Assessment of exposure to direct oral anticoagulants in elderly hospitalised patients.

It is unclear whether elderly patients established on direct oral anticoagulants (DOACs) have greater exposure to these drugs, which could subsequently increase their risk of bleeding. We assessed DOAC exposure and factors affecting it in a real-world elderly cohort of patients. For this, 151 medically stable hospital inpatients (76 established on apixaban, 61 on rivaroxaban, 14 on dabigatran) with a median [interquartile range (IQR)] age of 84 (78-89) years were recruited. Patients provided blood samples for measurement of peak and trough plasma DOAC concentrations. There was up to 48-fold and 13-fold variation in trough and peak plasma drug concentrations respectively. A significantly greater proportion of patients on apixaban had peak plasma drug concentrations within the reported ranges compared to those on either rivaroxaban or dabigatran (82·9% vs. 44·3% vs. 64·3% respectively; P < 0·001). A third of the variability in DOAC plasma concentrations was attributed to the influences of DOAC dosage, renal function and gender. To what extent the observed increases in DOAC exposure in the older patients is the cause of their increased risk of bleeding, which could potentially be ameliorated by dosing titration, requires further investigation.

Elderly people are inherently sensitive to the pharmacological activity of rivaroxaban: implications for DOAC prescribing.

According to both trial and clinical data on direct oral anticoagulants (DOACs) elderly patients are at greatest risk of bleeding. It is unclear whether age intrinsically affects anticoagulation response. To investigate the age-related sensitivity to DOACs, we compared the pharmacological activity of the direct factor Xa inhibitor, rivaroxaban, between young and elderly subjects ex-vivo. 36 fit elderly and 30 fit young subjects [median (IQR) age: 83(75-87) vs 30(26-38) years] provided a blood sample. Clotting parameters were measured in the resultant plasma samples incubated with rivaroxaban (100-500 ng/ml). Parametric, non-parametric tests and regression lines adjusted for rivaroxaban concentration and baseline values were used to compare data. Rivaroxaban produced a greater prolongation of both Prothrombin Time (PT) and modified Prothrombin Time (mPT) (both p < 0.001) in the elderly compared to young subjects (with difference in mean PT increasing from 1.6 to 6.1s and for mPT from 23.5 to 71.1s at 100 ng/ml and 500 ng/ml plasma rivaroxaban concentration, respectively). Factor X and factor II activity was significantly lower in the elderly in the presence of rivaroxaban (p < 0.001 for both). Rivaroxaban prolonged time-based parameters and suppressed the amount of thrombin generation to a significantly greater extent in the elderly compared to young subjects [%change from baseline for Endogenous Thrombin Potential (ETP): - 35.0 ± 4.4 vs - 29.8 ± 7.4 nM*min; p = 0.002]. The use of validated DOAC assays will be of considerable benefit for monitoring elderly patients who, because of their increased sensitivity to rivaroxaban, may require lower doses of the drug for therapeutic anticoagulation.

CYP2C9, VKORC1, and CYP4F2 polymorphisms and pediatric warfarin maintenance dose: a systematic review and meta-analysis.

Studies on the effect of cytochrome P450 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P450 4F2 (CYP4F2) polymorphisms on warfarin maintenance dose in children are conflicting. We conducted a systematic review and meta-analysis to evaluate the effect of these polymorphisms on warfarin maintenance dose in children. We searched relevant literature using the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trial libraries without any language restrictions from their inception to 23 July 2017. Dose differences are expressed as standardized mean difference (SMD) or mean difference (MD) with 95% confidence intervals (CI). This review was registered in the PROSPERO prospective register of systematic reviews (CRD42015016172). We included a total of nine studies (745 participants) in the meta-analysis. Patients with CYP2C9 *1/*2, *1/*3, *2/*2, *2/*3, or *3/*3 required a lower warfarin maintenance dose compared with patients with CYP2C9 *1/*1 (SMD = -0.610, 95% CI: -0.802 to -0.419, I2 = 0%). Patients with VKORC1-1639GA or AA required a lower warfarin maintenance dose compared with patients with VKORC1-1639GG (SMD = -0.666, 95% CI: -0.887 to -0.445, I2 = 33%). However, no associations were observed between CYP4F2 polymorphisms and warfarin maintenance dose (MD = 0.005 mg/kg/day, 95% CI: -0.006 to 0.015, I2 = 0%). These results were not affected by a sensitivity analysis. Our meta-analysis provides evidence that CYP2C9 and VKORC1 variant statuses affect warfarin maintenance dose in children, but not CYP4F2.

