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Determinants and consequences of differences in quality of anticoagulation therapy with vitamin K antagonists
TR-05956; No of Pages 2 Thrombosis Research xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Editorial
Determinants and consequences of differences in quality of anticoagulation therapy with vitamin K antagonists☆ Keywords: Vitamin K antagonists iTTR Quality DOACs Atrial fibrillation Venous thrombosis
Editorial Although direct oral anticoagulants (DOACs) are not novel anymore, vitamin K antagonists (VKAs) still comprise the core of anticoagulation therapy. In a cohort from the United States (2010-2012), 62% of patients with non-valvular atrial fibrillation (AF) were prescribed warfarin [1], and data from Europe (2013) showed a range of DOAC use between 0.3% (Italy) and 11.6% (Germany) [2] in the same patient group. Efficacy and safety of treatment with VKAs can be high but the therapeutic window (as measured by the international normalized ratio [INR]) is narrow. The individual time in therapeutic range (iTTR, generally between 2.0 and 3.0 INR) is an established measure of quality of treatment with VKAs [3] and has been recommended to be at least 65-70% in order to ensure high quality [4]. However, this benchmark is not always achieved due to many reasons. Among these are age, sex, type of VKA, target INR range, indication, frequency of control moments, experience of the physician and the patient with VKAs, and geographic location. A nice illustration of the latter two factors is provided by the study of Singer et al. from 2013 [5]. The authors looked into factors that were associated with a good iTTR in patients randomized to warfarin in the ROCKET AF trial, a large international trial comparing warfarin with dabigatran. After multivariate analysis, geographic region and previous VKA use were main determinants of iTTR. Mean iTTR of warfarin-experienced users was 61% overall versus 47% in VKA-naïve patients, while mean iTTR was lowest in India (36%) and highest in Canada/United States (64%) and Western Europe (63%). Numbers improved slightly after exclusion of the first 3 months of VKA initiation (India 40%, Canada/United States 66% and Western Europe 67%). Part of the differences found might be explained by significant differences in the interval between INR controls (Canada/United States and Western Europe mean 19 and 20 days respectively, Eastern Europe and East Asia mean 23 days). In a large retrospective cohort study of patients with AF from the United States the mean iTTR was 54% [6]. This increased to 58% when the patients and the treating physicians got more experienced in treatment with VKAs, as well as with lower age of the patient, male sex and a ☆ Editorial to: Warfarin treatment quality is consistently high in both anticoagulation clinics and primary care setting in Sweden (TR-D-15-00039).
higher income. Le Heuzey et al. reported iTTRs in Europe, that ranged from 64% to 79% in this study of patients with AF. Main determinant of variation was the half-life of the drug, with increasing iTTRs with increasing half-life [2]. This is contradicted by results from a new study on long-term quality of VKA treatment in patients with nonvalvular AF and venous thrombosis (VT) who were predominantly using acenocoumarol (half-life 8-11 hours) and monitored by a specialized anticoagulation clinic, which is common practise in the Netherlands. In stable long-term users the iTTR was as high as 81% (therapeutic range in the Netherlands is 2.0-3.5 INR) [7]. Other determinants of quality of VKA treatment in this study were female sex, AF as indication of anticoagulation and higher age, the latter in contrast with results of the study of Dlott et al. [6]. In a prospective cohort study of VKA-naïve patients older than 80 years from Italy [8], median iTTR was only 62%. However, this seemed not to increase the incidence rate of major bleedings according to ISTH criteria [9]. The incidence in this study was 1.87 per 100 patient years, which appears to be low when compared with the incidence of major bleedings in the general population reported by Kooistra et al. (2.8 per 100 person years in stable long-term VKA users with a mean age of 73.3 years) [7]. Second, in the Italian study, there was no difference in iTTR between patients who had experienced a major bleeding and who did not. Overall, it seems that in study settings the United States, Canada and Western Europe have the highest quality of anticoagulation treatment, although they hardly cross the minimum threshold of 65% iTTR. In real-life, iTTR benchmarks vary more between the United States and different countries in (Western) Europe, ranging from 58% in the United States [6] to