1159
Invited Editorial Focus
‘Real world’ use of non-vitamin K antagonist oral anticoagulants (NOACs): Lessons from the Dresden NOAC Registry John W. Eikelboom; Jeffrey I. Weitz McMaster University and the Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
The non-vitamin K antagonist oral anticoagulants (NOACs) have been compared with vitamin K antagonists (VKAs) in randomised controlled trials involving more than 150,000 patients. These studies demonstrate that the NOACs are not only at least as effective as VKAs for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism, but are associated with less life-threatening bleeding, particularly intracranial bleeding (1, 2), although unanswered questions will always remain (3, 4). In addition, the NOACs are more convenient to administer than VKAs because they can be given in fixed doses without routine coagulation monitoring, which enhances patient satisfaction. Indeed, the VKAs have many limitations, which have led to their suboptimal use in atrial fibrillation (5). Despite the wealth of information about the NOACs, however, some clinicians remain concerned about their safety when used as alternatives to VKAs outside the clinical trial setting. Reports from registries (6–9) and analyses of claims databases (10–13) suggest that the results with NOACs in the community are similar to those obtained in randomised trials. As outlined in ▶ Table 1, although these studies have strengths, they also have limitations. Thus, most of the observational data come from retrospective analyses of
Correspondence to: Jeffrey I. Weitz Thrombosis and Atherosclerosis Research Institute 237 Barton Street East Hamilton, Ontario, L8L 2X2, Canada Tel.: +1 905 574 8550, Fax: +1 905 575 2646 E-mail: [email protected] Received: February 20, 2015 Accepted: February 20, 2015 Epub ahead of print: April 16, 2015 http://dx.doi.org/10.1160/TH15-02-0158 Thromb Haemost 2015; 113: 1159–1161
© Schattauer 2015
aggregate data designed for other purposes. Specifically designed, prospective registries increase the likelihood of complete collection and reporting of data on the use of NOACs in the community setting and the outcome of patients given these agents, but even registries have problems. In this issue of Thrombosis and Haemostasis, Beyer-Westendorf et al. (23) report results from the prospective Dresden NOAC Registry on the efficacy, safety and adherence with dabigatran therapy in 341 patients with atrial fibrillation recruited between October 1, 2011 and February 28, 2013 (13). The primary efficacy outcome was stroke or systemic embolism and the primary safety outcome was major bleeding as defined by the ISTH criteria. Stroke or systemic embolism occurred at a rate of 2.93 per 100 patient years in the intentionto-treat analysis, and at a rate of 1.9 per 100 patient years in the on-treatment analysis. On-treatment event rates for stroke or systemic embolism were 3.3-fold higher in the 183 patients treated with dabigatran 110 mg twice daily than in the 158 patients given the higher 150 mg twice daily dabigatran regimen (2.88 and 0.86 per 100 patient years, respectively). On-treatment major bleeding rates also were 1.7-fold higher in patients given the lower dose of dabigatran than the higher dose (2.9 and 1.7 per 100 patient years, respectively), reflecting their older age (78 and 71 years, respectively; p< 0.001), higher CHADS2 scores (85.3 % and 58.2 % with a CHADS2 score ≥ 2, respectively; p< 0.001) and higher HAS-BLED scores (73.8 % and 53.2 % with a HAS-BLED score ≥ 2, respectively; p< 0.001). Dabigatran was discontinued at a rate of 25.4 per 100 years of treatment, and the majority of patients who stopped taking dabigatran were switched to an alternative NOAC, most commonly rivaroxaban. These results suggest that realworld use of dabigatran is associated with higher rates of stroke or systemic embol-
ism, lower rates of bleeding, and higher rates of premature discontinuation than were reported in the RE-LY trial (16). The strengths of the Dresden NOAC registry are that the findings reflect realworld experience and the data were prospectively collected; one of the first such studies to do so. In addition to the relatively small number of patients, another weakness is that the data are observational, which raises the potential for confounding. Unlike randomised trials, treatment recommendations were based on patient characteristics rather than random assignment, which limits the validity of comparisons across studies and between doses of dabigatran. Determination of the efficacy and safety of the 110 mg dose regimen of dabigatran relative to the 150 mg dose regimen is best achieved in the setting of a randomised controlled trial where an intentionto-treat approach minimises potential biases related to the reasons for premature discontinuation. The higher rates of stroke and bleeding in patients given the lower dose of dabigatran are not unexpected. Patients who received the lower dose regimen were older and had more co-morbidities, as evidenced by higher CHADS2 and HAS-BLED scores, than those who received the higher dose regimen; differences that limit comparisons between the two dabigatran dose groups. Likewise, the discontinuation rates are hard to interpret because some patients may have been started on dabigatran prior to cardioversion or catheter ablation, and may not have had an indication for longterm anticoagulation treatment. What are the implications of these findings for clinical practice? The results extend previous reports from the Dresden NOAC Registry (17–19), including data Editorial on Beyer-Westendorf et al. Thromb Haemost 2015; 113: 1247-1257.
