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Nearly 4 million patients in the U.S. take warfarin.1 Between 1998 and 2004, the number of prescriptions for warfarin increased from 21.1 million to 30.6 million.2 However, with the approval of new oral anticoagulants, between 2007 and 2011, warfarin treatment visits decreased from 2.1 million to 1.6 million per quarter.3 Despite the declining number of patients on warfarin, there are still significant monetary and time costs associated with warfarin therapy. One study estimated that patients spend 2.5 hours per clinic visit, accounting for travel time and time spent in clinic, with an average of 1 hour in the clinic, including waiting time.1 Another study estimated the cost of warfarin therapy per patient, per month to be $62.30 in 2004 dollars based on 1.1 clinic visits per patient per month.4
Warfarin Monitoring
Warfarin requires close monitoring. The relationship between the dose of warfarin and the response is widely variable and can be influenced by many genetic and environmental factors, making dosing difficult. Genetic variations in the CYP2C9 and vitamin K epoxide reductase genes can lead to different warfarin dosing requirements.
Some environmental factors that can affect warfarin therapy include dietary vitamin K, alcohol intake, nutritional supplements, or herbal products. Concomitant diseases such as hepatic dysfunction, thyroid dysfunction, hypermetabolic states, age, and acute decompensated heart failure can also influence warfarin therapy. Additionally, there are numerous drug interactions that may affect warfarin therapy. Many of these factors may vary not only between patients, but also within the same patient over time.5-7
Warfarin has a narrow therapeutic range, which presents the possibility of serious adverse events (AEs) if warfarin is not dosed properly. According to The Institute for Safe Medication Practices, warfarin was the second most commonly reported drug causing serious AEs in 2011, with 1,106 cases, including 72 deaths reported to the FDA.8 Bescause of the large number of patients on warfarin and the risk for serious AEs, careful monitoring is required.
Monitoring of warfarin therapy is done using the prothrombin time (PT) test, which reflects the level of activity of factors I, II, V, VII, and X (of these warfarin affects factors II, VII, and X). However, PT tests can vary greatly, so a standardized model known as the international normalized ratio (INR) is used. The INR goals require the lowest effective dose in order to minimize bleeding. Dosing should be individualized for patients based on indications and patient-specific factors, such as history of bleeds or clots. Although it has been suggested that stable patients should undergo INR monitoring every 12 weeks, most patients are monitored every 4 to 6 weeks or more frequently.5,9
Standard of Care
Previously, the standard of care was for primary care providers to monitor warfarin therapy. Recently, there has been a shift to monitoring patients in anticoagulation clinics. One study that compared a pharmacist-managed anticoagulation service vs usual medical care concluded that the pharmacist-managed anticoagulation service resulted in a higher percentage of INR values in the therapeutic range, statistically significantly fewer anticoagulation-related AEs, and lower costs.10
There also have been studies conducted to evaluate the safety and efficacy of anticoagulation therapy when monitored by telephone-based anticoagulation clinics. A study by Witt and colleagues compared patients being managed in a telephone-based, pharmacist-managed anticoagulation clinic with a physician-managed clinic over a 6-month period. The study found that patients in the pharmacist-managed group spent more time in the therapeutic INR range (TTR) compared with the physician-managed group. However, although thromboembolic complications or major bleeds occurred less frequently in the pharmacist-managed group, the difference was not statistically significant.11
In a different study by Wittkowsky and colleagues, patients who were managed by a telephone vs a face-to-face clinic had a similar number of INR values in the therapeutic range, rates of major hemorrhage, and recurrent thromboembolism.12
In a study by Staresinic and colleagues an anticoagulation management service (AMS) was compared with an interim telephone model (IT). There was no statistically significant difference in the time both groups spent in the TTR, rates of thromboembolism, or rates of major bleeding. The IT group had a higher rate of minor bleeding events compared with that of the AMS group.13 To date, there have not been any published studies evaluating individual patients who were switched from face-to-face to telephone-based management of anticoagulation.
Methods
This retrospective electronic chart review of 156 patients was approved by both the institutional review board and research and development committee at the Jesse Brown VAMC (JBVAMC) in Chicago, Illinois. The patient list was generated from patients enrolled in an anticoagulation telephone clinic as of September 1, 2013. Patients were included if they were aged ≥ 18 years, received warfarin therapy between May 1, 2008, and September 1, 2013, had at least 70% of their anticoagulation visits with the face-to-face anticoagulation clinic for a continuous 1-year period and were then switched to the telephone anticoagulation clinic, and had at least 70% of their anticoagulation visits with the telephone anticoagulation clinic in a continuous 1-year period after the switch. Patients were excluded if they did not meet all the inclusion criteria. Of the 156 patients reviewed, 61 patients met enrollment requirements.
Study Endpoints
The primary endpoints of the study included TTR, defined as the percentage of anticoagulation visits at which the INR values were in the patient-specific therapeutic range ± 0.2 (excluding any subtherapeutic INR values within 2 weeks after planned short-term discontinuation of warfarin), event rate of cerebral vascular accidents (CVA)/transient ischemic attacks (TIA) and venous thromboembolism (VTE), and event rate of major bleeds. Major bleeds were defined as any fatal bleed, a symptomatic bleed in a critical area or organ (intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial or intramuscular with compartment syndrome), a fall in hemoglobin (Hg) ≥ 2 g/dL, or requiring transfusion of ≥ 2 units of whole blood or packed red blood cells.
