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Oral Anticoagulants Update
Elizabeth Renner, PharmD, BCPS, BCACP, CACP
Outpatient Cardiology and Anticoagulation
Objectives
• List the direct oral anticoagulant (DOAC) drugs currently
available
• Describe advantages and disadvantages to DOAC use
• Compare efficacy and safety of DOACs with warfarin
• Describe adverse effect profile of DOACs
• Determine which patients are good candidates for DOAC therapy
vs warfarin
Warfarin
Kinetics
• Absorption: complete
• Distribution: 99% protein binding
– Only FREE warfarin is available for use at VKORC1
• Metabolism: broken down by cytochrome P450 enzymes in the liver
– R-warfarin – primary via 3A4
– S-warfarin (SERIOUS WARFARIN) – primary via 2C9
• 2C9 inhibitors will RAISE INR significantly.
• 3A4 inhibitors will RAISE INR to a lesser extent.
• Elimination: 92% renal
LOTS of reasons why genetics can have effects on warfarin
Factors that affect warfarin dosing
• Body size
• Age
• Renal function
• Liver function
• Drug-drug interactions
• Dietary vitamin K intake
• Acute & chronic illness
• Smoking
• Alcohol
• Physical activity
• Genetics
• Warfarin manufacturer
Warfarin
PROS
• Effective
• Inexpensive
• INR monitoring
• Reversible
CONS
• Variable Dosing
• INR Monitoring
• Drug-drug interactions
• Lifestyle interactions
• Requirement for
anticoagulation care
provider
Other Oral Options?
TSOACs / DOACs / NOACs
• Current favorite acronym: DOAC (Direct Oral AntiCoagulant)
• Mechanisms of action
– DIRECT binding to active sites of factor II (thrombin) or Xa
– DabigaTran (Pradaxa) – T for THROMBIN
– rivaroXaban (Xarelto), apiXaban (Eliquis), edoXaban (Savaysa) – factor Xa
• Cost per 30 days = $300-400
• Reversible?
The Clotting Cascade
What can we use DOACs for?
The Big Three:
• (non-valvular) Atrial Fibrillation
• Treatment of Venous Thromboembolism (VTE)
– Prevention of Recurrent VTE
• Post-joint-replacement VTE Prophylaxis
Still Being Investigated:
• VTE Associated with Cancer
• VTE Associated with Hypercoagulable State
• Patients with Bioprosthetic Heart Valves
• With Dual Antiplatelet Therapy (DAPT)
Not For Use In:
• Mechanical Heart Valves
• Left Ventricular Assist Devices
Dabigatran (Pradaxa)
• Absorption: 3-7% bioavailable
– Dosage form relies on low gastric pH
– No opening/crushing capsules
Dabigatran (Pradaxa)
• Absorption: 3-7% bioavailable
– Dosage form relies on low gastric pH
– No opening/crushing capsules
• Distribution: 35% protein bound
• Metabolism: metabolized readily after absorption from
dabigatran etexilate to the active moiety, dabigatran
– Gut: p-glycoprotein
• Elimination: 80% renal
– t1/2 = 12-17 hours in healthy people
Dabigatran (Pradaxa®)
• Dosage Forms
– Capsules: 150 mg, 110 mg, 75 mg
– Do not break, chew, or open capsules before administration. Keep
in original bottle.
• Monitoring
– Serum creatinine
• Adverse Effects
– Risk of bleeding
– Dyspepsia (11.3%)
Dabigatran in Atrial Fibrilation: RE-LY
P < 0.001 superiority
P = 0.31
Note: Dabigatran
150 mg increased the
rate of GI bleeding
(p<0.001),
decreased ICH
(p<0.001) when
compared to
warfarin.
