Br J Haematol. 2008 Jun;141(6):757-63
A review of guidelines and update in
emerging therapies
Brian Spoelhof, PharmD
April 19, 2012
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The presenter has no actual or potential
conflicts to disclose
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Summarize the indications for anticoagulation
Describe the pharmacology of new oral
anticoagulants
Evaluate the data that led to the approval of the
new oral anticoagulants
Discuss the advantages and disadvantages of
new anticoagulants;
Examine new potential indications for the new
anticoagulants.
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Anticoagulation
Guidelines
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Atrial Fibrillation
Post-op
Orthopedic
Surgery
Pharmacology of
current options
Dabigatran
Rivaroxaban
Apixiban
Summary
Questions
Safe
Effective
Oral
Easy
Reversible
Tissue Damage
Surface Contact
Common
Pathway
Dipiro: Pharmacotherapy: a
Pathophysiologic Approach, 2008
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Vitamin K
Antagonist
Unfractionated
Heparin (UFH)
Low Molecular
Weight Heparin
(LMWH)
Direct Thrombin
Inhibitors
Factor Xa Inhibitors
Warfarin
Heparin
Enoxaparin
Bivalirudin
Argatroban
Dabigatran
Fondaparinux
Rivaroxaban
Apixiban
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Vitamin K Antagonist
Narrow Therapeutic
Genetic variation
 Drug interactions
 Food interactions
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Required monitoring
Slow onset of action
Protein
Half Life
(Hours)
Prothrombin
(II)
60-100
Factor VII
6-8
Factor IX
20-30
Factor X
24-40
Protein C
8-10
Protein S
40-60
Is this the perfect anticoagulant?
Dipiro: Pharmacotherapy: a Pathophysiologic Approach, 2008
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AAOS – American Academy of Orthopedic
Surgeons
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Updated September 2011
Recommends no specific agent
ACCP – American College of Chest Physicians
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Updated February 2012
 Hip Fracture Surgery
 Total Hip Replacement
 Total Knee Replacement
Chest. 2008 Jun;133
AAOS VTE Prevention Guidelines
LMWH (preferred),
Fondaparinux, Warfarin
(INR 2-3), Dabigatran*,
Rivaroxaban*, Apixaban*
* Not recommend in hip
fracture surgery
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ACCP and ACCF/AHA /HRS guidelines
fairly similar
Risk Stratification
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C – Congestive heart failure
H - Hypertension
A – Age ≥ 75
D - Diabetes
Sx2 – Prior stroke or TIA x 2
J Am Coll Cardiol. 2011 Mar 15;57(11):1330-7
Chest. 2008 Jun;133
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CHADS2 score of 0
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CHADS2 score of 1
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Aspirin 81 to 325 mg daily
Aspirin 81 to 325 mg daily plus clopidogrel
or
Dabigatran or warfarin titrated to INR of 2.0-3.0
CHADS2 score 2 or greater
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Dabigatran or warfarin titrated to INR of 2.0-3.0
J Am Coll Cardiol. 2011 Mar 15;57(11):1330-7
Chest. 2008 Jun;133
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Oral anticoagulation preferred over dual
antiplatelet therapy
Dabigatran preferred over warfarin, except
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Mitral valve stenosis
Stable coronary artery disease
Intracoronary stents
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Dabigatran – Pradaxa
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Rivaroxaban – Xarelto
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Direct Thrombin Inhibitor
Approved to prevent stroke and systemic embolism
nonvalvular atrial fibrillation
Factor Xa Inhibitor
Approved to prevent stroke and systemic embolism
nonvalvular atrial fibrillation and Postoperative
thromboprophylaxis
Apixaban
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Factor Xa Inhibitor
Not currently approved
Rivaroxaban, Package Insert
Dabigatran, Package Insert
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Indication:
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Dosage:
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Prevent stroke and systemic embolism nonvalvular
atrial fibrillation
CrCl > 30 mL/min: 150 mg Twice Daily
Renal: Next slide
Dyspepsia
Dabigatran, Package Insert
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CrCl 15 – 30 mL/min: 75 mg Twice Daily
November 2011
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Consider reduced dose (75 md twice daily) in
patients with moderate renal impairment (30-50
mL/min) and concurrently taking ketoconazole or
dronedarone.