Secondary endpoints of the study included event rate of minor bleeds (defined as any bleed not defined as a major bleed); time between follow-up appointments; number of acute care visits, emergency department (ED) visits, or hospitalizations due to anticoagulation; time to follow-up after hospital discharge, ED visit or acute care visit due to anticoagulation (if applicable); number of critical INRs as defined by local policy (INRs ≥ 5); number of canceled or no-show appointments; and compliance with monitoring of liver function test (LFT) and complete blood count (CBC) every 6 months per local policy.
Data Collection
To arrive at study endpoints, data collection included (1) demographics: age, ethnicity, and gender; (2) laboratory values: albumin, CBC, INR, LFT, and thyroid-stimulating hormone (TSH); (3) warfarin information: chart-documented adherence, dose and schedule, fill history, indication, INR goal per chart documentation, and reason for sub- or supratherapeutic INR; (4) safety: CVA/TIA, VTE, major bleeds, minor bleeds, and hospitalization/ED visits/acute care visits; (5) comorbid conditions: alcohol use, anemia, atrial fibrillation (AF), atrial flutter, cancer, coagulation deficiencies, congestive heart failure (CHF), diabetes mellitus (DM), hemodialysis, history of bleed, hypertension, liver cirrhosis, peptic ulcer disease, peripheral vascular disease, previous VTE, previous CVA/TIA, and valve replacement; (6) concomitant medications: aspirin, aspirin/extended-release dipyridamole, clopidogrel, dalteparin, enoxaparin, fondaparinux, nonsteroidal anti-inflammatory drugs (NSAIDs), unfractionated heparin, and warfarin; and (7) appointment data: time between appointments; time to follow-up after hospital discharge, ED visit or acute care visit (if applicable); and number of canceled or no-show appointments. Patient data were collected for 24 months total: the 12 months immediately before switching to telephone anticoagulation clinic (while the patient was followed in the face-to-face anticoagulation clinic) and the 12 months immediately after switching to telephone anticoagulation clinic.
Statistical tests used in this study included paired t test and Fisher exact test. P < .05 was determined to be statistically significant.
Results
A total of 156 patient charts were reviewed. Ninety-five patients were excluded, and 61 patients were included (Figure 1). Patients were excluded because they were either not enrolled in a face-to-face clinic for 1 continuous year prior to the switch or not enrolled in a telephone clinic for 1 continuous year after the switch. Patients also were excluded if they alternated between a face-to-face and telephone clinic and did not have at least 70% of their anticoagulation visits at the face-to-face clinic before the switch or at least 70% of their anticoagulation visits with the telephone clinic after the switch.
Baseline Characteristics
The study population was predominantly male with a mean age of 67 years. Most of the patients were African American. The most common indications for anticoagulation included AF, atrial flutter, previous VTE, or multiple indications. The most common INR goal range for patients was 2 to 3. The most common comorbid conditions were hypertension, alcohol use, CHF, and DM. Concomitant medications were noted if they were used anytime during the observation period; the most common were aspirin, NSAIDs, enoxaparin and dalteparin (Table 1).
Endpoints
There was not a statistically significant difference between the average TTR for patients for the face-to-face and telephone groups (Table 2). More than 85% of patients had a similar TTR between the groups or were in TTR more often during telephone clinic vs face-to-face clinic (Figure 2). One patient had a CVA during the face-to-face clinic period, and another patient had a TIA during the telephone anticoagulation clinic period. No VTE events were reported in either group. Further, there was 1 major bleed in the face-to-face clinic period (asymptomatic Hg drop ≥ 2 g/dL) and 3 major bleeds (asymptomatic Hg drop ≥ 2 g/dL, intraocular bleed, and gastrointestinal bleed) in the telephone clinic period, but this difference also was not statistically significant.
There were no statistically significant differences for any of the secondary endpoints except for compliance with LFT monitoring, which was higher in the telephone clinic. There were 22 minor bleeds found during face-to-face anticoagulation clinic and 19 minor bleeds found during telephone anticoagulation clinic. The most common types of minor bleed for both clinic settings were bruising at injection site (while using low molecular-weight heparin) and epistaxis.
There were 2 additional endpoints in the study for telephone clinic patients to assess time spent on telephone visits and ability to reach the patient by phone if they had laboratory tests drawn. In the telephone clinic, patients with completed labs were unreachable 2.1% of the time. The average amount of time spent on telephone visits was 8.0 (± 0.89) minutes.
Discussion
This study showed no statistically significant differences in TTR for patients switched to the telephone anticoagulation clinic from the face-to-face anticoagulation clinic. There also were no statistically significant differences in event rates for CVA/TIA, VTE, or major bleeds. The only statistically significant difference in secondary endpoints was better compliance with LFT monitoring in the telephone clinic period. Additionally, patients served as their own control in this study, which helped eliminate confounding factors that may have been present when comparing 2 different patient groups.
