Novel Oral Anticoagulants - PowerPoint Presentation

Slide1

Novel Oral Anticoagulants(NOAC)

Dan

Moellentin

,

PharmD

, BCPS, Associate Professor

Husson

UniversitySlide2

Strokes in Atrial Fibrillation1/5 of strokes are caused by a. fib1/3 cardiac arrhythmias hospitalizations

2 million Americans affected by a. fib

~

50%

are anti-coagulated? Slide3

What would be the best anticoagulationFast onset

AntidoteSlide4

Brief History of Anticoagulation in Atrial Fibrillation (a. fib)

Warfarin was approved in 1954

INR wasn’t created by the World Health Organization until the 1980’s

Until 2009, warfarin was considered the gold standard for anticoagulation in a. fib.

Now there are three new oral anticoagulants FDA approved for anticoagulation in a. fibSlide5

Vitamin K antagonist

Drug

Warfarin

Blocks vitamin K dependent clotting factors creation, by inhibiting the vitamin

vitamin

K epoxide

reductase

complex 1 (VKORC1)

Vitamin K

epoxside

is responsible for the regeneration of vitamin K in the vitamin K cycle by blocking VKORC1

Inhibit vitamin K epoxide

reducatase

thus interfering with levels of II, V, VII, and IX

LOOK UP LEVELs##Slide6

Patient Case #1The majority of warfarin is elimination via metabolismClinical

example---

pt

post bowel resection--Slide7

Genetic Variance in 2C9Patients with 2C9 gene variance

require lower doses

for therapeutic INR and are at increased risk of bleeding

Activity of 2C19 and 2C9 are genetically determined, 2C9 is more important as it metabolizes the most potent enantiomer, S-warfarin.

20% of Caucasians, 5% Africa Americans (AA), 2% Asians have a least 1 gene variantSlide8

Genetic variations in Vitamin K epoxide reductase complex 1 (VKORC1)

Loss of function, results in increased sensitivity to warfarin and increased potential for drug interactions because VKORC1 does not function normally to produce vitamin K dependent clotting factors (II, VII, IX, X, proteins C and S)

37% of Caucasians, 14% of AAs, 89% of Asians have at least one variant of VKORC1 Slide9

Clinical Significance of Genetic Testing before Warfarin initiation

Not all centers have on-site testing

Genetic

testing costs about $

200

Is it paid for by

M

edicare part D or private insurance?

Adding a few extra days to hospitalization is

expensive

Is it only useful in guiding early dosing,

ie

. does it just save one dose?

“Drug interactions with warfarin may negate the influence of genetic variations and must be considered”. Slide10

Cytochrome P450 InteractionsDrugs that inhibit 2C9 Bactrim, fluconazole,

amiodarone

,

fluvastatin

,

lovastatin,

voriconazole

, metronidazole, acetaminophen 2g daily for more than a week, cimetidine 400mg daily or less, omeprazole at higher doses,

3A4 Strong Inhibitors

Erythromycin,

diltiazem

,

nefazadone

, verapamilSlide11

Major Drug Interactions with Warfarin

Elevates

INR

Interference

with CYP metabolism

Amiodarone

2C9 and 3A4 Inhibitor

Androgens

Erythromycin

, Clarithromycin, Ciprofloxacin, Azoles

3A4 Inhibitors

Celecoxib

2C9 Inhibitor

Cimetidine (400

mg QD or less)

2C9 and 3A4 Inhibitor

Azithromycin,

tetracyclines,

levofloxacin, moxifloxacinMetronidazole , Fenofibrate, Gemfibrozil, SMZ/TMP2C9 InhibitorsLovastatin and simvastatinQuinidineThrombolyticsThyroid HormonesVitamin E

Lower INR:

Barbiturates; 2C9 and 3A4 Inducers

Adapted from UW Medicine Anticoagulation Services; Warfarin Drug Interactions and Pharmacology Weekly; Comprehensive Drug Reference TableSlide12

Drugs Affecting Absorption Case #1Cholestyramine

or

Colestipol

Get Dan to write caseSlide13

WarfarinMOA: Vitamin K Antagonist (VKA)

Initial dose: 10 mg PO x 2 days, then dose based on INR

Half-life: 40 hours

Monitoring:

If INR is ≤ 0.5 from the target range, keep the same dose and check INR in 1-2 weeks.

