Management of Oral Anticoagulant Therapy

2. Management of Oral Anticoagulant Therapy Principles & Practice

3. Prepared for thePostgraduate Education Committee,Council on Clinical CardiologyAmerican Heart Associationby Jack Ansell, M.D. Jack Hirsh, M.D. Nanette K. Wenger, M.D. Supported by an Educational Grant from DuPont Pharmaceuticals

5. Clotting Cascade The blood coagulation process can be activated by one of two pathways, the tissue Factor pathway (formerly known as the extrinsic pathway) and the contact activation pathway (known as the intrinsic pathway). Tissue Factor binds to and activates Factor VII and the Tissue Factor/VIIa complex then activates Factor X and Factor IX to Xa and Ixa respectively. Factor X can also be converted to Xa by Ixa (in the presence of Factor VIII). The intrinsic pathway is activated when Factor XII comes in contact with a foreign surface. The resulting Factor XIIa then activates Factor XI, which in turn activates Factor IX. Factor Ixa then activates Factor X. Thus Factor Xa can be generated by activation of the tissue factor or contact activation pathways. Factor Xa then cleves prothrombin and the resulting thrombin converts fibrinogen to fibrin. Four of these clotting factors (Factors IX, VII, X and prothrombin) are Vitamin K dependent and therefore their activity is decreased by the Vitamin K antagonist, warfarin. The half-lives of these four Vitamin K dependent clotting factors are shown on this slide. Factor VII has the shortest half life of the Vitamin K dependent coagulation factors. However, for adequate anticoagulation one needs to reduce the other coagulation factors appropriately, including Factor II (prothrombin) which has a 60 hour half life. It takes several days after initiation of warfarin therapy to reduce Factor II and thus warfarin and heparin need to overlap for approximately 4�5 days when starting therapy. The blood coagulation process can be activated by one of two pathways, the tissue Factor pathway (formerly known as the extrinsic pathway) and the contact activation pathway (known as the intrinsic pathway). Tissue Factor binds to and activates Factor VII and the Tissue Factor/VIIa complex then activates Factor X and Factor IX to Xa and Ixa respectively. Factor X can also be converted to Xa by Ixa (in the presence of Factor VIII). The intrinsic pathway is activated when Factor XII comes in contact with a foreign surface. The resulting Factor XIIa then activates Factor XI, which in turn activates Factor IX. Factor Ixa then activates Factor X. Thus Factor Xa can be generated by activation of the tissue factor or contact activation pathways. Factor Xa then cleves prothrombin and the resulting thrombin converts fibrinogen to fibrin. Four of these clotting factors (Factors IX, VII, X and prothrombin) are Vitamin K dependent and therefore their activity is decreased by the Vitamin K antagonist, warfarin. The half-lives of these four Vitamin K dependent clotting factors are shown on this slide. Factor VII has the shortest half life of the Vitamin K dependent coagulation factors. However, for adequate anticoagulation one needs to reduce the other coagulation factors appropriately, including Factor II (prothrombin) which has a 60 hour half life. It takes several days after initiation of warfarin therapy to reduce Factor II and thus warfarin and heparin need to overlap for approximately 4�5 days when starting therapy.

6. Vitamin K-Dependent Clotting Factors The four Vitamin K dependent clotting factors are synthesized in the liver. The four Vitamin K dependent clotting factors are synthesized in the liver.

7. Vitamin K Mechanism of Action The Vitamin K dependent clotting factors are carboxylated in a reaction that is linked to the oxidation of the reduced form of the vitamin . The non carboxylated forms of these clotting factors are inactive because they cannot bind calcium. When Vitamin K is deficient, non-carboxylated prothrombin is secreted and this protein is non functional. Carboxylation of terminal glutamic acid side chains (known as the Glu to Gla conversion) allows the clotting factors to bind calcium which in turn bridges the clotting factors to phospholipid surfaces, a necessary requirement for their activity. The Vitamin K dependent clotting factors are carboxylated in a reaction that is linked to the oxidation of the reduced form of the vitamin . The non carboxylated forms of these clotting factors are inactive because they cannot bind calcium. When Vitamin K is deficient, non-carboxylated prothrombin is secreted and this protein is non functional. Carboxylation of terminal glutamic acid side chains (known as the Glu to Gla conversion) allows the clotting factors to bind calcium which in turn bridges the clotting factors to phospholipid surfaces, a necessary requirement for their activity.

8. Warfarin Mechanism of Action Warfarin acts as an anticoagulant by blocking the ability of Vitamin K to carboxylate the Vitamin K dependent clotting factors, thereby reducing their coagulant activity. Warfarin acts as an anticoagulant by blocking the ability of Vitamin K to carboxylate the Vitamin K dependent clotting factors, thereby reducing their coagulant activity.