Thrombosis and Haemostasis 113.6/2015 Downloaded from www.thrombosis-online.com on 2015-05-31 | ID: 1000466526 | IP: 147.188.128.74 For personal or educational use only. No other uses without permission. All rights reserved.
1160
Invited Editorial Focus
Table 1: Strengths and limitations of registries and claims databases to inform experience with the NOACs in the community setting.
Strengths
• Provide estimates of event rates in the “real world” setting across the spectrum of patient risk. • Provide information regarding the implementation of NOACs in the community, including switching between treatments, perioperative and bleeding management, and related outcomes.
• Provide reassurance of a favourable benefit-to-risk profile of the NOACs when used in the community. • Provide hypothesis-generating observations concerning the benefits and risks of different doses and treatments.
Limitations
• Increased likelihood of incomplete collection and reporting of exposure and outcome data. • Less reliable than randomized trials to compare the effects of different doses of NOACs and to compare the effects of the NOACs with those of vitamin K antagonists.
• Do not allow reliable comparison of event rates with those reported in randomized controlled trials. NOACs, non-vitamin K antagonist oral anticoagulants.
suggesting that not only are NOACs more convenient than warfarin, but the use of dabigatran or other NOACs also simplifies periprocedural management. Thus, most interventions were safely performed without interruption or with only a brief interruption of dabigatran treatment, thereby obviating the need for bridging (18). Overall, the Dresden NOAC Registry data complement the results of an analysis of three Danish registries, which demonstrated that both dabigatran doses (110 mg and 150 mg twice daily) were associated with lower rates of intracranial haemorrhage than that with VKAs (6). The rate of gastrointestinal bleeding with the 110 mg dose of dabigatran was similar to that with VKAs, while the rate with the 150 mg dose was higher; findings in keeping with those reported in the RE-LY trial (16). Retrospective database studies are also providing useful information on real-world experience with dabigatran. A US study using pharmacy data from patients with atrial fibrillation compared the risk of bleeding events, including gastrointestinal bleeding and intracranial bleeding, in patients who switched to dabigatran after at least six months of warfarin therapy with that in patients who continued on warfarin (13). The risk-adjusted rate of any bleeding was higher in patients who switched to dabigatran compared with those who remained on warfarin, largely driven by an increased rate of gastrointestinal bleeding. Rates of intracranial bleeding, other bleeding and death were similar between the two groups.