Assess renal function prior to starting and in patients
 ≥ 75 years old
 CrCl or < 50 mL/min
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Use with extreme caution in patient greater
than 80
Dabigatran, Package Insert
Dabigatran
Dipiro: Pharmacotherapy: a Pathophysiologic
Approach, 2008
Pharmacokinetics
 Prodrug
 Rapid absorption
 Time to peak: 1-2
hours
 Half-Life: 12-17 hours
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Longer in renal
impairment
Dabigatran, Package Insert
Monitoring:
 aPTT
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Qualitative not
Quantitative
TT (Thrombin Time)
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Linear dose
relationship
Not as readily
available
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Randomized, Dose blinded/regimen
unblinded, noninferiority trial
Dabigatran 110 mg twice daily vs. Dabigatran
150 mg twice daily vs . Warfarin titrated to INR
n = 18,113
N Engl J Med. 2009 Sep 17;361(12):1139-51
N Engl J Med. 2009 Sep 17;361(12):1139-51
N Engl J Med. 2009 Sep 17;361(12):1139-51
Increased efficacy
noninferior bleeding
Noninferior efficacy
lower bleeding
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No known reversal agent
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Study of 12 healthy individuals
 Prothrombin Complex Concentrate
 No effect on aPTT or TT
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Supportive care
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Blood
Fluid (to support kidney function)
Possible dialysis
Circulation. 2011 Oct 4;124(14):1573-9
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Oral direct thrombin inhibitor
Requires renal adjustments
More effective than warfarin
Same risk of bleeding
Twice daily dosing
Dyspepsia
Limited available monitoring
No reversal
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Indications:
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Approved to prevent stroke and systemic embolism
nonvalvular atrial fibrillation
Postoperative thromboprophylaxis (Knee and Hip)
Dosage
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Afib:
 CrCl >50 mL/min: 20 mg once daily
 CrCl 15 - 50 mL/min: 15 mg once daily
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Post-op VTE prophylaxis
 Knee replacement: 10 mg once daily x 12-14 days
 Hip replacement: 10mg once daily x 35 days
Rivaroxaban Package Insert
Pharmacodynamics
 Peak 2.5-4 hours
Monitoring
 PT
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Half Life: 3.2 – 22
hours
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Metabolized via 3A4
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aPTT
Anti-Xa
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Br J Clin Pharmacol. 2011 Oct;72(4):593-603
Thromb Haemost. 2010 Apr;103(4):815-25
More sensitive
Varies with different
reagents
Cannot be
standardized
Modified Anti-Xa
being developed
Rivaroxaban directly inhibits
Factor Xa
Rivaroxaban
Dipiro: Pharmacotherapy: a Pathophysiologic Approach,
2008
J Thromb Haemost. 2006 Jan;4(1):121-8
Trial
Setting Enoxaparin
regimen
Rivaroxaban DVT/PE/
regimen
death (%)
RRR Symptomatic RRR
(%) VTE (%)
(%)
RECORD1 THA
n=4541
40 mg daily x 10 mg daily x 3.7 vs 1.1
35 days
35 days
70
—
—
RECORD2 THA
n=2509
40 mg daily x 10 mg daily x 9.3 vs 2.0
10–14 days
31–39 days
79
1.2 vs 0.2
80
RECORD3 TKA
n=2531
40 mg daily x 10 mg daily x 18.9 vs 9.6
10–14 days
10–14 days
49
2.0 vs 0.7
66
RECORD4 TKA
n=3148
30 mg BID x 10 mg daily x 10.1 vs 6.9
10–14 days
10–14 days
31
1.2 vs 0.7
NS
Eikelboom JS and Weitz JI. Lancet 2008.
Outcome
Enoxaparin Rivaroxaban p
(%)
(%)
Symptomatic
VTE/all-cause
mortality
Major bleed
1.3
0.5
<0.001
0.2
0.3
0.305
Turpie AG et al. 2008 International Congress on Thrombosis; June 27, 2008;
Athens, Greece. Abstract O5.
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Comparison of rivaroxaban to warfarin in
patients with atrial fibrillation
Randomized, Double Blinded, Double Dummy,
Noninferiority
Consideration
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Time in Therapeutic Range
N Engl J Med. 2011 Sep 8;365(10):883-91
N Engl J Med. 2011 Sep 8;365(10):883-91
N Engl J Med. 2011 Sep 8;365(10):883-91
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Prothrombin Complex Concentrate
potentially reverses rivaroxaban
Study in 12 healthy males
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Returned to nearly normally levels within 15
minutes
Circulation. 2011 Oct 4;124(14):1573-9
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Oral direct Factor Xa inhibitor
Post-op thromboprophylaxis
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Superior to enoxaparin
Similar rates of major bleeds
Stroke prophylaxis in atrial fibrillation
Non-inferior to warfarin
 Less risk of major bleeding
 Discontinuation increases risk of thromboembolism
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Anticoagulation rapidly evolving
New option provide potential but haven’t
eradicated the need for warfarin
When choosing an agent must balance
compliance, risk, renal function
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Oral Factor Xa inhibitor
Not yet approved, no indications
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Approval expected 6/28/12
Dosing:
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5 mg twice daily
2.5 mg twice daily with two of the following:
 Age > 80 years
 Weight < 60 kg
 SCr > 1.5 mg/dL
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Apixaban vs warfarin for atrial fibrillation
Randomized, double blind, double dummy,
noninferiority trial
n= 18,201patient
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Apixaban awaiting FDA review
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Approval expected
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Apixaban reduced occurrence of stroke and
systemic embolism compared to warfarin
Apixaban associated with lower risk of
bleeding compared to warfarin
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Warfarin has reduced secondary endpoints but
risk of bleeding has not outweighed benefit
APPRAISE-2
Apixaban 5 mg BID vs Placebo post- MI
 No benefit
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ATLAS-ACS2 TIMI 51
Rivaroxaban 2.5 mg daily or 5 mg daily vs placebo postMI
 Rivaroxaban 2.5 mg = Benefit
 Rivaroxaban 5 mg = No benefit
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Hurlen M, et al. N Engl J Med. 2002 Sep 26;347(13):969-74
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Rivaroxaban 2.5 mg daily
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Decreased primary endpoint
 Cardiovascular Death, MI, or stroke
 9.1% vs 10.7% (HR 0.84, P=0.0.02)
 NNT = 63
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Decreased all cause mortality
 2.9 % vs 4.5 % (HR 0.68, P=0.002)
 NNT = 63
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Increased major bleeding (HR 3.46, P=0.001)
 1.8% vs 0.6%(HR 3.46, P=0.001)
 NNH = 83
Dabigatran
• Best stroke reduction data
• Twice daily dosing
• Dyspepsia/ GI Bleed
• No reversal
Rivaroxaban
• Reversible
• Once daily dosing
• Afib data not as strong
• Early discontinuation
increases events
Apixaban
• Better efficacy and safety
• Theoretically reversible
• Twice daily dosing
• Not yet approved
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