Transcript Anticoagulation

Anticoagulant therapies: how
do they work?
Mary Byrne, St James’s Hospital
Outline of presentation
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Anticoagulants
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Warfarin
Heparin
Dabigatran
Laboratory monitoring
Warfarin
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Most widely used anticoagulant in world
1% of UK population (8% of >80yrs)
40,000 people on Warfarin in Ireland
Clinical indications
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Treatment of venous thrombosis (VTE), pulmonary
embolism (PE) and their extension.
Prophylaxis and treatment of thromboembolic
complications associated with rheumatic heart
disease, atrial fibrillation (AF) and/or prosthetic heart
valve replacement.
Reduction in the risk of death, recurrent myocardial
infarction (MI), and thromboembolic events such as
stroke or systemic embolisation after myocardial
infarction.
Aim of Warfarin therapy
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Maintain a level of anticoagulation
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Minimise the risk of thrombosis
Minimise the risk of haemorrhagic
complication
Dependant on the length of time and
extent that a persons INR stays outside
the therapeutic range
History of Warfarin discovery
History of Warfarin discovery
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1920s: prairies of North America and
Canada
Cattle dying of internal bleeding with no
precipitating cause
Query dietary problem
“Sweet clover disease”
Farmers recommended not to feed
cattle the mouldy sweet clover hay
History of Warfarin discovery
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Karl Link experimented with
“uncoagulated” blood from affected
cattle
Team isolated compound
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3,3’-methylene-bis[4-hyfroxycoumarin]
Oxidised in mouldy hay to form
dicoumarol.
History of Warfarin discovery
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Research work funded by the:
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Wisconsin Alumni Research Foundation
Patented in 1941
Variation of dicoumarol (warfarin)
patented as rat poison in 1948
Transition to clinical
application (Coumadin)
The need for anticoagulation
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Why do thromboses occur?
How are they treated?
How are they prevented?
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Thrombosis and haemostasis
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Virchow’s Triad for thrombosis
What is haemostasis?
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Balance between four major components
 Vascular endothelium
 Platelets
 Coagulation pathway
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Procoagulant
Anticoagulant
Fibrinolysis
Coagulation pathway
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Procoagulant proteins
Anticoagulant proteins
Balance between activation and control
of coagulation
Coagulation pathway
Coagulation pathway
Mechanism of action of Warfarin
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Interferes with the biochemistry of vitamin K
dependant coagulation factors in the liver
Vitamin K dependant coagulation factors
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Factor II VII IX X Protein C and Protein S
Involved in coagulation and anticoagulation
pathways in haemostasis
Coagulation pathway
Warfarin
Vitamin K cycle and warfarin
Active coagulation
factors
Warfarin
Warfarin therapy
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Inter-individual differences
Narrow therapeutic range
Bleeding risk
Outside anticoagulation range
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Higher mortality
Increased risk of stroke
Increased rate of hospitalisation
Warfarin
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Environmental factors
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Vitamin K intake
Illness
Concurrent medication
Genetic variation (VKORC1 and CYP2C9)
Warfarin interactions
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Pharmacokinetic interactions
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Drugs which interfere with clearance
Antibiotics which affect intestinal flora
Pharmacodynamic interactions
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Drugs which have anti-platelet effect
(aspirin and NSAIDS)
Drugs associated with falls in the elderly
Drug interactions
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Reduce anticoagulant effect
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(cholestyramine)
Potentiate anticoagulant effect
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Reduce absorption
Inhibit clearance
(metronidazole, amiodarone)
Inhibit anticoagulant effect
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Enhance clearance
(barbiturates)
Warfarin and bleeding
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Major bleeding events 7.2/100 patient years
Fatal bleeding events 1.3/100 patient years
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Bleeding
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May be lower in specialised anticoagulation clinics
More likely within the first 90 days
Can occur when INR is raised or within the
therapeutic range
Wadelius M and Pirmohamed M. Pharmacogenetics of warfarin: current status and future challenges.