Using data from 134,414 Medicare patients with newly diagnosed atrial fibrillation, the US Food and Drug Administration compared the efficacy and safety of dabigatran with those of warfarin (15). Compared with warfarin, dabigatran was associated with a lower risk of ischaemic stroke, intracranial haemorrhage and death, but an increased risk of major gastrointestinal bleeding. The risk of myocardial infarction was similar with dabigatran and warfarin. Overall, therefore, the real-world experience with dabigatran is in line with the results of the RE-LY trial (1). Where do we go from here? Some clinicians have opined that when used in clinical practice, the trough anticoagulant activity of dabigatran or dabigatran drug levels should be measured soon after initiating therapy so as to enable upward dose adjustment if the level is too low to prevent ischaemic stroke, or downward adjustment to reduce the risk of serious bleeding if the level is too high (20). Current data provide no evidence to support this approach. Although gastrointestinal bleeding is increased with some NOACs (21), unmonitored dabigatran was at least as effective as monitored warfarin therapy for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism, and dabigatran was associated with less intracranial bleeding. Furthermore, not only are tests to measure dabigatran levels, such as the dilute thrombin time or the ecarin clot time, not widely available, but even if levels are measured, within patient variability in
the test results limits their utility. Thus, a recent study evaluating serial dabigatran levels in atrial fibrillation patients showed that up to 40 % of patients whose trough levels were in the upper extreme and up to 80 % of patients whose trough levels were in the lower extreme one month after starting the drug had subsequent dabigatran levels that fell within middle quartiles (22). Therefore, dose adjustments based on drug levels may be hazardous and without randomised clinical trial data demonstrating a net improvement in efficacy and safety, implementation of routine monitoring and dose adjustment could lead to net harm for patients. In summary, the data presented by Beyer-Westendorf et al. add to a growing body of evidence supporting the efficacy and safety of the NOACs for stroke prevention in atrial fibrillation across the spectrum of patient risk. These data should provide clinicians with the confidence to prescribe NOACs such as dabigatran. The findings also endorse guidelines (21, 22) which give preference to NOACs over warfarin for stroke prevention in most patients with non-valvular atrial fibrillation. Conflicts of interest
J. Eikelboom has received consulting fees and/or honoraria from Astra-Zeneca, Bayer, Boehringer-Ingelheim, BMS, Daiichi-Sankyo, Eli-Lilly, GSK, Pfizer, Janssen, and Sanofi-Aventis as well as grants and/or in-kind support from Astra-Zeneca, Bayer, Boehringer-Ingelheim, BMS, GSK, Pfizer, Janssen, and Sanofi-Aventis. J. Weitz has served as a consultant and received honoraria from Boehringer-Ingelheim, Bayer, Janssen, Johnson & Johnson, BMS, Pfizer, Daiichi-Sankyo, Portola, and Isis Pharmaceuticals.
References 1. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383: 955–962. 2. Yeh CH, Gross PL, Weitz JI. Evolving use of new oral anticoagulants for treatment of venous thromboembolism. Blood 2014; 124: 1020–1028. 3. Hankey GJ. Unanswered questions and research priorities to optimise stroke prevention in atrial fi-
Thrombosis and Haemostasis 113.6/2015 Downloaded from www.thrombosis-online.com on 2015-05-31 | ID: 1000466526 | IP: 147.188.128.74 For personal or educational use only. No other uses without permission. All rights reserved.
© Schattauer 2015
Invited Editorial Focus
4.
5.
6.
7.
8.
9.
brillation with the new oral anticoagulants. Thromb Haemost 2014; 111: 808–816. Hylek EM, Ko D, Cove CL. Gaps in translation from trials to practice: non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in atrial fibrillation. Thromb Haemost 2014; 111: 783–788. De Caterina R, Husted S, Wallentin L, et al. Vitamin K antagonists in heart disease: current status and perspectives (Section III). Position paper of the ESC Working Group on Thrombosis--Task Force on Anticoagulants in Heart Disease. Thromb Haemost 2013; 110: 1087–1107. Larsen TB, Rasmussen LH, Skjoth F, et al. Efficacy and safety of dabigatran etexilate and warfarin in „real-world“ patients with atrial fibrillation: a prospective nationwide cohort study. J Am Coll Cardiol 2013; 61: 2264–2273. Sorensen R, Gislason G, Torp-Pedersen C, et al. Dabigatran use in Danish atrial fibrillation patients in 2011: a nationwide study. Br Med J Open 2013; 3. Larsen TB, Gorst-Rasmussen A, Rasmussen LH, et al. Bleeding events among new starters and switchers to dabigatran compared with warfarin in atrial fibrillation. Am J Med 2014; 127: 650–656. Olesen JB, Sorensen R, Hansen ML, et al. Non-vitamin K antagonist oral anticoagulation agents in anticoagulant naive atrial fibrillation patients: Danish nationwide descriptive data 2011–2013. Europace 2015; 17: 187–193.
