New Developments in Oral
Anticoagulants: Treating and
Preventing Embolic Events in the
21st Century
David Stewart, PharmD, BCPS
Assistant Professor of Pharmacy Practice
East Tennessee State University
Bill Gatton College of Pharmacy
stewardw@etsu.edu
Disclosures
Speaker’s Bureau for:
Boehringer-Ingelheim Pharmaceuticals
Janssen Pharmaceuticals
At the conclusion of this program, the
audience should be able to:
• List the new oral anticoagulant medications currently
approved or in the approval process by the United
States Food and Drug Administration
• Communicate basic principles of pharmacokinetics to
other healthcare providers
• Identify appropriate indications for the use of new oral
anticoagulant medications
• Develop patient specific plans utilizing newly approved
oral anticoagulant agents for the treatment and
prevention of venous thromboembolic events in
various patient populations
Including warfarin, how many oral
anticoagulants are currently FDA
approved in the United States?
One
Two
Three
Four
Five
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5.
Warfarin
Pros
• Experience
• Inexpensive
• Reversible
• Monitoring available
Cons
• Time of onset
• Frequent monitoring
• Dosing variability
• Numerous drug interactions
21st Century
• New therapies with FDA Approval
– Dabigatran
– Rivaroxaban
• Additional emerging new therapies
– Apixaban (Phase III trials complete)
– Edoxaban (Phase III trials ongoing)
Which of the following best describes
your opinion regarding the novel new
anticoagulant medications?
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1. Warfarin is an adequate medication with
good data so I’ll continue to use
warfarin.
2. Warfarin has many shortcomings and I
would prefer to use newer agents.
3. I’m still a little hesitant about the newer
agents because I’m unfamiliar with
them.
4. I prefer the newer agents over warfarin;
however, I am concerned about the cost
of new agents.
5. I have serious concerns about the safety
of newer anticoagulant medications.
Which of the following best describes your
current prescribing of dabigatran
(Pradaxa®) or rivaroxaban (Xarelto®)?
1. I routinely prescribe them
2. I prescribe them in a limited and
select group of patients
3. I am very hesitant to prescribe them
4. I have never prescribed them
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Clinical Pharmacology
Comparison
Coagulation Cascade
Intrinsic Pathway (PTT)
XII
XIIa
XI
XIa
IX
VIIa
VII
IXa
VIII
Warfarin
Rivaroxan &
Apixaban
Extrinsic Pathway (PT)
XIII
Xa Va
X
II
IIa
XIIIa
Dabigatran
Fibrinogen
Fibrin
Summary Table
Parameter
Apixaban
Dabigatran
Rivaroxaban
Target Protein
Factor Xa
Thrombin (IIa)
Factor Xa
No
Yes (etexilate)
No
CYP3A4/P-gp
Renal
CYP3A4/P-gp
Avoid < 15 ml/min
↓ 15-30 ml/min
Avoid < 15 ml/min
Avoid < 30 ml/min
CYP3A4/P-gp
Rifampin (P-gp)
CYP3A4/P-gp
Onset of activity
3-4 hrs
1-2 hrs
2-4 hrs
t½
8-15 hrs
12-18 hrs
5-9 hrs
Dosing interval
Twice daily
Twice daily
Daily
Measuring tests
PT/Anti-factor Xa
ECT, TT, +/- aPTT
PT/Anti-factor Xa
Pro-Drug
1˚ Elimination
Renal Adjustment
Drug-Drug Interact.
Monitoring vs. Measuring
Measuring Dabigatran
Thromb Haemost 2010;103:1116-27.
Measuring Rivaroxaban & Apixaban
• Role of aPTT & PT/INR
• Anti-Xa Assays
– Chromagenic anti-Xa assays may be useful
• Different assays vary in sensitivity
• Must calibrate standard curve based on drug
concentration
– HepTest® is not accurate for rivaroxaban (and
likely apixaban)
• Incubation period too long
• Modified HepTest® may be useful but no current data
Ther Drug Monit 2010;32:673-9.
