Just Accepted by Current Medical Research & Opinion Review The current landscape of treatment options for venous thromboembolism: a focus on novel oral anticoagulants Russell D. Hull, MBBS, MSc, and Meryl Gersh, PhD doi: 10.1185/03007995.2014.975786
Curr Med Res Opin Downloaded from informahealthcare.com by University of Auckland on 10/16/14. For personal use only.
Abstract Background: Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a major cause of morbidity, mortality, and healthcare expenditure. Anticoagulant therapy is recommended for at least 3 months in patients with acute VTE and to prevent recurrence. Conventional anticoagulants are associated with inherent limitations including route of administration, required monitoring and dose adjustments, potential for food-drug and drug-drug interactions, unpredictable pharmacokinetics and pharmacodynamics, and possible severe adverse events. Scope: This manuscript reviews the pharmacology of the novel oral anticoagulants (NOACs), and analyzes the differences in phase 3 clinical trial designs, outcomes, and specific patient populations investigated for the treatment of acute and prevention of secondary VTE. Methods: A literature search was performed in PubMed using the key words dabigatran, apixaban, rivaroxaban, edoxaban, and venous thromboembolism in PubMed. The search included all years, English language, and peer-reviewed articles relating to phase 3 clinical trials, subanalyses, and meta analyses of these NOACs for the treatment of acute VTE and secondary prevention. Findings: NOACs have demonstrated comparable efficacy and comparable or superior safety safety in large, randomized clinical trials in the treatment and prevention of VTE compared with conventional therapy. New oral anticoagulants, including the direct thrombin (dabigatran etexilate) and direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban), have advantages over conventional agents such as oral administration at fixed doses, predictable pharmacokinetics and pharmacodynamics, minimal potential for food-drug and drug-drug interactions, and lack of required monitoring. Conclusions: NOACs offer additional oral anticoagulation treatment options for patients with VTE.
© 2014 Informa UK Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
REVIEW The current landscape of treatment options for venous thromboembolism: a focus on novel oral anticoagulants
Russell D. Hull, MBBS, MSc1, and Meryl Gersh, PhD2
Curr Med Res Opin Downloaded from informahealthcare.com by University of Auckland on 10/16/14. For personal use only.
1
University of Calgary, Calgary, Alberta, CA; 2AlphaBioCom, LLC, King of Prussia, PA, USA
Address for correspondence: Dr. Russell D. Hull University of Calgary Foothills Hospital 1403-29 Street N.W. Calgary, Alberta T2N 2T9, Canada Tel.: +1 403 944 8052, Fax: +1 403 270 7891 [email protected] Key words: New oral anticoagulants, direct thrombin inhibitor, direct factor Xa inhibitor, venous thromboembolism, deep vein thrombosis, pulmonary embolism
[Short title: Treatment options for venous thromboembolism]
ABSTRACT Background: Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a major cause of morbidity, mortality, and healthcare expenditure. Anticoagulant therapy is recommended for at least 3 months in patients with acute VTE and to prevent recurrence. Conventional anticoagulants are associated with inherent limitations including route of administration, required monitoring and dose adjustments, potential for fooddrug and drug-drug interactions, unpredictable pharmacokinetics and pharmacodynamics, and possible severe adverse events.
1
Scope: This manuscript reviews the pharmacology of the novel oral anticoagulants (NOACs), and analyzes the differences in phase 3 clinical trial designs, outcomes, and specific patient populations investigated for the treatment of acute and prevention of secondary VTE.
Curr Med Res Opin Downloaded from informahealthcare.com by University of Auckland on 10/16/14. For personal use only.
Methods: A literature search was performed in PubMed using the key words dabigatran, apixaban, rivaroxaban, edoxaban, and venous thromboembolism in PubMed. The search included all years, English language, and peer-reviewed articles relating to phase 3 clinical trials, subanalyses, and meta analyses of these NOACs for the treatment of acute VTE and secondary prevention. Findings: NOACs have demonstrated comparable efficacy and comparable or superior safety safety in large, randomized clinical trials in the treatment and prevention of VTE compared with conventional therapy. New oral anticoagulants, including the direct thrombin (dabigatran etexilate) and direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban), have advantages over conventional agents such as oral administration at fixed doses, predictable pharmacokinetics and pharmacodynamics, minimal potential for food-drug and drug-drug interactions, and lack of required monitoring. Conclusions: NOACs offer additional oral anticoagulation treatment options for patients with VTE.
