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PubMedDate not supplied

Warfarin-induced skin necrosis occurring four days after discontinuation of warfarin.

Warfarin-induced skin necrosis is a rare complication of warfarin therapy. It appears between days 1 and 10 of therapy while the patient is receiving warfarin. Warfarin-induced skin necrosis occurring several days after cessation of therapy has not been reported. We report an atypical case of warfarin-induced skin necrosis which occurred 96 h after the last dose of warfarin was given while the prothrombin time was still elevated.

Anticoagulants↗
PubMed2003

[Effect of Coenzyme Q10 and Ginkgo biloba on warfarin dosage in patients on long-term warfarin treatment. A randomized, double-blind, placebo-controlled cross-over trial].

INTRODUCTION: A few case-stories claim that the anti-oxidant Coenzyme Q10 and possibly also Ginkgo biloba interact with warfarin treatment. A decreased response to warfarin in the Coenzyme Q10 cases and an increased response in the Ginkgo biloba case have been described. MATERIAL AND METHODS: Twenty-four outpatients on stable, long-term warfarin treatment were included in a randomised, double blind, placebo-controlled crossover trial. Coenzyme Q10 100 mg daily, Ginkgo-Biloba 100 mg daily and placebo were given in random order over treatment periods of four weeks, each followed by a two week wash out period. The international normalized ratio (INR) INR was kept between 2.0 and 4.0 by appropriate adjustment of the warfarin dosage. RESULTS: Fourteen women and ten men, median ages 64.5 years (33-79) were included. Three patients withdrew from the study for personal reasons. The INR was stable during all treatment periods. The geometric mean dosage of warfarin did not change during the treatment periods: Ginkgo biloba 36.7 mg/week (95% confidence interval: 29.2-46.0); CoQ10 36.5 mg/week (29.1-45.8); placebo 36.0 mg/week (28.6-45.1). CONCLUSION: The study indicated that Coenzyme Q10 and Ginkgo biloba do not influence the clinical effect of warfarin.

Adult↗
PubMed1996

Fecal hemoglobin excretion in elderly patients with atrial fibrillation: combined aspirin and low-dose warfarin vs conventional warfarin therapy.

BACKGROUND: Antithrombotic prophylaxis using combined aspirin and low-dose warfarin is under evaluation in several clinical trials. However, therapy may result in increased gastrointestinal blood loss and clinical bleeding vs conventional single-agent antithrombotic therapy. METHODS: To assess differences in gastrointestinal blood loss, we measured quantitative fecal hemoglobin equivalents (HemoQuant, Mayo Medical Laboratory, Rochester, Minn) in 117 patients, mean age 71 years, 1 month after initiation of assigned therapy in the Stroke Prevention in Atrial Fibrillation III Study. Sixty-three of these patients who had characteristics for high risk of stroke were randomly assigned to conventional adjusted-dose warfarin therapy (international normalized ratio, 2.0 to 3.0) or low-dose combined therapy (warfarin [international normalization ratio,<1.5] plus 325 mg/d of enteric-coated aspirin). The remaining 54 patients with low risk of stroke received 325 mg/d of enteric-coated aspirin. RESULTS: Among the 63 at high risk of stroke, abnormal values (>2mg of hemoglobin per gram of stool) were detected in 11% and values greater than 4 mg of hemoglobin per gram of stool were found in 8%. Mean ( +/- SD) values were more for those randomly assigned to receive combined therapy (1.7 +/- 3.3 mg of hemoglobin per gram of stool vs adjusted-dose warfarin therapy, 1.0 +/- 1.9 mg/g; P=.003). The 54 nonrandomized patients with low risk of stroke receiving aspirin alone had a mean (+/- SD) HemoQuant value of 0.8 +/- 0.7mg of hemoglobin per gram of stool 1 month after entry in the study. CONCLUSIONS: Abnormal levels of fecal hemoglobin excretion were common in elderly patients with high risk of atrial fibrillation 1 month after randomization to prophylactic antithrombotic therapy. Combined warfarin and aspirin therapy was associated with greater fecal hemoglobin excretion than standard warfarin therapy, suggesting the potential for increased gastrointestinal hemorrhage.

Aged↗
PubMed1984

Inhibition by warfarin of liver microsomal vitamin K-reductase in warfarin-resistant and susceptible rats.

