Allyson Sarigianis, Pharm.D.
October 19, 2013
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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 Indications
Warfarin
• 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
Kinetics
Absorption
Oral: Rapid, complete
Distribution
0.14 L/kg
Metabolism
Hepatic, primarily via CYP2C9; minor
pathways include CYP2C8, 2C18, 2C19,
1A2, and 3A4
Excretion
Urine (92%, primarily as metabolites)
Half-life
20-60 hours
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Onset of action:
 5-7 days
 May requiring bridging
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Antidote:
 Vitamin K, FFP, PRBC
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Interactions:
 Foods with high vitamin K content
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 Prednisone
Medications
 Rifampin
 Amiodarone
 SSRIs
 Antiplatelets
 Sulfonamides (Bactrim)
 Azole antifungals (fluconazole)
 2nd/3rd-gen Cephalosporins
 Fluoroquinolones (ciprofloxacin)
 Tetracyclines (Doxycycline )
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Herbals
 Griseofulvin
 Ginger
 Isoniazid
 Gingko
 Macrolides (clarithromycin)
 Fenugreek
 Metronidazole
 Chamomile
 NSAIDs
 St. John’s Wort
 Penicillins (nafcillin)
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ADRs
 Bleeding/Hemorrhage/Hematuria
 Vasculitis
 Dermatitis, pruritus, urticaria
 Abdominal pain, N/V/D
 Anemia
 Skin necrosis, gangrene, “purple toes” syndrome
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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
Kinetics
Absorption
Rapid; initially slow postoperatively
Distribution
Vd: 50-70 L
Metabolism
Hepatic; rapidly and completely
hydrolyzed to active form by plasma
and hepatic esterases
Excretion
Renal (80%)
Half-life
12-17 hours
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Monitoring
 PPT
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Onset: 1 hour, delayed by food
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Antidote: None
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ADRs
 Bleeding (8% to 33%; major ≤ 6%)
 Dyspepsia (11%)
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Contraindications
 Hypersensitivity to dabigatran or any component
 Active bleeding
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Warnings/Precautions
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Bleeding
Renal impairment
Anticoagulants
Invasive/surgical invasions
P-gp inducers/inhibitors
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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
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FDA Bleeding Risk: [12-7-2011]
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Evaluating post-marketing reports of serious
bleeding
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“Bleeding that may lead to serious or even
fatal outcomes is a well-recognized
complication of all anticoagulant therapies.”
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ISMP Medication Safety Alert: Quarter Watch
[01-12-12]
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932 serious adverse events for 1st quarter of 2011
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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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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 ….”
18
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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. “
19
May be appropriate
Ability to comply with twice daily
drug regimen
Unstable INRs on warfarin
(unrelated to adherence)
Difficulty obtaining regular INRs
on warfarin
Complicated interacting drug
regimens on warfarin
MAY NOT be appropriate
NOT appropriate
History of non-adherence
Severe renal impairment (CrCl <30
ml/min)
Stable INRs on warfarin
History of GI bleeding or recent ulcers
Advanced age (75-80 yrs and
older; consider benefits and
risks)
Active liver disease
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 3050 ml/min) and the need for
concomitant treatment with the P-gp
inhibitors dronedarone or systemic
ketoconazole
Good renal function
No history of GI bleeding or
recent ulcers
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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
Creatine Clearance
(mL/min)
Atrial fibrillation
>50
20 mg po daily
50-30
29-15
15 mg po daily
<15 or HD
Avoid use
Postoperative
thromboprophylaxis
10 mg
po 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
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
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Monitoring
 Prothrombin time (PT)
 CBC with differential
 Renal/hepatic function
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Onset: 2-4 hours
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Antidote: None
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ADRs