9. Warfarin Mechanism of Action Warfarin works by interfering with internal recycling of oxidized Vitamin K to the reduced form. When warfarin is given, the oxidized form of Vitamin K builds up in the blood leading to a deficiency of reduced Vitamin K and a decrease in carboxylation of prothrombin. Warfarin interferes with g�carboxylation of terminal glutamic acids on the procoagulant proteins, Factors II, VII, IX, and X. g�carboxylation from the Glu to the Gla form of these proteins in a critical step in the biosynthesis of these proteins that is required their normal function in coagulation. g�carboxylation is a post-translational step that is Vitamin K dependent and linked to the oxidation of hydroquinone (the active clotting form of Vitamin K) to the Vitamin K epoxide. The reaction uses molecular oxygen for the conversion of hydroquinone to the epoxide, and CO2, for the g�carboxylation of the glutamic acid residues on the Vitamin K dependent proteins from the inactive carboxylation of the glutamic acid residues on the Vitamin K dependent proteins from the inactive Glu to the active Gla form. Under normal physiologic circumstances, Vitamin K is absorbed as the quinone form (Vitamin K1). The quinone is reduced to the hydroquinone (the reduced form), which in turn is oxidized to Vitamin K epoxide (the oxidized form). The active cofactor form of Vitamin K (hydroquinone) is then regenerated through two reduction steps. First the 2�3 epoxide is reduced to the quinone (the dietary source of Vitamin K1). This is then reduced to the hydroquinone which, when recycled to the epoxide, acts as the cofactor for the Glu to Gla conversion of the Vitamin K dependent coagulation factors by blocking both reduction steps, thereby depleting the stores of the hydroquinone form of Vitamin K. Warfarin works by interfering with internal recycling of oxidized Vitamin K to the reduced form. When warfarin is given, the oxidized form of Vitamin K builds up in the blood leading to a deficiency of reduced Vitamin K and a decrease in carboxylation of prothrombin. Warfarin interferes with g�carboxylation of terminal glutamic acids on the procoagulant proteins, Factors II, VII, IX, and X. g�carboxylation from the Glu to the Gla form of these proteins in a critical step in the biosynthesis of these proteins that is required their normal function in coagulation. g�carboxylation is a post-translational step that is Vitamin K dependent and linked to the oxidation of hydroquinone (the active clotting form of Vitamin K) to the Vitamin K epoxide. The reaction uses molecular oxygen for the conversion of hydroquinone to the epoxide, and CO2, for the g�carboxylation of the glutamic acid residues on the Vitamin K dependent proteins from the inactive carboxylation of the glutamic acid residues on the Vitamin K dependent proteins from the inactive Glu to the active Gla form. Under normal physiologic circumstances, Vitamin K is absorbed as the quinone form (Vitamin K1). The quinone is reduced to the hydroquinone (the reduced form), which in turn is oxidized to Vitamin K epoxide (the oxidized form). The active cofactor form of Vitamin K (hydroquinone) is then regenerated through two reduction steps. First the 2�3 epoxide is reduced to the quinone (the dietary source of Vitamin K1). This is then reduced to the hydroquinone which, when recycled to the epoxide, acts as the cofactor for the Glu to Gla conversion of the Vitamin K dependent coagulation factors by blocking both reduction steps, thereby depleting the stores of the hydroquinone form of Vitamin K.

10. Virchow�s Triad Virchow�s Triad defines the pathophysiology of thrombotic disease. Thrombosis occurs when one or more of the three components of Virchow�s Triad are present. Accordingly, thrombosis is caused by abnormalities of blood flow (stasis), abnormalities of blood vessels (endothelial injury), or abnormalities of the blood itself (a hypercoagulable state). Virchow�s Triad defines the pathophysiology of thrombotic disease. Thrombosis occurs when one or more of the three components of Virchow�s Triad are present. Accordingly, thrombosis is caused by abnormalities of blood flow (stasis), abnormalities of blood vessels (endothelial injury), or abnormalities of the blood itself (a hypercoagulable state).

11. Antithrombotic Agents: Mechanism of Action Anticoagulants: prevent clot formation and extension Antiplatelet drugs: interfere with platelet activity Thrombolytic agents: dissolve existing thrombi There are three classes of antithrombotic agents: anticoagulants, antiplatelet agents, and thrombolytic agents. This slide set reviews one type of anticoagulant, namely, warfarin. Anticoagulant therapy is always prophylactic in that it prevents new clot formation where none previously existed (primary prophylaxis) or it prevents extension of already developed blood clots (secondary prophylaxis), for example, in the setting of deep venous thrombosis or pulmonary embolism. Antiplatelet therapy can be thought of in the same way. Thrombolytic agents, on the other hand, are direct acting in that they hasten the dissolution of thrombi by activating the thrombolytic system. There are three classes of antithrombotic agents: anticoagulants, antiplatelet agents, and thrombolytic agents. This slide set reviews one type of anticoagulant, namely, warfarin. Anticoagulant therapy is always prophylactic in that it prevents new clot formation where none previously existed (primary prophylaxis) or it prevents extension of already developed blood clots (secondary prophylaxis), for example, in the setting of deep venous thrombosis or pulmonary embolism. Antiplatelet therapy can be thought of in the same way. Thrombolytic agents, on the other hand, are direct acting in that they hasten the dissolution of thrombi by activating the thrombolytic system.

12. Warfarin: Indications Prophylaxis and/or treatment of: Venous thrombosis and its extension Pulmonary embolism Thromboembolic complications associated with AF and cardiac valve replacement Post MI, to reduce the risk of death, recurrent MI, and thromboembolic events such as stroke or systemic embolization Prevention and treatment of cardiac embolism The established indications for warfarin are shown on this slide. These indications are derived from the Fifth American College of Chest Physicians Consensus Conference (1998) based on randomized prospective studies. There is good evidence (Level 1) from randomized trials, that warfarin is effective for all of the indications listed. The established indications for warfarin are shown on this slide. These indications are derived from the Fifth American College of Chest Physicians Consensus Conference (1998) based on randomized prospective studies. There is good evidence (Level 1) from randomized trials, that warfarin is effective for all of the indications listed.

