EDITORIAL The Changing Face of Anticoagulation Management: An Improving Countenance William L. Baker* University of Connecticut School of Pharmacy, Storrs, Connecticut
KEY WORDS anticoagulants, anticoagulation clinic, anticoagulation management, warfarin. (Pharmacotherapy 2013;33(11):1133--1135) doi: 10.1002/phar.1377
For decades, the lone oral anticoagulant available for the prevention and treatment of arterial and venous thromboembolic events in the United States was the vitamin K antagonist warfarin. The challenges and management issues related to warfarin use have been well documented.1 Because of the narrow therapeutic index of warfarin, continuous laboratory monitoring is required to maximize its antithrombotic effect and minimize bleeding risk. This has resulted in attempts to improve warfarin control by evaluating various anticoagulation management models, identifying patient factors that are predictive of poor control (e.g., pharmacogenomics), and adding concomitant therapies (e.g., oral low-dose vitamin K), as well as seeking alternative anticoagulants. Each of these areas is worthy of discussion, as they help shape the landscape of modern anticoagulation management and provide guidance for future directions in practice. A number of anticoagulation management models currently exist, including routine medical care, designated anticoagulation clinics, and patient self-testing and self-management.2, 3 Our group demonstrated that patients with atrial fibrillation who receive warfarin for prevention of stroke in the United States spend, on average, 55% of their time within the therapeutic international normalized ratio (INR) range (percentage of time that the INR is in therapeutic range *Author for correspondence: William L. Baker, Assistant Professor of Pharmacy Practice, University of Connecticut School of Pharmacy, 69 N. Eagleville Road, Unit 3092, Storrs, CT 06269-3092; e-mail: [email protected]. Ó 2013 American College of Clinical Pharmacy
[TTR]).4 This control differed based on management model, with patients seen in communitybased settings (e.g., routine medical care) having a TTR of approximately 51% and those seen in anticoagulation clinics having a much higher TTR (~63%). Moreover, studies have shown improved outcomes (fewer thrombotic and bleeding events) in patients seen in anticoagulation clinics versus those seen in routine medical care.5, 6 Given the large number (over 1500) of anticoagulation clinics throughout the United States registered with the Anticoagulation Forum (www.acforum.com), with many employing pharmacists, improvement in patient care remains a prominent research priority. In this issue of Pharmacotherapy, Dr. Tammy Bungard and colleagues report the results of a large survey of patients receiving anticoagulation management from a dedicated clinic.7 They showed that most patients were satisfied with their anticoagulation care at a clinic, and nearly three quarters preferred clinic management versus family physician care. Given that the patients were all being managed at anticoagulation clinics at the time of the survey, the results are not particularly surprising. The lack of a control arm of patients being managed by routine medical care potentially limits the applicability of their data, particularly regarding patient preference of management setting. However, this study did show that patients appreciated the more specialized attention they received from a dedicated anticoagulation clinic and felt that they were more appropriately educated on both their medical condition and their drug therapy.
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Additional improvements to anticoagulation care have been made within dedicated clinic settings with the advent of patient self-testing and self-management.8 A recent meta-analysis analyzed data from 22 trials, including more than 8400 patients evaluating whether patient self-testing, either alone or in combination with self-management (patient self-adjusting their anticoagulant dosage), improved major clinical outcomes (both thromboembolic and hemorrhagic) compared with usual care.9 They showed that mortality and major thromboembolism were both significantly reduced with patient self-testing and/or self-management, with no increase in major bleeding versus usual care. Recent studies have attempted to utilize the advantages of patient self-testing and self-management and combine them with technologic advances and pharmacists’ skills to improve anticoagulant management. In this issue of Pharmacotherapy, two studies report on a hybrid system entitled self-testing with online remote monitoring and management (STORM2).10, 11 With this system, patients were provided with extensive education, and they used an at-home point-of-care testing device, uploaded their results onto a secure Web site, and were able to interact virtually with an anticoagulation clinic member. Dr. Henry Bussey and colleagues showed that their STORM2 system resulted in a 25% point increase in the TTR compared with the preintervention period.10 This system has the benefit of utilizing technology in addition to anticoagulation expert input to maximize INR control while minimizing patient burden. Not surprisingly, Dr. Sarah Meyer and colleagues reported that this system of INR monitoring was preferred by 90% of patients compared with routine anticoagulation clinic monitoring.11 It also appeared that this system may be less costly to patients, although a formal cost analysis was not performed. A 2007 cost-effectiveness analysis of studies conducted in the United Kingdom suggested that patient self-management was unlikely to be more cost-effective than management in an anticoagulation clinic, although the comparability of these data to practices in the United States is unclear.12 Thus, the long-term benefits of this type of intensive, patient-driven anticoagulation monitoring system remains unclear. It is likely that the level of education and technologic savvy required for this system to be successful may be appropriate for a select subset of clinic patients but may not be generalizable for all.
