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Anticoagulation and Reversal John Howard, PharmD, BCPS Clinical Pharmacist – Internal Medicine Affiliate Associate Clinical Professor – South Carolina College of Pharmacy
Anticoagulation and Reversal
John Howard, PharmD, BCPS
Clinical Pharmacist – Internal Medicine
Affiliate Associate Clinical Professor –
South Carolina College of Pharmacy
Disclosures
• I have no Financial, Industry, or Proprietary
disclosures
• Off Label medication use will be discussed
Objectives
• After this presentation the audience will be able
to:
– Discuss pharmacology of novel oral agents
– Describe risk factors for hemorrhage
– Describe agents used to stop hemorrhaging
– Develop an algorithm for life threatening hemorrhages
Clotting Cascade
XII XIIa
XI XIa
IX IXa
X Xa X
Prothrombin II (Thrombin)
Fibrinogen Fibrin
VIIIa
Va
VIIa VII
Damaged surface
Trauma
Fibrin clot
Tissue
factor
XIIIa
UFH
LMWH
Xa inhibitors
VKA
DTI
Agents
• Vitamin K antagonists
– Warfarin
• Direct Thrombin Inhibitors (DTI):
– Dabigatran (Pradaxa®)
• Factor Xa Inhibitors:
– Rivaroxaban (Xarelto®)
– Apixaban (Eliquis®)
– Edoxaban (Under development)
FDA Supported Indications
Reduce the risk of systemic embolism in patients
with non-valvular AFib
Apixaban
Dabigatran
Rivaroxaban
DVT prophylaxis in knee/hip replacement Rivaroxaban
Treatment of DVT/PE and extended Tx Rivaroxaban
Non-FDA Approved Indications
Treatment of DVT/PE Apixaban
Dabigatran
DVT prophylaxis in knee/hip replacement Apixaban
Dabigatran
Acute Coronary Syndromes* Rivaroxaban
* Investigational
FDA Indications
Atrial Fibrillation Pharmacokinetic Comparison
Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban
Dosing Interval Daily BID Daily BID
Half life (t1/2) hr 40 12-17 4-9 12
Onset Slow Rapid Rapid Rapid
Peak Effect 5-7dys 1-2hrs 2-4hrs 3hrs
Monitoring Yes No No No
Drug
Interactions High
Drugs/food
Moderate
P-gp
Moderate
3A4, P-gp Low
3A4, P-gp
Reversal Yes No No No
Renal Dose No Yes Yes Yes
Bleeding ++ + + +/-
Warfarin, Dabigatran, Rivaroxaban,
Apixaban. LexiComp. Hudson, OH. 2013.
Hemorrhage Risk Factors
• Demographics – Age (>75y/o)
– Low Body Mass (<50kg)
• Comorbidities – Renal Insufficiency
– Liver Disease
– Prior hemorrhage
– Stroke Hx
– Peptic Ulcer Disease
• Concomitant
Medications
– Intensity of
anticoagulation
– P2Y12 inhibitor
(clopidogrel, prasugrel,
ticagrelor)
– Aspirin
– others
Ageno. Chest 2012; 141: e44s-e88s.
Risk Stratify – Safety
HASBLED
Risk Factor Points
Hypertension 1
Abnormal
Renal Function
Liver Function
1
1
Stroke 1
Bleeding 1
Labile INRs 1
Elderly 1
Drugs
Alcohol
1
1
Pisters et al. Chest 2010; 138: 1093-100
0
2
4
6
8
10
12
14
0 1 2 3 4 5
P
e
r
1
0
0
p
t
y
r
s
Points
Bleeds
Bleeding and Reversal
• Warfarin
– Vitamin K
• PO or IV
– Plasma
– Recombinant Factor VII
– Prothrombin Complex Concentrates (PCC)
Then
Ansell. CHEST. 2008;133;160-198
Now
INR Bleeding Therapeutic Options
> 3.0 – 10 No
bleeding
Hold warfarin until INR returns to normal range
>10 No
bleeding
Hold warfarin and give vitamin K 2.5 - 5mg PO*
Any INR
Serious or
life-
threatening
bleeding
Hold warfarin and administer PCC and
supplement with vitamin K 5-10mg IV* infusion
and repeat as necessary
Alternatively, FFP or recombinant VIIa may be
supplemented with vitamin K 5-10 mg IV
infusion may be used instead of PCC
Holbrook. CHEST. e152-e184
* Low dose reduces INRs 6.0-10 to < 4.0 in 1.4 days after PO or 24 hrs after IV.
High dose IV vit K begins reducing INR within 2 hrs with a correction to normal
generally by 24 hrs.
CHEST and ICH
Guidelines
Holbrook. CHEST. e152-e184, AHA/ASA ICH Guidelines. Stroke 2010;41:2108-2129.
Bleeding and Reversal
• DTI – No direct antidote
– Prothrombin Complex Concentrates (PCC)
– Recombinant Factor VII
– Plasma
– Dabigatran is dialyzable
• Xa Inhibitors – No direct antidote
• Under development (Andexanet alfa, Portola Pharmaceuticals)
– Prothrombin Complex Concentrates (PCC)
– Recombinant Factor VII
– Plasma
PCC Confusion
ISMP. Aug. 8, 2013.
