Global deregulation of ginseng products may be a safety hazard to warfarin takers: solid evidence of ginseng-warfarin interaction.

Recent global deregulation of ginseng as the table food raises our concern about the possible ginseng-warfarin interaction that could be life-threatening to patients who take warfarin for preventing fatal strokes and thromboembolism while using ginseng products for bioenergy recovery. Here we show that quality-control ginsenosides, extracted from ginseng and containing its major active ingredients, produce dose- and time-dependent antagonism in rats against warfarin's anti-coagulation assessed by INR and rat thrombosis model. The interactions between ginsenosides and warfarin on thrombosis, pharmacokinetics, activities of coagulation factors and liver cytochrome P450 isomers are determined by using thrombosis analyzer, UPLC/MS/MS, ELISA and real-time PCR, respectively. The antagonism correlates well with the related pharmacokinetic interaction showing that the blood plateaus of warfarin reached by one-week warfarin administration are significantly reduced after three-week co-administration of warfarin with ginsenosides while 7-hydroxywarfarin is increased. The one-week warfarin and three-week warfarin-ginsenosides regimen result in restoring the suppressed levels by warfarin of the coagulating factors II, VII and protein Z, and significantly enhance activities of P450 3A4 and 2C9 that metabolize warfarin. The present study, for the first time, provides the solid evidence to demonstrate the warfarin-ginsenoside interaction, and warns the warfarin users and regulation authorities of the dangerous interaction.

Laboratory Assessment of Direct Oral Anticoagulants.

Oral vitamin K anticoagulation (warfarin, Coumadin, coumarin) has long been used for long-term treatment and prophylaxis in a variety of clinical settings. Given the unpredictable pharmacokinetic and food impact of warfarin, episodic monitoring is required. Since the early 2000s, direct oral anticoagulants (DOACs) entered into clinical trials as a potential alternative strategy to oral vitamin K antagonists for long-term anticoagulation. As these drugs have predictable pharmacokinetics and pharmacodynamics, there was no requirement for episodic or routine monitoring. However, shortly after their introduction into clinical use, it became apparent that certain emergent or acute situations may require some capacity to measure these drugs, especially in a bleeding patient with DOAC exposure. The scramble for literature and data to support or suggest laboratory methods which can rapidly and accurately quantify or estimate DOAC concentration soon began. This review describes the literature to date, and recommendations for laboratories to provide tests that will assure either the presence/absence of DOAC or the capacity to quantify DOAC using rapid methods that could be implemented on most clinical laboratory instruments.

Quantitative Assessment of CYP2C9 Genetic Polymorphisms Effect on the Oral Clearance of S-Warfarin in Healthy Subjects.

BACKGROUND: Genetic polymorphisms in CYP2C9 account for 10-20% of the variability in warfarin dose requirement. As such CYP2C9 genetic polymorphisms are commonly included in algorithms aimed to optimize warfarin therapy as a way to account for variability in warfarin responsiveness that is due to altered pharmacokinetics. However, most of the currently available pharmacokinetic data were derived from studies among patients on chronic warfarin therapy and therefore suffer from the confounding effects of disease states and drug interactions. OBJECTIVE: The purpose of the present study was to provide an accurate quantitative estimate of S-warfarin oral clearance (CLS) among healthy subjects carrying different CYP2C9 genotypes. METHODS: Single dose of warfarin was administered to 150 non-smokers, age (mean ± SD) 23.3 ± 4.5 years, 60% male, non-obese, healthy subjects. Blood samples were taken for up to 168 h and urine was collected over the entire study period. RESULTS: Compared with carriers of the wild-type CYP2C9*1/*1 genotype (n = 69), CLS was reduced by 25, 39 and 47% among heterozygote for CYP2C9*2 (n = 41) CYP2C9*3 (n = 26) and carriers of 2 variant alleles (n = 14), respectively (p < 0.001). The corresponding decrease in the formation clearance of 6 and 7 S-hydroxy-warfarin was 45, 65 and 75%, respectively (p < 0.001). CONCLUSIONS: The current study provides an estimate concerning the effect of CYP2C9 polymorphisms on S-warfarin pharmacokinetics among healthy subjects. As such it is free of the confounding effects of disease states and drug interactions. Further research is needed to evaluate whether the incorporation of quantitative data obtained in the present study into pharmacogenetic warfarin algorithm may enhance its precision. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT00162474.

International normalized ratio monitoring of vitamin K antagonist therapy: comparative performance of point-of-care and laboratory-derived testing.

