Anticoagulation Management: Dispelling the Myths

1. Anticoagulation Management: Dispelling the Myths Angela Lesiuk NP, MN Sandra Christie NP,MN Cardiac Sciences Program St. Boniface Hospital

2. Outline Why anticoagulate Indications for Warfarin Tips on dosage and patient instructions CHADS scoring system Bridging with Low Molecular Weight Heparin Heparin Induced Thrombocytopenia New therapies

3. Thrombosis Arterial thrombosis High shear Platelets predominant Few RBCs Fibrin Venous thrombosis Low shear Disturbances in plasma coagulation Platelets minor role RBC�s Fibrin Normally there is a fine balance in the body which ensures that there is not too much bleeding or blood clotting. If this balance is disrupted, a blood clot may occur. Thrombosis is the leading cause of mortality and morbidity in developed countries. Why do some people clot too much? Arterial Thrombosis formation can occurs most commonly in patients with atherosclerosis. Plaque rupture causes activation of platelets and clotting factors. Platelets play the predomiant role with some participation of the plasma coagulation system. Venous thrombosis occurs in approx 1 in 1000 people in the general population annually. Underlying risk factors can be classified as either acquired or hereditary. Various mechanisms for the development of a prothrombotic state exist. Venous thrombosis is caused by disturbances in the plasma coagulation system with platelets playing a minor role. There are numerous risk factors associated with DVT risk including: smoking, pregnancy, use of oral contraceptives, surgery, prolonged immobility, distance air travel. Normally there is a fine balance in the body which ensures that there is not too much bleeding or blood clotting. If this balance is disrupted, a blood clot may occur. Thrombosis is the leading cause of mortality and morbidity in developed countries. Why do some people clot too much? Arterial Thrombosis formation can occurs most commonly in patients with atherosclerosis. Plaque rupture causes activation of platelets and clotting factors. Platelets play the predomiant role with some participation of the plasma coagulation system. Venous thrombosis occurs in approx 1 in 1000 people in the general population annually. Underlying risk factors can be classified as either acquired or hereditary. Various mechanisms for the development of a prothrombotic state exist. Venous thrombosis is caused by disturbances in the plasma coagulation system with platelets playing a minor role. There are numerous risk factors associated with DVT risk including: smoking, pregnancy, use of oral contraceptives, surgery, prolonged immobility, distance air travel.

4. Indications for Anticoagulation Coronary Artery Disease Acute MI/ ACS Valvular heart disease Prosthetic heart valves Atrial fibrillation/ flutter Cardiomyopathies Cerebral vascular accidents (AF) Venous thrombosis Hereditary or acquired thrombophilias Ventricular assist devices

5. Warfarin History Mechanism of Action Pharmacokinetics Absorption Distribution Metabolism Elimination I am going to discuss the oral anticoagulant warfarin. It is widely used to prevent or delay the clotting of the blood. Warfarin is the most common oral treatment of choice for the treatment and prevention of thromboembolic disorders. I will touch on the history, mechanism of action and pharmacokinetics, but will use most of the time to discuss the practical application of warfarin, and how it applies to practice in primary care. I am going to discuss the oral anticoagulant warfarin. It is widely used to prevent or delay the clotting of the blood. Warfarin is the most common oral treatment of choice for the treatment and prevention of thromboembolic disorders. I will touch on the history, mechanism of action and pharmacokinetics, but will use most of the time to discuss the practical application of warfarin, and how it applies to practice in primary care.

