- Email: [email protected]
Anticoagulation: A Pathway to Clinical Effectiveness
CLINICAL EFFECTIVENESS Kim A. Eagle, MD, Section Editor
Anticoagulation: A Pathway to Clinical Effectiveness Geoffrey D. Barnes, MD, James B. Froehlich, MD, MPH University of Michigan Cardiovascular Center, Ann Arbor, Mich.
The first patient is a 70-year-old woman with a history of intermittent atrial fibrillation and chronic anticoagulation who was discharged recently from the hospital after asthma exacerbation. On follow-up, she has an international normalized ratio (INR) of 1.6. When should her INR be checked next and what dose of warfarin should she take? The second patient is a 68-year-old man with a history of recurrent pulmonary embolism who currently is receiving long-term anticoagulation, but he was found to have an INR of 6.8 on routine laboratory tests. He does not have any bleeding. What interventions are necessary at this time? Should he be given vitamin K? Should warfarin be held, and the dose adjusted?
DISCUSSION Warfarin is one of the most commonly prescribed medications because of its effectiveness in preventing recurrence in patients with venous thromboembolism and stroke in patients with atrial fibrillation. Despite more than 50 years of clinical experience, studies suggest that patients taking warfarin do not have INRs in the therapeutic range up to 50% of the time.1-4 A national database estimated 29,000 yearly warfarin-related emergency department visits for bleeding complications.5 A recent meta-analysis of 71,000 anticoagulated patients found that 44% of hemorrhagic events and 48% of thromboembolic events occurred when INRs were out of the therapeutic range.6 The use of standard protocols for warfarin dose adjustment, frequency of INR testing, and management of out-of-range INRs may help to reduce the frequency of such adverse events. Table 1 is a sample protocol developed by the University of Michigan Antico-
Conflict of Interest: Consulting: Pfizer, Sanofi-Aventis (JBF). Speaker’s Bureau: Pfizer; Sanofi-Aventis; Merck/Shering-Plough (JBF). Research Grant: Blue-Cross/Blue Shield of Michigan; Novartis (JBF). None (GDB). Authorship: All authors had access to the data and a role in writing the article. Requests for reprints should be addressed to Geoffrey D. Barnes, MD, Cardiovascular Center, 1500 East Medical Center Drive, SPC 5853, Ann Arbor, MI 48109-5853. E-mail address: [email protected]
0002-9343/$ -see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2008.10.002
agulation service and based on the American College of Chest Physicians (ACCP) guidelines.7,8
STEPS TO IMPROVE THE SITUATION The first step in any quality improvement effort is to identify the goals and the barriers to achieving those goals. After implementing methods to achieve those goals, effectiveness must be assessed and continual changes made to optimize outcomes.9 Most primary care physicians do not have extensive training in the finer aspects of warfarin dosing and management. One study of primary care patients in France found that 14% of patients had inadequately monitored INR levels.10 However, use of expert-guided standards in the primary care office allows patients to receive care similar to expert-run anticoagulation clinics.11 A second advantage of standardized protocols and algorithms is to empower nursing staff to manage most patients receiving anticoagulation without the need for physician intervention. This can be both time and cost-effective for a busy practice with limited physician availability. It also allows patients to develop strong working relationships with clinic staff without the burden of frequent physician visits. Care for patients with out-of-range INR values varies greatly among the majority of practitioners. Therefore, standardized algorithms based on ACCP guidelines may help to standardize care and reduce adverse events.7,8 In addition, it is likely that time and cost burden on the nation’s overly taxed emergency departments can be lessened by avoiding unnecessary referrals for care of outof-range INRs. Table 2 is the protocol developed by the University of Michigan Anticoagulation Service and based on ACCP guidelines for management of INR in the range from 5.0 to 9.0.7,8 Studies have demonstrated the benefits of computerbased dose management and dedicated anticoagulation services.12 However, these are limited in number and availability, and often not reimbursed by insurance companies. The use of such algorithms (Tables 1 and 2) can provide any primary care office with the same expertise.
Barnes and Froehlich
Anticoagulation Clinical Effectiveness
127
Table 1 The American College of Chest Physicians Guideline-based Table from The University of Michigan Anticoagulation Service:7,8 Target International Normalized Ratio 2.5 (Range 2.0-3.0) Patient’s INR
⬍1.5
1.5-1.9
2.0-3.0
3.1-3.9
4.0-4.9
⬎5.0
Dose change
Increase 10%-20% Consider extra dose 4-8 d
Increase 5%-10%
No change
Decrease 5%-10%
Refer to Figure 1
7-14 d
See follow-up algorithm
7-14 d
Hold 0-2 d and decrease 10% 4-8 d
Next INR
Follow-up Algorithm
No. of Consecutive In-range INRs
Repeat INR in
1 2 3 4
5-10 d 2 wk 3 wk 4 wk
Note: If INR within 0.1 or target, consider repeat INR in 2 to 3 wk regardless of number of consecutive in-range INRs. INR ⫽ international normalized ratio. Always consider trend in INRs when making warfarin management decisions, and consider repeating INR the same day or the next day if observed value is markedly different than the expected value (potential for laboratory errors exists).
