Clinical and Applied Thrombosis/Hemostasis http://cat.sagepub.com/
Oral Anticoagulants and Status of Antidotes for the Reversal of Bleeding Risk Joseph Ebright and Shaker A. Mousa CLIN APPL THROMB HEMOST published online 12 August 2014 DOI: 10.1177/1076029614545211 The online version of this article can be found at: http://cat.sagepub.com/content/early/2014/07/31/1076029614545211
Published by: http://www.sagepublications.com
Additional services and information for Clinical and Applied Thrombosis/Hemostasis can be found at: Email Alerts: http://cat.sagepub.com/cgi/alerts Subscriptions: http://cat.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav Citations: http://cat.sagepub.com/content/early/2014/07/31/1076029614545211.refs.html
>> OnlineFirst Version of Record - Aug 12, 2014 What is This?
Downloaded from cat.sagepub.com at UNIV TORONTO on August 12, 2014
Review
Oral Anticoagulants and Status of Antidotes for the Reversal of Bleeding Risk
Clinical and Applied Thrombosis/Hemostasis 1-10 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1076029614545211 cat.sagepub.com
Joseph Ebright, PharmD1, and Shaker A. Mousa, PhD, MBA, FACC, FACB1
Abstract Anticoagulants have been used in clinical practice for more than 50 years. Their indications expand, as more people are diagnosed each year with atrial fibrillation and venous thromboembolism. Vitamin K antagonists have been the most popular choice due to their effectiveness and their ability to reverse bleeding using a known antidote; oral and intravenous vitamin K have long been known to reverse the effects of warfarin. With new classes of anticoagulants making their way onto the market, such as factor Xa inhibitors (rivaroxaban, apixaban) and direct thrombin inhibitors (dabigatran), the need for new reversal agents is paramount. Patients tend to be more receptive to these medications because they do not require routine blood monitoring, can be used at fixed doses, and do not have major drug or food interactions. Antidotes for these medications have shown promise in animal models and are currently in clinical trials. Keywords warfarin, vitamin K antagonist, factor Xa inhibitor, rivaroxaban, apixaban, direct thrombin inhibitor, dabigatran, prothrombin complex concentrate, vitamin K, fresh frozen plasma, andexanet alfa, bleeding, antidote, reversal agents
Introduction Oral anticoagulants have been used in clinical practice to prevent or treat venous thromboembolism (VTE) in patients with atrial fibrillation (AF) and in other thromboembolic disorders. The average annual incidence of VTE among caucasians is 108 per 100 000 person-years. This corresponds to approximately 250 000 cases occurring annually in the United States among caucasians.1 It is believed that the incidence of VTE is similar or even higher among African Americans and slightly lower among Asian Americans and Native Americans.1 The incidence of AF is expected to increase during the next decade. It is estimated that the current prevalence of AF is between 3 and 6 million Americans. This number is expected to rise to between 6 and 12 million by 2050.2,3 There are currently 4 oral anticoagulants available in the United States, comprising 3 unique classes of medications. Figure 1 shows a timeline of historical advances in the development of oral anticoagulants. It has been estimated by the Food and Drug Administration (FDA) that 2 million patients initiate warfarin therapy annually in the United States.3,4 Dabigatran, the first novel oral anticoagulant, is a direct thrombin inhibitor, and it was approved in October 2010 by the FDA. The final class is the factor Xa (FXa) inhibitors, which consist of rivaroxaban and apixaban, both approved by the FDA in late 2012. As a whole, oral anticoagulants are effective treatment options, but they also come with some inherent risk. Shifting the clotting cascade too far in either direction can lead to significant problems in patients. There
is evidence to suggest that clinically relevant nonmajor bleeding occurs at a rate of 18 per 100 patient-years, in a study comparing rivaroxaban and warfarin.5 Major bleeds also occur in approximately 0.5% to 3% of patients depending on definition and medication used.6,7
Warfarin Warfarin is an oral vitamin K antagonist (VKA) that works by blocking the regeneration of vitamin K epoxide, thus inhibiting the syntheses of vitamin K-dependent clotting factors, which include factors II, VII, IX, and X as well as the anticoagulant proteins C and S.8 It is indicated for a number of conditions, including prophylaxis and treatment of VTE, including pulmonary embolism (PE), prophylaxis, and treatment of thromboembolic complications associated with AF and/or cardiac valve replacement, and reducing the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction.7 Although effective, warfarin comes with a number of 1
