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David Stewart, PharmD, BCPS
Assistant Professor of Pharmacy Practice
f
f h
East Tennessee State University
Bill Gatton College of Pharmacy
[email protected] At the conclusion of this program, the audience should be able to:
d
h ld b bl
• List the new oral anticoagulant medications currently g
y
approved or in the approval process by the United States Food and Drug Administration
• Communicate basic principles of pharmacokinetics to C
i t b i
i i l
f h
ki ti t
other healthcare providers
• Identify appropriate indications for the use of new oral Identify appropriate indications for the use of new oral
anticoagulant medications
• Develop patient specific plans utilizing newly approved oral anticoagulant agents for the treatment and prevention of venous thromboembolic events in various
various patient populations
patient populations
Including warfarin, how many oral anticoagulants are currently FDA approved in the United States?
approved in the United States?
One
Two
Th
Three
Four
Five
ve
0%
Fi
ur
0%
Fo
T
w
T
0%
hr
ee
0%
o
0%
O
ne
1.
1
2.
3
3.
4.
5.
Anticoagulant Medications
Anticoagulant Medications
1943
1954
2005
2010
2011
2012
• Heparin • Warfarin • Ximelagatran • Dabigatran
• Rivaroxaban • Apixaban to Approved by Approved by Research Approved by Approved by be Voted on FDA
FDA
Discontinued FDA
FDA
by FDA
Humans in Space
p
1957
1961
1961
• Sputnik I & 2
S t ik I & 2 • Yuri Gargarin
Y iG
i • Alan Al
Orbits Earth
Shephard
Suborbital Flight
1969
1981
• Americans A
i
• 1st Flight of Fli ht f
Land on the Columbia Moon
(STS‐1)
1982
2000
• Soviets S i t
• International I t
ti
l
Deploy Space Station Manned is Inhabited
Space Station
Vitamin K Antagonists
(Warfarin)
Vitamin K Dependent Proteins
p
Protein
Factor II (Prothrombin
(Prothrombin))
HalfHalf-life (hours)
42--72
42
Factor VII
4-6
Factor IX
21
21--30
Factor X
27
27--48
Protein C
9
Protein S
60
Managing Oral Anticoagulation Therapy. St. Louis, MO: WKH, 2009:149‐60.
Warfarin
Pros
• Experience
• Inexpensive
• Reversible
• Monitoring available
Cons
• Time of onset
• Frequent monitoring
Frequent monitoring
• Dosing variability
• Numerous drug interactions
21st Century
• New therapies with phase III data
New therapies with phase III data
– Dabigatran
– Rivaroxaban
– Apixaban
• Developing therapies
D l i th
i
– Edoxaban
0%
0%
5
0%
3
0%
2
1
1. Warfarin is a an adequate medication with good data so I’ll continue to use warfarin.
2. Warfarin has many shortcomings and I would prefer to use newer agents.
3 II’m
3.
m still a little hesitant about the newer still a little hesitant about the newer
agents because I’m unfamiliar with them.
4 I prefer the newer agents over warfarin; 4.
I prefer the newer agents over warfarin;
however, I am concerned about the cost of new agents.
5 I have serious concerns about the safety 5.
I have serious concerns about the safety
0%
of newer anticoagulant medications.
4
Which of the following best describes your opinion regarding the novel new
your opinion regarding the novel new anticoagulant medications?
Which of the following best describes your current prescribing of dabigatran
your current prescribing of dabigatran
(Pradaxa®)?
0%
4
0%
3
0%
2
0%
1
1. I routinely prescribe dabigatran.
2. I prescribe dabigatran in a g p
limited and select group of patients.
3. I am very hesitant to prescribe I am very hesitant to prescribe
dabigatran.
4 I have never prescribed 4.
I have never prescribed
dabigatran.
