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Novel Anticoagulation

Agents

James W. Haynes, MD

Department of Family Medicine

Univ of TN Health Science Center (Chattanooga)

DISCLOSURES

Objectives

• Understand mechanism of action behind the

NOAC agents

• Understand FDA approved indications/dosing for

each agent

• Understand the risks of using these agents

NOAC Comparison DRUG DABIGATRAN

(PRADAXA)

RIVAROXABAN

(XARELTO)

APIXIBAN

(ELIQUIS)

MECH OF ACTION Direct Thrombin

Inhibitor

Direct Xa inhibitor Direct Xa inhibitor

INDICATIONS

DOSING

RENAL DOSING

PEAK LEVELS

ARTHROPLASTY

DVT PROPH

COAG TEST

EFFECT

ATRIAL FIBRILLATION

TRIALS

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RE-LY Trial • Compared dabigatran to warfarin in 18,113 patients with AF at

risk for stroke (PROBE - Prospective, randomized, outcome blinded trial)

• The mean CHADS 2 2.1, and median follow-up duration was 2 years

• Randomly assigned to 1 of 2 blinded doses of dabigatran, 110 or 150 mg twice daily, or open-label, dose-adjusted warfarin to study primary outcome of stroke or systemic embolization.

• Event rates of 1.71% per year in the warfarin group; 1.54% per year in the dabigatran 110 mg twice daily group( P <.001 for noninferiority to warfarin); and 1.11% per year with dabigatran, 150 mg twice daily ( P <.001 for superiority to warfarin).

• Significantly lower rates of intracerebral hemorrhage were noted with both doses of dabigatran when compared with warfarin.

RE-LY Trial • The higher dose of dabigatran yielded a higher rate of GI Bleed

but a similar rate of major bleeding as compared with warfarin

• All-cause mortality was lower with dabigatran (4.13% per year for warfarin; 3.75% per year for dabigatran, 110 mg twice daily; and 3.64% per year for dabigatran, 150 mg twice daily) but did not reach statistical significance ( P = .13 and P = .051 for the 110 and 150 mg twice daily doses, respectively)

• Following RE-LY, dabigatran, 150 mg twice daily, was approved to reduce the risk of stroke and systemic embolism in patients with NVAF worldwide

• Although patients with severe renal impairment (CrCl <30 mL/min) were excluded from RE-LY, the FDA approved a dose of 75 mg twice daily for patients with CrCl 15 to 30 mL/min, based on pharmacokinetic modeling

ROCKET-AF • Randomized, double-blind, double-dummy study carried

out over a median follow-up of 1.9 years comparing rivaroxaban with warfarin in 14,264 patients with NVAF who were at increased risk for stroke

• The study included patients with high stroke risk with a mean CHADS2 score of 3.5, with 55% of patients having a prior stroke or transient ischemic attack (TIA)

• Study arm patients received fixed-dose rivaroxaban, 20 mg once daily (15 mg daily for those with CrCl 30–49 mL/min)

• Rivaroxaban was superior to warfarin (hazard ratio [HR], 0.88; P = .015) in preventing stroke or systemic embolism

• Rivaroxaban reduced the frequency of hemorrhagic strokes compared with warfarin by 41% (HR, 0.59)

ARISTOTLE • 18,201 patients with NVAF and at least 1 additional risk factor for stroke

(mean CHADS2 , 2.1) were evaluated in a randomized, double-blind study comparing apixaban (5 mg twice daily [2.5 mg twice daily in high-risk patients]) with warfarin; median follow up was 1.8 yrs

• The lower dose was used for those with 2 or more of the following factors associated with increased drug exposure: age greater than 80 years, body weight less than 60 kg, or serum creatinine level greater than 1.5 mg/dL. About 19% of these patients had a previous TIA, stroke, or systemic embolism

• Apixaban was superior to warfarin in preventing stroke or systemic embolism (HR with apixaban, 0.79; 95% confidence interval [CI], 0.66–0.95; P <.001 for noninferiority; P = .01 for superiority)

• Apixaban also caused less bleeding and resulted in lower mortality (HR, 0.89; 95% CI, 0.80–0.99; P = .047) and reduced hemorrhagic stroke by 49% compared with warfarin ( P = <.001)

“Aristotle Relies on Rockets”

NOAC Comparison DRUG DABIGATRAN

(PRADAXA)

RIVAROXABAN

(XARELTO)

APIXIBAN

(ELIQUIS)