13. Warfarin: Major Adverse Effect�Hemorrhage Factors that may influence bleeding risk: Intensity of anticoagulation Concomitant clinical disorders Concomitant use of other medications Quality of management The major side effect of warfarin is hemorrhage. The factors that can influence the bleeding risk are shown on this slide; three of these potential risk factors, namely: the intensity of anticoagulation, concomitant use of other medications, and quality of management are controllable. The intensity of anticoagulation is an extremely important risk factor for adverse events. This is because warfarin, a narrow therapeutic index drug, has a small window of therapeutic effectiveness and dosing must be carefully managed. Such management is best achieved in the setting of an anticoagulation management service (anticoagulation clinic). The major side effect of warfarin is hemorrhage. The factors that can influence the bleeding risk are shown on this slide; three of these potential risk factors, namely: the intensity of anticoagulation, concomitant use of other medications, and quality of management are controllable. The intensity of anticoagulation is an extremely important risk factor for adverse events. This is because warfarin, a narrow therapeutic index drug, has a small window of therapeutic effectiveness and dosing must be carefully managed. Such management is best achieved in the setting of an anticoagulation management service (anticoagulation clinic).

14. Special Considerations in the Elderly�Bleeding Increased age associated with increased sensitivity at usual doses Comorbidity Medications used for associated illnesses lead to increased drug interactions ? Increased bleeding risk independent of the above: increased vascular fragility The elderly are at special risk for bleeding because:1) increased age is associated with an increased sensitivity to warfarin, therefore the elderly often require lower doses of warfarin to maintain their INR in the therapeutic range2) they often have concomitant disorders that either influence their response to warfarin or expose them to the risk of bleeding3) these disorders may require therapy with drugs that either interfere with the pharmacodynamics of warfarin or increase the risk of bleeding4) increased age itself (due to increased vascular fragility) might be an independent risk factor for warfarin-associated bleeding. Because of an increased sensitivity to warfarin, comorbidity and increased drug interactions, the elderly require even more careful management of dose adjustment.In the case of intracranial hemorrhage, there may be a slight, but real increased risk in the very elderly regardless of the quality of management. The elderly are at special risk for bleeding because:1) increased age is associated with an increased sensitivity to warfarin, therefore the elderly often require lower doses of warfarin to maintain their INR in the therapeutic range2) they often have concomitant disorders that either influence their response to warfarin or expose them to the risk of bleeding3) these disorders may require therapy with drugs that either interfere with the pharmacodynamics of warfarin or increase the risk of bleeding4) increased age itself (due to increased vascular fragility) might be an independent risk factor for warfarin-associated bleeding. Because of an increased sensitivity to warfarin, comorbidity and increased drug interactions, the elderly require even more careful management of dose adjustment.In the case of intracranial hemorrhage, there may be a slight, but real increased risk in the very elderly regardless of the quality of management.

15. Mean Warfarin Daily Dose (mg) Patient Age <50 50�59 60�69 70�79 >80 Gurwitz, et al, 1992 6.4 5.1 4.2 3.6 ND (n=530 patients total study) James, et al, 1992 6.1 5.3 4.3 3.9 3.5 (n=2,305 patients total study) Warfarin Dosing in Elderly Patients This slide summarizes the results of two studies demonstrating the inverse relationship between mean warfarin dosage requirements and increasing age. The elderly require a lower dose of warfarin to achieve the same level of therapeutic effectiveness. This slide summarizes the results of two studies demonstrating the inverse relationship between mean warfarin dosage requirements and increasing age. The elderly require a lower dose of warfarin to achieve the same level of therapeutic effectiveness.

16. Prothrombin Time (PT) Historically, a most reliable and �relied upon� clinical test However: Proliferation of thromboplastin reagents with widely varying sensitivities to reduced levels of vitamin K-dependent clotting factors has occurred Concept of correct �intensity� of anticoagulant therapy has changed significantly Problem addressed by use of INR (International Normalized Ratio) The prothrombin time (PT) is the test most commonly used to monitor warfarin dosing. The reliability of the result of the PT is influenced adversely by the variability in the sensitivity of thromboplastin reagents used by different laboratories. This problem has been markedly reduced by reporting the PT ratio as an International Normalized Ratio (INR). The prothrombin time (PT) is the test most commonly used to monitor warfarin dosing. The reliability of the result of the PT is influenced adversely by the variability in the sensitivity of thromboplastin reagents used by different laboratories. This problem has been markedly reduced by reporting the PT ratio as an International Normalized Ratio (INR).

17. INR: International Normalized Ratio A mathematical �correction� (of the PT ratio) for differences in the sensitivity of thromboplastin reagents Relies upon �reference� thromboplastins with known sensitivity to antithrombotic effects of oral anticoagulants INR is the PT ratio one would have obtained if the �reference� thromboplastin had been used Allows for comparison of results between labs and standardizes reporting of the prothrombin time The INR is a mathematical correction that normalizes the PT ratio by adjusting for the variability in the sensitivity of the different thromboplastins. The INR is a mathematical correction that normalizes the PT ratio by adjusting for the variability in the sensitivity of the different thromboplastins.

18. INR Equation The INR is calculated by the formula shown on this slide. The ISI is the International Sensitivity Index. Each thromboplastin is assigned an ISI which reflects the sensitivity of the thromboplastin to Warfarin-mediated reduction of the Vitamin K dependent clotting factors. By convention, the ISI of the reference thromboplastin is 1.0. The higher the ISI, the less sensitive the thromboplastin is to Warfarin-mediated reduction of the Vitamin K dependent clotting factors. The next two slides provide an example of how the ISI (sensitivity) of the thromboplastin influences the PT ratio (PTR) and how the resulting variability is corrected by expressing the results as an INR. The INR is calculated by the formula shown on this slide. The ISI is the International Sensitivity Index. Each thromboplastin is assigned an ISI which reflects the sensitivity of the thromboplastin to Warfarin-mediated reduction of the Vitamin K dependent clotting factors. By convention, the ISI of the reference thromboplastin is 1.0. The higher the ISI, the less sensitive the thromboplastin is to Warfarin-mediated reduction of the Vitamin K dependent clotting factors. The next two slides provide an example of how the ISI (sensitivity) of the thromboplastin influences the PT ratio (PTR) and how the resulting variability is corrected by expressing the results as an INR.

