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Controversies regarding the new oral anticoagulants for stroke prevention in patients with atrial fibrillation Bibhu D Mohanty, Patrick M Looser, Lakshmi R Gokanapudy, Rishi Handa, Sudipta Mohanty, Sharon S Choi, Martin E Goldman, Valentin Fuster and Jonathan L Halperin Vasc Med 2014 19: 190 DOI: 10.1177/1358863X14532869 The online version of this article can be found at: http://vmj.sagepub.com/content/19/3/190
Published by: http://www.sagepublications.com
On behalf of:
Society for Vascular Medicine
Additional services and information for Vascular Medicine can be found at: Email Alerts: http://vmj.sagepub.com/cgi/alerts Subscriptions: http://vmj.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> Version of Record - May 30, 2014 What is This?
Downloaded from vmj.sagepub.com at University of Texas Libraries on June 1, 2014
532869 research-article2014
VMJ0010.1177/1358863X14532869Vascular MedicineMohanty et al.
Review Article
Controversies regarding the new oral anticoagulants for stroke prevention in patients with atrial fibrillation
Vascular Medicine 2014, Vol. 19(3) 190–204 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1358863X14532869 vmj.sagepub.com
Bibhu D Mohanty1, Patrick M Looser2, Lakshmi R Gokanapudy3, Rishi Handa4, Sudipta Mohanty5, Sharon S Choi2, Martin E Goldman1, Valentin Fuster1 and Jonathan L Halperin1
Abstract Increasing use of the new oral anticoagulants (NOACs) – dabigatran, rivaroxaban, and apixaban – has prompted considerable discussion in the medical community even as warfarin remains the mainstay of therapy. This article raises 10 controversial issues regarding the use of NOACs for stroke prevention in patients with atrial fibrillation, and offers a review of the latest available evidence. We provide a brief overview of the mechanism and dosing of these drugs, as well as a summary of the key clinical trials that have brought them into the spotlight. Comparative considerations relative to warfarin such as NOAC safety, efficacy, bleeding risk, reversibility, drug-transitioning and use in patients well controlled on warfarin are addressed. Use in select populations such as the elderly, those with coronary disease, renal impairment, or on multiple anti-platelet drugs is also discussed. Finally, we consider such specific issues as comparative efficacy, off-label use, cost, rebound and management during events. Ultimately, the rise of the NOACs to mainstream use will depend on further data and clinical experience amongst the medical community. Keywords atrial fibrillation, oral anticoagulants, stroke prevention
Introduction Since its approval for therapeutic use in 1954, warfarin has remained the mainstay of oral anticoagulant therapy across multiple clinical indications. Despite aggressive attempts to develop agents that would be safer, more predictable and better tolerated, it has only been within the last few years that viable alternatives have arrived, three of which have been approved for clinical use in the US for patients with non-valvular atrial fibrillation (NVAF). One of these is also approved for venous thromboembolism (VTE) prophylaxis after knee or hip replacement surgery. In order of completion of large phase III clinical trials, dabigatran, rivaroxaban, apixaban and edoxaban (not FDA approved) – commonly termed the new oral anticoagulants (NOACs) – have been met with great anticipation by the medical community. Advantages of these agents over warfarin include fixed-dosing, once or twice daily (BID) regimens, rapid and predictable onset of anticoagulant effect, a wider therapeutic window between antithrombotic efficacy and the bleeding risk, few food or drug interactions, and no necessity of routine anticoagulant intensity monitoring.1 Faced with an aging population, the rising prevalence of atrial fibrillation (AF) (an estimated 17.8% among those over age 85 years), and the aggregate 64% reduction in
stroke risk conferred by warfarin compared to placebo or no therapy, the potential healthcare and economic impact of the NOACs is unquestionable.2,3 Although the development of these drugs is a landmark event in cardiovascular therapeutics, an array of issues has dampened the initial enthusiasm, and warfarin remains the
1Zena
and Michael A Wiener Cardiovascular Institute, Mount Sinai Heart Hospital, New York, NY, USA 2Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA 3St George’s University School of Medicine, Grenada, West Indies 4Department of Medicine, Morristown Medical Center, Morristown, NJ, USA 5University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA Corresponding author: Patrick M Looser Department of Internal Medicine Attn: Internal Medicine Residency Program 1 Gustave Levy Place New York, NY 10029 USA Email: [email protected]
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Figure 1. Anticoagulant site of action.4
most commonly prescribed anticoagulant even for patients newly starting therapy for NVAF. Clinicians must reconcile the benefits of NOACs with their drawbacks, including lack of an antidote or methods to assess compliance, cost, uncertainties in patients with kidney disease, and a tendency to migrate toward off-label use. However, scrutiny surrounding these issues has invigorated the discussion surrounding NOACs and promises not only to enhance understanding of these drugs and the mechanisms underlying thromboembolic events, but ultimately to improve patient outcomes. Following is a brief review of the pivotal, phase III clinical trials of the four NOACs and a discussion of the decisions that underlie their safe and appropriate use.