Validation of an algorithm to predict decline in INR following warfarin cessation in patients undergoing invasive procedures.

Patients on warfarin are required to withdraw from treatment for a fixed period (normally 5 days) prior to an invasive procedure. However, the anticoagulant effect of warfarin subsides at different rates among different patients, exposing some to increased risk of either thrombosis or bleeding. In a recent study in patients awaiting surgery, following warfarin cessation the INR declined slower over time in those with two CYP2C9 variant alleles, increasing age, weight and number of comorbidities and that INR decline was faster in those with higher maintenance INR value. Subsequently, we developed an algorithm which predicts INR decline in individual patients after 5 days of warfarin cessation. The current study validated the algorithm. An independent cohort of patients completing a short course of warfarin took part in the study. INR values for subsequent 9 days and CYP2C9 genotype were available. The predicted INR decline (INRday 1-INRday 5) was compared to the observed one (where an INR check on day 5 was unavailable, INR was estimated using a linear approximation model). There was a strong correlation between the decline in INR by day 5 and that predicted from the algorithm for the 117 patients (r = 0.949, p < 0.001). The algorithm was precise, with low degree of bias and variance of the prediction error. The algorithm can accurately predict the INR decline following warfarin cessation in individual adult patients. The use of this easily adoptable algorithm can reduce cancellation or delays of planned surgical procedures.

Individual and monitoring centre influences upon anticoagulation control of AF patients on warfarin: A longitudinal multi-centre UK-based study.

OBJECTIVES: Time within therapeutic INR range (TTR) predicts benefits/risk of warfarin therapy. Identification of individual- and centre-related factors that influence TTR, and addressing them to improve anticoagulation control, are important. This study examined the impact of individual and centre-related factors upon long-term anticoagulation control in atrial fibrillation patients in seven UK-based monitoring services. METHODS: Data between 2000 and 2014 on 25 270 patients (equating to 203 220 patient years) [18 120 (71.7%) in general practice, 2348 (9.3%) in hospital-based clinics and 4802 (19.0%) in domiciliary service] were analysed. RESULTS: TTR increased with increasing age, peaking around 77% at 70-75 years, and then declined, was lower in females than males, and in dependent home-monitored patients than those attending clinic (P < 0.0001). TTR, number of dose changes and INR monitoring events and the probability of TTR ≤ 65%, differed across the centres (P < 0.0001). CONCLUSIONS: Although all the participating centres ostensively followed a standard dosing algorithm, our results indicate that variations in practice do occur between different monitoring sites. We suggest feedback on TTR for individual monitoring sites gauged against the average values reported by others would empower the individual centres to improve quality outcomes of anticoagulation therapy by identifying and adjusting contributory factors within their management system.

Alcohol and other substance use among medical and law students at a UK university: a cross-sectional questionnaire survey.

PURPOSE OF THE STUDY: To examine the use of alcohol and other substances among medical and law students at a UK university. STUDY DESIGN: Anonymous cross-sectional questionnaire survey of first, second and final year medical and law students at a single UK university. RESULTS: 1242 of 1577 (78.8%) eligible students completed the questionnaire. Over half of first and second year medical students (first year 53.1%, second year 59.7%, final year 35.9%) had an Alcohol Use Disorders Identification Test (AUDIT) score suggestive of an alcohol use disorder (AUDIT≥8), compared with over two-thirds of first and second year law students (first year 67.2%, second year 69.5%, final year 47.3%). Approximately one-quarter of medical students (first year 26.4%, second year 28.4%, final year 23.7%) and over one-third of first and second year law students (first year 39.1%, second year 42.4%, final year 18.9%) reported other substance use within the past year. Over one-third of medical students (first year 34.4%, second year 35.6%, final year 46.3%) and approximately half or more of law students (first year 47.2%, second year 52.7%, final year 59.5%) had a Hospital Anxiety and Depression Scale anxiety score suggestive of a possible anxiety disorder. CONCLUSIONS: Study participants had high levels of substance misuse and anxiety. Some students' fitness to practice may be impaired as a result of their substance misuse or symptoms of psychological distress. Further efforts are needed to reduce substance misuse and to improve the mental well-being of students.

Assessment of the efficacy of a novel tailored vitamin K dosing regimen in lowering the International Normalised Ratio in over-anticoagulated patients: a randomised clinical trial.