Part I
Clinical Pharmacology Comparison
Coagulation Cascade
Coagulation Cascade
Intrinsic Pathway (PTT)
y(
)
XII
XIIa
XI
XIa
IX
VII
VIIa
VII
IXa
VIII
Warfarin
Rivaroxan & Apixaban
Extrinsic Pathway (PT)
y( )
XIII
Xa Va
X
II
IIa
XIIIa
Dabigatran
Fibrinogen
Fibrin
Dabigatran Etexilate (Pradaxa®)
(Approved 2010)
• Direct Thrombin Inhibitor
– Competitive
• Prodrug
– Hydrolysis
• Peak effect
– 1 hr (empty stomach)
– 2 hr (with food)
• t½
• Adverse Effects
– Bleeding
– GI symptoms (35%)
– GI bleeding
• ↑compared to warfarin
↑
d
f i
• Consider with ↓ ICH
• Note rate similar to warfarin in VTE trial
– 12‐18 hours
• Elimination
– Renal (> 80%)
• Monitoring
– Not routinely required
y q
Pharmacoth 2008;28(11):1345‐73. Drug Metab Dispos 2008;36(2):386‐99. Pradaxa PI Revised 8/11.
Rivaroxaban (Xarelto®)
(FDA Approved 2011)
• Direct Factor Xa Inhibitor
– Competitive
• Peak effect
– 1 hr (empty stomach)
– 4 hr (with food)
• t½
– 5‐9 hours
• Metabolism & Elimination
– CYP3A4/5 & P‐gp
• Renal (36 % parent)
• Biliary‐fecal (7% parent)
Bili
f l (7%
)
• Monitoring
– Not routinely required
Pharmacoth 2009;29(2):167‐81. Xarelto PI Revised 7/11.
• Adverse Events
– Bleeding
– Liver enzymes elevated less frequently in rivaroxaban
group compared to
group compared to enoxaparin
– GI bleeding
• ↑compared to warfarin
• Consider with ↓ ICH
• Note rate similar to warfarin in VTE trial
Apixaban (Eliquis®)
(Not currently approved by the FDA)
• Direct Factor Xa Inhibitor
– Competitive
• Peak effect
– 3‐4 hrs
• t½
– 8‐15 hrs
• Metabolism & Elimination
– CYP3A4/5 & P‐gp
• Renal (27 % parent)
• Biliary‐fecal
– Additional CYP isozymes
Additi
l CYP i
• Monitoring
– Not routinely required
Eliquis PI (EU) Revised 5/11.
• Adverse Events
– Bleeding
– Nausea
Monitoring vs Measuring
Monitoring vs. Measuring
Measuring Dabigatran
Measuring Dabigatran
Thromb Haemost 2010;103:1116‐27.
Measuring Rivaroxaban & Apixaban
Measuring Rivaroxaban
& Apixaban
• The aPTT is not sensitive enough for anti‐Xa agents
• The PT correlates well with serum concentrations
– The INR is specific to warfarin and is not accurate for anti‐
Xa agents
– PT is not sensitive enough to detect Ctrough
• Anti‐Xa Assays
– Chromagenic
h
anti‐Xa assays may be useful
b
f l
• Different assays vary in sensitivity
• Must calibrate standard curve based on drug concentration
– HepTest® is not accurate for rivaroxaban
®i
f i
b (and likely ( d lik l
apixaban)
• Incubation period too long
• M
Modified HepTest® may be useful but no current data difi d H T t®
b
f lb t
td t
Ther Drug Monit 2010;32:673‐9.
Which of the following are significantly affected by moderate/severe renal
affected by moderate/severe renal insufficiency?
Apixaban
Dabigatran
Rivaroxaban
Both 2 & 3
All of the above
R
iva
ro
xa
at
ra
0%
0%
B
ot
h 2 & 3
A
l l of
th
e ab
o.
..
0%
ba
n
n
0%
D
ab
ig
xa
b
an
0%
A
pi
1.
2.
3
3.
4.
5.