6. History Hemorrhagic disease of cattle in1920�s Reduction in plasma prothrombin Traced to sweet clover 1939 agent isolated (dicumarol) at University of Wisconsin The history of the development and clinical use of warfarin began in the 1920�s when a hemorrhagic disease of cattle appeared in the Midwestern United States and western Canada. The source of bleeding was traced to ingestion of improperly cured sweet clover and was associated with a reduction in plasma prothrombin. In 1939, the hemorrhagic agent was isolated at the University of Wisconsin and identified as dicumarol. While dicumarol was being studied as an anticoagulant in animal models and in humans, a similar compound was synthesized and initially marketed as a rodenticide. The agent was given the name warfarin, an acronym derived from the first letters of the Wisconsin Alumni Research Foundation. By 1955, it was available commercially as an anticoagulant for the treatment of thromboembolic disease. The history of the development and clinical use of warfarin began in the 1920�s when a hemorrhagic disease of cattle appeared in the Midwestern United States and western Canada. The source of bleeding was traced to ingestion of improperly cured sweet clover and was associated with a reduction in plasma prothrombin. In 1939, the hemorrhagic agent was isolated at the University of Wisconsin and identified as dicumarol. While dicumarol was being studied as an anticoagulant in animal models and in humans, a similar compound was synthesized and initially marketed as a rodenticide. The agent was given the name warfarin, an acronym derived from the first letters of the Wisconsin Alumni Research Foundation. By 1955, it was available commercially as an anticoagulant for the treatment of thromboembolic disease.

7. Mechanism of Action Interferes with hepatic synthesis of vitamin K dependent clotting factors Factors II, VII, IX and X Proteins C and S Warfarin exerts it�s anticoagulant effect by interfering with the hepatic synthesis of vitamin K dependent clotting factors, including factors 2, 7, 9 and 10 and proteins C and S. Warfarin exerts it�s anticoagulant effect by interfering with the hepatic synthesis of vitamin K dependent clotting factors, including factors 2, 7, 9 and 10 and proteins C and S.

8. Elimination Half Lives of Vitamin K-Dependent Coagulation Proteins Factor II - 42 to 72 hours Factor VII - 4 to 6 hours Factor IX - 21 to 30 hours Factor X - 27 to 48 hours Protein C - 9 hours Protein S - 60 hours Warfarin induced depletion of vitamin KH2 results in a reduction in the availability of vitamin K dependent proteins. Ongoing synthesis of these proteins is inhibited, and previously formed vitamin K dependent proteins are depleted at rates corresponding with their elimination half lives. Because of the long half lives of some of the clotting factors, it may take several days before achieving the full antithrombotic effect of warfarin. Warfarin induced depletion of vitamin KH2 results in a reduction in the availability of vitamin K dependent proteins. Ongoing synthesis of these proteins is inhibited, and previously formed vitamin K dependent proteins are depleted at rates corresponding with their elimination half lives. Because of the long half lives of some of the clotting factors, it may take several days before achieving the full antithrombotic effect of warfarin.

9. Pharmacokinetics Absorption Oral administration Rapidly absorbed from the stomach and small intestine Peak concentration between 0.3 and 4 hours Rate of absorption reported to be reduced by presence of food Following oral administration, warfarin is rapidly and extensively absorbed from the stomach and small intestine. Peak concentrations occur b/w 0.3 and 4 hours. The rate, but not the extent of absorption is reported to be reduced by the presence of food. Limited information regarding the comparative bioavailability of various brands of warfarin is available. A comparison of various brands were done, and found that the area under the serum concentration vs. time curve varied from 87 % - 101 %. Differences were also observed in the maximum serum concentration(78%-100%) and in time to peak concentration (1.8 to 3.7 hours). While these differences were not considered statistically significant, clinical significance could be considerable given the narrow therapeutic index of the anticoagulant effect of warfarin. If using generic brand stay with to ensure consistency with dosing and response. Following oral administration, warfarin is rapidly and extensively absorbed from the stomach and small intestine. Peak concentrations occur b/w 0.3 and 4 hours. The rate, but not the extent of absorption is reported to be reduced by the presence of food. Limited information regarding the comparative bioavailability of various brands of warfarin is available. A comparison of various brands were done, and found that the area under the serum concentration vs. time curve varied from 87 % - 101 %. Differences were also observed in the maximum serum concentration(78%-100%) and in time to peak concentration (1.8 to 3.7 hours). While these differences were not considered statistically significant, clinical significance could be considerable given the narrow therapeutic index of the anticoagulant effect of warfarin. If using generic brand stay with to ensure consistency with dosing and response.