Measuring Rivaroxaban
PT is sensitive (Don’t rely on INR)
aPTT not sensitive
Highlights peak concentrations
J Thromb Haemost 2011;9:133-9.
Which of the following are significantly
affected by moderate/severe renal
insufficiency?
Apixaban
Dabigatran
Rivaroxaban
Both 2 & 3
All of the above
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Ap
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2.
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5.
Clinical Utilization
What are the current approved
indications for dabigatran (Pradaxa®)
in the United States?
Non-valvular Afib
Prevention of VTE
Treatment of VTE
All of the above
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Atrial Fibrillation
Summary of Afib Data
Apixaban
(ARISTOTLE)
Dabigatran
(RE-LY)
Rivaroxaban
(ROCKET – AF)
> 18,000
> 18,000
> 14,000
Mean CHADS2
≈2
≈2
≈ 3.5
TTR
62%
64%
55%
Superior
Superior1
Non-Inferior
Decreased
Similar
Similar
# Patients
Efficacy vs. VKA
Bleeding2 vs. VKA
1Dabigatran 150
mg BID group. 2Major bleeding per study design.
RE-LY - Results
Event
Dabi 110 vs Warf
HR (95% CI)
Dabi 150 vs Warf
HR (95% CI)
Dabi 150 vs Dabi 110
HR (95% CI)
Efficacy
1˚ Endpoint*
0.91 (0.74-1.11)
0.66 (0.53-0.82)
0.73 (0.58-0.91)
All stroke
0.92 (0.74-1.13)
0.64 (0.51-0.81)
0.70 (0.56-0.89)
Ischemic Stroke
1.11 (0.89-1.40)
0.76 (0.60-0.98)
0.69 (0.54-0.88)
Hemorrhagic Stroke
0.31 (0.17-0.56)
0.26 (0.14-0.49)
0.85 (0.39-1.83)
MI published
1.35 (0.98-1.87)
1.38 (1.00-1.91)
1.02 (0.76-1.38)
MI revised
1.29 (0.96-1.75)
1.27 (0.94-1.71)
Not available
All cause mortality
0.91 (0.80-1.03)
0.88 (0.77-1.00)
0.97 (0.85-1.11)
Safety
Major bleeding
0.80 (0.69-0.93)
0.93 (0.81-1.07)
1.16 (1.00-1.34)
GI bleeding
1.10 (0.86-1.41)
1.50 (1.19-1.89)
1.36 (1.09-1.70)
All bleeding
0.78 (0.74-0.83)
0.91 (0.86-0.97)
1.16 (1.09-1.23)
IC bleeding
0.31 (0.20-0.47)
0.40 (0.27-0.60)
1.32 (0.80-2.17)
New Engl J Med 2009;361:1139-51. New Engl J Med 2010;363:1875-76.
*Non-inferiority margin = 1.46
RE-LY
Summary
• Dabigatran 110 mg BID vs. warfarin
– Non-Inferior Efficacy
– Lower major and overall bleeding rates
– Similar GI bleeding rates
• Dabigatran 150 mg BID vs. warfarin
–
–
–
–
Superior efficacy
Lower overall bleeding rates
Similar major bleeding rates
Elevated rates of GI bleeding
• Both doses showed decreased ICH compared to
warfarin (60-70% RRR)
ROCKET-AF
Results
Event
Rivaroxaban
(% per year)
Warfarin
(% per year)
HR (95% CI)
Efficacy
1˚ Endpoint*
2.1
2.4
0.88 (0.75-1.03)
All stroke
1.65
1.96
0.85 (0.70-1.03)
Ischemic Stroke
1.34
1.42
0.94 (0.75-1.17)
Hemorrhagic Stroke
0.26
0.44
0.59 (0.37-0.93)
MI
0.91
1.12
0.81 (0.63-1.06)
All-cause mortality
1.87
2.21
0.85 (0.70-1.02)
Safety
Major bleeding
3.6
3.4
1.04 (0.90-1.20)
All bleeding
14.9
14.5
1.03 (0.96-1.11)
3.2 (% overall)
2.2 (% overall)
p < 0.001
0.5
0.7
0.67 (0.47-0.93)
Major GI bleeding
IC bleeding
*Non-inferiority margin = 1.46
New Engl J Med 2011;365:883-91.
