a new era in anticoagulation management
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Allyson Sarigianis, Pharm.D. October 19, 2013. A New Era in Anticoagulation Management. Objectives. Review current practice recommendations for prevention of stroke/systemic embolism in atrial fibrillation - PowerPoint PPT PresentationTRANSCRIPT
A New Era in Anticoagulation Management
Allyson Sarigianis, Pharm.D.October 19, 2013
Objectives Review current practice recommendations for
prevention of stroke/systemic embolism in atrial fibrillation
Compare and contrast pharmacology between warfarin and target specific oral anticoagulants (TSOACs)
Summarize the efficacy and safety of TSOACs for atrial fibrillation
Examine the differences between warfarin and TSOACs for atrial fibrillation
Identify future clinical implication for new era in anticoagulation management based on AT9 2012 Chest Guidelines
Current FDA Approved IndicationsWarfarin • Prophylaxis and treatment of venous thrombosis
and its extension, pulmonary embolism (PE)• Prophylaxis and treatment of thromboembolic
complications associated with atrial fibrillation and/or cardiac valve replacement
• Reduction in the risk of death, recurrent myocardial infarction (MI), and thromboembolic events
Dabigatran • Stroke prevention in patients with non-valvular atrial fibrillation
Rivaroxaban
• Stroke prevention in patients with non-valvular atrial fibrillation
• Prevention of VTE in patients undergoing hip or knee replacement
• Acute treatment of DVT/PE• Secondary prevention of DVT/PE
Apixaban • Stroke prevention in patients with non-valvular atrial fibrillation
Warfarin
WarfarinKinetics Absorption Oral: Rapid, complete
Distribution 0.14 L/kgMetabolism Hepatic, primarily via CYP2C9;
minor pathways include CYP2C8, 2C18, 2C19, 1A2, and 3A4
Excretion Urine (92%, primarily as metabolites)
Half-life 20-60 hours
Warfarin
Onset of action: 5-7 days May requiring bridging
Antidote: Vitamin K, FFP, PRBC
Interactions: Foods with high vitamin K content
Warfarin
Medications Amiodarone Antiplatelets Azole antifungals
(fluconazole) 2nd/3rd-gen Cephalosporins Fluoroquinolones
(ciprofloxacin) Griseofulvin Isoniazid Macrolides
(clarithromycin) Metronidazole NSAIDs
Penicillins (nafcillin) Prednisone Rifampin SSRIs Sulfonamides (Bactrim) Tetracyclines
(Doxycycline ) Herbals
Ginger Gingko Fenugreek Chamomile St. John’s Wort
Warfarin
ADRs Bleeding/Hemorrhage/Hematuria Vasculitis Dermatitis, pruritus, urticaria Abdominal pain, N/V/D Anemia Skin necrosis, gangrene, “purple toes”
syndrome
Dabigatran (Pradaxa)
Dabigatran
MOA: direct thrombin inhibitor which inhibits: Both free and fibrin-bound thrombin Cleavage of fibrinogen to fibrin Activation of factors V, VIII, XI, and XIII Thrombin-induced platelet aggregation
Dabigatran
Kinetics Absorption Rapid; initially slow
postoperativelyDistribution Vd: 50-70 LMetabolism Hepatic; rapidly and completely
hydrolyzed to active form by plasma and hepatic esterases
Excretion Renal (80%)Half-life 12-17 hours
Dabigatran
Monitoring PPT
Onset: 1 hour, delayed by food
Antidote: None
ADRs Bleeding (8% to 33%; major ≤ 6%) Dyspepsia (11%)
Dabigatran Contraindications
Hypersensitivity to dabigatran or any component Active bleeding
Warnings/Precautions Bleeding Renal impairment Anticoagulants Invasive/surgical invasions P-gp inducers/inhibitors
Dabigatran
Drug interactions Category X: P-Gp inducers Category D: Amiodarone, P-Gp
inhibitors, quinidine, St. john’s Wort, verapamil
Category C: antacids, anticoagulants, antiplatelet agents, atorvastatin, dasantinib, ibritumonmab, NSAIDs, prostacyclin analogs, PPIs, salicylates, thrombolytic agents
Dabigatran
FDA Bleeding Risk: [12-7-2011]
Evaluating post-marketing reports of serious bleeding
“Bleeding that may lead to serious or even fatal outcomes is a well-recognized complication of all anticoagulant therapies.”
