1) Warfarin reversal is best achieved using 4-factor prothrombin complex concentrate (PCC) along with vitamin K due to the rapid onset of effect compared to fresh frozen plasma. 2) Dabigatran reversal can be attempted using activated PCC. Rivaroxaban reversal responds best to 4-factor PCC. 3) Antiplatelet effects from medications like aspirin are not uniformly proven to worsen outcomes, and platelet transfusion with or without desmopressin may help reverse antiplatelet effects. Speed of reversal for all anticoagulants and antiplatelets is important for reducing mortality and hemorrhage.

1. FALLS &
ANTICOAGULANTS
Jeffrey F. Barletta, Pharm.D., FCCM
Associate Professor & Vice Chair
Department of Pharmacy Practice
Midwestern University, College of Pharmacy
Glendale, Arizona

2. Disclosures
• Hospira, Inc. – Consultant
• Cubist Pharmaceuticals – Consultant
• I will be discussing off-label usage of medications used to
correct medication-induced coagulopathy.

3. Impact of Pre-Injury Warfarin
Study
Grandhi, et al.
2015
Collins, et al.
2014
Dossett, et al.
2011
Bonville, et al.
2011
Pieracci, et al.
2007
Population
1,552 elderly patients with TBI
11,078 Medicare beneficiaries
1,230,422 patients from
National Trauma Databank
3,436 trauma patients
225 elderly patients with TBI
Results
3 fold increase in mortality with
warfarin compared to ASA
40% increase in ICH, 2 fold
increase in mortality with warfarin
Adjusted OR for mortality with
warfarin use = 1.72, p<.001
Adjusted RR for morality with
warfarin use = 3.2, p<.05
Adjusted OR for mortality with
therapeutic warfarin = 3.42, p=.03
Grandhi, et al. J Trauma Acute Care Surg 2015;78:614-21.
Collins, et al. Am J Surg 2014;208:544-9.
Dossett, et al. Arch Surg 2011;146:565-70.
Bonville, et al. Surgery 2011;150:861-8.
Pieracci, et al. J Trauma 2007;63:525-30.

4. Assess the Situation: What is the goal?
When can anticoagulation
be restarted?
INR
10
9
8
7
6
5
4
3
2
1
Scenario
What does the CT scan show?
Is the bleed life threatening?
What was the indication for
anticoagulation?

5. The Cause of Bleeding May Be
Multifactorial
Normal
Anticoagulation
Anti-platelet
Fibrinolytic
Hypercoagulable
state
Gonzalez, et al. Semin Thromb Hemost;2010:36:723-37.
R = reaction time
MA = max amplitude
K α = rate of clot development
EPL = estimated % lysis

6. Clinical Algorithm
G < 5.0
Pt is bleeding EPL > 15
Aminocaproic
Acid
TEG ACT
> 110 sec
TEG α < 66 FFP
MA < 54 mm
Recheck TEG if pt
received FFP and
improving
Is MA still
< 54 mm?
Apheresis
Platelets
Is TEG α
still < 66?
Cryoprecipitate
Recheck TEG if pt
received FFP and
improving
YES YES
YESNO
YES
NO YES
YES
Gonzalez, et al. Semin Thromb Hemost;2010:36:723-37.

7. Coagulation Cascade and
Anticoagulant Sites of Action
Factor XII Factor XIIa
Factor XI Factor XIa
Factor IX Factor IXa
Factor X Factor Xa
Factor II Factor IIa (thrombin)
Factor VIIIa
Factor Va
Factor VIIa Factor VII
Tissue factor
Fibrinogen Fibrin
Warfarin
Rivaroxaban, Apixaban, Edoxaban
Dabigatran

8. Warfarin: Options for Reversal
• Fresh frozen plasma (FFP)
• Prothrombin complex concentrates (PCC)
• 3-factor
• 4-factor
• Activated
• Recombinant factor VIIa
• Vitamin K
• Hold warfarin therapy

9. Warfarin Reversal Strategies:
Onset & Duration of Effect
FFP
PCC
rFVIIa
Dager, WE. Am J Health-Syst Pharm 2013;70:S21-31.