As part of the STORM2 study, genetic polymorphism testing (cytochrome P450 [CYP] 2C9 and vitamin K epoxide reductase complex 1 [VKORC1]) was also performed to evaluate the relationship between genetic polymorphism and INR stability.10 Genetic variations in CYP2C9 and VKORC1, among others, may contribute to the interpatient variability of response to warfarin.13 A variety of algorithms utilizing genetic information have been created in an attempt to provide warfarin dosing recommendations, both initially as well as long-term, when combined with clinical information.14 Although clinical trials have shown that use of warfarin dosing algorithms that include pharmacogenetic information gets patients to a goal INR more quickly and results in fewer out-of-range INR values and increased TTR,15 current guidelines recommend against their routine use.16 Moreover, warfarinrelated genotyping has not been found to be costeffective in the management of patients with atrial fibrillation.17 Along these lines, Dr. Bussey and colleagues did not find differences in changes in warfarin dose or INR stability by genetic polymorphism subgroup.10 However, this was not a primary objective in their study, and the number of patients was low, potentially affecting the applicability of their data. Despite these findings, the Clinical Pharmacogenomics Implementation Consortium continues to advocate for the evaluation and proper interpretation of genetic information to aid in warfarin dosing.18 Additional clinical trials are ongoing that are comparing genotype-guided dosing with routine clinical dosing, with results for some trials expected to be available by the end of 2013.19 Pending positive results from these clinical trials, pharmacists are uniquely positioned to aid in the proper interpretation and utilization of pharmacogenomic data. In this issue of Pharmacotherapy, Dr. Edith Nutescu and colleagues report on the feasibility of implementing an inpatient clinical warfarin pharmacogenomic service.20 They found that when genotype data were available quickly (76% were available prior to the second warfarin dose), genotype-guided warfarin dose information could be provided within a median of 30 hours. Nearly three quarters of their warfarin dose recommendations were followed within 0.5 mg of the daily dose. The clinical impact of such a service was not reported. However, it does provide an avenue for properly trained clinical pharmacists to contribute to the health care team and potentially positively impact patient outcomes.
CHANGING FACE OF ANTICOAGULATION MANAGEMENT Baker The most recent advance in the area of anticoagulation management is the commercial availability of oral anticoagulants that are alternatives to warfarin: apixaban, dabigatran, and rivaroxaban. Studies have shown these new agents to be either noninferior or superior to warfarin and other antithrombotic agents, with similar or improved safety profiles.21 These agents have the possibility to significantly affect the landscape of anticoagulation management and the role of dedicated anticoagulation clinics moving forward. Pharmacists and those working in dedicated clinics can, however, plan an integral role in the management of patients receiving these newer agents. This could include, but may not be limited to, ensuring appropriate agent selection based on the patient’s clinical factors, screening for drug interactions, assessing compliance issues and safety parameters, and providing practitioner and patient disease state and drug education. In summary, changes in the anticoagulation landscape are coming that may significantly impact the roles of anticoagulation clinics in the future. These include an increased role for patient self-testing and self-management, availability of pharmacogenomic information and automated dosing algorithms, and approval of novel oral anticoagulants as alternatives to warfarin. However, with each of these advances, a role for a highly educated and well-trained anticoagulation specialist is evident. The need exists for educating patients and caregivers about emerging self-monitoring technologies, aiding in interpretation and utilization of pharmacogenomic information, and appropriately selecting and monitoring new oral anticoagulants. These services will continue to be in high demand. The anticoagulation specialist will also need to provide other antithrombotic functions such as formulary management, management of bleeding and anticoagulant reversal, periprocedural antithrombotic recommendations, coordination during transitions of care, and health care team education.22 The face of anticoagulation services has become brighter as tremendous opportunities continue to evolve for fruitful collaboration and research. References 1. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 suppl):e44S–88S. 2. Testa S, Paoletti O, Zimmermann A, Bassi L, Zambelli S, Cancellieri E. The role of anticoagulation clinics in the era of new oral anticoagulants. Thrombosis 2012;2012:835356.