Once INR is stabilized, one INR reading up to every 12 weeks is adequate.Slide14

Only One is Also Approved for DVT/PE Treatment/Prophylaxis

Rivaroxaban

“Treatment

of deep vein thrombosis (DVT

)

pulmonary

embolism”

“Reduction

in the risk of

recurrence

of

DVT”

“PE

for the prophylaxis of DVT, which may lead to PE in patients

undergoing knee

or hip replacement

surgery” Slide15

Newly Approved PO anticoagulants

All 3 are FDA indicated for

“reducing the risk of stroke and systemic embolism in patients with non-

valvular

atrial fibrillation”

Direct Thrombin Inhibitor

Pradaxa® (dabigatran)

Approved in 2010

Xa

Inhibitors

Xarelto

® (rivaroxaban)

Approved in

2011

Eliquis® (Apixaban)

Approved in 2013Slide16

Medication

Warfarin

Dabigatran

Rivaroxaban

Apixaban

Class

VKA

Direct

Thrombin Inhibitor

Xa

Inhibitor

Xa

Inhibitor

Half-life

40 hours

12

to 17 hours

5 to 9 hours

12 hours

Dosing for A. fib

10mg x 2 days, then based on INR150 mg twice daily20 mg once daily5mg twice dailyMajority of EliminationHepatic CYP2C980% RenalRenal 66%25% Hepatic CYP 3A427% RenalPlasma Protein Binding99%35%92 – 95%87%Dialyzable No60%NoNo DataSlide17

Medication

Warfarin

Dabigatran

Rivaroxaban

Apixaban

Renal

Dose Adjustments

Based

on INR

CrCL

15-30 mL/min

75 mg twice daily

CrCL

15-50 mL/min

15 mg once daily

If ≥2 of

the following

≥ 80 yoa

≤ 60 kg≥ 1.5 mg/dL2.5 mg twice dailyHepatic Dose AdjustmentsNoneAvoid UseCrCL < 15 mL/minMechanical prosthetic heart valvesBioprosthetic heart valvesCrCL < 15 mL/minModerate to Severe hepatic impairmentProsthetic heart valvesSlide18

24h

LAST DOSE

UFH IV INFUSION

FIRST DOSE RIVAROXABAN

FIRST DOSE DABIGATRAN

FIRST DOSE APIXABAN

Switching from UFH to PO AnticoagulantSlide19

FIRST DOSE

UFH IV INFUSION

LAST DOSE RIVAROXABAN

LAST DOSE DABIGATRAN

(

CrCl

> 30mL/min)*

LAST DOSE APIXABAN

12h

24h

*For patients with a

CrCl

<30mL/min, 24 hours before starting UFH infusion is recommended

12h

Switching from PO anticoagulant to UFHSlide20

Factor

Xa

Inhibitors

Rivaroxaban

Apixiban

Direct Thrombin Inhibitor

Dabigatran

Bivalirudin

Slide21

Coagulation CascadeSlide22

Pradaxa® (dabigatran)

MOA:

Direct Thrombin Inhibitor

Half-life:

12 to 17 hours

Dosing

:

150mg PO twice daily

CrCL

15-30 mL/min

75 mg twice daily

Adverse

Effects:

Dyspepsia

GI bleedingSlide23

Prescribing Information Drug Interactions for Dabigatran

USA

Amiodarone,

dronedarone

, quinidine, verapamil, clarithromycin, and ketoconazole, rifampin.

Canada

Amiodarone,

dronedarone

, verapamil, quinidine,

r

ifampicin

Contraindications:

Ketoconazole

EMA

Strong P-

gp

inhibitors: Amiodarone

,, verapamil, quinidine, clarithromycin

P-

gp

inducers: rifampicinContraindications: Ketoconazole, itraconazole, tacrolimus, dronedarone, cyclosporineSlide24

Xarelto® (rivaroxaban)

MOA:

Xa

Inhibitor

Half-life:

5 to 9 hours

Dosing:

A.Fib

:

CrCL

>50 mL/min

20 mg once daily

CrCL

15-50 mL/min

15 mg once daily

Adverse EffectsSlide25

Eliquis® (apixaban)

MOA:

Xa

Inhibitor

Half-life: 12 hours

Dosing:

5mg PO twice daily

2.5 mg twice daily

If ≥2 of the following

≥ 80 yoa

≤ 60 kg

≥ 1.5 mg/

dL

Adverse Effects: Slide26

Pt casen #1 dabigitran

plus

amiodarone

Pgp

- problem is

fda

litSlide27

P-glycoproteins (P-gp)?

P-

gps

are efflux drug transporters Slide28

P-gpP-

gp

function is to excrete or protect the tissues from xenobiotic absorption.

Also referred as PGY1, multidrug resistance protein-1 (MDR1).