10. Pharmacokinetics Distribution Warfarin is extensively bound to plasma proteins, primarily albumin Greater than 98% of Warfarin is protein bound Only the remaining free, unbound drug is pharmacologically active Warfarin is extensively bound to plasma proteins and primarily to albumin. More than 98% of warfarin is protein bound, and only the remaining free, unbound drug is pharmacologically active. The free fraction of warfarin is highly variable among patients and is independent of total warfarin plasma concentrations. However, the free fraction of warfarin increases proportionately with decreasing albumin concentrations. The clinical significance of this is for patients with disease states associated with decreased serum albumin concentrations, including idiopathic hypoalbuminemia, nephrotic syndrome, and malnutrition. Warfarin is extensively bound to plasma proteins and primarily to albumin. More than 98% of warfarin is protein bound, and only the remaining free, unbound drug is pharmacologically active. The free fraction of warfarin is highly variable among patients and is independent of total warfarin plasma concentrations. However, the free fraction of warfarin increases proportionately with decreasing albumin concentrations. The clinical significance of this is for patients with disease states associated with decreased serum albumin concentrations, including idiopathic hypoalbuminemia, nephrotic syndrome, and malnutrition.

11. Pharmacokinetics Metabolism Warfarin metabolized by hepatic enzymes of the CYP450 system in the liver Elimination Hepatic metabolites eliminated by urinary excretion Warfarin is metabolized by hepatic enzymes of the P450 system in the liver. Significant variability in patients exist, and likely influences the observed differences in warfarin dosing requirements between patients. There is some investigation into the use of genetic testing with Warfarin response. This is not widely available or deemed particularly clinically useful currently. The hepatic metabolites of warfarin are eliminated by urinary excretion.Warfarin is metabolized by hepatic enzymes of the P450 system in the liver. Significant variability in patients exist, and likely influences the observed differences in warfarin dosing requirements between patients. There is some investigation into the use of genetic testing with Warfarin response. This is not widely available or deemed particularly clinically useful currently. The hepatic metabolites of warfarin are eliminated by urinary excretion.

12. Warfarin Initiation Medical history Disease Diet Medications Alcohol use Labs CBC, INR Electrolytes, Urea, Creatinine Liver enzymes Oral anticoagulant therapy should be instituted only after careful consideration of the risk and benefit for an individual patient. The ability to deliver oral anticoagulant therapy is highly dependent on patient selection, vigilant INR monitoring and evidence based treatment recommendations. A few issues to look at while thinking about warfarin initiation with a patient include medical history, what lab tests to perform, completing a medication reconciliation to determine if any interactions exist, and of course, patient education. These factors that can influence warfarin requirements should be discussed at all subsequent routine visits. Lab monitoring that should occur before the initiation of warfarin include complete blood count, INR, electrolytes included urea and creatinine, and liver enzymes.Oral anticoagulant therapy should be instituted only after careful consideration of the risk and benefit for an individual patient. The ability to deliver oral anticoagulant therapy is highly dependent on patient selection, vigilant INR monitoring and evidence based treatment recommendations. A few issues to look at while thinking about warfarin initiation with a patient include medical history, what lab tests to perform, completing a medication reconciliation to determine if any interactions exist, and of course, patient education. These factors that can influence warfarin requirements should be discussed at all subsequent routine visits. Lab monitoring that should occur before the initiation of warfarin include complete blood count, INR, electrolytes included urea and creatinine, and liver enzymes.

13. Warfarin Initiation Medication reconciliation Interactions Prescription drugs Non prescription drugs Over the counter Vitamins Herbal Products Medication reconciliation is a very important aspect of not only initiation of warfarin, but long term management. As we know, many patients do not think that over the counter medications, vitamins or herbal products �count� when discussing what they take. Encourage patients to bring all products with them to their first visit and discuss how important it is to be aware of everything due to interactions and risk of bleeding/clotting. Medication reconciliation is a very important aspect of not only initiation of warfarin, but long term management. As we know, many patients do not think that over the counter medications, vitamins or herbal products �count� when discussing what they take. Encourage patients to bring all products with them to their first visit and discuss how important it is to be aware of everything due to interactions and risk of bleeding/clotting.