 Pruritus (2%)
 Bleeding
▪ DVT prophylaxis: 6% [major: <1%]
▪ Atrial fibrillation: 21% [major: 6%]
 Thrombocytopenia (3%)
 Increase in liver enzymes (7%-3%)
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Contraindications
 Hypersensitivity to rivaroxaban or any component
 Active bleeding
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Drug Interactions
 Category X: P-Gp or 3A4 inhibitors/inducers
 Category C: anticoagulants, antiplatelet agents,
NSAIDs, salicylates
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ISMP Medication Safety Alert: 10/4/2012
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Primary event: Thrombus
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158 cases, 44.4% of the total
Hemorrhage
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121 cases, 34% of the total
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MOA: oral direct Xa inhibitor
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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
Kinetics
Absorption
Rapid; Intestines
Distribution
Vd: 21 L
Metabolism
15% liver metabolism
CYP3A4/5
P-gp
Excretion
Primarily Biliary/Fecal (46-56%)
Renal (27%) unchanged
8 to 15 hours
Half-life
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Monitoring
 Minimal impact on the PT, INR, or aPTT
 Factor Xa inhibition
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Onset: 3-4 hours
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Antidote: None
RE-LY
ROCKET-AF
ARISTOTLE
Dabigatran 150mg BID
vs. warfarin
Rivaroxaban 20mg daily
vs. warfarin
Apixaban5mg BID
vs. warfarin
Study Design
Trial design
Sample size (n)
RCT Open blinded
assessment
RCT DB DD
RCT DB DD
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 AF
Use of ASA ≥100 mg/day
CrCl <30 ml/min
Valvular AF;
Use of ASA >100 mg/day
CrCl <30 ml/min
Valvular AF
Need for ASA >165 mg/day
SCr >2.5mg/dL or CrCl <25ml/min
Follow-up (mean)
Primary Efficacy
Major Bleeding
Mortality
Age (years)
Female (%)
CHADS2 (mean)
Previous embolic
episode (%)
TTR (%)
(Standard 60-65%)
2 yr
1.9 yr
1.8 yr
Outcome Definitions
Composite of systemic embolism and stroke (ischemic or hemorrhagic)
ISTH: fatal/critical organ bleed; decrease ≥2g/dL Hbg or transfusion of ≥2U blood
All causes
Baseline Characteristics
71 (mean)
73 (median)
70 (median)
36.4%
39.7%
35.2 %
2.1
3.5
2.1
20%
55%
19%
(stroke or TIA only)
(stroke,TIA, systemic embolism)
(stroke, TIA, systemic embolism)
64%
55%
62%
Comparison of Efficacy Results
RE-LY
Outcome (%/year)
Dabigatran
150mg BID
vs. warfarin
Primary Outcome
Stroke or systemic
embolism
Stroke
ROCKETAF
p Value
Apixaban
5mg BID
vs. warfarin
p Value
2.1 vs. 2.4%
p=0.12
1.3 vs. 1.6%
p=0.01
NNT 167
p<0.001
NNT 88
1.65 vs. 1.96%
p=0.09
1.2 vs. 1.5%
p=0.01
NNT 175
0.9 vs. 1.3%
p=0.03
NNT 132
1.3 vs. 1.4
p=0.58
0.97 vs. 1.05%
p=0.42
0.1vs0.4%
p<0.001
NNT 182
0.26 vs. 0.44%
p=0.02
NNT 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. 3.9
p=0.047
NNT 132
MI/ACS
0.7 vs. 0.5%
p=0.048
NNH 239
0.9 vs. 1.1%
p=0.12
0.5 vs. 0.6%
p=0.37
Ischemic stroke
Hemorrhagic stroke
p Value
Rivaroxaban
20mg daily
vs. warfarin
1.1 vs. 1.7%
p<0.001
NNT 88
1.0 vs. 1.6%
ARISTOTLE
Comparison of Safety Results
RE-LY
Major bleed
3.1 vs. 3.36%
Intracranial
bleed
GI bleed
ROCKETAF
p=0.31
ARISTOTLE
2.1 vs. 3.1%
p<0.001
NNT 67
0.5 vs. 0.7%
p=0.02
NNT 250
0.3 vs. 0.8%
p<0.001
NNT 128
3.2 vs.
2.2%**
p=0.001
NNH 100
0.76 vs.
0.86%
0.37
3.6 vs. 3.4%
p=0.58
p<0.001
0.3 vs. 0.74%
NNT 116
p<0.001
1.5 vs. 1.0% NNH 100
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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
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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
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2.1.8
 CHADS = 0
 No therapy rather than antithrombotic therapy
(Grade 2B)
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2.1.9
 CHADS = 1
 Oral anticoagulation rather than no therapy
(Grade 1B)
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2.1.10
 CHADS =2+
 Oral anticoagulation rather than no therapy
(Grade 1A)
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2.1.11
 Dabigatran 150 mg twice daily rather than
adjusted-dose VKA therapy (target INR range,
2.0-3.0) (Grade 2B)
Dabigatran
Rivaroxaban
Apixaban
Factor IIa
Factor Xa
Factor Xa
Nonvalvular AF
Nonvalvular AF
Ortho VTE Proph
Acute 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/min
Avoid < 15 ml/min
Avoid < 30 ml/min
Avoid < 15 ml/min
Drug Interactions
P-gp
CYP3A4/P-gp
CYP3A4/P-gp
Target
FDA Indications
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Efficacy
 superiority vs non- inferiority
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ADRs
 ACS / MI risk
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Cost
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Clinical guidelines
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