Urgent Reversal of Anticoagulants Trauma Quality Improvement Program (TQIP) Annual Scientific Meeting and Training 2012 October 29, 2012 K. Pavenski, St. Michael’s Hospital and University of Toronto, Toronto, Canada

Conflict of Interest/Disclosures

• Research funding from CSL Behring Canada Inc. • I will be discussing off-label use of PCC, rVIIa, and

FEIBA

Outline

• To review strategies for urgent reversal for warfarin, direct thrombin inhibitors, and Factor Xa inhibitors

• Assumptions:

• Reversal is urgently needed and waiting for the drug to be metabolized is not an option

• The information presented pertains to the management of adult patients

Case

• 65 yo male brought to ER with decreased level of consciousness following a fall from a ladder

• On “blood thinner” for stroke prevention • CT head: large subdural hematoma • Plan: to OR ASAP

Anticoagulants: Mechanism of Action

Warfarin

• Causes vitamin K deficiency • Decreased levels of anticoagulant proteins C and

S as well as coagulation factors II, VII, IX and X • Duration of action 2-5 days • Predictably prolongs PT/increases INR

Warfarin

• Common medication • Approx. 4% of trauma patients (Dossett 2010)

• Associated with worse outcomes in trauma patients • Adjusted mortality up to 30% higher in those on

warfarin (Dossett 2010) • Mortality 30% higher if warfarin plus traumatic brain

injury (McMillian 2009)

• Case fatality rate of major bleeding 9.5% (Guerrouij 2011)

Warfarin: Urgent Reversal

• Vitamin K • Replenishes Vitamin K allowing synthesis of

vitamin K dependent factors • When given IV by slow bolus, safe and onset of

action in 6-12 hrs

• Frozen plasma (and Vitamin K) • Contains all factors • Onset of action: immediate

Warfarin: Urgent Reversal

• Prothrombin complex concentrate (and Vitamin K) • Types:

• Four factor PCC (II, VII, IX and X) – Beriplex, Octaplex • Three factor PCC (II, IX and X) – ex. Bebulin

• Onset of action - immediate • American College of Chest Physicians guidelines 9th ed:

use 4 factor PCC (vs. plasma) for warfarin reversal in the setting of major bleeding (Grade 2C recommendation) (Guyatt et al 2012)

• FP vs. 4 factor PCC: • 1 RCT, 4 retrospective studies • 2 U.S. Phase III RCT – ongoing (one involves Beriplex, the other

Octaplex)

Warfarin: Urgent Reversal- FP vs. 4 factor PCC

FP 4 factor PCC

Human Human

No viral inactivation Viral inactivation, prion reduction

Determine blood group, thaw Reconstitute lyophilized powder

Large volume (15 mL/kg, 4-5 units) Small volume (40-120cc)

Long infusion (hrs) Fast infusion (5-15 min)

Risk of TRALI, TACO and anaphylaxis Thrombotic risk (about 2%)

Compared to FP, more rapid and complete correction of INR

Ageno 2009; Patanwala et al 2011

Warfarin: Urgent Reversal in USA

• Frozen plasma • 3 factor PCC – likely not effective • 3 factor PCC plus FP • 3 factor PCC plus rVIIa • FEIBA (activated PCC) – risk of adverse events • rVIIa – not effective

• Rosovsky &Crowther 2008: review of 8 studies of warfarin related CNS bleeding • rVIIa rapidly corrects INR but clinical impact not clear • Retrospective, case reports or case series, no adequate

controls and co-administration of other hemostatic therapy (FP, etc.)

rVIIa in Warfarinized Volunteers Undergoing Thigh Punch Skin Biopsy (Phase I, RCT)

Baseline 18.6 min

3.8mL

Warfarin 32 min 5.3 mL

High r7a 28 min 5.3 mL

Skolnick BE, Mathews DR, Khutoryansky NM, Pusateri AE, Carr ME. Exploratory study on the reversal of warfarin with rFVIIa in healthy subjects. Blood. 2010;116(5):693-701.

No difference in bleeding outcomes!

Dabigatran

• Direct thrombin (aka Factor IIa) inhibitor • Half-life 12-17 hrs, >80% renal excretion • Labs

• PT/INR – may be normal • aPTT – prolonged

• aPTT>40 sec: dabigatran is exerting an anticoagulant effect • TT - prolonged

• TT in the normal range: dabigatran is likely not present • Levels of fibrinogen, other factors - falsely low • TEG – may be normal • Cr – creatinine clearance gives an idea of how long the

drug will remain in the system Galanis et al 2011, Lison and Spannagl 2011

• NO ANTIDOTE • General measures aka “Non-specific blood

thickening therapy” • Attempt to obtain local hemostasis (compression,

angiography, surgery) • If possible, apply to the site of bleeding topical thrombin

or antifibrinolytic agent (ex. Tranexamic acid) • Consider tranexamic acid bolus (1 g IV in 100 cc 0.9% NaCl

over 10 minutes) • Administer crystalloid for hemodynamic support • Administer RBC, FP, cryoprecipitate, and platelets for

management of anemia, dilutional coagulopathy and thrombocytopenia

Warkentin & Crowther 2008

Dabigatran: Urgent Reversal

Dabigatran: Urgent Reversal

• If <2 hours since dabigatran intake, administer activated charcoal (in vitro data only)

• Consider hemodialysis/hemofiltration (low protein binding) • Volunteers with ESRD study; mean fraction of drug

removed 68% at 4 hrs (Stangier et al 2010)

Dabigatran: Options for Urgent Reversal for Ongoing Life-threatening Bleeding

Dabigatran: Options for Urgent Reversal for Ongoing Life-threatening Bleeding

• aPCC (FEIBA) • Healthy volunteers – corrected coagulation tests (Marlu 2012),

case report – poor effect on tests but ceased bleeding (Dager & Roberts 2011)

• Rat model – reduced bleeding (van Ryn 2008)

• PCC • Healthy volunteers – poor effect on tests (Eerenberg 2011, Marlu

2012) • Rabbit, mouse models – decreased bleeding (Pragst 2012;Zhou 2011)

• rVIIa • Healthy volunteers – corrected tests (Marlu et al 2012) • Rat model – reduced bleeding (van Ryn 2008)

Rivaroxaban, (Apixaban, siblings?)

• Inhibits Factor Xa • Half-life 8-15 hrs • Labs

• PT – may be prolonged • Suggests relative degree of anticoagulation • Normal PT suggests little/no rivaroxaban

• aPTT – may be prolonged • Xa inhibition – perhaps most accurate • TEG - ?

Lison and Spannagl 2011; Baglin et al 2012

Rivaroxaban: Urgent Reversal

• NO ANTIDOTE • General measures • If ongoing, life-threatening bleeding, consider:

• PCC • Healthy volunteers – corrects coagulation tests (Eeerenberg 2011) • Rabbit model – no effect on bleeding (Godier 2012)

• aPCC (FEIBA) • Healthy volunteers – corrects tests (Marlu et al 2012) • Rat, baboon model – reduces bleeding (Perzborn 2007, Gruber

2008)

• rVIIa • Healthy volunteers – corrects tests (Marlu et al 2012) • Rabbit model – no effect on bleeding (Godier 2012)

Conclusions

• Warfarin has a few effective antidotes • do not forget to give vitamin K if using

FP or PCC!

• There are no effective antidotes for direct thrombin inhibitors or Factor Xa inhibitors