REVIEW URRENT C OPINION
Comparison of novel oral anticoagulants versus vitamin K antagonists in patients with chronic kidney disease Ziv Harel a, Manish M. Sood b, and Jeffrey Perl a
Purpose of review Novel oral anticoagulants (NOACs) including apixaban, dabigatran and rivaroxaban have been approved by international regulatory agencies to prevent venous thromboembolism as well as treat atrial fibrillation and venous thromboembolism in individuals with chronic kidney disease (CKD). However, alterations in their metabolism in the setting of CKD may impact their efficacy and lead to an increased risk of bleeding. This review summarizes the current literature on the efficacy and safety of these agents in individuals with moderate CKD. Recent findings In clinical trials, the use of the NOACs in patients with moderate CKD has demonstrated efficacy and safety similar to those seen with vitamin K antagonists. However, no universal reversal agent for the anticoagulant effect of the NOACs exists in the setting of bleeding. Limited data have demonstrated that hemodialysis has been effectively used to aid in reversing the effects of dabigatran, and the use of prothrombin complex concentrate has also been used for serious and major adverse bleeding events with some success. Summary As the use of the NOACs in patients with CKD increases, it will be important to monitor their safety, and clinicians who prescribe them should carefully monitor kidney function and recognize the potential for adverse effects. Keywords apixaban, bleeding, chronic kidney disease, dabigatran, novel oral anticoagulants, rivaroxaban
INTRODUCTION For over 50 years, warfarin, a vitamin K antagonist (VKA), had been the solely available oral anticoagulant agent. Challenges with the safety, adherence, and efficacy of this agent have remained as a direct consequence of its fairly narrow therapeutic index, its multiple medication interactions, and its multiple dietary interactions. Moreover, difficulties in achieving optimal anticoagulation have also centered on its relatively slow onset of action, heterogeneous pharmacologic properties, and the need for continuous monitoring, necessitating routine blood sampling of international normalized ratios (INR) to ensure its anticoagulation is therapeutic. Recently, the development of novel oral anticoagulants (NOAC) has addressed many of the limitations imposed by VKAs. Targeting key coagulation factors, including factors Xa and IIa, the NOACs, including dabigatran, rivaroxaban and apixaban, have been approved for use in the United States, Canada and the European Union (Table 1).
The use of antithrombotic agents is rising in parallel with the increase in the prevalence of chronic kidney disease (CKD) in the United States and Canada and this raises concerns regarding the safety and efficacy of these agents in this population [1]. Numerous large-scale epidemiologic studies demonstrate that CKD patients experience not only higher rates of atherothrombotic disease and atrial fibrillation as compared with the general population, but also suffer from a higher risk of anticoagulant-related and nonanticoagulant-related a Division of Nephrology, St Michael’s Hospital, University of Toronto, and The Keenan Research Centre in the Li Ka Shing Knowledge Institute, St Michael’s Hospital, University of Toronto and bOttawa Hospital Research Institute, The Ottawa Hospital, Civic Campus, Ottawa, Ontario, Canada
Correspondence to Ziv Harel, St. Michael’s Hospital, 61 Queen Street, 7th floor, Toronto, Ontario M5C 2T2, Canada. Tel: +1 416-864-8462; fax: +1 416-864-9338; e-mail: [email protected] Curr Opin Nephrol Hypertens 2015, 24:183–192 DOI:10.1097/MNH.0000000000000098
1062-4821 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-nephrolhypertens.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Clinical nephrology
The NOACs are increasingly being prescribed in patients with CKD.
and efficacy profile of these agents as compared with VKAs. We will compare and contrast the properties and evidence for each of the NOACs in terms of the implications of treatment for patients with CKD.
The NOACs demonstrate similar efficacy and safety profiles in CKD patients as VKAs.
