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EMERGENT REVERSAL
OF NOVEL ORAL ANTICOAGULANTSDavid Barounis
R-2
Advocate Christ Medical Center
Some Questions to the Audience
1. How much does FFP cost and how much do you need to give in reversal of coumadin associated life threatening bleed??
Some Questions to the Audience
1. How much does FFP cost and how much do you need to give in reversal of coumadin associated life threatening bleed??
A: $1/ml, typically need 4U for reversal with 250cc/unit = $1000.
2. What other products are available here at christ hospital for reversal of oral anticoagulants?
Case 1
1. 65y/o F with A-fib presents on Pradaxa presents with an ICH approximately 25cc volume with no significant shift.
What’s you next move??
Case 2
58y/o M s/p total hip replacement on rivaroxaban for DVT prophylaxis presents with lightheadness and weakness. Hgb is 4.2 guaic negative from below.
Where is the bleed?
Case 2
58y/o M s/p total hip replacement on rivaroxaban for DVT prophylaxis presents with lightheadness and weakness. Hgb is 4.2 guaic negative from below.
Where is the bleed?
CT A/P: Large retroperitoneal hematoma
Coagulation Cascade
Coagulation Cascade
The ER coagulation cascade
1.FACTOR VIIa
==FACTOR X2.FACTOR Xa
Tissue Damage
3.PROTHROMBIN== THROMBIN
FIBRONGEN ==FIBRIN CLOTS
OTHER FACTORS V, VIII, IX, XI, XII
The ER coagulation cascade
1.FACTOR VIIa
==FACTOR X2.FACTOR Xa
Tissue Damage
3.PROTHROMBIN== THROMBIN
FIBRONGEN ==FIBRIN CLOTS
OTHER FACTORS V, VIII, IX, XI, XII
COUMADIN
The ER coagulation cascade
1.FACTOR VIIa
==FACTOR X2.FACTOR Xa
Tissue Damage
3.PROTHROMBIN== THROMBIN
FIBRONGEN ==FIBRIN CLOTS
OTHER FACTORS V, VIII, IX, XI, XII
HEPARIN
LOVENOX
AT III
Dabigatran(Pradaxa)
Direct Thrombin Inhibitor
Approved for anti-coagulation in patients with non-valvular atrial fibrillation
RE-LY trial comparing coumadin to Dabigatran
The ER coagulation cascade
1.FACTOR VIIa
==FACTOR X2.FACTOR Xa
Tissue Damage
3.PROTHROMBIN== THROMBIN
FIBRONGEN ==FIBRIN CLOTS
OTHER FACTORS V, VIII, IX, XI, XII
PRADAXA
Back to Case 1
ICB in patient on pradaxa
Step 1: What is the patients aPTT?
The PTT, typically 1.5X normal 12hours
after last dose. If < 32 seconds unlikely for
patient to have high enough blood
concentrations for benefit from reversal
Novel Reversal Agents 1. PCCWE DO NOT HAVE PCC’s here at Christ
Hospital.
Cost is similar to 4U of FFP($1000 vs $1200)
USA 3 factor PCC’s only (does not contain high quantity
of factor VII)
So assuming 4U (1L) of FFP vs 2000U of Profilnine
Factor II: 1000U FFP : 2900U Profilnine
Factor IX: 1000U FFP : 2000U Profilnine
Factor VII: 1000U FFP: 700U Profilnine
Factor X: 1000U FFP : 1200U Profilnine
PCC’s Safety
*1.4% complication rate (3 CVA, 2 DVT, and 2 non Q wave MI’s)
The ER coagulation cascade
1.FACTOR VIIa
==FACTOR X2.FACTOR Xa
Tissue Damage
3.PROTHROMBIN== THROMBIN
FIBRONGEN ==FIBRIN CLOTS
OTHER FACTORS V, VIII, IX, XI, XII
PRADAXA
PCC’s
Are they effective in patients with non-VKA?