The monitoring of warfarin therapy using the international normalized ratio (INR) has now moved outside the laboratory's control by use of point-of-care (POC) devices. Although this provides patients with the convenience of immediate results and clinical assessment, POC-INRs are often performed by nonlaboratory staff with little experience in quality control. The Royal College of Pathologists of Australasia Quality Assurance Program (RCPAQAP) Haematology has devised a POC-INR external quality assessment (EQA) program that is suitable for both laboratory and nonlaboratory operators (e.g., nurses) to perform INR testing with good accuracy and precision. A comparison of the performance of the POC versus the laboratory-derived INR testing over the past 8 years has shown that the variation in test results (expressed as coefficient of variation; CV) for laboratory INRs increases with more prolonged INR values, whereas CVs for the POC-INR testing were generally lower, with a reduced dependency on INR values. In our program, the CoaguChek XS (Roche, Basel, Switzerland) showed the best performance among the POC devices. A comparative assessment with other EQA providers showed agreement and disparity with our data in terms of comparative CVs obtained between the laboratory and POC-INRs. The growth of the RCPAQAP POC-INR program from 29 to 360 in the past 12 years highlights the importance of providing suitable EQA for POC-INR staff who are unfamiliar with laboratory practice. This helps maintaining consistent results, which have important implications for the therapeutic management of patients on vitamin K antagonist therapy.

Electrooxidation behavior of warfarin in Fe3O4 nanoparticles modified carbon paste electrode and its determination in real samples.

In the present work, a simple and sensitive electrochemical sensor based on magnetic Fe3O4 nanoparticles modified carbon paste electrode (CPE) was introduced for detection of low level with 0.21µM of warfarin. Under the optimum experimental conditions the oxidation peak current of warfarin was used for its monitoring for the first time. The analytical curve was linear for warfarin concentrations from 0.5 to 1000µM with a limit of detection of 0.21µM by square wave anodic stripping voltammetry (SWASV). The proposed sensor showed excellent stability and was used for the determination of warfarin in tablet, human serum and urine with satisfactory results.

Economic evaluation of a randomized controlled trial of pharmacist-supervized patient self-testing of warfarin therapy.

WHAT IS KNOWN AND OBJECTIVE: The increase in numbers of patients requiring oral anti-coagulation testing in outpatient clinics has focused attention on alternative flexible systems of anti-coagulation management. One option is pharmacist led patient self-testing (PST) of international normalised ratio (INR) levels. PST has demonstrated improvements in anti-coagulation control, but its cost-effectiveness is inconclusive. This study reports the first cost-effectiveness evaluation of a randomized controlled trial of an automated direct-to-patient expert system, enabling remote and effective management of patients on oral anti-coagulation therapy. METHODS: We conducted an economic evaluation alongside a randomised controlled trial investigating a pharmacist led PST method. The primary outcome was to determine the cost effectiveness of PST in comparison with usual care (management in a hospital based anti-coagulation clinic). Long term anti-coagulation patients were recruited to a 6 month cross over study between PST and routine care in an anti-coagulation clinic. Economic evaluation was from the healthcare payer perspective. RESULTS AND DISCUSSION: On a per patient basis over a 6 month period, PST resulted in an incremental cost of €59.08 in comparison with routine care. Patients achieved a significantly higher time in therapeutic range (TTR) during the PST arm in comparison with routine care, (72 ± 19.7% vs. 59 ± 13.5%). Overall cost of managing a patient through pharmacist supervised PST for a 6 month period is €226.45. Additional analysis of strategies from a societal perspective indicated that PST was the dominant strategy. WHAT IS NEW AND CONCLUSION: Pharmacist led patient self-testing is a viable method of management. It provides significant increases in anti-coagulation control for a minimal increase in cost.

Pharmacokinetic and pharmacodynamic drug-drug interaction assessment between pradigastat and digoxin or warfarin.

Pradigastat, a novel diacylglycerol acyltransferase-1 inhibitor, was evaluated for both pharmacokinetic (PK) and pharmacodynamic (PD) drug-drug interactions when co-administered with digoxin or warfarin in healthy subjects. This open-label study included two parallel subject cohorts each with three sequential treatment periods. Forty subjects were enrolled in the study with 20 subjects allocated to each cohort. PK and PD (PT/INR for warfarin only) samples were collected in each period. The statistical analysis results showed that the 90% CIs of the geometric mean ratios of digoxin, R-warfarin, and S-warfarin PK parameters (AUC and Cmax) were all within 0.80-1.25 interval. The 90% CIs of the geometric mean ratios of pradigastat PK parameters (AUC and Cmax) were within 0.80-1.25 interval when co-administered with warfarin; while co-administration with digoxin slightly reduced pradigastat exposure (∼15%). The results also showed that 90% CIs of the geometric mean ratios of warfarin PD parameters (AUC(PT), PTmax, AUC(INR), and INRmax) were within 0.80-1.25 interval. Pradigastat and digoxin or warfarin had no relevant clinical PK or PD drug-drug interactions. Administration of pradigastat and warfarin or pradigastat and digoxin as a mono or combined treatment appears to be safe and tolerated.