19. How Different Thromboplastins Influence the PT Ratio and INR This slide shows the results of the PT (expressed both as a time in seconds and a PTR) performed on five aliquots of the same plasma sample using five thromboplastins with different ISI values. The results of the PTR varies among the five aliquots of the same test plasma, reflecting the variability in the sensitivities of the thromboplastins. This slide shows the results of the PT (expressed both as a time in seconds and a PTR) performed on five aliquots of the same plasma sample using five thromboplastins with different ISI values. The results of the PTR varies among the five aliquots of the same test plasma, reflecting the variability in the sensitivities of the thromboplastins.

20. How Different Thromboplastins Influence the PT Ratio and INR This slide is similar to the last one, but the results of the ISI values of the five thromboplastins and the corresponding INR values are added. It is clear that the marked variability of the PTR is normalized by expressing the results as an INR. This slide is similar to the last one, but the results of the ISI values of the five thromboplastins and the corresponding INR values are added. It is clear that the marked variability of the PTR is normalized by expressing the results as an INR.

21. Relationship Between PT Ratio and INR Poller has constructed a nomogram from which the PTR can be converted to an INR if the ISI of the thromboplastin is known. Two examples are shown. One is of a PTR of 1.3 and the other of a PTR of 1.5. The ISI of the thromboplastin is 2.3. The corresponding INR values for PTRs of 1.3 and 1.5 can be read of the nomogram as approximately 1.8 and 2.5 respectively. The calculated INR values are shown in the inset to the right of the graph. Poller has constructed a nomogram from which the PTR can be converted to an INR if the ISI of the thromboplastin is known. Two examples are shown. One is of a PTR of 1.3 and the other of a PTR of 1.5. The ISI of the thromboplastin is 2.3. The corresponding INR values for PTRs of 1.3 and 1.5 can be read of the nomogram as approximately 1.8 and 2.5 respectively. The calculated INR values are shown in the inset to the right of the graph.

22. Potential Problems with the INR Limitations Unreliable during induction Loss of accuracy with high ISI thromboplastins Incorrect ISI assignment by manufacturer Incorrect calculation of INR due to failure to use proper mean normal plasma value to derive PT ratio Solutions Use thromboplastin reagents with low ISI values (less than 1.5) Use thromboplastin reagents with low ISI values Use thromboplastin reagents with low ISI values and use plasma calibrants with certified INR values Use �mean normal� PT derived from normal plasma samples for every new batch of thromboplastin reagent Although the INR method of reporting represents a marked improvement over the PTR, it is not perfect. It is less reliable during the induction than the maintenance period, although still much more reliable than the PTR. It loses accuracy when insensitive thromboplastins (with a high ISI) are used. It is subject to incorrect assignments of the ISI value by the manufacturer, and loses reliability if the control PT mean is calculated incorrectly. The solutions to these four problems are listed in the right hand column of the slide. Three of the problems are solved or reduced in magnitude by selecting thromboplastins with low ISI values. Although the INR method of reporting represents a marked improvement over the PTR, it is not perfect. It is less reliable during the induction than the maintenance period, although still much more reliable than the PTR. It loses accuracy when insensitive thromboplastins (with a high ISI) are used. It is subject to incorrect assignments of the ISI value by the manufacturer, and loses reliability if the control PT mean is calculated incorrectly. The solutions to these four problems are listed in the right hand column of the slide. Three of the problems are solved or reduced in magnitude by selecting thromboplastins with low ISI values.

23. Warfarin: Dosing Information Individualize dose according to patient response(as indicated by INR) Use of large loading dose >10 mg is not recommended* May increase hemorrhagic complications Does not offer more rapid protection Hypercoagulable state due to depletion of protein C (half life of 6 hours): warfarin-induced skin necrosis Low initiation doses are recommended for elderly / frail / liver-diseased / malnourished patients Three recommendations designed to increase the safety of warfarin use are listed on this slide. Large loading doses (>10 mg) are no longer recommended for the initiation of therapy. As demonstrated in slide 17c, large loading doses cause an abrupt and dramatic fall in Factor VII levels (close to 0%), but do not speed up the reduction of Factors IX, X, or II compared to lower doses. It still takes 4�5 days to get all of the Vitamin K dependent coagulation factors down to a therapeutic range, at which time, therapy needs to overlap with heparin therapy in patients with venous thrombotic disease. Because Factor VII levels can fall so low with large loading doses, there is a risk of hemorrhage during the first few days of therapy. Furthermore, large loading doses cause a precipitous fall in Protein C (a Vitamin K dependent coagulation inhibitor that also has a short half life of about six hours), and if this protein falls significantly during early therapy before all of the Vitamin K dependent factors are decreased, one could potentially develop a hypercoagulable state before a hypocoagulable state develops. Consequently, initiation of therapy today is recommended to start with 5 mg of warfarin (in some cases 10 mg may be used initially). Thereafter, subsequent doses are based on the INR response. For patients who may already have impaired coagulation (liver disease), who may have low levels of Vitamin K (malnourishment), or may be at a greater risk of bleeding, it is recommended to start with even lower initial doses such as 2.5 mg of warfarin. Three recommendations designed to increase the safety of warfarin use are listed on this slide. Large loading doses (>10 mg) are no longer recommended for the initiation of therapy. As demonstrated in slide 17c, large loading doses cause an abrupt and dramatic fall in Factor VII levels (close to 0%), but do not speed up the reduction of Factors IX, X, or II compared to lower doses. It still takes 4�5 days to get all of the Vitamin K dependent coagulation factors down to a therapeutic range, at which time, therapy needs to overlap with heparin therapy in patients with venous thrombotic disease. Because Factor VII levels can fall so low with large loading doses, there is a risk of hemorrhage during the first few days of therapy. Furthermore, large loading doses cause a precipitous fall in Protein C (a Vitamin K dependent coagulation inhibitor that also has a short half life of about six hours), and if this protein falls significantly during early therapy before all of the Vitamin K dependent factors are decreased, one could potentially develop a hypercoagulable state before a hypocoagulable state develops. Consequently, initiation of therapy today is recommended to start with 5 mg of warfarin (in some cases 10 mg may be used initially). Thereafter, subsequent doses are based on the INR response. For patients who may already have impaired coagulation (liver disease), who may have low levels of Vitamin K (malnourishment), or may be at a greater risk of bleeding, it is recommended to start with even lower initial doses such as 2.5 mg of warfarin.

