Objectives - DCPA · Review the pharmacology, indications, and place in therapy of the...

12/21/2015

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Jay Hazelcorn, Pharm.D.

PGY-1 Pharmacy Resident

Broward Health Medical Center

New Anticoagulation

Agents and Their

Reversal Agents

Objectives

� Review the pharmacology, indications, and place in

therapy of the target-specific oral anticoagulants

(TSOACs)

� Discuss how to switch between TSOACs and parenteral

anticoagulants, and how to manage them perioperatively

� Examine reversal strategies, management approaches,

and pipeline reversal agents

Background

� Venous thromboembolism and pulmonary embolism

� Third most common cause of cardiovascular disease and death

� 4 to 6 times higher in patients above 70 years of age

� Risk doubles with each decade of aging

� Nonvalvular atrial fibrillation

� Absence of mitral valve disease,

prosthetic heart valve, or

mitral valve repair

� 5-fold increased risk of stroke

• Increases with age and risk factors

January, Craig T., et al. "2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation” Journal of the American College of Cardiology

Kearon, Clive, et al. "Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis" CHEST Journal

Added

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Warfarin for Acute VTE/PE

� Treatment of an acute VTE/PE

� Parenteral anticoagulation and warfarin started on the same day

• Enoxaparin 1 mg/kg SQ every 12 hrs with warfarin

� Continue parenteral for a minimum of 5 days AND until INR is

> 2 for at least 24 hrs

� Warfarin

� Delayed onset (5-7 days)

� Inhibits synthesis of new factors

� Hyper-coagulable state (24-48 hrs)

• Depletion of protein C

• Bridge in high risk patients

Coagulation factors affected:

Factor VII t1/2

= 4-6 hrs

Factor IX t1/2

= 21-30 hrs

Factor X t1/2

= 27-48 hrs

Factor II t1/2 = > 60 hrs

Protein C t1/2 = 4-6 hrs

Protein S t1/2

= 40-60 hrs

Kearon, Clive, et al. "Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis" CHEST Journal

Advances in Treatment

20201950 1960 1970 1980 1990 2000 2010

Warfarin

1953

Dabigatran

2010

Apixaban

2012

2011

Rivaroxaban

2015

Edoxaban

2020

Nomenclature

� New (or novel) oral anticoagulants or Target-

Specific Oral Anticoagulants

� NOAC vs TSOAC

� ISMP has reported medication errors

� Cardiologist wrote in a note “consider NoAC due to drug

interactions with warfarin”

� Was interpreted as no anticoagulation

� Instead of “NOAC” use an alternative or nothing

� Direct oral anticoagulant (DOAC) or TSOAC

� Or just do not use abbreviations

Barnes, Geoffrey D., et al. Journal of Thrombosis and Haemostasis (2015)

ISMP Medication Safety Alert! Nurse Advise-ERR (ISSN 1550-6304) ©2014 Institute for Safe Medication Practices (ISMP)

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Target-Specific Oral

Anticoagulants

� Factor Xa inhibitors

� Rivaroxaban, apixaban, and edoxaban

� Direct thrombin (IIa) inhibitors

� Dabigatran

Clotting Cascade Targets

Factor Xa inhibitors

Apixaban, rivaroxaban, and

edoxaban

Rivaroxaban (Xarelto®)

Renal Dosing Nonvalvular Atrial Fibrillation

CrCl > 50 mL/min 20 mg daily with largest meal

CrCl 15-50 mL/min 15 mg daily with largest meal

CrCl <15 mL/min or

HDAvoid

Acute treatment of DVT/PE

CrCl > 30 mL/min 15 mg BID with food x 21 days, then 20 mg daily with largest meal

CrCl < 30 mL/min Avoid

Secondary prevention of DVT/PE

CrCl > 30 mL/min 20 mg daily with largest meal


Prophylaxis for DVT (after knee/hip replacement)