The NADH-dependent vitamin K-reductase activity of liver microsomes from three closely related rat strains has been studied. One strain (TAS) is susceptible and two strains (HW and HS) resistant to the anticoagulant and lethal effects of warfarin. The effects of cofactors, temperature, detergent and dithiothreitol on vitamin K1 reduction and solvent extraction of substrate and product have been investigated. Vitamin K-reductase activity was inhibited by approximately 13 and 8% respectively when microsomal preparations from TAS and HW animals were incubated with 50 microM vitamin K1 and 10 microM warfarin. In HS rat liver microsomes the enzyme was highly resistant to inhibition by warfarin. Evidence is presented and discussed that suggests that NADH-dependent vitamin K-reductase may be inhibited in the anticoagulant effect of warfarin and may be altered as a result of expression of the warfarin-resistance gene in HS rats. The enzyme activity studied was probably not a DT-diaphorase although both NADH and NADPH acted as cofactors for the reaction.

Animals↗
PubMed1974

Liquid chromatographic assay of warfarin: similarity of warfarin half-lives in human subjects.

A high pressure liquid chromatographic assay was developed to measure warfarin concentrations in biological fluids. Twelve healthy, unrelated volunteers received a single oral dose of warfarin (0.75 mg per kilogram of body weight). The mean plasma warfarin half-life was 36.3 +/- 3.5 hours by liquid chromatography but 55.9 +/- 8.4 hours by a currently used fluorimetric assay that fails to separate warfarin from its metabolites. Interindividual variation was greater and each half-life longer by the fluorimetric than by the chromatographic procedure. Warfarin shows less interindividual variation than that observed for other drugs primarily metabolized by hepatic microsomal mixed function oxidases. Advantages of specificity, rapidity, sensitivity, accuracy, and simplicity recommend liquid chromatography in the development of other drug assays.

Adult↗
PubMed1992

Warfarin-induced skin necrosis in 2 patients with protein S deficiency: successful reinstatement of warfarin therapy.

Warfarin-induced skin necrosis is a rare but serious complication of oral anticoagulant therapy. This condition has been associated with protein C deficiency but only rarely reported in patients with a deficiency of protein S. We have managed 2 patients with a history of warfarin-induced skin necrosis who were diagnosed as being protein-S-deficient. Since both patients were candidates for long-term anticoagulant therapy we elected to reintroduce warfarin using a regimen designed to minimize the risk of recurrent skin necrosis. While they were therapeutically anticoagulated with heparin, warfarin was started at 1 mg/day and the dose was increased gradually. Heparin was not discontinued until the prothrombin times were in the therapeutic range for at least 72 h. Both patients tolerated the reinstitution of warfarin without difficulty and they have now been followed for over 2 years on oral anticoagulants without complication.

Adult↗
PubMed2000

Retrospective evaluation of a potential interaction between azithromycine and warfarin in patients stabilized on warfarin.

STUDY OBJECTIVE: To investigate a potential interaction between azithromycin and warfarin. DESIGN: Retrospective case-control study. SETTING: Veterans Affairs medical center. PATIENTS: Fifty-two patients stable on anticoagulation therapy. INTERVENTION: Patients who received a prescription for azithromycin and warfarin at any time since the hospital was opened, June 1, 1995, to July 22, 1999, were identified through a computerized report generated from the pharmacy prescription package. MEASUREMENTS AND MAIN RESULTS: Patients having a stable international normalized ratio (INR; defined as a therapeutic INR +/- 0.2) for at least two consecutive visits before receiving an azithromycin prescription were reviewed. Changes in INR from before and after addition of azithromycin were compared with changes in a control group. Controls were identified from a computer-generated report of patients who received a prescription for terazosin and warfarin at any time since the hospital was opened to July 22, 1999 (terazosin was chosen as it has no known interaction with warfarin). These patients also had a stable INR for at least two consecutive visits before receiving the terazosin prescription. In patients with INRs on record within 14 days after starting azithromycin or terazosin (9 patients/group), the average change in INR was 0.18 +/- 0.48 in the azithromycin group and 0.07 +/- 0.49 in the terazosin group (p=0.60). For patients with an INR on record within 30 days after starting azithromycin or terazosin (26 patients/group), the average change in INR was 0.25 +/- 0.67 in the azithromycin group and 0.05 +/- 0.55 in the terazosin group (p=0.18). CONCLUSION: An interaction between azithromycin and warfarin was not observed in this retrospective review of patients with a stable INR receiving the combination.

Aged↗
PubMed2005

Increasing warfarin dosage reductions associated with concurrent warfarin and repeated cycles of 5-Fluorouracil therapy.

