common Reversal Agents

Vitamin K Fresh Frozen Plasma (FFP) Prothrombin Complex Concentrates (PCC)

3-factor 4- factor

Choice of Reversal Agents & Dosing is Based on INR!

+Vitamin K

fat soluble vitamin required for post-translational modification of proteins required for blood coagulation & other pathways

types K1 = synthesized by plants for use in photosynthesis; highest levels in

green leafy vegetables K2 = main storage form in animals, bacteria in the colon lengthen the

isoprenoid side change to create a range of subtypes

routes & dosing 5 < INR < 9 (no significant bleeding), give 1 2.5 mg PO q24 INR > 9 (no significant bleeding), give 2.5 5 mg PO q24-48 significant bleeding, 10 mg IV (slow to prevent allergic reaction)

administer lowest dose possible to prevent refractoriness to warfarin once restarted

+Fresh Frozen Plasma (FFP)

fluid portion of one unit of blood that has been centrifuged, separated, and frozen solid at -18°C or colder within 8 hours of collection has to thaw & has large volume

labile & stable components of coagulation, fibrinolytic, complement systems; oncotic & immunologic proteins; other proteins, fats, carbohydrates, minerals

use has increased ten-fold over the past decade (possible related to decreased availability of whole blood due to widespread acceptance of component therapy)

risks include: disease transmission, anaphylactoid reactions, alloimmunization, excessive intravascular volume, transfusion related lung injury (TRALI)

must ensure compatibility with type & match

+Prothrombin Complex Concentrates (PCCs)

Am J Health-Syst Pharm. 2013; 70(Suppl 1):S12-21

=

prepared from FFP factors II, VII, IX, X 3-factor is low in VII, 4-factor is high in VII risk of pro-thrombotic potential, especially with activated

products

+Choice of Reversal Agents is Based on INR and/or Presence of Significant Bleeding

CHEST 2008; 133:160S–198S (American College of Chest Physicians)

+Kcentra Receives FDA Approval in 2013, Prepare For an Onslaught of Ads

first 4-factor PCC approved for us in the United States marketed as Beriplex in 25 other countries alternative to making your own by adding rVIIa to 3-factor

PCC

+So, which is best? FFP or PCC?

Circulation. 2013;128:360-364

This is the first study comparing the use of FFP vs. PCC in the Emergency Department.

+Methods & Study Design

two tertiary care EDs in Canada (total ~120k visits per year)

retrospective, before-after study (2 years with FFP; 2 years with Octaplex, a 4-factor PCC)

inclusion = 18 years or older, on warfarin with INR > 1.5, received Octaplex or FFP in ED

exclusion = <18 years old, no warfarin documentation, no pre-treatment INR check, both Octaplex and FFP given within 7 days

314 patients (FFP = 149, Octaplex = 165)

+Study Enrollment

Circulation. 2013;128:360-364

+Outcome Measures

Primary (adverse outcomes within 7 days) death ischemic stroke myocardial infarction congestive heart failure venous thromboembolism peripheral arterial thromboembolism

Secondary time to INR reversal mean hospital length of stay number of units of pRBCs transfused within 48 hours

+Baseline Characteristics & PMH

+Reason for Anticoagulation

+Reason for Reversal

+Primary Outcomes: Adverse Events

+Secondary Outcomes

+Multivariable Regression to Obtain Adjusted Relative Risk of Adverse Events

+Limitations

retrospective data collection only 7 day follow up more FFP patients with history of CHF more FFP patients needed urgent reversal for ICH more PCC patient treated for pre-procedure unblinded outcome adjudication (although strict

definitions of each adverse event were established a priori)

+Conclusions

PCC can be administered quickly (no thaw time) PCC requires less infusion volume compared to FFP, administration of PCC led to:

quicker INR reversal fewer RBC transfusions fever adverse events

but remember, the only FDA-approved indication for 4-factor PCCs is life-threatening bleeding on warfarin

+References

Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palaretti G. Pharmacology and Management of the Vitamin K Antagonists. Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines. CHEST. 2008; 133:160S-198S.

Hickey M, Gatien M, Taljaard M, Aujnarain A, Giulivi A, Perry JJ. Outcomes of Urgent Warfarin Reversal With Frozen Plasma Versus Prothrombin Complex Concentrate in the Emergency Department. Circulation. 2013; 128:360-364.

Kalus JS. Pharmacologic interventions for reversing the effects of oral anticoagulants. Am J Health-Syst Pharm. 2013; 70 (Suppl 1):S12-21.

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Thank you!

Zach JarouMichigan State University