CrCl > 30 mL/min

10 mg daily WITHOUT regards to meals, start 6-10 hrs after surgery

Hip: 35 days (minimum 10 days)

Knee: 10 – 14 days


Indication and dosing:

Xarelto (rivaroxaban) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2011

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� Food increases bioavailability� Dose > 15 mg requires food to help with absorption

� Crushable� Yes; can administer with applesauce or mix with 50 mL of water

� Do not administer distal to the stomach

� Missed Doses� Administer dose as soon as possible on the same day

� Two 15 mg tablets can be taken simultaneously

• To ensure 30 mg per day, then continue BID dosing

Rivaroxaban (Xarelto®) Pearls


Rivaroxaban (Xarelto®) Pearls

� Elimination� 66% renal; 33% biliary

� Not dialyzable� High protein binding

� Boxed warnings� Premature discontinuation increases risk of thrombotic events

� Neuraxial anesthesia or spinal puncture

• Increased risk for hematomas and subsequent paralysis


Indication and dosing: Renal Dosing Nonvalvular Atrial Fibrillation

No risk factors present 5 mg BID

Patients with > 2 of the following:

Age > 80, weight < 60 kg, SCr > 1.5 2.5 mg twice a daily

CrCl < 15 mL/min or HD Avoid

Acute treatment of DVT/PE

Adult dosing 10 mg twice a day x 7 days, then 5 mg BID

Renal impairmentNo dose adjustments

NOT studied with SCr > 2.5 mg/dL or CrCl < 25 mL/min

Secondary prevention of DVT/PE after at least 6 months

of treatment

Adult dosing 2.5 mg BID

Renal impairmentNo dose adjustments

NOT studied with SCr > 2.5 mg/dL or CrCl < 25 mL/min

DVT Prophylaxis (after knee/hip replacement)

CrCl > 30 mL/min2.5 mg twice a day, start 12-24 hrs after surgery

Hip 35 days; Knee 12 days

CrCl < 30 mL/minNo dose adjustments

NOT studied in these patients

Apixaban (Eliquis®)

Apixaban (Eliquis) package insert. Bristol-Myers Squibb Company; Princeton, NJ. 2012

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Apixaban (Eliquis®) Pearls

� Grapefruit juice � May increase levels; otherwise not affected by food

� Monitor for signs and symptoms of bleeding

� Crushable� Yes; mix with 60 mL of D5W and administer immediately through

NG tube

� Missed Doses� Administer dose as soon as possible on the same day

� Do NOT double a dose to make up for a missed dose


Apixaban (Eliquis®) Pearls

� Elimination� 27% renal; biliary, and direct intestinal

� Not significantly dialyzable � High protein binding (92-94%)

� 14 % decrease in exposure

� Boxed warnings:� Premature discontinuation increases risk of thrombotic events






CrCl > 95 mL/min Not recommended (increase risk of ischemic stroke)

CrCl 51-95 mL/min 60 mg daily

CrCl 15-50 mL/min 30 mg daily

CrCl < 15 mL/min Not recommended

Acute treatment of DVT/PE; AFTER 5-10 days of parenteral

anticoagulation

CrCl > 51 mL/min 60 mg daily

CrCl 15-50 mL/min

Or

Weight < 60 kg

30 mg daily

CrCl < 15 mL/min Not recommended

Secondary prevention of DVT/PE

Not FDA approved

Edoxaban (Savaysa®)

Savaysa (edoxaban) package insert. Parsippany, NJ: Daiichi Sankyo, Inc. 2015

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Edoxaban (Savaysa®) Pearls

� Grapefruit juice � May increase levels; otherwise not affected by food

� Monitor for signs and symptoms of bleeding

� Crushable� No data available regarding crushing and/or mixing into food

� Missed Doses:� Administer dose as soon as possible on the same day

� Do NOT double a dose to make up for a missed dose

� Elimination� 50% renal; metabolism and intestinal/biliary


Edoxaban (Savaysa®) Pearls

� Not significantly dialyzable� Protein binding 55%

� 4 hour session reduced total exposure by < 7%

� Boxed warnings� Reduced efficacy in patients with CrCl > 95 mL/min

• Nonvalvular atrial fibrillation

� Premature discontinuation increases risk of thrombotic events




Edoxaban contraindicated

with good renal function?

