Transcript Review: New oral anticoagulants reduced stroke and systemic

Journal Club – September 2012
Coagulation – Brief Review
Brief Review: Warfarin
• Blocks vitamin Kdependent glutamate
carboxylation of precursor
factors II, VII, IX, X
• Vit K = cofactor
• Warfarin blocks the
reduction of Vit K
• Oral administration
Review: Heparin
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•
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•
Indirect thrombin inhibitor: IV only
Called UFH (unfractionated heparin)
Complexes with AT (heparin co-factor I)
AT by itself inactivates SLOWLY!
– Thrombin
– Factor Xa
– XIIa, XIa, IXa (lesser extent)
• AT + Heparin: conformational
change in AT = 1000-4000 fold acceleration in inactivation
• At high concentrations: Also binds to platelets and heparin
co-factor II—which inhibits thrombin
Limitations of Warfarin and Heparin:
• Both have narrow therapeutic windows
• Highly variable dose responses: requires
laboratory monitoring (PT, APTT)
– Heparin can bind to other plasma proteins making
bioavailability variable
– Warfarin has numerous food, drug interactions
• Limited ability to stop a clot from propagating:
– Heparin does not inactivate thrombin bound to fibrin
or Xa bound to platelets very well
LMWHs
• Molecular wt:
Heparin: 15,000 vs LMWH: 40005000
• LMWHs inactivate Xa but have
less effect on thrombin (some
molecules not long enough)
– ratio of anti-Xa to anti-thrombin
activity of 3:1
– Do not prolong PTT unless dose high
• Advantages over heparin:
– Easier to administer: sq, BID dosing
– Dosage and anticoagulant effect
easier to predict; dose based on
body weight
– Lab monitoring not necessary in all
patients
– Less chance of inducing immunemediated thrombocytopenia
New Anticoagulants
• Dabigatran
• Fondaparinux
Idraparinux
• Rivaroxaban
Apixaban
• LY517717
• YM150
• DU-176b
• Betrixaban
• TAK 442
New Anticoagulants
ORAL
PARENTERAL
TF/VIIa
TTP889
TFPI (tifacogin)
X
Rivaroxaban
Apixaban
LY517717
YM150
DU-176b
Betrixaban
TAK 442
IX
VIIIa
Va
Xa
APC (drotrecogin alfa)
sTM (ART-123)
IXa
AT
II
Dabigatran
DX-9065a
IIa
Fibrinogen
Fondaparinux
Idraparinux
Fibrin
Direct Thrombin inhibition
Tissue
factor
XIIa
XIa
VIIa
IXa
Xa
II
×
Factor IIa
(thrombin)
Dabigatran
Direct Factor Xa inhibition
XIIa
XIa
IXa
×
Xa
Factor II
(prothrombin)
Fibrinogen
Fibrin clot
Tissue
factor
VIIa
Rivaroxaban
Apixaban
YM150
DU-176b
LY517717
Betrixaban
TAK 442
Apixaban
 Oral, direct, selective factor Xa inhibitor
 Produces concentration-dependent
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
anticoagulation
No formation of reactive intermediates
No organ toxicity or LFT abnormalities in
chronic toxicology studies
Low likelihood of drug interactions or QTc
prolongation
Good oral bioavailability
No food effect
Balanced elimination (~25% renal)
Half-life ~12 hrs
He et al., ASH, 2006, Lassen, et al ASH, 2006
O
N
NH2
N
O
O
N
N
O
Rivaroxaban: oral direct Factor Xa inhibitor
 Predictable




pharmacology
High bioavailability
Low risk of drug–drug
interactions
Fixed dose
No requirement for
monitoring
Perzborn et al. 2005; Kubitza et al. 2005; 2006; 2007; Roehrig et al, 2005
O
O
N
O
N
O
Cl
S
H
N
O
Rivaroxaban® – rivaroxaban
Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ.
Meta-analysis of efficacy and
safety of new oral anticoagulants
(dabigatran, rivaroxaban,
apixaban) versus warfarin in
patients with atrial fibrillation.
Am J Cardiol. 2012;110:453-60.
In patients with atrial fibrillation (AF), are new
oral anticoagulants effective and safe for
preventing stroke and systemic embolism
compared with warfarin?
Scope of Review
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Included studies compared a new, non–vitamin K
antagonist oral anticoagulant with warfarin in patients
with AF, had >1 year follow-up, and were published
in peer-reviewed journals.
Primary efficacy outcome was a composite of stroke
(including hemorrhagic stroke) and systemic
embolism.
Secondary efficacy outcomes were ischemic and
unidentified stroke, hemorrhagic stroke, all-cause
mortality, vascular mortality, and myocardial
infarction.
Primary safety outcome was major bleeding;
secondary safety outcomes were gastrointestinal
bleeding and intracranial bleeding.
Review Method
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MEDLINE, EMBASE/Excerpta Medica,
Cochrane Library, Science Citation Index
Expanded, and ProQuest’s Dissertations and
Theses database (all to Jul 2011) clinical trials
databases; reviews; and reference lists were
searched for randomized controlled trials
(RCTs).
3 noninferiority RCTs met the selection criteria:
(n= 44 563, mean age 70 to 73 y, 60% to 65%
men, median follow-up 657 to 730 d)
 ARISTOTLE (n= 18 201) assessed apixaban
 RE-LY (n= 18 113) assessed dabigatran
 ROCKET-AF (n= 14 264) assessed rivaroxaban.
Results
Results
Results - Summary
Conclusions
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The new oral anticoagulants reduced the risk for a
composite end point of stroke and systemic
embolism compared to warfarin.
New oral anticoagulants were also found to be
associated with a lower risk for key secondary
efficacy outcomes, including ischemic and
unidentified stroke, hem-orrhagic stroke, all-cause
mortality, and vascular mortality, compared to
warfarin
The review was inconclusive with respect to major
bleeding and gastrointestinal bleeding but found a
substantial decrease in the risk for intracranial
bleeding.
Overall, the results support the use of the new oral
anticoagulants as alternatives to warfarin for longterm anticoagulation therapy in patients with AF.
Comments (1)
The highest benefit for prevention of stroke
and emboli in patients at moderate risk was
with dabigatran (150 mg)
 Rivaroxaban seemed best suited for
patients at highest risk.
 The safest bleeding profile was achieved
with apixaban or dabigatran (110 mg - a
dose that is unavailable in the US)
 The only drug that showed a significant
decrease in major bleeding was apixaban.
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Comments (2)
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Dabigatran is contraindicated in patients with
renal dysfunction.
Apixaban is safe for patients with moderate
renal disease.
Patients with creatinine clearance <30 mL/min
should use warfarin.
Once-daily rivaroxaban is more convenient
than twice-daily dabigatran or apixaban.
Patients on warfarin with good control of
international normalized ratio (>70% of time in
thera-peutic range) or those with valvular AF
should continue to use warfarin.
Comments (3)
There are no specific treatments to reverse
the new anticoagulants during bleeding
events, although dabigatran may be
dialyzable and prothrombin complex
concentrates to reverse apixaban and
rivaroxaban are being evaluated.
 Individualized drug selection is important
and can be achieved by using risk
stratification schemes for thrombosis
(CHA2DS 2 -VASc) and bleeding
(HASBLED).
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Thank you !!