10. Vitamin K: Dosing & Route of Administration
Tsu, et al. Ann Pharmacother 2012;46:1617-26.
No FFP All Patients
po
IV
0.25 – 1.25 mg 2 – 5 mg 10 mg
0.25 – 1.25 mg 2 – 5 mg 10 mg

11. Speed of Reversal
• A protocol targeting rapid identification and treatment of anticoagulated trauma patients
led to a reduction in the time to warfarin reversal, 4.3 hrs to 1.9 hrs (p<.001).
• Mortality pre- and post-protocol implementation was 48% and 10%.
• Early administration of FFP associated with more successful reversal (INR ≤ 1.4),
90 min vs. 210 min, p=.02.
• Every 30 minute delay in FFP administration was independently associated with a
20% decrease in the probability of successful INR reversal at 24 hours.
• Protocol using PCC led to a shorter time to INR < 1.5 lower (8.2 vs. 16 hrs, p=.033).
• PCC associated with a decrease in ICH extension (17% vs. 44%, p=.031).
Edavettal, et al. Am Surg 2014;80:372-6.
Goldstein, et al. Stroke 2006;37:151-5.
Ivascu, et al. J Trauma 2005;59:1131-9.

12. Concentrated Blood Factor Products
Bebulin
II, IX, X
(some VII)
No
Yes
Profilnine SD
II, IX, X
(some VII)
No
No
4-factor PCC
Kcentra
II, VII, IX, X
No
Yes
rFVIIa
Novo-Seven RT
VIIa
Yes
No
Brand name
Factors
provided
Activated
Heparin?
3- factor PCC aPCC
FEIBA
II, VIIa, IX, X
Yes
No

13. PCC, FFP and Functional Outcome
Frontera, et al. Neurocrit Care 2014;21:397-406.
3-factor PCC (50 IU/kg) + vitamin K 10 mg
PCC
2.3
88%
0
6%
44%
56%
FFP
1.7
84%
28%
52%
60%
84%
Baseline INR
% INR < 1.4
New or worsening ICH
Major hemorrhage
Death
Modified Rankin 4 – 6
PCC+FFP
3.0
70%
17%
26%
39%
61%
P-value
.003
NS
.020*
.003*
NS
.030
* FFP compared to PCC alone

14. 3-Factor PCC: With or Without FFP
0
20
40
60
80
100
FFP alone Low dose
PCC
High dose
PCC
Low dose
PCC+FFP
High dose
PCC+FFP
% INR < 3
* **p <.05 vs. PCC alone
Holland, et al. Transfusion 2009;49:1171-7.

15. The Influence of Obesity on
SuccessfulAnticoagulation Reversal
Chu, et al. Int J Neurosci 2014, Dec 27 [Epub ahead of print]
Variable
Obesity (BMI ≥ 30)
Initial INR > 2
Age
Gender
Appropriate PCC dose
Appropriate PCC dose + FFP
OR (95% CI)
7.39 (1.1 – 56)
12.5 (2.3 – 69)
0.94 (0.8 – 1.01)
0.35 (0.07 – 1.69)
2.96 (0.12 – 71)
0.19 (0.01 – 4.39)
P-value
<.05
<.05
NS
NS
NS
NS
Failure of Anticoagulation Reversal (INR ≥ 1.5)

16. 3-Factor vs. 4-Factor PCC
Baseline INR
Initial dose (units/kg)
INR post dose
% INR < 1.5 (post-PCC)
% Requiring 2nd dose
Thrombotic event
3.1 ± 2.3
30 ± 13
1.6 ± 0.6
50%
17%
15%
3.4 ± 3.7
26 ± 5
1.3 ± 0.2
83%
0
0
.520
.198
.001
.022*
.093
.177
3-factor PCC
(n=46)
4-factor PCC
(n=18) P-value
Cost-effectiveness = $5,382 (3-factor) vs. $3,797 (4-factor)
*Multivariate analysis for successful reversal:
Receipt of 4-factor PCC: OR (95% CI) = 5 (1.2 – 19.6), p=.021
Factors included in model = age, baseline INR, time INR assessed
post-dose & vitamin K administration
Mangram, et al. Southwestern Surgical Congress. 67th Annual Meeting. Monterey, CA. April, 2015