� Nonvalvular atrial fibrillation only

� Reduced efficacy in patients with CrCl > 95 mL/min

� 50% of the dose is eliminated by the kidneys

� � rate of ischemic stroke compared to warfarin

� Blood levels are lower in patients with better renal function

• 30% less in patients with CrCl of > 80 mL/min

• 40% less in patients with CrCl > 95 mL/min


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CrCl > 50 mL/min 150 mg BID

CrCl 30-50 mL/min, AND

concurrent P-gp inhibitors

dronedarone / ketoconazole

75 mg BID

CrCl 15-30 mL/min 75 mg BID (Contraindicated per CHEST)

CrCl < 15 mL/min or HD Contraindicated per CHEST

Acute treatment and secondary prevention of DVT/PE;

AFTER 5-10 days of parenteral anticoagulation

CrCl > 30 mL/min 150 mg BID

CrCl < 30 mL/minNo dose adjustments

NOT studied in these patients

“NEW” DVT Prophylaxis after hip replacement

CrCl > 30 mL/min110 mg once, followed by 220 mg daily for

28-35 days

CrCl < 30 mL/minNo dosing recommendations provided

NOT studied

Direct Thrombin Inhibitor:

Dabigatran (Pradaxa®)


Pradaxa (dabigatran) package insert. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 2010

� Acidic environment required� Acid suppressive therapy may decrease absorption

� Not Crushable� Do not break, chew, or open capsules, and do not put in NG tube

� 75% � in absorption and potentially serious adverse reactions

� Store in original container � Prodrug, if exposed to moisture will hydrolyze to inactive form

� Missed Doses� Take as soon as possible unless it is within 6 hours of next dose


Dabigatran (Pradaxa®) Pearls

Dabigatran (Pradaxa®) Pearls

� Elimination� 80% renal

� Dialyzable

� ~ 49% can be removed over 4 hours

� Boxed warnings� Contraindicated in patients with mechanical heart valves

� Premature discontinuation increases risk of thrombotic events




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Evidence for use in Nonvalvular

Atrial Fibrillation

Efficacy and Safety in Atrial Fibrillation versus Warfarin

Dabigatran

(Pradaxa®)

Rivaroxaban

(Xarelto®)

Apixaban

(Eliquis®)

Edoxaban

(Savaysa®)

Trial RE-LY ROCKET-AF ARISTOTLEENGAGE AF-TIMI

48

Study Design Non-inferiority Non-InferiorityNon-Inferiority /

SuperiorityNon-Inferiority

Primary Dose 150 mg BID 20 mg daily 5 mg BID 60 mg daily

Warfarin TTR 64% 55% 62.2% 64.9%

Stroke / SE Superior Non-inferior Superior Non-inferior

Major Bleeding Non-inferior Non-inferior Superior Superior

ICH Superior Superior Superior Superior

GI Bleeding Greater incidence Greater incidenceNo significant

difference Greater incidence

Other↑ risk of MI vs

Placebo

ICH= intracranial hemorrhage, SE= Systemic embolism , TTR= time in therapeutic range

Evidence for use in DVT/PE

Treatment

Efficacy and Safety in DVT/PE treatment versus Warfarin

Dabigatran

(Pradaxa®)

Rivaroxaban

(Xarelto®)

Apixaban

(Eliquis®)

Edoxaban

(Savaysa®)

Trial RE-COVER I-II EINSTEIN DVT-PE AMPLIFY HOKUSAI

Recurrent VTE Non-inferior Non-inferior Non-Inferiority Non-inferior

Major bleeding Non-inferior Non-inferior /

Superior in PE trialSuperior for

apixaban

Non-inferior

Relevant bleeding Superior for

dabigatran

Non-inferior Superior for

apixaban

Superior for edoxaban

Lekura, Jona. Annals of Pharmacotherapy 49.4 (2015): 448-457.

