Download An Update on Antithrombotic Therapy for A Fib---

An Update on Antithrombotic Therapy for A Fib--Are those new “–ban” drugs really better???
BACKGROUND
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Atrial Thrombi can embolize with any type of AF—Persistent, Paroxysmal or Persistent
Ischemic stroke is the most frequent clinical manifestation of embolization associated with AF
Chronic antithrombotic therapy with anticoagulant or antiplatelet agent needed
RISK FACTORS
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Choice of agent to use is based on assessment of patient risk
o 2012 CHEST guidelines recommend CHADS2 score
Source: Manning WJ, Singer CE, Lip GH. Antithrombotic Therapy to Prevent Embolization in A fib; Up to Date. Article last
updated 1/23/2013, Accessed 1/27/2013.
o
2012 European guidelines recommend CHA2DS2-VASc score (especially for patients with
CHADS2 score of 1)
Source: Manning WJ, Singer CE, Lip GH. Antithrombotic Therapy to Prevent Embolization in A fib; Up to Date. Article last
updated 1/23/2013, Accessed 1/27/2013.
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Current Treatment Recommendations based on CHADS2 score
o CHADS2=0
 No therapy recommended by 2012 CHEST guidelines—no benefit shown with ASA
either, risk outweighs benefit
 If CHA2DS2-VASc=1 with CHADS2=0, weak recommendation for oral anticoagulants
is made in 2012 European guidelines
o CHADS2=1 (??? possible look at CHA2DS2-VASc)
 Oral Anticoagulant—vitamin K antagonist, direct thrombin inhibitor or Factor Xa
inhibitor preferred
 ASA 75-325 mg plus clopidogrel75 mg daily (ACTIVE A and ACTIVE W trials)—
inferior to warfarin with same bleeding risk (may be option for ACS or stent
patients)
 ASA
o CHADS2 > 2
 Oral anticoagulant—vitamin K antagonist, direct thrombin inhibitor or Factor Xa
inhibitor
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Exception to the Rule: Patients with valvular heart disease—warfarin only
o Prosthetic Heart Valves
o Mitral Stenosis
o Decompenstated Valvular Heart Disease likely to have valve replacement
o ??? patients—mitral valve prolapse, non-rheumatic mitral regurgitation or aortic valve
lesions (have been in new drug trials in very small numbers)
DRUG THERAPY
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Vitamin K Antagonist-Warfarin
o Shown in numerous clinical trials to reduce stroke risk by 2/3rds as compared to no
therapy
 Most trials completed > 15 years ago
 Real life application with ?time in therapeutic range—needs to be at least 60% for
patient to have benefit from warfarin
o Dose based on INR most patients 2.0-3.0 (valve=2.5-3.5)
o Safety concern is risk of major bleeding-especially ICH
 Commonly associated with supratherapeutic INR, prior stroke and age > 75
 ICH found to be most common with INR > 5.0
o Drug interactions=Numerous
o Renal Dosing-adjusted by dosing on patient INR value
o Situations in which warfarin is preferred
 Pts on warfarin, comfortable with INR monitoring and easy to control
 Pts not likely to comply with BID dosing (abixapan and dabigatran)
 Pts who can not afford newer agents
 Pts with chronic kidney disease, CrCl< 15 ml/min
o Warfarin any strength 30 tabs=$4.00 list or 90 tabs=$10.00 list
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Direct Thrombin Inhibitor-Dabigatran (Pradaxa)
o RE-LY trial enrolled 18, 113 patients with mean CHADS2 score 2.1
 Blinded dabigatran 110 BID vs. dabigatran 150 BID vs. Open label warfarin
 Excluded liver dz, high risk of bleeding, valvular heart dz and CrCl< 30
 Dabigatran 110 non inferior to warfarin and dabigatran 150 superior to warfarin
in prevention of stroke (mostly ischemic) and systemic VTE
 Major bleeding was significantly less with dabigatran 110, equal in dabigatran 150
and warfarin groups
Trend for higher rate of extracranial bleeding in patients > 74 in dabigatran 150
group
Post hoc analysis showed non significant but higher rate of MI in both dabigatran groups
FDA conducted post marketing review Nov 2012 for bleeding adverse events
 Examined GI and intracranical bleeding rates for dabigatran and warfarin in AF
patients using insurance claims and administrative data
 Rates associated with dabigatran do not appear to be higher than those see with