© Schattauer 2015
10. Southworth MR, Reichman ME, Unger EF. Dabigatran and postmarketing reports of bleeding. N Engl J Med 2013; 368: 1272–1274. 11. Vaughan Sarrazin MS, Jones M, et al. Bleeding rates in Veterans Affairs patients with atrial fibrillation who switch from warfarin to dabigatran. Am J Med 2014; 127: 1179–1185. 12. Hernandez I, Baik SH, Pinera A, et al. Risk of bleeding with dabigatran in atrial fibrillation. J Am Med Assoc Intern Med 2015; 175: 18–24. 13. Graham DJ, Reichman ME, Wernecke M, et al. Cardiovascular, bleeding, and mortality risks in elderly medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation 2015; 131: 157–164. 14. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139–1151. 15. Beyer-Westendorf J, Gelbricht V, Forster K, et al. Safety of switching from vitamin K antagonists to dabigatran or rivaroxaban in daily care--results from the Dresden NOAC registry. Br J Clin Pharmacol 2014; 78: 908–917. 16. Beyer-Westendorf J, Gelbricht V, Forster K, et al. Peri-interventional management of novel oral anticoagulants in daily care: results from the prospective Dresden NOAC registry. Eur Heart J 2014; 35: 1888–1896. 17. Beyer-Westendorf J, Forster K, Pannach S, et al. Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry. Blood 2014; 124: 955–962.
18. Chin PK, Wright DF, Patterson DM, et al. A proposal for dose-adjustment of dabigatran etexilate in atrial fibrillation guided by thrombin time. Br J Clin Pharmacol 2014; 78: 599–609. 19. Vanassche T, Hirsh J, Eikelboom JW, et al. Organspecific bleeding patterns of anticoagulated patient: lessons from clinical trials. Thromb Haemost 2014; 112: 918–923. 20. Chan NC, Coppens M, Hirsh J, et al. Real-world variability in dabigatran levels in patients with atrial fibrillation. J Thromb Haemost 2014; Epub ahead of print. 21. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012; 33: 2719–2747. 22. Verma A, Cairns JA, Mitchell LB, et al. 2014 focused update of the Canadian Cardiovascular Society Guidelines for the management of atrial fibrillation. Can J Cardiol 2014; 30: 1114–1130. 23. Beyer-Westendorf J, Ebertz F, Förster K, et al. Effectiveness and safety of dabigatran therapy in daily-care patients with atrial fibrillation. Results from the Dresden NOAC Registry. Thromb Haemost 2015; 113: 1247-1257.
Thrombosis and Haemostasis 113.6/2015 Downloaded from www.thrombosis-online.com on 2015-05-31 | ID: 1000466526 | IP: 147.188.128.74 For personal or educational use only. No other uses without permission. All rights reserved.
1161
Invited Editorial Focus
‘Real world’ use of non-vitamin K antagonist oral anticoagulants (NOACs): Lessons from the Dresden NOAC Registry John W. Eikelboom; Jeffrey I. Weitz McMaster University and the Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
The non-vitamin K antagonist oral anticoagulants (NOACs) have been compared with vitamin K antagonists (VKAs) in randomised controlled trials involving more than 150,000 patients. These studies demonstrate that the NOACs are not only at least as effective as VKAs for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism, but are associated with less life-threatening bleeding, particularly intracranial bleeding (1, 2), although unanswered questions will always remain (3, 4). In addition, the NOACs are more convenient to administer than VKAs because they can be given in fixed doses without routine coagulation monitoring, which enhances patient satisfaction. Indeed, the VKAs have many limitations, which have led to their suboptimal use in atrial fibrillation (5). Despite the wealth of information about the NOACs, however, some clinicians remain concerned about their safety when used as alternatives to VKAs outside the clinical trial setting. Reports from registries (6–9) and analyses of claims databases (10–13) suggest that the results with NOACs in the community are similar to those obtained in randomised trials. As outlined in ▶ Table 1, although these studies have strengths, they also have limitations. Thus, most of the observational data come from retrospective analyses of
Correspondence to: Jeffrey I. Weitz Thrombosis and Atherosclerosis Research Institute 237 Barton Street East Hamilton, Ontario, L8L 2X2, Canada Tel.: +1 905 574 8550, Fax: +1 905 575 2646 E-mail: [email protected] Received: February 20, 2015 Accepted: February 20, 2015 Epub ahead of print: April 16, 2015 http://dx.doi.org/10.1160/TH15-02-0158 Thromb Haemost 2015; 113: 1159–1161
© Schattauer 2015