ATRIAL FIBRILLATION
KEY POINTS
The NOACs are not approved for patients on dialysis. No universal reversal agent for the anticoagulant effect of the NOACs exists in the setting of bleeding, so that cautious use of these agents is required when prescribing them to patients with CKD.
bleeding complications [2]. These findings continue to highlight the need for appropriate antithrombotic strategies in these patients. As a result, the role of chronic anticoagulation therapy among these patients continues to remain controversial. Approved by the Food and Drug Administration and Health Canada for patients with an estimated glomerular filtration rate (eGFR) of at least 25 ml/min for apixaban and 30 ml/min for dabigatran and rivaroxaban, it is anticipated that there will be a shift in prescribing patterns with a growing number of individuals with CKD receiving treatment with a NOAC over warfarin [3]. Although not indicated at lower levels of kidney function, unanticipated episodes of acute kidney injury or progressive deterioration in kidney function, particularly in the absence of routine monitoring, will mean that many patients will unknowingly be exposed to a NOAC at lower than intended levels of eGFR. Therefore, the primary objective of the present review is to discuss the available evidence for the use of NOACs in patients with CKD with a particular emphasis on the overall safety
In the general population, atrial fibrillation is the most common arrhythmia with a prevalence of approximately 1% [4]. In contrast, the prevalence of atrial fibrillation in patients with CKD is significantly higher, as has been demonstrated by multiple recent studies [5–7]. For example, The Chronic Renal Insufficiency Cohort (CRIC) study reported a prevalence of 20.4% for atrial fibrillation in patients with an eGFR of less than 45 ml/min [5]. It is well established that patients with atrial fibrillation are at increased risk for stroke, which has a marked impact on quality of life and survival. In patients with CKD and atrial fibrillation, the risk of thromboembolism, mostly ischemic stroke, is significantly increased. In a recent Danish national registry, patients with CKD who were not on dialysis had an almost 50% increased relative risk of stroke or systemic thromboembolism compared with patients with normal kidney function [8]. This finding has been confirmed in a large meta-analysis of thrombosis risk in patients with CKD and atrial fibrillation [2]. Given the increased risk of stroke among patients with atrial fibrillation, oral anticoagulation has become the mainstay of therapy in the primary prevention of stroke in the general population among patients with high-risk features. In the absence of robust randomized controlled trial (RCT) data among CKD patients, their role in patients with CKD and atrial fibrillation continues to remain less definitive [9,10].
Table 1. Comparative properties of warfarin and the novel oral anticoagulants Characteristic
Warfarin
Dabigatran
Rivaroxaban
Apixaban
Target
Vitamin K etoposide reductase
Factor IIa (free and clot-bound thrombin)
Factor Xa
Factor Xa
Prodrug
No
Yes
No
No
Bioavailability (%)
>95
6.5
>80
50
Plasma protein binding (%)
94
34–35
92–95 (primarily albumin)
87
Half-life (h)
40
14–17
5–9
10–14
Elimination
92% renal
80% renal
66% renal
27% renal
20% fecal
34% fecal
63% fecal
Monitoring
INR adjusted
None
None
None
Peak effect (h)
72–96
2
2–4
3–4
Antidote
Vitamin K
None
None
None
Reversal via hemodialysis
No
Yes
No
No
INR, international normalized ratio.
184
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Anticoagulation in chronic kidney disease Harel et al.
VITAMIN K ANTAGONISTS FOR THE PREVENTION OF STROKE IN ATRIAL FIBRILLATION: EFFICACY AND SAFETY Observational studies in patients with CKD have consistently demonstrated that the use of warfarin is associated with a decreased risk of stroke. The largest study was a Danish 12-year registry study of patients with nondialysis CKD that compared the risk of stroke and systemic thromboembolism among these patients prescribed warfarin anticoagulation compared with no anticoagulation [8]. Among CKD patients taking warfarin therapy for atrial fibrillation, there was a 16% reduction in the risk of stroke compared with those with atrial fibrillation on no anticoagulation. Interestingly the reduction in the risk of stroke was accompanied by an increased risk of bleeding among CKD patients prescribed warfarin [hazard ratio (HR) 1.36; 95% confidence interval (CI) 1.17–1.59; P < 0.001]. An additional observational study of 399 patients with different stages of CKD and atrial fibrillation who were treated with warfarin to maintain an INR between 2.0 and 3.0 versus no warfarin, also demonstrated a significant reduction in the incidence of thromboembolic stroke (9% for warfarin versus 26% for no anticoagulation; P < 0.001), but an insignificant risk of major bleeding (14% for warfarin versus 9% for no anticoagulation) [11]. In this study, the decrease in incidence of thromboembolic stroke in patients treated with warfarin persisted across all stages of CKD. Thus far, the Stroke Prevention in Atrial Fibrillation III trial is the only randomized trial that has assessed the role of warfarin in stroke prevention among patients with atrial fibrillation and CKD [12]. In a subgroup analysis, 805 patients with stage 3 CKD who were treated with dose-adjusted warfarin (titrated to INR 2–3) were compared with patients with stage 3 CKD who were treated with a combination of aspirin and low-dose (1–3 mg) warfarin. CKD patients who were prescribed dose-adjusted warfarin had a 76% decreased relative risk of ischemic stroke and systemic embolism compared with those receiving low-dose warfarin and aspirin (95% CI 42–90; P < 0.001). There was no difference in the risk of major bleeding (five patients for doseadjusted warfarin versus six patients for low-dose warfarin and aspirin). Taken together, few studies have examined the efficacy of VKAs in the prevention of strokes in patients with CKD [8,11,12]. Recommendations to anticoagulate patients with CKD with atrial fibrillation have, therefore, largely been extrapolated from the general population. Where studies of CKD patients do exist, they are largely observational in nature, and suffer from confounding by treatment
indication, lack of robust case-mix comorbidity adjustment, and heterogeneity in both the therapies being studied, and patient populations. RCT data also remain challenged by subgroup analyses of CKD patients that are largely exploratory in nature, and remain underpowered because of inadequate sample size.