Warfarin monitoring economic evaluation of point of care self-monitoring compared to clinic settings.

OBJECTIVE: To determine the cost-effectiveness of home-based point-of-care self-monitoring compared to clinic-based care for patients managed on long-term warfarin medication. Current evidence is inconsistent; results should reduce uncertainty and inform service delivery. METHODS: A Markov model compared self-testing and self-management, using point-of-care devices to usual care in patients with atrial fibrillation and mechanical heart valves. The primary clinical end-points were stroke and mortality avoided; costs and utilities were associated with these events. The costs of warfarin monitoring were included in the model. RESULTS: Over 10 years, self-monitoring saved £1187 per person compared to usual care. Patients who self-monitored had notably fewer strokes and deaths. The results were sensitive to life-years gained and cost of the device. If the NHS purchased the device, financial break-even was achieved at the end of the second year; if the patient bought the device the NHS saved money every year. If 10% of the current 950,000 patients switched to point-of-care devices for 10 years, the NHS could save over £112million. LIMITATIONS: Clinical studies had a relatively short duration and only data on composite end-points were reported. CONCLUSIONS: With training, self-testing and self-management are safe, reliable, and cost-effective for a sizable proportion of patients receiving long-term warfarin. Compared to clinic-based services, self-monitoring offers the NHS the potential to make cost savings and release bed-days by reducing the number of strokes experienced by these high-risk patients.

Simultaneous pharmacokinetics assessment of caffeine, warfarin, omeprazole, metoprolol, and midazolam intravenously or orally administered to Microminipigs.

Small minipigs (Microminipig, registered as a novel variety of pig in Japan) were developed for use in non-clinical pharmacological/toxicological studies for new drug development. To assess the pharmacokinetics of selective substrates of human cytochrome P450s in Microminipigs, caffeine (human P450 1A2), warfarin (P450 2C9), omeprazole (P450 2C19), metoprolol (P450 2D6), and midazolam (P450 3A) were administered in combination, intravenously (0.20 mg kg(-1))( )or orally (1.0 mg kg(-1)). Plasma samples obtained, up to 24 hr after dosing, from four male and four female Microminipigs were analyzed by liquid chromatography tandem mass spectrometry to estimate typical pharmacokinetic parameters for each analyte. Bioavailabilities were approximately 80% for caffeine and warfarin, but less than 10% for omeprazole, metoprolol, and midazolam. No significant differences were noted, for the five probes, in area under the plasma concentration-time curve and peak plasma concentration values obtained from male and female Microminipigs. Clearance of caffeine, warfarin, omeprazole or midazolam in vivo, mediated mainly by cytochrome P450s 1A, 2C or 3A in Microminipigs, was similar to data reported for human. However, metoprolol metabolism, mediated by P450 2D enzymes in Microminipigs, was faster than reported for in vivo human kinetic parameters and in vitro in a human liver microsomal system. The results of this study suggest that the Microminipig is a suitable animal model for use in biological experiments for comparisons of pharmacokinetics of drugs in humans. The five-probes in combination used in this study demonstrate the disposition of typical P450 drugs in Microminipigs in vivo, with the aim of use in non-clinical pharmacological/toxicological studies.

Telemedicine improves the monitoring process in anticoagulant treatment.

We compared the INR (International Normalized Ratio) monitoring process using a telemedicine device with the conventional approach in which blood samples were sent to the hospital for analysis. We conducted a randomized controlled trial. We enrolled 40 patients on chronic warfarin therapy from two primary healthcare centres (PHCs). Half were monitored using the telemedicine device and half were monitored conventionally. Each patient received three INR measurements. The total processing time was measured from blood sampling until warfarin dosing was performed in the anticoagulant clinic. The median total processing time was significantly shorter with telemedicine than usual care (34 vs. 260 min, P < 0.001). This was mainly because sample transport was avoided using the point-of-care device and automatic data transmission. Telemedicine reduced the total processing time for INR monitoring and has the potential to improve the management of patients undergoing anticoagulant treatment at PHCs.

Potential benefits of warfarin monitoring by a clinical pharmacist in a long term care facility.

