anticoagulant therapies: how do they work? mary byrne, st james’s hospital
TRANSCRIPT
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Anticoagulant therapies: how do they work?
Mary Byrne, St James’s Hospital
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Outline of presentation
Anticoagulants Warfarin Heparin Dabigatran
Laboratory monitoring
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Warfarin
Most widely used anticoagulant in world
1% of UK population (8% of >80yrs)
40,000 people on Warfarin in Ireland
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Clinical indications 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.
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Aim of Warfarin therapy
Maintain a level of anticoagulation 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
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History of Warfarin discovery
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History of Warfarin discovery 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
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History of Warfarin discovery
Karl Link experimented with “uncoagulated” blood from affected cattle
Team isolated compound 3,3’-methylene-bis[4-hyfroxycoumarin]
Oxidised in mouldy hay to form dicoumarol.
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History of Warfarin discovery
Research work funded by the: Wisconsin Alumni Research
Foundation Patented in 1941
Variation of dicoumarol (warfarin) patented as rat poison in 1948
Transition to clinical application (Coumadin)
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The need for anticoagulation
Why do thromboses occur? How are they treated? How are they prevented?
Thrombosis and haemostasis
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Virchow’s Triad for thrombosis
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What is haemostasis? Balance between four major components
Vascular endothelium Platelets Coagulation pathway
Procoagulant Anticoagulant
Fibrinolysis
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Coagulation pathway
Procoagulant proteins Anticoagulant proteins
Balance between activation and control of coagulation
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Coagulation pathway
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Coagulation pathway
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Mechanism of action of Warfarin
Interferes with the biochemistry of vitamin K dependant coagulation factors in the liver
Vitamin K dependant coagulation factors Factor II VII IX X Protein C and Protein S
Involved in coagulation and anticoagulation pathways in haemostasis
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Coagulation pathway
Warfarin
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Vitamin K cycle and warfarin
Active coagulation factors
Warfarin
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Warfarin therapy
Inter-individual differences Narrow therapeutic range Bleeding risk Outside anticoagulation range
Higher mortality Increased risk of stroke Increased rate of hospitalisation
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Warfarin
Environmental factors Vitamin K intake Illness Concurrent medication Genetic variation (VKORC1 and CYP2C9)
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Warfarin interactions
Pharmacokinetic interactions Drugs which interfere with clearance Antibiotics which affect intestinal flora
Pharmacodynamic interactions Drugs which have anti-platelet effect
(aspirin and NSAIDS) Drugs associated with falls in the
elderly
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Drug interactions
Reduce anticoagulant effect Reduce absorption (cholestyramine)
Potentiate anticoagulant effect Inhibit clearance (metronidazole, amiodarone)
Inhibit anticoagulant effect Enhance clearance (barbiturates)
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Warfarin and bleeding Major bleeding events 7.2/100 patient years Fatal bleeding events 1.3/100 patient years
Bleeding 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
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Warfarin and bleeding
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Reversal of warfarin
Discontinue warfarin Vitamin K Prothrombin complex concentrates
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Monitoring Warfarin therapy
Laboratory testing Point of care testing Self testing
Test = INR (International Normalised Ratio)
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INR PT (Prothrombin Time)
INR calculated from the Prothrombin Time (PT)
Reported as time (sec), INR Sensitive to factor II V VII X fibrinogen Normal range variations PT:
Measures the plasma clotting time in the presence of a highly sensitive activating reagent
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INR
Surrogate measure of the effectiveness of Warfarin therapy
Different reagent and analytical systems are widely used
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INR
ISI: International Sensitivity Index Compares local reagent with
international reference preparation
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Coagulation pathway
PT
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Delivery of Warfarin monitoring
In-patient Out-patient
Warfarin clinic (SJH: 1500 active patients)
Primary Care Team Warfarin clinic
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Delivery of Warfarin monitoring
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
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Other anticoagulants
Indirect Xa inhibitors (Heparin) Direct thrombin inhibitors
(Dabigitran, Argatroban) Direct Xa inhibitors
Different modes of action on coagulation cascade
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Other anticoagulants
Indirect Xa inhibitors (Heparin) Direct thrombin inhibitors
(Dabigatran, Argatroban)
Different modes of action on coagulation cascade
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Indirect Xa inhibitors
Enhance action of antithrombin Heparin
unfractionated UFH low molecular weight LMWH
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Heparin 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 SafetyHirsh J et al CHEST 2001; 119:64S–94S
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Low Molecular Weight Heparin
Prevention of VTE and treatment of DVT and PE
Early treatment of unstable angina and MI
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Heparin: mechanism of action
Mechanism is mediated through antithrombin in the coagulation cascade
Inhibits platelet function
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Coagulation pathway
Heparin
Antithrombin1000X
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Unfractionated heparin Continuous IV route
Low molecular weight heparin SC route
enoxaparin (Clexane) tinzaparin (Innohep)
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Heparin and bleeding The risk of heparin-associated bleeding
increases with Dose Concomitant thrombolytic therapy or
other drugs Recent surgery Trauma Invasive procedures Concomitant haemostatic defects
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Heparin and bleeding Reversal of heparin
Stop treatment (Half life = 90 minutes) Protamine Sulphate
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Limitations of heparin
Osteopoenia Heparin Induced
Thrombocytopoenia
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Monitoring heparin therapy
Relationship between heparin dose, efficacy and safety
Need for laboratory monitoring APTT (Unfractionated heparin)
Anti Xa assay (Low molecular weight heparin)
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APTT
Activated Partial Thromboplastin Time APTT ratio calculated from the APTT Sensitive to factor VIII IX XI XII Normal range variations APTT:
Measures the clotting time of plasma after the activation of the coagulation cascade with Silica.
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Coagulation pathway
Heparin
Antithrombin1000X
APTT
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Direct Thrombin Inhibitors (DTI)
Dabigatran Inhibits thrombin directly, no
cofactor required as in heparin Predictable anticoagulant response Dabigatran etexilate, oral prodrug
that is converted to dabigatran
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Dabigatran
Rapid onset of action Lack of interaction with food and
drugs No need for routine monitoring Broad therapeutic window Fixed dose administration Renal excretion
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Dabigatran licence (EU)
2008 Prevention of VTE after elective TKR
or THR 2011
Stroke prevention in and systemic embolism in adult patients with nonvalvular atrial fibrillation (AF)
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Direct Thrombin Inhibitors (DTI)
Direct Thrombin Inhibitor
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Dabigatran trials
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
Dose of 110mg: same as warfarin Dose of 150mg: lower than warfarin
Rates of major haemorrhage Dose of 110mg: lower than warfarin Dose of 150 mg: same rate as warfarin
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Considerations with dabigatran
Non compliance No reversible agent Safety vs efficacy at extremes of
body weight Renal impairment Cost
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Dabigatran and bleeding
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
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Laboratory monitoring Not necessary generally Rarely needed
Suspected overdose Bleeding Need for emergency surgery Impaired renal function Pregnancy Obesity Children
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Laboratory monitoring
APTT of limited use Specific test using a snake venom
called Ecarin Not widely available
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Dabigatran headlinesBleeding Risk with Dabigatran in the Frail
ElderlyN 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 EventsPosted 12/07/2011
Irreversible catastrophic brain haemorrhage after minor injury in a patient on dabigatran
Journal of Neurosurgery,published online March 6, 2012;
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Thank you for your attention!