Editorials
Transition from apixaban to warfarin— addressing excess stroke, systemic embolism, and major bleeding John A. Cairns, MD, FRCPC, a and Jeffrey I. Weitz, MD, FRCPC b British Columbia, and Ontario, Canada
Three recent, randomized, double-blind clinical trials have each compared a new oral anticoagulant (NOAC) with warfarin for stroke prevention in patients with atrial fibrillation. 1–3 At trial completion, most patients were switched from study drug to open-label vitamin K antagonist (VKA). Because the NOACs have short halflives, patients switched from a NOAC to a VKA require bridging until the VKA produces a therapeutic international normalized ratio (INR). The goal of such bridging is to minimize the risk of stroke or systemic embolism during the transition period without increasing the risk of bleeding. Although the optimal bridging regimens remain elusive, investigators in the ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI 48 trials were provided with formal recommendations for transition from study drug to openlabel VKA, and the rates of stroke and major bleeding in the month after cessation of rivaroxaban, apixaban, and edoxaban or warfarin, respectively, were documented. The open-label RE-LY trial comparing 2 doses of dabigatran with warfarin had no such component because most patients in the dabigatran arms were continued on study drug as part of the RE-LYABLE study. 4 In this issue of the journal, the results from the ARISTOTLE trial are reported. 5 Comparison of these data with those from the other trials will help in the design of more effective and safer protocols for transitioning patients from a NOAC to a VKA. The ARISTOTLE trial compared apixaban with warfarin among 18,201 atrial fibrillation patients with a mean CHADS2 score of 2.1 at entry. 1,5 After a median follow-up of 1.8 years, From the aDepartment of Medicine, University of British Columbia, Vancouver, British Columbia, Canada, and bDepartment of Medicine, McMaster University, and the Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada. Stuart J. Connolly, MD, served as guest editor for this article. Conflicts of interest: Dr Cairns has served as a consultant and has received honoraria from Boehringer Ingelheim, Bayer, Bristol-Myers Squibb, and Pfizer. He chairs the DSMB of the ARTESIA trial of apixaban vs aspirin among patients with subclinical atrial fibrillation, sponsored in part by Bristol-Myers Squibb, and Pfizer, and he is vice chair of the DSMB of the COMPASS trial of rivaroxaban vs aspirin in patients at risk of vascular events, sponsored by Bayer.Dr Weitz has served as a consultant and has received honoraria from Boehringer Ingelheim, Bayer, Janssen, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo. He is co-chair of the ongoing EINSTEIN-Choice trial and a member of the Steering Committee of the MARINER trial, both of which are with rivaroxaban. Submitted July 23, 2014; accepted September 5, 2014. Reprint requests: John A. Cairns, MD, FRCPC, UBC Division of Cardiology, Rm 9113, GLD Health Care Centre, 2775 Laurel St, Vancouver, BC, Canada V5Z 1M9. E-mail: [email protected] 0002-8703 © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2014.09.007
patients still taking allocated study drug at the end of the trial were advised to stop treatment. It was recommended that treating physicians switch these patients to open-label VKA using a 2-day bridging regimen of apixaban or apixaban placebo for patients who were on apixaban or warfarin, respectively. Apixaban has a half-life of about 12 hours, whereas the pharmacodynamic half-life of warfarin is 3 to 5 days. It was anticipated that the 2 days of apixaban bridging would be sufficient to reduce the risk of embolic events in patients transitioning from apixaban to a VKA. Of the 13,397 patients still on study drug at trial termination, 83% were switched to open-label VKA and rates of stroke and systemic embolism and major bleeding were assessed over the subsequent 30-day period. The rate of stoke and systemic embolism in patients who had been receiving apixaban was higher than that in patients who had received warfarin (annualized rates of 4.02% and 0.99%, respectively), as was the rate of major bleeding. The increase in embolic events in the apixaban group was evident within the first week after stopping study drug and persisted through the fourth week. Consequently, the event rate during the 30day period after stopping study-allocated apixaban and switching to a VKA was about 3-fold higher than that observed during apixaban administration and was