An observational study examining the impact of capecitabine on warfarin antithrombotic activity and bleeding complications

OBJECTIVE: The objectives of this study are to quantify the frequency of concomitant use of capecitabine and warfarin, and to quantify the rate of bleeding events and elevated international normalized ratio (INR) among concomitant users of warfarin and capecitabine. RESEARCH DESIGN AND METHODS: We conducted a retrospective population-based study within the Henry Ford Health System (Detroit, MI) and the Kaiser Permanente Medical Care Program of Northern California (Oakland, CA). The study population included patients prescribed concomitant capecitabine and warfarin from 1 April 1997 through 31 July 2002. Data from the medical records of concurrent users were extracted through 31 August 2002. MAIN OUTCOME MEASURES: Concomitant use of capecitabine and warfarin, bleeding events, and INR laboratory results, collected from computerized databases and medical record review. RESULTS: Overall, 11% of capecitabine users also received warfarin (99 / 883). Among 17 patients who received warfarin for venous access device prophylaxis, one bleeding event occurred during concomitant capecitabine/warfarin use (rate = 35.7 bleeding events per 100 person-years, 95% confidence interval [CI] 0.9-198.9), and no events occurred during use of warfarin alone (95% CI 0.0-136.2) (p = 0.50). Among patients prescribed warfarin for indications other than port prophylaxis, no bleeding events occurred during concomitant use of capecitabine and warfarin (95% CI 0.0-34.6), and one event occurred during warfarin use alone (rate = 9.2 bleeding events per 100 person-years, 95% CI 0.2-51.3) (p = 0.54). We found one INR elevation > 3.0 among concomitant capecitabine/warfarin users receiving warfarin for port prophylaxis (rate = 35.7 per 100 person-years) and no INR elevations > 3.0 during use of warfarin alone (p = 0.46). Among patients using warfarin for indications other than port prophylaxis, the rates of INR > 3.0 were 309.7 per 100 person-years (95% CI 213.2-434.9) during concomitant capecitabine/warfarin use and 193.5 events per 100 person-years (95% CI 119.8-295.8) during use of warfarin alone (p = 0.09). CONCLUSIONS: The results of our study show a low prevalence of capecitabine and warfarin concomitant use. We did not find large differences in the rates of bleeding events and elevated INR in patients receiving concomitant capecitabine and warfarin when compared with use of warfarin alone. While these results do not imply a lack of biologic interaction, our findings indicate that patients appear to be appropriately managed in clinical practice.     

Effect of levofloxacin coadministration on the international normalized ratios during warfarin therapy

STUDY OBJECTIVE: To evaluate the effect of levofloxacin coadministration on the international normalized ratio (INR) in patients receiving warfarin therapy. DESIGN: Prospective analysis. SETTING: Outpatient clinic at a Veterans Affairs medical center. PATIENTS: Eighteen adult patients receiving warfarin. INTERVENTION: On the basis of clinical diagnosis and judgment, levofloxacin was prescribed to the 18 patients for treatment of various types of infection. The INR was measured before and at 2-8-day intervals after the coadministration of levofloxacin therapy, and once after completing therapy. Warfarin dosages were adjusted when necessary. MEASUREMENTS AND MAIN RESULTS: Warfarin dosages were changed in seven patients as a result of the first nontherapeutic INR values obtained after start of levofloxacin therapy. Owing to a concern regarding noncompliance and the adverse effect of bleeding, warfarin dosage was adjusted in one patient even though his first INR value was in the high end of the therapeutic range (2.98, therapeutic range 2-3). One patient withdrew from the study after the first INR measurement after levofloxacin coadministration. Because of a concern about the possible bleeding complication, warfarin dosage was also adjusted in this patient after obtaining his first INR value. Therefore, only the INR values obtained before and the first INR values obtained after levofloxacin administration were compared to evaluate the effect of levofloxacin on INR determination of warfarin therapy. The INR values obtained before levofloxacin administration did not differ significantly from the first INR values obtained after levofloxacin coadministration (mean +/- SD 2.61 +/- 0.44 vs 2.74 +/- 0.83, 95% confidence interval -0.449-0.196, p=0.419). CONCLUSION: The INR values measured before and after concomitant levofloxacin therapy were not significantly different. However, the ability to detect a significant difference may be affected by the small number of patients studied. Further studies with a larger sample are required to better determine the effect of levofloxacin coadministration on INR monitoring during warfarin therapy     

Warfarin-associated bleeding events and concomitant use of potentially interacting medicines reported to the Norwegian spontaneous reporting system

AIMS

To study warfarin associated bleeding events reported to the Norwegian spontaneous reporting system and evaluate the differences in assessment of potentially interacting medicines between reporters and evaluators.