The pharacogenetics Journal (2007) 7, 99-111
Warfarin and bleeding
Reversal of warfarin
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Discontinue warfarin
Vitamin K
Prothrombin complex concentrates
Monitoring Warfarin therapy
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Laboratory testing
Point of care testing
Self testing
Test = INR (International Normalised
Ratio)
INR PT (Prothrombin Time)
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INR calculated from the Prothrombin
Time (PT)
Reported as time (sec), INR
Sensitive to factor II V VII X fibrinogen
Normal range variations
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PT:
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Measures the plasma clotting time in the presence
of a highly sensitive activating reagent
INR
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Surrogate measure of the effectiveness
of Warfarin therapy
Different reagent and analytical systems
are widely used
INR
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ISI: International Sensitivity Index
Compares local reagent with
international reference preparation
Coagulation pathway
PT
Delivery of Warfarin monitoring
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In-patient
Out-patient
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Warfarin clinic
(SJH: 1500 active patients)
Primary Care Team
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Warfarin clinic
Delivery of Warfarin monitoring
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Point of care / self testing
Coagucheck XS Plus
Hemosense INRatio
Protime 3 (ITC)
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Published 2009
162 patients recruited
Crossover study
Self selected group
On long tem anticoagulant
Other anticoagulants
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Indirect Xa inhibitors (Heparin)
Direct thrombin inhibitors (Dabigitran,
Argatroban)
Direct Xa inhibitors
Different modes of action on
coagulation cascade
Other anticoagulants
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Indirect Xa inhibitors (Heparin)
Direct thrombin inhibitors (Dabigatran,
Argatroban)
Different modes of action on
coagulation cascade
Indirect Xa inhibitors
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Enhance action of antithrombin
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Heparin
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unfractionated UFH
low molecular weight LMWH
Heparin
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Discovered in 1916
Utilised when there is need for rapid anticoagulant
effect
Prevention of VTE and treatment of DVT and PE
Early treatment of unstable angina and MI
Cardiac surgery, bypass, vascular surgery, and
coronary angioplasty
Selected patients with disseminated intravascular
coagulation
Heparin and Low-Molecular-Weight Heparin, Mechanisms of Action, Pharmacokinetics,Dosing, Monitoring, Efficacy, and Safety
Hirsh J et al CHEST 2001; 119:64S–94S
Low Molecular Weight Heparin
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Prevention of VTE and treatment of
DVT and PE
Early treatment of unstable angina and
MI
Heparin: mechanism of action
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Mechanism is mediated through
antithrombin in the coagulation cascade
Inhibits platelet function
Coagulation pathway
Heparin
1000X Antithrombin
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Unfractionated heparin
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Continuous IV route
Low molecular weight heparin
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SC route
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enoxaparin
tinzaparin
(Clexane)
(Innohep)
Heparin and bleeding
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The risk of heparin-associated bleeding
increases with
 Dose
 Concomitant thrombolytic therapy or other
drugs
 Recent surgery
 Trauma
 Invasive procedures
 Concomitant haemostatic defects
Heparin and bleeding
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Reversal of heparin
 Stop treatment (Half life = 90 minutes)
 Protamine Sulphate
Limitations of heparin
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Osteopoenia
Heparin Induced Thrombocytopoenia
Monitoring heparin therapy
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Relationship between heparin dose,
efficacy and safety
Need for laboratory monitoring
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APTT (Unfractionated heparin)
Anti Xa assay (Low molecular weight heparin)
APTT
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Activated Partial Thromboplastin Time
APTT ratio calculated from the APTT
Sensitive to factor VIII IX XI XII
Normal range variations
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APTT:
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Measures the clotting time of plasma after the
activation of the coagulation cascade with Silica.
Coagulation pathway
APTT
Heparin
1000X Antithrombin
Direct Thrombin Inhibitors
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(DTI)
Dabigatran
Inhibits thrombin directly, no cofactor
required as in heparin
Predictable anticoagulant response
Dabigatran etexilate, oral prodrug that
is converted to dabigatran
Dabigatran
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Rapid onset of action
Lack of interaction with food and drugs
No need for routine monitoring
Broad therapeutic window
Fixed dose administration
Renal excretion
Dabigatran licence (EU)
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2008
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Prevention of VTE after elective TKR or
THR
2011
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Stroke prevention in and systemic
embolism in adult patients with nonvalvular
atrial fibrillation (AF)
Direct Thrombin Inhibitors
(DTI)
Direct Thrombin
Inhibitor
Dabigatran trials
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REDEEM (post MI)
RE-LY (AF)
RE-NOVATE (DVT prophylaxis)
RE-MODEL
RE-MOBILISE
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Non-inferiority trial, 18113 patients recruited
AF and risk of stroke
Rates of stroke and systemic embolism
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Dose of 110mg: same as warfarin
Dose of 150mg: lower than warfarin
Rates of major haemorrhage
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Dose of 110mg: lower than warfarin
Dose of 150 mg: same rate as warfarin
Considerations with dabigatran
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Non compliance
No reversible agent
Safety vs efficacy at extremes of body
weight
Renal impairment
Cost
Dabigatran and bleeding
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No reversal agent or antidote currently
Supportive care and control of bleeding
Eliminate by natural excretion through
kidney unless renal impairment
Plasma half life: 12 – 17 hrs
Laboratory monitoring
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Not necessary generally
Rarely needed
 Suspected overdose
 Bleeding
 Need for emergency surgery
 Impaired renal function
 Pregnancy
 Obesity
 Children
Laboratory monitoring
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APTT of limited use
Specific test using a snake venom called
Ecarin
Not widely available
Dabigatran headlines
Bleeding Risk with Dabigatran in the Frail Elderly
N ENGL J MED 2012; 366:864-866 March 1, 2012
Pradaxa (dabigatran etexilate mesylate): Drug Safety Communication
- Safety Review of Post-Market Reports of Serious Bleeding Events
Posted 12/07/2011
Journal of Neurosurgery,
published online March 6, 2012;
Irreversible catastrophic brain
haemorrhage after minor injury in a
patient on dabigatran
Thank you for your attention!