Member of the adenosine triphosphate (ATP) binding cassette (ABC)

gene

ABCB1 is the gene that encodes for P-

gpSlide29

P-gp in the bodySlide30

P-gp Substrates, Inhibitor, Inducer

P-

gp

Substrates

P-

gp

Inhibitors

P-

gp

Inducers

Amiodarone

Amiodarone

Prazosin

Atorvastatin

Atorvastatin

St.

John’s

Wort

Dabigatran

Carvedilol

DigoxinDiltiazemDiltiazemDipyridamoleLidocaineDronedaroneLovastatinLidocaineNadololLovastatinNicardipineQuinidinePravastatinPropranololPropranololNIcardipineQuinidineNIfedipineRivaroxaban

Simvastatin

Simvastatin

Verapamil

VerapamilSlide31

Clinically Significant P-gp Inhibitor

≥ 1.25 ratio for

AUCi

/AUC Ratio and

Cmax

i

,ss

/

Cmax,ss

Ratio

1.25

Clinically Significant

P-

gp

InhibitorsSlide32

Source http://www.medscape.org/viewarticle/467503

P-

gp

Substrates

P-

gp

Inhibitors

P-

gp

Inducers

Digoxin

Amiodarone

Amiodarone

Diltiazem

Atorvastatin

Diltiazem

Quinidine

Diltiazem

Nicardipine

VerapamilFelodipineNifedipine LidocaineVerapamilNicardipineQuinidineVerapamilSlide33

Dabigatran P-gp interactions

Dabigatran + P-

gp

inhibitor

Results in increased dabigatran concentrations and adverse events

P-

gp

Substrate

P-

gp

Inhibitor

Dabigatran

Dronedarone

Amiordarone

Quinidine

VerapamilSlide34

Rivaroxaban P-gp Interactions

Removed from the intestines by P-

gp

Don’t

use with rivaroxaban

Greater risk with decreased renal function

Strong P-

gp

and 3A4 Inhibitors

Moderate

P-

gp

and 3A4

Inhibitors

Ketoconazole

Amiodarone

Itraconazole

Dronedarone

Diltiazem

VerapamilFelodipineQuinidineRanolazineSlide35

Apixaban P-gp Interactions

Apixaban

↑Apixaban conc.

Itraconazole

, ketoconazole, ritonavir, and clarithromycinSlide36

Case #3 rivaroxaban Slide37

Time in Therapeutic Range (TTR) for Warfarin

TTR

% of days that the patients INR is from 2.0 to 3.0

“TTR in all the other modern warfarin-controlled studies of

anticoagulatns

ranged from 63% to 73%”

Phase III Trials’ TTR %

RELY (Dabigatran)

64%

Rocket AF (Rivaroxaban)

55%

Aristotle (Apixaban)

62.2%Slide38

Is Rivaroxaban Dosing Appropriate?Half-life: 5 to 9 hours

Non-

valvular

A. Fib

20 mg PO

once daily

Phase II trials suggested that 10 mg twice daily could be safer than 20 mg once dailySlide39

FDA WORDINGINADEQUATE ON DABIGITRANDOSING LIKELY WRONG FOR DVT PROP ON RIVAROX

APIXIBAN DOSING CORRECTNESS IS UNKNOWN

WHAT IS DIFFERENT ON LAST 2 DRUGS IS THAT DECISION FOR DOSE ADJUSTMENT IS NOW A PROVIDER JUDGEMENT BASED ON 3A4 AND PGPSlide40

No NOAC Are Approved for ACSSlide41

Medications

Phase II Trials

Clinically

Significant Bleeding

Hazard Ratio

Dabigatran

RE-DEEM

75 mg:

4.3%, 150 mg: 7.8%,

P < 0.001

150

mg

4.27 (95 % CI 1.86 -9.81)

Rivaroxaban

ATLAS ACS-TIMI 46

Percentages were not listed,

P <0.0001

10 mg:

3.35

15 mg: 3.6

20 mg: 5.06Apixaban APPRAISE2.5 mg BID: 3.2%10 mg QD: 5.5%10 mg BID and 20 mg QD were stopped because of too many bleeding episodes2.5 mg BID: 1.7810 mg QD: 2.45Slide42

Safety of Triple Antithrombotic Therapy in ACS Patients

Single Antiplatelet + NOAC

Aspirin

↓’d the occurrence of major adverse cardiovascular events (MACE)

HR 0.70, (95% CI 0.59- 0.84)

BUT ↑’d clinically relevant

b

leeding

HR 1.79 (95% CI 1.54-2.09)