14. Warfarin Initiation - Dosing Many Nomograms/ algorithms out there Guidelines only Use clinical judgment � patient specific adjustments for INR response, drug interactions, co-morbid condition Frequent INR monitoring during first month of therapy or until INR stable Initiation dosing of warfarin therapy may be accomplished by a number of methods. Although once common in clinical practice, fixed loading doses (10-15 mg daily for several days) and loading doses based on body weight are no longer recommended because of their association with an increased risk of overanticoagulation and subsequent hemorrhage. Patients who do not meet specific criteria that indicate sensitivity to the effects of warfarin are initiated at 4-5 mg once daily (usually 5 mg) with INR values checked within 2-3 days (literature also suggests daily). Dosing adjustments are made based on response to these initial doses, and the INR is re-evaluated. This pattern is continued until the INR reaches the lower limit of the therapeutic range, after which a maintenance dose is selected based on the doses given up to this point. Pts who may be particularly sensitive to the effects of warfarin also can begin warfarin therapy using this initiation strategy, but at doses of 1-3 mg daily (usually 2.5 mg). When using this initiation strategy, it is imperative that the INR be reevaluated repeatedly and rapidly b/c waiting for an extended period of time b/w INR checks can result in a significant delay in reaching the lower limit of the therapeutic range, or result in over anticoagulation. Initiation dosing of warfarin therapy may be accomplished by a number of methods. Although once common in clinical practice, fixed loading doses (10-15 mg daily for several days) and loading doses based on body weight are no longer recommended because of their association with an increased risk of overanticoagulation and subsequent hemorrhage. Patients who do not meet specific criteria that indicate sensitivity to the effects of warfarin are initiated at 4-5 mg once daily (usually 5 mg) with INR values checked within 2-3 days (literature also suggests daily). Dosing adjustments are made based on response to these initial doses, and the INR is re-evaluated. This pattern is continued until the INR reaches the lower limit of the therapeutic range, after which a maintenance dose is selected based on the doses given up to this point. Pts who may be particularly sensitive to the effects of warfarin also can begin warfarin therapy using this initiation strategy, but at doses of 1-3 mg daily (usually 2.5 mg). When using this initiation strategy, it is imperative that the INR be reevaluated repeatedly and rapidly b/c waiting for an extended period of time b/w INR checks can result in a significant delay in reaching the lower limit of the therapeutic range, or result in over anticoagulation.

15. Factors Likely to Increase Warfarin Sensitivity Age > 75 Clinical CHF Clinical hyperthyroidism Decreased oral intake Diarrhea Drug interactions Fever/infection Elevated baseline INR Following heart valve replacement Hepatic disease Hypoalbuminemia Malignancy ESRF These factors are likely to increase warfarin sensitivity. Age over 75, clinical chf, hyperthyroidism, malnutrition, diarrhea, drug interactions, fever/infection, elevated baseline INR, post heart valve replacement, hepatic disease, malignancy and end stage renal failure. Start low and go slow with initiation and titration of warfarin due to risk of overanticoagulation.These factors are likely to increase warfarin sensitivity. Age over 75, clinical chf, hyperthyroidism, malnutrition, diarrhea, drug interactions, fever/infection, elevated baseline INR, post heart valve replacement, hepatic disease, malignancy and end stage renal failure. Start low and go slow with initiation and titration of warfarin due to risk of overanticoagulation.

16. International Normalized Ratio (INR) Targets INR 2-3 Atrial fibrillation/ flutter DVT PE Aortic mechanical valves Aortic tissue valves for first three months post placement (surgeon dependent)

17. International Normalized Ratio (INR) Targets INR 2.5 � 3.5 Mechanical Mitral valves INR with variable targets Dependent on type of Ventricular Assist Device (VADs)