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3. Nutescu EA. The future of anticoagulation clinics. J Thromb Thrombolysis 2003;16:61–3. 4. Baker WL, Cios DA, Sander SD, Coleman CI. Meta-analysis to assess the quality of warfarin control in atrial fibrillation patients in the United States. J Manag Care Pharm 2009;15:244–52. 5. Hall D, Buchanan J, Helms B, et al. Health care expenditures and therapeutic outcomes of a pharmacist-managed anticoagulation service versus usual medical care. Pharmacotherapy 2011;31:686–94. 6. Wilson SJ, Wells PS, Kovacs MJ, et al. Comparing the quality of oral anticoagulant management by anticoagulation clinics and by family physicians: a randomized controlled trial. CMAJ 2003;169:293–8. 7. Bungard TJ, Barry AR, Jones C, Brocklebank C. Patient satisfaction with services provided by multidisciplinary anticoagulation clinics. Pharmacotherapy 2013;33:1246–51. 8. Nutescu EA, Bathija S, Sharp LK, Gerber BS, Schumock GT, Fitzgibbon ML. Anticoagulation patient self-monitoring in the Unites States: considerations for clinical practice adoption. Pharmacotherapy 2011;31:1161–74. 9. Bloomfield HE, Krause A, Greer N, et al. Meta-analysis: effect of patient self-testing and self-management of long-term anticoagulation on major clinical outcomes. Ann Intern Med 2011;154:472–82. 10. Bussey HI, Bussey M, Bussey-Smith KL, et al. Evaluation of warfarin management with international normalized ratio selftesting and online remote monitoring and management plus low-dose vitamin K and genomic considerations: a pilot study. Pharmacotherapy 2013;33:1136–46. 11. Meyer S, Frei CR, Daniels KR, et al. Impact of a new method of warfarin management on patient satisfaction, time, and cost. Pharmacotherapy 2013;33:1147–55. 12. Cannock M, Stevens C, Fry-Smith A, et al. Clinical effectiveness and cost-effectiveness of different models of managing long-term anticoagulation therapy: a systematic review and economic modeling. Health Technol Assess 2007;11:iii–iv, ix-66. 13. Jorgensen AL, Fitzgerald RJ, Oyee J, et al. Influence of CYP2C9 and VKORC1 on patient response to warfarin: a systematic review and meta-analysis. PLoS ONE 2012;7:e44064. 14. Sconce EA, Khan TI, Wynne HA, et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 2005;106:2329–33. 15. Anderson JL, Horne BD, Stevens SM, et al. A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-II). Circulation 2012;125:1997– 2005. 16. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):e152S–84S. 17. Eckman MH, Rosand J, Greenberg SM, Gage BF. Cost-effectiveness of using pharmacogenetic information in warfarin dosing for patients with nonvalvular atrial fibrillation. Ann Intern Med 2009;150:73–83. 18. Johnson JA, Gong L, Whirl-Carrillo M, et al. Clinical Pharmacogenetics Implementation Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011;90:625–9. 19. Kimmel SE, French B, Anderson JL, et al. Rationale and design of the clarification of optimal anticoagulation through genetics trial. Am Heart J 2013;166:435–41. 20. Nutescu EA, Drozda K, Bress AP, et al. Feasibility of implementing a comprehensive warfarin pharmacogenetics service. Pharmacotherapy 2013;33:1156–64. 21. Baker WL, Phung OJ. Systematic review and adjusted indirect comparison meta-analysis of oral anticoagulants in atrial fibrillation. Circ Cardiovasc Qual Outcomes 2012;5:711–9. 22. Nutescu EA. Anticoagulation management services: entering a new era. Pharmacotherapy 2010;30:327–9.
