Target-Specific Oral
Anticoagulants
Deborah Sturpe, PharmD, MA, BCPS
The speaker has no actual or potential disclosures to report.
Session Goals
 Compare and contrast the efficacy and safety of oral
anticoagulant drugs
 Select an oral anticoagulant that maximizes benefit-torisk ratio for an individual patient
 Recommend a plan for managing bleeding complications
of oral anticoagulants
2
Target Specific Oral Anticoagulants
TSOAC BASICS
3
OAC Options and Mechanism of Action
Vit K Antagonist
Warfarin (Coumadin®)
Direct Thrombin Inhibitor
Dabigatran (Pradaxa®)
Factor Xa Inhibitor
Apixaban (Eliquis®)
Edoxaban (Savaysa™)
Rivaroxaban (Xarelto®)
4
TSOAC Indications
Non-Valvular
AFib
Dabigatran
✔
Apixaban
✔
Edoxaban
✔
Rivaroxaban
✔
Acute VTE
treatment
✔
(after 5-10 days
parenteral tx)
✔
Recurrent
VTE ppx
VTE ppx post
hip/knee
replacement
✔
✔
✔
✔
✔
✔
(after 5-10 days
parenteral tx)
✔
5
TSOAC Usual Dosing
Non-Valvular
AFib
Dabigatran
Acute VTE
treatment
Recurrent VTE
ppx
VTE ppx post
hip/knee
replacement
150 mg BID
150 mg BID
150 mg BID
N/A
Apixaban
5 mg BID
10 mg BID x 7
days, then 5 mg
BID
2.5 mg BID
2.5 mg BID
Edoxaban
60 mg daily
60 mg daily
N/A
N/A
20 mg daily with
evening meal
15 mg BID with
food x 21 days,
then 20 mg daily
with food
Rivaroxaban
20 mg daily with
food
10 mg daily
Note that 15 mg and 20 mg rivaroxaban tablets must be taken with food, but 10 mg tablet does not.
Remember that dabigatran MUST remain in original packaging!
6
TSOAC “Dosing Pains”
Based on Patient Characteristics
AFib
Do not use CrCl < 15 mL/min
Reduce dose to 75 mg BID if CrCl 15-30 mL/min
VTE
Do not use CrCl < 30 mL/min
AFib
Reduce to 2.5 mg BID if TWO of the following:
Age ≥ 80
Scr ≥ 1.5 mg/dL
Weight ≤ 60 kg (132 lbs)
VTE
No adjustments
AFib
Do not use if CrCl < 15 mL/min or > 95 mL/min
Reduce dose to 30 mg daily if CrCl 15-50 mL/min
VTE
Do not use if CrCl < 15 mL/min
Reduce dose to 30 mg daily if CrCl 15-50 mL/min or
weight ≤ 60 kg (132 lbs)
AFib
Do not use if CrCl < 15 mL/min
Reduce dose to 15 mg daily with evening meal if CrCl 15-50 mL/min
VTE
No adjustments
Dabigatran
Apixaban
Edoxaban
Rivaroxaban
7
TSOAC “Dosing Pains”
Based on Co-Administered Drugs
Dabigatran
Dronaderone or ketoconazole:
If for AFib and CrCl < 30, do not use
If for AFib and CrCl 30-50, reduce dose to 75 mg BID
If for VTE and CrCl < 50, do not use
Rifampin – do not use (any indication)
Apixaban
Ketoconazole, itraconazole, ritonavir, or clarithromycin:
If supposed to be on 2.5 mg BID, do not use
If supposed to be on dose > 2.5 BID, reduce dose by 50%
Rifampin, carbamazepine, phenytoin, or St. Johns’ wort
Avoid use (any indication)
Edoxaban
Verapamil, quinidine, azithromycin, clarithromycin, erythromycin, itraconazole, or
ketoconazole:
If for VTE, reduce dose to 30 mg daily (no adjustment in AFib)
Rifampin
Avoid use (any indication)
Rivaroxaban
Ketoconazole, itraconazole, ritonavir, indinavir, or conivaptan:
Avoid use
Rifampin, carbamazepine, phenytoin, or St. Johns’ wort
Avoid use (any indication)
8
Are Prescribing Practices Appropriate?