18. Medication Interactions Increased INR Tylenol Alcohol Allpurinol Amiodarone Azoles Co-trimoxazole Fluoroquinolones Macrolides Statins Decreased INR Carbamazepine Phenobarbitol Cholestyramine Alcohol Vitamin K containing foods (dark leafy greens, green tea) Smoking/tobacco This is by no means a thorough list of medications that interact with warfarin, but includes some of the more common interactions. And of course, in some patients an interaction will be seen, and others not. To manage the initiation of these drugs with patients on warfarin, it is important to check the INR 3 days after the interacting drug has been started. Adjust warfarin accordingly and check INR frequently during therapy. When interacting drug has been discontinued or dose decreased, check INR 3-5 days after stopped. Tylenol, allopurinol, amiodarone, the azoles , co-trimoxazole, fluroroquinolones, macrolides and statins may increase INR due to decreased warfarin metabolism, CYP450 enzyme inhibitors. Some patients will have no INR change while others may have high INRs. For amiodarone, remember the half life is 2 months, and it will take 5 half lives to reach steady state. During this time, warfarin dosages will fluctuate (usually decreasing to maintain therapeutic INR) For the medications that decrease INR, they are CYP450 inducers. All barbituates are inducers. Alcohol is on both lists. Acute alcohol overconsumption is usually accompanied by high INR�s Check the INR within 24 hours of the binge drinking. May need to be held and check daily until therapeutic. Chronic alcohol consumption induces enzymes and decreases INR. Vitamin K containing foods such as dark leafy greens, green tea will decrease the INR. These foods do not need to be cut out, but amount should be consistent from day to day. This is by no means a thorough list of medications that interact with warfarin, but includes some of the more common interactions. And of course, in some patients an interaction will be seen, and others not. To manage the initiation of these drugs with patients on warfarin, it is important to check the INR 3 days after the interacting drug has been started. Adjust warfarin accordingly and check INR frequently during therapy. When interacting drug has been discontinued or dose decreased, check INR 3-5 days after stopped. Tylenol, allopurinol, amiodarone, the azoles , co-trimoxazole, fluroroquinolones, macrolides and statins may increase INR due to decreased warfarin metabolism, CYP450 enzyme inhibitors. Some patients will have no INR change while others may have high INRs. For amiodarone, remember the half life is 2 months, and it will take 5 half lives to reach steady state. During this time, warfarin dosages will fluctuate (usually decreasing to maintain therapeutic INR) For the medications that decrease INR, they are CYP450 inducers. All barbituates are inducers. Alcohol is on both lists. Acute alcohol overconsumption is usually accompanied by high INR�s Check the INR within 24 hours of the binge drinking. May need to be held and check daily until therapeutic. Chronic alcohol consumption induces enzymes and decreases INR. Vitamin K containing foods such as dark leafy greens, green tea will decrease the INR. These foods do not need to be cut out, but amount should be consistent from day to day.

19. Warfarin Adverse events Hemorrhagic Non hemorrhagic Skin necrosis Purple toes Warfarin is one of the most common causes of adverse events in or out of hospital. The adverse drug reactions with vitamin K antagonists are almost exclusively hemorrhagic. Non hemorrhagic reactions include rash, alopecia, diarrhea, skin necrosis, purple toe syndrome and osteoporosis. I will briefly review the thrombotic complications of skin necrosis and purple toes as those are the most serious non hemorrhagic complications. Warfarin is one of the most common causes of adverse events in or out of hospital. The adverse drug reactions with vitamin K antagonists are almost exclusively hemorrhagic. Non hemorrhagic reactions include rash, alopecia, diarrhea, skin necrosis, purple toe syndrome and osteoporosis. I will briefly review the thrombotic complications of skin necrosis and purple toes as those are the most serious non hemorrhagic complications.

20. Hemorrhage Major Life threatening or occurs in critical organ Stopping the bleeding more important than thrombotic risk Minor Can be clinically important Epistaxis, macroscopic hematuria, muscle hematoma Always ID source of bleed Bleeding risk is based largely on level of anticoagulation. Bleeding risk is based largely on level of anticoagulation.