Current guidelines advocate using fixed-doses of oral vitamin K to reverse excessive anticoagulation in warfarinised patients who are either asymptomatic or have minor bleeds. Over-anticoagulated patients present with a wide range of International Normalised Ratio (INR) values and response to fixed doses of vitamin K varies. Consequently a significant proportion of patients remain outside their target INR after vitamin K administration, making them prone to either haemorrhage or thromboembolism. We compared the performance of a novel tailored vitamin K dosing regimen to that of a fixed-dose regimen with the primary measure being the proportion of over-anticoagulated patients returning to their target INR within 24 h. One hundred and eighty-one patients with an index INR > 6·0 (asymptomatic or with minor bleeding) were randomly allocated to receive oral administration of either a tailored dose (based upon index INR and body surface area) or a fixed-dose (1 or 2 mg) of vitamin K. A greater proportion of patients treated with the tailored dose returned to within target INR range compared to the fixed-dose regimen (68·9% vs. 52·8%; P = 0·026), whilst a smaller proportion of patients remained above target INR range (12·2% vs. 34·0%; P < 0·001). Individualised vitamin K dosing is more accurate than fixed-dose regimen in lowering INR to within target range in excessively anticoagulated patients.

Association between CYP4F2 genotype and circulating plasma vitamin K concentration in children on chronic warfarin therapy: Possible long-term implications for bone development and vascular health.

Vitamin K is essential, for the activation of clotting proteins, as well as the biosynthesis of osteocalcin in bones and the activation of matrix-Gla protein needed in maintaining vasculature health. Cytochrome p450 4F2 (CYP4F2) enzyme is involved in vitamin K catabolism. Genetic polymorphism in CYP4F2 is thus likely to affect vitamin K systemic availability. We show that children on chronic warfarin therapy have low levels of vitamin K and vitamin K levels are linked to CYP4F2 genotype. Long-term low levels of vitamin K, influenced by CYP4F2 genotype, might affect bone development and vascular health in children on chronic warfarin therapy.

A randomized trial of genotype-guided dosing of warfarin.

BACKGROUND: The level of anticoagulation in response to a fixed-dose regimen of warfarin is difficult to predict during the initiation of therapy. We prospectively compared the effect of genotype-guided dosing with that of standard dosing on anticoagulation control in patients starting warfarin therapy. METHODS: We conducted a multicenter, randomized, controlled trial involving patients with atrial fibrillation or venous thromboembolism. Genotyping for CYP2C9*2, CYP2C9*3, and VKORC1 (-1639G→A) was performed with the use of a point-of-care test. For patients assigned to the genotype-guided group, warfarin doses were prescribed according to pharmacogenetic-based algorithms for the first 5 days. Patients in the control (standard dosing) group received a 3-day loading-dose regimen. After the initiation period, the treatment of all patients was managed according to routine clinical practice. The primary outcome measure was the percentage of time in the therapeutic range of 2.0 to 3.0 for the international normalized ratio (INR) during the first 12 weeks after warfarin initiation. RESULTS: A total of 455 patients were recruited, with 227 randomly assigned to the genotype-guided group and 228 assigned to the control group. The mean percentage of time in the therapeutic range was 67.4% in the genotype-guided group as compared with 60.3% in the control group (adjusted difference, 7.0 percentage points; 95% confidence interval, 3.3 to 10.6; P<0.001). There were significantly fewer incidences of excessive anticoagulation (INR ≥4.0) in the genotype-guided group. The median time to reach a therapeutic INR was 21 days in the genotype-guided group as compared with 29 days in the control group (P<0.001). CONCLUSIONS: Pharmacogenetic-based dosing was associated with a higher percentage of time in the therapeutic INR range than was standard dosing during the initiation of warfarin therapy. (Funded by the European Commission Seventh Framework Programme and others; ClinicalTrials.gov number, NCT01119300.).

Impact of age on long-term anticoagulation and how gender and monitoring setting affect it: implications for decision making and patient management.