INTRODUCTION Venous thromboembolism (VTE) is a major cause of morbidity, mortality, and healthcare expenditure. VTE includes deep vein thrombosis (DVT) and pulmonary embolism (PE). Guidelines recommend that patients who experience a DVT should receive anticoagulant therapy for at least 3 months in order to prevent recurrence1, 2. Treatment of VTE can be divided into 3 phases; acute, defined as the first 5-10 days; long-term, extending for 3-6 months; and extended, lasting beyond 6 months. Current guidelines for acute treatment call for treatment with therapeutic doses of unfractionated heparin, low molecular weight heparin, (LMWH), fondaparinux, or rivaroxaban in patients with DVT, and initial treatment with parenteral anticoagulation, and potentially thrombolytic therapy for patients with PE. Current recommendations for extended and long-term treatment call for anticoagulation with vitamin K antagonists, dabigatran, or rivaroxaban1, 2. Conventional anticoagulants including unfractionated heparin (UFH), LMWHs, fondaparinux, and vitamin K antagonists (VKAs) are associated with significant drawbacks such as unpredictable pharmacokinetics (PK) and pharmacodynamics (PD), parenteral administration, routine monitoring, potential for significant drug-drug or drug-food interactions, and potential 2
Curr Med Res Opin Downloaded from informahealthcare.com by University of Auckland on 10/16/14. For personal use only.
for serious adverse reactions. Novel oral anticoagulants (NOACs) that have been studied for efficacy and safety in the treatment of acute VTE and prevention of recurrence include the direct thrombin inhibitor (dabigatran etexilate) and direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) in phase 3 clinical trials. NOACs may be valuable options for anticoagulant therapy in patients with acute VTE. This article will review the pharmacology of the NOACs and analyze the differences in phase 3 clinical trial designs, outcomes, and specific patient populations investigated, with the goal of providing practitioners one source of information to aid in making clinical practice decisions. CONVENTIONAL ANTICOAGULANTS Unfractionated heparin The anticoagulant effect of UFH, a glycosaminoglycan, is due to a distinctive pentasaccharide with a high binding affinity for antithrombin III that is present in about one-third of heparin molecules.3 When bound, UFH increases the ability of antithrombin III to inactivate thrombin, factor Xa, and factor IXa. Unfractionated heparin is administered by subcutaneous or intravenous injection. Monitoring of the activated partial thromboplastin time (aPTT) is required to assess the anticoagulant effect of UFH4. The American College of Chest Physicians’ (ACCP) and the International Consensus Statement guidelines for the treatment of VTE1, 2 recommend UFH as an option for initial treatment of patients with DVT for at least 5 days. Clinical guidelines such as these are intended to improve the quality of health care, decrease costs, and standardize practices, and are used by physicians, hospitals, and others to make decisions regarding patient treatment and care. The recommendation for the use of UFH is based on a high level of evidence according to the International Consensus Statement and is a strong recommendation based on moderate-quality evidence from the ACCP. Initial UFH treatment in VTE affects the long-term outcome of therapy, and early therapeutic anticoagulation has been associated with reduced mortality5. For example, in a study of 400 patients with acute PE, patients who achieved therapeutic aPTT within 24 hours had lower in-hospital (1.5% vs. 5.6%; P=0.093) and 30-day (5.6% vs. 14.8%; P=0.037) mortality as compared with patients who achieved a therapeutic aPTT after 24 hours6. UFH therapy is associated with a risk of developing heparin-induced thrombocytopenia and, with long-term therapy, osteoporosis4. Low-molecular weight heparins Low-molecular weight heparins are derived from UFH by chemical or enzymatic depolymerization and are one-third the molecular weight of UFH4. Low-molecular weight heparins are administered by subcutaneous injection and produce a more predictable anticoagulant response than UFH because of a reduced affinity for binding to proteins and cells other than antithrombin and a reduced ability to inactivate thrombin. Short-term LMWH therapy is seldom associated with thrombocytopenia7. Routine coagulation monitoring is not usually required but may be necessary in certain patient populations such as the obese and or among 3
Curr Med Res Opin Downloaded from informahealthcare.com by University of Auckland on 10/16/14. For personal use only.
patients with renal insufficiency. Low molecular weight heparin therapy is recommended over UFH therapy for the initial treatment of VTE by both ACCP guidelines (weak recommendation) and the International Consensus Statement, and should be administered for at least 5 days1, 2. In a systematic review, LMWH therapy was associated with a favorable improvement in clot-burden compared with UFH (relative risk 0.82; 95% confidence interval [CI], 0.76 to 0.88; P
Curr Med Res Opin Downloaded from informahealthcare.com by University of Auckland on 10/16/14. For personal use only.