Concurrent use of warfarin and 5-fluorouracil has resulted in elevated international normalized ratios (INRs). Although this drug interaction is well established in the literature, we found no documented cases that address its effects on anticoagulation parameters in patients requiring repeated cycles of 5-fluorouracil and continuous warfarin therapy. We describe the effect of multiple cycles of 5-fluorouracil administration in a patient receiving warfarin therapy. The patient's INR increased 11-14 days after each cycle of chemotherapy with 5-fluorouracil and leucovorin. In addition, she required additive reductions of 33-42% in her weekly warfarin dose with each chemotherapy cycle to maintain a therapeutic INR (goal range 2.0-3.0). After three cycles of chemotherapy over a 10-week period, the patient's dosage requirements returned to her baseline level (before treatment with 5-fluorouracil and leucovorin had started). Pertinent literature was reviewed to provide supporting evidence for the mechanism and clinical implications of the drug interaction. Based on this report and previous case reports, caution is advised when concurrent warfarin and 5-fluorouracil are prescribed. In addition, patients should be closely monitored for a possible delayed interaction that may occur with each repeated cycle of 5-fluorouracil chemotherapy.

Adenocarcinoma↗
PubMed1994

Warfarin 2.0--a computer program for warfarin management. Design and clinical use.

Warfarin 2.0 is a computer program that helps physicians optimize treatment of outpatients with warfarin. The main reason for its development was to achieve a good anticoagulation level, avoiding both undertreatment--which causes thromboembolic complications--and overtreatment--which causes hemorrhagic complications. The program was also designed to help educate the anticoagulated patient, standardize warfarin management and audit results of what had been done. The philosophy of continuous quality improvement was applied. Warfarin 2.0 is in clinical operation in the University Hospital, Montevideo, Uruguay, and it has also been used since the end of 1993 in the Favaloro Foundation, Dept. of Hematology, Buenos Aires, Argentina. The results from the first 15 months of use in Montevideo showed an increase in the number of patients being followed (from 91 to 132) and the average number of visits per patient (from one visit every 10.6 weeks to one every 6.5 weeks): The frequency of visits has been in the internationally accepted ranges since the program was implemented. Better anticoagulation levels were achieved after an adjusting period. Unfortunately, the number of undertreated patients is still large, and a thorough analysis of the data is going to be undertaken to continue improving warfarin management.

Drug Therapy, Computer-Assisted↗
PubMed1985

Induction of liver cytochrome P-450 in mice by warfarin. Comparison of warfarin-, phenobarbitone-, and cobalt-induced hepatic microsomal protein patterns by PAGE after partial purification on octyl-sepharose CL-4B.

A rapid method is presented to separate mouse liver cytochrome P-450 from other components of the microsomal monooxygenase system and to increase specific activity by hydrophobic interaction chromatography on Octyl-Sepharose CL-4B by a factor of between 3.8 and 5.3. In addition it is shown that varieties of cytochrome P-450 can be separated from each other by Octyl-Sepharose CL-4B. After oral applications of 120 mg/kg warfarin once daily for three days SDS-PAGE analysis of the partially purified cytochrome P-450 fraction revealed a protein pattern in the 50 Kd region that is practically indistinguishable from that after conventional phenobarbitone pretreatment. On the other hand, cobalt pretreatment results in a different pattern that is distinguished from that of normals as well as from that of phenobarbitone- and warfarin-pretreated mice. From these results in conjunction with the previous finding of increased drug metabolic activity after warfarin pretreatment it is concluded that warfarin elicits phenobarbitone-like induction of the hepatic monooxygenases in mice.

Animals↗
PubMed1992

Pulmonary embolism in total hip and knee arthroplasty. Risk factors in patients on warfarin prophylaxis and analysis of the prothrombin time as an indicator of warfarin's prophylactic effect.

This study was designed to identify those total arthroplasty patients at high risk for embolism even while on a proven warfarin prophylactic regimen and to identify the measure of anticoagulation that would be most efficacious in the prevention of pulmonary embolism (PE). A series of 2348 total arthroplasty patients had a preoperative perfusion scan and a postoperative ventilation/perfusion scan. All patients were placed on a low-dose warfarin protocol. Eighty-one patients were identified as having a PE by pulmonary arteriography (incidence of 3.4%). Of these, 89% were asymptomatic and no case was fatal. A control group of 159 patients without PE was used for comparison. Patients older than 65 years of age with a history of genitourinary infection were identified as being at higher risk of PE while on a proven warfarin prophylactic program. These patients may need additional prophylactic measures to reduce the risk of PE. In contrast, patients with a history of phlebitis, PE, obesity, or varicosities were not at excess risk for PE while on warfarin prophylaxis; therefore, no additional prophylactic measures are required. All prothrombin time profiles were within the prophylactic range. Therefore, the actual prothrombin time may not be the critical determinant of the level of anticoagulation or prophylaxis achieved.