The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USA
Corresponding Author: Shaker A. Mousa, The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, 1 Discovery Drive, Rensselaer, NY 12144, USA. Email: [email protected]
Downloaded from cat.sagepub.com at UNIV TORONTO on August 12, 2014
2
Clinical and Applied Thrombosis/Hemostasis
Figure 1. Advances in oral anticoagulation from 1940 to present. There are currently 3 broad classes (vitamin K antagonists, anti-IIa, and anti-Xa) of oral anticoagulants available in the United States. Individual agents are warfarin, dabigatran, rivaroxaban, and apixaban. Table 1. 2012 American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines.18 INR Level and Presence of Bleed
Recommendation
Evidence Level
INR 4.5-10 and no evidence of bleed INR >10 and no evidence of bleed Major bleeding
Suggest against the use of vitamin K Suggest oral vitamin K be administered Rapid reversal with 4-factor PCC rather than plasma Suggest additional use of vitamin K 5-10 mg by slow IV injection
2B 2C 2C 2C
Abbreviations: INR, international normalized ratio; IV, intravenous; PCC, prothrombin complex concentrate; 2B, weak recommendation, moderate-quality evidence; 2C, weak recommendation, low- or very low-quality evidence.
limitations. Warfarin is a narrow therapeutic medication that requires the individualization of doses for each patient according to their international normalized ratio (INR) and indication, although a general range is 2.0 to 3.0.9 It typically takes 4 to 5 days for a patient to become therapeutic on warfarin. In addition, due to the drug’s mechanism of action, it is susceptible to a number of food and drug interactions. For example, green leafy vegetables contain a significant amount of vitamin K that can alter the clotting cascade in patients. It is always important to counsel all patients on the importance of eating a balanced, consistent diet. Warfarin is highly water soluble, is rapidly absorbed from the gastrointestinal tract, has high bioavailability, and reaches maximal blood concentrations about 90 minutes after oral administration.10,11 It is highly protein bound with a half-life of 36 to 42 hours12 and is highly metabolized by cytochrome P (CYP) 2C9 and CYP3A4.13 The risk of bleeding is a major concern in all warfarintreated patients. According to a meta-analysis, patients were
in therapeutic range only 63.6% of the time.14 According to the package insert from Bristol-Myers Squibb, the rate of major bleeding in warfarin-treated patients is between 0.6% and 2.7%.15 There are a number of factors that predispose patients to bleeding episodes. The most important factor is the intensity of anticoagulant therapy.13,16,17 Patients with a higher goal INR are more likely to develop a bleed than those with a conservative number. It is important to set a reasonable target range depending on the indication trying to be reached (not discussed here) and the specific patient. There are a number of other risk factors for developing a bleed including advanced age, cancer, renal or hepatic dysfunction, alcohol abuse, stroke, a history of bleeding, or concomitant use of other therapies including antiplatelet drugs. If a patient presents requiring anticoagulant reversal, there are a few medications and strategies that can be used. The American College of Chest Physicians guidelines (Table 1) outline the treatment options depending on the patient who
Downloaded from cat.sagepub.com at UNIV TORONTO on August 12, 2014
Ebright and Mousa
3
presents.18 Withholding 1 or more doses is an effective option in patients who are not actively bleeding. These patients may present for an elective procedure or only with an elevated INR and low risk of bleeding. It is important for patients to know that their INR will remain elevated for a couple of days, and during that time there will be an increased risk of bleeding. Reporting any signs and symptoms of bleeding immediately is important. If withholding doses is not enough, the patient can be supplemented with oral or intravenous (IV) vitamin K. Other products available include fresh frozen plasma (FFP), 3-factor prothrombin complex concentrate (3-F PCC), and 4-factor prothrombin complex concentrate (4-F PCC). There are a number of differences between these 3 products. Fresh frozen plasma is obtained by either separation of supernatant plasma from a whole blood donation or an apheresis technique. The plasma must be frozen within 8 hours to preserve factors V and VIII. Fresh frozen plasma must be stored at 18 C in order to maintain its effectiveness. Prior to administration, FFP must be thawed at 37 C.19 The main difference between the 3-F PCC and 4-F PCC is the addition of factor VII in meaningful amounts. Factor VII has the shortest half-life, 4 to 6 hours, and when replaced is able to return a patient’s INR to nearnormal levels.