Abstract Background: Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a major cause of morbidity, mortality, and healthcare expenditure. Anticoagulant therapy is recommended for at least 3 months in patients with acute VTE and to prevent recurrence. Conventional anticoagulants are associated with inherent limitations including route of administration, required monitoring and dose adjustments, potential for food-drug and drug-drug interactions, unpredictable pharmacokinetics and pharmacodynamics, and possible severe adverse events. Scope: This manuscript reviews the pharmacology of the novel oral anticoagulants (NOACs), and analyzes the differences in phase 3 clinical trial designs, outcomes, and specific patient populations investigated for the treatment of acute and prevention of secondary VTE. Methods: A literature search was performed in PubMed using the key words dabigatran, apixaban, rivaroxaban, edoxaban, and venous thromboembolism in PubMed. The search included all years, English language, and peer-reviewed articles relating to phase 3 clinical trials, subanalyses, and meta analyses of these NOACs for the treatment of acute VTE and secondary prevention. Findings: NOACs have demonstrated comparable efficacy and comparable or superior safety safety in large, randomized clinical trials in the treatment and prevention of VTE compared with conventional therapy. New oral anticoagulants, including the direct thrombin (dabigatran etexilate) and direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban), have advantages over conventional agents such as oral administration at fixed doses, predictable pharmacokinetics and pharmacodynamics, minimal potential for food-drug and drug-drug interactions, and lack of required monitoring. Conclusions: NOACs offer additional oral anticoagulation treatment options for patients with VTE.
© 2014 Informa UK Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
REVIEW The current landscape of treatment options for venous thromboembolism: a focus on novel oral anticoagulants
Russell D. Hull, MBBS, MSc1, and Meryl Gersh, PhD2
Curr Med Res Opin Downloaded from informahealthcare.com by University of Auckland on 10/16/14. For personal use only.
1
University of Calgary, Calgary, Alberta, CA; 2AlphaBioCom, LLC, King of Prussia, PA, USA
Address for correspondence: Dr. Russell D. Hull University of Calgary Foothills Hospital 1403-29 Street N.W. Calgary, Alberta T2N 2T9, Canada Tel.: +1 403 944 8052, Fax: +1 403 270 7891 [email protected] Key words: New oral anticoagulants, direct thrombin inhibitor, direct factor Xa inhibitor, venous thromboembolism, deep vein thrombosis, pulmonary embolism
[Short title: Treatment options for venous thromboembolism]
ABSTRACT Background: Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a major cause of morbidity, mortality, and healthcare expenditure. Anticoagulant therapy is recommended for at least 3 months in patients with acute VTE and to prevent recurrence. Conventional anticoagulants are associated with inherent limitations including route of administration, required monitoring and dose adjustments, potential for fooddrug and drug-drug interactions, unpredictable pharmacokinetics and pharmacodynamics, and possible severe adverse events.
1
Scope: This manuscript reviews the pharmacology of the novel oral anticoagulants (NOACs), and analyzes the differences in phase 3 clinical trial designs, outcomes, and specific patient populations investigated for the treatment of acute and prevention of secondary VTE.
Curr Med Res Opin Downloaded from informahealthcare.com by University of Auckland on 10/16/14. For personal use only.
Methods: A literature search was performed in PubMed using the key words dabigatran, apixaban, rivaroxaban, edoxaban, and venous thromboembolism in PubMed. The search included all years, English language, and peer-reviewed articles relating to phase 3 clinical trials, subanalyses, and meta analyses of these NOACs for the treatment of acute VTE and secondary prevention. Findings: NOACs have demonstrated comparable efficacy and comparable or superior safety safety in large, randomized clinical trials in the treatment and prevention of VTE compared with conventional therapy. New oral anticoagulants, including the direct thrombin (dabigatran etexilate) and direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban), have advantages over conventional agents such as oral administration at fixed doses, predictable pharmacokinetics and pharmacodynamics, minimal potential for food-drug and drug-drug interactions, and lack of required monitoring. Conclusions: NOACs offer additional oral anticoagulation treatment options for patients with VTE.
