Recent Advances in Anticoagulant Therapy

52 Pages·2011·1.92 MB·English

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Theraapy:
Will New Oral Aggents Render Warfarin a Thingg
of the Past?
TTobby CC. TTrujjiillllo, PPhharm.DDDD., BBCCPPSS ((AAQQ CCarddiiollogy))
Associate Professor
University of Colorado Dennver – School of Pharmacy
Clinical Specialist – Carddiology/Anticoagulation
Director: Inpatient Anticoagulation – Thrombosis Management Service
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•• DDiiffffeerreennttiiaattee nneeww aannttiiccooooaagguullaanntt aaggeennttss wwiitthh
respect to their pharmaacokinetics,
pharmacodynamics, annd recommended dosing
ssttrraatteeggiieess
• OOuuttlliinnee ccuurrrreenntt lliitteerraattuurree ssuuppppoorrttiinngg tthhee rroollee ooff
new anticoagulant agents in the prevention and
treatment of thromboemmbolic disorders
• Given a patient who is receiving a new
anticoaggulant aggent, asssess whether current
therapy is appropriate
Oral Anticoagulation - Warfarin
• Main oral agent for long tterm prevention and treatment
of thromboembolic diseasse > 50 years
• Advances
– IINNRR
– Anticoagulation Managemeent Services
• DDeessppiittee AAddvvaanncceess
– Challenges still exist in dettermining optimal and safest dose
– Individualized patient to ppatient
– Warfarin continues to rankk among top 10 medications
associated with adverse evvents
• Bleeding
– CCumullattiive iincrease over ttttiime
– Rates vary depending on inndication
– Rate is highest during initiaation of therapy
Warfarin Key Varriables for Dosing
• Metabolism
• Initiation
– CYP system
– Loading vs predicted maintenance
– DDrug iintteracttiions dose
• Variable response
• EEtthhnniicciittyy aanndd aavveerraaggee ddaaiillyy
– Food dose
– Age
– Concomitant disease states
– 66.11 mmgg:: AAffrriiccaann-AAmmeerriiccaannss
– ETOH
– Ethnicity
– 5.1 mg: Caucasians
• Half-life
– 3.4 mg: Asians
– 36-48 hours
– PPeeaakk eeffffeecctt ssiinnggllee ddoossee
– Steady state 2 weeks
Johnson JA. Circulation 2008;118:1383-1393
Warfarin for Atrrial Fibrillation
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Ideal Anticoaggulant
Need for Injectable agent
New Oral Anticoaagulants - Targets
Bereznicki et al. New antithrombotics for atrial fibrillation. Cardiovascular Therapeutics 2010 (28) 278–286
DABIGATRANN ETEXILATE
((PPrraaddaaxaa, BBooeerriiiinngghheerr-IInnggeellhheeiimm))
• PHARMACOLOGY:
– PProddrug, converttedd tto tthhe acttiive ddddabbiigattran moiietty bby hhyddrollysiis viia
nonspecific esterases.
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– Dabigatran inhibits human thrombbin and thrombin-induced platelet
aaggggrreeggaattiioonn.
– Dabigatran inhibits both clot-bounnd and fluid-phase thrombin.
• FDA indication (Approved Octoober 2010):
– Dabigatran is a direct thrombin inhibitor indicated to reduce the risk of
ssttrrookkee aanndd ssysstteemmiicc eemmbboolliissmm iinn ppaattiieennttss wiitthh nnoonn-vaallvullaarr aattrriiaall
fibrillation
RE-LY: Stuudy Design
Atrial fibbrillation
≥1 Risk Factor
Absence of conntra-indications
995511 centters iinn 4444 counttriies
Open Blinded
N = 18,113
Warfarin Dabiggatran Dabigatran
adjjusted Etexilate Etexilate
(INR 2.0-3.0) 110 mg BID 150 mg BID
N=6000 N=66000 N=6000
Patients were eliggible if theyy had atrial fibrillation docummented on electrocardioggrapphyy pperformed at screeningg or
within 6 months beforehand and at least one of the folloowing characteristics:
1. Previous stroke or transient ischemic attack
2. A left ventricular ejection fraction of less than 40%
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4. An age of at least 75 years or an age of 65 to 744 years plus diabetes mellitus, hypertension, or coronary
artery disease.
Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151
RE-LY: Baselinne Characteristics
Characteristic Dabigatran 110 mg Dabigatran 150 mg Warfarin
Randomized 6015 6076 6022
Mean age (years) 71.4 71.5 71.6
Male (%) 64.3 63.2 63.3
CCHADSS2 ssccooree
22.11 22.22 22.11
(mean)
0-1 (%)
32.6 32.2 30.9
2 (%)
34.7 35.2 37.0
33++ ((%%))
3322.77 3322.66 3322.11
Prior stroke/TIA (%) 19.9 20.3 19.8
Prior MI ((%)) 16.8 16.9 16.1
CHF (%) 32.2 31.8 31.9
Baseline ASA (%) 40.0 38.7 40.6
Warfarin Naïve (%) 49.9 49.8 51.4
C. Michael Gibson, M.S., M.D. CConnolly SJ, et al. N Engl J Med. 2009;361:1139-1151