as a high as 77% in a recent Swedish study [10] and 81% in the Netherlands [7]. Although a correct comparison can hardly be made between these studies, one other determinant of quality of anticoagulation with VKAs could be the site of monitoring (specialized centres versus primary care physicians). In this issue of Thrombosis Research Björck et al. show that general quality of VKA treatment in patients with AF, VT or heart valve disease in Sweden is very high, with a mean iTTR of 76.5% [11]. Mean age was 72.9 years of patients treated in specialized anticoagulation centres and 75.5 years in the primary health care setting. In the former, indication for treatment was more often heart valve disease or planned direct current cardio conversion (DC), and patients had more frequent a history of stroke. Although two different settings were compared, both primary care and specialized centres used the same computerized algorithm. There appears to be a small but statistically significant advantage in iTTR between monitoring at a primary care setting versus specialized anticoagulation clinics (79.6% versus 75.7%), although both achieved iTTRs well above the 65-70% threshold recommended by the European Society of Cardiology [4] and NICE guidelines [12]. Numbers increased to 80% and 77% respectively after exclusion of patients with
http://dx.doi.org/10.1016/j.thromres.2015.05.009 0049-3848/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article as: V. Tichelaar, K. Meijer, Determinants and consequences of differences in quality of anticoagulation therapy with vitamin K antagonists, Thromb Res (2015), http://dx.doi.org/10.1016/j.thromres.2015.05.009
2
Editorial
AF and DC, propensity score matching and limiting to the majority of patients (93%) who had a therapeutic range of 2.0-3.0 INR. A possible explanation for the difference in iTTR between primary health care centres and specialized anticoagulation clinics might be that the first have a higher proportion of VKA-experienced patients. The authors did not find a difference in the incidence of major bleeding (2.26 versus 2.22 per 100 person years [py]) or thromboembolism (2.66 versus 2.66 per 100 py). Although patients were selected from a Swedish national quality register (AuriculA), bias regarding the overall quality of VKA treatment is not likely as about 50% of all patients on warfarin in Sweden are in this register without a regional preference for the use of this register. Even though the small difference in iTTR favours primary health care, which might be due to residual bias, this study does not clearly indicate that further centralization would be beneficial in the Swedish system. Together, we can conclude that treatment with VKAs in North-West Europe is of high quality. Two important questions remain: can this high quality treatment with individualized intense monitoring stand up against the good performance of DOACs in real life? In phase III trials compared to warfarin, DOACs are more feasible, at least as effective and probably safer in the treatment of VT and prevention of stroke in patients with AF. Especially the safety profile of apixaban seems appealing (relative risk of major bleeding in VT patients with apixaban compared to warfarin 0.31 [95%CI 0.17-0.55] [13] and in AF patients 0.69 [95%CI 0.60-0.80] [14]) compared to that of rivaroxaban and dabigatran, although all three caused less intracranial bleeding in AF patients in phase III trials [14]. However, a direct head-to-head comparison between DOACs has not been performed and probably will never be, so some caution must be taken into account when comparing these data mutually as well as with data from observational studies of patients on warfarin. Second, as calculated by van der Hulle et al. in a metaanalysis of phase III trials that compared DOACs with VKAs in patients with an acute VT, the number needed to treat with DOACs to prevent 1 major bleed was 149 (95%CI 88-476) [13], pointing out considerable costs of this strategy. As we speak, a Dutch multicentre randomized clinical trial is running in order to assess real-life efficacy, safety and costeffectiveness of DOACs compared to standard care (in the Netherlands mainly with phenoprocoumon and acenocoumarol) in patients with non-valvular AF who are stable, long-term users of VKAs with an iTTR N 70% (http://www.trialregister.nl, NTR4770). Finally, what to do when the high quality of anticoagulation cannot be achieved (anymore) in some patients? Recently, Kooistra et al. showed that this might happen suddenly, even in patients who were previously perfectly well anticoagulated. They defined extreme over anticoagulation (EO) as an INR N 8.0 or unscheduled supplementation of vitamin K. Fifty-one percent of patients with