KEY WORDS anticoagulants, anticoagulation clinic, anticoagulation management, warfarin. (Pharmacotherapy 2013;33(11):1133--1135) doi: 10.1002/phar.1377
For decades, the lone oral anticoagulant available for the prevention and treatment of arterial and venous thromboembolic events in the United States was the vitamin K antagonist warfarin. The challenges and management issues related to warfarin use have been well documented.1 Because of the narrow therapeutic index of warfarin, continuous laboratory monitoring is required to maximize its antithrombotic effect and minimize bleeding risk. This has resulted in attempts to improve warfarin control by evaluating various anticoagulation management models, identifying patient factors that are predictive of poor control (e.g., pharmacogenomics), and adding concomitant therapies (e.g., oral low-dose vitamin K), as well as seeking alternative anticoagulants. Each of these areas is worthy of discussion, as they help shape the landscape of modern anticoagulation management and provide guidance for future directions in practice. A number of anticoagulation management models currently exist, including routine medical care, designated anticoagulation clinics, and patient self-testing and self-management.2, 3 Our group demonstrated that patients with atrial fibrillation who receive warfarin for prevention of stroke in the United States spend, on average, 55% of their time within the therapeutic international normalized ratio (INR) range (percentage of time that the INR is in therapeutic range *Author for correspondence: William L. Baker, Assistant Professor of Pharmacy Practice, University of Connecticut School of Pharmacy, 69 N. Eagleville Road, Unit 3092, Storrs, CT 06269-3092; e-mail: [email protected]. Ó 2013 American College of Clinical Pharmacy
[TTR]).4 This control differed based on management model, with patients seen in communitybased settings (e.g., routine medical care) having a TTR of approximately 51% and those seen in anticoagulation clinics having a much higher TTR (~63%). Moreover, studies have shown improved outcomes (fewer thrombotic and bleeding events) in patients seen in anticoagulation clinics versus those seen in routine medical care.5, 6 Given the large number (over 1500) of anticoagulation clinics throughout the United States registered with the Anticoagulation Forum (www.acforum.com), with many employing pharmacists, improvement in patient care remains a prominent research priority. In this issue of Pharmacotherapy, Dr. Tammy Bungard and colleagues report the results of a large survey of patients receiving anticoagulation management from a dedicated clinic.7 They showed that most patients were satisfied with their anticoagulation care at a clinic, and nearly three quarters preferred clinic management versus family physician care. Given that the patients were all being managed at anticoagulation clinics at the time of the survey, the results are not particularly surprising. The lack of a control arm of patients being managed by routine medical care potentially limits the applicability of their data, particularly regarding patient preference of management setting. However, this study did show that patients appreciated the more specialized attention they received from a dedicated anticoagulation clinic and felt that they were more appropriately educated on both their medical condition and their drug therapy.
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Additional improvements to anticoagulation care have been made within dedicated clinic settings with the advent of patient self-testing and self-management.8 A recent meta-analysis analyzed data from 22 trials, including more than 8400 patients evaluating whether patient self-testing, either alone or in combination with self-management (patient self-adjusting their anticoagulant dosage), improved major clinical outcomes (both thromboembolic and hemorrhagic) compared with usual care.9 They showed that mortality and major thromboembolism were both significantly reduced with patient self-testing and/or self-management, with no increase in major bleeding versus usual care. Recent studies have attempted to utilize the advantages of patient self-testing and self-management and combine them with technologic advances and pharmacists’ skills to improve anticoagulant management. In this issue of Pharmacotherapy, two studies report on a hybrid system entitled self-testing with online remote monitoring and management (STORM2).10, 11 With this system, patients were provided with extensive education, and they used an at-home point-of-care testing device, uploaded their results onto a secure Web site, and were able to interact virtually with an anticoagulation clinic member. Dr. Henry Bussey and colleagues showed that their STORM2 system resulted in a 25% point increase in the TTR compared with the preintervention period.10 This system has the benefit of utilizing technology in addition to anticoagulation expert input to maximize INR control while minimizing patient burden. Not surprisingly, Dr. Sarah Meyer and colleagues reported that this system of INR monitoring was preferred by 90% of patients compared with routine anticoagulation clinic monitoring.11 It also appeared that this system may be less costly to patients, although a formal cost analysis was not performed. A 2007 cost-effectiveness analysis of studies conducted in the United Kingdom suggested that patient self-management was unlikely to be more cost-effective than management in an anticoagulation clinic, although the comparability of these data to practices in the United States is unclear.12 Thus, the long-term benefits of this type of intensive, patient-driven anticoagulation monitoring system remains unclear. It is likely that the level of education and technologic savvy required for this system to be successful may be appropriate for a select subset of clinic patients but may not be generalizable for all.
