The effect of acetaminophen on the international normalized ratio in patients stabilized on warfarin therapy

STUDY OBJECTIVE: To determine whether an interaction exists between acetaminophen and warfarin that alters the international normalized ratio (INR). DESIGN: Prospective, randomized, double-blind, placebo-controlled trial. SETTING: Anticoagulation clinic at a Veterans Affairs Medical Center. PATIENTS: Thirty-six adult patients receiving warfarin with stable INRs, defined as two consecutive INRs at least 3 weeks apart that were within the therapeutic range. INTERVENTION: Patients were randomly assigned to receive acetaminophen 1 g twice/day along with matching placebo twice/day (12 patients), acetaminophen 1 g 4 times/day (12 patients), or matching placebo 4 times/day (12 patients) for 4 weeks. MEASUREMENTS AND MAIN RESULTS: The primary end point was the difference in mean INR between groups at weekly intervals. Secondary end points were the percentages of patients in each group with supratherapeutic (INR > or = 0.3 above the upper limit of their therapeutic range) or subtherapeutic (INR > or = 0.2 or 0.3 below the lower limit of their respective therapeutic range of 2.0-3.0 or 2.5-3.5) INRs, and the difference in mean serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels between groups at biweekly intervals. Slow enrollment and a preliminary observation that 15 patients experienced an elevated INR prompted early termination of the study. At week 2, the group receiving acetaminophen 2 g/day had a significantly higher mean INR versus the placebo group (p=0.01). At weeks 1, 2, and 3, the acetaminophen 4-g/day group had significantly higher mean INRs compared with those in the placebo group (p=0.04, p=0.01, p=0.01, respectively). In addition, 13 (54%) of 24 patients in the acetaminophen groups combined exceeded the upper limit of their therapeutic range by 0.3 or greater compared with only 2 (17%) of 12 patients in the placebo group. No statistically significant differences in serum ALT or AST levels between either acetaminophen group versus the placebo group were found at week 4; however, there was a statistically significant increase in mean ALT level at week 2 in the acetaminophen 4-g/day group versus the placebo group. CONCLUSION: These findings support the existence of a clinically significant interaction between warfarin and daily use of acetaminophen 2-4 g, necessitating close monitoring of patients who receive this drug combination. Whether this interaction occurs when acetaminophen is taken in lower doses or is used sporadically requires further study.     

Increase in international normalized ratio after smoking cessation in a patient receiving warfarin

A 58-year-old man who was taking warfarin at a stable dosage was admitted to the hospital with a diagnosis of bacterial meningitis. Although he had previously been a smoker, after this admission, he decided to give up smoking. He was continued on his previous warfarin maintenance dosage when discharged, and his international normalized ratio (INR) soon began to climb substantially. When questioned, the patient reported no diet or lifestyle changes other than his smoking cessation. The patient's INR was stabilized at a warfarin dosage 23% lower than the maintenance dosage before he stopped smoking. This case report illustrates the potential for an interaction between warfarin and cigarette smoking and further suggests that the effect could be significant if a patient starts or stops smoking during warfarin therapy.     

Unreliability of international normalized ratio for monitoring warfarin therapy in patients with lupus anticoagulant

STUDY OBJECTIVE: To compare the international normalized ratios (INRs) of patients positive for lupus anticoagulant and the INRs of control patients receiving warfarin therapy with equivalent therapeutic chromogenic factor X levels. DESIGN: Prospective case series. SETTING: A 625-bed, adult, private, tertiary care teaching hospital. PATIENTS: Sixty-eight outpatients positive for lupus anticoagulant and 57 control patients receiving long-term warfarin therapy. MEASUREMENTS AND MAIN RESULTS: Concomitant INR and chromogenic factor X activity were measured in all patients. In 44 control patients (77%) and 46 patients with lupus anticoagulant (68%), chromogenic factor X activity was 22-40% of normal, which is therapeutic. Of the 44 control patients, 4 (9%) had an INR above 3.0, and none had an INR above 4.0. In contrast, 18 (39%) of the 46 patients with lupus anticoagulant had an INR above 3.0, and 5 (11%) had an INR above 4.0. CONCLUSION: At least 10% of patients with lupus anticoagulant receiving long-term warfarin therapy may have falsely high INR values, which could lead to inappropriate warfarin dosage reduction. Monitoring warfarin therapy by chromogenic factor X activity in patients with lupus anticoagulant avoids this INR artifact.     

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     

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.     

Effect of pitavastatin vs. rosuvastatin on international normalized ratio in healthy volunteers on steady-state warfarin

Abstract

Objective:

Statins have been shown to impact international normalized ratio (INR) when coadministered with warfarin. The aim of this study was to assess the effect of pitavastatin compared with rosuvastatin on steady-state pharmacodynamics (PD) of warfarin by measuring INR in healthy adult subjects.     