an EO had an iTTR N 65% [median iTTR just before EO 66%]. Notably, after an EO, quality of VKA treatment worsened even more, increasing the proportion of patients with iTTR b65% from 49% before EO to 62%. This was mainly due to an increase in under anticoagulation with 12% (from 2% pre-EO to 18% post-EO), even though the frequency of INR monitoring increased after the EO. Having an EO was associated with an increased risk of major bleeding (hazard ratio 7.4 [95% CI 1.5-36.7]), any thrombotic event (hazard ratio 5.7 [95%CI 1.5-22.2]) and VKA related death (hazard ratio 17.0 [95%CI 2.1-138]) [7]. Some suggested that these patients might benefit from switching to DOACs [15] because these drugs might be less susceptible to variation in efficacy and safety because of less drug-drug and drug-food interactions. However, this hypothesis has not been tested in any clinical study yet. In conclusion, Björck et al. show in this issue of Thrombosis Research that the quality of anticoagulation with VKAs in patients with VT or AF is very high in Sweden whether monitored by highly specialized anticoagulation centres or primary health care centre (physician) in an individualized way [11]. However, this is not representative for all regions in the world. Accordingly, it seems that DOACs play a different role in anticoagulation therapy in different geographical regions, although the
real-life benefit and cost-effectiveness of this strategy has yet to be determined in patients who have a high quality of anticoagulation with VKAs. Conflicts of interest The authors have no conflicts of interest. References [1] J.C. Lauffenburger, J.F. Farley, A.K. Gehi, D.H. Rhoney, M.A. Brookhart, G. Fang, Factors driving anticoagulant selection in patients with atrial fibrillation in the United States, Am J Cardiol 115 (2015) 1095–1101. [2] J.Y. Le Heuzey, B. Ammentorp, H. Darius, R. De Caterina, R.J. Schilling, J. Schmitt, et al., Differences among western European countries in anticoagulation management of atrial fibrillation. Data from the PREFER IN AF registry, Thromb Haemost 111 (2014) 833–841. [3] F.R. Rosendaal, S.C. Cannegieter, F.J. van der Meer, E. Briet, A method to determine the optimal intensity of oral anticoagulant therapy, Thromb Haemost 69 (1993) 236–239. [4] A.J. Camm, G.Y. Lip, R. De Caterina, I. Savelieva, D. Atar, S.H. Hohnloser, 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 33 (2012) 2719–2747. [5] D.E. Singer, A.S. Hellkamp, J.P. Piccini, K.W. Mahaffey, Y. Lokhnygina, G. Pan, et al., Impact of global geographic region on time in therapeutic range on warfarin anticoagulant therapy: data from the ROCKET AF clinical trial, J Am Heart Assoc 2 (2013) e000067. [6] J.S. Dlott, R.A. George, X. Huang, M. Odeh, H.W. Kaufman, J. Ansell, et al., National assessment of warfarin anticoagulation therapy for stroke prevention in atrial fibrillation, Circulation 129 (2014) 1407–1414. [7] H.A. Kooistra, N.J. Veeger, N. Khorsand, H.C. Kluin-Nelemans, K. Meijer, M. PiersmaWichers, Long-term quality of VKA treatment and clinical outcome after extreme overanticoagulation in 14,777 AF and VTE patients, Thromb Haemost 113 (2015) 881–890. [8] D. Poli, E. Antonucci, S. Testa, A. Tosetto, W. Ageno, G. Palareti, et al., Bleeding risk in very old patients on vitamin K antagonist treatment: results of a prospective collaborative study on elderly patients followed by Italian Centres for Anticoagulation, Circulation 124 (2011) 824–829. [9] S. Schulman, C. Kearon, Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients, J. Thromb Haemost 3 (2005) 692–694. [10] V. Sjogren, B. Grzymala-Lubanski, H. Renlund, L. Friberg, G.Y. Lip, P.J. Svensson, et al., Safety and efficacy of well managed warfarin. A report from the Swedish quality register Auricula, Thromb Haemost 113 (2015). [11] F. Björck, P. Sandén, H. Renlund, P.J. Svensson, A. Själander, Warfarin treatment quality is consistently high in both anticoagulation clinics and primary care setting in Sweden, Thromb Res (Apr 22 2015). http://dx.doi.org/10.1016/j.thromres.2015.04. 016 (pii: S0049-3848(15)00188-7, in this issue). [12] National Clinical Guideline C, Atrial Fibrillation: The Management of Atrial Fibrillation, National Clinical Guideline Centre, London, 2014. [13] T. van der Hulle, J. Kooiman, P.L. den Exter, O.M. Dekkers, F.A. Klok, M.V. Huisman, Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis, J Thromb Haemost 12 (2014) 320–328. [14] C.S. Miller, S.M. Grandi, A. Shimony, K.B. Filion, M.J. Eisenberg, Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation, Am J Cardiol 110 (2012) 453–460. [15] V. Roldan, F. Marin, The importance of excellence in the quality of anticoagulation control whilst taking vitamin K antagonists, Thromb Haemost 113 (2015) 671–673.