Summary Table
Parameter
Apixaban
Dabigatran
Rivaroxaban
Target Protein
Factor Xa
Thrombin (IIa)
Factor Xa
No
Yes (etexilate)
No
CYP3A4/P‐gp
Renal
CYP3A4/P‐gp
Avoid < 15 ml/min
Avoid < 15 ml/min
↓ 15
↓
15‐29ml/min
29ml/min
Avoid < 15 ml/min
Avoid < 30 ml/min
< 30 ml/min
CYP3A4/P‐gp
Rifampin (P‐gp)
CYP3A4/P‐gp
Onset of activity
Onset of activity
3 4 hrs
3‐4
1 2 hrs
1‐2 hrs
2 4 hrs
2‐4 hrs
t½
8‐15 hrs
12‐18 hrs
5‐9 hrs
Twice daily
Twice daily
Daily
Anti‐factor Xa
ECT, TT, +/‐ aPTT
Anti‐factor Xa
Pro‐Drug
1˚ Elimination
Renal Adjustment
Renal Adjustment
Drug‐Drug Interact.
Dosing interval
Monitoring tests
Part II
Clinical Utilization
What are the current approved indications for dabigatran in the United States?
United States?
Non valvular Afib
Non‐valvular
Prevention of VTE
T
Treatment of VTE
f VTE
All of the above
he
a
bo
.. .
0%
of
t
m
en
t o
f V
. ..
0%
A
l l T
re
at
..
.
0%
P
re
ve
nt
io
n of
al
vu
l
ar
A
...
0%
N
on
‐v
1.
1
2.
3
3.
4.
Atrial Fibrillation
Dabigatran vs. Warfarin in Atrial
Fibrillation (RE‐LY)
b ll
(
)
>18,000 patients with non
>18
000 patients with non‐valvular
valvular Afib
Non‐inferiority design
O
Open label
l b l
Warfarin vs. dabigatran 110 mg BID & dabigatran 150 mg BID
• Follow‐up approximately 2 years
p pp
y y
• INR Time in Therapeutic Range (TTR): 64%
•
•
•
•
New Engl J Med 2009;361:1139‐51.
RE‐LY
Patient Population
l
Inclusion Criteria
Inclusion
Criteria
• Afib in addition to:
–
–
–
–
–
Hx Stroke/TIA
LVEF < 40%
≥ NYHA Class II HF
Age ≥ 75
Age ≥ 75
Age 65‐74 in addition to:
• DM
• HTN
• CAD
New Engl J Med 2009;361:1139‐51.
Exclusion Criteria
Exclusion
Criteria
• Severe heart valve disorder
• Recent stroke
Recent stroke
• CrCl < 30 ml/min
• Liver disease
RE‐LY
Endpoints
d
• Primary
– Composite: stroke & systemic embolization
New Engl J Med 2009;361:1139‐51.
• Secondary/Other
–
–
–
–
–
–
Stroke
Systemic embolization
MI
PE
TIA
Mortality
RE‐LY
Patient Demographics
h
Ch
Characteristic
i i
D bi
Dabigatran
110
110 mg
D bi
Dabigatran
150
150 mg
W f i
Warfarin
71.4 ± 8.6
71.5 ± 8.8
71.6 ± 8.6
64.3 %
63.2%
63.3%
2.1 ± 1.1
2.2 ± 1.2
2.1 ± 1.1
Prior Stroke or TIA
19.9%
20.3%
19.8%
Prior MI
Prior MI
16 8%
16.8%
16 9%
16.9%
16 1%
16.1%
Aspirin at baseline
40.0%
38.7%
40.6%
VKA at baseline
50.1%
50.2%
48.6%
Age
Male Sex
CHADS2 Score
New Engl J Med 2009;361:1139‐51.
RE‐LY ‐ Results
E t
Event
Dabi
D
bi 110 vs
110 Warf
W f
HR (95% CI)
Dabi
D
bi 150 vs Warf
W f
HR (95% CI)
Dabi
D
bi 150 vs Dabi
D bi 110
HR (95% CI)
Efficacy
1˚ Endpoint*
0.91 (0.74‐1.11)
0.66 (0.53‐0.82)
0.73 (0.58‐0.91)
All stroke
0.92 (0.74‐1.13)
0.64 (0.51‐0.81)
0.70 (0.56‐0.89)
Ischemic Stroke
sc e c St o e
1.11 (0.89‐1.40)
. (0.89 . 0)
0.76 (0.60‐0.98)
0.
