New Oral Anticoagulants: A Review

Babak Moini, MDVeterans Affairs Hospital

Noon Lecture Series

Acknowledgment:Some of the slides were borrowed from Amanda

Miller Phar.D.

Case168 male with hx of DM, CHF and prior ischemic

CVA admitted for new afib. He has a hx of non-compliance.

CHADs2: 4.Which anticoagulant to send him home with?

Oral Anticoagulants Available in US

Coumadin

warfarin

1954

Pradaxa®

dabigatran

201

0

Xarelto®rivaroxab

an

2011

Eliquis®apixaban

2012

Mechanism of ActionMedication Mechanism of ActionCoumadin (warfarin) Vitamin K AntagonistPradaxa (dabigatran)

Direct Thrombin Inhibitor

Xarelto (rivaroxaban) Factor Xa Inhibitor Eliquis (apixaban) Factor Xa Inhibitor

http://www.healio.com/~/media/Images/News/Online/Orthopedics/2009/12_December/01/79_fig_400_307_57368.gif

rivaroxabanapixaban

dabigatran

Pharmacology:Coumadin Dabigatran Rivaroxaba

nApixaban

Bioavailability

100% 3-7% 60-100% 50%

Protein bound

99% 30% 90-95% 80-85%

Metabolism CYP Conjugation CYP CYP

Half Life 40hrs 12-17hrs 5-9hrs 12hrs

Onset of action

72hrs 1-2hrs 2-4hrs 2-4hrs

Elimination Liver Renal Renal Renal

Indications: USCoumadin Dabigatrn Rivaroxaba

nApixaban

Afib + + (RELY) + (ROCKET-AF)

+ (Aristotle)+ (AVERROES)

DVT/PE + Not yet. (RECOVER) +

(EINSTEIN)Post TKA/THADVT prophylaxis

+ + + (RECORD 1-3)

+ (ADVANCE)

Not yet approved: Rivaroxaban for prophylaxis of DVT in medically ill patients (MAGELLAN). Rivaroxaban vs Enoxaparin. NI < 30 days, superior at 35 days.

Usual Dosing (A fib) •Once daily, titrate to INR 2-3Warfarin•150 mg BID •75 mg BID (CrCl 15-30 ml/min) Dabigatran•20 mg daily•15 mg daily (CrCl 15-50 ml/min) Rivaroxaban• 5 mg BID• 2.5 mg BID if any 2 of the

following: age > 80, wt < 60kg, SCr > 1.5

Apixaban

Usual Dosing (VTE)Only FDA-approved agent = rivaroxaban

VTE Prophylaxis (knee/hip surgery) 10mg once daily (up to 35 days) No renal dose (CrCl < 30 ml/min avoid)

VTE Treatment: 15 mg BID x 3 weeks then 20mg daily No renal dose (CrCl < 30 ml/min avoid)

Perioperative Recommendations • Hold 1-2 days before procedure • CrCl < 50 hold 3-5 days

Dabigatran

• Low bleed risk hold 1 day• CrCl < 30/ low risk hold 2 days• High bleed risk hold 2 days• CrCl < 30/ high risk hold 4 days

Rivaroxaban

• Low bleed risk hold x 1 day • High bleed risk hold x 2 daysApixaban

Dabigatran PI, Blood 2012;119:3016-23

Major Side Effects:Bleeding: varied definition in each study.

GI ICHMajor (drop in Hgb by 2, life threatening).

Dabigatran: Pills are made in acidic content, hence has 20%

rate of GI side effects. ? Observed increase risk of GI bleeding.

Monitoring Levels:Coumadin: INRNew Oral anticoagulants: no standardized

studies. No accurate quantitative measures.

Dabigatran: ECT, Thrombin clotting timeRivaroxaban: special anti-Xa activityAbixaban special anti-Xa activity

Drug-Drug Interactions:No where as severe as with Warfarin.Dabigatran: P-glycoprotein, pro-drug.

Needs acidic environment, avoid co-administration with PPI.

Rivaroxaban: CYP-450 and P-glycoprotein. Caution with dual inhibitors (Ketoconazole,

Itroconazole, Clarithromycin). No dose adjustments needed.

Abixaban: CYP3A4 and P-glycoprotein.Decrease dose to 2.5mg bid in dual inhibitors.

Switching To/From Warfarin

Medication Recommendations for Conversion

DabigatranStop warfarin, initiate dabigatran when INR < 2

Initiate warfarin 3 days before D/C dabigatran

Rivaroxaban

Stop warfarin, initiate rivaroxaban when INR < 2-3

Initiate warfarin with bridging 24 hours after D/C rivaroxaban

ApixabanStop warfarin, initiate apixaban when INR < 2

Initiate warfarin with bridging when next apixaban dose is due.

Gonsalves Et al. Mayo Clinic Proc. 5-2013

Treatment of Bleeding:No evidence based guidelines.Remember that unlike Coumadin, the new OAC will

continuously bind to factor Xa or thrombin, hence making FFP less useful.