As part of the STORM2 study, genetic polymorphism testing (cytochrome P450 [CYP] 2C9 and vitamin K epoxide reductase complex 1 [VKORC1]) was also performed to evaluate the relationship between genetic polymorphism and INR stability.10 Genetic variations in CYP2C9 and VKORC1, among others, may contribute to the interpatient variability of response to warfarin.13 A variety of algorithms utilizing genetic information have been created in an attempt to provide warfarin dosing recommendations, both initially as well as long-term, when combined with clinical information.14 Although clinical trials have shown that use of warfarin dosing algorithms that include pharmacogenetic information gets patients to a goal INR more quickly and results in fewer out-of-range INR values and increased TTR,15 current guidelines recommend against their routine use.16 Moreover, warfarinrelated genotyping has not been found to be costeffective in the management of patients with atrial fibrillation.17 Along these lines, Dr. Bussey and colleagues did not find differences in changes in warfarin dose or INR stability by genetic polymorphism subgroup.10 However, this was not a primary objective in their study, and the number of patients was low, potentially affecting the applicability of their data. Despite these findings, the Clinical Pharmacogenomics Implementation Consortium continues to advocate for the evaluation and proper interpretation of genetic information to aid in warfarin dosing.18 Additional clinical trials are ongoing that are comparing genotype-guided dosing with routine clinical dosing, with results for some trials expected to be available by the end of 2013.19 Pending positive results from these clinical trials, pharmacists are uniquely positioned to aid in the proper interpretation and utilization of pharmacogenomic data. In this issue of Pharmacotherapy, Dr. Edith Nutescu and colleagues report on the feasibility of implementing an inpatient clinical warfarin pharmacogenomic service.20 They found that when genotype data were available quickly (76% were available prior to the second warfarin dose), genotype-guided warfarin dose information could be provided within a median of 30 hours. Nearly three quarters of their warfarin dose recommendations were followed within 0.5 mg of the daily dose. The clinical impact of such a service was not reported. However, it does provide an avenue for properly trained clinical pharmacists to contribute to the health care team and potentially positively impact patient outcomes.
CHANGING FACE OF ANTICOAGULATION MANAGEMENT Baker The most recent advance in the area of anticoagulation management is the commercial availability of oral anticoagulants that are alternatives to warfarin: apixaban, dabigatran, and rivaroxaban. Studies have shown these new agents to be either noninferior or superior to warfarin and other antithrombotic agents, with similar or improved safety profiles.21 These agents have the possibility to significantly affect the landscape of anticoagulation management and the role of dedicated anticoagulation clinics moving forward. Pharmacists and those working in dedicated clinics can, however, plan an integral role in the management of patients receiving these newer agents. This could include, but may not be limited to, ensuring appropriate agent selection based on the patient’s clinical factors, screening for drug interactions, assessing compliance issues and safety parameters, and providing practitioner and patient disease state and drug education. In summary, changes in the anticoagulation landscape are coming that may significantly impact the roles of anticoagulation clinics in the future. These include an increased role for patient self-testing and self-management, availability of pharmacogenomic information and automated dosing algorithms, and approval of novel oral anticoagulants as alternatives to warfarin. However, with each of these advances, a role for a highly educated and well-trained anticoagulation specialist is evident. The need exists for educating patients and caregivers about emerging self-monitoring technologies, aiding in interpretation and utilization of pharmacogenomic information, and appropriately selecting and monitoring new oral anticoagulants. These services will continue to be in high demand. The anticoagulation specialist will also need to provide other antithrombotic functions such as formulary management, management of bleeding and anticoagulant reversal, periprocedural antithrombotic recommendations, coordination during transitions of care, and health care team education.22 The face of anticoagulation services has become brighter as tremendous opportunities continue to evolve for fruitful collaboration and research. References 1. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 suppl):e44S–88S. 2. Testa S, Paoletti O, Zimmermann A, Bassi L, Zambelli S, Cancellieri E. The role of anticoagulation clinics in the era of new oral anticoagulants. Thrombosis 2012;2012:835356.