Possible effect of refrigeration of warfarin on the international normalized ratio.

A 43-year-old African-American woman taking warfarin for prevention of ischemic stroke experienced fluctuating international normalized ratio (INR) values over 8.5 months; no cause could be identified. After reading a pharmacy information sheet that accompanied a warfarin refill, she reported that she had been refrigerating her warfarin because her other drugs had been "sticking together." She then was instructed to store her warfarin at room temperature. During the 8.5 months she had been refrigerating her warfarin, 80% of her INR values had been outside her goal range versus 37.5% during 9 months of storage at room temperature. A MEDLINE search and communication with the drug's manufacturer provided no information regarding storage of warfarin outside the temperature range of 59-86 degrees F and resultant changes in potency of the drug. Because of potential fluctuation in anticoagulation control, patients should be reminded to store their warfarin at room temperature.     

Prediction of the international normalized ratio and maintenance dose during the initiation of warfarin therapy

AIMS: A pharmacokinetic/pharmacodynamic model, with Bayesian parameter estimation, was used to retrospectively predict the daily International Normalized Ratios (INRs) and the maintenance doses during the initiation of warfarin therapy in 74 inpatients. METHODS: INRs and maintenance doses predicted by the model were compared with the actual INRs and the eventual maintenance dose. Cases with drugs or medical conditions interacting with warfarin or receiving concurrent heparin therapy were not excluded. As the study was retrospective, model predictions of the maintenance dose were not those that were administered. Mean prediction error (MPE) and percentage absolute prediction errors (PAPE) were used to assess the model predictions. RESULTS: INR MPE ranged from -0.07 to 0.06 and median PAPE from 10% to 20%. Dose MPE ranged from -0.7 to 0.17 mg and median PAPE from 16.7% to 37.5%. Accurate and precise dose predictions were obtained after 3 or more INR feedback's. CONCLUSIONS: This study shows that the model can accurately predict daily INRs and the maintenance dose in this sample of cases. The model can be incorporated into computer decision-support systems for warfarin therapy and may lead to improvement in the initiation of warfarin therapy.     

华法林与苯溴马隆联用致国际标准化比值升高

1例45岁男性患者,因扩张型心肌病、心房颤动、肺动脉高压、心力衰竭给予托拉塞米、呋塞米、螺内酯、培哚普利、美托洛尔、头孢地嗪、多烯磷脂酰胆碱治疗,同时口服华法林2.5 mg,1次/d.第3天实验室检查：国际标准化比值（INR） 1.16,尿素8.9 mmol/L,尿酸625 μmol/L.加服苯溴马隆50 mg,3次/d.次日患者INR升至3.43,第9天升至4.56.当日停用华法林.停用华法林第7天INR降至1.28,第14天恢复华法林2.5 mg口服,1次/d.6d后,INR升至3.52.当日停用苯溴马隆,次日停用华法林.3d后,INR降至1.98.     

Study on warfarin plasma concentration and its correlation with international normalized ratio

A sensitive high-performance liquid chromatographic (HPLC) method was developed for warfarin determination in plasma of patients who undertook cardiac valve replacement and were on anticoagulation with warfarin. The method described proved to be accurate, sensitive, easy to perform, reproducible and specific for plasma warfarin measurement with relative standard deviation (R.S.D.) of <5.27% for inter-day and <6.89% for intra-day. The assay was linear in warfarin concentration ranges of 0.12-3 microg/ml (r=0.9995) with mean recovery of 94.6%. The mean warfarin plasma concentration of 58 patients with heart valve replacement within 1 month of post operation was 567.6+/-122.3 ng/ml. The anticoagulant effect of the drug was monitored by international normalized ratio (INR). The correlation of warfarin dosage and concentration with INR was analysed, and the coefficients were 0.21, 0.1相似文献   

慢性房颤华法令抗凝治疗的理想INR值探讨

目的:探讨慢性房颤华法令抗凝治疗的理想国际标准化比值(INR)。方法:对115例有血栓栓塞高危因素的慢性房颤患者给予华法令抗凝治疗,定期随访INR,同时观察治疗中发生的血栓栓塞和出血事件。结果:115例患者中有8例共10次发生血栓栓塞事件,7例7次发生与抗凝有关的出血事件,10次血栓栓塞事件中9次发生在INR<1.7,而所有的出血事件都发生在INR>3.5,INR 1.7～3.5时栓塞或出血发生率均较低。结论:INR 1.7～3.5是慢性房颤华法令抗凝治疗较理想的抗凝强度。     