METHODS

Data on bleeding events on warfarin were retrieved from the Norwegian spontaneous reporting system database. Key measurements were time to bleeding, use of concomitant medications and the evaluation done by reporters.

RESULTS

In 289 case reports a total of 1261 medicines (median 4.0 per patient, range 1–17) was used. The evaluators (authors of this article) identified 546 medicines including warfarin (median 2.0 per patient, range 1–7) that could possibly cause bleeding alone or in combination. Reporters assessed 349 medicines (median 1.0 per patient, range 1–4) as suspect. Evaluators identified 156 pharmacokinetic and 101 pharmacodynamic interactions, compared with 19 pharmacokinetic and 56 pharmacodynamic interactions reported as suspected by the reporters. Time to bleeding was stated in 224 reports. Among the early bleeding events, the reports on warfarin without interacting medicines showed the highest INR (international normalized ratio). Heparin was used in 17/21 reported bleeding events during the first week on warfarin. Among the late bleeding events, reports with pharmacokinetic interacting medicines had the highest INR.

CONCLUSIONS

Concomitant use of potentially interacting medicines was involved in the majority of the warfarin-associated bleeding events reported to the Norwegian spontaneous reporting system. Reporters assessed mostly warfarin as the only contributor to bleeding. In particular, pharmacokinetically interacting medicines were not suspected as contributing to bleeding.     

Randomized, placebo-controlled trial of oral phytonadione for excessive anticoagulation

STUDY OBJECTIVE: To compare the efficacy of managing excessive anticoagulation in the absence of bleeding by either omitting warfarin therapy alone or administering oral phytonadione in addition to omitting warfarin therapy. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Clinical pharmacy anticoagulation service in a group model health maintenance organization. SUBJECTS: Thirty nonbleeding patients with international normalized ratios (INRs) ranging from 6.0-10.0. INTERVENTIONS: Patients were randomized to receive either a single oral dose of phytonadione 2.5 mg or placebo. Both groups omitted warfarin doses until the INR became less than or equal to 4.0. MEASUREMENTS AND RESULTS: The mean calculated time to reach an INR of 4.0 was significantly greater in the placebo than the phytonadione group (2.6 vs 1.4 days, p=0.006). Overcorrection of anticoagulation was significantly more common in patients receiving phytonadione. Overt warfarin resistance was not observed in either group after reinitiating warfarin therapy. No major bleeding or thromboembolic complications occurred, and minor bleeding episodes were similar in both groups. CONCLUSION: The addition of oral phytonadione 2.5 mg reduced the time to achieve an INR of 4.0 by approximately 1 day compared with omitting warfarin therapy alone. Adverse events did not differ between the two groups. Both strategies were effective in managing asymptomatic patients with INRs of 6.0-10.0. Oral phytonadione may be most appropriate for patients at high risk for bleeding in whom the benefit of prompt INR reduction would outweigh the thromboembolic risk associated with INR overcorrection.     

Quantity and quality of potential drug interactions with coumarin anticoagulants in the Netherlands