The telephone clinic offered patients multiple advantages, including decreased wait time, as patients did not have to wait for their laboratory results to return or wait to be seen in clinic, increased volume of patients managed due to shorter appointment times, better coordination of other appointments on the same day, and improved medication reconciliation when patients have their medications in front of them. The disadvantages of telephone anticoagulation clinic included the inability of the providers to see any nonverbal cues, difficulty evaluating other issues for patients already at home and unwilling to return to the clinic, and the inability to provide written information (eg, changes in warfarin dosing or appointment scheduling) to the patient during the visit.
Limitations
In addition to the sample size and retrospective design of the study, there were several other study limitations. When the telephone anticoagulation clinic first started, patients with more stable INRs were chosen to enroll, which may have led to selection bias. Other limitations included the lack of documentation, patient reporting, or outside medical records documenting bleeds, VTE, or CVA/TIA. In addition, power was not calculated prior to beginning the study, because only, a small patient pool was available, and all patients that met inclusion criteria were to be included. Therefore, the sample size may have been too small to detect a difference.
Conclusion
In this retrospective chart review, the JBVAMC patients using the face-to-face and telephone anticoagulation clinics had similar outcomes. Telephone anticoagulation clinic was shown to be a viable alternative for some patients.
1. Jonas DE, Bryant Shilliday B, Laundon WR, Pignone M. Patient time requirements for anticoagulation therapy with warfarin. Med Decis Making. 2010;30(2):206-216.
2. Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch Intern Med. 2007;167(13):1414-1419.
3. Kirley K, Qato DM, Kornfield R, Stafford RS, Alexander GC. National trends in oral anticoagulant use in the United States, 2007 to 2011. Circ Cadiovasc Qual Outcomes. 2012;5(5):615-621.
4. Anderson RJ. Cost analysis of a managed care decentralized outpatient pharmacy anticoagulation service. J Manag Care Pharm. 2004;10(2):159-165.
5. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G; American College of Chest Physicians. 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-e88S.
6. Choonara IA, Malia RG, Haynes BP, et al. The relationship between inhibition of vitamin K1 2,3-epoxide reductase and reduction of clotting factor activity with warfarin. Br J Clin Pharmacol. 1988;25(1):1-7.
7. Scordo MG, Pengo V, Spina E, Dahl ML, Gusella M, Padrini R. Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance. Clin Pharmacol Ther. 2002;72(6):702-710.
8. Institute for Safe Medication Practices. Quarter watch: anticoagulants the leading reported drug risk in 2011. Institute for Safe Medication Practices website. http://www.ismp.org/quarterwatch/pdfs/2011Q4.pdf. Published Fourth Quarter 2011. Accessed June 6, 2016.
9. Holbrook A, Schulman S, Witt DM, et al; American College of Chest Physicians. 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-e184S.
10. 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(7):686-694.
11. Witt DM, Sadler MA, Shanahan RL, Mazzoli G, Tillman DJ. Effect of a centralized clinical pharmacy anticoagulation service on the outcomes of anticoagulation therapy. Chest. 2005;127(5):1515-1522.
12. Wittkowsky AK, Nutescu EA, Blackburn J, et al. Outcomes of oral anticoagulant therapy managed by telephone vs in-office visits in an anticoagulation clinic setting. Chest. 2006;130(5):1385-1389.
13. Staresinic AG, Sorkness CA, Goodman BM, Pigarelli DW. Comparison of outcomes using 2 delivery models of anticoagulation care. Arch Intern Med. 2006;166(9):997-1002.
Nearly 4 million patients in the U.S. take warfarin.1 Between 1998 and 2004, the number of prescriptions for warfarin increased from 21.1 million to 30.6 million.2 However, with the approval of new oral anticoagulants, between 2007 and 2011, warfarin treatment visits decreased from 2.1 million to 1.6 million per quarter.3 Despite the declining number of patients on warfarin, there are still significant monetary and time costs associated with warfarin therapy. One study estimated that patients spend 2.5 hours per clinic visit, accounting for travel time and time spent in clinic, with an average of 1 hour in the clinic, including waiting time.1 Another study estimated the cost of warfarin therapy per patient, per month to be $62.30 in 2004 dollars based on 1.1 clinic visits per patient per month.4
Warfarin Monitoring
Warfarin requires close monitoring. The relationship between the dose of warfarin and the response is widely variable and can be influenced by many genetic and environmental factors, making dosing difficult. Genetic variations in the CYP2C9 and vitamin K epoxide reductase genes can lead to different warfarin dosing requirements.
Some environmental factors that can affect warfarin therapy include dietary vitamin K, alcohol intake, nutritional supplements, or herbal products. Concomitant diseases such as hepatic dysfunction, thyroid dysfunction, hypermetabolic states, age, and acute decompensated heart failure can also influence warfarin therapy. Additionally, there are numerous drug interactions that may affect warfarin therapy. Many of these factors may vary not only between patients, but also within the same patient over time.5-7
Warfarin has a narrow therapeutic range, which presents the possibility of serious adverse events (AEs) if warfarin is not dosed properly. According to The Institute for Safe Medication Practices, warfarin was the second most commonly reported drug causing serious AEs in 2011, with 1,106 cases, including 72 deaths reported to the FDA.8 Bescause of the large number of patients on warfarin and the risk for serious AEs, careful monitoring is required.