The primary objective of this study was to determine whether warfarin therapy monitoring by a pharmacist would benefit a long-term care facility, by maintaining patients within therapeutic INR range more consistently than the current practice of physician monitoring.Secondary objectives included whether adverse events resulting from non-therapeutic INR levels differed significantly between groups and whether pharmacist interventions resulted in decreased overall costs to the facility. A retrospective chart review was conducted on all patients treated with warfarin for a minimum of 14 days within a Long-Term Care (LTC) facility to compare Time within Therapeutic Range (TTR) between staff treated patients versus pharmacist treated patients. A total of 552 INRs were obtained for all patients during the study period: 499 (90.4%) under staff supervision and 53 (9.6%) under clinical pharmacist supervision. Of the 499 tests performed by the River Garden staff, 203 were within the desired range, compared with 29 of the 53 tests performed by the clinical pharmacist being in range. For the primary endpoint, a total of 1483 INRs were imputed, corresponding to the number of days between true INR measurements. INRs attributable to clinic staff management were within the therapeutic range 47.1% of the time, whereas INRs attributable to clinical pharmacist management were within the therapeutic range 58.7% of the time (P < 0.0001 for the comparison). Warfarin can be effectively monitored by a clinical pharmacist and routinely lead to appropriate INR levels in the nursing home setting, while potentially saving the facility healthcare dollars.

Reorganization of oral anticoagulant (warfarin) treatment follow-up.

OBJECTIVE: To evaluate the impact of the reorganization of oral AC treatment management in a primary healthcare setting in terms of quality of care and cost of care. The evaluated reorganization involved the adoption of an AC nurse service model supported by the use of information and communication technology for storing and handling follow-up data. DESIGN: Statistical analysis of AC follow-up data, personnel task distribution and resource use analysis, and survey of personnel experiences. SETTING: The Paloheinä health station in Helsinki, Finland. SUBJECTS: All 122 Paloheinä patients on oral AC treatment and the related Paloheinä personnel. Also, follow-ups from two comparison health stations from Helsinki were used. MAIN OUTCOME MEASURES: Laboratory P-INR and follow-up density distributions before and after follow-up reorganization for Paloheinä and comparison station patients, task distribution, and personnel resource use in treatment guideline assignment before and after reorganization and gathered personnel experiences. RESULTS: No statistically significant changes (Pearson's chi-square test, p < 0.05) were observed in P-INR distributions, considering also the comparison stations. Adoption of the AC nurse model resulted in a 66%/34% task distribution between nurses and physicians in guideline assignment. Personnel resource use analysis showed a cost decrease of 1.61 euros per follow-up in guideline assignment. Users who responded to the survey were generally satisfied with the reorganization and its subjective impacts. CONCLUSION: Reorganization resulted in a potential reduction in cost of care per follow-up without a change in the observed quality of care in the Paloheinä setting. Personnel generally accepted the reorganization.

Assessment of ruminal degradation, oral bioavailability, and toxic effects of anticoagulant rodenticides in sheep.

OBJECTIVE: To assess the rate and extent of ruminal degradation of warfarin, chlorophacinone, and bromadiolone in vitro and determine the oral availability and clinical and hemostatic effects of each anticoagulant rodenticide in adult sheep. ANIMALS: 3 Texel sheep. PROCEDURE: Samples of ruminal fluid were incubated with each of the anticoagulants to assess the kinetics of ruminal degradation over 24 hours. To determine the plasma kinetics of the anticoagulants, each sheep received each of the anticoagulants IV or via a rumenimplanted cannula at 2-month intervals (3 rodenticide exposures/sheep). At intervals during a 240- to 360- hour period after treatment, prothrombin time (PT) was measured, plasma anticoagulant concentration was assessed, and clinical signs of rodenticide poisoning were monitored. In plasma and rumen extracts, anticoagulant concentrations were determined via high-performance liquid chromatography. RESULTS: In the rumen extracts, anticoagulants were slightly degraded (< 15%) over 24 hours. In vivo, oral availability of warfarin, chlorophacinone, and bromadiolone was estimated at 79%, 92%, and 88%, respectively. Although maximum PT was 80 seconds after chlorophacinone and bromadiolone treatments, no clinical signs of toxicosis were detected; PT returned to baseline values within 2 weeks. CONCLUSIONS AND CLINICAL RELEVANCE: In sheep, warfarin, chlorophacinone, and bromadiolone were not degraded in the rumen but their bioavailabilities were high after oral administration; the kinetics of these compounds in sheep and other mammals are quite similar. These data suggest that the lack of susceptibility of ruminants to these anticoagulant rodenticides cannot be explained by either ruminal degradation or the specific toxicokinetics of these anticoagulants.