Objective Coumarin anticoagulants are prone to potentially life-threatening drug-drug interactions due to a combination of unfavorable properties. However, real life data on the actual occurrence are scarce. The aim of this study was to quantify and qualify potential drug interactions with coumarin anticoagulants in daily practice. Methods A cohort study including all users of phenprocoumon or acenocoumarol during the period 1991–2003 in the PHARMO Record Linkage System. All 24 individual drugs and 11 drug groups interacting with coumarins according to central database used in the Dutch pharmacies were considered. Main outcome measure Frequency and type of potential drug interactions during anticoagulant therapy with coumarins. Results 48,627 out of 76,455 mainly acenocoumarol-users (64%) were dispensed at least one potentially interacting drug (PID) during anticoagulant therapy. About 35% of these cases were dispensed a (very) strongly interacting drug, whereas 3% were dispensed a contraindicated drug. Antibacterial drugs and NSAIDs (39% and 37% of all users, respectively) were the most frequently dispensed PIDs. Conclusion Potential drug interactions with coumarins frequently occur in daily practice, confronting two-thirds of patients with an increased risk of bleeding. To a large part, this is attributable to commonly prescribed medication like antibacterial drugs and NSAIDs. This situation substantiates the need for proper monitoring or new anticoagulants with less drug–drug interactions.     

Effect of age on international normalized ratio at the time of major bleeding in patients treated with warfarin

STUDY OBJECTIVES: Because the risk of major bleeding associated with warfarin increases with increasing international normalized ratio (INR) as well as with advanced age, we evaluated the association between age and INR in patients with major bleeding events related to anticoagulation with warfarin. DESIGN: Retrospective record review. SETTING: Two university-affiliated anticoagulation clinics. PATIENTS: Sixty-six patients (mean age 61.2 yrs, range 21-90 yrs) receiving warfarin therapy who experienced major bleeding, defined as bleeding requiring hospitalization, during a 20-month index period. MEASUREMENTS AND MAIN RESULTS: In patients aged 65 years or older, the mean INR at the time of a major bleeding event was significantly lower than that in patients younger than 65 years (INR 3.1 vs 4.2, respectively; p=0.01). For every 1-year increase in age, mean INR at the time of a major bleeding event decreased by 0.03 (p=0.02). CONCLUSION: Patients aged 65 years or older experience warfarin-related major bleeding events at a mean INR 1.1 units lower (95% confidence interval -1.9 to -0.27) than patients younger than 65 years. Older patients may require more aggressive management of overanticoagulation to minimize the risk of major bleeding.     

Thromboembolic consequences of subtherapeutic anticoagulation in patients stabilized on warfarin therapy: the low INR study

STUDY OBJECTIVE: To quantify the absolute risk of thromboembolism associated with a significant subtherapeutic international normalized ratio (INR) in patients with previously stable anticoagulation while receiving warfarin. DESIGN: Retrospective, matched cohort analysis. SETTING: Centralized anticoagulation service in an integrated health care delivery system. PATIENTS: A total of 2597 adult patients receiving warfarin from January 1998-December 2005; 1080 patients were in the low INR cohort and were matched to 1517 patients in the therapeutic INR cohort based on index INR date, indication for warfarin, and age. MEASUREMENTS AND MAIN RESULTS: Stable, therapeutic anticoagulation was defined as two INR values, measured at least 2 weeks apart, within or above the therapeutic range. The low INR cohort included patients with a third INR value of 0.5 or more units below their therapeutic range. The therapeutic INR cohort included patients with a third therapeutic INR value and no INR value 0.2 or more units below their target INR range in the ensuing 90 days. The primary outcome was anticoagulation-related thromboembolism during the 90 days after the index INR. Secondary outcomes were times to the first occurrence of anticoagulation-related complications (bleeding, thromboembolism, or death) in the 90 days after the index INR. Four thromboembolic events (0.4%) occurred in the low INR cohort and one event (0.1%) in the therapeutic INR cohort (p=0.214). The differences in the proportions of thromboembolism, bleeding, or death were not significant between the cohorts (p>0.05). No significant differences were noted in the hazard of thromboembolism, bleeding, or death between the cohorts (p>0.05). CONCLUSION: Patients with stable INRs while receiving warfarin who experience a significant subtherapeutic INR value have a low risk of thromboembolism in the ensuing 90 days. The risk was similar to that observed in a matched control population in whom therapeutic anticoagulation was maintained. These findings do not support the practice of anticoagulant bridge therapy for patients stabilized on warfarin therapy to reduce their risk for thromboembolism during isolated periods of subtherapeutic anticoagulation.     