6 (0.60 0.98)
0.69 (0.54‐0.88)
0.69
(0.5 0.88)
Hemorrhagic Stroke
0.31 (0.17‐0.56)
0.26 (0.14‐0.49)
0.85 (0.39‐1.83)
MI published
1.35 (0.98‐1.87)
1.38 (1.00‐1.91)
1.02 (0.76‐1.38)
MI
MI revised
i d
1 29 (0 96 1 75)
1.29 (0.96‐1.75)
1 27 (0 94 1 71)
1.27 (0.94‐1.71)
N t available
Not
il bl
All cause mortality
0.91 (0.80‐1.03)
0.88 (0.77‐1.00)
0.97 (0.85‐1.11)
Safetyy
Major bleeding
0.80 (0.69‐0.93)
0.93 (0.81‐1.07)
1.16 (1.00‐1.34)
GI bleeding
1.10 (0.86‐1.41)
1.50 (1.19‐1.89)
1.36 (1.09‐1.70)
All bl di
All bleeding
0 78 (0 74 0 83)
0.78 (0.74‐0.83)
0 91 (0 86 0 97)
0.91 (0.86‐0.97)
1 16 (1 09 1 23)
1.16 (1.09‐1.23)
IC bleeding
0.31 (0.20‐0.47)
0.40 (0.27‐0.60)
1.32 (0.80‐2.17)
New Engl J Med 2009;361:1139‐51. New Engl J Med 2010;363:1875‐76.
*Non‐inferiority margin = 1.46
RE‐LY
Summary
• Dabigatran
g
110 mg BID vs. warfarin
g
– Non‐Inferior Efficacy
– Lower major and overall bleeding rates
– Similar GI bleeding rates
Si il GI bl di
t
• Dabigatran 150 mg BID vs. warfarin
–
–
–
–
Superior efficacy
Superior
efficacy
Lower overall bleeding rates
Similar major bleeding rates
Elevated rates of GI bleeding
• Both doses showed decreased ICH compared to warfarin
warfarin (60‐70% RRR)
(60‐70% RRR)
Rivaroxaban vs. Warfarin in Atrial
Fibrillation (ROCKET‐AF) b ll
(
)
• >14,000 patients
,
p
– Non‐valvular Afib
– High risk of stroke
• Non‐inferiority design
N i f i i d i
• Double blind, double dummy
• Warfarin vs. rivaroxaban
Warfarin vs rivaroxaban
– 20 mg daily (CrCl ≥ 50 ml/min)
– 15 mg daily (CrCl
g
y(
30‐49 ml/min)
/
)
• Follow‐up approximately 2 years
• INR Time in Therapeutic Range (TTR): 55%
New Engl J Med 2011;365:883‐91.
ROCKET‐AF
Patient Population
l
Inclusion Criteria
Inclusion
Criteria
• Afib with CHADS2 Score ≥ 2
New Engl J Med 2011;365:883‐91.
Exclusion Criteria
Exclusion
Criteria
• Severe heart valve disorder
• Recent stroke
Recent stroke
• CrCl < 30 ml/min
• Liver disease
ROCKET‐AF
Endpoints
d
• Primary
– Composite: stroke or systemic embolization
New Engl J Med 2011;365:883‐91.
• Secondary/Other
– Composite: Stroke, systemic embolization, CV death, or MI
– Individual components
ROCKET‐AF
Patient Demographics
h
Ch
Characteristic
i i
Ri
Rivaroxaban
b
W f i
Warfarin
73
73
60.3%
60.3%
3.5 ± 0.9
3.5 ± 0.9
Prior Stroke or TIA
54.9%
54.6%
Prior MI
Prior MI
16 6%
16.6%
18%
Aspirin at baseline
36.3%
36.7%
VKA at baseline
62.3%
62.5%
Age
Male Sex
CHADS2 Score
New Engl J Med 2011;365:883‐91.
