Anticoagulation: The risks Anticoagulant therapy 1990 2002: 600 incidents reported 120 resulted in death of patient 92 deaths related to warfarin usage 28 reports related to heparin usage Incidents in N. Ireland Warfarin 5 x 5mg taken instead of warfarin 5mg Heparin sodium 5000 units/5ml dispensed instead of heparin sodium flush 10units/ml NPSA Alert 18 Information for community pharmacists Information for community pharmacists Ensure all staff are properly trained Ensure procedures and protocols reflect safe practice Ensure that patients on oral anticoagulant therapy have received appropriate information Check INR is being monitored regularly before dispensing a repeat prescription for anticoagulant medication Information for community pharmacists Check for drug interactions Ensure doses are expressed in the yellow book in mg, not number of tablets Ensure that a risk assessment is undertaken on the use of MDS for anticoagulant for individual patients Participate in an annual audit of anticoagulant services 1
Rationale for therapy Aim to delay clotting time of blood to prevent occurrence of a thromboembolic event or to prevent extension of an existing thrombus in a patient who is at risk Factors influencing thrombus formation: abnormalities of blood flow abnormalities of surfaces in contact with blood abnormalities of clotting components Primary indications Treatment and prevention of deep vein thrombosis and pulmonary embolism Atrial fibrillation Treatment of patients with mechanical heart valves The coagulation cascade The coagulation cascade Parenteral Anticoagulants in use (I) Low Molecular Weight Heparins bemiparin dalteparin enoxaparin tinzaparin Heparin Alternative injectable anticoagulants danaparoid lepirudin, Bivalirudin fondaparinux Oral Anticoagulants in use (II) Vitamin K Antagonists coumarins, e.g., warfarin, acenocoumarol phenindione New oral anticoagulants dabigatran rivaroxaban 2
Heparin Parenteral Anticoagulants Inactivates thrombin and factor Xa Short half life = 60 minutes Given IV or by SC injection Actions fully reversed by protamine Dose adjusted according to APTT Side effects: heparin-induced thrombocytopenia hyperkalaemia Heparin: Indications Deep vein thrombosis Pulmonary embolism Unstable angina Acute peripheral arterial occlusion Prophylaxis in surgery Haemodialysis MI Prevention of clotting in extracorporeal circuits Heparin: High risk drug Rarely used in primary care Routine use of heparin flushes for IV lines should be minimised sodium chloride 0.9% flushes preferred Extreme care if dispensing: clarify reason for prescribing check dose speak directly to prescriber Low molecular weight heparins (LMWHs) Bemiparin (Zibor ), dalteparin (Fragmin ), enoxaparin (Clexane ) and tinzaparin (Innohep ) Largely replaced heparin: as effective more predictable activity longer duration of action lower risk of heparin-induced thrombocytopaenia standard prophylactic regimen does not require therapeutic monitoring Low molecular weight heparins Indications Prevention and treatment of DVT Treatment of pulmonary embolism MI Unstable coronary artery disease Prevention of clotting in extracorporeal circuits Dalteparin only: treatment and prophylaxis of venous thromboembolism in patients with solid tumours 3
Low molecular weight heparins Recent rapid response report January 2005 September 2009: 2, 716 reports relating to dosing errors concerning LMWHs Where prescribing, administering, monitoring and dispensing LMWHs: weight in kg used as basis of calculating dose renal function is considered dose calculation tools available essential information shared during transfers of care dosing checks made by all those who review, dispense or adminster LMWHs Other parenteral anticoagulants Examples include: Danaparoid, lepirudin, bivalirudin, fondaparinux Used when heparin and LMWHs are contra-indicated: when the patient has heparin-induced thrombocytopenia patient at risk of heparin-induced thrombocytopaenia Oral anticoagulants Oral Anticoagulants Warfarin is the most commonly used oral anticoagulant Alternatives are acenocoumarol and phenindione rarely used Antagonise the effects of Vitamin K Action of drugs is reversed by the administration of vitamin K Therapeutic monitoring required - INR Warfarin: Mode of action Warfarin: Pharmacokinetics Warfarin takes around 5-7 days to achieve steady state this is because the half-lives of clotting factors are different Clotting Factor II 50 VII 6 IX 24 X 36 Protein C 8 Protein S 30 Half-life (hours) 100% bioavailability when administered orally can be taken any time of day Half-life is approximately 35 hours once daily dosing Warfarin is eliminated almost entirely by hepatic metabolism and is metabolised by the cytochrome P450 system 4