Monitoring of warfarin therapy is done using the prothrombin time (PT) test, which reflects the level of activity of factors I, II, V, VII, and X (of these warfarin affects factors II, VII, and X). However, PT tests can vary greatly, so a standardized model known as the international normalized ratio (INR) is used. The INR goals require the lowest effective dose in order to minimize bleeding. Dosing should be individualized for patients based on indications and patient-specific factors, such as history of bleeds or clots. Although it has been suggested that stable patients should undergo INR monitoring every 12 weeks, most patients are monitored every 4 to 6 weeks or more frequently.5,9
Standard of Care
Previously, the standard of care was for primary care providers to monitor warfarin therapy. Recently, there has been a shift to monitoring patients in anticoagulation clinics. One study that compared a pharmacist-managed anticoagulation service vs usual medical care concluded that the pharmacist-managed anticoagulation service resulted in a higher percentage of INR values in the therapeutic range, statistically significantly fewer anticoagulation-related AEs, and lower costs.10
There also have been studies conducted to evaluate the safety and efficacy of anticoagulation therapy when monitored by telephone-based anticoagulation clinics. A study by Witt and colleagues compared patients being managed in a telephone-based, pharmacist-managed anticoagulation clinic with a physician-managed clinic over a 6-month period. The study found that patients in the pharmacist-managed group spent more time in the therapeutic INR range (TTR) compared with the physician-managed group. However, although thromboembolic complications or major bleeds occurred less frequently in the pharmacist-managed group, the difference was not statistically significant.11
In a different study by Wittkowsky and colleagues, patients who were managed by a telephone vs a face-to-face clinic had a similar number of INR values in the therapeutic range, rates of major hemorrhage, and recurrent thromboembolism.12
In a study by Staresinic and colleagues an anticoagulation management service (AMS) was compared with an interim telephone model (IT). There was no statistically significant difference in the time both groups spent in the TTR, rates of thromboembolism, or rates of major bleeding. The IT group had a higher rate of minor bleeding events compared with that of the AMS group.13 To date, there have not been any published studies evaluating individual patients who were switched from face-to-face to telephone-based management of anticoagulation.
Methods
This retrospective electronic chart review of 156 patients was approved by both the institutional review board and research and development committee at the Jesse Brown VAMC (JBVAMC) in Chicago, Illinois. The patient list was generated from patients enrolled in an anticoagulation telephone clinic as of September 1, 2013. Patients were included if they were aged ≥ 18 years, received warfarin therapy between May 1, 2008, and September 1, 2013, had at least 70% of their anticoagulation visits with the face-to-face anticoagulation clinic for a continuous 1-year period and were then switched to the telephone anticoagulation clinic, and had at least 70% of their anticoagulation visits with the telephone anticoagulation clinic in a continuous 1-year period after the switch. Patients were excluded if they did not meet all the inclusion criteria. Of the 156 patients reviewed, 61 patients met enrollment requirements.
Study Endpoints
The primary endpoints of the study included TTR, defined as the percentage of anticoagulation visits at which the INR values were in the patient-specific therapeutic range ± 0.2 (excluding any subtherapeutic INR values within 2 weeks after planned short-term discontinuation of warfarin), event rate of cerebral vascular accidents (CVA)/transient ischemic attacks (TIA) and venous thromboembolism (VTE), and event rate of major bleeds. Major bleeds were defined as any fatal bleed, a symptomatic bleed in a critical area or organ (intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial or intramuscular with compartment syndrome), a fall in hemoglobin (Hg) ≥ 2 g/dL, or requiring transfusion of ≥ 2 units of whole blood or packed red blood cells.
Secondary endpoints of the study included event rate of minor bleeds (defined as any bleed not defined as a major bleed); time between follow-up appointments; number of acute care visits, emergency department (ED) visits, or hospitalizations due to anticoagulation; time to follow-up after hospital discharge, ED visit or acute care visit due to anticoagulation (if applicable); number of critical INRs as defined by local policy (INRs ≥ 5); number of canceled or no-show appointments; and compliance with monitoring of liver function test (LFT) and complete blood count (CBC) every 6 months per local policy.
Data Collection
To arrive at study endpoints, data collection included (1) demographics: age, ethnicity, and gender; (2) laboratory values: albumin, CBC, INR, LFT, and thyroid-stimulating hormone (TSH); (3) warfarin information: chart-documented adherence, dose and schedule, fill history, indication, INR goal per chart documentation, and reason for sub- or supratherapeutic INR; (4) safety: CVA/TIA, VTE, major bleeds, minor bleeds, and hospitalization/ED visits/acute care visits; (5) comorbid conditions: alcohol use, anemia, atrial fibrillation (AF), atrial flutter, cancer, coagulation deficiencies, congestive heart failure (CHF), diabetes mellitus (DM), hemodialysis, history of bleed, hypertension, liver cirrhosis, peptic ulcer disease, peripheral vascular disease, previous VTE, previous CVA/TIA, and valve replacement; (6) concomitant medications: aspirin, aspirin/extended-release dipyridamole, clopidogrel, dalteparin, enoxaparin, fondaparinux, nonsteroidal anti-inflammatory drugs (NSAIDs), unfractionated heparin, and warfarin; and (7) appointment data: time between appointments; time to follow-up after hospital discharge, ED visit or acute care visit (if applicable); and number of canceled or no-show appointments. Patient data were collected for 24 months total: the 12 months immediately before switching to telephone anticoagulation clinic (while the patient was followed in the face-to-face anticoagulation clinic) and the 12 months immediately after switching to telephone anticoagulation clinic.