Patient Self-Monitoring of Oral Anticoagulant Therapy

Coumarin derivatives are widely used oral anticoagulants for patients with chronic atrial fibrillation, venous thromboembolism, valvular heart disease, myocardial infarction or a mechanical prosthetic heart valve. Because of the narrow therapeutic window associated with coumarins and the potential for drug interactions, frequent monitoring of anticoagulation is required to maintain the International Normalized Ratio (INR) between 2.0 to 3.5 for most clinical indications. Monitoring of oral anticoagulant therapy is placing a considerable burden on healthcare providers because many patients require life-long treatment with coumarins, and because of an increasing number of elderly patients with conditions that are treated with coumarins. A novel approach that might, in part, address this healthcare need is patient self-monitoring of anticoagulation with a portable coagulometer. Several cohort studies and randomized controlled trials have found that anticoagulation self-monitoring is as good as, or better than, conventional monitoring in a specialized anticoagulation clinic or by a general practitioner. The advantages of anticoagulation self-monitoring include reduced patient inconvenience relating to anticoagulation clinic visits and laboratory monitoring of warfarin therapy, and fewer INR levels outside the therapeutic INR range if INR measurements are preformed more frequently with anticoagulation self-monitoring. Thus, anticoagulation self-monitoring has the potential to reduce the incidence of thromboembolic and bleeding episodes in patients who are receiving long term oral anticoagulant therapy. The potential drawbacks of anticoagulation self-monitoring include the costs of the portable coagulometer. Additionally, self-monitoring is limited to patients who have the cognitive and physical capabilities to perform the technique required for the portable coagulometer.     

Pharmacodynamics of uniform versus nonuniform warfarin dosages

STUDY OBJECTIVE: To compare the pharmacodynamics of uniform versus nonuniform warfarin dosages. DESIGN: Prospective, randomized, crossover study. SETTING: Anticoagulation clinic. SUBJECTS: Twenty healthy subjects who had the extensive metabolizer cytochrome P450 (CYP) genotype of 2C9*1/*1 or CYP2C9*1/*3. INTERVENTION: Subjects received either warfarin 5.75 mg once/day (two 1-mg tablets plus one and a half 2.5-mg tablets) as part of the uniform dosage group or warfarin 7.5 mg/day on Mondays and Fridays and 5 mg/day on each of the remaining days of the week as part of the nonuniform dosage group. Subjects received the first regimen for 17 days, had a 2-week washout period, and then were switched to the other regimen for another 17 days. MEASUREMENTS AND MAIN RESULTS: During both treatment periods, international normalized ratios (INRs) were checked daily using a fingerstick method. Any changes in concomitant drug therapy, including over-the-counter and supplement products, as well as health status were recorded. The Scheffe post hoc test revealed no significant differences in mean INR values obtained during receipt of the two dosage regimens. In both dosage groups, variation in the INR became more pronounced as INR values increased. No adverse events (i.e., major or minor bleeding) or changes in drug therapy were reported during the study. CONCLUSION: Our findings suggest that it is safe to use a nonuniform dosage regimen of warfarin to reach a target INR range. With both uniform and nonuniform regimens, close monitoring remains important to ensure that patients remain within the desired INR range.     

Comparison of Two Methods for INR Determination in a Pharmacist-Based Oral Anticoagulation Clinic

Warfarin is a commonly used oral anticoagulant that is usually initiated after the definitive diagnosis of a certain thromboembolic disorder or disease. Warfarin therapy will usually be prescribed for 6–12 weeks or more, and some patients may continue therapy throughout life, depending on the type of thromboembolic disorder. Major problems associated with warfarin therapy include adverse effects such as bleeding complications and drug-drug or drug-food interactions. In addition, thromboembolic complications may occur due to subtherapeutic dosages of warfarin. The laboratory reference standards for monitoring warfarin therapy are the prothrombin time (PT) and the International Normalized Ratio (INR). While both the PT or INR will reflect the clinical response in the patient, results reported as INR values have been shown to be more accurate than those reported as PT values. Thirty-two patients were enrolled in this study. Our objectives were to compare INR values measured by both the Coumatrak and conventional laboratory method, and to demonstrate the effects of pharmacist intervention on managing patients receiving warfarin therapy. Results from our study reveal that INR monitoring by Coumatrak is similar to the conventional laboratory method. In addition, our study indicates that patients receiving warfarin therapy can be monitored and managed effectively by pharmacists.     