17. Low-dose Factor VII & Warfarin Reversal
0
1
2
3
4
5
6
7
0 10 20 30 40 50 60 70 80
INR
Time (minutes)
Dager WE, et al. Pharmacotherapy 2006;26:1091-8.
Mean INR, 2.8  1.07 in 35 minutes
Recombinant Factor VIIa 1.2 mg

18. 3-Factor PCC vs. rFVIIa
Chapman, et al. World J Emerg Surg 2014;9:27.
0
0.5
1
1.5
2
2.5
3
3.5
0 1 2 3 4 5
%INR ≤ 1.5:
• PCC-3, 34%
• rFVIIa, 72%
• p=.001
Initial INR, p=.52
Final INR, p<.05
INR
Time (hours)
1.75
1.25
3.1
2.8

19. Guidelines: Warfarin Reversal
• European guidelines for bleeding & coagulopathy following
major trauma
• We recommend the early use of PCC for the emergency reversal of
vitamin K-dependent oral anticoagulants (Grade 1B).
• Australian Society of Thrombosis and Haemostasis
• For life-threatening bleeding, vitamin K 5 – 10 mg IV and PCC and
FFP (2C).
• For non-life-threatening bleeding, vitamin K 5 – 10 mg IV and PCC
(2C).
• ACCP
• We suggest rapid reversal of anticoagulation with 4-factor PCC rather
than with plasma (Grade 2C).
• We suggest the additional use of vitamin K 5 – 10 mg IV (Grade 2C).
Spahn, et al. Critical Care 2013,17:R76.
Tran, et al. MJA 2013;198:1-7.
Holbrook, et al. Chest 2012;141(2)(Suppl):e152S-84S

20. Newer agents
Nutescu, Am J Health-Syst Pharm 2013;70(Suppl 1):S3-11.
Dabigatran
Pradaxa®
Direct IIa Inh.
6%
14 – 17 hrs
80%
Yes
Rivaroxaban
Xarelto®
Direct Xa Inh.
80%
5 – 9 hrs
33%
No
Apixaban
Eliquis®
Direct Xa Inh.
50%
8 – 15 hrs
25%
No
Brand name
Mechanism
Bioavailability
Half-life
% Renal Cl
Dialyzable
Edoxaban
Lixiana®
Direct Xa Inh.
62%
9 – 11 hrs
50%
No

21. Dabigatran: Laboratory Assessment
MeanINR
Dabigatran levels
MeanaPTT
Thrombintime
Dager, et al. Ann Pharmacother 2012;46:1627-36.

22. Dabigatran Reversal: FEIBA
Dager, et al. Crit Care Med 2013;41:e42-6.

23. Dabigatran Rivaroxiban
Placebo
PCC
Placebo
PCC
Reversal with 4-factor PCC
Eerenberg, et al. Circulation 2011;124:1573-9.

24. Rivaroxiban: 3-factor or 4 factor PCC
PCC-4
Beriplex P/N
PCC-3
Profilnine SD
Levi, et al. J Thromb Haemost 2014;12:1428-36.

25. Antiplatelet Medications
• The data do not uniformly demonstrate worse outcome
with pre-injury antiplatelet medications.
• Many studies show no benefit with platelet transfusions to
reverse the effect of antiplatelet medications.
• Reversal strategies:
• 5 – 10 units of platelets
• Desmopressin 0.3 units/kg
• Recurring platelet transfusions may be necessary
Gordon, et al. J Trauma Acute Care Surg 2013;75:475-86.
Campbell, et al. World Neurosurg 2010;74:279-85.
Nishijima, et al. J Trauma Acute Care Surg 2012;72:1658-63.
Spahn, Critical Care 2013;17:R76.

26. Summary
• Speed of reversal is a crucial factor influencing outcome.
• PCCs allow for more rapid reversal compared to FFP.
• Agent specific strategies:
• Anticoagulants
• Warfarin: 4-factor PCC + Vitamin K
• Dabigatran: aPCC
• Rivaroxabin: 4-factor PCC
• Antiplatelet medications
• Platelet transfusion ± desmopressin