Statistical tests used in this study included paired t test and Fisher exact test. P < .05 was determined to be statistically significant.
Results
A total of 156 patient charts were reviewed. Ninety-five patients were excluded, and 61 patients were included (Figure 1). Patients were excluded because they were either not enrolled in a face-to-face clinic for 1 continuous year prior to the switch or not enrolled in a telephone clinic for 1 continuous year after the switch. Patients also were excluded if they alternated between a face-to-face and telephone clinic and did not have at least 70% of their anticoagulation visits at the face-to-face clinic before the switch or at least 70% of their anticoagulation visits with the telephone clinic after the switch.
Baseline Characteristics
The study population was predominantly male with a mean age of 67 years. Most of the patients were African American. The most common indications for anticoagulation included AF, atrial flutter, previous VTE, or multiple indications. The most common INR goal range for patients was 2 to 3. The most common comorbid conditions were hypertension, alcohol use, CHF, and DM. Concomitant medications were noted if they were used anytime during the observation period; the most common were aspirin, NSAIDs, enoxaparin and dalteparin (Table 1).
Endpoints
There was not a statistically significant difference between the average TTR for patients for the face-to-face and telephone groups (Table 2). More than 85% of patients had a similar TTR between the groups or were in TTR more often during telephone clinic vs face-to-face clinic (Figure 2). One patient had a CVA during the face-to-face clinic period, and another patient had a TIA during the telephone anticoagulation clinic period. No VTE events were reported in either group. Further, there was 1 major bleed in the face-to-face clinic period (asymptomatic Hg drop ≥ 2 g/dL) and 3 major bleeds (asymptomatic Hg drop ≥ 2 g/dL, intraocular bleed, and gastrointestinal bleed) in the telephone clinic period, but this difference also was not statistically significant.
There were no statistically significant differences for any of the secondary endpoints except for compliance with LFT monitoring, which was higher in the telephone clinic. There were 22 minor bleeds found during face-to-face anticoagulation clinic and 19 minor bleeds found during telephone anticoagulation clinic. The most common types of minor bleed for both clinic settings were bruising at injection site (while using low molecular-weight heparin) and epistaxis.
There were 2 additional endpoints in the study for telephone clinic patients to assess time spent on telephone visits and ability to reach the patient by phone if they had laboratory tests drawn. In the telephone clinic, patients with completed labs were unreachable 2.1% of the time. The average amount of time spent on telephone visits was 8.0 (± 0.89) minutes.
Discussion
This study showed no statistically significant differences in TTR for patients switched to the telephone anticoagulation clinic from the face-to-face anticoagulation clinic. There also were no statistically significant differences in event rates for CVA/TIA, VTE, or major bleeds. The only statistically significant difference in secondary endpoints was better compliance with LFT monitoring in the telephone clinic period. Additionally, patients served as their own control in this study, which helped eliminate confounding factors that may have been present when comparing 2 different patient groups.
The telephone clinic offered patients multiple advantages, including decreased wait time, as patients did not have to wait for their laboratory results to return or wait to be seen in clinic, increased volume of patients managed due to shorter appointment times, better coordination of other appointments on the same day, and improved medication reconciliation when patients have their medications in front of them. The disadvantages of telephone anticoagulation clinic included the inability of the providers to see any nonverbal cues, difficulty evaluating other issues for patients already at home and unwilling to return to the clinic, and the inability to provide written information (eg, changes in warfarin dosing or appointment scheduling) to the patient during the visit.
Limitations
In addition to the sample size and retrospective design of the study, there were several other study limitations. When the telephone anticoagulation clinic first started, patients with more stable INRs were chosen to enroll, which may have led to selection bias. Other limitations included the lack of documentation, patient reporting, or outside medical records documenting bleeds, VTE, or CVA/TIA. In addition, power was not calculated prior to beginning the study, because only, a small patient pool was available, and all patients that met inclusion criteria were to be included. Therefore, the sample size may have been too small to detect a difference.
Conclusion
In this retrospective chart review, the JBVAMC patients using the face-to-face and telephone anticoagulation clinics had similar outcomes. Telephone anticoagulation clinic was shown to be a viable alternative for some patients.
Nearly 4 million patients in the U.S. take warfarin.1 Between 1998 and 2004, the number of prescriptions for warfarin increased from 21.1 million to 30.6 million.2 However, with the approval of new oral anticoagulants, between 2007 and 2011, warfarin treatment visits decreased from 2.1 million to 1.6 million per quarter.3 Despite the declining number of patients on warfarin, there are still significant monetary and time costs associated with warfarin therapy. One study estimated that patients spend 2.5 hours per clinic visit, accounting for travel time and time spent in clinic, with an average of 1 hour in the clinic, including waiting time.1 Another study estimated the cost of warfarin therapy per patient, per month to be $62.30 in 2004 dollars based on 1.1 clinic visits per patient per month.4
Warfarin Monitoring
Warfarin requires close monitoring. The relationship between the dose of warfarin and the response is widely variable and can be influenced by many genetic and environmental factors, making dosing difficult. Genetic variations in the CYP2C9 and vitamin K epoxide reductase genes can lead to different warfarin dosing requirements.