ROCKET-AF
Summary
• Rivaroxaban vs. warfarin
– Non-Inferior Efficacy
– Similar bleeding rates
– Lower ICH rates
• High risk patient population (Mean CHADS2 score >
3)
• TTR 55%
New Engl J Med 2011;365:883-91.
ARISTOTLE
Results
Event
Apixaban
(% per year)
Warfarin
(% per year)
HR (95% CI)
Efficacy
1˚ Endpoint*
1.27
1.60
0.79 (0.66-0.95)
All stroke
1.19
1.51
0.79 (0.65-0.95)
Ischemic Stroke
0.97
1.05
0.92 (0.74-1.13)
Hemorrhagic Stroke
0.24
0.47
0.51 (0.35-0.75)
MI
0.53
0.61
0.88 (0.66-1.17)
All-cause mortality
3.52
3.94
0.89 (0.80-0.998)
Safety
Major bleeding
4.07
6.01
0.68 (0.61-0.75)
All bleeding
18.1
25.8
0.71 (0.68-0.75)
IC bleeding
0.33
0.80
0.42 (0.30-0.58)
*Non-inferiority margin = 1.38
New Engl J Med 2011;365:981-92.
ARISTOTLE
Summary
• Apixaban vs. warfarin
–
–
–
–
Superior efficacy with apixaban
↓ overall mortality with apixaban (NNT = 238)
Lower bleeding rates with apixaban
Lower ICH rates
• Apixaban vs. Aspirin
–
–
–
–
–
6,000 high-risk patients (mean CHADS2 = 2)
Not candidates for warfarin
1 year follow-up
Superior efficacy to aspirin
Similar bleeding (including ICH) rates
New Engl J Med 2011;365:981-92. New Engl J Med 2011;364:806-17.
Which of the following have been
shown at least as effective as warfarin
for the prevention of stroke in patients
with atrial fibrillation?
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Ri
va
Apixaban
Dabigatran
Rivaroxaban
Both 1 & 2
All of the above
Ap
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1.
2.
3.
4.
5.
Treatment of Acute Venous
Thromboembolism
Both dabigatran and rivaroxaban have
been shown to be effective in the
treatment of acute VTE.
1. True
2. False
se
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Summary of VTE Data1
Dabigatran
(RE-COVER)
Rivaroxaban
(EINSTEIN)
> 2,500
> 3,400
6 months
6 months
LMWH
Rivaroxaban
60%
58%
Efficacy vs. VKA
Non-Inferior
Non-Inferior
Bleeding vs. VKA
Similar
Similar
DVT & PE
DVT
# Patients
Treatment Duration
Initial Therapy2
TTR
VTE Type
1Apixaban
data in VTE are not available, AMPLIFY & AMPLIFY-EXT are ongoing. 2Initial therapy in study group, both studies
“bridged” control group.
Prevention of Venous
Thromboembolism in Orthopedic
Surgery Patients
Summary of Orthopedic VTE Data1
Comparator
1Includes
Apixaban
Dabigatran
Edoxaban
(2.5 mg q12h)
(150 or 220mg/day)
(30 mg/day)
Rivaroxaban
(10 mg/day)
Enoxaparin
40 mg daily
Superior
Non-Inferior
---
Superior
Enoxaparin
20 mg q12h
---
---
Superior
---
Enoxaparin
30 mg q12h
Non-Inferior
Inferior
---
Superior
Bleeding vs.
Enoxaparin
Similar
Similar
Similar
Similar
patients undergoing both TKA and THA. Most studies excluded patients with CrCl < 30 ml/min.
Summary of these data available in: Pharmacother 2011;31:1175-91.