Dabigatran ISMP Medication Safety Alert: Quarter Watch
[01-12-12]
932 serious adverse events for 1st quarter of 2011 120 deaths 25 cases of permanent disability 543 cases requiring hospitalization 505 cases involved hemorrhage: elderly
patients (Median age of 80)▪ 120 cases of hemorrhagic stroke
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Dabigatran
FDA Drug Safety Communication: [11‐02‐2012] “… FDA investigated the actual rates of
gastrointestinal bleeding and intracranial hemorrhage for new users of [dabigatran] compared to new users of warfarin. The results of this Mini‐Sentinel assessment indicate that bleeding rates associated with new use of [dabigatran] do not appear to be higher than bleeding rates associated with new use of warfarin ….”
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Dabigatran
FDA Drug Safety Communication: [12-19-2012] “A clinical trial in Europe (the RE-ALIGN trial)
was recently stopped because [dabigatran] users were more likely to experience strokes, heart attacks, and blood clots forming on the mechanical heart valves than were users of the anticoagulant warfarin. There was also more bleeding after valve surgery in the [dabigatran] users than in the warfarin users [dabigatran] is not approved for patients with AF caused by heart valve problems. “
DabigatranMay be appropriate MAY NOT be
appropriate NOT appropriate
Ability to comply with twice daily drug regimen
History of non-adherence
Severe renal impairment (CrCl <30 ml/min)
Unstable INRs on warfarin (unrelated to adherence)
Stable INRs on warfarin History of GI bleeding or recent ulcers
Difficulty obtaining regular INRs on warfarin
Advanced age (75-80 yrs and older; consider benefits and risks)
Active liver disease
Complicated interacting drug regimens on warfarin
Pregnancy, at risk of pregnancy, or lactating
High risk of intracranial bleed
Need for concomitant treatment with P-gp inducer (e.g,. rifampin, St. John’s Wort)
Medication regimen does not include drugs that interact with dabigatran
Moderate renal impairment (CrCl 30-50 ml/min) and the need for concomitant treatment with the P-gp inhibitors dronedarone or systemic ketoconazole
Good renal functionNo history of GI bleeding or recent ulcers
Rivaroxaban (Xarelto)
Rivaroxaban
MOA: selective/reversible direct inhibitor of factor Xa
Prevents the conversion of prothrombin to thrombin
Thrombin both activates platelets and catalyzes the conversion of fibrinogen to fibrin
RivaroxabanCreatine
Clearance (mL/min)
>50 50-30 29-15 <15 or HD
Atrial fibrillation 20 mg po daily
15 mg po daily Avoid use
Postoperative thromboprophylaxis
10 mgpo daily
Knee: 12-14 days
Hip: 35 days
10 mg po daily, use
with caution
Avoid use
Avoid use
Treatment of PE/VTE
15 mg twice daily x21
days, then 20 mg po
daily
Use with caution
Avoid use
Avoid use
Secondary Prophaxis for PE/VTE
20 mg po daily
Use with caution
Avoid use
Avoid use
Rivaroxaban
Kinetics Absorption Rapid
Distribution Vdss: ~50 L
Metabolism Hepatic (33%) via CYP3A4/5 and CYP2J2
Excretion Renal (66% primarily via active tubular secretion); feces (28%)
Half-life 5-9 hours
Rivaroxaban