Vitamin K Vitamin K or phytonadione has been used for warfarin reversal for many years. It is available orally, subcutaneously, and intravenously. It is currently not recommended to use subcutaneous vitamin K because the response is rather unpredictable and may be delayed. Oral vitamin K is an effective treatment option for patients who do not require rapid reversal. It is safe, effective, and more convenient than parenteral routes. The limitation for oral vitamin K is that it lowers INR within 24 to 48 hours.20 A randomized, placebo-controlled trial evaluated withholding the dose versus oral phytonadione þ withholding the dose for patients with excessive anticoagulation. This study looked at 30 nonbleeding patients with INRs of 6 to 10. The mean calculated time to reach an INR of 4.0 was significantly greater in the placebo group than in the phytonadione group (2.6 vs 1.4 days, P ¼ .006). Adding oral vitamin K to patients with elevated INRs is able to reduce the patients’ INR level more rapidly than withholding the dose alone.21 It is important to continue to monitor the patient’s INR because warfarin has a much longer duration of action than vitamin K. In cases of extreme overdose or ongoing bleeds, it may be necessary to readminister vitamin K.20 Vitamin K administered intravenously can effectively lower the patient’s INR more rapidly than oral vitamin K, within 12 to 14 hours. There have been head-to-head comparison trials between the oral and the IV agents. In one study of patients presenting with a baseline INR of 6 to 10, the decline was significantly more rapid in the IV group. At 12 hours, the IV group reached a mean INR of 3.8 + 1.4, while the oral group had an INR of 4.4 + 1.1 at 12 hours. At 24 hours, there
was no longer a statistical difference; the IV group had a mean INR of 2.6 + 0.8 compared with 2.9 + 0.8 for the oral group. This suggests that IV vitamin K is able to provide a more rapid reversal, but over time, the results do not differ.22
Fresh Frozen Plasma and PCCs For patients presenting with acute bleeds, it will not be possible to wait for oral or even IV vitamin K to start working. These patients require immediate supplementation with coagulation factors to assist in stopping the bleed. Fresh frozen plasma remains the most widely used coagulation factor replacement product for urgent reversal of warfarin anticoagulation.23 It contains all coagulation factors in their normal amounts, which limit the risk of thrombosis. However, there are a number of limitations with this product as outlined in Table 2. There is an administration delay due to the need to thaw it and the need for FFP to be ABO matched to the patient, it has a slow onset (13-48 hours), and patients are at risk of fluid overload, infectious disease, allergic reactions, and transfusion-related acute lung injury.24,25 Prothrombin complex concentrates do not require ABO matching, and they have a smaller volume of administration, faster onset, faster time to lower INR, and are probably more effective. These products do come with an increased risk of thrombosis, and 4-F PCC is contraindicated in patients with recent heparin-induced thrombocytopenia. The 4-F PCC was approved in the United States in April 2013, although it has been used in Europe for years.25-29 Although 3-F PCC is not approved for use in this patient population, there is some evidence to suggest it can be an effective treatment option for patients requiring rapid INR reversal during an acute bleeding episode. One trial conducted by Chapman et al compared 3-F PCC þ FFP þ vitamin K versus FFP þ vitamin K to determine whether the addition of 3-F PCC could rapidly correct the INR. The percentage of patients who reached goal INR (
Oral Anticoagulants and Status of Antidotes for the Reversal of Bleeding Risk Joseph Ebright and Shaker A. Mousa CLIN APPL THROMB HEMOST published online 12 August 2014 DOI: 10.1177/1076029614545211 The online version of this article can be found at: http://cat.sagepub.com/content/early/2014/07/31/1076029614545211
Published by: http://www.sagepublications.com
Additional services and information for Clinical and Applied Thrombosis/Hemostasis can be found at: Email Alerts: http://cat.sagepub.com/cgi/alerts Subscriptions: http://cat.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav Citations: http://cat.sagepub.com/content/early/2014/07/31/1076029614545211.refs.html
>> OnlineFirst Version of Record - Aug 12, 2014 What is This?