MECH OF

ACTION

Direct Thrombin

Inhibitor

Direct Xa inhibitor Direct Xa inhibitor

INDICATIONS Stroke Prev Nonvalv

AFib

Stroke Prev Nonvalv

AFib

Stroke Prev Nonvalv

AFib

DOSING

RENAL DOSING

PEAK LEVELS

ARTHROPLASTY

DVT PROPH

COAG TEST

EFFECT

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Vasa 2014, 43: 353-364

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Acute DVT/PE

• All 3 agents were NON-INFERIOR to Warfarin

• Lower rates major bleeding

• Rivaroxaban, Apixaban fewer bleeding events

• Dabigatran non-inferior bleeding event rate

VTE Recurrence

• Dabigatran NON-INFERIOR to Warfarin

• Lower bleeding risk

• All 3 superior to placebo prevention VTE recurrence

• Apixaban did not have significantly higher rates of

long-term major bleeding (Dab + Riv did)

NOAC Comparison DRUG DABIGATRAN

(PRADAXA)

RIVAROXABAN

(XARELTO)

APIXIBAN

(ELIQUIS)

MECH OF

ACTION

Direct Thrombin

Inhibitor

Direct Xa inhibitor Direct Xa inhibitor

INDICATIONS Stroke Prev Nonvalv

AFib

-VTE Tx

-Recurrent VTE Prev

Stroke Prev Nonvalv

AFib

-VTE Tx

-Recurrent VTE Prev

-VTE Proph after

Hip/Knee Surg*

Stroke Prev Nonvalv

AFib

-VTE Tx

-Recurrent VTE Prev

-VTE Proph after

Hip/Knee Surg*

DOSING

RENAL DOSING

PEAK LEVELS

ARTHROPLASTY

DVT PROPH

COAG TEST

EFFECT

NOAC Comparison DRUG DABIGATRAN

(PRADAXA)

RIVAROXABAN

(XARELTO)

APIXIBAN

(ELIQUIS)

MECH OF

ACTION

Direct Thrombin

Inhibitor

Direct Xa inhibitor Direct Xa inhibitor

INDICATIONS Stroke Prev Nonvalv

AFib

-VTE Tx

-Recurrent VTE Prev

Stroke Prev Nonvalv

AFib

-VTE Tx

-Recurrent VTE Prev

-VTE Proph after

Hip/Knee Surg*

Stroke Prev Nonvalv

AFib

-VTE Tx

-Recurrent VTE Prev

-VTE Proph after

Hip/Knee Surg*

DOSING 150 mg bid 20 mg daily 5 mg bid

RENAL DOSING 75 mg bid

(CrCl 15-30 mL/min)

15 mg daily

(CrCl 15-50 mL/min)

2.5 mg bid

(Age >80; Wt < 60

kg; sCr >1.5)

PEAK LEVELS

ARTHROPLASTY

DVT PROPH

COAG TEST

EFFECT

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NOAC Comparison DRUG DABIGATRAN

(PRADAXA)

RIVAROXABAN

(XARELTO)

APIXIBAN

(ELIQUIS)

MECH OF

ACTION

Direct Thrombin

inhibitor

Direct Xa inhibitor Direct Xa inhibitor

INDICATIONS Stroke Prev

Nonvalv AFib

-VTE Tx

-Recurrent VTE

Prev

Stroke Prev Nonvalv

AFib

-VTE Tx

-Recurrent VTE Prev

-VTE Proph after

Hip/Knee Surg*

Stroke Prev Nonvalv

AFib

-VTE Tx

-Recurrent VTE Prev

-VTE Proph after

Hip/Knee Surg*

DOSING 150 mg bid 20 mg daily 5 mg bid

RENAL DOSING 75 mg bid

(CrCl 15-30

mL/min)

15 mg daily

(CrCl 15-50 mL/min)

2.5 mg bid

(Age >80; Wt < 60

kg; sCr >1.5)

PEAK LEVELS 2 h 2 - 4 h 3 h

ARTHROPLASTY

DVT PROPH

COAG TEST

EFFECT

NOAC Comparison DRUG DABIGATRAN

(PRADAXA)

RIVAROXABAN

(XARELTO)

APIXIBAN

(ELIQUIS)

MECH OF

ACTION

Direct Thrombin

Inhibitor

Direct Xa inhibitor Direct Xa inhibitor

INDICATIONS Stroke Prev Nonvalv

AFib

-VTE Tx

-Recurrent VTE Prev

Stroke Prev Nonvalv

AFib

-VTE Tx

-Recurrent VTE Prev

-VTE Proph after

Hip/Knee Surg*

Stroke Prev Nonvalv

AFib

-VTE Tx

-Recurrent VTE Prev

-VTE Proph after

Hip/Knee Surg*

DOSING 150 mg bid 20 mg daily 5 mg bid

RENAL DOSING 75 mg bid

(CrCl 15-30 mL/min)

15 mg daily

(CrCl 15-50 mL/min)

2.5 mg bid

(Age >80; Wt < 60

kg; sCr >1.5)