Reversal of Rivaroxaban and Dabigatran by Prothrombin
Complex Concentrate. Circulation 2011
12 healthy volunteers: No effect of PCC on Dabigatran
reversal, completely reversed measured anticoagulation in
subjects receiving Rivaroxaban.
JUST REMEMBER THIS IS IN HEALTHY PT VOLUNTEERS
WITHOUT HEAD BLEEDS!!!
Activated Factor VIIa (Novo7) Recommended by the makers of Dabigatran as
the “Reversal agent of choice”.
Dose 90mcg/kg = 1mg
Very short half life and often requires repeated dosing ($1.13/mcg, usually need 1mg X 4 INITIAL X 4 MAINTENCE OVER 4-6 HOURS= $55,000)
Safety of Novo7 Thromboembolic Adverse Events (TAE)
249/3184 = 7.8% (placebo 6.2% RR 1.37)
*Arterial TAE OR 1.5 (95%CI 0.93-2.41)
Venous TAE OR 0.76 (95% CI 0.49-1.15)
*Trend toward statistical significance (>5%
incidence in the elderly > 65.)
Efficacy for reversal in ICH
Hemostatic Drug Therapies for Acute Spontaneous
Intracerebral Hemorrhage. Cochrane Database of
System Rev 2009.
Death 18.5% (rFVIIa) vs 19.4% (Placebo) RR 0.85
Death and/or Dependence 49.6% vs 51.7% RR 0.91
Essentially ineffective when looking at outcomes like
Mortality, which is all that really matters.
The ER coagulation cascade
1.FACTOR VIIa
==FACTOR X2.FACTOR Xa
Tissue Damage
3.PROTHROMBIN== THROMBIN
FIBRONGEN ==FIBRIN CLOTS
OTHER FACTORS V, VIII, IX, XI, XII
PRADAXA
NOVO 7
FEIBA
Activated Prothrombin Complex Concentrates (II, VII, IX, and X)
Dose 500U -1000U Often repeated for sustained effect up to 2000Units
Cost $1.59U/1000U = $1600/dose Typically 1-3 doses given
SafetyCezary et al. Activated prothrombin complex concentrate
factor VIII inhibitor bypassing activity (FEIBA) for the
reversal of warfarin-induced coagulopathy. Int J Emerg
Med 2009.
Complications:
4/72 or 7% (1 peri-operative MI, 1 thrombosis of
CVC, 2 NSTEMI) VERY conservative.
FEIBA Efficacy
FEIBA used in warfarin reversal:
72 patients with life-threatening bleeds on coumadin.
54% Had INR < 1.4, vs 30% of patients who received
FFP.
No mortality benefit, reduced hematoma expansion
after ICH, rapid reversal of INR immediately (<15
minutes)
The ER coagulation cascade
1.FACTOR VIIa
==FACTOR X2.FACTOR Xa
Tissue Damage
3.PROTHROMBIN== THROMBIN
FIBRONGEN ==FIBRIN CLOTS
OTHER FACTORS V, VIII, IX, XI, XII
FEIBA
PRADAXA
Recommendations Evidence is poor
Really endpoints like mortality are lacking
No good RCT comparing these options exist.
Head bleeds are bad, GI bleeds are better, and maybe reversing people doesn’t do anything at all.
In light of good evidence
1. Pradaxa: check aPTT, if < 1.5normal = DONE- FEIBA 500U- rFVIIa 90mch/kg X 1 or about 1mg- FFP and HEMODIALYSIS (if you can find someone to dialyze them)- Activated Charcoal if within 2 hours of ingestion
2. Rivoroxaban: - PCC’s 50U/kg Profilnine - FEIBA 500-1000U
3. Warfarin- FFP 15-20cc/kg minimum of 4U- PCC’s > FFP for time to reversal (cost is similar)- We have FEIBA (cost is more but rapidly reduces reversal time)
THANKS!!!