 Three publications (2 hospital, 1 outpatient) focusing on dabigatran
and/or rivaroxaban
 Total n = > 700 patients
 High rates of inappropriate use in all reports (up to 50%)
 Non-indicated conditions (especially valvular disease)
 Use in those with CrCl below cutoffs or in those without data to
calculate baseline CrCl
 Wrong dose
 Wrong administration
 Concurrent heparin or LMWH
Larock AS et al. Ann Pharmacother 2014;48;1258-68.
Carley B et al. Am J Cardiol 2014;113:650-54.
Armbruster AL et al. Am Halth Drug Benefits 2014;7:376-84.
9
Are Patients Adhering to Therapy?
 National cohort (n = 5376) of Veterans Affairs patients started on
dabigatran between Oct 2010-Sept 2012 for NVAF
 28% of cohort non-adherent to therapy at 1 year (<80%)
 Poor adherence associated with increased stroke and all-cause
mortality
Shore S et al. Am Heart J 2014;167:810-17.
10
TSOACs
CLINICAL DATA
11
TSOAC – Major Clinical Trials
Non-Valvular AFib
VTE Treatment /
Prevention
VTE ppx post
hip/knee
replacement
Dabigatran
RE-LY
RE-COVER
RE-MEDY
RE-SONATE
Apixaban
ARISTOTLE
AVERROES
AMPLIFY
ADVANCE
Edoxaban
ENGAGE AF-TIMI48
Hokusai VTE
N/A
Rivaroxaban
ROCKET-AF
EINSTEIN
RECORD
N/A
12
Clinical Trials
Definitions of Bleeding Outcomes
 Major bleeding = accompanied by Hgb drop ≥ 2 gm/dL or
transfusion of ≥ 2 units PRBC occurring at a critical site or resulting
in death
 Clinically relevant nonmajor bleeding = does not satisfy criteria for
major bleeding, but does lead to hospitalization, physician
intervention, and/or alteration in antithrombotic therapy
13
TSOAC Atrial Fibrillation Trial Characteristics
APIX = apixaban
RIVA = rivaroxaban
DE = dabigatran etexilate
VKA = vitamin K antagonist
ARISTOTLE
RE-LY
EDOX = edoxaban
ENGAGE AF-TIMI48
ROCKET-AF
Treatment Arms
of Interest
APIX 5mg (or 2.5) BID
Warfarin to INR 2-3
DE 150 mg BID
Warfarin to INR 2-3
EDOX 60 mg (or 30) daily
Warfarin to INR 2-3
RIVA 20 mg (or 15) daily
Warfarin to INR 2-3
Study Goal
Non-inferiority
Non-inferiority
Non-inferiority
Non-inferiority
Major Inclusion
Criteria
Afib or AFlutter and at least
one additional stroke risk
factor
Afib and at least one
additional stroke risk factor
AFib with CHADS2 ≥ 2
AFib with CHADS2 ≥ 2
Major Exclusion
Criteria
CrCl < 25 mL/min
Concurrent ASA/Plavix
Increased bleeding risk
CrCl < 30 mL/min
High bleed risk
CrCl < 30 mL/min
High bleed risk
CrCl < 30 mL/min
Baseline
Characteristics
Median age 70
35% female
57% prior VKA use
15% CrCl 30-50 mL/min
30% CHADS2 ≥ 3
Median age 71
37% female
50% prior VKA use
32% CHADS2 ≥ 3
Median age 72
38% female
59% prior VKA use
23% CHADS2 4-6
Median age 73
40% female
62% prior VKA use
87% CHADS2 ≥ 3
Granger CB et al. NEJM 2011;365:981-92.
Patel MR et al. NEJM 2011; 365:883-91.