PEAK LEVELS 2 h 2 - 4 h 3 h

ARTHROPLASTY

DVT PROPH

10 mg daily 2.5 mg bid

COAG TEST

EFFECT

Use of Assays • Dabigatran

• Thrombin Clotting Time (TCT) most sensitive assay to determine presence

• aPTT – if normal then Dabigatran not contributing significantly to bleeding

• Rivaroxaban

• PT – if normal suggests level is not high; does not exclude presence

• No effect on TCT

• Apixiban

• Normal PT or aPTT DOES NOT rule out significant anticoag effect

• NOTE: RECORDING LAST DOSE TIME IMPORTANT FOR INTERPRETATION

NOAC Comparison DRUG DABIGATRAN

(PRADAXA)

RIVAROXABAN

(XARELTO)

APIXIBAN

(ELIQUIS)

MECH OF

ACTION

Direct Thrombin

Inhibitor

Direct Xa inhibitor Direct Xa inhibitor

INDICATIONS Stroke Prev Nonvalv

AFib

-VTE Tx

-Recurrent VTE Prev

Stroke Prev Nonvalv AFib

-VTE Tx

-Recurrent VTE Prev

-VTE Proph after Hip/Knee

Surg*

Stroke Prev Nonvalv

AFib

-VTE Tx

-Recurrent VTE Prev

-VTE Proph after

Hip/Knee Surg*

DOSING 150 mg bid 20 mg daily 5 mg bid

RENAL DOSING 75 mg bid

(CrCl 15-30 mL/min)

15 mg daily

(CrCl 15-50 mL/min)

2.5 mg bid

(Age >80; Wt < 60 kg;

sCr >1.5)

PEAK LEVELS 2 h 2 - 4 h 3 h

ARTHROPLASTY

DVT PROPH

10 mg daily 2.5 mg bid

COAG TEST

EFFECT

INCR: aPTT, TCT

INCR Anti-factor Xa

INCR or =: PT, aPTT

NO CHANGE: TCT

INCR Anti-factor Xa

INCR or =: PT, aPTT

NO CHANGE: TCT

SWITCHING AGENTS

SWITCHING TO(FROM) A NOAC

Transition FROM Warfarin

to NOAC

Transition TO Warfarin

from NOAC

- Monitor INR closely

- Start NOAC when INR <

2

- Parenteral Anticoag not

necessary

Dabigatran

- Start Warfarin 1-3 days prior to d/c

- Consider parenteral “bridging” if

high risk

Apixiban / Rivaroxaban

- DO NOT overlap agents

- STOP Agent – START Warfarin

when next dose due

- Consider parenteral “bridging” if

high risk

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SWITCHING TO(FROM) A NOAC Transition FROM

UFH/LMWH to NOAC

Transition TO UFH/LMWH

from NOAC

- Start NOAC 2 hrs after

UFH discontinued

- Start NOAC at next

sched LMWH dose

- Start UFH/LMWH when

next dose NOAC due

Risk of major bleeding in different indications for new

oral anticoagulants: Insights from a meta-analysis of

approved dosages from 50 randomized trials

International Journal of Cardiology, 2015-01-20, Volume 179, Pages 279-287

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COST

• ~ 7K pt on warfarin or NOAC studied over 33 month

period

• Out of pocket for patient - 5x higher

• Insurer costs - 15 x higher; ~ $900 / month

• Warfarin - most “$4 lists”; NOACs $250-350/mo

Advantages

• Convenience for patients

• No lab monitoring

• Lower rates of MAJOR bleeds

• No bridging therapy

• Potentially less HIT (decr use bridging therapy)

• Less drug / diet interactions

Disadvantages • No antidote / reversal agents

• Measuring Compliance / Drug concentration

• Dabigatran - aPTT normal; little to none present

• Rivaroxaban - PT normal; little to no presence

• Higher GI bleeding rate

• Higher cost

• Contraindicated mechanical heart valves / severe renal impairment

Other Issues

• Dabigatran - Dyspepsia (33%)

• P-gp transport system

• CYP3A4 enzyme system

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Drug interactions

Ideal Candidate

• < 65

• NL Renal Function

• Uncontrolled INR w/ compliance

• Non-compliance monitoring

NOT!!!!!!

• Mechanical Valves

• Dabigatran - incr risk bleeding and stroke vs.