INTRODUCTION Venous thromboembolism (VTE) is a major cause of morbidity, mortality, and healthcare expenditure. VTE includes deep vein thrombosis (DVT) and pulmonary embolism (PE). Guidelines recommend that patients who experience a DVT should receive anticoagulant therapy for at least 3 months in order to prevent recurrence1, 2. Treatment of VTE can be divided into 3 phases; acute, defined as the first 5-10 days; long-term, extending for 3-6 months; and extended, lasting beyond 6 months. Current guidelines for acute treatment call for treatment with therapeutic doses of unfractionated heparin, low molecular weight heparin, (LMWH), fondaparinux, or rivaroxaban in patients with DVT, and initial treatment with parenteral anticoagulation, and potentially thrombolytic therapy for patients with PE. Current recommendations for extended and long-term treatment call for anticoagulation with vitamin K antagonists, dabigatran, or rivaroxaban1, 2. Conventional anticoagulants including unfractionated heparin (UFH), LMWHs, fondaparinux, and vitamin K antagonists (VKAs) are associated with significant drawbacks such as unpredictable pharmacokinetics (PK) and pharmacodynamics (PD), parenteral administration, routine monitoring, potential for significant drug-drug or drug-food interactions, and potential 2
Curr Med Res Opin Downloaded from informahealthcare.com by University of Auckland on 10/16/14. For personal use only.
for serious adverse reactions. Novel oral anticoagulants (NOACs) that have been studied for efficacy and safety in the treatment of acute VTE and prevention of recurrence include the direct thrombin inhibitor (dabigatran etexilate) and direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) in phase 3 clinical trials. NOACs may be valuable options for anticoagulant therapy in patients with acute VTE. This article will review the pharmacology of the NOACs and analyze the differences in phase 3 clinical trial designs, outcomes, and specific patient populations investigated, with the goal of providing practitioners one source of information to aid in making clinical practice decisions. CONVENTIONAL ANTICOAGULANTS Unfractionated heparin The anticoagulant effect of UFH, a glycosaminoglycan, is due to a distinctive pentasaccharide with a high binding affinity for antithrombin III that is present in about one-third of heparin molecules.3 When bound, UFH increases the ability of antithrombin III to inactivate thrombin, factor Xa, and factor IXa. Unfractionated heparin is administered by subcutaneous or intravenous injection. Monitoring of the activated partial thromboplastin time (aPTT) is required to assess the anticoagulant effect of UFH4. The American College of Chest Physicians’ (ACCP) and the International Consensus Statement guidelines for the treatment of VTE1, 2 recommend UFH as an option for initial treatment of patients with DVT for at least 5 days. Clinical guidelines such as these are intended to improve the quality of health care, decrease costs, and standardize practices, and are used by physicians, hospitals, and others to make decisions regarding patient treatment and care. The recommendation for the use of UFH is based on a high level of evidence according to the International Consensus Statement and is a strong recommendation based on moderate-quality evidence from the ACCP. Initial UFH treatment in VTE affects the long-term outcome of therapy, and early therapeutic anticoagulation has been associated with reduced mortality5. For example, in a study of 400 patients with acute PE, patients who achieved therapeutic aPTT within 24 hours had lower in-hospital (1.5% vs. 5.6%; P=0.093) and 30-day (5.6% vs. 14.8%; P=0.037) mortality as compared with patients who achieved a therapeutic aPTT after 24 hours6. UFH therapy is associated with a risk of developing heparin-induced thrombocytopenia and, with long-term therapy, osteoporosis4. Low-molecular weight heparins Low-molecular weight heparins are derived from UFH by chemical or enzymatic depolymerization and are one-third the molecular weight of UFH4. Low-molecular weight heparins are administered by subcutaneous injection and produce a more predictable anticoagulant response than UFH because of a reduced affinity for binding to proteins and cells other than antithrombin and a reduced ability to inactivate thrombin. Short-term LMWH therapy is seldom associated with thrombocytopenia7. Routine coagulation monitoring is not usually required but may be necessary in certain patient populations such as the obese and or among 3
Curr Med Res Opin Downloaded from informahealthcare.com by University of Auckland on 10/16/14. For personal use only.
patients with renal insufficiency. Low molecular weight heparin therapy is recommended over UFH therapy for the initial treatment of VTE by both ACCP guidelines (weak recommendation) and the International Consensus Statement, and should be administered for at least 5 days1, 2. In a systematic review, LMWH therapy was associated with a favorable improvement in clot-burden compared with UFH (relative risk 0.82; 95% confidence interval [CI], 0.76 to 0.88; P