Connolly SJ et al. NEJM 2009;361:1139-51.
Riugliano RP et al. NEJM 2013;369:2093-104.
14
TSOAC Atrial Fibrillation Results
Event Rates per Year
ARISTOTLE
Mean TTR 62%
RE-LY
Mean TTR 64%
ENGAGE AF-TIMI48
Mean TTR 65%
ROCKET-AF
Mean TTR 55%
Stroke or Systemic
Embolism
APIX
Warfarin
1.27%*
1.60%
NNT 303
DE
Warfarin
1.11%*
1.69%
NNT 172
EDOX§
Warfarin
1.18%*
1.50%
NNT 313
RIVA
Warfarin
1.7%
2.2%
Ischemic
APIX
Warfarin
0.97%
1.05%
DE
Warfarin
0.92%*
1.20%
NNT 357
EDOX
Warfarin
1.25%
1.25%
RIVA
Warfarin
1.34%
1.42%
Hemorrhagic
APIX
Warfarin
0.24%*
0.47%
NNT 434
DE
Warfarin
0.10%*
0.38%
NNT 357
EDOX
Warfarin
0.26%*
0.47%
NNT 476
RIVA
Warfarin
0.26%*
0.44%
NNT 556
Major Bleeding
APIX
Warfarin
2.13%*
3.09%
NNT 104
DE
Warfarin
3.11%
3.36%
EDOX
Warfarin
2.75%*
3.43%
NNT 147
RIVA
Warfarin
3.6%
3.4%
Intracranial
APIX
Warfarin
0.33%*
0.80%
NNT 213
DE
Warfarin
0.30%*
0.74%
NNT 227
EDOX
Warfarin
0.39%*
0.85%
NNT 217
RIVA
Warfarin
0.5%*
0.7%
NNT 500
Gastrointestinal
APIX
Warfarin
0.76%
0.86%
DE
Warfarin
1.51%
1.02%*
NNH 204
EDOX
Warfarin
1.51%
1.23%*
NNH 357
RIVA
Warfarin
3.2%
2.2%*
NNH 100
Major or Clinically
Relevant Bleeding
APIX
Warfarin
4.07%*
6.01%
NNT 52
EDOX
Warfarin
11.10%*
13.02%
NNT 52
RIVA
Warfarin
14.9%
14.5%
Not reported
* = statistically superior at p < 0.05
§ In patients with CrCl > 95 mL/min, warfarin outperformed edoxaban in CVA reduction (edoxaban NNH 250)
15
TSOAC Atrial Fibrilliation Results
Impact of Time in the Therapeutic Range
 Real-world time in therapeutic range (TTR) is only ~ 50%
 10% improvement in TTR = 10% reduction in event rates
 Event rates are highest at INR extremes (INR < 1.5 or > 5) with
more than half of major events occuring in those in the bottom TTR
quartile (10-20% TTR)
 Published data showing no impact of TTR on superiority of
dabigatran and rivaroxaban are criticized for examing center TTR
(cTTR) as opposed to individual TTR (iTTR)
Dlott JS et al. Circulation 2014;129:1407-14.
Jones M et al. Heart 2005;91:472-77.
Wallentin L et al. Lancet 2010;376:975-83.
White HD et al. Arch Int Med 2007;167:239-45.
Veeger NJ et al. J Thromb Haemost 2006;4:1625-27.
Piccini JP et al. J Am Heart Assoc 2014;3:e000521.
16
Re-examining RE-LY and ARISTOTLE
Event Rates/Year Based on iTTR
Warfarin
All quartiles
Warfarin iTTR > 67%
1st and 2nd quartile
Warfarin iTTR < 53%
4th quartile
Dabigatran
150 mg BID
Stroke or Systemic
Embolism
1.69%
1.3%
2.2%
1.11%
Major Bleeding
3.36%
2.7%
4.6%
3.11%
For composite outcome of stroke, systemic embolism, major bleeding and death versus 4th quartile warfarin:
• Dabigatran
NNT 20
• Warfarin 1st-2nd quartile NNT 15
Bussey HI. http://www.clotcare.com/warfarin_vs_dabigatran.aspx
Favor apixaban
Favor warfarin
Wallentin L et al. Circulation 2013;127:2166-2176.