Some environmental factors that can affect warfarin therapy include dietary vitamin K, alcohol intake, nutritional supplements, or herbal products. Concomitant diseases such as hepatic dysfunction, thyroid dysfunction, hypermetabolic states, age, and acute decompensated heart failure can also influence warfarin therapy. Additionally, there are numerous drug interactions that may affect warfarin therapy. Many of these factors may vary not only between patients, but also within the same patient over time.5-7
Warfarin has a narrow therapeutic range, which presents the possibility of serious adverse events (AEs) if warfarin is not dosed properly. According to The Institute for Safe Medication Practices, warfarin was the second most commonly reported drug causing serious AEs in 2011, with 1,106 cases, including 72 deaths reported to the FDA.8 Bescause of the large number of patients on warfarin and the risk for serious AEs, careful monitoring is required.
Monitoring of warfarin therapy is done using the prothrombin time (PT) test, which reflects the level of activity of factors I, II, V, VII, and X (of these warfarin affects factors II, VII, and X). However, PT tests can vary greatly, so a standardized model known as the international normalized ratio (INR) is used. The INR goals require the lowest effective dose in order to minimize bleeding. Dosing should be individualized for patients based on indications and patient-specific factors, such as history of bleeds or clots. Although it has been suggested that stable patients should undergo INR monitoring every 12 weeks, most patients are monitored every 4 to 6 weeks or more frequently.5,9
Standard of Care
Previously, the standard of care was for primary care providers to monitor warfarin therapy. Recently, there has been a shift to monitoring patients in anticoagulation clinics. One study that compared a pharmacist-managed anticoagulation service vs usual medical care concluded that the pharmacist-managed anticoagulation service resulted in a higher percentage of INR values in the therapeutic range, statistically significantly fewer anticoagulation-related AEs, and lower costs.10
There also have been studies conducted to evaluate the safety and efficacy of anticoagulation therapy when monitored by telephone-based anticoagulation clinics. A study by Witt and colleagues compared patients being managed in a telephone-based, pharmacist-managed anticoagulation clinic with a physician-managed clinic over a 6-month period. The study found that patients in the pharmacist-managed group spent more time in the therapeutic INR range (TTR) compared with the physician-managed group. However, although thromboembolic complications or major bleeds occurred less frequently in the pharmacist-managed group, the difference was not statistically significant.11
In a different study by Wittkowsky and colleagues, patients who were managed by a telephone vs a face-to-face clinic had a similar number of INR values in the therapeutic range, rates of major hemorrhage, and recurrent thromboembolism.12
In a study by Staresinic and colleagues an anticoagulation management service (AMS) was compared with an interim telephone model (IT). There was no statistically significant difference in the time both groups spent in the TTR, rates of thromboembolism, or rates of major bleeding. The IT group had a higher rate of minor bleeding events compared with that of the AMS group.13 To date, there have not been any published studies evaluating individual patients who were switched from face-to-face to telephone-based management of anticoagulation.
Methods
This retrospective electronic chart review of 156 patients was approved by both the institutional review board and research and development committee at the Jesse Brown VAMC (JBVAMC) in Chicago, Illinois. The patient list was generated from patients enrolled in an anticoagulation telephone clinic as of September 1, 2013. Patients were included if they were aged ≥ 18 years, received warfarin therapy between May 1, 2008, and September 1, 2013, had at least 70% of their anticoagulation visits with the face-to-face anticoagulation clinic for a continuous 1-year period and were then switched to the telephone anticoagulation clinic, and had at least 70% of their anticoagulation visits with the telephone anticoagulation clinic in a continuous 1-year period after the switch. Patients were excluded if they did not meet all the inclusion criteria. Of the 156 patients reviewed, 61 patients met enrollment requirements.
Study Endpoints
The primary endpoints of the study included TTR, defined as the percentage of anticoagulation visits at which the INR values were in the patient-specific therapeutic range ± 0.2 (excluding any subtherapeutic INR values within 2 weeks after planned short-term discontinuation of warfarin), event rate of cerebral vascular accidents (CVA)/transient ischemic attacks (TIA) and venous thromboembolism (VTE), and event rate of major bleeds. Major bleeds were defined as any fatal bleed, a symptomatic bleed in a critical area or organ (intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial or intramuscular with compartment syndrome), a fall in hemoglobin (Hg) ≥ 2 g/dL, or requiring transfusion of ≥ 2 units of whole blood or packed red blood cells.
Secondary endpoints of the study included event rate of minor bleeds (defined as any bleed not defined as a major bleed); time between follow-up appointments; number of acute care visits, emergency department (ED) visits, or hospitalizations due to anticoagulation; time to follow-up after hospital discharge, ED visit or acute care visit due to anticoagulation (if applicable); number of critical INRs as defined by local policy (INRs ≥ 5); number of canceled or no-show appointments; and compliance with monitoring of liver function test (LFT) and complete blood count (CBC) every 6 months per local policy.