21. Skin Necrosis 1 in 5,000 Women 6:1 Breasts, buttocks, thighs 3-10 days after warfarin initiation Localized pain with maculopapular rash 24-48 hours � hemorrhagic lesions, bullae and necrosis Hypercoagulable state Stop warfarin therapy Heparin IV/thrombin inhibitor Warfarin induced skin necrosis is a rare but severe complication. Women are more prone than men and it typically affects areas rich in subcutaneous fat such as the breast, buttocks and thighs. Characteristically the onset is 3-10 days after initiation of anticoagulation but can occur later. The first symptom is localized pain associated with a maculopapular rash. Within 24-48 hours, the condition progresses with hemorrhagic lesions, bullae and necrosis. Healing is slow and plastic surgery may be necessary. Although the syndrome includes hemorrhagic manifestations, the pathogenic mechanism is a hypercoagulable state. Heparin IV or a thrombin inhibitor is used to counteract the hypercoagulability.Warfarin induced skin necrosis is a rare but severe complication. Women are more prone than men and it typically affects areas rich in subcutaneous fat such as the breast, buttocks and thighs. Characteristically the onset is 3-10 days after initiation of anticoagulation but can occur later. The first symptom is localized pain associated with a maculopapular rash. Within 24-48 hours, the condition progresses with hemorrhagic lesions, bullae and necrosis. Healing is slow and plastic surgery may be necessary. Although the syndrome includes hemorrhagic manifestations, the pathogenic mechanism is a hypercoagulable state. Heparin IV or a thrombin inhibitor is used to counteract the hypercoagulability.

22. Purple Toe Syndrome Rare 3-8 weeks after Warfarin initiation Bilateral burning pain Dark bluish discoloration Symptoms resolve Cholesterol embolization or plaque hemorrhage Purple toe syndrome is very rare. Characteristically will occur 3- 8 weeks after initiation of warfarin. The pt presents with bilateral burning pain and dark blue discoloration of the toes and sides of feet with blanching of the skin on pressure. The pathogenic mechanism is presumably cholesterol embolization from atherosclerotic plaques that have become friable b/c of less fibrin deposition or from hemorrhage in the plaque caused by warfarinPurple toe syndrome is very rare. Characteristically will occur 3- 8 weeks after initiation of warfarin. The pt presents with bilateral burning pain and dark blue discoloration of the toes and sides of feet with blanching of the skin on pressure. The pathogenic mechanism is presumably cholesterol embolization from atherosclerotic plaques that have become friable b/c of less fibrin deposition or from hemorrhage in the plaque caused by warfarin

23. Supratherapeutic INR < 5.0 No significant bleeding Hold or lower dose Restart when in range at adjusted dose 5.0-9.0 No significant bleeding Hold 1-2 doses More frequent INRs Restart when in range >9.0 No significant bleeding Hold warfarin Vitamin K by mouth Restart when in range More frequent INRs Assessment, med review According to the 2008 Chest guidelines, here are the recommendations for supratherapeutic INR management. For patients with INRs above the therapeutic range but < 5.0 and with no significant bleeding, it is recommended to hold or lower the dose, monitoring more frequently and resuming therapy at an appropriately adjusted dose when the INR is at a therapeutic level. If only minimally above therapeutic range or associated with a transient causative factor, no dose reduction may be required. For pts with INRs of > 5 but less than 9, and no significant bleeding, omit one or two doses, monitor more frequently and resume therapy at an appropriately adjusted dose with the INR is at therapeutic level. Alternately, if the pt is at increased risk of bleeding, administering vitamin K 1-2.5 mg orally is acceptable. For pts with INR > 9.0 and no significant bleeding, holding warfarin therapy and administering a higher dose of vitamin K (2.5-5 mg) orally with the expectation that the INR will be reduced substantially in 24-48 hours. The INR should be monitored more frequently and additional vitamin K can be administered if necessary. According to the 2008 Chest guidelines, here are the recommendations for supratherapeutic INR management. For patients with INRs above the therapeutic range but < 5.0 and with no significant bleeding, it is recommended to hold or lower the dose, monitoring more frequently and resuming therapy at an appropriately adjusted dose when the INR is at a therapeutic level. If only minimally above therapeutic range or associated with a transient causative factor, no dose reduction may be required. For pts with INRs of > 5 but less than 9, and no significant bleeding, omit one or two doses, monitor more frequently and resume therapy at an appropriately adjusted dose with the INR is at therapeutic level. Alternately, if the pt is at increased risk of bleeding, administering vitamin K 1-2.5 mg orally is acceptable. For pts with INR > 9.0 and no significant bleeding, holding warfarin therapy and administering a higher dose of vitamin K (2.5-5 mg) orally with the expectation that the INR will be reduced substantially in 24-48 hours. The INR should be monitored more frequently and additional vitamin K can be administered if necessary.