warfarin, same findings as RE-LY trial
Dosing= 150 mg PO BID, CrCl 15-30 ml/min 75 mg PO BID, contraindicated if CrCl< 15
ml/min
 Starting post parenteral anticoagulant-give <2 hours prior to next scheduled dose
(enoxaparin) and D/C parenteral medication
 Convert from warfarin-start dabigatran when INR < 2.0
Drug Interactions
 Dronedarone or ketoconazole and CrCl 30-50 ml/min-use 75 mg BID
 Any p-glycoprotein inhibitor and CrCl<30 ml.min- avoid dabigatran
No specific antidote exists for reversal-is dialyzable (60% removed in 2-3 hours)
Dabigatran capsules very sensitive to moisture, must be kept in blister pack or original
bottle with desiccant (use within 4 months)—do not place in pill boxes
Dabigatran 150 mg BID or 75 mg BID-$ 300.44 AWP for 60 capsules
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Factor Xa Inhibitor-rivaroxaban (Xarelto)
o ROCKET-AF trial enrolled 14, 264 patients with AF (mean CHADS2 score=3.5)
 Rivaroxaban 20 mg vs. Rivaroxaban 15 mg (CrCl 30-49) vs. blinded warfarin
 Rivaroxaban was non inferior to warfarin in avoidance of stroke and systemic
embolism in per protocol analysis
 Major and non-major clinically relevant bleeding showed no statistical difference
in groups
 ICH and fatal bleeding occurred significantly less in rivaroxaban groups
o Dosing for AF=20 mg daily with evening meal (CrCl> 50) or 15 mg daily with evening meal
if CrCl 15-50 ml/min, contraindicated if CrCl< 15 ml/min **Note different renal cut offs for
other indications**
 Convert from warfarin-start rivaroxaban when INR < 3.0
 Starting post parenteral anticoagulant-give <2 hours prior to next scheduled dose
(enoxaparin) and D/C parenteral medication
o No specific antidote available in US, but four factor PCC (Cofact) does reverse
anticoagulant effect
o Drug Interactions:
 Avoid concurrent use with CYP3A4/p-glycoprotein strong inducers—
carbamazepine, phenytoin, rifampin
 Avoid concurrent use with CYP3A4/p-glycoprotein strong inhibitors--ketoconazole, itraconazole, ritonavir, conivaptan, lopinavir
o Tablet contains lactose, not recommended for patients with lactose intolerance
o Rivaroxaban 15 or 20 mg daily-$300.27 AWP for 30 tablets
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Factor Xa Inhibitor-apixaban (Eliquis)
o ARISTOTLE trial enrolled 18, 201 patients with AF (mean CHADS2 score=2.1)
 Apixaban 5 mg BID (or 2.5 mg BID if needed) vs. blinded warfarin
 Excluded patients with SCr> 2.5 or eGFR< 25 ml/min
 Apixaban non-inferior and superior to warfarin in prevention of stroke and
systemic embolism
 Apixaban showed significantly lower major clinical bleeding and hemorrhagic
stroke than warfarin group
 First study to show reduction in all cause mortality over warfarin
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Subgroup analysis looked at patients with prior stroke or TIA and showed no
statistical difference in apixaban and warfarin groups
Dosing for AF=5 mg BID, unless patient meets 2 of the following criteria:
age> 80 years, SCr> 1.5 or weight <60 kg then dose is 2.5 mg BID
 AHA recommends avoid use if CrCl< 25 ml/min
 Convert from warfarin-start apixaban when INR < 2.0
 Use 2.5 mg BID for patients on clarithromycin, ketoconazole, itraconazole or
ritonavir
No specific antidote exists for reversal-is NOT dialyzable
Abixapan 2.5 or 5 mg BID=$300.44 AWP for 60 tablets
SUMMARY of 3 NEW DRUGS AND LANDMARK TRIALS
Drug/Trial
Dabigatran in RE-LY
Rivaroxaban in
ROCKET
Abixaban in
ARISTOTLE
Efficacy: Stroke/VTE
Prevention
34% reduction
Non inferior to warfarin
AE: Hemorrhagic
Stroke
74% reduction
40% reduction
AE: Major Bleeding
20% reduction
50% reduction
30% reduction
Similar to warfarin
Similar to warfarin
Source: Hughes S, Abixapan approved: Now which anticoagulant to use? Medscape News for Pharmacists. Last updated 1/18/2013,
Accessed 1/27/2013.
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Manning WJ, Singer CE, Lip GH. Antithrombotic Therapy to Prevent Embolization in A fib; Up to Date. www.uptodate.com .
Article last updated 1/23/2013, Accessed 1/27/2013.
Hughes S, Abixapan approved: Now which anticoagulant to use? Medscape News for Pharmacists.
www.medscape.com/viewarticle/777887. Last updated 1/18/2013, Accessed 1/27/2013.
Complied by:
Angie Pegram, PharmD, BCPS, CDE
February 14, 2013