similar to the rate predicted for patients with a mean CHADS2 score of 2.1 who are not receiving anticoagulation prophylaxis. In contrast, the event rate after stopping study-allocated warfarin was similar to that observed during the trial. What went wrong in the transition from apixaban to a VKA? It takes at least 5 days, and often longer, to achieve therapeutic anticoagulation with a VKA. Although detailed INR data are unavailable, basic pharmacology suggests that the anticoagulant effect of a VKA would be suboptimal after a 2-day period of apixaban bridging. That this is the likely explanation for the excess in stroke and systemic embolism after stopping apixaban is supported by comparison of the rates of stroke and systemic embolism during the first 30 days of the trial among warfarin-naïve and warfarin-experienced patients assigned to warfarin therapy. 5 The annualized rate of stroke and systemic embolism among the warfarin-naïve patients was about 3-fold higher than that in the warfarinexperienced group; this difference likely reflected the delay in achieving therapeutic anticoagulation in patients who had not received prior warfarin treatment. Transitioning patients from a short-acting parenteral
2 Cairns and Weitz
anticoagulant, such as low-molecular-weight heparin, to warfarin requires a minimum of a 5-day overlap and often longer. 6 A similar duration of overlap is likely to be required for transition from apixaban to warfarin. Further light is shed on the problem of the increased rate of stroke and systemic embolism when transitioning from a NOAC to a VKA by observations from the ROCKET-AF trial, which compared rivaroxaban with warfarin among atrial fibrillation patients with a mean CHADS2 of 3.5 at study entry. 2,7,8 After study termination, 92% of patients were transitioned to open-label VKA with no systematic bridging. The rate of stroke and systemic embolism was 3.7-fold higher in patients transitioned from rivaroxaban than in those transitioned from blinded warfarin. The median time to the first therapeutic INR was 13 days in the patients switched from rivaroxaban and only 3 days in those transitioned from warfarin. By day 30, only 52 % of patients transitioned to a VKA from rivaroxaban had 1 or more INR values in the therapeutic range, whereas 83% of those switched from warfarin had at least 1 therapeutic INR. 8Therefore, these findings indicate that it takes time to achieve a therapeutic anticoagulant response with a VKA and suggest that to reduce the risk of stroke and systemic embolism during this period, bridging should be provided. The ENGAGE AF-TIMI 48 trial, which compared edoxaban with warfarin among atrial fibrillation patients with a mean CHADS2 score of 2.8 at baseline, specified a detailed protocol for cessation of edoxaban and transition to warfarin. 3 Using a transition kit that contained a 14-day supply of low-dose edoxaban and a rigorous VKA-dosing algorithm, patients transitioned from edoxaban to open-label VKA were maintained on edoxaban for up to 2 weeks, or until the INR was therapeutic. With this approach, the INR was therapeutic in 98% of patients at 30 days, and there was no increase in the rate of stroke or major bleeding. A detailed report of this experience is in press, but these findings support the notion that the risk of stroke and systemic embolism when switching patients from a NOAC to a VKA can be minimized by bridging patients with the NOAC until the INR with the VKA is therapeutic. The risk of bleeding increases when patients are switched from one anticoagulant to another. 6 In the ARISTOTLE trial, the annualized rate of major bleeding during the 30 days after cessation of study drug was 2.5fold higher in patients who had been receiving apixaban than it was in those taking warfarin (4.97% and 1.97%, respectively), and the annualized rate of major bleeding after stopping apixaban was 2.5-fold higher than that observed with apixaban during the trial. 5 The excess bleeding after stopping apixaban, which was evident by week 2 and persisted through weeks 3 and 4, was presumably caused by episodes of excessive anticoagulation during the period that the patients were transitioned to a VKA, a well-described phenomenon when warfarinnaïve patients are started on warfarin. 9 Detailed INR data
American Heart Journal January 2015
