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
Questions?
• 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?