Vladimir Tichelaar K.G. Jebsen Thrombosis Research and Expertise Centre (TREC), Department of Clinical Medicine, The Arctic University of Norway, Tromsø, Norway Division of Haemostasis and Thrombosis, Department of Haematology, University Medical Centre Groningen, Groningen, the Netherlands Corresponding author at: K.G. Jebsen TREC, det Helsevitenskapelige fakultet, UiT - Norges Arktiske Universitet, Farmasibygget, 9037 Tromsø, Norge. E-mail address: [email protected]. Karina Meijer Division of Haemostasis and Thrombosis, Department of Haematology, University Medical Centre Groningen, Groningen, the Netherlands 5 May 2015 Available online xxxx
Please cite this article as: V. Tichelaar, K. Meijer, Determinants and consequences of differences in quality of anticoagulation therapy with vitamin K antagonists, Thromb Res (2015), http://dx.doi.org/10.1016/j.thromres.2015.05.009
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Editorial
Determinants and consequences of differences in quality of anticoagulation therapy with vitamin K antagonists☆ Keywords: Vitamin K antagonists iTTR Quality DOACs Atrial fibrillation Venous thrombosis
Editorial Although direct oral anticoagulants (DOACs) are not novel anymore, vitamin K antagonists (VKAs) still comprise the core of anticoagulation therapy. In a cohort from the United States (2010-2012), 62% of patients with non-valvular atrial fibrillation (AF) were prescribed warfarin [1], and data from Europe (2013) showed a range of DOAC use between 0.3% (Italy) and 11.6% (Germany) [2] in the same patient group. Efficacy and safety of treatment with VKAs can be high but the therapeutic window (as measured by the international normalized ratio [INR]) is narrow. The individual time in therapeutic range (iTTR, generally between 2.0 and 3.0 INR) is an established measure of quality of treatment with VKAs [3] and has been recommended to be at least 65-70% in order to ensure high quality [4]. However, this benchmark is not always achieved due to many reasons. Among these are age, sex, type of VKA, target INR range, indication, frequency of control moments, experience of the physician and the patient with VKAs, and geographic location. A nice illustration of the latter two factors is provided by the study of Singer et al. from 2013 [5]. The authors looked into factors that were associated with a good iTTR in patients randomized to warfarin in the ROCKET AF trial, a large international trial comparing warfarin with dabigatran. After multivariate analysis, geographic region and previous VKA use were main determinants of iTTR. Mean iTTR of warfarin-experienced users was 61% overall versus 47% in VKA-naïve patients, while mean iTTR was lowest in India (36%) and highest in Canada/United States (64%) and Western Europe (63%). Numbers improved slightly after exclusion of the first 3 months of VKA initiation (India 40%, Canada/United States 66% and Western Europe 67%). Part of the differences found might be explained by significant differences in the interval between INR controls (Canada/United States and Western Europe mean 19 and 20 days respectively, Eastern Europe and East Asia mean 23 days). In a large retrospective cohort study of patients with AF from the United States the mean iTTR was 54% [6]. This increased to 58% when the patients and the treating physicians got more experienced in treatment with VKAs, as well as with lower age of the patient, male sex and a ☆ Editorial to: Warfarin treatment quality is consistently high in both anticoagulation clinics and primary care setting in Sweden (TR-D-15-00039).
