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Background: An elevated international normalized ratio (INR) increases the risk for major hemorrhage during warfarin therapy. Optimal management of patients with asymptomatic elevations in INR is hampered by the lack of understanding of the time course of INR decay after cessation of warfarin therapy., Objective: To identify predictors of the rate of INR normalization after excessive anticoagulation., Design: Retrospective cohort study., Setting: Outpatient anticoagulant therapy unit., Patients: Outpatients with an INR greater than 6.0 were identified from August 1993 to September 1998. Patients in whom two doses of warfarin were withheld and a follow-up INR was obtained on the second calendar day were enrolled. No patient received vitamin K(1)., Measurements: The INR was measured 2 days after an INR greater than 6.0 was recorded., Results: Of 633 study patients with an initial INR greater than 6.0, 232 (37%) still had an INR of 4.0 or greater after two doses of warfarin were withheld. Patients who required larger weekly maintenance doses of warfarin were less likely to have an INR of 4.0 or greater on day 2 (adjusted odds ratio per 10 mg of warfarin, 0.87 [95% CI, 0.79 to 0.97]). Other risk factors for having an INR of 4.0 or greater on day 2 included age (odds ratio per decade of life, 1.18 [CI, 1.01 to 1.38]), index INR (odds ratio per unit, 1.25 [CI, 1.14 to 1.37]), decompensated congestive heart failure (odds ratio, 2.79 [CI, 1.30 to 5.98]), and active cancer (odds ratio, 2.48 [CI, 1.11 to 5.57])., Conclusions: Steady-state warfarin dose, advanced age, and extreme elevation in INR are risk factors for prolonged delay in return of the INR to within the therapeutic range. Decompensated congestive heart failure and active cancer greatly increase this risk.

Background: Warfarin sodium therapy is highly effective in preventing thromboembolism. Its major toxic effect is hemorrhage, the risk of which increases with the international normalized ratio (INR). Data on the rate of major hemorrhage and the rate of INR decay after an episode of excessive anticoagulation therapy would help guide management of elevated INRs in the outpatient setting., Methods: We prospectively followed up outpatients in an anticoagulant therapy unit from April 24, 1995, through March 1, 1996. Study patients had to be taking warfarin for longer than 1 month and have an INR target range of 2.0 to 3.0. Consecutive outpatients with an INR greater than 6.0 were identified and compared with a randomly selected concurrent set of patients whose INR was in the target range. Major hemorrhage was defined as fatal, intracranial, or requiring hospitalization and transfusion of at least 2 U of blood., Results: One hundred fourteen patients with INRs greater than 6.0 were identified and compared with 268 patients with INRs in the target range. None of the patients had clinically apparent bleeding at the time of the INR measurement, and none received phytonadione (vitamin K1). Patients did not differ significantly in age, sex, indication, or duration of warfarin therapy. Ten patients with an INR greater than 6.0 (8.8%; 95% confidence interval, 4.3%-15.5%) sought medical attention for abnormal bleeding, and 5 of these experienced a major hemorrhage during 14-day follow-up (4.4%; 95% confidence interval, 1.4%-9.9%) compared with none of the patients with an in-range INR (P<.001). Thirty-three percent of patients with INRs greater than 6.0 had INRs less than 4.0 within 24 hours, 55% within 48 hours, 73% within 72 hours, and nearly 90% within 96 hours of temporary discontinuation of warfarin therapy., Conclusions: Outpatients with INRs greater than 6.0 face a significant short-term risk of major hemorrhage. Randomized trials are needed to determine the net benefit of preventive treatment with phytonadione.