1135
3. Nutescu EA. The future of anticoagulation clinics. J Thromb Thrombolysis 2003;16:61–3. 4. Baker WL, Cios DA, Sander SD, Coleman CI. Meta-analysis to assess the quality of warfarin control in atrial fibrillation patients in the United States. J Manag Care Pharm 2009;15:244–52. 5. Hall D, Buchanan J, Helms B, et al. Health care expenditures and therapeutic outcomes of a pharmacist-managed anticoagulation service versus usual medical care. Pharmacotherapy 2011;31:686–94. 6. Wilson SJ, Wells PS, Kovacs MJ, et al. Comparing the quality of oral anticoagulant management by anticoagulation clinics and by family physicians: a randomized controlled trial. CMAJ 2003;169:293–8. 7. Bungard TJ, Barry AR, Jones C, Brocklebank C. Patient satisfaction with services provided by multidisciplinary anticoagulation clinics. Pharmacotherapy 2013;33:1246–51. 8. Nutescu EA, Bathija S, Sharp LK, Gerber BS, Schumock GT, Fitzgibbon ML. Anticoagulation patient self-monitoring in the Unites States: considerations for clinical practice adoption. Pharmacotherapy 2011;31:1161–74. 9. Bloomfield HE, Krause A, Greer N, et al. Meta-analysis: effect of patient self-testing and self-management of long-term anticoagulation on major clinical outcomes. Ann Intern Med 2011;154:472–82. 10. Bussey HI, Bussey M, Bussey-Smith KL, et al. Evaluation of warfarin management with international normalized ratio selftesting and online remote monitoring and management plus low-dose vitamin K and genomic considerations: a pilot study. Pharmacotherapy 2013;33:1136–46. 11. Meyer S, Frei CR, Daniels KR, et al. Impact of a new method of warfarin management on patient satisfaction, time, and cost. Pharmacotherapy 2013;33:1147–55. 12. Cannock M, Stevens C, Fry-Smith A, et al. Clinical effectiveness and cost-effectiveness of different models of managing long-term anticoagulation therapy: a systematic review and economic modeling. Health Technol Assess 2007;11:iii–iv, ix-66. 13. Jorgensen AL, Fitzgerald RJ, Oyee J, et al. Influence of CYP2C9 and VKORC1 on patient response to warfarin: a systematic review and meta-analysis. PLoS ONE 2012;7:e44064. 14. Sconce EA, Khan TI, Wynne HA, et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 2005;106:2329–33. 15. Anderson JL, Horne BD, Stevens SM, et al. A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-II). Circulation 2012;125:1997– 2005. 16. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):e152S–84S. 17. Eckman MH, Rosand J, Greenberg SM, Gage BF. Cost-effectiveness of using pharmacogenetic information in warfarin dosing for patients with nonvalvular atrial fibrillation. Ann Intern Med 2009;150:73–83. 18. Johnson JA, Gong L, Whirl-Carrillo M, et al. Clinical Pharmacogenetics Implementation Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011;90:625–9. 19. Kimmel SE, French B, Anderson JL, et al. Rationale and design of the clarification of optimal anticoagulation through genetics trial. Am Heart J 2013;166:435–41. 20. Nutescu EA, Drozda K, Bress AP, et al. Feasibility of implementing a comprehensive warfarin pharmacogenetics service. Pharmacotherapy 2013;33:1156–64. 21. Baker WL, Phung OJ. Systematic review and adjusted indirect comparison meta-analysis of oral anticoagulants in atrial fibrillation. Circ Cardiovasc Qual Outcomes 2012;5:711–9. 22. Nutescu EA. Anticoagulation management services: entering a new era. Pharmacotherapy 2010;30:327–9.