higher income. Le Heuzey et al. reported iTTRs in Europe, that ranged from 64% to 79% in this study of patients with AF. Main determinant of variation was the half-life of the drug, with increasing iTTRs with increasing half-life [2]. This is contradicted by results from a new study on long-term quality of VKA treatment in patients with nonvalvular AF and venous thrombosis (VT) who were predominantly using acenocoumarol (half-life 8-11 hours) and monitored by a specialized anticoagulation clinic, which is common practise in the Netherlands. In stable long-term users the iTTR was as high as 81% (therapeutic range in the Netherlands is 2.0-3.5 INR) [7]. Other determinants of quality of VKA treatment in this study were female sex, AF as indication of anticoagulation and higher age, the latter in contrast with results of the study of Dlott et al. [6]. In a prospective cohort study of VKA-naïve patients older than 80 years from Italy [8], median iTTR was only 62%. However, this seemed not to increase the incidence rate of major bleedings according to ISTH criteria [9]. The incidence in this study was 1.87 per 100 patient years, which appears to be low when compared with the incidence of major bleedings in the general population reported by Kooistra et al. (2.8 per 100 person years in stable long-term VKA users with a mean age of 73.3 years) [7]. Second, in the Italian study, there was no difference in iTTR between patients who had experienced a major bleeding and who did not. Overall, it seems that in study settings the United States, Canada and Western Europe have the highest quality of anticoagulation treatment, although they hardly cross the minimum threshold of 65% iTTR. In real-life, iTTR benchmarks vary more between the United States and different countries in (Western) Europe, ranging from 58% in the United States [6] to as a high as 77% in a recent Swedish study [10] and 81% in the Netherlands [7]. Although a correct comparison can hardly be made between these studies, one other determinant of quality of anticoagulation with VKAs could be the site of monitoring (specialized centres versus primary care physicians). In this issue of Thrombosis Research Björck et al. show that general quality of VKA treatment in patients with AF, VT or heart valve disease in Sweden is very high, with a mean iTTR of 76.5% [11]. Mean age was 72.9 years of patients treated in specialized anticoagulation centres and 75.5 years in the primary health care setting. In the former, indication for treatment was more often heart valve disease or planned direct current cardio conversion (DC), and patients had more frequent a history of stroke. Although two different settings were compared, both primary care and specialized centres used the same computerized algorithm. There appears to be a small but statistically significant advantage in iTTR between monitoring at a primary care setting versus specialized anticoagulation clinics (79.6% versus 75.7%), although both achieved iTTRs well above the 65-70% threshold recommended by the European Society of Cardiology [4] and NICE guidelines [12]. Numbers increased to 80% and 77% respectively after exclusion of patients with
http://dx.doi.org/10.1016/j.thromres.2015.05.009 0049-3848/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article as: V. Tichelaar, K. Meijer, Determinants and consequences of differences in quality of anticoagulation therapy with vitamin K antagonists, Thromb Res (2015), http://dx.doi.org/10.1016/j.thromres.2015.05.009
2
Editorial
