Emergent reversal

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


1.FACTOR VIIa


Tissue Damage




COUMADIN


1.FACTOR VIIa


Tissue Damage




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


1.FACTOR VIIa


Tissue Damage




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)


1.FACTOR VIIa


Tissue Damage




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.


1.FACTOR VIIa


Tissue Damage




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)


1.FACTOR VIIa


Tissue Damage




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!!!

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Emergent reversal