MEASUREMENT OF EFFECTIVENESS As with any good quality improvement initiative, the effectiveness of interventions must be measured, monitored, and continually improved. A regional or national database to monitor clinical processes and outcomes in patients receiving anticoagulation would allow for the identification of best practices that lead to improved patient outcomes and measurements of cost-effectiveness. However, in a primary care office, a simple survey identifying the number of emergency department referrals before and after implementation of standardized guidelines may help to identify the performance of such a program. In addition, an informal survey of nursing staff may clarify their comfort using the standardized protocols without physician intervention and identify opportunities for adjustment.
Table 2 Algorithm for International Normalized Ratio 5.0 to 9.0 from The University of Michigan Anticoagulation Clinic (Based on the American College of Chest Physicians guidelines7,8) Any reasons for prolonged INR (eg, drug interaction, change in diet, acute illness)? Any significant active bleeding? If yes, refer to emergency department or clinic for evaluation. Avoid excessive physical activity while INR is prolonged. Hold warfarin for 1 to 2 doses. Consider vitamin K 1.25 to 2.5 mg per os if patient is at increased risk of bleeding. Follow-up INR in 1 to 2 days. If vitamin K 1.25 to 2.5 mg per os was given, check INR daily for several days. Resume warfarin once INR is therapeutic. Consider reducing weekly warfarin dose by 10% to 15%, unless a cause for the prolonged INR was established and corrected. Consider restarting warfarin before INR therapeutic if vitamin K given. INR ⫽ international normalized ratio.
For such a common therapy, it should not be acceptable that patients’ INRs are out of the therapeutic range up to 50% of the time. We must find ways to improve this outcome to reduce adverse events and do so in a cost-effective manner. ACCP guideline-based protocols are simple yet effective interventions that primary care physicians can use to improve patient care and reduce physician time demands.
CLINICAL CASE FOLLOW-UP The first patient, whose INR is subtherapeutic with her current warfarin dose, will require close follow-up to ensure that her INR becomes therapeutic but does not become supratherapeutic with her current warfarin dose. On the basis of the protocols in Table 1, her weekly warfarin dose should be increased by 5% to 10%, and her next INR should be checked in 7 to 10 days. The second patient, who was found to have an INR of 6.8, certainly requires intervention, but does he need to be seen in the emergency department? According to the protocol in Table 2 (based on ACCP guidelines), holding his current warfarin and rechecking the INR in 1 to 2 days are likely adequate interventions. One also might consider a weekly dose reduction of 10% to 20%, but he does not need to be seen in the emergency department unless he is experiencing bleeding symptoms.
References 1. Albers GW, Diener HC, Frison L, et al. SPORTIF Executive Steering Committee for the SPORTIF V Investigators. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. JAMA. 2005;293:690-698. 2. Gurwitz JH, Field TS, Radford MJ, et al. The safety of warfarin therapy in the nursing home setting. Am J Med. 2007;120:539-544. 3. van Walraven C, Jennings A, Oake N, et al. Effect of study setting on anticoagulation control: a systematic review and metaregression. Chest. 2006;129:1155-1166. 4. Macik BG. The future of anticoagulation clinics. J Thromb Thrombolysis. 2003;16:55-59.
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5. Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch Intern Med. 2007;167:1414-1419. 6. Oake N, Fergusson DA, Forster AJ, van Walraven C. Frequency of adverse events in patients with poor anticoagulation: a meta-analysis. CMAJ. 2007;176:1589-1594. 7. Ansell J, Hirsh J, Poller L, et al. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 Suppl): 204S-233S. 8. Ansell J, Hirsh J, Hylek E, et al; American College of Chest Physicians. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based
9.
10.
11.
12.
Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 Suppl):160S-198S. Bosch M, van der Weijden T, Wensing M, Grol R. Tailoring quality improvement interventions to identified barriers: a multiple case analysis. J Eval Clin Pract. 2007;13:161-168. Ruivard M, Berger C, Achaibi A, et al. Physician compliance with outpatient oral anticoagulant guidelines in Auvergne, France. J Gen Intern Med. 2003;18:903-907. Wilson SE, Costantini L, Crowther MA. Paper-based dosing algorithms for maintenance of warfarin anticoagulation. J Thromb Thrombolysis. 2007;23:195-198. Gage BF, Fihn SD, White RH. Management and dosing of warfarin therapy. Am J Med. 2000;109:481-488.