17
TSOAC “Acute” VTE Trial Characteristics
AMPLIFY
(6 months duration)
RE-COVER
(6 months duration)
Hokusai
(3-12 months)
EINSTEIN & EINSTEIN-PE
(3, 6, or 12 months)
Treatment Arms
of Interest
APIX 10 mg BID x 7 days,
then 5 mg BID
Enox + Warfarin to INR 2-3
≥ 5 day parenteral tx and
INR ≥ 2.0, then:
DE 150 mg BID
Warfarin to INR 2-3
≥ 5 day parenteral tx and
INR ≥ 2.0, then:
EDOX 60 mg (or 30) daily
Warfarin to INR 2-3
RIVA 15 mg BID x 21 days,
then 20 mg daily
Enox + VKA to INR 2-3
Study Goal
Non-inferiority
Non-inferiority
Non-inferiority
Non-inferiority
Major Inclusion
Criteria
DVT or PE
Unprovoked DVT or PE
DVT or PE
Confirmed DVT w/o PE
(EINSTEIN)
Confirmed PE w/ or w/o
DVT (EINSTEIN-PE)
Major Exclusion
Criteria
High bleed risk
IVC filter
Potent CYP3A4 inhibitors
CrCl < 25 mL/min
High bleed risk
IVC filter
PE + hemodynamic issues
CrCl < 30 mL/min
High bleed risk
IVC filter
CrCl < 30 mL/min
High bleed risk
IVC filter
Strong CYP3A4 drugs
CrCl < 30 mL/min
Baseline
Characteristics
Median age 57
61% female
65% DVT
25% PE
9% DVT + PE
16% previous VTE
2.5% thrombophilia
10% provoked
Median age 55
42% female
69% DVT
21% PE
10% DVT + PE
25% previous VTE
Agnelli G et al. NEJM 2013;369:799-808.
Hokusai-VTE. NEJM 2013;369:1406-15.
Mean age 56
43% female
60% DVT
30% PE
10% DVT + PE
18% previous VTE
28% provoked
Schulman S et al. NEJM 2009;361:2342-52.
EINSTEIN. NEJM 2010;363:2499-510
Mean age 56 and 58
43% and 48% female
25% co-DVT/PE (PE
study)
19% previous VTE
6.5% and 5%
thrombophilia
40% and 36% provoked
.
EINSTEIN-PE. NEJM 2012;366:1287-97.
18
TSOAC “Acute” VTE Studies
Event Rates
AMPLIFY
TTR 61%
Recurrent VTE or
VTE-related Death
Major Bleeding
Major or Clinically
Relevant Bleeding
APIX
Warfarin
2.3%
2.7%
RE-COVER
TTR 60%
DE
Warfarin
2.4%
2.1%
APIX
Warfarin
0.6%*
1.8%
NNT 83
DE
Warfarin
1.6%
1.9%
GI: APIX
GI: Warf
0.3%
0.7%
GI: DE
GI: Warf
53 events
35 events
APIX
Warfarin
4.3%*
9.7%
NNT 19
DE
Warfarin
5.6%*
8.8%
NNT 31
Hokusai§
TTR 63.5%
EDOX
Warfarin
EDOX
Warfarin
3.2%
3.5%
1.4%
1.6%
EINSTEIN⌃ (TTR 57.7%)
EINSTEIN-PE⌘ (TTR 62.7%)
EINSTEIN
RIVA
Warfarin
2.1%
3.0%
EINSTEIN-PE
RIVA
Warfarin
2.1%
1.8%
EINSTEIN
RIVA
Warfarin
0.8%
1.2%
EINSTEIN-PE
RIVA
Warfarin
EDOX
Warfarin
8.5%*
10.3%
NNT 55
* = statistically superior at p < 0.05
§ = 12% treated x 3 months, 26% treated x 3-6 months, 62% treated > 6 months (with 40% reaching 12 months)
⌃ = 12% treated x 3 months, 63% treated x 6 months, 25% treated x 12 months
⌘ = treated x 3 months, 57% treated x 6 months, 38% treated x 12 months
1.1%*
2.2%
NNT 91
EINSTEIN
RIVA
Warfarin
8.1%
8.1%
EINSTEIN-PE
RIVA
Warfarin
10.3%
11.4%
19
TSOAC VTE Extension Trial Characteristics