Context: Warfarin is highly effective in preventing thromboembolism, but increases the risk of hemorrhage, particularly at an international normalized ratio (INR) greater than 4.0. Identifying causes of excessive anticoagulation in clinical practice could help target patients at risk for elevated INRs., Objective: To determine causes of INRs greater than 6.0 in a clinical practice setting., Design: Case-control study., Setting: Outpatient anticoagulant therapy unit., Patients: Outpatients followed up prospectively from April 1995 to March 1996 who had been taking warfarin for more than 1 month, had a target INR of 2.0 to 3.0, and were able to be interviewed within 24 hours of their reported INR. Case patients had INRs greater than 6.0; controls were randomly selected from patients having INRs between 1.7 and 3.3., Main Outcome Measures: Factors associated with INRs greater than 6.0, including medication use, recent diet, illness, alcohol consumption, and actual warfarin use., Results: A total of 93 cases and 196 controls were interviewed; they did not differ in age, indication for warfarin, length of therapy, warfarin dose, number of prescription medications, or previous INR or long-term INR variability. Acetaminophen ingestion was independently associated in a dose-dependent manner with having an INR greater than 6.0 (P for trend <.001). For the highest-dose category of acetaminophen intake, 9100 mg/wk or more, the odds of having an INR greater than 6.0 were increased 10-fold (95% confidence interval [CI], 2.6-37.9). Other factors independently associated with an INR greater than 6.0 were new medication known to potentiate warfarin (odds ratio [OR], 8.5; 95% CI, 2.9-24.7), advanced malignancy (OR, 16.4; 95% CI, 2.4-111.0), recent diarrheal illness (OR, 3.5; 95% CI,1.4-8.6), decreased oral intake (OR, 3.6; 95% CI, 1.3-9.7), and taking more warfarin than prescribed (OR, 8.1; 95% CI, 2.2-30.0). Higher vitamin K intake (OR, 0.7; 95% CI, 0.5-0.9) and habitual alcohol consumption of from 1 drink every other day to 2 drinks a day (OR, 0.2; 95% CI, 0.1-0.7) were associated with decreased risk., Conclusions: These data suggest that acetaminophen is an underrecognized cause of overanticoagulation in the outpatient setting. Several other clinically important risk factors were identified. Increased monitoring of INR values when such risk factors are present or modification of the risk factors themselves should reduce the frequency of dangerously high levels of anticoagulation.

Background: To avert major hemorrhage, physicians need to know the lowest intensity of anticoagulation that is effective in preventing stroke in patients with atrial fibrillation. Since the low rate of stroke has made it difficult to perform prospective studies to resolve this issue, we conducted a case-control study., Methods: We studied 74 consecutive patients with atrial fibrillation who were admitted to our hospital from 1989 through 1994 after having an ischemic stroke while taking warfarin. For each patient with stroke, three controls with nonrheumatic atrial fibrillation who were treated as outpatients were randomly selected from the 1994 registry of the anticoagulant-therapy unit (222 controls). We used the international normalized ratio (INR) to measure the intensity of anticoagulation. For the patients with stroke, we used INR at admission; for the controls, we selected the INR that was measured closest to the month and day of the matched case patient's hospital admission., Results: The risk of stroke rose steeply at INRs below 2.0. At an INR of 1.7, the adjusted odds ratio for stroke, as compared with the risk at an INR of 2.0, was 2.0 (95 percent confidence interval, 1.6 to 2.4); at an INR of 1.5, it was 3.3 (95 percent confidence interval, 2.4 to 4.6); and at an INR of 1.3, it was 6.0 (95 percent confidence interval, 3.6 to 9.8). Other independent risk factors were previous stroke (odds ratio, 10.4; 95 percent confidence interval, 4.4 to 24.5), diabetes mellitus (odds ratio, 2.95; 95 percent confidence interval, 1.3 to 6.5), hypertension (odds ratio, 2.5; 95 percent confidence interval, 1.1 to 5.7), and current smoking (odds ratio, 5.7; 95 percent confidence interval, 1.4 to 24.0)., Conclusions: Among patients with atrial fibrillation, anticoagulant prophylaxis is effective at INRs of 2.0 or greater. Since previous studies have indicated that the risk of hemorrhage rises rapidly at INRs greater than 4.0 to 5.0, tight control of anticoagulant therapy to maintain the INR between 2.0 and 3.0 is a better strategy than targeting lower, less effective levels of anticoagulation.