Mechanism and dosing While vitamin K antagonists inhibit the production of several factors in the coagulation cascade, newer agents target single steps, resulting in greater predictability of anticoagulant effect (Figure 1).4 Dabigatran is a direct thrombin inhibitor (DTI) that impairs the ability of thrombin to (i) convert fibrinogen to fibrin, (ii) promote self-propagation by activation of other coagulation factors, and (iii) activate platelets.5 Unlike indirect inhibitors of thrombin such as heparin, dabigatran reversibly binds the catalytic site of both free and clot-bound thrombin.6 Administered as an inactive prodrug, dabigatran undergoes complete esterasemediated conversion to its active form, reaches peak plasma levels within 2–3 hours and has a half-life of 12–17 hours.7 The usual dose is 150 mg BID. A lower dose of 110 mg BID, approved in other parts of the world for patients over age 75 or at high risk of bleeding, is not available in the US.
The FDA approved 75 mg BID for patients with creatinine clearance (CrCl) of 15–30 ml/min based on pharmacokinetic models predicting that this would result in plasma concentrations of the drug comparable to standard dosing in patients with normal renal function.8 Rivaroxaban, apixaban and edoxaban are extremely selective, reversible, direct factor Xa inhibitors. Rivaroxaban reaches peak plasma levels 2–4 hours after administration, is dosed at 20 mg once daily with a halflife of 5–13 hours, and should be taken with food to increase bioavailability.9 A 15 mg dose is available for patients with a CrCl of 15–30 ml/min, as 33% of absorbed rivaroxaban is excreted unchanged renally, while the remainder is metabolized by both cytochrome P450dependent and independent processes, including CYP3A4, CYPP2J2, and P-glycoprotein.1 Caution should be exerted when using rivaroxaban in conjunction with pharmacologic inducers or inhibitors of these enzymes. A dose of 10 mg once daily is used for prophylaxis of VTE following major orthopedic surgery of the hip or knee. Twice daily dosing is indicated for acute coronary syndromes. It is also approved for treatment of venous thromboembolism. Apixaban reaches peak plasma levels 3–4 hours after administration, has a half-life of 8–15 hours and is dosed at 5 mg BID.10 Approximately a quarter of the administered dose is excreted by the kidneys unchanged and the remainder is metabolized by CYP3A4-dependent and independent mechanisms, and should be avoided with other drugs metabolized in the same manner. A 2.5 mg BID dose is available for patients with two or more of the following criteria: age greater than 80 years, body weight less than 60 kg or serum creatinine above 1.5 mg/dl.1
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Edoxaban is rapidly absorbed, reaching peak plasma levels 1–2 hours after oral administration and has a half-life of 9–11 hours.11,12 It has a bioavailability of 50%, and there is no inactive pro-drug requiring modification into an active form. The drug is eliminated via two mechanisms. Approximately 35% undergoes renal elimination, while the remainder is excreted in the feces.13 Dosing regimens have not yet been defined for widespread use, but in the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factors Xa Next Generation in Atrial Fibrillation – Thrombolysis in Myocardial Infarction 48) trial, patients received either 60 mg or 30 mg fixed daily dosing, with rates of stroke or systemic embolism comparable to those with warfarin and significantly lower rates of bleeding and death from cardiovascular causes.14 Edoxaban is also a potent inhibitor of cytochrome P450 3A4 and P-glycoprotein13 (Table 1).
Pivotal trials in patients with NVAF Dabigatran Approval of dabigatran was based on the RE-LY (Randomized Evaluation of Long term anticoagulant therapY) trial, a phase III study that randomized 18,113 patients with NVAF and at least one additional risk factor for stroke (mean CHADS2 score = 2.1) to one of two blinded doses of dabigatran (110 mg BID or 150 mg BID) or open-label, adjusted-dose warfarin (goal INR 2.0–3.0).15 For the primary outcome of all stroke (ischemic or hemorrhagic) and systemic embolism, the rate was 1.7%/year with warfarin, 1.5%/year with dabigatran, 110 mg BID (non-inferior: HR=0.90, 95% CI 0.74–1.10, p
Controversies regarding the new oral anticoagulants for stroke prevention in patients with atrial fibrillation Bibhu D Mohanty, Patrick M Looser, Lakshmi R Gokanapudy, Rishi Handa, Sudipta Mohanty, Sharon S Choi, Martin E Goldman, Valentin Fuster and Jonathan L Halperin Vasc Med 2014 19: 190 DOI: 10.1177/1358863X14532869 The online version of this article can be found at: http://vmj.sagepub.com/content/19/3/190
Published by: http://www.sagepublications.com
On behalf of:
Society for Vascular Medicine
Additional services and information for Vascular Medicine can be found at: Email Alerts: http://vmj.sagepub.com/cgi/alerts Subscriptions: http://vmj.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> Version of Record - May 30, 2014 What is This?