during the period of transition would help to confirm this possibility. In the ROCKET-AF trial, the rate of major bleeding was 3.6-fold higher in patients transitioned from rivaroxaban to open-label VKA at study completion than in those switched from blinded warfarin, 7,8 an increase similar to that observed in the ARISTOTLE trial. This finding is not readily explained by the available INR data during the transition period; in general, the INR values were more often subtherapeutic than supratherapeutic during the 30-day period after study drug discontinuation. Despite bridging with edoxaban for up to 2 weeks, there was no excess in major bleeding during the transition from edoxaban to a VKA in the ENGAGE trial. 3 Whether this was the result of using a half-dose edoxaban regimen for bridging is unclear. How do we overcome the problem of excess stroke and systemic embolism and major bleeding when transitioning patients from one anticoagulant to another? The simplest solution is to avoid switching anticoagulants whenever possible. If there is a need to transition patients from a short-acting NOAC to a VKA, data from the ENGAGE trial provide an effective strategy for edoxaban and suggest approaches that could be used to transition patients from apixaban, rivaroxaban, or dabigatran to a VKA, although additional research is needed. 3 Clearly, the NOAC should be continued until the VKA has produced a therapeutic INR. It would be sensible to give the NOAC at full doses for 2 to 3 days after initiation of the VKA because it will take at least this long for the VKA to begin to lower the level of the vitamin K–dependent clotting factors into the therapeutic range. To avoid overanticoagulation, a lower dose of the NOAC could be used thereafter. The INR should be measured at trough before the next dose of the NOAC is given because all of the NOACs have some effect on the INR. 10 This is less of an issue with apixaban, which has minimal effects on the INR than it is with rivaroxaban. Even dabigatran can prolong the INR, performing the test at trough will minimize this effect. 10 To optimize the transition, frequent INR determinations will be required, as will some tailoring of the timing of NOAC dosing, to ensure that the INR is measured at trough and to minimize the period that patients are exposed to 2 anticoagulants. The Food and Drug Administration now requires the manufacturers of apixaban, rivaroxaban, and dabigatran to include a black box warning regarding the increased risk of embolic events after NOAC discontinuation, with the recommendation that if the NOAC is stopped for other than pathological bleeding or completion of a planned course of therapy, another anticoagulant should be substituted. The package inserts for apixaban and rivaroxaban both suggest the use of a parenteral anticoagulant for bridging until a therapeutic INR is reached with warfarin. The dabigatran package insert suggests bridging with dabigatran until a therapeutic INR is achieved with warfarin. Given the clear evidence for excess stroke and systemic embolism after cessation of
American Heart Journal Volume 169, Number 1
apixaban and rivaroxaban and the complexities of bridging with a parenteral anticoagulant, transition protocols that overlap the NOAC with warfarin would be worthwhile. Although such protocols would need to be evaluated prospectively, their use might avoid about 2 episodes of stroke or systemic embolism during the 30day period after NOAC discontinuation for every 1,000 patients switched from apixaban or rivaroxaban to a VKA and might also decrease the incidence of major bleeding.
References 1. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92. 2. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91. 3. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093-104.
Cairns and Weitz 3
4. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51. 5. Granger CB, Lopes RD, Hanna M, et al. Clinical events after transitioning from apixaban versus warfarin to warfarin at the end of the ARISTOTLE trial. Am Heart J 2014. [in this issue]. 6. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e419S-94S. 7. Patel MR, Hellkamp AS, Lokhnygina Y, et al. Outcomes of discontinuing rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation. J Am Coll Cardiol 2013;61:651-8. 8. Mahaffey KW, Hellkamp AS, Patel M, et al. End of study transition from study drug to open-label vitamin K antagonist therapy. The ROCKET AF experience. Circ Cardiovasc Qual Outcomes 2013;06:470-8. 9. Hylek EM, Evans-Molina C, Shea C, et al. Major haemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 2007;115:2689-96. 10. Garcia D, Barrett YC, Ramacciotti E, et al. Laboratory assessment of the anticoagulant effects of the next generation of oral anticoagulants. J Thromb Haemost 2013;11:245-52.