Anticoagulation: A Pathway to Clinical Effectiveness Geoffrey D. Barnes, MD, James B. Froehlich, MD, MPH University of Michigan Cardiovascular Center, Ann Arbor, Mich.
The first patient is a 70-year-old woman with a history of intermittent atrial fibrillation and chronic anticoagulation who was discharged recently from the hospital after asthma exacerbation. On follow-up, she has an international normalized ratio (INR) of 1.6. When should her INR be checked next and what dose of warfarin should she take? The second patient is a 68-year-old man with a history of recurrent pulmonary embolism who currently is receiving long-term anticoagulation, but he was found to have an INR of 6.8 on routine laboratory tests. He does not have any bleeding. What interventions are necessary at this time? Should he be given vitamin K? Should warfarin be held, and the dose adjusted?
DISCUSSION Warfarin is one of the most commonly prescribed medications because of its effectiveness in preventing recurrence in patients with venous thromboembolism and stroke in patients with atrial fibrillation. Despite more than 50 years of clinical experience, studies suggest that patients taking warfarin do not have INRs in the therapeutic range up to 50% of the time.1-4 A national database estimated 29,000 yearly warfarin-related emergency department visits for bleeding complications.5 A recent meta-analysis of 71,000 anticoagulated patients found that 44% of hemorrhagic events and 48% of thromboembolic events occurred when INRs were out of the therapeutic range.6 The use of standard protocols for warfarin dose adjustment, frequency of INR testing, and management of out-of-range INRs may help to reduce the frequency of such adverse events. Table 1 is a sample protocol developed by the University of Michigan Antico-
Conflict of Interest: Consulting: Pfizer, Sanofi-Aventis (JBF). Speaker’s Bureau: Pfizer; Sanofi-Aventis; Merck/Shering-Plough (JBF). Research Grant: Blue-Cross/Blue Shield of Michigan; Novartis (JBF). None (GDB). Authorship: All authors had access to the data and a role in writing the article. Requests for reprints should be addressed to Geoffrey D. Barnes, MD, Cardiovascular Center, 1500 East Medical Center Drive, SPC 5853, Ann Arbor, MI 48109-5853. E-mail address: [email protected]
0002-9343/$ -see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2008.10.002
agulation service and based on the American College of Chest Physicians (ACCP) guidelines.7,8
STEPS TO IMPROVE THE SITUATION The first step in any quality improvement effort is to identify the goals and the barriers to achieving those goals. After implementing methods to achieve those goals, effectiveness must be assessed and continual changes made to optimize outcomes.9 Most primary care physicians do not have extensive training in the finer aspects of warfarin dosing and management. One study of primary care patients in France found that 14% of patients had inadequately monitored INR levels.10 However, use of expert-guided standards in the primary care office allows patients to receive care similar to expert-run anticoagulation clinics.11 A second advantage of standardized protocols and algorithms is to empower nursing staff to manage most patients receiving anticoagulation without the need for physician intervention. This can be both time and cost-effective for a busy practice with limited physician availability. It also allows patients to develop strong working relationships with clinic staff without the burden of frequent physician visits. Care for patients with out-of-range INR values varies greatly among the majority of practitioners. Therefore, standardized algorithms based on ACCP guidelines may help to standardize care and reduce adverse events.7,8 In addition, it is likely that time and cost burden on the nation’s overly taxed emergency departments can be lessened by avoiding unnecessary referrals for care of outof-range INRs. Table 2 is the protocol developed by the University of Michigan Anticoagulation Service and based on ACCP guidelines for management of INR in the range from 5.0 to 9.0.7,8 Studies have demonstrated the benefits of computerbased dose management and dedicated anticoagulation services.12 However, these are limited in number and availability, and often not reimbursed by insurance companies. The use of such algorithms (Tables 1 and 2) can provide any primary care office with the same expertise.
Barnes and Froehlich
Anticoagulation Clinical Effectiveness
127
Table 1 The American College of Chest Physicians Guideline-based Table from The University of Michigan Anticoagulation Service:7,8 Target International Normalized Ratio 2.5 (Range 2.0-3.0) Patient’s INR
⬍1.5
1.5-1.9
2.0-3.0
3.1-3.9
4.0-4.9
⬎5.0
Dose change
Increase 10%-20% Consider extra dose 4-8 d
Increase 5%-10%
No change
Decrease 5%-10%
Refer to Figure 1
7-14 d
See follow-up algorithm
7-14 d
Hold 0-2 d and decrease 10% 4-8 d
Next INR
Follow-up Algorithm
No. of Consecutive In-range INRs
Repeat INR in
1 2 3 4
5-10 d 2 wk 3 wk 4 wk
Note: If INR within 0.1 or target, consider repeat INR in 2 to 3 wk regardless of number of consecutive in-range INRs. INR ⫽ international normalized ratio. Always consider trend in INRs when making warfarin management decisions, and consider repeating INR the same day or the next day if observed value is markedly different than the expected value (potential for laboratory errors exists).