24. Loading Dose then Maintenance Dose This slide shows the time course of reduction of the four Vitamin K dependent clotting factors when a loading dose is used. There is a rapid fall in Factor VII, because this has the shortest half life. as a result, the INR increases and the dose of warfarin is reduced so that by about day 5, the four clotting factors are reduced to a similar extent and the INR is in the therapeutic range. In addition, the anticoagulant protein, Protein C is reduced to a similar extent as Factor VII because both Vitamin K dependent proteins have a similar (short) half life. This slide shows the time course of reduction of the four Vitamin K dependent clotting factors when a loading dose is used. There is a rapid fall in Factor VII, because this has the shortest half life. as a result, the INR increases and the dose of warfarin is reduced so that by about day 5, the four clotting factors are reduced to a similar extent and the INR is in the therapeutic range. In addition, the anticoagulant protein, Protein C is reduced to a similar extent as Factor VII because both Vitamin K dependent proteins have a similar (short) half life.

25. Maintenance Dose Only This slide shows the time course of reduction of the four Vitamin K dependent clotting factors when treatment is initiated with a maintenance dose. The rapid fall in Factor VII is avoided and by about day 5, the four clotting factors are reduced to a similar extent and the INR is in the therapeutic range. The initiation of warfarin with a maintenance dose avoids the hazard of early overcoagulation and reduces the risk of warfarin-induced skin necrosis, a rare but serious complication of warfarin therapy that is thought to be associated with marked reductions in the level of protein C during the induction phase of warfarin therapy. This slide shows the time course of reduction of the four Vitamin K dependent clotting factors when treatment is initiated with a maintenance dose. The rapid fall in Factor VII is avoided and by about day 5, the four clotting factors are reduced to a similar extent and the INR is in the therapeutic range. The initiation of warfarin with a maintenance dose avoids the hazard of early overcoagulation and reduces the risk of warfarin-induced skin necrosis, a rare but serious complication of warfarin therapy that is thought to be associated with marked reductions in the level of protein C during the induction phase of warfarin therapy.

26. This shows the comparative effects on the Vitamin K dependent coagulation factors of initiating warfarin with a loading or a maintenance dose. This shows the comparative effects on the Vitamin K dependent coagulation factors of initiating warfarin with a loading or a maintenance dose.

27. Conversion from Heparin to Warfarin May begin concomitantly with heparin therapy Heparin should be continued for a minimum of four days Time to peak antithrombotic effect of warfarin is delayed 96 hours (despite INR) When INR reaches desired therapeutic range, discontinue heparin (after a minimum of four days) When short-term heparin followed by long-term warfarin are used, both anticoagulants can be started simultaneously. Heparin should be continued for a minimum of four days because the peak antithrombotic effect of warfarin is delayed for about 96 hours, independently of the INR, until Factor II (prothrombin is reduced). Heparin can be discontinued after a minimum of four days when the INR reaches the therapeutic range. When short-term heparin followed by long-term warfarin are used, both anticoagulants can be started simultaneously. Heparin should be continued for a minimum of four days because the peak antithrombotic effect of warfarin is delayed for about 96 hours, independently of the INR, until Factor II (prothrombin is reduced). Heparin can be discontinued after a minimum of four days when the INR reaches the therapeutic range.

28. Warfarin: Dosing & Monitoring Start low Initiate 5 mg daily* Educate patient Stabilize Titrate to appropriate INR Monitor INR frequently (daily then weekly) Adjust as necessary Monitor INR regularly (every 1�4 weeks) and adjust This slide provides guidelines for safe and effective warfarin use. The dose of warfarin should be monitored daily until the INR is in the therapeutic range and then less frequently when a stable dose-response relationship is achieved. Regardless of the degree of stability in warfarin dosing and INR value in the hospital, it is important to monitor the INR frequently post hospital discharge (i.e., at least 1�3 days after discharge) and to spread out the interval of monitoring thereafter depending on INR response. Monitoring is necessary in all patients, but can be reduced to four weekly intervals in the low risk (for bleeding) patient who shows a stable dose-response. This slide provides guidelines for safe and effective warfarin use. The dose of warfarin should be monitored daily until the INR is in the therapeutic range and then less frequently when a stable dose-response relationship is achieved. Regardless of the degree of stability in warfarin dosing and INR value in the hospital, it is important to monitor the INR frequently post hospital discharge (i.e., at least 1�3 days after discharge) and to spread out the interval of monitoring thereafter depending on INR response. Monitoring is necessary in all patients, but can be reduced to four weekly intervals in the low risk (for bleeding) patient who shows a stable dose-response.