Warfarin: Indications Warfarin: Availability Prophylaxis of embolisation in rheumatic heart disease and AF Prophylaxis after insertion of prosthetic heart valve Prophylaxis and treatment of venous thromboembolism and pulmonary embolism Transient ischaemic attacks Warfarin: Associated problems Under-anticoagulation thrombosis Over-anticoagulation - haemorrhage Individual dosage requirements Narrow therapeutic index Need for frequent blood tests Interacts with many other medicines, foods, alcohol Requirements for a new oral anticoagulant As effective as the existing drugs Standard dose Does not require blood monitoring Minimal drug interactions Risk of bleeding should not be any higher than warfarin Dabigatran and rivaroxaban Oral administration Rapid onset of action Oral anticoagulants: Dabigatran No therapeutic monitoring required Indications: prevention of VTE following elective total knee or hip replacement Future indications: atrial fibrillation Oral administration Rapid onset of action Oral anticoagulants: Rivaroxaban No therapeutic monitoring required Indications: prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery Ongoing clinical trials for patients with AF and acute coronary syndrome 5
Oral anticoagulant therapy: The future Await the licensing of Dabigatran for AF Await the outcomes of ongoing clinical trials for both drugs Feedback from clinicians using dabigatran and rivaroxaban in orthopaedics Cost of drugs will affect its use At present and in the foreseeable future, there is still a place for warfarin Monitoring oral anticoagulant therapy Monitoring oral anticoagulant therapy What is INR? Importance of monitoring INR Measuring the INR Target INR ranges Factors that can affect the INR Monitoring oral anticoagulant therapy: What is INR? International Normalised Ratio Measures how long it takes blood to clot Developed by the WHO in 1983 INR = [PT (test) / PT (control)] ISI Person not on warfarin, INR = 1.0 If INR = 2.0, blood takes twice as long to clot Monitoring oral anticoagulation therapy: Rationale and frequency Rationale for monitoring: Ensure patient is within therapeutic range Prevent any adverse events Frequency of monitoring: Initially monitoring is very frequent At least weekly Once stabilised on warfarin, review appointments can be extended up to a maximum of three monthly intervals Monitoring oral anticoagulation therapy: Measuring INR determined by a blood sample Venous sample is analysed by the laboratory to determine the INR Near-patient testing machines can also measure INR: use a capillary blood sample rapid result must ensure accurate, reproducible and valid results 6
Target INR ranges Monitoring oral anticoagulant therapy: Factors affecting the INR Dose of warfarin Food Alcohol Disease Drugs Factors affecting the INR: Dose of warfarin Too little warfarin will result in subtherapeutic INR Too much warfarin will result in supratherapeutic INR Dose of warfarin is tailored specifically for the individual patient as each patient responds differently to the drug Change in dose of warfarin should affect INR COMPLIANCE (or lack of) will also affect INR Factors affecting the INR: Food Food that contains high quantities of vitamin K may reduce the INR: green vegetables wheat containing cereals liver Vitamin K is also found in some multi-vitamin preparations and dietary supplements Avoid grapefruit, pomegranate and cranberry juice - increase INR Green tea decreases INR Factors affecting the INR: Alcohol Alcohol and warfarin metabolised by the liver Alcohol binge wafarin metabolism â leading to an á INR Chronic alcoholics generally require higher doses of warfarin because the liver metabolises everything more quickly if alcohol intake is â or stopped abruptly, the INR will á as liver function returns to normal Higher risk of bleeding due to increased risk of injury whilst under influence of alcohol Liver disease Thyroid disease Congestive heart disease Infection Stress Factors affecting the INR: Disease 7
Factors affecting the INR: Drugs Prescribed medication Over the counter medication Alternative preparations Multivitamins / Tonics Illicit drugs 8