Data Collection
To arrive at study endpoints, data collection included (1) demographics: age, ethnicity, and gender; (2) laboratory values: albumin, CBC, INR, LFT, and thyroid-stimulating hormone (TSH); (3) warfarin information: chart-documented adherence, dose and schedule, fill history, indication, INR goal per chart documentation, and reason for sub- or supratherapeutic INR; (4) safety: CVA/TIA, VTE, major bleeds, minor bleeds, and hospitalization/ED visits/acute care visits; (5) comorbid conditions: alcohol use, anemia, atrial fibrillation (AF), atrial flutter, cancer, coagulation deficiencies, congestive heart failure (CHF), diabetes mellitus (DM), hemodialysis, history of bleed, hypertension, liver cirrhosis, peptic ulcer disease, peripheral vascular disease, previous VTE, previous CVA/TIA, and valve replacement; (6) concomitant medications: aspirin, aspirin/extended-release dipyridamole, clopidogrel, dalteparin, enoxaparin, fondaparinux, nonsteroidal anti-inflammatory drugs (NSAIDs), unfractionated heparin, and warfarin; and (7) appointment data: time between appointments; time to follow-up after hospital discharge, ED visit or acute care visit (if applicable); and number of canceled or no-show appointments. Patient data were collected for 24 months total: the 12 months immediately before switching to telephone anticoagulation clinic (while the patient was followed in the face-to-face anticoagulation clinic) and the 12 months immediately after switching to telephone anticoagulation clinic.
Statistical tests used in this study included paired t test and Fisher exact test. P < .05 was determined to be statistically significant.
Results
A total of 156 patient charts were reviewed. Ninety-five patients were excluded, and 61 patients were included (Figure 1). Patients were excluded because they were either not enrolled in a face-to-face clinic for 1 continuous year prior to the switch or not enrolled in a telephone clinic for 1 continuous year after the switch. Patients also were excluded if they alternated between a face-to-face and telephone clinic and did not have at least 70% of their anticoagulation visits at the face-to-face clinic before the switch or at least 70% of their anticoagulation visits with the telephone clinic after the switch.
Baseline Characteristics
The study population was predominantly male with a mean age of 67 years. Most of the patients were African American. The most common indications for anticoagulation included AF, atrial flutter, previous VTE, or multiple indications. The most common INR goal range for patients was 2 to 3. The most common comorbid conditions were hypertension, alcohol use, CHF, and DM. Concomitant medications were noted if they were used anytime during the observation period; the most common were aspirin, NSAIDs, enoxaparin and dalteparin (Table 1).
Endpoints
There was not a statistically significant difference between the average TTR for patients for the face-to-face and telephone groups (Table 2). More than 85% of patients had a similar TTR between the groups or were in TTR more often during telephone clinic vs face-to-face clinic (Figure 2). One patient had a CVA during the face-to-face clinic period, and another patient had a TIA during the telephone anticoagulation clinic period. No VTE events were reported in either group. Further, there was 1 major bleed in the face-to-face clinic period (asymptomatic Hg drop ≥ 2 g/dL) and 3 major bleeds (asymptomatic Hg drop ≥ 2 g/dL, intraocular bleed, and gastrointestinal bleed) in the telephone clinic period, but this difference also was not statistically significant.
There were no statistically significant differences for any of the secondary endpoints except for compliance with LFT monitoring, which was higher in the telephone clinic. There were 22 minor bleeds found during face-to-face anticoagulation clinic and 19 minor bleeds found during telephone anticoagulation clinic. The most common types of minor bleed for both clinic settings were bruising at injection site (while using low molecular-weight heparin) and epistaxis.
There were 2 additional endpoints in the study for telephone clinic patients to assess time spent on telephone visits and ability to reach the patient by phone if they had laboratory tests drawn. In the telephone clinic, patients with completed labs were unreachable 2.1% of the time. The average amount of time spent on telephone visits was 8.0 (± 0.89) minutes.
Discussion
This study showed no statistically significant differences in TTR for patients switched to the telephone anticoagulation clinic from the face-to-face anticoagulation clinic. There also were no statistically significant differences in event rates for CVA/TIA, VTE, or major bleeds. The only statistically significant difference in secondary endpoints was better compliance with LFT monitoring in the telephone clinic period. Additionally, patients served as their own control in this study, which helped eliminate confounding factors that may have been present when comparing 2 different patient groups.
The telephone clinic offered patients multiple advantages, including decreased wait time, as patients did not have to wait for their laboratory results to return or wait to be seen in clinic, increased volume of patients managed due to shorter appointment times, better coordination of other appointments on the same day, and improved medication reconciliation when patients have their medications in front of them. The disadvantages of telephone anticoagulation clinic included the inability of the providers to see any nonverbal cues, difficulty evaluating other issues for patients already at home and unwilling to return to the clinic, and the inability to provide written information (eg, changes in warfarin dosing or appointment scheduling) to the patient during the visit.