aggregate data designed for other purposes. Specifically designed, prospective registries increase the likelihood of complete collection and reporting of data on the use of NOACs in the community setting and the outcome of patients given these agents, but even registries have problems. In this issue of Thrombosis and Haemostasis, Beyer-Westendorf et al. (23) report results from the prospective Dresden NOAC Registry on the efficacy, safety and adherence with dabigatran therapy in 341 patients with atrial fibrillation recruited between October 1, 2011 and February 28, 2013 (13). The primary efficacy outcome was stroke or systemic embolism and the primary safety outcome was major bleeding as defined by the ISTH criteria. Stroke or systemic embolism occurred at a rate of 2.93 per 100 patient years in the intentionto-treat analysis, and at a rate of 1.9 per 100 patient years in the on-treatment analysis. On-treatment event rates for stroke or systemic embolism were 3.3-fold higher in the 183 patients treated with dabigatran 110 mg twice daily than in the 158 patients given the higher 150 mg twice daily dabigatran regimen (2.88 and 0.86 per 100 patient years, respectively). On-treatment major bleeding rates also were 1.7-fold higher in patients given the lower dose of dabigatran than the higher dose (2.9 and 1.7 per 100 patient years, respectively), reflecting their older age (78 and 71 years, respectively; p< 0.001), higher CHADS2 scores (85.3 % and 58.2 % with a CHADS2 score ≥ 2, respectively; p< 0.001) and higher HAS-BLED scores (73.8 % and 53.2 % with a HAS-BLED score ≥ 2, respectively; p< 0.001). Dabigatran was discontinued at a rate of 25.4 per 100 years of treatment, and the majority of patients who stopped taking dabigatran were switched to an alternative NOAC, most commonly rivaroxaban. These results suggest that realworld use of dabigatran is associated with higher rates of stroke or systemic embol-
ism, lower rates of bleeding, and higher rates of premature discontinuation than were reported in the RE-LY trial (16). The strengths of the Dresden NOAC registry are that the findings reflect realworld experience and the data were prospectively collected; one of the first such studies to do so. In addition to the relatively small number of patients, another weakness is that the data are observational, which raises the potential for confounding. Unlike randomised trials, treatment recommendations were based on patient characteristics rather than random assignment, which limits the validity of comparisons across studies and between doses of dabigatran. Determination of the efficacy and safety of the 110 mg dose regimen of dabigatran relative to the 150 mg dose regimen is best achieved in the setting of a randomised controlled trial where an intentionto-treat approach minimises potential biases related to the reasons for premature discontinuation. The higher rates of stroke and bleeding in patients given the lower dose of dabigatran are not unexpected. Patients who received the lower dose regimen were older and had more co-morbidities, as evidenced by higher CHADS2 and HAS-BLED scores, than those who received the higher dose regimen; differences that limit comparisons between the two dabigatran dose groups. Likewise, the discontinuation rates are hard to interpret because some patients may have been started on dabigatran prior to cardioversion or catheter ablation, and may not have had an indication for longterm anticoagulation treatment. What are the implications of these findings for clinical practice? The results extend previous reports from the Dresden NOAC Registry (17–19), including data Editorial on Beyer-Westendorf et al. Thromb Haemost 2015; 113: 1247-1257.
Thrombosis and Haemostasis 113.6/2015 Downloaded from www.thrombosis-online.com on 2015-05-31 | ID: 1000466526 | IP: 147.188.128.74 For personal or educational use only. No other uses without permission. All rights reserved.
1160
Invited Editorial Focus
Table 1: Strengths and limitations of registries and claims databases to inform experience with the NOACs in the community setting.
Strengths
• Provide estimates of event rates in the “real world” setting across the spectrum of patient risk. • Provide information regarding the implementation of NOACs in the community, including switching between treatments, perioperative and bleeding management, and related outcomes.
• Provide reassurance of a favourable benefit-to-risk profile of the NOACs when used in the community. • Provide hypothesis-generating observations concerning the benefits and risks of different doses and treatments.
Limitations
• Increased likelihood of incomplete collection and reporting of exposure and outcome data. • Less reliable than randomized trials to compare the effects of different doses of NOACs and to compare the effects of the NOACs with those of vitamin K antagonists.