Dabigatran in Atrial Fibrilation: RE-LY
Dabigatran in VTE: RE-COVER
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
warfarin (INR 2-3) dabigatran 150mg BID
2.1
2.4
Rate of Recurrent VTE
P < 0.001 for noninferiority
Dabigatran in VTE: RE-COVER
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
warfarin (INR 2-3) dabigatran 150mg BID
1.9
1.6
Rate of Major Bleeding
Other Clinical Trials for Pradaxa
• RE-ALIGN: Mechanical Heart Valves
• RE-SONATE: prevention of recurrent VTE vs placebo
• RE-MEDY: prevention of recurrent VTE vs warfarin
• RE-NOVATE: prevention of VTE after hip replacement surgery (vs
enoxaparin)
Dabigatran Dosing
VTE prevention after
hip-replacement
surgery
Crcl 30ml/min or above 220mg daily
Crcl less than 30ml/min Avoid
Crcl 50ml/min or above
with P-gp inhibitor
220mg daily
Crcl less than 50ml/min
with P-gp inhibitor
Avoid
Xa Inhibitors
Rivaroxaban (Xarelto)
• Absorption: 66-100% bioavailable
– Better absorption with smaller doses & with food
• Distribution: 92-95% protein binding
• Metabolism:
– Gut: p-glycoprotein
– Liver: CYP450 3A4
• Elimination: 66% renal
– T1/2 : 5-12 hours
Rivaroxaban (Xarelto®)
• Dosage Forms
– Tablets: 20 mg, 15 mg, 10 mg
– Breakable/Crushable
• Monitoring
– Renal function
• Adverse Effects
– Bleeding risk
Rivaroxaban in Atrial Fib: ROCKET-AF
0
0.5
1
1.5
2
2.5
Warfarin Rivaroxaban
2.2
1.7
Rate of stroke or systemic embolism (%)
P<0.001 for non-inferiority
Rivaroxaban in Atrial Fib: ROCKET-AF
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
Warfarin Rivaroxaban
3.4 3.6
Rate of major bleeding (%)
Rivaroxaban in VTE: EINSTEIN
2.1 2.1
3
1.8
0
0.5
1
1.5
2
2.5
3
3.5
Einstein DVT Einstein PE
Rate of Recurrent VTE
Rivaroxaban
Warfarin
P<0.001 for
non-
inferiorityP=0.003 for non-
inferiority
Rivaroxaban in VTE: EINSTEIN
0.8
1.1
1.2
2.2
0
0.5
1
1.5
2
2.5
Einstein DVT Einstein PE
Rate of Major Bleeding (%)
Rivaroxaban
Warfarin
P=0.21
P=0.03
Other Rivaroxaban Clinical Trials
• Einstein Choice: Rivaroxaban 10mg daily for extended
prophylaxis of VTE
• RECORD 1-4: post-joint-replacement VTE prophylaxis
• PIONEER: low-dose riva + P2Y12 vs. ultra-low-dose riva + DAPT
vs. VKA + DAPT for post-PCI afib patients
Rivaroxaban Dosing
Apixaban (Eliquis)
• Absorption: 50% bioavailable
– No effect of food
• Distribution: 92-95% protein binding
• Metabolism:
– Gut: p-glycoprotein
– Liver: CYP450 3A4
• Elimination: 27% renal
– T1/2 : 7-15 hours
Apixaban (Eliquis®)
• Dosage Forms
– Tablets: 5 mg, 2.5 mg
– Breakable, crushable
– May be administered without regard to food
• Monitoring
– Serum creatinine
• Adverse Effects
– Risk of bleeding
Apixaban in Atrial Fibrillation: ARISTOTLE
0
0.5
1
1.5
2
2.5
3
Warfarin Apixaban
1.6
1.27
Rate of Stroke or Systemic Embolism (%)
P=0.01 for superiority
Apixaban in Atrial Fibrillation: ARISTOTLE
0
0.5
1
1.5
2
2.5
3
Warfarin Apixaban
1.69
0.96
Rate of Major Bleed (%)
P<0.001
Apixaban in VTE: AMPLIFY & AMPLIFY-EXT
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
Warfarin Apixaban
2.72.3
Rate of Recurrent VTE (%) in AMPLIFY
P<0.001 for
non-inferiority
0
1
2
3
4
5
6
7
8
9
Apixaban 2.5mg
BID
Apixaban 5mg BID Placebo
1.7 1.7
8.8
Rate of Recurrent VTE (%) in AMPLIFY-EXT
P<0.001 for
superiority of
both doses
vs placebo
Apixaban in VTE: AMPLIFY & AMPLIFY-EXT
0
0.5
1
1.5
2
2.5
3
Warfarin Apixaban
1.8
0.6
Rate of Major Bleeding (%) in AMPLIFY
P<0.001
0
0.5
1
1.5
2
2.5
3
Apixaban 2.5mg BID Apixaban 5mg BID Placebo
0.2 0.1
0.5
Rate of Major Bleeding (%) in AMPLIFY-EXT
Apixaban: Other Clinical Trials
• AVERROES: atrial fib trial vs. ASA
• ADVANCE 1-3: post-joint-replacement VTE prophylaxis
Apixaban Dosing
Extended VTE treatment Without concomitant P-
gp/CYP3A4 inhibitor
2.5mg BID
With concomitant P-
gp/CYP3A4 inhibitor
Avoid
Edoxaban (Savaysa)
• Absorption: 62% bioavailable
– No effect of food
• Distribution: 55% protein binding
• Metabolism:
– Gut: p-glycoprotein
• Elimination: 50% renal
– T1/2 : 10-14 hours
Edoxaban (Savaysa®)
• Dosage Forms
– Tablets: 15mg, 30mg, 60mg
– May be administered without regard to food
• Monitoring
– Renal function
• Adverse Effects
– Risk of bleeding
Edoxaban Clinical Trials