24. Supratherapeutic INR Serious/life threatening bleeding regardless of magnitude of elevation in INR Emergency Hold Warfarin Vitamin K 10 mg slow IV infusion FFP/Prothromin Complex Concentrate/Recombinant Factor VIIa In serious and life threatening bleeding regardless of the magnitude of elevation in INR, emergency. Warfarin to be held, vitamin K 10 mg slow IV infusion and FFP or other blood product given to halt the bleeding.In serious and life threatening bleeding regardless of the magnitude of elevation in INR, emergency. Warfarin to be held, vitamin K 10 mg slow IV infusion and FFP or other blood product given to halt the bleeding.

25. Patient Education Indicate reason for anticoagulation therapy and importance of taking as prescribed Review generic and trade name and discuss how the anticoagulant drug works to reduce the risk of clotting Discuss potential duration of therapy Explain the meaning and significance of the INR and the need for frequent testing Discuss target INR for patient condition I�m going to spend a little bit of time on pt education, as I�ve found it�s a huge part of my job. Pt safely is enhanced when pts are actively involved, understand and take responsibility in their care. In the anticoagulation clinic, we have a multiple choice adherence and knowledge questionnaire that tests pts on all this information. This is geared mostly toward warfarin therapy, but can also be used for LMWH as well. I�m going to spend a little bit of time on pt education, as I�ve found it�s a huge part of my job. Pt safely is enhanced when pts are actively involved, understand and take responsibility in their care. In the anticoagulation clinic, we have a multiple choice adherence and knowledge questionnaire that tests pts on all this information. This is geared mostly toward warfarin therapy, but can also be used for LMWH as well.

26. Patient Education Discuss the importance of regular laboratory tests to help minimize the risk of bleeding/thrombosis Describe the common signs of bleeding and clotting complications and action to take Discuss Vitamin K and its effects on VKA Discuss drug/food and herbal interactions and to notify their health care provider Read � explain?Read � explain?

27. Patient Education Discuss the use of alcohol and its potential risks and effects on INR Discuss the need for birth control for women of child bearing age Explain the importance of notifying all health care providers (doctor/dentist) of anticoagulant therapy Explain action to take if dose is missed or doubled ReadRead

28. Patient Education Discuss the importance carrying ID to identify patient is on anticoagulant for emergency caregivers The importance of the health care provider having correct contact information

29. CHADS2 C � Chronic Heart Failure H � HTN A � Age > 75 years D � Diabetes Mellitus S � Prior Stroke or TIA (worth 2 points) All in presence of AF Chads scoring is a system that is used to determine the risk of stroke in the face of AFChads scoring is a system that is used to determine the risk of stroke in the face of AF

30. Thrombotic RiskChest, 2008 High Any mitral valve prosthesis, CHADS score of 5 or 6, recent stroke or TIA, rheumatic heart disease, recent venothrombotic event (VTE) (3 months), severe thrombophilia Moderate VTE in last 3 � 12 months or recurrent VTE, active cancer, non severe thrombophilia; Aortic valve prosthesis and one of the following: AF, prior stroke or TIA, HTN, DM, CHF or Age > 75 CHADS score of 3 - 4

31. Thrombotic RiskChest, 2008 Low Aortic valve prosthesis without AF and no other risk factors for stroke CHADS score of 0 � 2 Single VTE occurring over 12 months prior

32. Low Molecular Weight Heparin (LMWH) Advantages Outpatient Predictable response based on body weight Prolonged half life (once or twice daily dosing) Lower incidence of HITT and osteoporosis Disadvantages Therapeutic level (anti Xa) not easily measured (obesity, renal dysfunction, pregnancy) Protamine not as effective as reversal Cost/EDS part 3 NP�s cannot prescribe

33. Bridging with initiation of Warfarin LMWH can and likely should be used when patient is initiated on Warfarin when subtherapeutic for high thrombotic risk patients Give patient Fragmin full dose to cover the patient (anticoagulate) until INR in therapeutic range, then discontinue Fragmin Guidelines suggest two consecutive days of therapeutic INRs before discontinuing Fragmin � we don�t do this.Guidelines suggest two consecutive days of therapeutic INRs before discontinuing Fragmin � we don�t do this.

