Anticoagulation and Reversal
John Howard, PharmD, BCPS
Clinical Pharmacist – Internal Medicine
Affiliate Associate Clinical Professor –
South Carolina College of Pharmacy
Disclosures
• I do not have a vested interest in or affiliation
with any corporate organization offering financial
support or grant monies for this continuing
education activity, or any affiliation with an
organization whose philosophy could potentially
bias my presentation
• Non-FDA approved indications 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
Terminology
• Vitamin K antagonists = Warfarin
• NOAC
– Novel Oral Anticoagulant
– No Anticoagulation drug error
• DOAC
– Direct Oral Anticoagulant
• TSOAC
– Target-Specific Oral Anticoagulant
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 (Savaysa®)
FDA Supported Indications
Reduce the risk of systemic embolism in patients with
non-valvular AFib
Apixaban
Dabigatran
Edoxaban
Rivaroxaban
DVT prophylaxis in knee/hip replacement Apixaban
Rivaroxaban
Treatment of DVT/PE and
Apixaban
Dabigatran
Edoxaban
Rivaroxaban
Extended Tx of DVT/PE
Apixaban
Dabigatran
Rivaroxaban
FDA Indications
Warfarin, Dabigatran, Rivaroxaban, Apixaban. LexiComp. Hudson, OH. 2013. Giugliano.
Non-FDA Approved Indications
DVT prophylaxis in knee/hip replacement Dabigatran
Acute Coronary Syndromes* Rivaroxaban
* Investigational
FDA Indications
Warfarin, Dabigatran, Rivaroxaban, Apixaban. LexiComp. Hudson, OH. 2013. Giugliano.
Atrial Fibrillation Comparison
Pivotal AFib Trial Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban
Outcome Superior Not Inferior Superior Superior
CHADS2 2.1 3.5 2.1 2.8
Mean Warfarin TTR 64% 55% 62.2% 64.9%
Dosing Interval Daily BID Daily BID Daily
Half life (t1/2) hr 40 12-17 4-9 12 8-10
Onset Slow Rapid Rapid Rapid Rapid
Peak Effect 5-7dys 1-2hrs 2-4hrs 3hrs 1-3hrs
Monitoring Yes No No No No
Drug Interactions High Drugs/food
Moderate P-gp
Moderate 3A4, P-gp
Low 3A4, P-gp
Low P-gp
Reversal Yes No No No No
Renal Dose No Yes Yes Yes Yes
Bleeding ++ + + +/- +/-
Warfarin, Dabigatran, Rivaroxaban, Apixaban. LexiComp. Hudson, OH. 2013. Giugliano. NEJM 369;22:2093-2104. Patel et al. NEJM
2011;365:883-91. Granger et al. NEJM 2011;365:981-92. Connolly. NEJM 2009;361:1139-51. Bathala. DMD 2012. 40;12:2250-2255.
Bleed Location
• GI
– TSOAC > Warfarin
• Brain
– Warfarin > TSOAC
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
Prescribing Shift
Warfarin Candidate
Prescribing Barriers
(falls, appts)
Non-Adherent
Drug Interactions
Health Literacy
TALK OUT
TSOAC Candidate
Prescribing Barriers
(falls, appts)
Non-Adherent
Drug Interactions
Health Literacy
TALK IN
“Albumin, age, weight, kidneys, liver, drug intx, falls, cognition…”
Reviewing Literature
• Reversal definition
– Lab outcome vs clinical outcome
• Normalization of INR, PTT, antifactor Xa
• Hemostasis
– Literature support varies based on outcome
Bleeding and Reversal
• Vitamin K
– Warfarin
• PO or IV
• Plasma
• Recombinant Factor VII
• Prothrombin Complex Concentrates (PCC)
PCC Confusion
ISMP. Aug. 8, 2013.
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
Infu
sio
n T
ime
Ad
mix
Tim
e
O
n
s
e
t
Th
aw
time
Effe
ctiv
en
ess
Infe
ctio
n R
isk
Th
rom
bo
sis
Ris
k
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
post PCC 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
Warfarin
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
• Investigational: Idarucizumab
– 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
Dabigatran -
Idarucizumab
• Monoclonal antibody
• Binds dabigatran, higher affinity than thrombin
– Binds free and thrombin bound dabigatran
– Neutralizes activity of free/thrombin bound dabigatran
• Cost estimation similar to 4 factor PCC
• FDA accelerated approval status
– End of 2015 launch?
Pollack. NEJM. June 22, 2015 at NEJM.org.
RE-VERSE AD Study
• Adult pts with practitioner defined uncontrollable or life threatening bleeding (group A) or patients that require invasive procedure (group B) – Multi-center, prospective, cohort study
– Interim analysis: n=90 (goal 300) • 51 group A and 39 group B
• Idarucizumab 2.5mg/50ml bolus infusion x2
• Primary endpoint: maximum percentage reversal (thrombin time or ecarin clotting time)
• Secondary endpoints: several clinical outcomes
Pollack. NEJM. June 22, 2015 at NEJM.org.
RE-VERSE AD Study
Population
Age 76.5 y/o
CrCl <30ml/min 12
30-50ml/min 20
Weight 71.9kg (42-127kg)
Time from Last dose 15.4hrs
Dose (bid)
150mg 29
110mg 58
75mg 1
Other 2 Pollack. NEJM. June 22, 2015 at NEJM.org.
Lab
Outcomes • TT
– Group A = 98%
– Group B = 93%
• ECT – Group A = 89%
– Group B = 88%
• N=68 – 22 with nml coags;
all with better renal function
• Edoxaban phenomenon?
Pollack. NEJM. June 22, 2015 at NEJM.org.
Clinical Outcomes
• Median time to bleed stop = 11.4hrs
• Normal intra-op hemostasis (B) = 92%
• Mortality =18%; 9 per group
– 1 AIS
• 5 thromboembolic events
– Literature ~7%
– Prothrombotic state from sudden stoppage of TSOAC
+ loading body with exogenous procoagulants
Pollack. NEJM. June 22, 2015 at NEJM.org.
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
Savaysa
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, or edoxaban 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?
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