Dual Antiplatelet +NOAC

Aspirin + Clopidogrel

↓’d the occurrence

of MACE

HR 0.87 (95% CI 0.80-0.95)

More than two fold

↑

in clinically

relevant bleeding

HR 2.34 (95% CI 2.06-2.66)Slide43

Risk AssessmentPhysicians will need assess the patient’s risk for

Thromboembolism

CHADS

2

Score ≥ 2 = probably require triple antithrombotic therapy

Hemorrhaging

“ Clinicians should strive to limit the use of dual antiplatelet agents with concurrent

antithrombotics

in patients who are at the highest risk for

thromoembolic

events and ensure that these patients are instructed to report any signs and

sympotms

of bleeding or recurrent thrombosis”

Dager

W

PharmD PCPS (AQ Cardiology)Slide44

Reversal and Monitoring of nOACSlide45
Slide46
Slide47

Reversal of DabigatranSlide48

Management of Dabigatran BleedingSlide49

Management Algorithm for Dabigatran BleedingSlide50
Slide51

Management for bleeding from Xa InhibitorsSlide52

Management Algorithm for Rivaroxaban and Apixaban BleedingSlide53

Reversal of DabigatranSince dabigatran directly blocks thrombin and does not decrease the coagulation factors, using coagulation factors like, PCC, FFP is NOT expected to be completely effective as a reversal agent.

The best method of reversing dabigatran is to be excreted out by the kidneys.Slide54

What are PCCs?

Prothrombin

Complex Concentrates (PCC)

Note: No PCC is FDA approved for reversing anticoagulants

Three Factor (II, IX, X)

FDA approved

Profilnine

®

SD

Bebulin

®

VH

Four Factor (II, VII, IX, X)

Unactivated

(NOT FDA Approved)

Beriplex

P/N

OctaplexActivatedFeiba NF (Factor VII blocker bypassing function) Factor VII Blockers)Only factor VII is activatedSlide55

Antibody Antidote for Dabigatran?

Boehringer Ingelheim

:

m

anufacture

dabigatran (Pradaxa

®)

Currently

developing

and studying

pre-clinically

a

humanized antibody fragment (Fab) that could be used as a reversal agent for dabigatran.

Rats were given dabigatran and “there was a rapid, dose-dependent decrease in bleeding time after IV injection of Fab”

Additionally, the Fab reversed clotting ex vivo as well.Slide56

Reversal of Rivaroxaban?

Phase I Trials

Four Factor PCC (Factor II, VII, IX and X)

After 3 days of rivaroxaban and one dose of PCC PT and ETP was statistically significantly decreased

PRT4445

New recombinant protein that blocks

Xa

inhibitors by serving as a decoy.

The

manufacters

of PRT4445 has report its safe and tolerable and claims it reverses

Xa

inhibitors in 5 minutes and last 3 hours, however, the study isn’t available online yet.Slide57

So What is the “Right” Answer?

Pre-clinical studies

Studies showing PCC only improves labs

not bleeding

in apixaban and

rivaroxabanSlide58

WarfarinReversalIs warfarin really “reversed?”

Example intracranial hemorrhage (ICH)….Slide59

Reversal of Warfarin Slide60

Reversal of Apixaban and Rivaroxaban?

Urgent Reversal for life threatening hemorrhaging

If 2 hours or less from ingestion

Activated charcoal

Give 2 units of FFP

Give 25 units/kg of

Bebulin

® over 10 minutes (unactivated three-factor PCC)

Check PT/INR and anti-

Xa

levels to validate the reversalSlide61

Gastrointestinal Bleeding

Higher risk

for DVT/PE

treatment

vs. DVT/PE prophylaxis after hip/knee replacement surgery

Rivaroxaban 10 mg once daily

Hip: 35 days

Knee: 12 days

Maybe a dose-dependent effect

Dabigatran and rivaroxaban

Higher risk than apixabanSlide62

Numbers of post-marketing cases of ICH and retroperitoneal hemorrhagesApixaban

Rivaroxaban

DabigatranSlide63

Post MarketingIncidence of stroke, major bleeding, ICHSlide64

Post MarketingBleeding Risk with Dabigatran in the Frail Elderly NEJM h

ttp

://www.nejm.org/doi/full/10.1056/NEJMc1112874Slide65

Surgery

Dabigatran

CrCL

≥ 50mL/min stop 1-2 days prior to surgery

CrCL

< 50mL/min stop 3-5 days prior to

surgery

Rivaroxaban

Stop ≥ 48 hours prior to surgery for moderate to severe bleeding risk

Stop ≥ 24 hours prior to surgery for normal risk of bleeding

Apixaban

Stop ≥ 48 hours prior to surgery for moderate to severe bleeding risk

Stop ≥ 24 hours prior to surgery to low risk of bleedingSlide66

MonitoringDabigatran

Useful in establishing if drug in present or not

Normal

aPTT

: barely any

dabigatran

present

TT (Thrombin Time): linear dose-response curve for

dabigatran

, NOT after steady-state.