34. Bridging Periprocedural bridging Consider thrombotic risk (CHADS scoring) Complete history, physical, medication reconciliation and lab results Calculate Creatinine clearance Most common drug used is Fragmin Weight based dosing 200 units/kg/day (Full dose) Once the patient is assessed and lab values are know it is reasonable to put the plan for bridging into play Add formula for creatinine clearanceOnce the patient is assessed and lab values are know it is reasonable to put the plan for bridging into play Add formula for creatinine clearance

35. Bridging Typical bridging plan 5 days before procedure assess INR 4 days before procedure no Warfarin or Fragmin Days 3 and 2 before procedure full dose Fragmin Day before procedure half dose Fragmin For cardiac surgery and some ablation procedures half dose For angiogram full dose day before procedure Surgeon/interventionalist preference Interventionalist/ surgeon assumes bleeding risk of patient CHEST guidelines state � dose day before procedure, our docs are dependent based on bleeding vs clotting risk. For cardiac surgery and some ablation procedures half dose For angiogram full dose day before procedure Surgeon/interventionalist preference Interventionalist/ surgeon assumes bleeding risk of patient CHEST guidelines state � dose day before procedure, our docs are dependent based on bleeding vs clotting risk.

36. Post Procedural Bridging Day of procedure begin initiation of Warfarin, but continue Fragmin with either half or full dose (variable) Begin Warfarin at 1.5 times normal dose for 1 or 2 days Continue Fragmin during this time Follow INR/CBC and continue Fragmin until INR therapeutic Assess patient for signs of bleeding

37. Why Fragmin? Ease of use Once daily dosing Less injections Dosing straight forward � weight based Always assess for signs of bleeding Especially important when home care giving injectionsEspecially important when home care giving injections

38. Heparin Induced Thrombocytopenia (HIT) HIT-2 (more severe form) Immune mediated Platelet count falls in between 5 -12 days following administration of Heparin Complications include Gangrene, Arterial thrombosis, MI, Stroke, Disseminated Intravascular Coagulation (DIC) Must discontinue all sources of Heparin and begin Fondaparinux Two types of Hit Thrombosis due to white clots (composed of platelets and fibrin) Fondaparinux antithrombotic, weight based dose range 5-10 mgTwo types of Hit Thrombosis due to white clots (composed of platelets and fibrin) Fondaparinux antithrombotic, weight based dose range 5-10 mg

39. Test for HITT Diagnosis Heparin Induced Thrombocytopenia and Thrombosis (HITT) assay Serotonin Release Assay (SRA) If positive, consider Fondaparinux HITT assay is a blood test performed that tells us when the patient develops antibodies in response to receiving heparin a sensitive test but some patients can be missed and require further testing. This is when an SRA is ordered The SRA is the gold standard for diagnosis of HITT as it is highly sensitive and specific for the diagnosis of HITTHITT assay is a blood test performed that tells us when the patient develops antibodies in response to receiving heparin a sensitive test but some patients can be missed and require further testing. This is when an SRA is ordered The SRA is the gold standard for diagnosis of HITT as it is highly sensitive and specific for the diagnosis of HITT

40. New Therapies Direct thrombin Inhibitors Dabigatran Fondaparinux Anti Xa factor inhibitor Usual dose 2.5 to 5 mg once daily subcutanteous injection Dabigatran does not require frequent monitoring by blood test Does not interact with food or other drug/drug interactions In trials has had a low incidence and severity of major bleeding Has a lesser effect on elevating LFT�sDabigatran does not require frequent monitoring by blood test Does not interact with food or other drug/drug interactions In trials has had a low incidence and severity of major bleeding Has a lesser effect on elevating LFT�s

41. Questions Warfarin Heparin