Novel Oral Anticoagulants(NOAC)

Dan Moellentin, PharmD, BCPS, Associate Professor Husson

University

Strokes in Atrial Fibrillation

• 1/5 of strokes are caused by a. fib• 1/3 cardiac arrhythmias hospitalizations • 2 million Americans affected by a. fib

~50% are anti-coagulated?

What would be the best anticoagulation

Fast onset Antidote

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. fib

Vitamin K antagonistDrug• 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##

Patient Case #1

• The majority of warfarin is elimination via metabolism– Clinical example---pt post bowel resection--

Genetic Variance in 2C9

• Patients 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 variant

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

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 Medicare 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”.

Cytochrome P450 Interactions

• Drugs 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, verapamil

Drugs Affecting Absorption Case #1

Cholestyramine or Colestipol • Get Dan to write case

Warfarin

MOA: Vitamin K Antagonist (VKA)Initial dose: 10 mg PO x 2 days, then dose based on INRHalf-life: 40 hoursMonitoring: • 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.

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”

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 2013

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 INR

150 mg twice daily 20 mg once daily 5mg twice daily

Majority of Elimination

Hepatic CYP• 2C9

80% Renal Renal 66% 25% Hepatic • CYP 3A427% Renal

Plasma Protein Binding

99% 35% 92 – 95% 87%

Dialyzable No 60% No No Data

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 daily

Hepatic Dose Adjustments

None

Avoid Use • CrCL < 15 mL/min

• Mechanical prosthetic heart valves

• Bioprosthetic heart valves

• CrCL < 15 mL/min

• Moderate to Severe hepatic impairment

• Prosthetic heart valves

24h

LAST DOSEUFH IV

INFUSION

FIRST DOSE RIVAROXABAN

FIRST DOSE DABIGATRAN

FIRST DOSE APIXABAN

Switching from UFH to PO Anticoagulant

FIRST DOSEUFH 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 UFH

Coagulation Cascade

Pradaxa® (dabigatran)

MOA: Direct Thrombin InhibitorHalf-life: 12 to 17 hoursDosing: • 150mg PO twice daily • CrCL 15-30 mL/min – 75 mg twice daily

Adverse Effects: • Dyspepsia • GI bleeding

Prescribing Information Drug Interactions for Dabigatran

• USA– Amiodarone, dronedarone, quinidine, verapamil,

clarithromycin, and ketoconazole, rifampin.• Canada – Amiodarone, dronedarone, verapamil, quinidine, rifampicin– Contraindications: Ketoconazole

• EMA– Strong P-gp inhibitors: Amiodarone,, verapamil, quinidine,

clarithromycin – P-gp inducers: rifampicin– Contraindications: Ketoconazole, itraconazole, tacrolimus,

dronedarone, cyclosporine

Xarelto® (rivaroxaban)

MOA: Xa InhibitorHalf-life: 5 to 9 hoursDosing: • A.Fib: – CrCL >50 mL/min• 20 mg once daily

– CrCL 15-50 mL/min• 15 mg once daily

Adverse Effects

Eliquis® (apixaban)

MOA: Xa InhibitorHalf-life: 12 hoursDosing: 5mg PO twice daily• 2.5 mg twice daily– If ≥2 of the following• ≥ 80 yoa• ≤ 60 kg• ≥ 1.5 mg/dL

Adverse Effects:

Pt casen #1 dabigitran plus amiodarone

• Pgp- problem is fda lit

P-glycoproteins (P-gp)?

P-gps are efflux drug transporters

P-gp

P-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-gp

P-gp in the body

P-gp Substrates, Inhibitor, Inducer

P-gp Substrates P-gp Inhibitors P-gp InducersAmiodarone Amiodarone Prazosin

Atorvastatin Atorvastatin St. John’s Wort

Dabigatran Carvedilol

Digoxin Diltiazem

Diltiazem Dipyridamole

Lidocaine Dronedarone

Lovastatin Lidocaine

Nadolol Lovastatin

Nicardipine Quinidine

Pravastatin Propranolol

Propranolol NIcardipine

Quinidine NIfedipine

Rivaroxaban Simvastatin

Simvastatin Verapamil

Verapamil

Clinically Significant P-gp Inhibitor• ≥ 1.25 ratio for AUCi/AUC Ratio and Cmaxi,ss/Cmax,ss Ratio

1.25

Ranolazine

Amiodarone (800mg x 1 wk)

Amiodarone (400 mg x 5 wks)

Verapamil

Quinidine

Quinidine

Ranolazine

Carvedilol (Males)