Current available Rx for life threatening active bleeding: based on case reports. Factor VII PCC: 3 and 4 factor concentrates. HD: only for Dabigatran. Large volume of distribution. Charcoal

Trials vs Warfarin for A Fib RE-LY

DAB vs WARROCKET-AFRIV vs WAR

ARISTOTLEAPIX vs WAR

Comparator Dabigatran Rivaroxaban ApixabanDesign Open-label,

blind outcomes, noninferiority

Double-blind, noninferiority

Double-blind, noninferiority

Sample size n = 18,113 n = 14,264 n = 18,201Randomization D 150mg BID

D 110mg BIDW (INR 2-3)

R 20mg daily* W (INR 2-3)

A 5mg BID* W (INR 2-3)

InclusionCriteria Nonvalvular AF

with increased stroke risk

Nonvalvular AF with prior

stroke or >2 risk factors

Nonvalvular AF with >1 risk

factor for stroke

Exclusion CrCl < 30 CrCl < 30 CrCl < 25* Dose reductions for renal impairment

Trials vs Warfarin for A fibRE-LY

DAB vs WARROCKET-AFRIV vs WAR

ARISTOTLE APIX vs WAR

Average age (yrs) 71 73 70

Mean CHADS2 2.1 3.5 2.1 0-1 32% 0% 34% 2 36% 13% 36% 3-6 32% 87% 30%Prior TIA/stroke 20% 55% 19%TTR (INR @ goal) 64% 55% 62% Median follow-up 2 yrs 1.9 yrs 1.8 yrs

Primary endpoint Stroke (ischemic, hemorrhagic) + systemic embolism

Major Findings:RELY

Dabigatran 110mg NI to Warfarin (1.53% vs 1.69%). Dabigatran 150mg superior to Warfarin ONLY if

compared with sub-optimal INR subgroup (1.11 % vs 1.69%).

Major bleeding less with 110mg (2.71 vs 3.11%). ROCKET-AF

Rivaroxaban NI to Warfarin (2.1% vs 2.4%)Less ICH or fatal bleeding (0.4% vs 0.8% )

ARISTOTLE:Abixaban Superior to Warfarin (1.27% vs 1.6% )Less Major bleeding (1.4% vs 2.1% )

Key Safety Endpoints (% per year) RE-LY ROCKET AF ARISTOTLE

D110 D150 WAR RIV WAR APIX WAR

1o bleeding endpoint* 2.71 3.11 3.36 14.9 14.5 2.13 3.09

Major bleed 2.71 3.11 3.36 5.55 5.42 2.13 3.09

GI bleeding 1.12 1.51 1.02 3.2 2.2 0.76 0.86

Intracranial hemorrhage

0.23 0.3 0.74 0.5 0.7 0.33 0.8

*: Primary safety endpoint:o RE-LY major hemorrhage o ROCKET-AF major + non-major clinically relevant bleeding o ARISTOTLE ISTH (Int Soc Thromosis & Hemostasis) major bleeding

Figure 3 Forest plot for (A) major bleeding, (B) intracranial bleeding, and (C) gastrointestinal bleeding, new oral anticoagulants (NOA) versus warfarin in patients with AF.

http://dx.doi.org/10.1016/j.amjcard.2012.03.049

Quick Review of Evidence- Based Medicine:

I A: Systemic review of multiple RCTs / multiple RTCs B: High quality single RTC

II: A: Systemic review of cohort studies B: High quality cohort studie(s)

III: Systemic review of Case/Control studies / Case Control studies

IV Case reports

IV Expert opinion

Anticoagulation Recommendations (AF) Risk/CHADS2 CHEST 2012 AHA/ASA

Low RiskCHADS2 = 0

No therapy > antithrombotic therapy (2B)

Aspirin (75-325mg) > OAC (2B) or aspirin + clopidogrel (2B)

Aspirin (1A)

Intermediate CHADS2 = 1

OAC > no therapy (1B)

OAC > aspirin (2B) or aspirin + clopidogrel (2B)

OAC unsuitable or pt refuses: aspirin + clopidogrel over aspirin monotherapy (2B)

Warfarin (1A)

Aspirin, if patient preference (1A)

High RiskCHADS2 > 2

OAC > no therapy (1A)

OAC > aspirin (1B) or aspirin + clopidogrel (1B)

OAC unsuitable or pt refuses: aspirin + clopidogrel over aspirin monotherapy (1B)

Dabigatran 150mg BID > warfarin (2B)

Warfarin (1A)Dabigatran (1B)Rivaroxaban (2A)Apixaban (1B)

OAC = oral anticoagulation

Chest 2012; 141:e531S-e575SStroke 2012;43: 3442-3453

New OAC: Pros:

Easy administration Immediate effect Much less food and drug

interactions One dose fits all The names sound so

much cooler than WARFARIN.

Cons: Expensive Inability to monitor

compliance Short duration: loss of

effect with a single missed dose

No safe/reliable antidotes ? Bleeding. Observational

bias vs real difference. Renal dosing

Take home message:Coumadin still remains the drug of choice for many

patients due to cost, past experience and known side effects.

Many new OAC are in the pipeline, expect a barrage of pharma bombardments, must remain objective as many of the studies have different inclusion/exclusion criteria, definition of end points and side effects.

Each patient may benefit from a different type of OAC based on comorbidities and drug side effect profile.

Watch out for recall bias with the new OAC among your own colleagues.

Patient compliance is a major factor: remember with the new OAC one missed dose means a lot!

The End!