Analysis of Variance↗
PubMed1980

The effect of albumin conformation on the binding of warfarin to human serum albumin. The dependence of the binding of warfarin to human serum albumin on the hydrogen, calcium, and chloride ion concentrations as studied by circular dichroism, fluorescence, and equilibrium dialysis.

The pH dependence of the binding of warfarin to human serum albumin has been studies by circular dichroism, fluorescence, and equilibrium dialysis. The pH dependences of the induced ellipticity and the fluorescent intensity of the warfarin . albumin complexes at low drug to protein ratios parallel the neutral to base transition, occurring in the protein over the pH range 6 to 9. Dialysis data show albumin to have a single high affinity site for warfarin over this pH range. This affinity is higher for the basic than for the neutral conformation. Calcium ions increase the high affinity constant of warfarin for albumin over the same pH region, by affecting the neutral to base transition. On the other hand, chloride ions reduce the induced ellipticity and the fluorescent intensity of the complexes at all pH investigated, the mechanism being primarily that of displacement of the drug from albumin.

Binding Sites↗
PubMed1996

Warfarin-fluconazole. I. Inhibition of the human cytochrome P450-dependent metabolism of warfarin by fluconazole: in vitro studies.

The antifungal agent fluconazole was found to be a potent inhibitor of cytochrome P450 (P450) 2C9 (Ki = 7-8 microM), the principal enzyme responsible for the clearance (85%) of the more potent anticoagulant (S)-warfarin to the inactive (S)-7- and (S)-6-hydroxywarfarin metabolites in vivo. Fluconazole was also found to be a potent inhibitor of the P4503A4-catalyzed formation of (R)-10-hydroxywarfarin (Ki = 15-18 microM) as well as the low KM P450 enzymes responsible for the formation of (R)-6-, (R)-7-, and (R)-8-hydroxywarfarin (Ki = 2-6 microM). By contrast, experiments with the P4501A2 inhibitor furafylline and cDNA-expressed P4501A2 indicate that fluconazole is a weak inhibitor of this enzyme (Ki > 800 microM), as measured by the inability of fluconazole to significantly suppress the P4501A2-dependent 6-hydroxylation of (R)-warfarin. The prediction generated from these studies, that fluconazole is a potent in vivo inhibitor of warfarin metabolism, , is tested in complementary studies reported in the accompanying article, "Warfarin-Fluconazole II".

Anticoagulants↗
PubMed2001

Comparison of a daily fixed 2.5-mg warfarin dose with a 5-mg, international normalized ratio adjusted, warfarin dose initially following heart valve replacement.

Patients starting oral anticoagulant therapy after heart valve replacement initially require a lower target international normalized ratio (INR) (2.0, range 1.5 to 2.6) because of a higher risk of bleeding until pericardial wires are removed. In a previous retrospective analysis, we observed a higher sensitivity to warfarin in these patients compared with nonsurgical patients. In a randomized clinical trial, we compared a fixed, lower dose of warfarin (2.5 mg) with the standard treatment consisting of a 5-mg loading dose, then adjusted to the target INR during the first 5 days of anticoagulation. INRs were measured daily, but the fixed dose was only modified on day 3 if the INR was <1.5 or >3.0. One hundred ninety-seven patients were considered eligible for the study. The 2 groups were well matched according to age, gender, body mass index, concomitant treatments, and type of valves implanted. The proportion of INRs >2.6 during the study period was 42.5% in the 5-mg group and 26.2% in the 2.5-mg group (p <0.05), and the proportion of INRs >3.0 on day 3 was 23.9% and 9.5% (p <0.05), respectively. In the 2.5-mg group, 35.7% of patients had an INR <1.5 on day 3 and had the dose increased (vs 3.5%, p <0.001); however, in the 5-mg group, 95.6% had the initial dose reduced, 49.6% had the dose withheld for at least 1 day, and the mean dose during the 5 days of study was 3.08 mg. Average time to achieve therapeutic range was higher in the 2.5-mg group (2.72 vs 1.98 days, p <0.0001), but the approach to the targeted INR was more regular, and the gap between target and mean INR on day 5 was smaller. There were no bleeding or thromboembolic complications in either group. Thus, a lower loading dose of warfarin in patients after heart valve replacement reduces excessive anticoagulation and offers a more regular achievement of the therapeutic target by reducing the number of dose adjustments. Daily monitoring of the INR is still recommended.