• Do not allow reliable comparison of event rates with those reported in randomized controlled trials. NOACs, non-vitamin K antagonist oral anticoagulants.
suggesting that not only are NOACs more convenient than warfarin, but the use of dabigatran or other NOACs also simplifies periprocedural management. Thus, most interventions were safely performed without interruption or with only a brief interruption of dabigatran treatment, thereby obviating the need for bridging (18). Overall, the Dresden NOAC Registry data complement the results of an analysis of three Danish registries, which demonstrated that both dabigatran doses (110 mg and 150 mg twice daily) were associated with lower rates of intracranial haemorrhage than that with VKAs (6). The rate of gastrointestinal bleeding with the 110 mg dose of dabigatran was similar to that with VKAs, while the rate with the 150 mg dose was higher; findings in keeping with those reported in the RE-LY trial (16). Retrospective database studies are also providing useful information on real-world experience with dabigatran. A US study using pharmacy data from patients with atrial fibrillation compared the risk of bleeding events, including gastrointestinal bleeding and intracranial bleeding, in patients who switched to dabigatran after at least six months of warfarin therapy with that in patients who continued on warfarin (13). The risk-adjusted rate of any bleeding was higher in patients who switched to dabigatran compared with those who remained on warfarin, largely driven by an increased rate of gastrointestinal bleeding. Rates of intracranial bleeding, other bleeding and death were similar between the two groups.
Using data from 134,414 Medicare patients with newly diagnosed atrial fibrillation, the US Food and Drug Administration compared the efficacy and safety of dabigatran with those of warfarin (15). Compared with warfarin, dabigatran was associated with a lower risk of ischaemic stroke, intracranial haemorrhage and death, but an increased risk of major gastrointestinal bleeding. The risk of myocardial infarction was similar with dabigatran and warfarin. Overall, therefore, the real-world experience with dabigatran is in line with the results of the RE-LY trial (1). Where do we go from here? Some clinicians have opined that when used in clinical practice, the trough anticoagulant activity of dabigatran or dabigatran drug levels should be measured soon after initiating therapy so as to enable upward dose adjustment if the level is too low to prevent ischaemic stroke, or downward adjustment to reduce the risk of serious bleeding if the level is too high (20). Current data provide no evidence to support this approach. Although gastrointestinal bleeding is increased with some NOACs (21), unmonitored dabigatran was at least as effective as monitored warfarin therapy for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism, and dabigatran was associated with less intracranial bleeding. Furthermore, not only are tests to measure dabigatran levels, such as the dilute thrombin time or the ecarin clot time, not widely available, but even if levels are measured, within patient variability in
the test results limits their utility. Thus, a recent study evaluating serial dabigatran levels in atrial fibrillation patients showed that up to 40 % of patients whose trough levels were in the upper extreme and up to 80 % of patients whose trough levels were in the lower extreme one month after starting the drug had subsequent dabigatran levels that fell within middle quartiles (22). Therefore, dose adjustments based on drug levels may be hazardous and without randomised clinical trial data demonstrating a net improvement in efficacy and safety, implementation of routine monitoring and dose adjustment could lead to net harm for patients. In summary, the data presented by Beyer-Westendorf et al. add to a growing body of evidence supporting the efficacy and safety of the NOACs for stroke prevention in atrial fibrillation across the spectrum of patient risk. These data should provide clinicians with the confidence to prescribe NOACs such as dabigatran. The findings also endorse guidelines (21, 22) which give preference to NOACs over warfarin for stroke prevention in most patients with non-valvular atrial fibrillation. Conflicts of interest
J. Eikelboom has received consulting fees and/or honoraria from Astra-Zeneca, Bayer, Boehringer-Ingelheim, BMS, Daiichi-Sankyo, Eli-Lilly, GSK, Pfizer, Janssen, and Sanofi-Aventis as well as grants and/or in-kind support from Astra-Zeneca, Bayer, Boehringer-Ingelheim, BMS, GSK, Pfizer, Janssen, and Sanofi-Aventis. J. Weitz has served as a consultant and received honoraria from Boehringer-Ingelheim, Bayer, Janssen, Johnson & Johnson, BMS, Pfizer, Daiichi-Sankyo, Portola, and Isis Pharmaceuticals.
References 1. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383: 955–962. 2. Yeh CH, Gross PL, Weitz JI. Evolving use of new oral anticoagulants for treatment of venous thromboembolism. Blood 2014; 124: 1020–1028. 3. Hankey GJ. Unanswered questions and research priorities to optimise stroke prevention in atrial fi-
Thrombosis and Haemostasis 113.6/2015 Downloaded from www.thrombosis-online.com on 2015-05-31 | ID: 1000466526 | IP: 147.188.128.74 For personal or educational use only. No other uses without permission. All rights reserved.