Downloaded from cat.sagepub.com at UNIV TORONTO on August 12, 2014
Review
Oral Anticoagulants and Status of Antidotes for the Reversal of Bleeding Risk
Clinical and Applied Thrombosis/Hemostasis 1-10 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1076029614545211 cat.sagepub.com
Joseph Ebright, PharmD1, and Shaker A. Mousa, PhD, MBA, FACC, FACB1
Abstract Anticoagulants have been used in clinical practice for more than 50 years. Their indications expand, as more people are diagnosed each year with atrial fibrillation and venous thromboembolism. Vitamin K antagonists have been the most popular choice due to their effectiveness and their ability to reverse bleeding using a known antidote; oral and intravenous vitamin K have long been known to reverse the effects of warfarin. With new classes of anticoagulants making their way onto the market, such as factor Xa inhibitors (rivaroxaban, apixaban) and direct thrombin inhibitors (dabigatran), the need for new reversal agents is paramount. Patients tend to be more receptive to these medications because they do not require routine blood monitoring, can be used at fixed doses, and do not have major drug or food interactions. Antidotes for these medications have shown promise in animal models and are currently in clinical trials. Keywords warfarin, vitamin K antagonist, factor Xa inhibitor, rivaroxaban, apixaban, direct thrombin inhibitor, dabigatran, prothrombin complex concentrate, vitamin K, fresh frozen plasma, andexanet alfa, bleeding, antidote, reversal agents
Introduction Oral anticoagulants have been used in clinical practice to prevent or treat venous thromboembolism (VTE) in patients with atrial fibrillation (AF) and in other thromboembolic disorders. The average annual incidence of VTE among caucasians is 108 per 100 000 person-years. This corresponds to approximately 250 000 cases occurring annually in the United States among caucasians.1 It is believed that the incidence of VTE is similar or even higher among African Americans and slightly lower among Asian Americans and Native Americans.1 The incidence of AF is expected to increase during the next decade. It is estimated that the current prevalence of AF is between 3 and 6 million Americans. This number is expected to rise to between 6 and 12 million by 2050.2,3 There are currently 4 oral anticoagulants available in the United States, comprising 3 unique classes of medications. Figure 1 shows a timeline of historical advances in the development of oral anticoagulants. It has been estimated by the Food and Drug Administration (FDA) that 2 million patients initiate warfarin therapy annually in the United States.3,4 Dabigatran, the first novel oral anticoagulant, is a direct thrombin inhibitor, and it was approved in October 2010 by the FDA. The final class is the factor Xa (FXa) inhibitors, which consist of rivaroxaban and apixaban, both approved by the FDA in late 2012. As a whole, oral anticoagulants are effective treatment options, but they also come with some inherent risk. Shifting the clotting cascade too far in either direction can lead to significant problems in patients. There
is evidence to suggest that clinically relevant nonmajor bleeding occurs at a rate of 18 per 100 patient-years, in a study comparing rivaroxaban and warfarin.5 Major bleeds also occur in approximately 0.5% to 3% of patients depending on definition and medication used.6,7
Warfarin Warfarin is an oral vitamin K antagonist (VKA) that works by blocking the regeneration of vitamin K epoxide, thus inhibiting the syntheses of vitamin K-dependent clotting factors, which include factors II, VII, IX, and X as well as the anticoagulant proteins C and S.8 It is indicated for a number of conditions, including prophylaxis and treatment of VTE, including pulmonary embolism (PE), prophylaxis, and treatment of thromboembolic complications associated with AF and/or cardiac valve replacement, and reducing the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction.7 Although effective, warfarin comes with a number of 1
The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USA
Corresponding Author: Shaker A. Mousa, The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, 1 Discovery Drive, Rensselaer, NY 12144, USA. Email: [email protected]
Downloaded from cat.sagepub.com at UNIV TORONTO on August 12, 2014
2
Clinical and Applied Thrombosis/Hemostasis