Hazards of Warfarin

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TSOAC Advantages

� TSOACs offer several advantages over warfarin

Ruff CT, et. al. Lancet 2013, 383(9921):955–962.

Feature Warfarin TSOAC

Onset Slow Rapid

Dosing Variable Fixed

Food Interactions Yes No

Interactions Many Few

Blood Monitoring Yes No

Offset Long Short

Drug Interactions?

� TSOACs are mainly metabolized by CYP3A4 or

are substrates of P-gp

Big Inducers (PS PORCS) Big Inhibitors (G <3 PACMAN)

Phenytoin Grapefruit

Smoking Protease Inhibitors

Phenobarbital Azoles

Oxcarbazepine Cyclosporine & Cimetidine

Rifampin Macrolides

Carbamazepine Amiodarone/Dronedarone

St. John’s Wort Non-DHP CCB

Converting FROM Warfarin

Rivaroxaban

(Xarelto®)

Dabigatran (Pradaxa®)

Apixaban (Eliquis ®)

Edoxaban

(Savaysa ®)

D/C warfarin, start

rivaroxaban when

INR < 3.0

D/C warfarin, start

apixaban or dabigatran

when INR < 2.0

D/C warfarin, start

edoxaban when

INR ≤ 2.5



Apixaban (Eliquis) package insert. Princeton, NJ: Bristol-Myers Squibb Company, Inc. 2012


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Converting TO Warfarin

Dabigatran (Pradaxa ®) Rivaroxaban (Xarelto ®)

Apixaban (Eliquis ®)

Edoxaban

(Savaysa ®)

Dabigatran affects INR.

Warfarin’s effect on the INR

can be measured only after

dabigatran has been stopped

for ≥ 2 days.

Starting time of warfarin is

based on CrCl:

CrCl ≥ 50: start 3 days

before D/C dabigatran

CrCl ≥ 30-50: start 2 days


CrCl ≥ 15-30: start 1 day


CrCl < 15: no recommendation

Rivaroxaban and apixaban affects

the INR.

Discontinue the TSOAC and

initiate both warfarin and a

parenteral anticoagulant at the

time the next dose of the

TSOAC would have been due.

Edoxaban can affect the

INR. When monitoring

patient’s INR, check just

prior to edoxaban dose.

60 mg: Reduce to 30 mg

and start warfarin. Stop

edoxaban when INR ≥ 2.0

30 mg: Reduce to 15 mg

and start warfarin. Stop

edoxaban when INR ≥ 2.0

Perioperative Management

Dabigatran

(Pradaxa®)

Rivaroxaban

(Xarelto®)

Apixaban

(Eliquis®)

Edoxaban

(Savaysa®)

Switch FROM

parenteral

anticoagulants

Start dabigatran 0 to 2

hrs prior to the next

scheduled dose of the

parenteral AC;

discontinue parenteral

AC

UFH infusion: stop

infusion and initiate

simultaneously

Start rivaroxaban 0 to

2 hrs prior to the next

scheduled dose of the

parenteral AC;


AC

UFH infusion: stop

infusion and initiate

simultaneously

Start apixaban at

the next

scheduled dose

of the parenteral

AC; discontinue

parenteral AC

Start edoxaban at the

next scheduled dose of

the parenteral AC;


AC

UFH infusion: start

edoxaban 4 hrs after

stopping infusion

Switch TO

parenteral

anticoagulants

CrCl ≥ 30 – Wait 12

hrs CrCl < 30 – Wait

24 hrs AFTER the last

dose of dabigatran

before initiating

parenteral AC

Start the parenteral AC at the time the next scheduled dose of the

factor Xa inhibitor was to be administered

AC= anticoagulant

Perioperative Management

Dabigatran

(Pradaxa®)