Monitoring Prothrombin time (PT) CBC with differential Renal/hepatic function
Onset: 2-4 hours
Antidote: None
Rivaroxaban
ADRs Pruritus (2%) Bleeding ▪ DVT prophylaxis: 6% [major: <1%] ▪ Atrial fibrillation: 21% [major: 6%]
Thrombocytopenia (3%) Increase in liver enzymes (7%-3%)
Rivaroxaban
Contraindications Hypersensitivity to rivaroxaban or any
component Active bleeding
Drug Interactions Category X: P-Gp or 3A4
inhibitors/inducers Category C: anticoagulants, antiplatelet
agents, NSAIDs, salicylates
Rivaroxaban
ISMP Medication Safety Alert: 10/4/2012
Primary event: Thrombus 158 cases, 44.4% of the total
Hemorrhage 121 cases, 34% of the total
Apixaban (Eliquis)
Apixaban
MOA: oral direct Xa inhibitor
Dose: 5mg twice daily Dose reduction to 2.5mg twice daily if
2+ of the following: ▪ Age ≥80 years▪ Body weight ≤60kg▪ Scr ≥1.5mg/dl
AVOID in CrCl <15 ml/min
Apixaban Kinetics Absorption Rapid; Intestines
Distribution Vd: 21 LMetabolism 15% liver metabolism
CYP3A4/5P-gp
Excretion Primarily Biliary/Fecal (46-56%)Renal (27%) unchanged
Half-life 8 to 15 hours
Apixaban
Monitoring Minimal impact on the PT, INR, or aPTT Factor Xa inhibition
Onset: 3-4 hours
Antidote: None
Clinical Evidence
RE-LY ROCKET-AF ARISTOTLE
Dabigatran 150mg
BID vs. warfarin
Rivaroxaban 20mg daily
vs. warfarinApixaban5mg BID
vs. warfarinStudy Design
Trial design RCT Open blinded assessment RCT DB DD RCT DB DD
Sample size (n) 18,000+ 14,000+ 18,000+
Inclusion criteria AF and selected risk factor(s) for embolization
AF and CHADS2 ≥2
AF or flutter and CHADS2 ≥1
Key exclusion criteria
Valvular AFUse of ASA ≥100 mg/dayCrCl <30 ml/min
Valvular AF;Use of ASA >100 mg/dayCrCl <30 ml/min
Valvular AFNeed for ASA >165 mg/daySCr >2.5mg/dL or CrCl <25ml/min
Follow-up (mean) 2 yr 1.9 yr 1.8 yrOutcome Definitions
Primary Efficacy Composite of systemic embolism and stroke (ischemic or hemorrhagic)Major Bleeding ISTH: fatal/critical organ bleed; decrease ≥2g/dL Hbg or transfusion of ≥2U bloodMortality All causes
Baseline CharacteristicsAge (years) 71 (mean) 73 (median) 70 (median) Female (%) 36.4% 39.7% 35.2 %CHADS2 (mean) 2.1 3.5 2.1Previous embolic episode (%)
20% (stroke or TIA only)
55%(stroke,TIA, systemic
embolism)19%
(stroke, TIA, systemic embolism)
TTR (%) (Standard 60-65%) 64% 55% 62%
Comparison of Efficacy Results
RE-LY ROCKETAF ARISTOTLE
Outcome (%/year)
Dabigatran 150mg BID
vs. warfarin
p Value
Rivaroxaban 20mg
daily vs.
warfarin
p ValueApixaban 5mg BID
vs. warfarin
p Value
Primary OutcomeStroke or systemic embolism
1.1 vs. 1.7%
p<0.001 NNT 88
2.1 vs. 2.4% p=0.12 1.3 vs.
1.6%
p=0.01
NNT 167
Stroke 1.0 vs. 1.6%
p<0.001NNT 88
1.65 vs. 1.96% p=0.09 1.2 vs.
1.5%
p=0.01
NNT 175
Ischemic stroke
0.9 vs. 1.3%
p=0.03NNT 132 1.3 vs. 1.4 p=0.58 0.97 vs.
1.05%p=0.4
2
Hemorrhagic stroke 0.1vs0.4% p<0.001
NNT 1820.26 vs. 0.44%
p=0.02NNT 333
0.24 vs. 0.47%
p<0.001
NNT 238
All cause death 3.6 vs. 4.1% p=0.051 4.5 vs.
4.9% p=0.15 3.5 vs. 3.9p=0.0
47NNT 132
MI/ACS 0.7 vs. 0.5%
p=0.048NNH 239
0.9 vs. 1.1% p=0.12 0.5 vs.
0.6%p=0.3
7
Comparison of Safety Results
RE-LY ROCKETAF ARISTOTLE
Major bleed
3.1 vs. 3.36% p=0.31 3.6 vs.