Figure 1. Advances in oral anticoagulation from 1940 to present. There are currently 3 broad classes (vitamin K antagonists, anti-IIa, and anti-Xa) of oral anticoagulants available in the United States. Individual agents are warfarin, dabigatran, rivaroxaban, and apixaban. Table 1. 2012 American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines.18 INR Level and Presence of Bleed
Recommendation
Evidence Level
INR 4.5-10 and no evidence of bleed INR >10 and no evidence of bleed Major bleeding
Suggest against the use of vitamin K Suggest oral vitamin K be administered Rapid reversal with 4-factor PCC rather than plasma Suggest additional use of vitamin K 5-10 mg by slow IV injection
2B 2C 2C 2C
Abbreviations: INR, international normalized ratio; IV, intravenous; PCC, prothrombin complex concentrate; 2B, weak recommendation, moderate-quality evidence; 2C, weak recommendation, low- or very low-quality evidence.
limitations. Warfarin is a narrow therapeutic medication that requires the individualization of doses for each patient according to their international normalized ratio (INR) and indication, although a general range is 2.0 to 3.0.9 It typically takes 4 to 5 days for a patient to become therapeutic on warfarin. In addition, due to the drug’s mechanism of action, it is susceptible to a number of food and drug interactions. For example, green leafy vegetables contain a significant amount of vitamin K that can alter the clotting cascade in patients. It is always important to counsel all patients on the importance of eating a balanced, consistent diet. Warfarin is highly water soluble, is rapidly absorbed from the gastrointestinal tract, has high bioavailability, and reaches maximal blood concentrations about 90 minutes after oral administration.10,11 It is highly protein bound with a half-life of 36 to 42 hours12 and is highly metabolized by cytochrome P (CYP) 2C9 and CYP3A4.13 The risk of bleeding is a major concern in all warfarintreated patients. According to a meta-analysis, patients were
in therapeutic range only 63.6% of the time.14 According to the package insert from Bristol-Myers Squibb, the rate of major bleeding in warfarin-treated patients is between 0.6% and 2.7%.15 There are a number of factors that predispose patients to bleeding episodes. The most important factor is the intensity of anticoagulant therapy.13,16,17 Patients with a higher goal INR are more likely to develop a bleed than those with a conservative number. It is important to set a reasonable target range depending on the indication trying to be reached (not discussed here) and the specific patient. There are a number of other risk factors for developing a bleed including advanced age, cancer, renal or hepatic dysfunction, alcohol abuse, stroke, a history of bleeding, or concomitant use of other therapies including antiplatelet drugs. If a patient presents requiring anticoagulant reversal, there are a few medications and strategies that can be used. The American College of Chest Physicians guidelines (Table 1) outline the treatment options depending on the patient who
Downloaded from cat.sagepub.com at UNIV TORONTO on August 12, 2014
Ebright and Mousa
3
presents.18 Withholding 1 or more doses is an effective option in patients who are not actively bleeding. These patients may present for an elective procedure or only with an elevated INR and low risk of bleeding. It is important for patients to know that their INR will remain elevated for a couple of days, and during that time there will be an increased risk of bleeding. Reporting any signs and symptoms of bleeding immediately is important. If withholding doses is not enough, the patient can be supplemented with oral or intravenous (IV) vitamin K. Other products available include fresh frozen plasma (FFP), 3-factor prothrombin complex concentrate (3-F PCC), and 4-factor prothrombin complex concentrate (4-F PCC). There are a number of differences between these 3 products. Fresh frozen plasma is obtained by either separation of supernatant plasma from a whole blood donation or an apheresis technique. The plasma must be frozen within 8 hours to preserve factors V and VIII. Fresh frozen plasma must be stored at 18 C in order to maintain its effectiveness. Prior to administration, FFP must be thawed at 37 C.19 The main difference between the 3-F PCC and 4-F PCC is the addition of factor VII in meaningful amounts. Factor VII has the shortest half-life, 4 to 6 hours, and when replaced is able to return a patient’s INR to nearnormal levels.