Clotting Cascade
XII XIIa
XI XIa
IX IXa
X Xa X
Prothrombin II (Thrombin)
Fibrinogen Fibrin
VIIIa
Va
VIIa VII
Damaged surface
Trauma
Fibrin clot
Tissue
factor
XIIIa
Xa inhibitors
VKA
DTI
Agents
Generic Name Brand Name Approved Uses
PCC - 4 Factor
Kcentra
(Octaplex, Beriplex)
Reversal of acute major
bleeding due to warfarin
Activated PCC - 4 Factor Feiba Hemophilia A and B
PCC – 3 Factor Profilnine® SD Hemophilia B with factor IX
deficiency
Recombinant Factor VIIa NovoSeven® RT
Patients with factor VII
deficiency or with hemophilia
A or B
Kcentra Package Insert. CSL. April;2013.
Feiba. Medical letter. Baxter. 2;2011.
Profilnine SD. Factor Levels. Grifols. 03/12.
NovoSeven. LexiComp. Hudson, OH. 2013.
Factor Content
Kcentra 4 18 11 16 23 19 14
Feiba NF 4 18 12 21 19 15 15
Profilnine SD 3 40 Trace 37 23
rFVIIa N/A 100
Kcentra Package Insert. CSL. April;2013.
Feiba. Medical letter. Baxter. 2;2011.
Profilnine SD. Factor Levels. Grifols. 03/12.
NovoSeven. LexiComp. Hudson, OH. 2013.
Pro Con Table
Agent
C
o
s
t
A
v
a
i
l
V
o
l
u
m
e
Infus
Time
Admix
Time
O
n
s
e
t
Effectiv
eness
Infect
Risk
Thrombo
sis
Risk
FFP ¢ + Lg 120 min - - - ++ -
Kcentra $$ - Sm 20 min ++ ++ ++ + +
FEIBA $$$ - Sm 15 min + ++ ++ + ++
Profilnine $ - Sm 15 min + + + + +
NovoSeven $$ - Sm Push + + - - +++
Kcentra. LexiComp. Hudson, OH. 2013.
Feiba. LexiComp. Hudson, OH. 2013.
Profilnine SD. LexiComp. Hudson, OH. 2013.
NovoSeven. LexiComp. Hudson, OH. 2013.
Cupp. Pharmacist’s Letter 291012. Oct. 2013.
Rebound Drug Effects
Anticoagulation Reversal Pharmacokinetics
Agent Onset Duration Rebound of Anticoagulant
Protamine 5 min Irreversible Likely with SBQ dosing from
postponed drug delivery
Vitamin K 4-12hrs Days for
INR Dose dependent
Fresh Frozen
Plasma (FFP) 1-4hrs 6hrs 4-6hrs
Prothrombin
Complex
Concentrate (PCC)
10-
15min 12-24hrs ≈12hrs
rFactor VII 10min 4-6hrs 6-12hrs
Full Anticoagulation Reversal for Life Threatening Hemorrhage
Oral Drug Generic Brand Reversal Strategy
Vit K
Antagonist Warfarin Coumadin PCC - 4 factor + Vitamin K 10mg IV
Factor Xa
Inhibitor
Rivaroxaban
Apixaban
Edoxaban
Xarelto
Eliquis
PCC - 4 factor
DTI Dabigatran Pradaxa PCC - 4 factor
UFH Heparin N/A
Immediately after IV
UFH bolus: 1mg
protamine per 100
units heparin
30-60min post UFH:
0.5mg protamine per
100 units heparin
LMWH
Enoxaparin Lovenox
≤8hrs since dose:
1mg of protamine per
1 mg of enoxaparin
8-12hrs since dose:
0.5mg of protamine per
1 mg of enoxaparin
Dalteparin Fragmin
≤8hrs since dose:
1 mg of protamine
per 100 anti-Xa units
8-12hrs since dose:
0.5 mg of protamine per
100 anti-Xa units
Factor Xa
Inhibitor Fondaparinux Arixtra PCC - 4 Factor
Dosing
• As literature comes forth, focus on the outcome! – Laboratory reversal versus hematoma reduction!
• The goal is to stop the bleed, not the surrogate marker lab value that may lag behind.
• Which dose should your warfarin, rivaroxaban, dabigatran, apixaban patient receive? – CHEST guidelines suggest?
Pre-Treatment INR Dose of 4F-PCC
(Units of Factor IX)
Maximum Dose
(Units of Factor IX)
2 to <4 25 units/kg 2500 units
4-6 35 units/kg 3500 units
>6 50 units/kg 5000 units
• Which of the following would you order for a
65y/o male with a life threatening ICH on
warfarin with an INR of 3.0 GFR of 60ml/min?
A. Vitamin K 10mg IV
B. Plasma
C. Vitamin K 10mg IV + Plasma
D. PCC - 3 factor + Vitamin K 10mg IV
E. PCC - 4 factor + Vitamin K 10mg IV
• Which of the following would you order for a
65y/o male with a major bleed on warfarin with
an INR of 5.0 and GFR of 60ml/min?
A. Vitamin K 10mg IV
B. Plasma
C. Vitamin K 10mg IV + Plasma
D. PCC - 3 factor + Vitamin K 10mg IV
E. PCC - 4 factor + Vitamin K 10mg IV
• Which of the following agents has the highest thrombosis risk? – PCC - 3 factor
– Factor VII containing products
– Plasma
– Vitamin K infusion
• Does multiple doses of PCCs increases thrombosis risk? – True
– False
• What is surgical risk of thrombosis from routine use of PCCs? – Pt is on anticoagulant for a reason (prothrombotic)
– Addition of PCC ↑ thrombosis risk, infection risk, cost • Safer to delay surgery until anticoagulant eliminated?