Warfarin

• Renal dysfunction - check at baseline (especially

dabigatran)

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NOAC Comparison DRUG DABIGATRAN

(PRADAXA)

RIVAROXABAN

(XARELTO)

APIXIBAN

(ELIQUIS)

MECH OF

ACTION

Direct Thrombin

Inhibitor

Direct Xa inhibitor Direct Xa inhibitor

INDICATIONS Stroke Prev Nonvalv

AFib

-VTE Tx

-Recurrent VTE Prev

Stroke Prev Nonvalv AFib

-VTE Tx

-Recurrent VTE Prev

-VTE Proph after Hip/Knee

Surg*

Stroke Prev Nonvalv

AFib

-VTE Tx

-Recurrent VTE Prev

-VTE Proph after

Hip/Knee Surg*

DOSING 150 mg bid 20 mg daily 5 mg bid

RENAL DOSING 75 mg bid

(CrCl 15-30 mL/min)

15 mg daily

(CrCl 15-50 mL/min)

2.5 mg bid

(Age >80; Wt < 60 kg;

sCr >1.5)

PEAK LEVELS 2 h 2 - 4 h 3 h

ARTHROPLASTY

DVT PROPH

10 mg daily 2.5 mg bid

COAG TEST

EFFECT

INCR: aPTT, TCT

INCR Anti-factor Xa

INCR or =: PT, aPTT

NO CHANGE: TCT

INCR Anti-factor Xa

INCR or =: PT, aPTT

NO CHANGE: TCT

QUESTIONS?

REFERENCES 1. Ferns SJ, Naccarelli GV. New Oral Anticoagulants – Their role in stroke

prevention in high-risk patients with Atrial Fibrillation. Med Clin N Am 2015,

99: 759-780

2. Vandiver JW, et al. Is a novel anticoagulant right for your patient? J Fam

Prac, Jan 2014, 63(1): 22-28

3. Hirschl M, Kundi M. New oral anticoagulants in the treatment of acute venous

thromboembolism – a systematic review with indirect comparisons. VASA

2014, 43: 353-364

4. Shivanshu M, et al. Use of novel oral anticoagulation agents in atrial

fibrillation: current evidence and future perspectives. Cardiovasc Diagn Ther

2014, 4(4): 314-323.

BACKGROUND

NOAC Comparison DRUG DABIGATRAN RIVAROXABAN APIXIBAN

MECH OF ACTION Direct Thrombin Inhibitor Direct Xa inhibitor Direct Xa inhibitor

INDICATIONS Stroke Prev Nonvalv AFib

-VTE Tx,

-VTE Prev

Stroke Prev Nonvalv AFib

-VTE Tx,

-Recurrent VTE Prev

-VTE Proph after Hip/Knee Surg

Stroke Prev Nonvalv AFib

- VTE Proph after Hip/Knee Surg

DOSING 150 mg bid 20 mg daily 5 mg bid

RENAL DOSING 75 mg bid

CrCl 15-30 mL/min

15 mg daily

CrCl 15-50 mL/min 2.5 mg bid

Age > 80; Wt < 60 Kg;

sCr > 1.5 BIOAVAILABILITY 3-7% 80-100% 50%

PEAK PLASMA LEVELS 2 h 2 - 4 h 3 h

HALF-LIFE

12-17 h 5-9 h 8-15 h RENAL ELIMINATION > 80% 66% 25-27%

MONITORING None None None

COAG TEST EFFECT

INCR: aPTT, TCT

INCR or =: PT

INCR Anti-factor

Xa

INCR or =: PT,

aPTT

NO CHANGE:

INCR Anti-factor Xa

INCR or =: PT,

aPTT

NO CHANGE: TCT

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RESULTS

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NOAC Comparison DRUG DABIGATRAN RIVAROXABAN APIXIBAN

MECH OF

ACTION

Direct Thrombin

Inhibitor

Direct Xa inhibitor Direct Xa inhibitor

INDICATIONS Stroke Prev Nonvalv

AFib

-VTE Tx

-VTE Prev

Stroke Prev Nonvalv AFib

-VTE Tx

-Recurrent VTE Prev

-VTE Proph after Hip/Knee

Surg

Stroke Prev Nonvalv

AFib

- VTE Proph after

Hip/Knee Surg

DOSING 150 mg bid 20 mg daily 5 mg bid

RENAL DOSING 75 mg bid

(CrCl 15-30 mL/min)

15 mg daily

(CrCl 15-50 mL/min)

2.5 mg bid

(Age >80; Wt < 60 kg;

sCr >1.5)

PEAK PLASMA

LEVELS

2 h 2 - 4 h 3 h

HALF-LIFE 12 – 17 h 5 – 9 h 8 - 15 h

COAG TEST

EFFECT

Acute Bleeding

• Mild to Mod

• Stop Medication & Supportive Measures

• Acute Ingestion or Overdose

• Activated Charcoal if ingestion within 3 hours

Severe Bleeding

• Hemodialysis for Dabigatran

• Most effective intervention

• 75-80 units/kg Activated Prothrombin Complex

Concentrate (aPCC)

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Perioperative Use

• Primarily based on expert opinion