Warfarin monitoring in ambulatory older individuals receiving antimicrobial therapy.

STUDY OBJECTIVE: To determine the frequency of monitoring of international normalized ratio (INR) within 14 days of coprescription of warfarin and antimicrobial therapy and to evaluate differences in INR monitoring among antimicrobials. DESIGN: Retrospective cohort study. SETTING: Group model health maintenance organization. SUBJECTS: Patients aged 65 years or older who were taking warfarin and an antimicrobial agent. MEASUREMENTS AND MAIN RESULTS: Patients who received dispensings of both warfarin and an antimicrobial agent were identified. We found 2959 coprescribing instances in 1816 patients. The INR values were obtained for 2267 (77%) coprescribing situations within 14 days. Monitoring occurred more frequently (p<0.001) when warfarin was coprescribed with fluoroquinolones (641 [85%] of 755 situations), metronidazole (59 [81%] of 73), tetracyclines (274 [80%] of 341), or macrolides (201 [83%] of 243) than when warfarin was coprescribed with sulfonamides (35 [66%] of 53), penicillins (604 [71%] of 856), or cephalosporins (419 [71%] of 591). Among monitored patients, a higher proportion of monitoring (p<0.001) occurred within 7 days for patients prescribed antifungals (87%), fluoroquinolones (88%), tetracyclines (82%), metronidazole (86%), sulfonamides (86%), or macrolides (85%) than for patients prescribed cephalosporins (68%) or penicillins (75%). CONCLUSION: Most older patients coprescribed warfarin and an antimicrobial in our organization had INR monitoring within 7 days. This is consistent with appropriate practice to manage a risk of clinically important drug-drug interaction between an antimicrobial agent and warfarin. Prospective identification of patients requiring INR monitoring after coprescription of interacting drugs by using merged administrative pharmacy and laboratory data should be further evaluated as a tool to improve clinical outcomes.

External quality assessment for warfarin dosing using computerised decision support software.

AIM: To establish and evaluate an external quality assessment scheme for warfarin dosing for users of a computerised decision support system, BAP-PC. DESIGN: Analysis of 12 months of clinical data from 10 primary care centres using BAP-PC within an oral anticoagulation clinic. Data were analysed for individual centres and compared with aggregated data for all practices. Individual feedback forms were provided to participating centres. RESULTS: A total patient population of 367 (range, 17-65/centre) was analysed. On average, patients spent 69% of time in the therapeutic range (range, 60-76%). Patients were seen on average every 27 days (range, 24-30). The average point prevalence was 86% (range, 76-100%). In total, 33 adverse events were reported (0-13/practice). Serious adverse events ranged from 0 to 1 for each practice. This translates into a serious adverse event rate of 1.6/100 patient years. CONCLUSIONS: Practices were successful in maintaining good therapeutic international normalised ratio control, with centres achieving 60% or higher time in range. There are some doubts about the quality of data collection at a practice level because there were no reported events in half of the participating centres. The observed event rates do concur with previously reported data, however. Further cycles of the scheme are necessary to establish it as a useful research and benchmarking tool.

Quality assessment of oral anticoagulant treatment in the Beer-Sheba district.

OBJECTIVE: To evaluate the adequacy of oral anticoagulation therapy in patients with either prosthetic heart valves or atrial fibrillation. DESIGN: Adequacy of anticoagulation therapy of patients treated with warfarin was determined before and after implementation of an improvement programme. SETTING: The central haematology laboratory of the Soroka Medical Center, Beer-Sheba Israel. STUDY PARTICIPANTS: One hundred and ten patients treated with chronic anticoagulation therapy were evaluated by measuring the international normalized ratio of the prothrombin time before and after implementation of an improvement plan aimed at improving anticoagulation control. INTERVENTION: A programme that included physician and patient education and procedural changes covering all aspects of anticoagulation therapy was implemented. MAIN OUTCOME MEASURE: The percent of international normalized ratio tests below, within and above the therapeutic range was determined. RESULTS: Prior to implementation of an improvement plan, only 32% of the measured international normalized ratio values were within the therapeutic range. 16% were above and 52% were below therapeutic range. Improvement intervention led to an increase in the proportion of international normalized ratio tests that fell within the therapeutic range from 32% to 43.2%. CONCLUSIONS: Improvement in the control of anticoagulation therapy of patients receiving long-term warfarin treatment is possible. A combined effort involving the community, physician and patient is required.