29. Relative Contraindications to Warfarin Therapy Pregnancy : Teratogenic in the first trimester: Warfarin embryopathy in 5% of exposed neonates Fetopathic after the first trimester Situations where the risk of hemorrhage is greater than the potential clinical benefits of therapy Uncontrolled alcohol/drug abuse Unsupervised dementia/psychosis The relative contraindications for warfarin are listed on this slide. Warfarin crosses the placenta and is teratogenic in the first trimester, producing warfarin embryopathy in about 5% of exposed neonates. It is also fetopathic when used after the first trimester in an unknown (but much smaller) percentage of fetuses. Warfarin is contraindicated (relative or absolute) in patients with an increased risk of serious bleeding. The indication for warfarin should be reviewed carefully in patients with relative contraindications. The relative contraindications for warfarin are listed on this slide. Warfarin crosses the placenta and is teratogenic in the first trimester, producing warfarin embryopathy in about 5% of exposed neonates. It is also fetopathic when used after the first trimester in an unknown (but much smaller) percentage of fetuses. Warfarin is contraindicated (relative or absolute) in patients with an increased risk of serious bleeding. The indication for warfarin should be reviewed carefully in patients with relative contraindications.

30. Signs of Warfarin Overdosage Any unusual bleeding: Blood in stools or urine Excessive menstrual bleeding Bruising Excessive nose bleeds/bleeding gums Persistent oozing from superficial injuries Bleeding from tumor, ulcer, or other lesion The signs of warfarin overdosage are listed on this slide. Hemorrhagic complications from warfarin therapy are more likely to occur with excessive degrees of anticoagulation, but even with an INR in the therapeutic range, bleeding can occur. Because of the likelihood of finding an underlying lesion in an individual who has gastrointestinal bleeding or significant genito-urinary bleeding in the face of therapeutic levels of anticoagulation, one is advised to consider and evaluate for underlying abnormalities predisposing to the bleeding. The return on such evaluations in the face of an excessive degree of anticoagulation diminishes, and one must use judgement whether or not to pursue an evaluation. The signs of warfarin overdosage are listed on this slide. Hemorrhagic complications from warfarin therapy are more likely to occur with excessive degrees of anticoagulation, but even with an INR in the therapeutic range, bleeding can occur. Because of the likelihood of finding an underlying lesion in an individual who has gastrointestinal bleeding or significant genito-urinary bleeding in the face of therapeutic levels of anticoagulation, one is advised to consider and evaluate for underlying abnormalities predisposing to the bleeding. The return on such evaluations in the face of an excessive degree of anticoagulation diminishes, and one must use judgement whether or not to pursue an evaluation.

31. Managing Patients with High INR Values/Minor or No Bleeding An approach to the management of patients who are excessively over anticoagulated and either have minor bleeding or no obvious bleeding is outlined on this slide. In all cases, warfarin treatment should be interrupted the INR checked and warfarin restarted at a lower dose when the INR returns to the therapeutic range. If the INR is above 5 but below 9, oral Vitamin K, should be considered if the patient is at excessive risk of bleeding. An approach to the management of patients who are excessively over anticoagulated and either have minor bleeding or no obvious bleeding is outlined on this slide. In all cases, warfarin treatment should be interrupted the INR checked and warfarin restarted at a lower dose when the INR returns to the therapeutic range. If the INR is above 5 but below 9, oral Vitamin K, should be considered if the patient is at excessive risk of bleeding.

32. Managing Patients with High INR Values/Serious Bleeding If the INR is between 9 and 20; oral Vitamin K1 should be administered in a dose of 2.5 mg. If the INR is >20 more aggressive measures should be used. Vitamin K should be administered by slow intravenous infusion over 10 minutes in a dose of at least 5�mg, an infusion of fresh frozen plasma and hospitalization should be considered, and the hematocrit checked for hidden bleeding. If the INR is excessively out of range and dose not make sense with the recent trend in INR results in individual patients, the clinician is advised to consider the possibility of laboratory error before a dose adjustment is made. In this case, it is optimal to repeat the INR before a dose change is made to verify the results. If there is serious bleeding, the patient should be hospitalized. Vitamin K should be administered by slow intravenous infusion over 10 minutes in a dose of 5�10 mg, an infusion of fresh frozen plasma should be given Prothrombin concentrate should be considered if bleeding is life-threatening. If the INR is between 9 and 20; oral Vitamin K1 should be administered in a dose of 2.5 mg. If the INR is >20 more aggressive measures should be used. Vitamin K should be administered by slow intravenous infusion over 10 minutes in a dose of at least 5�mg, an infusion of fresh frozen plasma and hospitalization should be considered, and the hematocrit checked for hidden bleeding. If the INR is excessively out of range and dose not make sense with the recent trend in INR results in individual patients, the clinician is advised to consider the possibility of laboratory error before a dose adjustment is made. In this case, it is optimal to repeat the INR before a dose change is made to verify the results. If there is serious bleeding, the patient should be hospitalized. Vitamin K should be administered by slow intravenous infusion over 10 minutes in a dose of 5�10 mg, an infusion of fresh frozen plasma should be given Prothrombin concentrate should be considered if bleeding is life-threatening.

33. Relationship Between INR and Efficacy/Safety Warfarin has a narrow therapeutic index Low-intensity treatment: Efficacy rapidly diminishes below INR 2.0* No efficacy below INR 1.5 High-intensity treatment: Safety compromised above INR 4 Warfarin has a narrow therapeutic window. Its efficacy is reduced if the INR is less than 2.0 and the risk of bleeding is increased when the INR exceeds 4.0. The clinician is advised not to over react to mildly elevated INRs (4�9) or to mildly reduced INRs (<2) unless there is a very high risk of bleeding or thrombosis in the individual patient. Most patients can be managed by watchful waiting and more frequent INRs to be certain it is not a transient result but a more persistent finding. Warfarin has a narrow therapeutic window. Its efficacy is reduced if the INR is less than 2.0 and the risk of bleeding is increased when the INR exceeds 4.0. The clinician is advised not to over react to mildly elevated INRs (4�9) or to mildly reduced INRs (<2) unless there is a very high risk of bleeding or thrombosis in the individual patient. Most patients can be managed by watchful waiting and more frequent INRs to be certain it is not a transient result but a more persistent finding.