Vitamin K Vitamin K or phytonadione has been used for warfarin reversal for many years. It is available orally, subcutaneously, and intravenously. It is currently not recommended to use subcutaneous vitamin K because the response is rather unpredictable and may be delayed. Oral vitamin K is an effective treatment option for patients who do not require rapid reversal. It is safe, effective, and more convenient than parenteral routes. The limitation for oral vitamin K is that it lowers INR within 24 to 48 hours.20 A randomized, placebo-controlled trial evaluated withholding the dose versus oral phytonadione þ withholding the dose for patients with excessive anticoagulation. This study looked at 30 nonbleeding patients with INRs of 6 to 10. The mean calculated time to reach an INR of 4.0 was significantly greater in the placebo group than in the phytonadione group (2.6 vs 1.4 days, P ¼ .006). Adding oral vitamin K to patients with elevated INRs is able to reduce the patients’ INR level more rapidly than withholding the dose alone.21 It is important to continue to monitor the patient’s INR because warfarin has a much longer duration of action than vitamin K. In cases of extreme overdose or ongoing bleeds, it may be necessary to readminister vitamin K.20 Vitamin K administered intravenously can effectively lower the patient’s INR more rapidly than oral vitamin K, within 12 to 14 hours. There have been head-to-head comparison trials between the oral and the IV agents. In one study of patients presenting with a baseline INR of 6 to 10, the decline was significantly more rapid in the IV group. At 12 hours, the IV group reached a mean INR of 3.8 + 1.4, while the oral group had an INR of 4.4 + 1.1 at 12 hours. At 24 hours, there
was no longer a statistical difference; the IV group had a mean INR of 2.6 + 0.8 compared with 2.9 + 0.8 for the oral group. This suggests that IV vitamin K is able to provide a more rapid reversal, but over time, the results do not differ.22
Fresh Frozen Plasma and PCCs For patients presenting with acute bleeds, it will not be possible to wait for oral or even IV vitamin K to start working. These patients require immediate supplementation with coagulation factors to assist in stopping the bleed. Fresh frozen plasma remains the most widely used coagulation factor replacement product for urgent reversal of warfarin anticoagulation.23 It contains all coagulation factors in their normal amounts, which limit the risk of thrombosis. However, there are a number of limitations with this product as outlined in Table 2. There is an administration delay due to the need to thaw it and the need for FFP to be ABO matched to the patient, it has a slow onset (13-48 hours), and patients are at risk of fluid overload, infectious disease, allergic reactions, and transfusion-related acute lung injury.24,25 Prothrombin complex concentrates do not require ABO matching, and they have a smaller volume of administration, faster onset, faster time to lower INR, and are probably more effective. These products do come with an increased risk of thrombosis, and 4-F PCC is contraindicated in patients with recent heparin-induced thrombocytopenia. The 4-F PCC was approved in the United States in April 2013, although it has been used in Europe for years.25-29 Although 3-F PCC is not approved for use in this patient population, there is some evidence to suggest it can be an effective treatment option for patients requiring rapid INR reversal during an acute bleeding episode. One trial conducted by Chapman et al compared 3-F PCC þ FFP þ vitamin K versus FFP þ vitamin K to determine whether the addition of 3-F PCC could rapidly correct the INR. The percentage of patients who reached goal INR (
