urgent reversal of anticoagulants - american college of...
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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