3.4% p=0.58 2.1 vs. 3.1%
p<0.001NNT 67
Intracranial bleed
0.3 vs. 0.74%
p<0.001
NNT 116
0.5 vs. 0.7%
p=0.02NNT 250
0.3 vs. 0.8%
p<0.001NNT 128
GI bleed 1.5 vs. 1.0%
p<0.001
NNH 100
3.2 vs. 2.2%**
p=0.001NNH 100
0.76 vs. 0.86% 0.37
Guidelines
ACC/AHA/HRS 2011 Focused update recommendation:
Dabigatran is a useful alternative to warfarin for the prevention of stroke and systemic embolism in patients with paroxysmal to permanent AF and risk factors for stroke and systemic embolism
Do not have a prosthetic heart valve, hemodynamically significant valve disease, severe renal failure (CrCl < 15mL/min), or impaired liver disease
Alternative to warfarin for moderate-high risk patients:▪ Difficulty achieving therapeutic INRs▪ Inability obtaining regular bloodwork monitoring▪ Low risk for GI bleeding▪ Low risk for cardiovascular events
AT9 2012 Chest
2.1.8 CHADS = 0 No therapy rather than
antithrombotic therapy (Grade 2B) 2.1.9
CHADS = 1 Oral anticoagulation rather than no
therapy (Grade 1B)
AT9 2012 Chest
2.1.10 CHADS =2+ Oral anticoagulation rather than no
therapy (Grade 1A) 2.1.11
Dabigatran 150 mg twice daily rather than adjusted-dose VKA therapy (target INR range, 2.0-3.0) (Grade 2B)
The Future
Conclusions
Comparison of agentsDabigatra
nRivaroxa
ban Apixaban
Target Factor IIa Factor Xa Factor Xa
FDA Indications Nonvalvular AF Nonvalvular AFOrtho VTE ProphAcute Treatment
VTE
Nonvalvular AF
Prodrug Yes No No
Dosing Twice daily Daily, with food Twice daily
Onset 1-2 hrs 2-4 hrs 3-4 hrs
Half-life (h) 14–17 7–11 8–14
Renal Adjustment ↓ 15-29ml/minAvoid < 15
ml/min
Avoid < 30 ml/min
Avoid < 15 ml/min
Drug Interactions P-gp CYP3A4/P-gp CYP3A4/P-gp
Conclusions
Efficacy superiority vs non- inferiority
ADRs ACS / MI risk
Cost
Clinical guidelines
References Antibiotic/Antifungal Drug Interactions and Warfarin. Pharmacist's Letter 2012; 28(1):280102. Connolly SJ, Ezekowitz MD, Yusuf S, et al. RELY Trial: Dabigatran versus warfarin in patients with atrial
fibrillation. NEJM.2009; 361(12): 1139-51. Wallentin L, Yusuf S, Ezekowitz MD, et al. Efficacy and safety of dabigatran compared with warfarin at
different levels of international normalized ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet. 2010; 376: 975-83.
Reversing Dabigatran and Rivaroxaban. Pharmacist's Letter 2011; 27(9):270912. Weitz JI. New oral anticoagulants in development. Thromb Haemost 2010; 103: 62–70. Institute of Safe Medication Practices. ISMP Medication Safety Alert, January 12, 2012. “Outpatient Anticoagulation Management” VA Medical Center: MCM 11-20. Updated August 2011. Dabigatran (Pradaxa®) National Drug Monograph, VA Pharmacy Benefits Management Services, Medical
Advisory Panel, and VISN Pharmacist Executives, April 2011. “Dabigatran etexilate: drug information.” www.uptodate.com. Accessed 20 January , 2012. Rivaroxaban. Monograph. Medscape. Accessed 24 January, 2012.
http://reference.medscape.com/drug/xarelto-rivaroxaban-999670#10 Patel MA, Mahaffey KE, Garg JY, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Eng
J Med. 2011. Lassen MR, Raskob GE, Gallus A, et al. Apixaban or enoxaparin for thromboprophylaxis after knee
replacement. N Engl J Med. 2009;361:594-604. Lopes RD, Alexander JH, Al-Khatib SM, et al; ARISTOTLE Investigators. Apixaban for reduction in stroke
and other thromboembolic events in atrial fibrillation (ARISTOTLE) trial: design and rationale. Am Heart J. 2010;159:331-9.
Eikelboom JW, O’Donnell M, Yusuf S, et al. Rationale and design of AVERROES: apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment. Am Heart J. 2010;159:348-53.
Comparison of Oral Antithrombotics. Pharmacist's Letter. 2012; 28(1):280102. Dentali F, Riva N, Crowther M, et al. Efficacy and safety of the novel oral anticoagulants in atrial
fibrillation: a systematic review and meta-analysis of the literature. Circulation 2012; 126:2381. Guyatt GH , Akl EA, Crowther M, et al. Antithrombotic Therapy and Prevention of Thrombosis.. American
College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th Edition). Chest 2012; 141:7S-47S