ROCKET‐AF
Results
Event
Rivaroxaban
(% per year)
Warfarin
(% per year)
HR (95% CI)
Efficacy
Effi
1˚ Endpoint*
2.1
2.4
0.88 (0.75‐1.03)
All stroke
1.65
1.96
0.85 (0.70‐1.03)
Ischemic Stroke
1.34
1.42
0.94 (0.75‐1.17)
Hemorrhagic Stroke
0.26
0.44
0.59 (0.37‐0.93)
MI
0 91
0.91
1 12
1.12
0 81 (0 63 1 06)
0.81 (0.63‐1.06)
All‐cause mortality
1.87
2.21
0.85 (0.70‐1.02)
Safety
Major bleeding
3.6
3.4
1.04 (0.90‐1.20)
All bleeding
14.9
14.5
1.03 (0.96‐1.11)
3 2 (% overall)
3.2 (% overall)
2 2 (% overall)
2.2 (% overall)
p < 0 001
p < 0.001
0.5
0.7
0.67 (0.47‐0.93)
Major GI bleeding
GI bleeding
IC bleeding
*Non‐inferiority margin = 1.46
New Engl J Med 2011;365:883‐91.
ROCKET‐AF
Summary
• Rivaroxaban vs. warfarin
vs warfarin
– Similar bleeding rates
– Lower ICH rates
Lower ICH rates
• High risk patient population (Mean CHADS2 score > 3)
• TTR 55%
New Engl J Med 2011;365:883‐91.
Apixaban vs. Warfarin in Atrial
Fibrillation (ARISTOTLE)
b ll
(
)
•
•
•
•
>18,000 patients with non‐valvular Afib
Non‐inferiority design
Double blind, double dummy
W f i
Warfarin vs. apixaban
i b
– 5 mg twice daily
– 2.5 mg twice daily if:
g
y
• Age ≥ 80
• Weight ≤ 60 kg
• SCr ≥ 1.5 mg/dl
• Follow‐up approximately years
• INR Time in Therapeutic Range (TTR): 62%
New Engl J Med 2011;365:981‐92.
ARISTOTLE
Patient Population
l
Inclusion Criteria
Inclusion
Criteria
• Afib in addition to:
–
–
–
–
–
Age ≥ 75 years
Hx Stroke/TIA
HF or LVEF ≤ 40%
DM
THN
New Engl J Med 2011;365:981‐92.
Exclusion Criteria
Exclusion
Criteria
• Severe heart valve disorder
• Recent stroke
Recent stroke
• SCr. > 2.5 mg/dl or CrCl < 25 ml/min
• Liver disease
ARISTOTLE
Endpoints
d
• Primary
– Composite: stroke or systemic embolization
New Engl J Med 2011;365:981‐92.
• Secondary/Other
– All cause mortality
– MI
ARISTOTLE
Patient Demographics
h
Ch
Characteristic
i i
A i b
Apixaban
W f i
Warfarin
70
70
64.5%
65.0%
2.1 ± 1.1
2.1 ± 1.1
Prior Stroke or TIA
19.2%
19.7%
Prior MI
Prior MI
14 5%
14.5%
13 9%
13.9%
Aspirin at baseline
31.3%
30.5%
VKA at baseline
57.1%
57.2%
Age
Male Sex
CHADS2 Score
New Engl J Med 2011;365:981‐92.
ARISTOTLE
Results
Event
Apixaban
(% per year)
Warfarin
(% per year)
HR (95% CI)
Efficacy
1˚ Endpoint*
1.27
1.60
0.79 (0.66‐0.95)
All stroke
All stroke
1.19
1.51
0.79 (0.65‐0.95)
0.79 (0.65
0.95)
Ischemic Stroke
0.97
1.05
0.92 (0.74‐1.13)
Hemorrhagic Stroke
0.24
0.47
0.51 (0.35‐0.75)
MI
0 53
0.53
0 61
0.61
0 88 (0 66 1 17)
0.88 (0.66‐1.17)
All‐cause mortality
3.52
3.94
0.89 (0.80‐0.998)
Safetyy
Major bleeding
4.07
6.01
0.68 (0.61‐0.75)
All bleeding
18.1
25.8
0.71 (0.68‐0.75)
IC bleeding
bl di
0 33
0.33
0 80
0.80
0 42 (0.30‐0.58)
0.42
(0 30 0 58)
*Non‐inferiority margin = 1.38
New Engl J Med 2011;365:981‐92.