Downloaded from vmj.sagepub.com at University of Texas Libraries on June 1, 2014
532869 research-article2014
VMJ0010.1177/1358863X14532869Vascular MedicineMohanty et al.
Review Article
Controversies regarding the new oral anticoagulants for stroke prevention in patients with atrial fibrillation
Vascular Medicine 2014, Vol. 19(3) 190–204 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1358863X14532869 vmj.sagepub.com
Bibhu D Mohanty1, Patrick M Looser2, Lakshmi R Gokanapudy3, Rishi Handa4, Sudipta Mohanty5, Sharon S Choi2, Martin E Goldman1, Valentin Fuster1 and Jonathan L Halperin1
Abstract Increasing use of the new oral anticoagulants (NOACs) – dabigatran, rivaroxaban, and apixaban – has prompted considerable discussion in the medical community even as warfarin remains the mainstay of therapy. This article raises 10 controversial issues regarding the use of NOACs for stroke prevention in patients with atrial fibrillation, and offers a review of the latest available evidence. We provide a brief overview of the mechanism and dosing of these drugs, as well as a summary of the key clinical trials that have brought them into the spotlight. Comparative considerations relative to warfarin such as NOAC safety, efficacy, bleeding risk, reversibility, drug-transitioning and use in patients well controlled on warfarin are addressed. Use in select populations such as the elderly, those with coronary disease, renal impairment, or on multiple anti-platelet drugs is also discussed. Finally, we consider such specific issues as comparative efficacy, off-label use, cost, rebound and management during events. Ultimately, the rise of the NOACs to mainstream use will depend on further data and clinical experience amongst the medical community. Keywords atrial fibrillation, oral anticoagulants, stroke prevention
Introduction Since its approval for therapeutic use in 1954, warfarin has remained the mainstay of oral anticoagulant therapy across multiple clinical indications. Despite aggressive attempts to develop agents that would be safer, more predictable and better tolerated, it has only been within the last few years that viable alternatives have arrived, three of which have been approved for clinical use in the US for patients with non-valvular atrial fibrillation (NVAF). One of these is also approved for venous thromboembolism (VTE) prophylaxis after knee or hip replacement surgery. In order of completion of large phase III clinical trials, dabigatran, rivaroxaban, apixaban and edoxaban (not FDA approved) – commonly termed the new oral anticoagulants (NOACs) – have been met with great anticipation by the medical community. Advantages of these agents over warfarin include fixed-dosing, once or twice daily (BID) regimens, rapid and predictable onset of anticoagulant effect, a wider therapeutic window between antithrombotic efficacy and the bleeding risk, few food or drug interactions, and no necessity of routine anticoagulant intensity monitoring.1 Faced with an aging population, the rising prevalence of atrial fibrillation (AF) (an estimated 17.8% among those over age 85 years), and the aggregate 64% reduction in
stroke risk conferred by warfarin compared to placebo or no therapy, the potential healthcare and economic impact of the NOACs is unquestionable.2,3 Although the development of these drugs is a landmark event in cardiovascular therapeutics, an array of issues has dampened the initial enthusiasm, and warfarin remains the
1Zena
and Michael A Wiener Cardiovascular Institute, Mount Sinai Heart Hospital, New York, NY, USA 2Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA 3St George’s University School of Medicine, Grenada, West Indies 4Department of Medicine, Morristown Medical Center, Morristown, NJ, USA 5University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA Corresponding author: Patrick M Looser Department of Internal Medicine Attn: Internal Medicine Residency Program 1 Gustave Levy Place New York, NY 10029 USA Email: [email protected]
Downloaded from vmj.sagepub.com at University of Texas Libraries on June 1, 2014
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Mohanty et al.