AMPLIFY EXT
(12 months)
RE-MEDY
(6-36 months)
EINSTEIN EXT
(6 or 12 months)
ELATE
(mean 2.4 years)
Treatment Arms
of Interest
APIX 2.5 mg BID
Placebo
DE 150 mg BID
Warfarin to INR 2-3
RIVA 20 mg daily
Placebo
Warfarin to INR 1.5-1.9
Warfarin to INR 2-3
Study Goal
Superiority
Non-inferiority
Superiority
Non-inferiority (efficacy)
Superiority (safety)
Major Inclusion
Criteria
DVT and/or PE and
Already tx for 6-12 months
No recurrent events
Clinical equipoise to cont tx
DVT and/or PE and
Already tx for 3-12 months
Investigators deemed
patient at increased risk for
recurrence
DVT and/or PE and
Already tx for 6-12 months
Clinical equipoise to cont tx
Unprovoked VTE and
Already tx ≥ 3 months
Major Exclusion
Criteria
High bleed risk
Documented thrombogenic
mutation
CrCl < 25 mL/min
High bleed risk
IVC filter
High bleed risk
IVC filter
Strong CYP3A4 drugs
CrCl < 30 mL/min
High bleed risk
APLA positive
Baseline
Characteristics
Mean age 57
42% female
91.5% unprovoked VTE
13% previous VTE
Mean age 54.5
39% female
18% known thrombophilia
Mean age 58
42% female
73.5% unprovoked VTE
16% previous VTE
8% known thrombophilia
Mean age 57
45% female
70% previous VTE
26% Factor V Leiden
10% prothrombin mutation
Agnelli G et al. NEJM 2013;368:699-708.
EINSTEIN. NEJM 2010;363:2499-510.
Schulman S et al. NEJM 2013;368:709-18.
Kearon C et al. NEJM 2003;349:631-9.
.
20
TSOAC Extended VTE Studies
Event Rates
RE-MEDY
TTR 65.3%
AMPLIFY EXT
EINSTEIN-EXT§
ELATE
TTR 63% for low-intensity
TTR 69% for usual-intensity
Recurrent VTE or
VTE-related Death
APIX
Placebo
1.7%*
8.8%
NNT 14
DE
Warfarin
1.8%
1.3%
RIVA
Placebo
1.3%*
7.1%
NNT 17
Low intensity
Usual intensity
1.9%
0.7%*
NNH 83
Major Bleeding
APIX
Placebo
0.2%
0.5%
DE
Warfarin
0.9%
1.8%
RIVA
Placebo
0.7%
0.0%
Low intensity
Usual intensity
1.1%
0.9%
Major or Clinically
Relevant Bleeding
APIX
Placebo
3.2%
2.7%
DE
Warfarin
5.6%*
10.2%
NNT 22
RIVA
Placebo
6.0%
1.2%*
NNH 21
N/A
* = statistically superior at p < 0.05
§ = 60% treated x 6 months, 40% treated x 12 months
21
Additional Safety Concern
Acute Coronary Events and Dabigatran
 Across all clinical trials, dabigatran does appear to result in
statistically higher rates of acute coronary events compared to
warfarin (odds ratio ~ 1.3 to 1.4)
 Events have been noted in “real world” after patients switched from
warfarin to dabigatran
 Trend seen with most direct thrombin inhibitors (not observed to
date with Factor Xa inhibitors)
 Unknown if direct thrombin inhibitors actually harmful or if warfarin
simply more effective
 Anticipate that this will be an area of continued surveillance for all
TSOACs
Loke YK et al. Br J Clin Pharmacol 2014;78:707-17.