AF and DC, propensity score matching and limiting to the majority of patients (93%) who had a therapeutic range of 2.0-3.0 INR. A possible explanation for the difference in iTTR between primary health care centres and specialized anticoagulation clinics might be that the first have a higher proportion of VKA-experienced patients. The authors did not find a difference in the incidence of major bleeding (2.26 versus 2.22 per 100 person years [py]) or thromboembolism (2.66 versus 2.66 per 100 py). Although patients were selected from a Swedish national quality register (AuriculA), bias regarding the overall quality of VKA treatment is not likely as about 50% of all patients on warfarin in Sweden are in this register without a regional preference for the use of this register. Even though the small difference in iTTR favours primary health care, which might be due to residual bias, this study does not clearly indicate that further centralization would be beneficial in the Swedish system. Together, we can conclude that treatment with VKAs in North-West Europe is of high quality. Two important questions remain: can this high quality treatment with individualized intense monitoring stand up against the good performance of DOACs in real life? In phase III trials compared to warfarin, DOACs are more feasible, at least as effective and probably safer in the treatment of VT and prevention of stroke in patients with AF. Especially the safety profile of apixaban seems appealing (relative risk of major bleeding in VT patients with apixaban compared to warfarin 0.31 [95%CI 0.17-0.55] [13] and in AF patients 0.69 [95%CI 0.60-0.80] [14]) compared to that of rivaroxaban and dabigatran, although all three caused less intracranial bleeding in AF patients in phase III trials [14]. However, a direct head-to-head comparison between DOACs has not been performed and probably will never be, so some caution must be taken into account when comparing these data mutually as well as with data from observational studies of patients on warfarin. Second, as calculated by van der Hulle et al. in a metaanalysis of phase III trials that compared DOACs with VKAs in patients with an acute VT, the number needed to treat with DOACs to prevent 1 major bleed was 149 (95%CI 88-476) [13], pointing out considerable costs of this strategy. As we speak, a Dutch multicentre randomized clinical trial is running in order to assess real-life efficacy, safety and costeffectiveness of DOACs compared to standard care (in the Netherlands mainly with phenoprocoumon and acenocoumarol) in patients with non-valvular AF who are stable, long-term users of VKAs with an iTTR N 70% (http://www.trialregister.nl, NTR4770). Finally, what to do when the high quality of anticoagulation cannot be achieved (anymore) in some patients? Recently, Kooistra et al. showed that this might happen suddenly, even in patients who were previously perfectly well anticoagulated. They defined extreme over anticoagulation (EO) as an INR N 8.0 or unscheduled supplementation of vitamin K. Fifty-one percent of patients with an EO had an iTTR N 65% [median iTTR just before EO 66%]. Notably, after an EO, quality of VKA treatment worsened even more, increasing the proportion of patients with iTTR b65% from 49% before EO to 62%. This was mainly due to an increase in under anticoagulation with 12% (from 2% pre-EO to 18% post-EO), even though the frequency of INR monitoring increased after the EO. Having an EO was associated with an increased risk of major bleeding (hazard ratio 7.4 [95% CI 1.5-36.7]), any thrombotic event (hazard ratio 5.7 [95%CI 1.5-22.2]) and VKA related death (hazard ratio 17.0 [95%CI 2.1-138]) [7]. Some suggested that these patients might benefit from switching to DOACs [15] because these drugs might be less susceptible to variation in efficacy and safety because of less drug-drug and drug-food interactions. However, this hypothesis has not been tested in any clinical study yet. In conclusion, Björck et al. show in this issue of Thrombosis Research that the quality of anticoagulation with VKAs in patients with VT or AF is very high in Sweden whether monitored by highly specialized anticoagulation centres or primary health care centre (physician) in an individualized way [11]. However, this is not representative for all regions in the world. Accordingly, it seems that DOACs play a different role in anticoagulation therapy in different geographical regions, although the