Rivaroxaban

(Xarelto®)

Apixaban

(Eliquis®)

Edoxaban

(Savaysa®)

Procedural

Pre-op

CrCl ≥50: 1-2 days

prior to standard risk

procedures; Stop 3-5

days prior to high risk

procedures

CrCl < 50: Stop 3 to 5

days prior to standard

risk procedures;

Stop > 5 days prior to

high risk procedures

CrCl ≥30: Stop at least 24 hours prior to

standard risk procedures; Stop at least 48

hrs prior to high risk procedures

CrCl < 30: Stop at least 48 hours prior

to standard risk procedures; Stop at least

72 hours prior to high risk procedures.

Stop at least 24 hours

prior to procedures

Procedural

Post-op

Low risk surgery restart 12-24 hours post-op;

High risk surgery restart 48-72 hours post-op

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No More Monitoring?

� No routine blood monitoring

� Monitoring still necessary

� Patient education

� Correct dosing

� Transitioning of care

� Drug interactions

� Renal function

TSOAC Concerns

� Increased risk of exposure with reduced renal clearance

� Dabigatran in particular

� Short t ½ of TSOACs poses risk with non-compliance

� BID dosing

� Price and formulary issues

� The ability to reverse TSOACs

� For emergency surgery / urgent procedures

� In life-threatening / uncontrolled bleeding

Sarich, Troy C., et al. American Heart Journal 169.6 (2015): 751-757.

Reversal Based on Urgency

� Categorized into 3 groups

� No rush (> 24 hr)

� Expedited (1-24 hr)

� Emergent (1 hr)

� Intervention may need to be modified

based on clinical status

Nutescu, Edith A., et al, American Journal of Health-System Pharmacy 70.21 (2013): 1914-1929.

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Assessing Bleeding in Patients

Receiving TOSACs

� Physical examination / medication history� Perform vitals and check for external evidence of hemorrhage

� Diagnosis of internal hemorrhage� Endoscopy, CT scan, ultrasound

� Bleeding severity� Epistaxis vs > 2 g/dL drop in hemoglobin

� Laboratory tests

� Need for emergent procedures

� Allergies

� Concern for heparin-induced thrombocytopenia


Coagulation Assays

� Activated partial thromboplastin time (aPTT)

� Intrinsic pathway

� Prothrombin time (PT) & International normalized ratio (INR)

� Extrinsic and common pathway

� Thrombin time (TT)

� Directly assesses activity of thrombin

� Ecarin clotting time (ECT)

� Specific assay for thrombin generation

� A measure of direct thrombin inhibitor activity

� Anti-factor Xa

� Can calculate plasma concentrations of factor Xa

Patel, Deepa V., US Pharm 2 (2015): 18.

Utility of Coagulation Assays

Direct Thrombin

Inhibitor

Factor Xa

Inhibitors

aPTT (+/-) (-)

PT/INR (-) (+/-)

TT (+/-) (-)

ECT (+/+) (-)

Anti-factor Xa (-) (+/+)

(+/+) = Clinically reliable assay

(+/-) = May impact/variable response at supratherapeutic levels

(-) = No evidence to support use

Patel, Deepa V., US Pharm 2 (2015): 18.

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Management of Emergent

Bleeding � Stop anticoagulant

� Hemodynamic and hemostatic resuscitation

� Volume replacement

• Massive transfusion protocol

� Hemostasis of bleeding site

� Consider activated charcoal� If last dose < 2 hrs ago and patient can protect their airway

� Clotting factor supplementation

� Reversal agent


Clotting Factors for Reversing

Anticoagulants

� Prothrombin Complex Concentrates (PCC)

� Three-factor PCC (PCC3)

� Four-factor PCC (PCC4)

� Activated PCC (aPCC)

� Recombinant Factor VIIa (rFVIIa)

� Fresh frozen plasma (FFP)

PL Detail-Document, Clotting Factors for Reversing Anticoagulants Pharmacist's Letter/Prescriber’s Letter. October 2013

