Anticoagulation

Anticoagulant therapies: how Mary Byrne, St James's Hospital Outline of presentation  Anticoagulants  Laboratory monitoring

 Most widely used anticoagulant in world  1% of UK population (8% of >80yrs)  40,000 people on Warfarin in Ireland 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 Aim of Warfarin therapy  Maintain a level of anticoagulation  Minimise the risk of thrombosis  Minimise the risk of haemorrhagic  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  1920s: prairies of North America and  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  Karl Link experimented with "uncoagulated" blood from affected  Team isolated compound  Oxidised in mouldy hay to form

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) The need for anticoagulation  Why do thromboses occur?  How are they treated?  How are they prevented?  Thrombosis and haemostasis

Virchow's Triad for thrombosis What is haemostasis? Balance between four major components  Vascular endothelium  Coagulation pathway  Procoagulant  Anticoagulant  Fibrinolysis Coagulation pathway  Procoagulant proteins  Anticoagulant proteins  Balance between activation and control Coagulation pathway Coagulation pathway 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 Coagulation pathway Warfarin
Vitamin K cycle and warfarin Active coagulation Warfarin
Warfarin therapy  Inter-individual differences  Narrow therapeutic range  Bleeding risk  Outside anticoagulation range  Higher mortality  Increased risk of stroke  Increased rate of hospitalisation  Environmental factors  Vitamin K intake  Concurrent medication  Genetic variation (VKORC1 and CYP2C9) 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 Drug interactions  Reduce anticoagulant effect  Reduce absorption (cholestyramine)  Potentiate anticoagulant effect  Inhibit clearance (metronidazole, amiodarone)  Inhibit anticoagulant effect  Enhance clearance (barbiturates) Warfarin and bleeding  Major bleeding events 7.2/100 patient years  Fatal bleeding events 1.3/100 patient years  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  Discontinue warfarin  Prothrombin complex concentrates Monitoring Warfarin therapy  Laboratory testing  Point of care testing  Self testing  Test = INR (International Normalised INR PT (Prothrombin Time)  INR calculated from the Prothrombin  Reported as time (sec), INR  Sensitive to factor II V VII X fibrinogen  Normal range variations  Measures the plasma clotting time in the presence of a highly sensitive activating reagent  Surrogate measure of the effectiveness of Warfarin therapy  Different reagent and analytical systems  ISI: International Sensitivity Index  Compares local reagent with international reference preparation Coagulation pathway Delivery of Warfarin monitoring  Warfarin clinic (SJH: 1500 active patients)  Primary Care Team  Warfarin clinic Delivery of Warfarin monitoring  Point of care / self testing  Coagucheck XS Plus  Hemosense INRatio  Protime 3 (ITC) 162 patients recruited Self selected group On long tem anticoagulant Other anticoagulants  Indirect Xa inhibitors (Heparin)  Direct thrombin inhibitors (Dabigitran,  Direct Xa inhibitors  Different modes of action on coagulation cascade Other anticoagulants  Indirect Xa inhibitors (Heparin)  Direct thrombin inhibitors (Dabigatran,  Different modes of action on coagulation cascade Indirect Xa inhibitors  Enhance action of antithrombin  unfractionated UFH  low molecular weight LMWH Discovered in 1916 Utilised when there is need for rapid anticoagulant 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 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  Prevention of VTE and treatment of  Early treatment of unstable angina and Heparin: mechanism of action  Mechanism is mediated through antithrombin in the coagulation cascade  Inhibits platelet function Coagulation pathway 1000X Antithrombin
 Unfractionated heparin  Continuous IV route  Low molecular weight heparin Heparin and bleeding  The risk of heparin-associated bleeding  Concomitant thrombolytic therapy or other  Recent surgery  Invasive procedures  Concomitant haemostatic defects Heparin and bleeding  Reversal of heparin  Stop treatment (Half life = 90 minutes)  Protamine Sulphate Limitations of heparin  Heparin Induced Thrombocytopoenia Monitoring heparin therapy  Relationship between heparin dose, efficacy and safety  Need for laboratory monitoring  APTT (Unfractionated heparin)  Anti Xa assay (Low molecular weight heparin)  Activated Partial Thromboplastin Time  APTT ratio calculated from the APTT  Sensitive to factor VIII IX XI XII  Normal range variations  Measures the clotting time of plasma after the activation of the coagulation cascade with Silica. Coagulation pathway 1000X Antithrombin
Direct Thrombin Inhibitors (DTI)  Inhibits thrombin directly, no cofactor required as in heparin  Predictable anticoagulant response  Dabigatran etexilate, oral prodrug that is converted to 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 Dabigatran licence (EU)  Prevention of VTE after elective TKR or  Stroke prevention in and systemic embolism in adult patients with nonvalvular atrial fibrillation (AF) Direct Thrombin Inhibitors (DTI) Dabigatran trials  REDEEM (post MI)  RE-NOVATE (DVT prophylaxis)  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 Considerations with dabigatran  Non compliance  No reversible agent  Safety vs efficacy at extremes of body  Renal impairment 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 Laboratory monitoring Not necessary generally  Suspected overdose  Need for emergency surgery  Impaired renal function Laboratory monitoring  APTT of limited use  Specific test using a snake venom called  Not widely available Dabigatran headlines Bleeding Risk with Dabigatran in the Frail Elderly
N ENGL J MED 2012; 366:864-866 Pradaxa (dabigatran etexilate mesylate): Drug Safety Communication
- Safety Review of Post-Market Reports of Serious Bleeding Events
Posted 12/07/2011 Irreversible catastrophic brain
Journal of Neurosurgery, haemorrhage after minor injury in a
published online March 6, 2012; patient on dabigatran
Thank you for your attention!

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