ARISTOTLE Summary
• Apixaban
p
vs. warfarin
–
–
–
–
Superior efficacy with apixaban
↓ overall mortality with apixaban (NNT = 238)
L
Lower bleeding rates with apixaban
bl di
t
ith i b
Lower ICH rates
• Apixaban vs. Aspirin
vs Aspirin
–
–
–
–
–
6,000 high‐risk patients (mean CHADS2 = 2)
Not candidates for warfarin
1 year follow‐up
Superior efficacy to aspirin
Similar
Similar bleeding (including ICH) rates
bleeding (including ICH) rates
New Engl J Med 2011;365:981‐92. New Engl J Med 2011;364:806‐17.
Which of the following have been shown at least as effective as warfarin
shown at least as effective as warfarin for the prevention of stroke in patients with atrial
i h i l fibrillation?
fib ill i ?
iva
ro
xa
at
ra
0%
0%
B
ot
h 1 & 2
A
l l of
th
e ab
o.
..
0%
ba
n
n
0%
D
ab
ig
xa
b
an
0%
R
Apixaban
Dabigatran
Rivaroxaban
Both 1 & 2
All of the above
A
pi
1.
2
2.
3.
4.
5.
S
Summary of Afib
f Afib Data
D t
Apixaban
(ARISTOTLE)
Dabigatran
(RE‐LY)
Rivaroxaban
(ROCKET – AF)
> 18,000
> 18,000
> 14,000
Mean CHADS2
≈ 2
≈ 2
≈ 3.5
TTR
62%
64%
55%
Superior
Superior1
Non Inferior
Non‐Inferior
Decreased
Similar
Similar
CYP3A4/P‐gp
Renal
CYP3A4/P‐gp/Renal
# Patients
Efficacy vs VKA
Efficacy vs. VKA
Bleeding2 vs. VKA
Elimination
1Dabigatran 150 mg BID group. 2Major bleeding per study design.
Use of Concomitant Antiplatelet
Agents
Antiplatelet
Agents
ARISTOTLE
(Apixaban)
RELY
(Dabigatran)
ROCKET‐AF
(Rivaroxaban)
< 165 mg/day
Yes
< 100 mg/day
Clopidogrel
Yes
Yes
Yes
Combination
No
Yes
No
Aspirin Use (%)
Use (%)
31%
40%
36%
ASA
New Engl J Med 2009;361:1139‐51. New Engl J Med 2011;365:883‐91. New Engl J Med 2011;365:981‐92.
Treatment of Acute Venous Thromboembolism
Both dabigatran and rivaroxaban have been shown to be effective in the treatment of acute VTE
treatment of acute VTE.
1. True
2 False
2.
F l
0%
F
al
se
T
ru
e
0%
Dabigatran vs. Warfarin
Treatment of VTE (RE‐COVER)
Treatment of VTE (RE‐COVER)
•
Acute DVT or PE for 6 months
– Double blind, double dummy, RCT
– Non‐inferiority trial
– > 2,500 patients
•
Treatment
– UFH or LMWH X 5 days and INR > 2.0
UFH or LMWH X 5 days and INR > 2 0
– Then dabigatran 150 mg BID or warfarin
•
Outcomes
– Efficacy (1˚ endpoint = VTE or related death)
• Dabigatran non‐inferior to warfarin
– Safety
• Major bleeding: dabigatran & warfarin had similar rates
• Overall bleeding: dabigatran had lower rates
•
Conclusions
– Dabigatran was non‐inferior to warfarin for the acute treatment of VTE
– Did use standard “bridging” regimen for both groups
• UFH/LMWH
• Dabigatran (active & placebo) started after “therapeutic” INR in both groups
New Engl J Med 2009;361:2342‐52.