• ENGAGE AF TIMI 48 (atrial fibrillation)
– Efficacy: non-inferior to warfarin
– Safety: less bleeding than warfarin
• HOKUSAI (VTE treatment)
– Efficacy: non-inferior to warfarin
– Safety: less bleeding than warfarin
Edoxaban Dosing
Indication Dose Crcl 15-
50ml/min
Crcl >95
ml/min
Body weight
< 60kg
P-gp
inhibitor
Atrial
fibrillation
60mg daily 30mg daily Do not use No
adjustment
No
adjustment
DVT/PE 60mg daily
(after 5-10
days of
parenteral)
30mg daily No
adjustment
30mg daily 30mg daily
Post-joint
replacement
30mg daily
DOAC Trial Data Summary
Atrial Fibrillation DVT/PE treatment
stroke prevention
(compared to
warfarin)
rates of bleeding
(compared to
warfarin)
rate of recurrent VTE
(compared to LMWH
bridged warfarin)
rates of bleeding
(compared to
warfarin)
Pradaxa
(dabigatran) superior same same same
Xarelto
(rivaroxaban) same same same same
Eliquis
(apixaban) superior superior same superior
Savaysa
(edoxaban) same superior same superior
DOAC Drug-Drug Interactions
• Dabigatran (substrate of p-glycoprotein)
– Inducers (rifampin): avoid co-administration
– Inhibitors (dronedarone, ketoconazole): dose reduce or avoid (see
prescribing info)
– Verapamil: separate by 2 hours
• Xa Inhibitors (substrates of CYP 3A4 & p-gp)
– Dual inducers (carbamazepine, phenytoin, phenobarb, rifampin, St.
John’s wort): avoid coadministration
– Dual inhibitors (ketoconazole, itraconazole, ritonavir,
clarithromycin): reduce dose or avoid (see prescribing info)
Reversal Agents
• Supportive therapies (all anticoagulants)
– Fresh frozen plasma, fluids, blood products
• Prothrombin complex concentrates (all anticoagulants)
– 3-Factor: factors II, IX, X
– 4-Factor: factors II, VII, IX, X
• Warfarin: Vitamin K
• Dabigatran: idarucizumab (Praxbind)
• Xa Inhibitors: andexanet alfa (not available yet)
Peri-Procedural Management
PLEASE DON’T “BRIDGE” DOACs!!
The Ideal DOAC Patient
• Diagnosed with one of the ‘Big Three’
• Good kidney function
• Compliant with medications
• Average body size
• Not on strong p-gp or 3A4 inhibitors or inducers
• History of unstable INRs not related to medication non-
compliance
• Commercially insured
Patient-Centered Care
• Indication & clinical data
• Patient preferences
• Don’t make assumptions
• Utilize manufacturer assistance when appropriate
• Beware the donut hole
Clinical References at Your Fingertips
• Anticoagulationtoolkit.org
• European Heart Rhythm Associate Practical Guide on the Use of
Non-Vitamin K Antagonist Anticoagulants in Patients with Non-
Valvular Atrial Fibrillation
References
• Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; January 2012.
• Connolly SJ et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. NEJM. 2009; 361:1139-1151
• Schulman S et al. Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism. NEJM 2009; 361:2342-2352.
• Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; November 2011.
• Patel MR. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. NEJM 2011; 365:883-891.
• The Einstein Investigators. Oral Rivaroxaban for Symptomatic Venous Thromboembolism. NEJM 2010; 363:2499-2510.
• Eliquis [Package insert]. Princeton, NJ: Bristol-Myers Squibb Company. July, 2016.
• Granger CB et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. NEJM 2011; 365:981-992.
• Agnelli G et al. Oral Apixaban for the Treatment of Acute Venous Thromboembolism. NEJM 2013; 369:799-808.
• Agnelli G et al. Apixaban for Extended Treatment of Venous Thromboembolism. NEJM 2013: 368;699-708.
• Savaysa [package insert]. Parsippany, NJ. Daiichi Sankyo, Inc. 2015.
• Giugliano RP et al. Edoxaban versus Warfarin in Patients with Atrial Fibrillation. NEJM 2013; 369:2093-2104.
• The Hokusai-VTE Investigators. Edoxaban versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism. NEJM 2013; 369:1406-1415.
• 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients with Nonvalvular Atrial Fibrillation: A Report of the American College of Cardiology Clinical Expert Consensus Document Task Force. JACC 2017 ePub ahead of print.
• Heidbuchel H et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvularatrial fibrillation. Europace 2013; 15(5):625-51.