34. Hylek, et al, studied the risk of intracranial hemorrhage in outpatients treated with warfarin. They determined that an intensity of anticoagulation expressed as a prothrombin time ratio (PTR) above 2.0 (roughly corresponding to an INR of 3.7 to 4.3) resulted in an increase in the risk of bleeding. Risk of Intracranial Hemorrhage in Outpatients The relationship between the incidence of intracranial bleeding and INR in warfarin-treated patients is shown in this slide. The risk (expressed as an odds ratio) increases dramatically with increasing INR levels. The relationship between the incidence of intracranial bleeding and INR in warfarin-treated patients is shown in this slide. The risk (expressed as an odds ratio) increases dramatically with increasing INR levels.

35. Lowest Effective Intensity for Warfarin Therapy for Stroke Prevention in Atrial Fibrillation The relationship between the risk of stroke anti INR in patients with atrial fibrillation treated with warfarin is shown on this slide. The risk of stroke increases dramatically when the INR falls below 2.0, although there appears to be some protection when the INR is above 1.5. The relationship between the risk of stroke anti INR in patients with atrial fibrillation treated with warfarin is shown on this slide. The risk of stroke increases dramatically when the INR falls below 2.0, although there appears to be some protection when the INR is above 1.5.

36. Indication INR Range Target Prophylaxis of venous thrombosis (high-risk surgery) 2.0�3.0 2.5 Treatment of venous thrombosis Treatment of PE Prevention of systemic embolism Tissue heart valves AMI (to prevent systemic embolism) Valvular heart disease Atrial fibrillation Mechanical prosthetic valves (high risk) 2.5�3.5 3.0 Certain patients with thrombosis and the antiphospholipid syndrome AMI (to prevent recurrent AMI) Bileaflet mechanical valve in aortic position, NSR 2.0�3.0 2.5 Warfarin: Current Indications/Intensity These indications and recommended intensities of treatment are derived from the Fifth American College of Chest Physicians Consensus Conference (1998). For most indications a therapeutic range of 2.0 to 3.0 is recommended. A higher INR range of 2.5 to 3.5 is recommended for parents with mechanical prosthetic valves and post myocardial infarction and for some patients with antiphospholipid syndrome and a history of thrombosis. These indications and recommended intensities of treatment are derived from the Fifth American College of Chest Physicians Consensus Conference (1998). For most indications a therapeutic range of 2.0 to 3.0 is recommended. A higher INR range of 2.5 to 3.5 is recommended for parents with mechanical prosthetic valves and post myocardial infarction and for some patients with antiphospholipid syndrome and a history of thrombosis.

37. Mechanical Prosthetic Heart Valves

38. Examples of Low & High Risk InvasiveProcedures & Clinical Conditions The above 2x2 table gives examples of various invasive procedures that represent either a low or high risk of bleeding on anticoagulants, and various clinical conditions that represent either a low or high risk of thromboembolism without anticoagulation. Thus, an individual who has a clinical condition with a high risk of thromboembolism and is undergoing a procedure with a low risk for bleeding would have that procedure performed under full warfarin anticoagulation (i.e., INR in therapeutic range), or perhaps with the anticoagulation reduced to the lower limits or just below the therapeutic range. The above 2x2 table gives examples of various invasive procedures that represent either a low or high risk of bleeding on anticoagulants, and various clinical conditions that represent either a low or high risk of thromboembolism without anticoagulation. Thus, an individual who has a clinical condition with a high risk of thromboembolism and is undergoing a procedure with a low risk for bleeding would have that procedure performed under full warfarin anticoagulation (i.e., INR in therapeutic range), or perhaps with the anticoagulation reduced to the lower limits or just below the therapeutic range.

39. Management of Warfarin for Invasive Procedures The management of patients who require warfarin therapy and who require surgical intervention is problematic. The risk and benefits, of stopping or continuing, anticoagulant therapy must be weighed. One must assess the risk of bleeding during the procedure versus the risk of thrombosis with a reduced level of anticoagulation. This 2x2 table describes a range of options for patients depending on the procedure and the bleeding risk and the patient�s risk of thrombosis. The next slide gives an example of a range of procedures that might be considered a low or high risk for bleeding and a range of conditions that would be considered a low or high risk for thromboembolism. For patients at low risk of bleeding, the procedure can be performed under warfarin cover, targeting subtherapeutic INR values when the risk of thrombosis is low and higher (even therapeutic) INR values when the risk of thrombosis is high. For patients at high risk of bleeding;. because of the procedure, warfarin should be discontinued four days before the procedure to ensure that the INR has returned to the normal range, and if at high risk for thrombosis, the patient can be covered with either full dose heparin or low dose heparin before and after the procedure. The management of patients who require warfarin therapy and who require surgical intervention is problematic. The risk and benefits, of stopping or continuing, anticoagulant therapy must be weighed. One must assess the risk of bleeding during the procedure versus the risk of thrombosis with a reduced level of anticoagulation. This 2x2 table describes a range of options for patients depending on the procedure and the bleeding risk and the patient�s risk of thrombosis. The next slide gives an example of a range of procedures that might be considered a low or high risk for bleeding and a range of conditions that would be considered a low or high risk for thromboembolism. For patients at low risk of bleeding, the procedure can be performed under warfarin cover, targeting subtherapeutic INR values when the risk of thrombosis is low and higher (even therapeutic) INR values when the risk of thrombosis is high. For patients at high risk of bleeding;. because of the procedure, warfarin should be discontinued four days before the procedure to ensure that the INR has returned to the normal range, and if at high risk for thrombosis, the patient can be covered with either full dose heparin or low dose heparin before and after the procedure.