Rivaroxaban vs. Warfarin
Treatment of VTE (EINSTEIN)
(
)
•
Acute DVT for 3, 6, or 12 months
– Open‐label, RCT
– Non‐inferiority trial
y
– > 3,400 patients
•
Treatment
– Rivaroxaban
• 15 mg BID X 3 weeks, then 20 mg daily for 3, 6, or 12 mos. (duration determined by MD)
15 mg BID X 3 weeks then 20 mg daily for 3 6 or 12 mos (duration determined by MD)
– Enoxaparin followed by warfarin (INR 2.0‐3.0)
•
Outcomes
– Efficacy (1˚ endpoint = Recurrence of VTE)
• Rivaroxaban non‐inferior to warfarin
– Safety
• Major bleeding: rivaroxaban & warfarin had similar rates
• Overall bleeding: rivaroxaban & warfarin had similar rates
•
Conclusions
–
–
–
–
Rivaroxaban was non‐inferior to warfarin for the acute treatment of DVT
Used Rivaroxaban monotherapy compared to standard of care
Rivaroxaban better
better than placebo in the Extension study (EINSTEIN‐EXT)
than placebo in the Extension study (EINSTEIN EXT)
PE arm of the study series is still ongoing
New Engl J Med 2009;363:2499‐510.
SSummary of VTE Data
f VTE D t 1
Dabigatran
(RE‐COVER)
Rivaroxaban
(EINSTEIN)
> 2,500
> 3,400
6 months
6 months
LMWH
Rivaroxaban
60%
58%
Efficacy vs. VKA
Non‐Inferior
Non‐Inferior
Bleeding vs. VKA
Similar
Similar
DVT & PE
DVT
# Patients
Treatment Duration
Initial Therapy2
TTR
VTE Type
1Apixaban data in VTE are not available, AMPLIFY & AMPLIFY‐EXT are ongoing. 2Initial therapy in study group, both studies “bridged” control group.
Prevention of Venous Thromboembolism in Orthopedic in Orthopedic
Surgery Patients
Dabigatran
• Studied in TKA and THA
• Compared to enoxaparin (European dosing)
– 40 mg daily
– Commonly administered prior to surgery
• Dabigatran
b
dosed once daily
l
– 220 mg & 150 mg evaluated
– EU labeling is 220 mg daily & adjusted for age and CrCl
– ½ maintenance dose administered post‐op day 0
½
i t
d
d i it d
t
d 0
• Efficacy
– Non‐inferior to European dosing of enoxaparin
– Inferior to US FDA approved dosing of enoxparin
Inferior to US FDA approved dosing of enoxparin (30
(30 mg SQ q12h)
mg SQ q12h)
• Safety
– Bleeding rates similar between all groups
J Thromb Haemost 2005;3:103‐11. J Thromb Haemost 2007;5:2175‐7. Lancet 2007;370:949‐56. J Arthro 2009;24:1‐9.
Rivaroxaban
• Studied in TKA and THA
Stud ed
a d
• Compared to enoxaparin
– 40 mg SQ daily
g Q
y
– 30 mg SQ twice daily
• Rivaroxaban dosed 10 mg once daily
• Efficacy
– Superior to enoxaparin at both dosages
• Safety
– Similar rates of bleeding compared to enoxaparin
New Engl J Med 2008;358:2765‐75. Lancet 2008;372:31‐9. N Engl J Med 2008;358:2776‐86. Lancet 2009;373:1673‐80.