Transition from apixaban to warfarin— addressing excess stroke, systemic embolism, and major bleeding John A. Cairns, MD, FRCPC, a and Jeffrey I. Weitz, MD, FRCPC b British Columbia, and Ontario, Canada
Three recent, randomized, double-blind clinical trials have each compared a new oral anticoagulant (NOAC) with warfarin for stroke prevention in patients with atrial fibrillation. 1–3 At trial completion, most patients were switched from study drug to open-label vitamin K antagonist (VKA). Because the NOACs have short halflives, patients switched from a NOAC to a VKA require bridging until the VKA produces a therapeutic international normalized ratio (INR). The goal of such bridging is to minimize the risk of stroke or systemic embolism during the transition period without increasing the risk of bleeding. Although the optimal bridging regimens remain elusive, investigators in the ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI 48 trials were provided with formal recommendations for transition from study drug to openlabel VKA, and the rates of stroke and major bleeding in the month after cessation of rivaroxaban, apixaban, and edoxaban or warfarin, respectively, were documented. The open-label RE-LY trial comparing 2 doses of dabigatran with warfarin had no such component because most patients in the dabigatran arms were continued on study drug as part of the RE-LYABLE study. 4 In this issue of the journal, the results from the ARISTOTLE trial are reported. 5 Comparison of these data with those from the other trials will help in the design of more effective and safer protocols for transitioning patients from a NOAC to a VKA. The ARISTOTLE trial compared apixaban with warfarin among 18,201 atrial fibrillation patients with a mean CHADS2 score of 2.1 at entry. 1,5 After a median follow-up of 1.8 years, From the aDepartment of Medicine, University of British Columbia, Vancouver, British Columbia, Canada, and bDepartment of Medicine, McMaster University, and the Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada. Stuart J. Connolly, MD, served as guest editor for this article. Conflicts of interest: Dr Cairns has served as a consultant and has received honoraria from Boehringer Ingelheim, Bayer, Bristol-Myers Squibb, and Pfizer. He chairs the DSMB of the ARTESIA trial of apixaban vs aspirin among patients with subclinical atrial fibrillation, sponsored in part by Bristol-Myers Squibb, and Pfizer, and he is vice chair of the DSMB of the COMPASS trial of rivaroxaban vs aspirin in patients at risk of vascular events, sponsored by Bayer.Dr Weitz has served as a consultant and has received honoraria from Boehringer Ingelheim, Bayer, Janssen, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo. He is co-chair of the ongoing EINSTEIN-Choice trial and a member of the Steering Committee of the MARINER trial, both of which are with rivaroxaban. Submitted July 23, 2014; accepted September 5, 2014. Reprint requests: John A. Cairns, MD, FRCPC, UBC Division of Cardiology, Rm 9113, GLD Health Care Centre, 2775 Laurel St, Vancouver, BC, Canada V5Z 1M9. E-mail: [email protected] 0002-8703 © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2014.09.007
patients still taking allocated study drug at the end of the trial were advised to stop treatment. It was recommended that treating physicians switch these patients to open-label VKA using a 2-day bridging regimen of apixaban or apixaban placebo for patients who were on apixaban or warfarin, respectively. Apixaban has a half-life of about 12 hours, whereas the pharmacodynamic half-life of warfarin is 3 to 5 days. It was anticipated that the 2 days of apixaban bridging would be sufficient to reduce the risk of embolic events in patients transitioning from apixaban to a VKA. Of the 13,397 patients still on study drug at trial termination, 83% were switched to open-label VKA and rates of stroke and systemic embolism and major bleeding were assessed over the subsequent 30-day period. The rate of stoke and systemic embolism in patients who had been receiving apixaban was higher than that in patients who had received warfarin (annualized rates of 4.02% and 0.99%, respectively), as was the rate of major bleeding. The increase in embolic events in the apixaban group was evident within the first week after stopping study drug and persisted through the fourth week. Consequently, the event rate during the 30day period after stopping study-allocated apixaban and switching to a VKA was about 3-fold higher than that observed during apixaban administration and was similar