Aged↗
PubMed2000

Effects of warfarin, aspirin and the two combined, on mortality and thromboembolic morbidity after myocardial infarction. The WARIS-II (Warfarin-Aspirin Reinfarction Study) design.

The efficacy and safety of warfarin, aspirin, and the two combined are compared in a long-term, randomized, open, multicentre study involving 3606 patients after acute myocardial infarction (1202 in each treatment group). In this trial three groups receive either warfarin, aimed at a therapeutic level of the International Normalized Ratio (INR) 2.8-4.2, or 160 mg aspirin daily, or 75 mg aspirin daily combined with warfarin with INR 2.0-2.5. A placebo group is not included. Patients are screened before randomization and are given major examinations at 4 weeks and at the end of the study. In addition, all patients are given a questionnaire every 6 months. Composite endpoints include death, non-fatal reinfarction and cerebral stroke. All analyses are conducted on the intention-to-treat principle and on on-efficacy basis. The analyses control for recruiting centre, use of beta blockade, use of thrombolytic therapy and use of angiotensin converting enzyme (ACE) inhibitors.

Adult↗
PubMed1996

Reinstituting warfarin in patients who develop warfarin skin necrosis.

Skin necrosis is a rare but serious complication of oral anticoagulation with coumarin derivatives. Frequently, the necrosis can be extensive and may result in major morbidity and mortality. The majority of these patients require prolonged anticoagulation for life-threatening conditions such as deep various thrombosis and pulmonary embolism. Resuming oral anticoagulants in the face of skin necrosis is a difficult decision for both the patient and the physician. Because long-term heparin therapy is inconvenient and is associated with significant side effects, we reviewed the literature to find alternative treatment strategies. A Medline search was done, and all papers published in English since 1967 were reviewed. Of 58 cases with skin necrosis attributed to oral anticoagulants, oral anticoagulation was resumed in 7 patients with no resulting adverse effects. Warfarin is the most widely used coumarin derivative in the United States. Based on our review, we make recommendations for resuming warfarin in patients who have developed skin necrosis when the clinical condition absolutely requires prolonged anticoagulation.

Adult↗
PubMed2005

Warfarin induction at 5 mg daily is safe with a low risk of anticoagulant overdose: results of an audit of patients with deep vein thrombosis commencing warfarin.

BACKGROUND: Conventionally warfarin therapy is initiated using a loading dose given over several days. Daily international normalised ratio (INR) monitoring is recommended to prevent overdose; however, with a large proportion of patients with deep vein thrombosis now receiving treatment out of hospital daily blood tests are inconvenient. We introduced a low-dose protocol for starting anticoagulant therapy that only required INR testing on days 4 and 6 and audited the results to assess safety and efficacy. METHODS: Two-hundred and forty-eight patients with confirmed deep vein thrombosis were started on warfarin therapy at 5 mg daily for 3 days. INR measurements were taken at day 4 and day 6. RESULTS: Of these patients, 21% had an INR within the therapeutic range on day 4 and 52% had a therapeutic INR on day 6. The risk of overdose was small with only one case with an INR above 4.0 on day 4 and nine cases on day 6. There were no reported cases of bleeding. CONCLUSION: The low-dose protocol with infrequent testing is safe and convenient for outpatient management. However, our results suggest that patients on this protocol take between 6-10 days to achieve a stable INR.

Adolescent↗
PubMed1979

An in vitro study of drug displacement interactions: warfarin-salicylate and warfarin-phenylbutazone.

The binding interactions between warfarin-salicylate and warfarin-phenylbutazone in the presence of 4 g percent bovine serum albumin at 37 degrees C were studied using equilibrium dialysis. Methods of representing and analysing drug binding interactions are discussed. Scatchard plots, double reciprocal plots and the like are shown to be of no use in representing drug displacement interactions since they display only one drug and they can be potentially misleading. It is argued that a preferable method of analysing drug displacement interaction data is in terms of a stepwise multiple equilibria model. The numerical problems associated with fitting this kind of model to the data are discussed. A three-dimensional representation of the binding surface is proposed as a superior means of visualizing drug displacement interactions.

Animals↗