NOVEL ORAL ANTICOAGULANTS FOR THE PREVENTION OF STROKE IN ATRIAL FIBRILLATION: EFFICACY AND SAFETY There have been six recently published randomized trials that have compared the NOACs and VKAs for the prevention of stroke and thromboembolism among subgroups of patients with CKD [13–18]. The Dabigatran versus Warfarin in Patients with Atrial Fibrillation (RE-LY) [16] and Long-Term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) [17] trials compared dabigatran and warfarin, the Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation (ROCKET-AF) [14] and J-ROCKET-AF [15] trials compared rivaroxaban and VKA’s, and the Apixaban versus Warfarin in Patients with Atrial Fibrillation (ARISTOTLE) [13] and Safety and Efficacy of the Oral Direct Factor xa Inhibitor Apixaban in Japanese Patients with Non-valvular Atrial Fibrillation (ARISTOTLE-J) trials compared apixaban and warfarin (data for the RELY-ABLE [17] and ARISTOTLE-J [18] trials CKD subgroups have been embargoed). For most of these trials, results were reported for subgroups with an estimated creatinine clearance (CrCl; using the Cockcroft–Gault formula) between 30 and 49 ml/min (except for ARISTOTLE [13] wherein the estimated CrCl was between 25 and 50 ml/min). Despite all bleeding events being defined according to International Society on Thrombosis and Hemostasis criteria, heterogeneity existed for the reporting of the bleeding endpoint among the studies (Table 2). The RE-LY [19] trial enrolled a subgroup of three 505 patients with atrial fibrillation and a CrCl of 30– 49 ml/min and compared the rate of stroke or noncentral nervous system systemic embolism among those prescribed dabigatran (110 mg twice daily and 150 mg twice daily) versus dose-adjusted warfarin (target INR 2–3). The rate of stroke or systemic embolism was no different in CKD patients prescribed the 110 mg dose of dabigatran, and significantly lower in those prescribed the 150 mg dose of dabigatran compared with warfarin [2.8% per-year with warfarin versus 2.2% per year with dabigatran 110 mg twice daily (nonsignificant), and 1.5% per year with dabigatran 150 mg twice daily (P < 0.01)]. There were no significant differences in the rate of
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185
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Apixaban (Xa inhibitor) versus warfarin
Rivaroxaban (Xa inhibitor) versus warfarin or acenocoumarole
ARISTOTLE, 2011
EINSTEIN-DVT, 2010 (acute)
Rivaroxaban (Xa inhibitor) versus warfarin or acenocoumarole
Apixaban (Xa inhibitor) versus warfarina
AMPLIFY, 2013
EINSTEIN-PE, 2012
Intervention
Study
Table 2. Summary of studies
15 mg twice daily (rivaroxaban) for the first three weeks then 20 mg daily versus target INR of 2–3 (VKA)
10 mg of apixaban twice daily for the first 7 days, followed by 5 mg twice daily for 6 months versus target INR of 2– 3 (warfarin) 5 mg twice daily (apixaban) versus target INR of 2–3 (warfarin); or 2.5 mg twice daily versus target INR of 2–3b 15 mg twice daily (rivaroxaban) for the first 3 weeks then 20 mg daily versus target INR of 2–3 (VKA)
Dose
80: 3172 50–79: 1230 30–49: 398; 80: 3478 >50–80: 1093 >30–50: 309
Comparison of novel oral anticoagulants versus vitamin K antagonists in patients with chronic kidney disease Ziv Harel a, Manish M. Sood b, and Jeffrey Perl a