Effect of influenza vaccine in patients receiving long-term warfarin therapy

The effect of influenza vaccine on anticoagulant response in 12 patients receiving long-term warfarin therapy was studied. Study criteria required that all patients have stable prothrombin times and be on stable warfarin dosages before immunization. Patients were immunized with 1982-83 trivalent influenza vaccine (subvirion), types A and B 0.5 mL i.m. on day 0 of the study. Prothrombin times were determined on days--7, 0, 2, 5, 7, 14, and 21, and results were reported as ratios with control values. Influenza immunization produced a small but significant increase in the prothrombin-time ratio. Before immunization the mean ratio was 1.68, and the mean ratio increased to 1.81 after immunization. The maximal increase occurred on day 14 and represented a 7.6% increase over the baseline (day 0) value. The prothrombin-time ratio was not influenced by warfarin sodium dosage (less than or equal to 5 mg/day versus greater than 5 mg/day) or by the sex of the patient. During the 1984-85 influenza season, an additional 26 patients were immunized with the 1984-85 trivalent influenza vaccine (subvirion), types A and B. The prothrombin-time ratio on days 0 and 14 were not significantly different in these patients. Although the administration of influenza vaccine to patients receiving long-term treatment with warfarin appears to be safe, patients should be monitored after immunization for possible increases in anticoagulant response.     

华法林与氟康唑联合应用致国际标准化比值升高

1例72岁女性患者因可疑肺栓塞给予华法林及那屈肝素钙联合治疗,国际标准化比值(INR)稳定在1.23～2.81。联合用药8 d后,停用那屈肝素钙,单用华法林3 mg/d口服2 d后,检查INR为3.31。因行痰培养检查示白色念珠菌阳性,遂加用氟康唑0.4 g,1次/d静脉滴注,且华法林剂量调整为1.5 mg/d。氟康唑与华法林联用后第1、6天INR分别为3.91,7.31。立即停用华法林,氟康唑继续按原剂量应用,并给予维生素K1 40 mg肌内注射。停药后第1、2、3天INR分别为4.91,2.01,1.30。停药后第5天再次应用华法林1.5 mg/d,同时氟康唑调整至0.2 g/d。两药联用后第4天INR为1.68。     

Reversal of elevated international normalized ratios and bleeding with low-dose recombinant activated factor VII in patients receiving warfarin

STUDY OBJECTIVE: To assess the effectiveness of using low-dose recombinant activated factor VII (rFVIIa) to reverse the effects of warfarin in critically ill patients with major bleeding events. DESIGN: Prospective observational study. SETTING: Intensive care unit of a 500-bed university-affiliated hospital. PATIENTS: Sixteen nonhemophiliac patients who had been receiving warfarin and had an acute major bleeding event. INTERVENTION: Patients received rFVIIa 1.2 mg for reversal of anticoagulation. MEASUREMENTS AND MAIN RESULTS: Patients were identified from clinical pharmacology consult service electronic tracking records, and their data were cross-checked with the pharmacy information system. Information collected for each patient included extent of bleeding and magnitude of elevation in international normalized ratio (INR). A mean +/- SD dose of rFVIIa 16.3 +/- 4.1 microg/kg (range 11-25 microg/kg) reduced the mean INR from 2.8 +/- 1.6 (range 1.44-6.34) to 1.07 +/- 0.27 (range 0.86-1.92, p<0.001). A rapid onset of response for achieving a desirable hemostatic effect was observed in 14 of the 16 patients. CONCLUSION: Low-dose rFVIIa appears to be an effective, rapid reversal modality for major bleeding events in the presence of warfarin and an elevated INR. The agent's response is quicker than that expected with fresh frozen plasma combined with vitamin K. In emergency situations, rFVIIa 1.2 mg can be used to reverse the anticoagulant effect of warfarin and other vitamin K antagonists without inducing a hypercoagulable state; the product, however, is expensive.     

联合应用华法林与胺碘酮致国际标准化比值升高和血尿

1例42岁女性患者三尖瓣置换术后为预防血栓服用华法林（3．00mg／d）。用药第3天查凝血酶原时间（Pr）15．5S,国际标准化比值（INR）1．3,将华法林调整为3．75mg／d。第8天患者出现心房颤动,心率81次／min,遂加用胺碘酮0．2g,1次／d口服。第16天患者出现肉眼血尿。实验室检查：阿60．0S,INR5．1,尿红细胞计数300／m。停用华法林,胺碘酮维持原剂量,肌内注射维生素K110mg。4h后胛48．2S,INR4．1,再次肌内注射维生素K,10mg。4h后PT18．7S,INR1．6,尿液颜色逐渐恢复正常。第17天复查,PT16．6S,INR1．4,尿红细胞计数阴性,恢复华法林抗凝治疗（1．50mg／d）。