Bjerregaard T et al. Am J Med 2014;127:329-36.
Uchino K et al. Arch Intern Med 2012;172:397-402.
Davidson BL. CHEST 2015;147:21-24.
.
22
Oral Anticoagulants
Reversal & Treatment Strategies
for Acute Major Bleeding
23
A Review
Available Clotting Factor Supplements for VKAs
PCC4
PCC3
Contains inactivated
factors II, VII, IX, and X
Advantages
More rapid/complete VKA
reversal compared to FFP
aPCC
FFP
Contains inactivated
factors II, IX and X
Contains activated factor
VII and inactivated factors
II, IX, and X
Contains all vitamin-K
dependent clotting factors
Expensive
Most prothrombotic
Potential for allergy
Potential for infection
Preparation time
High volume
FEIBA NF
NA
Disadvantages
Expensive
Expensive
Little to no factor VII
Available US
Products
Kcentra®
Bebulin® VH
Profilnine® SD
PCC = prothrombin complex concentrate
FFP = fresh frozen plasma
TSOAC Issues:
•
No antidotes (yet)
•
FFP does not work (TSOAC simply inhibits what is being replaced)
•
PCC may work (by hitting system with supraphysiologic levels of clotting factor) but data is scare and
mostly from animal models or in vitro studies
Holbrook A et al. CHEST 2012;141(2)(Suppl):e152S-e184S.
24
Approaches to Life-threatening Bleeding
VKA
Direct Thrombin Inhibitor
Factor Xa Inhibitor
Hold drug
Hold drug
Hold drug
Vitamin K 10 mg IV (to sustain
options below)
Activated charcoal if last dose
taken within 2 hours
Activated charcoal if last dose
taken within past 2 hours
Clotting factor supplement (listed
in order of preference)
• PCC4
• aPCC
• PCC3
• FFP
Hemodialysis
Clotting factor supplement (listed
in order of preference)
• PCC4
• aPCC
• PCC3
Clotting factor supplement (listed
in order of preference)
• aPCC
• PCC4
Nutescu EA et al. Am J Health-Syst Pharm 2013;70:1914-29.
25
Oral Anticoagulants
Putting It All Together
26
Reasonable Conclusions
TSOACs versus Warfarin
 Would reserve TSOACs for patients with similar characteristics to
those enrolled in clinical trials until more data available
 Would be cautious using TSOACs in those with renal impairment
 Would avoid TSOACs in patients who have demonstrated poor
adherence with past medications
 Would avoid TSOACs in patients who have high(er) baseline
bleeding risk until antidotes are available
.
27
Reasonable Conclusions
TSOACs versus Warfarin cont.
 TSOACs may be preferred over warfarin for treating AFib in those
with poor INR control
 Warfarin likely remains drug of choice for treating AFib in those with
good INR control
 TSOACs appear to be equally effective to enoxaparin/warfarin in
treating VTE (“acute” and chronic)
 TSOACs appear to have overall lower bleeding events compared to
warfarin, but
 Incidence of GI bleeding higher with many TSOACs compared to
warfarin
.
28
Reasonable Conclusions
Selecting Between TSOACs
 Narrow down choices based on CrCl, concurrent medications, ability
to adhere to BID regimens, pill box requirements, and formulary
status
 Apixaban may have an edge over the other TSOACs in terms of GI
bleed risk
 For AFib, would lean to apixaban or dabigatran

Rivaroxaban not superior to warfarin

Edoxaban cannot be used in those with normal renal function
 For VTE, would lean to apixaban or rivaroxaban (do not require
parenteral therapy first)
.
29
Thanks for attending!
Questions?
30