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Toward Safer Warfarin Therapy: Does Precise Daily Dosing Improve International Normalized Ratio Control?

      To the Editor: Warfarin therapy is prescribed for the prevention of stroke and embolism, not only for patients who have a prosthetic valve but also for a growing number of elderly patients with atrial fibrillation. Control of the international normalized ratio (INR), by which warfarin therapy is monitored, is a daunting challenge. As stated by Gage, “Variation in the INR is unavoidable. …”
      • Gage BF
      • Fihn SD
      • White RH
      Warfarin therapy for an octogenarian who has atrial fibrillation.
      The annual risk of major hemorrhage can approach 3% to 4% and is proportional to the percentage of patient-days of INR at 5.0 or higher.
      • Gage BF
      • Fihn SD
      • White RH
      Warfarin therapy for an octogenarian who has atrial fibrillation.
      In my prescribing experience, a key factor is the dosing schedule, about which little has been published. Warfarin is available in several strengths (1, 2, 2.5, 3, 4, and 5 mg) of scored tablets. Patients often require a daily dose that is neither a precise multiple of a single tablet nor a multiple of its half-strength. For example, a weekly requirement of 30 mg (4.28 mg/d) is customarily prescribed in some alternating-day fashion (that is, one 5-mg tablet on Sunday, Tuesday, Wednesday, Friday, and Saturday and one-half tablet on Monday and Thursday).
      • Gage BF
      • Fihn SD
      • White RH
      Warfarin therapy for an octogenarian who has atrial fibrillation.
      • Ansell JE
      Oral anticoagulant therapy3/450 years later.
      The term “customary” is used advisedly. This dosing pattern is not found in the manufacturer's package insert, standard pharmacological texts, or clinical trials. Rather, it is commonly used on the basis of tradition
      • Gage BF
      • Fihn SD
      • White RH
      Warfarin therapy for an octogenarian who has atrial fibrillation.
      or personal experience.
      • Ansell JE
      Oral anticoagulant therapy3/450 years later.
      Because of day-to-day variation, confusion may arise on the part of the patient or prescriber.
      • Gage BF
      • Fihn SD
      • White RH
      Warfarin therapy for an octogenarian who has atrial fibrillation.
      Wong et al
      • Wong W
      • Wilson Norton J
      • Wittkowsky AK
      Influence of warfarin regimen type on clinical and monitoring outcomes in stable patients in an anticoagulation management services.
      compared “customary” dosing with “consistent” daily dosing (in multiples of 1 mg). Patients marginally preferred consistent daily dosing, but INR control was unaffected.
      • Wong W
      • Wilson Norton J
      • Wittkowsky AK
      Influence of warfarin regimen type on clinical and monitoring outcomes in stable patients in an anticoagulation management services.
      As part of a continuous-improvement effort within my private practice in Pittsburgh, Pa, beginning January 1991 I switched all 22 patients (15 with prosthetic valves) receiving warfarin therapy to a consistent daily dose. This regimen differed from Wong's in that the warfarin dosing “menu” was constructed not in increments of 1 mg, but rather in increments of 0.25 mg. This “precise daily dose” strategy necessitated a 2-tablet system (Table 1). Patients were given 2 different-strength tablets (generally 2.5-mg and 1-mg tablets for patients age 65 and older and 5-mg and 1-mg tablets for younger patients). In the aforementioned example, a patient requiring 30 mg weekly would have been prescribed 4.25 mg daily. Periodic dose adjustments, in response to INR changes, were made in the customary way. Dose changes became transparent. Dosages were easier for the physician to calculate and communicate and easier for the patient (or surrogate) to understand. Only a brief educational effort for the patient was required. In 1992, I retrospectively reviewed the (then standard) prothrombin time test results of all my patients receiving customary warfarin therapy and compared these results with the prothrombin time test results of my patients who were managed with warfarin therapy in the 3 years before the warfarin dosing system conversion and then were managed with precise daily dosing for the next 2 years (Table 2).
      Table 1Warfarin Doses in a 2-Tablet System
      NA = not applicable.