Figure 1. Anticoagulant site of action.4
most commonly prescribed anticoagulant even for patients newly starting therapy for NVAF. Clinicians must reconcile the benefits of NOACs with their drawbacks, including lack of an antidote or methods to assess compliance, cost, uncertainties in patients with kidney disease, and a tendency to migrate toward off-label use. However, scrutiny surrounding these issues has invigorated the discussion surrounding NOACs and promises not only to enhance understanding of these drugs and the mechanisms underlying thromboembolic events, but ultimately to improve patient outcomes. Following is a brief review of the pivotal, phase III clinical trials of the four NOACs and a discussion of the decisions that underlie their safe and appropriate use.
Mechanism and dosing While vitamin K antagonists inhibit the production of several factors in the coagulation cascade, newer agents target single steps, resulting in greater predictability of anticoagulant effect (Figure 1).4 Dabigatran is a direct thrombin inhibitor (DTI) that impairs the ability of thrombin to (i) convert fibrinogen to fibrin, (ii) promote self-propagation by activation of other coagulation factors, and (iii) activate platelets.5 Unlike indirect inhibitors of thrombin such as heparin, dabigatran reversibly binds the catalytic site of both free and clot-bound thrombin.6 Administered as an inactive prodrug, dabigatran undergoes complete esterasemediated conversion to its active form, reaches peak plasma levels within 2–3 hours and has a half-life of 12–17 hours.7 The usual dose is 150 mg BID. A lower dose of 110 mg BID, approved in other parts of the world for patients over age 75 or at high risk of bleeding, is not available in the US.
The FDA approved 75 mg BID for patients with creatinine clearance (CrCl) of 15–30 ml/min based on pharmacokinetic models predicting that this would result in plasma concentrations of the drug comparable to standard dosing in patients with normal renal function.8 Rivaroxaban, apixaban and edoxaban are extremely selective, reversible, direct factor Xa inhibitors. Rivaroxaban reaches peak plasma levels 2–4 hours after administration, is dosed at 20 mg once daily with a halflife of 5–13 hours, and should be taken with food to increase bioavailability.9 A 15 mg dose is available for patients with a CrCl of 15–30 ml/min, as 33% of absorbed rivaroxaban is excreted unchanged renally, while the remainder is metabolized by both cytochrome P450dependent and independent processes, including CYP3A4, CYPP2J2, and P-glycoprotein.1 Caution should be exerted when using rivaroxaban in conjunction with pharmacologic inducers or inhibitors of these enzymes. A dose of 10 mg once daily is used for prophylaxis of VTE following major orthopedic surgery of the hip or knee. Twice daily dosing is indicated for acute coronary syndromes. It is also approved for treatment of venous thromboembolism. Apixaban reaches peak plasma levels 3–4 hours after administration, has a half-life of 8–15 hours and is dosed at 5 mg BID.10 Approximately a quarter of the administered dose is excreted by the kidneys unchanged and the remainder is metabolized by CYP3A4-dependent and independent mechanisms, and should be avoided with other drugs metabolized in the same manner. A 2.5 mg BID dose is available for patients with two or more of the following criteria: age greater than 80 years, body weight less than 60 kg or serum creatinine above 1.5 mg/dl.1
Downloaded from vmj.sagepub.com at University of Texas Libraries on June 1, 2014
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Edoxaban is rapidly absorbed, reaching peak plasma levels 1–2 hours after oral administration and has a half-life of 9–11 hours.11,12 It has a bioavailability of 50%, and there is no inactive pro-drug requiring modification into an active form. The drug is eliminated via two mechanisms. Approximately 35% undergoes renal elimination, while the remainder is excreted in the feces.13 Dosing regimens have not yet been defined for widespread use, but in the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factors Xa Next Generation in Atrial Fibrillation – Thrombolysis in Myocardial Infarction 48) trial, patients received either 60 mg or 30 mg fixed daily dosing, with rates of stroke or systemic embolism comparable to those with warfarin and significantly lower rates of bleeding and death from cardiovascular causes.14 Edoxaban is also a potent inhibitor of cytochrome P450 3A4 and P-glycoprotein13 (Table 1).
Pivotal trials in patients with NVAF Dabigatran Approval of dabigatran was based on the RE-LY (Randomized Evaluation of Long term anticoagulant therapY) trial, a phase III study that randomized 18,113 patients with NVAF and at least one additional risk factor for stroke (mean CHADS2 score = 2.1) to one of two blinded doses of dabigatran (110 mg BID or 150 mg BID) or open-label, adjusted-dose warfarin (goal INR 2.0–3.0).15 For the primary outcome of all stroke (ischemic or hemorrhagic) and systemic embolism, the rate was 1.7%/year with warfarin, 1.5%/year with dabigatran, 110 mg BID (non-inferior: HR=0.90, 95% CI 0.74–1.10, p