Apixaban
• Studied in TKA and THA
• Compared to enoxaparin
– 40 mg SQ daily
– 30 mg SQ twice daily
30 mg SQ twice daily
• Apixaban dosed 2.5 mg twice daily
• Efficacyy
– Superior to enoxaparin at 40 mg daily
– Non‐inferior to enoxaparin 30 mg twice daily
• Safety
– Similar bleeding compared to enoxaparin 40 mg daily
– Less bleeding compared to enoxaparin 30 mg twice daily
New Engl J Med 2009;361:594‐604. Lancet 2010;375:807‐15. New Engl J Med 2010;363:2487‐98. Acute Coronary Syndrome
Acute Coronary Syndrome
Apixaban
Acute Coronary Syndrome (APPRAISE‐2)
• Double blind, placebo controlled, RCT
• ACS plus 2 additional risk factors
• Apixaban
– 5 mg twice daily
5
t i d il
– 2.5 mg twice daily (CrCl < 40 ml/min)
• No benefit in any efficacy outcomes
y
y
• Safety
– Major & minor TIMI, ISTH, and GUSTO criteria bleeding was increased with apixaban
was increased with apixaban
– Increased fatal and intracranial bleeding
• Study terminated early at 1 year
New Engl J Med 2011;365:699‐708.
Rivaroxaban
• ATLAS
ATLAS‐ACS
ACS 2 TIMI 51 Trial is ongoing
2 TIMI 51 Trial is ongoing
• All patients received low dose ASA with either:
– Rivaroxaban
Ri
b 2.5 mg twice daily or
25
t i d il
– Rivaroxaban 5 mg twice daily
– Groups were stratified based on clopidogrel use
• Results expected in November
Am Heart J 2011;161:815‐21.
Additional
Developing Information
l
f
• api
apixaban
aban is currently being evaluated for VTE is c rrentl being e al ated for VTE
prophylaxis in medical patients
• An additional factor Xa inhibitor (edoxaban) is currently in phase 3 clinical trials
– Afib
– VTE treatment
Patient Information
Patient Information
• Dabigatran
– Store in original container
– Discard opened product after 60 days
p
p
y
– Dyspepsia most common side effect (15%)
– Do not open capsule
p
p
• Rivaroxaban
– Ask pharmacist or physician about DDIs
p
p y
– Do not crush, chew, or split tablet
– Overall tolerated well
Which of the following best describes your opinion regarding prescribing of dabigatran
opinion regarding prescribing of dabigatran
(Pradaxa®) or rivaroxaban (Xarelto®) after this program?
...
re
t p
no
st
I a
m
I w
ill ill ve
r ib
sc
re
ay
p
I m
0%
r ..
.
r.
.
gi n
be
0%
.
0%
.. .
0%
I w
ill 1. II will begin routinely prescribing will begin routinely prescribing
these agents.
2. I may prescribe them in a limited yp
and select group of patients.
3. I am still very hesitant to prescribe them.
4. I will not prescribe them at all for now.
Summary Table
Parameter
Apixaban
Dabigatran
Rivaroxaban
Target Protein
Factor Xa
Thrombin (IIa)
Factor Xa
No
Yes (etexilate)
No
CYP3A4/P‐gp
Renal
CYP3A4/P‐gp
Avoid < 15 ml/min
Avoid < 15 ml/min
↓ 15
↓
15‐29ml/min
29ml/min
Avoid < 15 ml/min
Avoid < 30 ml/min
< 30 ml/min
CYP3A4/P‐gp
Rifampin (P‐gp)
CYP3A4/P‐gp
Onset of activity
Onset of activity
3 4 hrs
3‐4
1 2 hrs
1‐2 hrs
2 4 hrs
2‐4 hrs
t½
8‐15 hrs
12‐18 hrs
5‐9 hrs
Twice daily
Twice daily
Daily
Monitoring tests
Anti‐factor Xa
ECT, TT, +/‐ aPTT
Anti‐factor Xa
FDA Indications
None
Non‐valvular Afib.
Ortho VTE Proph.
Clinical Uses
Afib
Afib, VTE
Afib, Ortho VTE Proph, VTE
Pro‐Drug
1˚ Elimination
Renal Adjustment
Renal Adjustment
Drug‐Drug Interact.
Dosing interval
David Stewart, PharmD, BCPS
Assistant Professor of Pharmacy Practice
f
f h
East Tennessee State University
Bill Gatton College of Pharmacy
[email protected]