to the rate predicted for patients with a mean CHADS2 score of 2.1 who are not receiving anticoagulation prophylaxis. In contrast, the event rate after stopping study-allocated warfarin was similar to that observed during the trial. What went wrong in the transition from apixaban to a VKA? It takes at least 5 days, and often longer, to achieve therapeutic anticoagulation with a VKA. Although detailed INR data are unavailable, basic pharmacology suggests that the anticoagulant effect of a VKA would be suboptimal after a 2-day period of apixaban bridging. That this is the likely explanation for the excess in stroke and systemic embolism after stopping apixaban is supported by comparison of the rates of stroke and systemic embolism during the first 30 days of the trial among warfarin-naïve and warfarin-experienced patients assigned to warfarin therapy. 5 The annualized rate of stroke and systemic embolism among the warfarin-naïve patients was about 3-fold higher than that in the warfarinexperienced group; this difference likely reflected the delay in achieving therapeutic anticoagulation in patients who had not received prior warfarin treatment. Transitioning patients from a short-acting parenteral
2 Cairns and Weitz
anticoagulant, such as low-molecular-weight heparin, to warfarin requires a minimum of a 5-day overlap and often longer. 6 A similar duration of overlap is likely to be required for transition from apixaban to warfarin. Further light is shed on the problem of the increased rate of stroke and systemic embolism when transitioning from a NOAC to a VKA by observations from the ROCKET-AF trial, which compared rivaroxaban with warfarin among atrial fibrillation patients with a mean CHADS2 of 3.5 at study entry. 2,7,8 After study termination, 92% of patients were transitioned to open-label VKA with no systematic bridging. The rate of stroke and systemic embolism was 3.7-fold higher in patients transitioned from rivaroxaban than in those transitioned from blinded warfarin. The median time to the first therapeutic INR was 13 days in the patients switched from rivaroxaban and only 3 days in those transitioned from warfarin. By day 30, only 52 % of patients transitioned to a VKA from rivaroxaban had 1 or more INR values in the therapeutic range, whereas 83% of those switched from warfarin had at least 1 therapeutic INR. 8Therefore, these findings indicate that it takes time to achieve a therapeutic anticoagulant response with a VKA and suggest that to reduce the risk of stroke and systemic embolism during this period, bridging should be provided. The ENGAGE AF-TIMI 48 trial, which compared edoxaban with warfarin among atrial fibrillation patients with a mean CHADS2 score of 2.8 at baseline, specified a detailed protocol for cessation of edoxaban and transition to warfarin. 3 Using a transition kit that contained a 14-day supply of low-dose edoxaban and a rigorous VKA-dosing algorithm, patients transitioned from edoxaban to open-label VKA were maintained on edoxaban for up to 2 weeks, or until the INR was therapeutic. With this approach, the INR was therapeutic in 98% of patients at 30 days, and there was no increase in the rate of stroke or major bleeding. A detailed report of this experience is in press, but these findings support the notion that the risk of stroke and systemic embolism when switching patients from a NOAC to a VKA can be minimized by bridging patients with the NOAC until the INR with the VKA is therapeutic. The risk of bleeding increases when patients are switched from one anticoagulant to another. 6 In the ARISTOTLE trial, the annualized rate of major bleeding during the 30 days after cessation of study drug was 2.5fold higher in patients who had been receiving apixaban than it was in those taking warfarin (4.97% and 1.97%, respectively), and the annualized rate of major bleeding after stopping apixaban was 2.5-fold higher than that observed with apixaban during the trial. 5 The excess bleeding after stopping apixaban, which was evident by week 2 and persisted through weeks 3 and 4, was presumably caused by episodes of excessive anticoagulation during the period that the patients were transitioned to a VKA, a well-described phenomenon when warfarinnaïve patients are started on warfarin. 9 Detailed INR data
American Heart Journal January 2015