      No. of tablets
      Daily amount (mg)1-mg (pink)2.5-mg (green)5-mg (peach)
      0.5½nana
      11nana
      1.25na½na
      1.51 ½nana
      1.75½½na
      22nana
      2.251½na
      2.5na1na
      2.751 ½½na
      3½1na
      3.252½na
      3.511na
      3.75na1 ½na
      41 ½1na
      4.25½1 ½na
      4.521na
      4.7511 ½na
      5na2na
      nana1
      5.251 ½172na
      5.5½na1
      5.752172na
      61na1
      6.51 ½na1
      72na1
      7.5nana172
      83na1
      * NA = not applicable.
      Table 2Comparison of Prothrombin Time Test Results for Customary and Precise Daily Dosing
      PT = prothrombin time.
      Manner of warfarin dosing (calendar years)No. of patientsNo. of PT testsNo. (%) of PT tests within target rangeNo. (%) of PT tests ±1 second of target range
      Customary (1988-1990)22511222 (43)311 (61)
      Precise daily dosing (1991-1992)37
      Includes 15 new patients after January 1991.
      581328 (57)421 (72)
      * PT = prothrombin time.
      Includes 15 new patients after January 1991.
      I continued to use the refined and consistent daily dose in all patients in my practice throughout the next decade, even as additional clarity and control were gained through laboratories reporting results in INR.
      In 2000, Samsa et al
      • Samsa GP
      • Matchar DB
      • Goldstein LB
      • et al.
      Quality of anticoagulation management among patients with atrial fibrillation: results of a review of medical records from 2 communities.
      published the first normative data of INR control of patients with chronic atrial fibrillation. Twenty-five systematically surveyed physician practices did not have anticoagulation services available. They serve as the benchmark against which most physicians’ practices can be compared. Discouragingly, patients’ INRs were within the target range on less than half of the days (Table 3, rows 1 and 2).
      Table 3Comparison of INR Control in Normative Data to Author's Clinical Observation in Patients With Chronic Atrial Fibrillation
      INR = international normalized ratio.
      Practice locationNo. of practice sitesNo. of patientsPatient-days INR within target range
      2.0-3.0.
      (%)
      Patient-days (per 1000) of INR ≥5
      Research Triangle Park, NC
      • Samsa GP
      • Matchar DB
      • Goldstein LB
      • et al.
      Quality of anticoagulation management among patients with atrial fibrillation: results of a review of medical records from 2 communities.
      892
      Estimated.
      3628
      Rochester, NY
      • Samsa GP
      • Matchar DB
      • Goldstein LB
      • et al.
      Quality of anticoagulation management among patients with atrial fibrillation: results of a review of medical records from 2 communities.
      Without anticoagulation service available.
      1758
      Estimated.
      4714
      Pittsburgh, Pa
      Author's private practice audit.
      125692
      * INR = international normalized ratio.
      2.0-3.0.
      Estimated.
      § Without anticoagulation service available.
      Author's private practice audit.
      In an accompanying editorial, Ansell
      • Ansell JE
      The quality of anticoagulation management [editorial].
      commented that this work brought much-needed insight into the everyday real-world management of oral anticoagulation therapy. Ansell also called for better understanding of the manner in which other smaller practices fare in this regard.
      Using the method described by Samsa et al,
      • Samsa GP
      • Matchar DB
      • Goldstein LB
      • et al.
      Quality of anticoagulation management among patients with atrial fibrillation: results of a review of medical records from 2 communities.
      I reviewed the INR control of my 25 patients with atrial fibrillation (2000-2001) (Table 3, row 3). In comparison with the patients in Samsa's study, my patients were older (21 patients [84%] were age =70 years; 15 patients [60%] were age =75 years) and had greater comorbidity. Moreover, this degree of INR control was accomplished with a longer (mean) interval between blood tests, 24.9 days vs 22.2 days in Samsa et al
      • Samsa GP
      • Matchar DB
      • Goldstein LB
      • et al.
      Quality of anticoagulation management among patients with atrial fibrillation: results of a review of medical records from 2 communities.
      (25 practices). The only disadvantage of the precise daily dosing system was the expense of 50% more tablet consumption.

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