Warfarin and acetaminophen interaction

A 74-year-old man who was receiving warfarin for atrial fibrillation experienced an abrupt increase in his international normalized ratio (INR) after taking acetaminophen. To investigate this effect, the patient's anticoagulation therapy was stabilized, and he was given acetaminophen 1 g 4 times/day for 3 days. His INR rose from 2.3 before receiving acetaminophen to 6.4 on the day after acetaminophen was discontinued. Warfarin was stopped for 2 days, and the patient's INR returned to 2.0. Warfarin was restarted at the same dosage, and his INR remained within 2.0-3.0 for 6 months. Factor VII activity decreased from 29.4% before acetaminophen therapy to 15.5% when his INR was 6.4, and factor X activity fell from 27.0% to 20.2%. His warfarin plasma concentration was 1.54 microg/ml before acetaminophen compared with 1.34 microg/ml when his INR was 6.4. No significant changes in drug intake, clinical status, diet, or lifestyle were noted. Changes in INR of this magnitude with the addition of another drug during stable anticoagulation therapy suggest a drug interaction. The lack of an increase in warfarin plasma concentration associated with the increased INR suggests a possible pharmacodynamic mechanism for this interaction. Acetaminophen or a metabolite may enhance the effect of oral coumarin anticoagulants by augmenting vitamin K antagonism. Thus, the anticoagulant effect of warfarin may be significantly elevated after only a few days of acetaminophen therapy. Patients receiving warfarin should be counseled to have their INR monitored more frequently when starting acetaminophen at dosages exceeding 2 g/day.     

Difficulties in anticoagulation management during coadministration of warfarin and rifampin

The clinical significance of rifampin's induction of warfarin metabolism is well documented, but no published studies or case reports have quantified this interaction with respect to the international normalized ratio (INR). A patient receiving concomitant rifampin and warfarin to treat a mycobacterial infection and intraventricular thrombus, respectively, underwent routine INR testing at a pharmacist-managed anticoagulation clinic to assess his anticoagulation regimen. A 233% increase in warfarin dosage over 4 months proved insufficient to attain a therapeutic INR during long-term rifampin therapy More aggressive titration of the warfarin dosage was needed. In addition, a gradual 70% reduction in warfarin dosage over 4-5 weeks was necessary to maintain a therapeutic INR after rifampin discontinuation, demonstrating the clinically significant offset of this drug interaction. Extensive changes in warfarin dosage are required to attain and maintain a therapeutic INR during the initiation, maintenance, and discontinuation of rifampin.     

Is INR between 2.0 and 3.0 the optimal level for Chinese patients on warfarin therapy for moderate-intensity anticoagulation?

AIM: To examine the optimal range of International Normalized Ratio (INR) for Chinese patients receiving warfarin for moderate-intensity anticoagulation. METHODS: This was a retrospective cohort study conducted at the ambulatory setting of a 1400-bed public teaching hospital in Hong Kong. The INR measurements and occurrence of serious or life-threatening haemorrhagic and thromboembolic events among patients newly started on warfarin from 1 January 1999 to 30 June 2001 for indications with target INR 2-3 were analysed. The INR-specific incidence of bleeding and thromboembolism were calculated. RESULTS: A total of 491 patients were included, contributing to 453 patient-years of observation period. Forty-seven of the 491 patients experienced 25 haemorrhagic events (5.5 per 100 patient-years) and 27 thromboembolic events (6.0 per 100 patient-years). The percentage of patient-time spent within therapeutic INR range (2-3), INR <2 and INR >3 were 50, 44 and 6%, respectively. The incidence of either haemorrhagic or thromboembolic events was lowest (< or =4 events per 100 patient-years) at INR values between 1.8 and 2.4. CONCLUSIONS: An INR of 1.8-2.4 appeared to be associated with the lowest incidence rate of major bleeding or thromboembolic events in a cohort of Hong Kong Chinese patients receiving warfarin therapy for moderate-intensity anticoagulation.     