40. Management of Warfarin During Invasive Procedures For subtherapeutic or normal INR: Hold warfarin for 3�5 days pre-procedure Low Dose Heparin (LDH): Low-dose heparin (5,000 IU SQ BID); hold warfarin 3�5 days pre-procedure and begin LDH therapy 1�2 days pre-procedure Adjusted Dose Heparin (AdjDH): Same as LDH but higher doses of heparin (between 8,000�10,000 IU BID or TID) to achieve an aPTT in upper range of normal or slightly higher midway between doses Full Dose Heparin (FDH): full doses of heparin, IV continuous infusion, to achieve a therapeutic aPTT (~1.5�2x control); implement as for LDH Restart heparin or warfarin post-op when considered safe to do so The details of stopping warfarin and introducing heparin are listed on this slide. Full dose heparin should be discontinued approximately 4 hours preoperatively to allow the APTT to fall to normal during the invasive procedure. Thereafter, heparin can be restarted when considered safe to do so depending on the procedure. Adjusted dose subcutaneous heparin or low dose subcutaneous heparin should be discontinued approximately 12 hours pre-procedure. The details of stopping warfarin and introducing heparin are listed on this slide. Full dose heparin should be discontinued approximately 4 hours preoperatively to allow the APTT to fall to normal during the invasive procedure. Thereafter, heparin can be restarted when considered safe to do so depending on the procedure. Adjusted dose subcutaneous heparin or low dose subcutaneous heparin should be discontinued approximately 12 hours pre-procedure.

41. Warfarin Dosing Schedule The half life of warfarin is about 40 hours and the half life of prothrombin is about 60 hours. Therefore there is a delay of 2 to 3 days before the full effects of alterations of warfarin dosing is reflected in the INR This slide provides an example of daily warfarin dosing to achieve weekly dosing of 35mg, 30mg and 27.5mg. Thus if the INR is excessive an a weekly dose of 35mg, the dose of warfarin can be reduced by 5 or 7.5 mg/week by altering the daily dosing as shown in rows two and three of the table. It is recommended to treat most patients with a single strength of warfarin tablet and to use multiples or fractions of that tablet on alternate days of the week for different dosing schemes. The half life of warfarin is about 40 hours and the half life of prothrombin is about 60 hours. Therefore there is a delay of 2 to 3 days before the full effects of alterations of warfarin dosing is reflected in the INR This slide provides an example of daily warfarin dosing to achieve weekly dosing of 35mg, 30mg and 27.5mg. Thus if the INR is excessive an a weekly dose of 35mg, the dose of warfarin can be reduced by 5 or 7.5 mg/week by altering the daily dosing as shown in rows two and three of the table. It is recommended to treat most patients with a single strength of warfarin tablet and to use multiples or fractions of that tablet on alternate days of the week for different dosing schemes.

42. Dosage Adjustment Algorithm This shows a dosage adjustment algorithm which has been used successfully in an anticoagulation clinic. This shows a dosage adjustment algorithm which has been used successfully in an anticoagulation clinic.

43. Drug Interactions with Warfarin: Potentiation This slide lists the various drugs that have been reported to interact with and potentate warfarin The strength of the evidence is shown in the left hand column with level I being strongest and level IV the weakest based on the study design of the report. This slide lists the various drugs that have been reported to interact with and potentate warfarin The strength of the evidence is shown in the left hand column with level I being strongest and level IV the weakest based on the study design of the report.

44. Drug Interactions with Warfarin: Inhibition This slide lists the various drugs and foods that have been reported to interact with and inhibit warfarin. The strength of the evidence is shown in the left hand column. This slide lists the various drugs and foods that have been reported to interact with and inhibit warfarin. The strength of the evidence is shown in the left hand column.

45. Drug Interactions with Warfarin: No Effect This slide lists the venous drugs and foods that have been reported to have no effect on warfarin The strength of the evidence is shown in the left hand column. With excessive consumption, alcohol potentiates the effect (Slide 33), but when limited to two glasses of wine /day, it has been reported not to influence the ant/coagulant effect of warfarin. This slide lists the venous drugs and foods that have been reported to have no effect on warfarin The strength of the evidence is shown in the left hand column. With excessive consumption, alcohol potentiates the effect (Slide 33), but when limited to two glasses of wine /day, it has been reported not to influence the ant/coagulant effect of warfarin.

46. Effective Patient Education Teach basic concepts of safe, effective anticoagulation Discuss importance of regular INR monitoring Counsel on use of other medications, alcohol Develop creative strategies for improving compliance

47. Factors Influencing Variability Maintaining patients within the therapeutic range (or �window�) can be complicated by numerous factors, which alone or in combination are a source of variability. For the sake of organization, these factors may be placed into three general categories. The patient and his/her disease state(s), the process of care that accompanies a given therapy such as education and monitoring, and the narrow therapeutic nature of the drug product itself. Maintaining patients within the therapeutic range (or �window�) can be complicated by numerous factors, which alone or in combination are a source of variability. For the sake of organization, these factors may be placed into three general categories. The patient and his/her disease state(s), the process of care that accompanies a given therapy such as education and monitoring, and the narrow therapeutic nature of the drug product itself.