VTE Prophylaxis in Medical
Patients
Extended Apixaban vs. Standard
Enoxaparin in Medical Patients
• ADOPT Trial
• Medical patients at high risk for VTE (n=4,495)
• Treatment Groups
– Apixaban 2.5 mg BID for 30 days
– Enoxaparin 40 mg SQ daily during admission
• Results
– No difference in primary outcome
• VTE death, PE, symptomatic DVT or asymptomatic proximal DVT (0.87; 0.62-1.23)
– No difference in other outcomes
• Did not meet criteria for non-inferiority (Key 2˚ outcome)
– Higher rate of major bleeding (2.58; 1.02-7.24)
• Summary
– Extended apixaban was not better than standard enoxaparin in this superiority
trial
– Study was underpowered by over 2,250 patients (goal of 6,758)
New Engl J Med 2011;365:2167-77.
Extended Rivaroxaban vs. Standard
Enoxaparin
• Data not yet published
• 8,101 medical patients
• Treatment Groups
– Rivaroxaban 10 mg daily for 35 days
– Enoxaparin 40 mg SQ daily for 6-14 days
• Primary Outcome Reduced
– 0.77 (0.62-0.96)
• Increased Major & Clinically Relevant Bleeding
• No net clinical benefit
http://www.theheart.org/article/1207331.do
Acute Coronary Syndrome
Apixaban
Acute Coronary Syndrome (APPRAISE-2)
• Double blind, placebo controlled, RCT
• ACS plus 2 additional risk factors
• Apixaban
– 5 mg twice daily
– 2.5 mg twice daily (CrCl < 40 ml/min)
• No benefit in any efficacy outcomes
• Safety
– Major & minor TIMI, ISTH, and GUSTO criteria bleeding
was increased with apixaban
– Increased fatal and intracranial bleeding
• Study terminated early at 1 year
New Engl J Med 2011;365:699-708.
Rivaroxaban
• ATLAS-ACS 2 TIMI 51 Trial
• All patients received low dose ASA with either:
–
–
–
–
Rivaroxaban 2.5 mg twice daily or
Rivaroxaban 5 mg twice daily
Groups were stratified based on clopidogrel use
Large number of patients from Eastern Europe (40%); however North America
data were independently consistent/significant
• Results
– Primary Endpoint (CV Death, MI or CVA)
• Both doses better than placebo
– TIMI Major Bleeding
• Rivaroxaban 2.5 mg BID vs Placebo: HR = 3.46 (2.08-5.77)
• Rivaroxaban 5 mg BID vs Placebo: HR = 4.47 (2.71-7.36)
– Intracranial Hemorrhage
• Rivaroxaban 2.5 mg BID vs Placebo: HR = 2.83 (1.02-7.86)
• Rivaroxaban 5 mg BID vs Placebo: HR = 3.74 (1.39-10.07)
• Summary
– Improved outcomes but 3-fold increased risk of major bleeding
New Engl J Med 2012;366:9-19.
Dabigatran
• Phase II study completed & published 2/2011
• Meta-analysis (January 2012)
–
–
–
–
30,514 patients included
Multiple indications/populations
Majority of patients & events from RE-LY
MI vs. Warfarin
• RR: 1.33 (1.03-1.71)
• AR: 0.40%
– Mortality vs. Warfarin
• RR: 0.89 (0.80-0.99)
• AR: 0.19
– Interpret in light of stroke reduction
– More investigation warranted
Summary
Take Home Points for Providers
• Several new options currently or will exist to replace warfarin
• Current approved indications include:
– Prophylaxis of VTE in orthopedic patients
– Prevention of stroke in patients with Afib
• Date also exists to support their use in:
– Treatment of VTE
• Agents vary based on various pharmacologic and pharmacokinetic
parameters
–
–
–
–
None of the new agents require monitoring
Would base choice of agent o patient specific factors
All of them can be “measured” if needed
Best technique for reversal is unknown for most at this time
• Cost will be a limitation if not covered by insurance
Practical Provider Information
Parameter
Dabigatran
Rivaroxaban
150 mg BID (CrCl > 30 ml/min)
75 mg BID (CrCl 15-30 ml/min)
20 mg QD (CrCl > 50 ml/min)
15 mg QD (CrCl 15-50 ml/min)
N/A
10 mg QD
Primary Elimination
Renal
CYP3A4/P-gp1
Drug-Drug Interact.