Low-molecular-weight heparin may alter point-of-care assay for international normalized ratio

STUDY OBJECTIVE: To compare the international normalized ratio (INR) measured by a point-of-care testing device with that measured by a reference laboratory method for patients receiving either warfarin only or warfarin plus low-molecular-weight heparin (LMWH). DESIGN: Retrospective study. SETTING: Outpatient anticoagulation clinic. SUBJECTS: Ninety-one patients receiving warfarin for various indications; 59 of them receiving only warfarin and 32 receiving warfarin plus LMWH. INTERVENTION: Capillary blood was obtained for INR determination by a point-of-care device, and venous blood was obtained for INR determination in a standard reference laboratory. MEASUREMENTS AND MAIN RESULTS: Ninety-one patients had INR pairs run on a point-of-care device and by the laboratory. In both the patients receiving only warfarin and in those receiving warfarin plus LMWH, the mean INR as determined by the point-of-care testing device was statistically significantly higher than the mean INR determined by the laboratory. Although the differences were statistically significant in both groups, the clinical significance of this difference was accentuated in the patients receiving warfarin plus LMWH. The measure of divergence between the point-of-care and laboratory methods was greater in the group receiving warfarin plus LMWH than in the warfarin-only group, with a mean +/- SD percent change between the INR values of 24.19 +/- 27.54% in the warfarin plus LMWH group and 7.21 +/- 17.73% in the warfarin-only group. In assessing the clinical impact of such variability, a greater degree of discordance in dosing adjustment decisions was noted for patients receiving warfarin plus LMWH. In this group, a 25% rate of discordance was noted compared with 8% in the warfarin-only group. Such discrepancy in dosing decisions based on the point-of-care INR would have resulted in discontinuation of LMWH therapy before the patient acquired a true therapeutic INR, with use of the laboratory measurement. CONCLUSION: The INR measured with the point-of-care device in patients receiving concurrent LMWH and warfarin therapy may be inaccurate. Patients receiving LMWH in addition to warfarin should have INRs checked by means of the standard reference laboratory method.     

Anticoagulation-related outcomes in patients receiving warfarin after starting levofloxacin or gatifloxacin

STUDY OBJECTIVE: To compare anticoagulation-related outcomes in patients receiving stable dosages of warfarin who started levofloxacin or gatifloxacin therapy. DESIGN: Retrospective medical record review. SETTING: Veterans Affairs medical center. PATIENTS: Of 92 patients receiving the same dosages of warfarin for at least 4 weeks before starting antibiotic therapy, 54 received levofloxacin between January and September 2003, and 38 received gatifloxacin between January and September 2004. MEASUREMENTS AND MAIN RESULTS: Data were obtained through the hospital's pharmacy, laboratory, and general patient databases and through electronic medical records. The INRs evaluated were prefluoroquinolone use, defined as the last INR measured before the start of antibiotic therapy (up to 4 wks earlier), and postfluoroquinolone use, defined as any INR measured during antibiotic therapy through 1 week after discontinuation of the antibiotic. Analyzed outcomes included the percentage of patients with postfluoroquinolone INRs that were above 4, that exceeded the therapeutic goal, or that exceeded the goal by more than 1 point; INR changes of more than 0.5, 1, or 1.5 points above the INR before fluoroquinolone use; major or minor bleeding events; requirement for vitamin K administration; warfarin dosage reduction or withholding doses; and warfarin-related hospital, emergency, or urgent care admissions or visits. No significant differences were noted in baseline characteristics with regard to age, sex, prefluoroquinolone INR, or anticoagulation indications between the two groups. The percentage of patients with a postfluoroquinolone INR above 4 was 2% (1 of 54 patients) in the levofloxacin group versus 21% (8 of 38 patients) in the gatifloxacin group (p=0.003). The percentage of patients receiving vitamin K in the levofloxacin and gatifloxacin groups was 0% (0 of 54 patients) and 11% (4 of 38, p=0.026), respectively. For the other anticoagulation-related outcomes, no significant differences were noted between the groups. CONCLUSION: Patients receiving warfarin who take gatifloxacin may be at higher risk for an INR above 4 compared with those taking levofloxacin. Close monitoring of warfarin therapy while concomitantly receiving gatifloxacin is warranted.