Anticoagulation
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Transcript Anticoagulation
Br J Haematol. 2008 Jun;141(6):757-63
A review of guidelines and update in
emerging therapies
Brian Spoelhof, PharmD
April 19, 2012
The presenter has no actual or potential
conflicts to disclose
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.
Anticoagulation
Guidelines
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
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
Vitamin K Antagonist
Narrow Therapeutic
Genetic variation
Drug interactions
Food interactions
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
AAOS – American Academy of Orthopedic
Surgeons
Updated September 2011
Recommends no specific agent
ACCP – American College of Chest Physicians
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
ACCP and ACCF/AHA /HRS guidelines
fairly similar
Risk Stratification
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
CHADS2 score of 0
CHADS2 score of 1
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
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
Oral anticoagulation preferred over dual
antiplatelet therapy
Dabigatran preferred over warfarin, except
Mitral valve stenosis
Stable coronary artery disease
Intracoronary stents
Dabigatran – Pradaxa
Rivaroxaban – Xarelto
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
Factor Xa Inhibitor
Not currently approved
Rivaroxaban, Package Insert
Dabigatran, Package Insert
Indication:
Dosage:
Prevent stroke and systemic embolism nonvalvular
atrial fibrillation
CrCl > 30 mL/min: 150 mg Twice Daily
Renal: Next slide
Dyspepsia
Dabigatran, Package Insert
CrCl 15 – 30 mL/min: 75 mg Twice Daily
November 2011
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
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
Longer in renal
impairment
Dabigatran, Package Insert
Monitoring:
aPTT
Qualitative not
Quantitative
TT (Thrombin Time)
Linear dose
relationship
Not as readily
available
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
No known reversal agent
Study of 12 healthy individuals
Prothrombin Complex Concentrate
No effect on aPTT or TT
Supportive care
Blood
Fluid (to support kidney function)
Possible dialysis
Circulation. 2011 Oct 4;124(14):1573-9
Oral direct thrombin inhibitor
Requires renal adjustments
More effective than warfarin
Same risk of bleeding
Twice daily dosing
Dyspepsia
Limited available monitoring
No reversal
Indications:
Approved to prevent stroke and systemic embolism
nonvalvular atrial fibrillation
Postoperative thromboprophylaxis (Knee and Hip)
Dosage
Afib:
CrCl >50 mL/min: 20 mg once daily
CrCl 15 - 50 mL/min: 15 mg once daily
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
Half Life: 3.2 – 22
hours
Metabolized via 3A4
aPTT
Anti-Xa
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.
Comparison of rivaroxaban to warfarin in
patients with atrial fibrillation
Randomized, Double Blinded, Double Dummy,
Noninferiority
Consideration
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
Prothrombin Complex Concentrate
potentially reverses rivaroxaban
Study in 12 healthy males
Returned to nearly normally levels within 15
minutes
Circulation. 2011 Oct 4;124(14):1573-9
Oral direct Factor Xa inhibitor
Post-op thromboprophylaxis
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
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
Oral Factor Xa inhibitor
Not yet approved, no indications
Approval expected 6/28/12
Dosing:
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
Apixaban vs warfarin for atrial fibrillation
Randomized, double blind, double dummy,
noninferiority trial
n= 18,201patient
Apixaban awaiting FDA review
Approval expected
Apixaban reduced occurrence of stroke and
systemic embolism compared to warfarin
Apixaban associated with lower risk of
bleeding compared to warfarin
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
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
Hurlen M, et al. N Engl J Med. 2002 Sep 26;347(13):969-74
Rivaroxaban 2.5 mg daily
Decreased primary endpoint
Cardiovascular Death, MI, or stroke
9.1% vs 10.7% (HR 0.84, P=0.0.02)
NNT = 63
Decreased all cause mortality
2.9 % vs 4.5 % (HR 0.68, P=0.002)
NNT = 63
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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