Factor Pearls

Product Description Pros Cons

Fresh Frozen

Plasma (FFP)

• Human plasma

containing all the

clotting factors

• Cheap

• Widely

available

• Requires cross matching

• Takes hours to thaw

• Risk of infection

Kcentra® • PCC4

(II,VII,IX,X)

• Factors are non-

activated

• Contains

proteins C & S

• Fast infusion

• Lower risk of

infection than

FFP

• Non-inferior to

FFP for

hemostasis and

lowers INR

faster

• Expensive

• Higher thrombosis risk

then FFP

• Contains small amounts

of heparin (allergy risk)

Bebulin®

Profilnine®

• PCC3 (II,IX,X)

• Non-therapeutic

amounts of factor

VII

• Small volume

• Faster than

FFP

• Low infection

risk

• Factor VII also required

• Expensive

• Bebulin® contains small

amounts of heparin

(allergy risk)


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Factor Pearls

Product Description Pros Cons

FEIBA® • aPCC (II, VII, IX, X)

• Factor VII mainly

activated (VIIa)

• Other factors in

non-activated form

• Small volume

• Fast infusion

• Lower risk of

infection than

FFP

• Expensive

• Carries 6% risk of

thrombosis due to

activated factor VII

NovoSeven

RT ®

• Recombinant

activated factor VII

• Not a blood

product

• Small volume

• Expensive

• Short duration of action

• Not recommended as

monotherapy

• Thrombosis risk similar

to FEIBA®


FEIBA=

Antidotes for TOSACs

� Dabigatran

� Idarucizumab (Praxbind®)

� Oral factor Xa inhibitors

� Andexanet alfa (Phase 3 trials)

Antidotes for TOSACs

� Idarucizumab (Praxbind®)

� Recently approved for the reversal of dabigatran

� Humanized monoclonal antibody fragment (Fab)

� ~350 x higher affinity to dabigatran than thrombin

� Neutralizes anticoagulant effect within minutes

� Advantages

• Target specific, will not affect other anticoagulants

• Should not be pro-thrombotic

� Rebound effect

• 12-24 hrs later, may need to re-dose

Praxbind (idarucizumab) package insert. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 2015

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Antidotes for TSOACs

� Andexanet alfa (Phase 3 trials)

� Inactive human recombinant factor Xa inhibitor

� Factor Xa decoy that targets factor Xa inhibitors

� Potential to reverse Xa inhibitors and low molecular

weight heparin

Crowther, Mark, et al., Circulation 130.23 (2014): 2105-2126.


Bleeding� Dabigatran

� Withhold drug


� Activated charcoal (if last dose < 2 hrs ago)

� Hemodialysis

� Reversal strategies in order of preference

• Idarucizumab

• aPCC

• PCC4

• PCC3 plus rFVIIa (PCC4)



Bleeding � Oral factor Xa inhibitors

� Withhold drug


� Activated charcoal (if last dose < 2 hrs ago)

� Not significantly dialyzable

� Reversal strategies in order of preference

• PCC4

• aPCC

• PCC3 plus rFVIIa (PCC4)

• PCC3


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Conclusion

� TSOACs offer unique advantages over warfarin

� Anticoagulation services can play a pivotal role managing

the different TSOAC nuances

� Current limited data highlights the importance of post

marketing reporting

� Conventional laboratory assays do not correlate well with

bleeding or reversal of anticoagulation

� A protocolized approach to reversing anticoagulation

should be established based on urgency

True or False

Assessment Questions � Dabigatran’s bioavailability will be decreased in patients

who take proton pump inhibitors

� True

� Food increases absorption of the 20 mg rivaroxaban dose

but does not affect the 10 mg rivaroxaban dose

� True

� All TSOACs require 5-10 days of parenteral

anticoagulation prior to treatment for a DVT or PE

� False

Questions?

Objectives - DCPA · Review the pharmacology, indications, and place in therapy of the...

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