Purpose of review Novel oral anticoagulants (NOACs) including apixaban, dabigatran and rivaroxaban have been approved by international regulatory agencies to prevent venous thromboembolism as well as treat atrial fibrillation and venous thromboembolism in individuals with chronic kidney disease (CKD). However, alterations in their metabolism in the setting of CKD may impact their efficacy and lead to an increased risk of bleeding. This review summarizes the current literature on the efficacy and safety of these agents in individuals with moderate CKD. Recent findings In clinical trials, the use of the NOACs in patients with moderate CKD has demonstrated efficacy and safety similar to those seen with vitamin K antagonists. However, no universal reversal agent for the anticoagulant effect of the NOACs exists in the setting of bleeding. Limited data have demonstrated that hemodialysis has been effectively used to aid in reversing the effects of dabigatran, and the use of prothrombin complex concentrate has also been used for serious and major adverse bleeding events with some success. Summary As the use of the NOACs in patients with CKD increases, it will be important to monitor their safety, and clinicians who prescribe them should carefully monitor kidney function and recognize the potential for adverse effects. Keywords apixaban, bleeding, chronic kidney disease, dabigatran, novel oral anticoagulants, rivaroxaban
INTRODUCTION For over 50 years, warfarin, a vitamin K antagonist (VKA), had been the solely available oral anticoagulant agent. Challenges with the safety, adherence, and efficacy of this agent have remained as a direct consequence of its fairly narrow therapeutic index, its multiple medication interactions, and its multiple dietary interactions. Moreover, difficulties in achieving optimal anticoagulation have also centered on its relatively slow onset of action, heterogeneous pharmacologic properties, and the need for continuous monitoring, necessitating routine blood sampling of international normalized ratios (INR) to ensure its anticoagulation is therapeutic. Recently, the development of novel oral anticoagulants (NOAC) has addressed many of the limitations imposed by VKAs. Targeting key coagulation factors, including factors Xa and IIa, the NOACs, including dabigatran, rivaroxaban and apixaban, have been approved for use in the United States, Canada and the European Union (Table 1).
The use of antithrombotic agents is rising in parallel with the increase in the prevalence of chronic kidney disease (CKD) in the United States and Canada and this raises concerns regarding the safety and efficacy of these agents in this population [1]. Numerous large-scale epidemiologic studies demonstrate that CKD patients experience not only higher rates of atherothrombotic disease and atrial fibrillation as compared with the general population, but also suffer from a higher risk of anticoagulant-related and nonanticoagulant-related a Division of Nephrology, St Michael’s Hospital, University of Toronto, and The Keenan Research Centre in the Li Ka Shing Knowledge Institute, St Michael’s Hospital, University of Toronto and bOttawa Hospital Research Institute, The Ottawa Hospital, Civic Campus, Ottawa, Ontario, Canada
Correspondence to Ziv Harel, St. Michael’s Hospital, 61 Queen Street, 7th floor, Toronto, Ontario M5C 2T2, Canada. Tel: +1 416-864-8462; fax: +1 416-864-9338; e-mail: [email protected] Curr Opin Nephrol Hypertens 2015, 24:183–192 DOI:10.1097/MNH.0000000000000098
1062-4821 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-nephrolhypertens.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Clinical nephrology
The NOACs are increasingly being prescribed in patients with CKD.
and efficacy profile of these agents as compared with VKAs. We will compare and contrast the properties and evidence for each of the NOACs in terms of the implications of treatment for patients with CKD.
The NOACs demonstrate similar efficacy and safety profiles in CKD patients as VKAs.
ATRIAL FIBRILLATION
KEY POINTS
The NOACs are not approved for patients on dialysis. No universal reversal agent for the anticoagulant effect of the NOACs exists in the setting of bleeding, so that cautious use of these agents is required when prescribing them to patients with CKD.
