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?