AIMS: Stabilization of anticoagulation control is seminal to reducing the risk of adverse effects of vitamin K antagonists. Reliable information on how ageing influences this is lacking. We set out to assess the true age-related changes in anticoagulation control, how gender and patient setting influence this, and the possible implications of these for patient outcomes and management. METHODS: In atrial fibrillation (AF) patients of a unified anticoagulant service monitoring patients in general practice or hospital-based clinics and housebound patients at home, international normalized ratio (INR) and warfarin dose data between 2000 and 2013 were extracted via the DAWN dosing program. Anticoagulation control was assessed by calculating percentage time spent within target INR (TTR). RESULTS: A total of 2094 AF patients [938 (44.8%) in general practice (GP) and 531 (25.4%) in hospital (H)-based clinics and 625 (29.8%) through the domiciliary service (D)] were evaluated. The frequency of warfarin dose changes and INR monitoring events declined until about age 67, then increased as patients got older. The TTR according to age was significantly lower and the probability of having a TTR ≤65% according to age was higher for D than for H and GP, and females had a greater probability of having a TTR ≤65% than age-matched males. CONCLUSION: Identification of factors underlying poorer anticoagulation control in older housebound patients and the introduction of effective modifications to improve the clinical effectiveness of anticoagulation in such patients is needed.

The impact of genetics on the management of patients on warfarin awaiting surgery.

Two older patients with atrial fibrillation, receiving warfarin for thromboembolic prophylaxis, with a target range of 2.0-3.0, were significantly over anticoagulated prior to elective intervention, in spite of having adhered to the standard protocol of 5 days of warfarin interruption. Neither patient had any abnormality of liver function nor was taking any interacting drug known to inhibit warfarin metabolism or affect sensitivity to warfarin. Both had variant cytochrome P2C9 (CYP2C9) alleles which reduce the metabolic capacity of the CYP2C9 enzyme responsible for the metabolism of the S-warfarin enantiomer. Need for preoperative administration of vitamin K or postponement of an operation because of an INR >1.5 could be explained by variant alleles for CYP2C9 and age.

VKORC1 and CYP2C9 genotype and patient characteristics explain a large proportion of the variability in warfarin dose requirement among children.

Although genetic and environmental factors explain approximately half of the interindividual variability in warfarin dose requirement in adults, there is limited information available in children. In a cross-sectional study of anticoagulated children from 5 tertiary care centers, 120 children with a stable warfarin dose were genotyped for VKORC1 (-1639G > A; rs9923231), CYP2C9 (*2 and *3 alleles; rs1799853 and rs1057910), and CYP4F2 (V433M; rs2108622) polymorphisms. Clinical and demographic features were recorded. Multiple regression analysis of the data showed that, although CYP4F2 made no contribution to the dose model, 72.4% of the variability in warfarin dose requirement is attributed to by patient height, genetic polymorphisms in VKORC1 and CYP2C9, and indication for warfarin. The recently published International Warfarin Pharmacogenetics Consortium pharmacogenetic-based warfarin dosing algorithm (based on data derived from anticoagulated adults) consistently overestimated warfarin dose for our cohort of children. A similar proportion of the interindividual variability in warfarin dose is explained by genetic factors in children compared with adult patients, although height is a greater predictor in children. A pharmacogenomic approach to warfarin dosing has the potential to improve the efficacy and safety of warfarin therapy in children. However, algorithms should be derived from data in children if their potential benefit is to be realized.

Characterizing variability in warfarin dose requirements in children using modelling and simulation.

AIMS: Although genetic, clinical and demographic factors have been shown to explain approximately half of the inter-individual variability in warfarin dose requirement in adults, less is known about causes of dose variability in children. This study aimed to identify and quantify major genetic, clinical and demographic sources of warfarin dose variability in children using modelling and simulation. METHODS: Clinical, demographic and genetic data from 163 children with a median age of 6.3 years (range 0.06-18.9 years), covering over 183 years of warfarin therapy and 6445 INR observations were used to update and optimize a published adult pharmacometric warfarin model for use in children. RESULTS: Genotype effects in children were found to be comparable with what has been reported for adults, with CYP2C9 explaining up to a four-fold difference in dose (CYP2C9 *1/*1 vs. *3/*3) and VKORC1 explaining up to a two-fold difference in dose (VKORC1 G/G vs. A/A), respectively. The relationship between bodyweight and warfarin dose was non-linear, with a three-fold difference in dose for a four-fold difference in bodyweight. In addition, age, baseline and target INR, and time since initiation of therapy, but not CYP4F2 genotype, had a significant impact on typical warfarin dose requirements in children. CONCLUSIONS: The updated model provides quantitative estimates of major clinical, demographic and genetic factors impacting on warfarin dose variability in children. With this new knowledge more individualized dosing regimens can be developed and prospectively evaluated in the pursuit of improving both efficacy and safety of warfarin therapy in children.

Anticoagulation control and cost of monitoring of older patients on chronic warfarin therapy in three settings in North East England.