Rifampin, Dronedarone2,
Ketoconazole2
CYP3A4/P-gp Inhibitors
Timing of Dose
Anytime
(With or Without Food)
15, 20 mg Dose – With Food
10 mg Dose – Anytime
aPTT
PT
Dyspepsia3
Well Tolerated3
Dosing
Non-valvular
Atrial Fibrillation
Orthopedic VTE Px
Practical Measuring Test
Common Complaints
133%
of elimination is renal and rivaroxaban does require dosage adjustment with CrCl < 50 ml/min. 2With dronedarone &
ketoconazole when CrCl is 30-50 ml/min, decrease dabigatran to 75 mg BID; do not use when CrCl < 30 ml/min. 3As with
any anticoagulant, adverse bleeding is still a concern. Both dabigatran and rivaroxaban demonstrated increased rates of GI
bleeding, but lower rates of intracranial hemorrhage and similar overall rates of bleeding compared to warfarin.
Practical Patient Information
• Dabigatran
–
–
–
–
–
Store in original container
Discard opened product after 4 months
Dyspepsia most common side effect (up to 30%)
Do not open capsule
Comprehensive Patient Guide Available Online1
• Rivaroxaban
–
–
–
–
1Circ
Ask pharmacist or physician about DDIs
At Afib dose should take with supper
Do not crush, chew, or split tablet
Overall tolerated well
2011;124:e209-e211. (DOI: 10.1161/CIRCULATIONAHA.111.019786)
Which of the following best describes your
opinion regarding prescribing of dabigatran
(Pradaxa®) or rivaroxaban (Xarelto®) after this
program?
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1. I will begin routinely prescribing
these agents.
2. I may prescribe them in a limited
and select group of patients.
3. I am still very hesitant to prescribe
them.
4. I will not prescribe them at all for
now.
New Developments in Oral
Anticoagulants: Treating and
Preventing Embolic Events in the
21st Century
David Stewart, PharmD, BCPS
Assistant Professor of Pharmacy Practice
East Tennessee State University
Bill Gatton College of Pharmacy
stewardw@etsu.edu
Use of Concomitant Antiplatelet
Agents
Antiplatelet
Agents
ARISTOTLE
(Apixaban)
RELY
(Dabigatran)
ROCKET-AF
(Rivaroxaban)
< 165 mg/day
Yes
< 100 mg/day
Clopidogrel
Yes
Yes
Yes
Combination
No
Yes
No
Aspirin Use (%)
31%
40%
36%
ASA
New Engl J Med 2009;361:1139-51. New Engl J Med 2011;365:883-91. New Engl J Med 2011;365:981-92.
Summary Table
Parameter
Apixaban
Dabigatran
Rivaroxaban
Target Protein
Factor Xa
Thrombin (IIa)
Factor Xa
No
Yes (etexilate)
No
CYP3A4/P-gp
Renal
CYP3A4/P-gp
Avoid < 15 ml/min
↓ 15-29ml/min
Avoid < 15 ml/min
Avoid < 30 ml/min
CYP3A4/P-gp
Rifampin (P-gp)
CYP3A4/P-gp
Onset of activity
3-4 hrs
1-2 hrs
2-4 hrs
t½
8-15 hrs
12-18 hrs
5-9 hrs
Twice daily
Twice daily
Daily
Monitoring tests
Anti-factor Xa
ECT, TT, +/- aPTT
Anti-factor Xa
FDA Indications
None
Non-valvular Afib.
Non-valvular Afib.
Ortho VTE Proph.
Afib
Ortho VTE Proph
Afib, VTE
Afib, Ortho VTE
Proph, VTE
Pro-Drug
1˚ Elimination
Renal Adjustment
Drug-Drug Interact.
Dosing interval
Clinical Uses