bleeding complications [2]. These findings continue to highlight the need for appropriate antithrombotic strategies in these patients. As a result, the role of chronic anticoagulation therapy among these patients continues to remain controversial. Approved by the Food and Drug Administration and Health Canada for patients with an estimated glomerular filtration rate (eGFR) of at least 25 ml/min for apixaban and 30 ml/min for dabigatran and rivaroxaban, it is anticipated that there will be a shift in prescribing patterns with a growing number of individuals with CKD receiving treatment with a NOAC over warfarin [3]. Although not indicated at lower levels of kidney function, unanticipated episodes of acute kidney injury or progressive deterioration in kidney function, particularly in the absence of routine monitoring, will mean that many patients will unknowingly be exposed to a NOAC at lower than intended levels of eGFR. Therefore, the primary objective of the present review is to discuss the available evidence for the use of NOACs in patients with CKD with a particular emphasis on the overall safety
In the general population, atrial fibrillation is the most common arrhythmia with a prevalence of approximately 1% [4]. In contrast, the prevalence of atrial fibrillation in patients with CKD is significantly higher, as has been demonstrated by multiple recent studies [5–7]. For example, The Chronic Renal Insufficiency Cohort (CRIC) study reported a prevalence of 20.4% for atrial fibrillation in patients with an eGFR of less than 45 ml/min [5]. It is well established that patients with atrial fibrillation are at increased risk for stroke, which has a marked impact on quality of life and survival. In patients with CKD and atrial fibrillation, the risk of thromboembolism, mostly ischemic stroke, is significantly increased. In a recent Danish national registry, patients with CKD who were not on dialysis had an almost 50% increased relative risk of stroke or systemic thromboembolism compared with patients with normal kidney function [8]. This finding has been confirmed in a large meta-analysis of thrombosis risk in patients with CKD and atrial fibrillation [2]. Given the increased risk of stroke among patients with atrial fibrillation, oral anticoagulation has become the mainstay of therapy in the primary prevention of stroke in the general population among patients with high-risk features. In the absence of robust randomized controlled trial (RCT) data among CKD patients, their role in patients with CKD and atrial fibrillation continues to remain less definitive [9,10].
Table 1. Comparative properties of warfarin and the novel oral anticoagulants Characteristic
Warfarin
Dabigatran
Rivaroxaban
Apixaban
Target
Vitamin K etoposide reductase
Factor IIa (free and clot-bound thrombin)
Factor Xa
Factor Xa
Prodrug
No
Yes
No
No
Bioavailability (%)
>95
6.5
>80
50
Plasma protein binding (%)
94
34–35
92–95 (primarily albumin)
87
Half-life (h)
40
14–17
5–9
10–14
Elimination
92% renal
80% renal
66% renal
27% renal
20% fecal
34% fecal
63% fecal
Monitoring
INR adjusted
None
None
None
Peak effect (h)
72–96
2
2–4
3–4
Antidote
Vitamin K
None
None
None
Reversal via hemodialysis
No
Yes
No
No
INR, international normalized ratio.
184
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Volume 24 Number 2 March 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Anticoagulation in chronic kidney disease Harel et al.
VITAMIN K ANTAGONISTS FOR THE PREVENTION OF STROKE IN ATRIAL FIBRILLATION: EFFICACY AND SAFETY Observational studies in patients with CKD have consistently demonstrated that the use of warfarin is associated with a decreased risk of stroke. The largest study was a Danish 12-year registry study of patients with nondialysis CKD that compared the risk of stroke and systemic thromboembolism among these patients prescribed warfarin anticoagulation compared with no anticoagulation [8]. Among CKD patients taking warfarin therapy for atrial fibrillation, there was a 16% reduction in the risk of stroke compared with those with atrial fibrillation on no anticoagulation. Interestingly the reduction in the risk of stroke was accompanied by an increased risk of bleeding among CKD patients prescribed warfarin [hazard ratio (HR) 1.36; 95% confidence interval (CI) 1.17–1.59; P < 0.001]. An additional observational study of 399 patients with different stages of CKD and atrial fibrillation who were treated with warfarin to maintain an INR between 2.0 and 3.0 versus no warfarin, also demonstrated a significant reduction in the incidence of thromboembolic stroke (9% for warfarin versus 26% for no anticoagulation; P < 0.001), but an insignificant risk of major bleeding (14% for warfarin versus 9% for no anticoagulation) [11]. In this study, the decrease in incidence of thromboembolic stroke in patients treated with warfarin persisted across all stages of CKD. Thus far, the Stroke Prevention in Atrial Fibrillation III trial is the only randomized trial that has assessed the role of warfarin in stroke prevention among patients with atrial fibrillation and CKD [12]. In a subgroup analysis, 805 patients with stage 3 CKD who were treated with dose-adjusted warfarin (titrated to INR 2–3) were compared with patients with stage 3 CKD who were treated with a combination of aspirin and low-dose (1–3 mg) warfarin. CKD patients who were prescribed dose-adjusted warfarin had a 76% decreased relative risk of ischemic stroke and systemic embolism compared with those receiving low-dose warfarin and aspirin (95% CI 42–90; P < 0.001). There was no difference in the risk of major bleeding (five patients for doseadjusted warfarin versus six patients for low-dose warfarin and aspirin). Taken together, few studies have examined the efficacy of VKAs in the prevention of strokes in patients with CKD [8,11,12]. Recommendations to anticoagulate patients with CKD with atrial fibrillation have, therefore, largely been extrapolated from the general population. Where studies of CKD patients do exist, they are largely observational in nature, and suffer from confounding by treatment
indication, lack of robust case-mix comorbidity adjustment, and heterogeneity in both the therapies being studied, and patient populations. RCT data also remain challenged by subgroup analyses of CKD patients that are largely exploratory in nature, and remain underpowered because of inadequate sample size.