© Schattauer 2015
Invited Editorial Focus
4.
5.
6.
7.
8.
9.
brillation with the new oral anticoagulants. Thromb Haemost 2014; 111: 808–816. Hylek EM, Ko D, Cove CL. Gaps in translation from trials to practice: non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in atrial fibrillation. Thromb Haemost 2014; 111: 783–788. De Caterina R, Husted S, Wallentin L, et al. Vitamin K antagonists in heart disease: current status and perspectives (Section III). Position paper of the ESC Working Group on Thrombosis--Task Force on Anticoagulants in Heart Disease. Thromb Haemost 2013; 110: 1087–1107. Larsen TB, Rasmussen LH, Skjoth F, et al. Efficacy and safety of dabigatran etexilate and warfarin in „real-world“ patients with atrial fibrillation: a prospective nationwide cohort study. J Am Coll Cardiol 2013; 61: 2264–2273. Sorensen R, Gislason G, Torp-Pedersen C, et al. Dabigatran use in Danish atrial fibrillation patients in 2011: a nationwide study. Br Med J Open 2013; 3. Larsen TB, Gorst-Rasmussen A, Rasmussen LH, et al. Bleeding events among new starters and switchers to dabigatran compared with warfarin in atrial fibrillation. Am J Med 2014; 127: 650–656. Olesen JB, Sorensen R, Hansen ML, et al. Non-vitamin K antagonist oral anticoagulation agents in anticoagulant naive atrial fibrillation patients: Danish nationwide descriptive data 2011–2013. Europace 2015; 17: 187–193.
© Schattauer 2015
10. Southworth MR, Reichman ME, Unger EF. Dabigatran and postmarketing reports of bleeding. N Engl J Med 2013; 368: 1272–1274. 11. Vaughan Sarrazin MS, Jones M, et al. Bleeding rates in Veterans Affairs patients with atrial fibrillation who switch from warfarin to dabigatran. Am J Med 2014; 127: 1179–1185. 12. Hernandez I, Baik SH, Pinera A, et al. Risk of bleeding with dabigatran in atrial fibrillation. J Am Med Assoc Intern Med 2015; 175: 18–24. 13. Graham DJ, Reichman ME, Wernecke M, et al. Cardiovascular, bleeding, and mortality risks in elderly medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation 2015; 131: 157–164. 14. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139–1151. 15. Beyer-Westendorf J, Gelbricht V, Forster K, et al. Safety of switching from vitamin K antagonists to dabigatran or rivaroxaban in daily care--results from the Dresden NOAC registry. Br J Clin Pharmacol 2014; 78: 908–917. 16. Beyer-Westendorf J, Gelbricht V, Forster K, et al. Peri-interventional management of novel oral anticoagulants in daily care: results from the prospective Dresden NOAC registry. Eur Heart J 2014; 35: 1888–1896. 17. Beyer-Westendorf J, Forster K, Pannach S, et al. Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry. Blood 2014; 124: 955–962.
18. Chin PK, Wright DF, Patterson DM, et al. A proposal for dose-adjustment of dabigatran etexilate in atrial fibrillation guided by thrombin time. Br J Clin Pharmacol 2014; 78: 599–609. 19. Vanassche T, Hirsh J, Eikelboom JW, et al. Organspecific bleeding patterns of anticoagulated patient: lessons from clinical trials. Thromb Haemost 2014; 112: 918–923. 20. Chan NC, Coppens M, Hirsh J, et al. Real-world variability in dabigatran levels in patients with atrial fibrillation. J Thromb Haemost 2014; Epub ahead of print. 21. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012; 33: 2719–2747. 22. Verma A, Cairns JA, Mitchell LB, et al. 2014 focused update of the Canadian Cardiovascular Society Guidelines for the management of atrial fibrillation. Can J Cardiol 2014; 30: 1114–1130. 23. Beyer-Westendorf J, Ebertz F, Förster K, et al. Effectiveness and safety of dabigatran therapy in daily-care patients with atrial fibrillation. Results from the Dresden NOAC Registry. Thromb Haemost 2015; 113: 1247-1257.
Thrombosis and Haemostasis 113.6/2015 Downloaded from www.thrombosis-online.com on 2015-05-31 | ID: 1000466526 | IP: 147.188.128.74 For personal or educational use only. No other uses without permission. All rights reserved.
1161