during the period of transition would help to confirm this possibility. In the ROCKET-AF trial, the rate of major bleeding was 3.6-fold higher in patients transitioned from rivaroxaban to open-label VKA at study completion than in those switched from blinded warfarin, 7,8 an increase similar to that observed in the ARISTOTLE trial. This finding is not readily explained by the available INR data during the transition period; in general, the INR values were more often subtherapeutic than supratherapeutic during the 30-day period after study drug discontinuation. Despite bridging with edoxaban for up to 2 weeks, there was no excess in major bleeding during the transition from edoxaban to a VKA in the ENGAGE trial. 3 Whether this was the result of using a half-dose edoxaban regimen for bridging is unclear. How do we overcome the problem of excess stroke and systemic embolism and major bleeding when transitioning patients from one anticoagulant to another? The simplest solution is to avoid switching anticoagulants whenever possible. If there is a need to transition patients from a short-acting NOAC to a VKA, data from the ENGAGE trial provide an effective strategy for edoxaban and suggest approaches that could be used to transition patients from apixaban, rivaroxaban, or dabigatran to a VKA, although additional research is needed. 3 Clearly, the NOAC should be continued until the VKA has produced a therapeutic INR. It would be sensible to give the NOAC at full doses for 2 to 3 days after initiation of the VKA because it will take at least this long for the VKA to begin to lower the level of the vitamin K–dependent clotting factors into the therapeutic range. To avoid overanticoagulation, a lower dose of the NOAC could be used thereafter. The INR should be measured at trough before the next dose of the NOAC is given because all of the NOACs have some effect on the INR. 10 This is less of an issue with apixaban, which has minimal effects on the INR than it is with rivaroxaban. Even dabigatran can prolong the INR, performing the test at trough will minimize this effect. 10 To optimize the transition, frequent INR determinations will be required, as will some tailoring of the timing of NOAC dosing, to ensure that the INR is measured at trough and to minimize the period that patients are exposed to 2 anticoagulants. The Food and Drug Administration now requires the manufacturers of apixaban, rivaroxaban, and dabigatran to include a black box warning regarding the increased risk of embolic events after NOAC discontinuation, with the recommendation that if the NOAC is stopped for other than pathological bleeding or completion of a planned course of therapy, another anticoagulant should be substituted. The package inserts for apixaban and rivaroxaban both suggest the use of a parenteral anticoagulant for bridging until a therapeutic INR is reached with warfarin. The dabigatran package insert suggests bridging with dabigatran until a therapeutic INR is achieved with warfarin. Given the clear evidence for excess stroke and systemic embolism after cessation of
American Heart Journal Volume 169, Number 1
apixaban and rivaroxaban and the complexities of bridging with a parenteral anticoagulant, transition protocols that overlap the NOAC with warfarin would be worthwhile. Although such protocols would need to be evaluated prospectively, their use might avoid about 2 episodes of stroke or systemic embolism during the 30day period after NOAC discontinuation for every 1,000 patients switched from apixaban or rivaroxaban to a VKA and might also decrease the incidence of major bleeding.
References 1. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92. 2. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91. 3. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093-104.
Cairns and Weitz 3
4. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51. 5. Granger CB, Lopes RD, Hanna M, et al. Clinical events after transitioning from apixaban versus warfarin to warfarin at the end of the ARISTOTLE trial. Am Heart J 2014. [in this issue]. 6. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e419S-94S. 7. Patel MR, Hellkamp AS, Lokhnygina Y, et al. Outcomes of discontinuing rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation. J Am Coll Cardiol 2013;61:651-8. 8. Mahaffey KW, Hellkamp AS, Patel M, et al. End of study transition from study drug to open-label vitamin K antagonist therapy. The ROCKET AF experience. Circ Cardiovasc Qual Outcomes 2013;06:470-8. 9. Hylek EM, Evans-Molina C, Shea C, et al. Major haemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 2007;115:2689-96. 10. Garcia D, Barrett YC, Ramacciotti E, et al. Laboratory assessment of the anticoagulant effects of the next generation of oral anticoagulants. J Thromb Haemost 2013;11:245-52.