Rivaroxaban and Apixaban??

aPTT

PT/INR

Anti-

Xa

LevelSlide67

Monitoring for DabigatranSlide68

Monitoring on Xa Inhibitors(Rivaroxaban & Apixaban)Slide69

Why Not Just Use Anti-Xa Assays to Monitor Xa InhibitorsSlide70

Intrathecal/Epidural

Recommended duration elapsed

before

Injection

Warfarin

When INR <1.5

Dabigatran

72 hours (greater duration for renal impairment)

Recommended duration elapsed

after

injection

Warfarin

Restart in 2 hours

Dabigatran

Restart in 2 hoursSlide71
Slide72
Slide73

Dosing AdjustmentsSlide74

Hepatic ImpairmentApixaban

Mild

No dose reduction is required

Moderate

No data available

Severe

Not recommendedSlide75

Hepatic ImpairmentRivaroxban

Don’t use

Moderate and severe impairment

Liver disease that involves bleeding disordersSlide76

Hepatic ImpairmentPradaxaSlide77

Renal ImpairmentApixaban

2.5 mg twice daily if 2 or more of the following exist

≥ 80 years of age

Weight ≤ 60 kg

Scr

≥ 1.5 mg/

dL

Currently per package insert there is “no date inform use in patients with CrCl <15 min/ml or on dialysis”Slide78

Renal ImpairmentRivaroxaban

A. fib

CrCl >50 ml/min

20 mg daily with dinner

CrCl 15-50 ml/min

15 mg daily with dinner

Don’t use if CrCl <15ml/min

Treatment of DVT, PE and decreasing the risk of another DVT and PE

Don’t use if CrCl <30 ml/min Slide79

Renal Impairment

Dabigatran

80% excreted

renally

~60% is removed by dialysis

Half-life > 24 hours during renal impairment

CrCL

15 to 30mL/min

75mg twice daily

< 15mL/min or on dialysis :

Don’t useSlide80

Institute for Safe Medication Practices (ISMP)ISMP

Federally certified, nonprofit organization dedicated to patient safety by

Education on safe medication use

Compile and examine medication errors, side effects, and near misses.

Distribute up to date medication safety news, provide ways of preventing errors, and tools to decrease risksSlide81

ISMP 1st Quarter Watch 2012

Rivaroxaban

356

Reports of

severe, damaging, or deadly adverse effects

44

%: thrombotic

events

Majority: PE

Appearing in prophylaxis for DVT/PE post surgery and in younger patents than dabigatran adverse effects

(average age 66)

Dabigatran

Bleeding was appearing in elderly patients (average 80 years old)Slide82

ISMP 2012 2nd Quarter Watch

Dabigatran

The odds of recorded death from dabigatran were about

five fold greater

than warfarin.

Rivaroxaban

The odds of recorded death from rivaroxaban were about less than two times greater than warfarin.

10 mg once daily vs. 20 mg once daily

10 mg once daily

7 fold greater

odds of a recoded

emoblic

-thrombotic occurrence.Slide83

FDA Draft Briefing Document for the Cardiovascular and Renal Drugs Advisory committee (CRDAC) for Rivaroxaban

“Mean

compliance rates ranged from a low of 95.2% (North America, warfarin arm) to a high of 97.1% (Eastern Europe,

rivaroxaban

arm

)”

Day 1-30: % of warfarin naïve patients with an INR in 2-3 range

30.68%

It wasn’t until day 181-360 that over 50% warfarin naïve patients

By Day 181-360 50% of warfarin naïve patients had an INR of 2-3.Slide84

Incidence of Myocardial Infarction (MI)

Dabiagatran

Displays a

significantly greater

risk for MI/Acute Coronary Syndromes (ACS).

Rivaroxaban

Lower risk for MI/ACSSlide85

When to discontinueApixaban

Rivaroxaban

DabigatranSlide86

CardioversionDabigatran has been shown to be an acceptable alternative to warfarin

No studies have evaluated rivaroxaban or apixaban Slide87

Maybe a slidewhaT PERCENTAGE OF NEW RX FOR A FIB ARE NON WARFARIN DRUGSSlide88

Summary