real-life benefit and cost-effectiveness of this strategy has yet to be determined in patients who have a high quality of anticoagulation with VKAs. Conflicts of interest The authors have no conflicts of interest. References [1] J.C. Lauffenburger, J.F. Farley, A.K. Gehi, D.H. Rhoney, M.A. Brookhart, G. Fang, Factors driving anticoagulant selection in patients with atrial fibrillation in the United States, Am J Cardiol 115 (2015) 1095–1101. [2] J.Y. Le Heuzey, B. Ammentorp, H. Darius, R. De Caterina, R.J. Schilling, J. Schmitt, et al., Differences among western European countries in anticoagulation management of atrial fibrillation. Data from the PREFER IN AF registry, Thromb Haemost 111 (2014) 833–841. [3] F.R. Rosendaal, S.C. Cannegieter, F.J. van der Meer, E. Briet, A method to determine the optimal intensity of oral anticoagulant therapy, Thromb Haemost 69 (1993) 236–239. [4] A.J. Camm, G.Y. Lip, R. De Caterina, I. Savelieva, D. Atar, S.H. Hohnloser, 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 33 (2012) 2719–2747. [5] D.E. Singer, A.S. Hellkamp, J.P. Piccini, K.W. Mahaffey, Y. Lokhnygina, G. Pan, et al., Impact of global geographic region on time in therapeutic range on warfarin anticoagulant therapy: data from the ROCKET AF clinical trial, J Am Heart Assoc 2 (2013) e000067. [6] J.S. Dlott, R.A. George, X. Huang, M. Odeh, H.W. Kaufman, J. Ansell, et al., National assessment of warfarin anticoagulation therapy for stroke prevention in atrial fibrillation, Circulation 129 (2014) 1407–1414. [7] H.A. Kooistra, N.J. Veeger, N. Khorsand, H.C. Kluin-Nelemans, K. Meijer, M. PiersmaWichers, Long-term quality of VKA treatment and clinical outcome after extreme overanticoagulation in 14,777 AF and VTE patients, Thromb Haemost 113 (2015) 881–890. [8] D. Poli, E. Antonucci, S. Testa, A. Tosetto, W. Ageno, G. Palareti, et al., Bleeding risk in very old patients on vitamin K antagonist treatment: results of a prospective collaborative study on elderly patients followed by Italian Centres for Anticoagulation, Circulation 124 (2011) 824–829. [9] S. Schulman, C. Kearon, Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients, J. Thromb Haemost 3 (2005) 692–694. [10] V. Sjogren, B. Grzymala-Lubanski, H. Renlund, L. Friberg, G.Y. Lip, P.J. Svensson, et al., Safety and efficacy of well managed warfarin. A report from the Swedish quality register Auricula, Thromb Haemost 113 (2015). [11] F. Björck, P. Sandén, H. Renlund, P.J. Svensson, A. Själander, Warfarin treatment quality is consistently high in both anticoagulation clinics and primary care setting in Sweden, Thromb Res (Apr 22 2015). http://dx.doi.org/10.1016/j.thromres.2015.04. 016 (pii: S0049-3848(15)00188-7, in this issue). [12] National Clinical Guideline C, Atrial Fibrillation: The Management of Atrial Fibrillation, National Clinical Guideline Centre, London, 2014. [13] T. van der Hulle, J. Kooiman, P.L. den Exter, O.M. Dekkers, F.A. Klok, M.V. Huisman, Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis, J Thromb Haemost 12 (2014) 320–328. [14] C.S. Miller, S.M. Grandi, A. Shimony, K.B. Filion, M.J. Eisenberg, Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation, Am J Cardiol 110 (2012) 453–460. [15] V. Roldan, F. Marin, The importance of excellence in the quality of anticoagulation control whilst taking vitamin K antagonists, Thromb Haemost 113 (2015) 671–673.
Vladimir Tichelaar K.G. Jebsen Thrombosis Research and Expertise Centre (TREC), Department of Clinical Medicine, The Arctic University of Norway, Tromsø, Norway Division of Haemostasis and Thrombosis, Department of Haematology, University Medical Centre Groningen, Groningen, the Netherlands Corresponding author at: K.G. Jebsen TREC, det Helsevitenskapelige fakultet, UiT - Norges Arktiske Universitet, Farmasibygget, 9037 Tromsø, Norge. E-mail address: [email protected]. Karina Meijer Division of Haemostasis and Thrombosis, Department of Haematology, University Medical Centre Groningen, Groningen, the Netherlands 5 May 2015 Available online xxxx
Please cite this article as: V. Tichelaar, K. Meijer, Determinants and consequences of differences in quality of anticoagulation therapy with vitamin K antagonists, Thromb Res (2015), http://dx.doi.org/10.1016/j.thromres.2015.05.009