NOVEL ORAL ANTICOAGULANTS FOR THE PREVENTION OF STROKE IN ATRIAL FIBRILLATION: EFFICACY AND SAFETY There have been six recently published randomized trials that have compared the NOACs and VKAs for the prevention of stroke and thromboembolism among subgroups of patients with CKD [13–18]. The Dabigatran versus Warfarin in Patients with Atrial Fibrillation (RE-LY) [16] and Long-Term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) [17] trials compared dabigatran and warfarin, the Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation (ROCKET-AF) [14] and J-ROCKET-AF [15] trials compared rivaroxaban and VKA’s, and the Apixaban versus Warfarin in Patients with Atrial Fibrillation (ARISTOTLE) [13] and Safety and Efficacy of the Oral Direct Factor xa Inhibitor Apixaban in Japanese Patients with Non-valvular Atrial Fibrillation (ARISTOTLE-J) trials compared apixaban and warfarin (data for the RELY-ABLE [17] and ARISTOTLE-J [18] trials CKD subgroups have been embargoed). For most of these trials, results were reported for subgroups with an estimated creatinine clearance (CrCl; using the Cockcroft–Gault formula) between 30 and 49 ml/min (except for ARISTOTLE [13] wherein the estimated CrCl was between 25 and 50 ml/min). Despite all bleeding events being defined according to International Society on Thrombosis and Hemostasis criteria, heterogeneity existed for the reporting of the bleeding endpoint among the studies (Table 2). The RE-LY [19] trial enrolled a subgroup of three 505 patients with atrial fibrillation and a CrCl of 30– 49 ml/min and compared the rate of stroke or noncentral nervous system systemic embolism among those prescribed dabigatran (110 mg twice daily and 150 mg twice daily) versus dose-adjusted warfarin (target INR 2–3). The rate of stroke or systemic embolism was no different in CKD patients prescribed the 110 mg dose of dabigatran, and significantly lower in those prescribed the 150 mg dose of dabigatran compared with warfarin [2.8% per-year with warfarin versus 2.2% per year with dabigatran 110 mg twice daily (nonsignificant), and 1.5% per year with dabigatran 150 mg twice daily (P < 0.01)]. There were no significant differences in the rate of
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Apixaban (Xa inhibitor) versus warfarin
Rivaroxaban (Xa inhibitor) versus warfarin or acenocoumarole
ARISTOTLE, 2011
EINSTEIN-DVT, 2010 (acute)
Rivaroxaban (Xa inhibitor) versus warfarin or acenocoumarole
Apixaban (Xa inhibitor) versus warfarina
AMPLIFY, 2013
EINSTEIN-PE, 2012
Intervention
Study
Table 2. Summary of studies
15 mg twice daily (rivaroxaban) for the first three weeks then 20 mg daily versus target INR of 2–3 (VKA)
10 mg of apixaban twice daily for the first 7 days, followed by 5 mg twice daily for 6 months versus target INR of 2– 3 (warfarin) 5 mg twice daily (apixaban) versus target INR of 2–3 (warfarin); or 2.5 mg twice daily versus target INR of 2–3b 15 mg twice daily (rivaroxaban) for the first 3 weeks then 20 mg daily versus target INR of 2–3 (VKA)
Dose
80: 3172 50–79: 1230 30–49: 398; 80: 3478 >50–80: 1093 >30–50: 309