Captopril

0 0.5 1 1.5 2 2.5 3

Cmaxi ,ss/Cmax,ss RatioAUCi/AUC Ratio

Clinically SignificantP-gp Inhibitors

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

Verapamil Felodipine Nifedipine

Lidocaine Verapamil

Nicardipine

Quinidine

Verapamil

Dabigatran P-gp interactions

Dabigatran + P-gp inhibitor• Results in increased dabigatran concentrations

and adverse events

P-gp Substrate P-gp InhibitorDabigatran Dronedarone

Amiordarone

Quinidine

Verapamil

Rivaroxaban P-gp InteractionsRemoved from the intestines by P-gp

Don’t use with rivaroxabanGreater risk with decreased renal function

Strong P-gp and 3A4 Inhibitors

Moderate P-gp and 3A4 Inhibitors

Ketoconazole AmiodaroneItraconazole Dronedarone

DiltiazemVerapamilFelodipineQuinidineRanolazine

Apixaban P-gp Interactions

Apixaban• ↑Apixaban conc. – Itraconazole, ketoconazole, ritonavir, and

clarithromycin

Case #3 rivaroxaban

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%

Is Rivaroxaban Dosing Appropriate?

Half-life: 5 to 9 hoursNon-valvular A. Fib• 20 mg PO once dailyPhase II trials suggested that 10 mg twice daily could be safer than 20 mg once daily

FDA WORDING

• INADEQUATE ON DABIGITRAN• DOSING LIKELY WRONG FOR DVT PROP ON

RIVAROXAPIXIBAN 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 PGP

No NOAC Are Approved for ACS

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: 3.3515 mg: 3.620 mg: 5.06

Apixaban APPRAISE 2.5 mg BID: 3.2%10 mg QD: 5.5%10 mg BID and 20 mg QD were stopped because of too many bleeding episodes

2.5 mg BID: 1.7810 mg QD: 2.45

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 bleeding • 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)

Risk Assessment

Physicians will need assess the patient’s risk for• Thromboembolism

– CHADS2 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)

Reversal and Monitoring of nOAC

Reversal of Dabigatran

Management of Dabigatran Bleeding

Management Algorithm for Dabigatran Bleeding

Management for bleeding

from Xa Inhibitors

Management Algorithm for Rivaroxaban and Apixaban

Bleeding

Reversal of Dabigatran

• Since 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.

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 – Octaplex

• Activated– Feiba NF (Factor VII blocker bypassing function) Factor VII

Blockers)• Only factor VII is activated

Antibody Antidote for Dabigatran?

Boehringer Ingelheim: manufacture 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.

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.

So What is the “Right” Answer?Pre-clinical studiesStudies showing PCC only improves labs not bleeding in apixaban and rivaroxaban

Warfarin

Reversal• Is warfarin really “reversed?”• Example intracranial hemorrhage (ICH)….

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 apixaban

Numbers of post-marketing cases of ICH and retroperitoneal hemorrhages

Apixaban

Rivaroxaban

Dabigatran

Post Marketing

• Incidence of stroke, major bleeding, ICH

Post Marketing

• Bleeding Risk with Dabigatran in the Frail Elderly NEJM http://www.nejm.org/doi/full/10.1056/NEJMc1112874

SurgeryDabigatran• CrCL ≥ 50mL/min stop 1-2 days prior to surgery• CrCL < 50mL/min stop 3-5 days prior to surgeryRivaroxaban• Stop ≥ 48 hours prior to surgery for moderate to severe

bleeding risk• Stop ≥ 24 hours prior to surgery for normal risk of bleedingApixaban • Stop ≥ 48 hours prior to surgery for moderate to severe

bleeding risk• Stop ≥ 24 hours prior to surgery to low risk of bleeding

Monitoring

Dabigatran• 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 Level

Monitoring for Dabigatran

Monitoring on Xa Inhibitors(Rivaroxaban & Apixaban)

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

Dosing Adjustments

Hepatic Impairment

ApixabanMild• No dose reduction is requiredModerate • No data available Severe• Not recommended

Hepatic Impairment

Rivaroxban• Don’t use – Moderate and severe impairment– Liver disease that involves bleeding disorders

Renal Impairment

Apixaban• 2.5 mg twice daily if 2 or more of the following

exist1. ≥ 80 years of age2. Weight ≤ 60 kg3. 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”

Renal Impairment

Rivaroxaban• 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

Renal ImpairmentDabigatran

• 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 use

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 risks

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)

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.

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.

Incidence of Myocardial Infarction (MI)

Dabiagatran• Displays a significantly greater risk for MI/Acute

Coronary Syndromes (ACS).Rivaroxaban• Lower risk for MI/ACS

When to discontinue

ApixabanRivaroxabanDabigatran

Cardioversion

• Dabigatran has been shown to be an acceptable alternative to warfarin

• No studies have evaluated rivaroxaban or apixaban

Maybe a slide

• whaT PERCENTAGE OF NEW RX FOR A FIB ARE NON WARFARIN DRUGS

Summary