Limitations
In addition to the sample size and retrospective design of the study, there were several other study limitations. When the telephone anticoagulation clinic first started, patients with more stable INRs were chosen to enroll, which may have led to selection bias. Other limitations included the lack of documentation, patient reporting, or outside medical records documenting bleeds, VTE, or CVA/TIA. In addition, power was not calculated prior to beginning the study, because only, a small patient pool was available, and all patients that met inclusion criteria were to be included. Therefore, the sample size may have been too small to detect a difference.
Conclusion
In this retrospective chart review, the JBVAMC patients using the face-to-face and telephone anticoagulation clinics had similar outcomes. Telephone anticoagulation clinic was shown to be a viable alternative for some patients.
1. Jonas DE, Bryant Shilliday B, Laundon WR, Pignone M. Patient time requirements for anticoagulation therapy with warfarin. Med Decis Making. 2010;30(2):206-216.
2. Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch Intern Med. 2007;167(13):1414-1419.
3. Kirley K, Qato DM, Kornfield R, Stafford RS, Alexander GC. National trends in oral anticoagulant use in the United States, 2007 to 2011. Circ Cadiovasc Qual Outcomes. 2012;5(5):615-621.
4. Anderson RJ. Cost analysis of a managed care decentralized outpatient pharmacy anticoagulation service. J Manag Care Pharm. 2004;10(2):159-165.
5. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G; American College of Chest Physicians. 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-e88S.
6. Choonara IA, Malia RG, Haynes BP, et al. The relationship between inhibition of vitamin K1 2,3-epoxide reductase and reduction of clotting factor activity with warfarin. Br J Clin Pharmacol. 1988;25(1):1-7.
7. Scordo MG, Pengo V, Spina E, Dahl ML, Gusella M, Padrini R. Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance. Clin Pharmacol Ther. 2002;72(6):702-710.
8. Institute for Safe Medication Practices. Quarter watch: anticoagulants the leading reported drug risk in 2011. Institute for Safe Medication Practices website. http://www.ismp.org/quarterwatch/pdfs/2011Q4.pdf. Published Fourth Quarter 2011. Accessed June 6, 2016.
9. Holbrook A, Schulman S, Witt DM, et al; American College of Chest Physicians. 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-e184S.
10. 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(7):686-694.
11. Witt DM, Sadler MA, Shanahan RL, Mazzoli G, Tillman DJ. Effect of a centralized clinical pharmacy anticoagulation service on the outcomes of anticoagulation therapy. Chest. 2005;127(5):1515-1522.
12. Wittkowsky AK, Nutescu EA, Blackburn J, et al. Outcomes of oral anticoagulant therapy managed by telephone vs in-office visits in an anticoagulation clinic setting. Chest. 2006;130(5):1385-1389.
13. Staresinic AG, Sorkness CA, Goodman BM, Pigarelli DW. Comparison of outcomes using 2 delivery models of anticoagulation care. Arch Intern Med. 2006;166(9):997-1002.
1. Jonas DE, Bryant Shilliday B, Laundon WR, Pignone M. Patient time requirements for anticoagulation therapy with warfarin. Med Decis Making. 2010;30(2):206-216.
2. Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch Intern Med. 2007;167(13):1414-1419.
3. Kirley K, Qato DM, Kornfield R, Stafford RS, Alexander GC. National trends in oral anticoagulant use in the United States, 2007 to 2011. Circ Cadiovasc Qual Outcomes. 2012;5(5):615-621.
4. Anderson RJ. Cost analysis of a managed care decentralized outpatient pharmacy anticoagulation service. J Manag Care Pharm. 2004;10(2):159-165.
5. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G; American College of Chest Physicians. 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-e88S.
6. Choonara IA, Malia RG, Haynes BP, et al. The relationship between inhibition of vitamin K1 2,3-epoxide reductase and reduction of clotting factor activity with warfarin. Br J Clin Pharmacol. 1988;25(1):1-7.
7. Scordo MG, Pengo V, Spina E, Dahl ML, Gusella M, Padrini R. Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance. Clin Pharmacol Ther. 2002;72(6):702-710.
8. Institute for Safe Medication Practices. Quarter watch: anticoagulants the leading reported drug risk in 2011. Institute for Safe Medication Practices website. http://www.ismp.org/quarterwatch/pdfs/2011Q4.pdf. Published Fourth Quarter 2011. Accessed June 6, 2016.
9. Holbrook A, Schulman S, Witt DM, et al; American College of Chest Physicians. 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-e184S.
10. 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(7):686-694.
11. Witt DM, Sadler MA, Shanahan RL, Mazzoli G, Tillman DJ. Effect of a centralized clinical pharmacy anticoagulation service on the outcomes of anticoagulation therapy. Chest. 2005;127(5):1515-1522.
12. Wittkowsky AK, Nutescu EA, Blackburn J, et al. Outcomes of oral anticoagulant therapy managed by telephone vs in-office visits in an anticoagulation clinic setting. Chest. 2006;130(5):1385-1389.
13. Staresinic AG, Sorkness CA, Goodman BM, Pigarelli DW. Comparison of outcomes using 2 delivery models of anticoagulation care. Arch Intern Med. 2006;166(9):997-1002.