MEASUREMENT OF EFFECTIVENESS As with any good quality improvement initiative, the effectiveness of interventions must be measured, monitored, and continually improved. A regional or national database to monitor clinical processes and outcomes in patients receiving anticoagulation would allow for the identification of best practices that lead to improved patient outcomes and measurements of cost-effectiveness. However, in a primary care office, a simple survey identifying the number of emergency department referrals before and after implementation of standardized guidelines may help to identify the performance of such a program. In addition, an informal survey of nursing staff may clarify their comfort using the standardized protocols without physician intervention and identify opportunities for adjustment.
Table 2 Algorithm for International Normalized Ratio 5.0 to 9.0 from The University of Michigan Anticoagulation Clinic (Based on the American College of Chest Physicians guidelines7,8) Any reasons for prolonged INR (eg, drug interaction, change in diet, acute illness)? Any significant active bleeding? If yes, refer to emergency department or clinic for evaluation. Avoid excessive physical activity while INR is prolonged. Hold warfarin for 1 to 2 doses. Consider vitamin K 1.25 to 2.5 mg per os if patient is at increased risk of bleeding. Follow-up INR in 1 to 2 days. If vitamin K 1.25 to 2.5 mg per os was given, check INR daily for several days. Resume warfarin once INR is therapeutic. Consider reducing weekly warfarin dose by 10% to 15%, unless a cause for the prolonged INR was established and corrected. Consider restarting warfarin before INR therapeutic if vitamin K given. INR ⫽ international normalized ratio.
For such a common therapy, it should not be acceptable that patients’ INRs are out of the therapeutic range up to 50% of the time. We must find ways to improve this outcome to reduce adverse events and do so in a cost-effective manner. ACCP guideline-based protocols are simple yet effective interventions that primary care physicians can use to improve patient care and reduce physician time demands.
CLINICAL CASE FOLLOW-UP The first patient, whose INR is subtherapeutic with her current warfarin dose, will require close follow-up to ensure that her INR becomes therapeutic but does not become supratherapeutic with her current warfarin dose. On the basis of the protocols in Table 1, her weekly warfarin dose should be increased by 5% to 10%, and her next INR should be checked in 7 to 10 days. The second patient, who was found to have an INR of 6.8, certainly requires intervention, but does he need to be seen in the emergency department? According to the protocol in Table 2 (based on ACCP guidelines), holding his current warfarin and rechecking the INR in 1 to 2 days are likely adequate interventions. One also might consider a weekly dose reduction of 10% to 20%, but he does not need to be seen in the emergency department unless he is experiencing bleeding symptoms.
References 1. Albers GW, Diener HC, Frison L, et al. SPORTIF Executive Steering Committee for the SPORTIF V Investigators. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. JAMA. 2005;293:690-698. 2. Gurwitz JH, Field TS, Radford MJ, et al. The safety of warfarin therapy in the nursing home setting. Am J Med. 2007;120:539-544. 3. van Walraven C, Jennings A, Oake N, et al. Effect of study setting on anticoagulation control: a systematic review and metaregression. Chest. 2006;129:1155-1166. 4. Macik BG. The future of anticoagulation clinics. J Thromb Thrombolysis. 2003;16:55-59.
128
The American Journal of Medicine, Vol 122, No 2, February 2009
5. Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch Intern Med. 2007;167:1414-1419. 6. Oake N, Fergusson DA, Forster AJ, van Walraven C. Frequency of adverse events in patients with poor anticoagulation: a meta-analysis. CMAJ. 2007;176:1589-1594. 7. Ansell J, Hirsh J, Poller L, et al. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 Suppl): 204S-233S. 8. Ansell J, Hirsh J, Hylek E, et al; American College of Chest Physicians. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based
9.
10.
11.
12.
Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 Suppl):160S-198S. Bosch M, van der Weijden T, Wensing M, Grol R. Tailoring quality improvement interventions to identified barriers: a multiple case analysis. J Eval Clin Pract. 2007;13:161-168. Ruivard M, Berger C, Achaibi A, et al. Physician compliance with outpatient oral anticoagulant guidelines in Auvergne, France. J Gen Intern Med. 2003;18:903-907. Wilson SE, Costantini L, Crowther MA. Paper-based dosing algorithms for maintenance of warfarin anticoagulation. J Thromb Thrombolysis. 2007;23:195-198. Gage BF, Fihn SD, White RH. Management and dosing of warfarin therapy. Am J Med. 2000;109:481-488.