BACKGROUND: novel oral anticoagulants may be particularly cost-effective when INR control (TTR) with warfarin is poor or monitoring difficult. SETTING: the Newcastle upon Tyne monitoring service, set in hospital or general practice and a domiciliary-based service for housebound patients. OBJECTIVES: to examine anticoagulation stability and costs of monitoring. SUBJECTS: three hundred and twenty-six atrial fibrillation patients, 75 years and over, with target INR of two to three, accessing hospital (n = 100), general practice (n = 122) and domiciliary (n = 104) service. METHODS: age, co-morbidities, length of warfarin treatment, medications, INR values and dose changes from January to December 2011 were recorded, and costs analysed. RESULTS: home-monitored patients had taken warfarin for longer, mean 5.2 years, than hospital (3.7) or general practice (3.1) patients. Age and total number of drugs prescribed chronically were negatively related to TTR. INR measurements and dose changes were negatively associated with the duration of treatment, positively correlated with co-morbidities. The mean TTR was 78% in hospital, 71% in general practice and 68% in domiciliary monitored patients. INR was monitored more often in hospital and domiciliary groups than in general practice and more dose changes occurred in the domiciliary group than in others. Costs of warfarin and monitoring were £128 per patient per year for hospital, £126 for general practice and £222 for domiciliary patients. CONCLUSIONS: further exploration of the clinical effectiveness of novel anticoagulants in dependent patients is warranted to determine to what extent trial outcomes so far achieved in a fitter elderly population are influenced by the chronic co-morbidities of old age.

Self-monitoring of oral anticoagulation: systematic review and meta-analysis of individual patient data.

BACKGROUND: Uptake of self-testing and self-management of oral anticoagulation [corrected] has remained inconsistent, despite good evidence of their effectiveness. To clarify the value of self-monitoring of oral anticoagulation, we did a meta-analysis of individual patient data addressing several important gaps in the evidence, including an estimate of the effect on time to death, first major haemorrhage, and thromboembolism. METHODS: We searched Ovid versions of Embase (1980-2009) and Medline (1966-2009), limiting searches to randomised trials with a maximally sensitive strategy. We approached all authors of included trials and requested individual patient data: primary outcomes were time to death, first major haemorrhage, and first thromboembolic event. We did prespecified subgroup analyses according to age, type of control-group care (anticoagulation-clinic care vs primary care), self-testing alone versus self-management, and sex. We analysed patients with mechanical heart valves or atrial fibrillation separately. We used a random-effect model method to calculate pooled hazard ratios and did tests for interaction and heterogeneity, and calculated a time-specific number needed to treat. FINDINGS: Of 1357 abstracts, we included 11 trials with data for 6417 participants and 12,800 person-years of follow-up. We reported a significant reduction in thromboembolic events in the self-monitoring group (hazard ratio 0·51; 95% CI 0·31-0·85) but not for major haemorrhagic events (0·88, 0·74-1·06) or death (0·82, 0·62-1·09). Participants younger than 55 years showed a striking reduction in thrombotic events (hazard ratio 0·33, 95% CI 0·17-0·66), as did participants with mechanical heart valve (0·52, 0·35-0·77). Analysis of major outcomes in the very elderly (age ≥85 years, n=99) showed no significant adverse effects of the intervention for all outcomes. INTERPRETATION: Our analysis showed that self-monitoring and self-management of oral coagulation is a safe option for suitable patients of all ages. Patients should also be offered the option to self-manage their disease with suitable health-care support as back-up. FUNDING: UK National Institute for Health Research (NIHR) Technology Assessment Programme, UK NIHR National School for Primary Care Research.

Pharmacogenetics of warfarin.

Warfarin is a drug with a narrow therapeutic index and a wide interindividual variability in dose requirement. Because it is difficult to predict an accurate dose for an individual, patients starting the drug are at risk of thromboembolism or bleeding associated with underdosing or overdosing, respectively. Single nucleotide polymorphisms in the cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKOR) genes have been shown to have a significant effect on warfarin dose requirement. Other genes mediating the action of warfarin make either little or no contribution to dose requirement. Although the polymorphisms in CYP2C9 and VKORC1 explain a significant proportion of the interindividual variability in warfarin dose requirement, currently available evidence based on a few small studies relating to the use of pharmacogenetics-guided dosing in the initiation of warfarin therapy has not shown improved outcomes in either safety or efficacy of therapy. Better clinical evidence of beneficial effects on patient outcome, particularly at the extremes of the dose requirements in geographically and ethnically diverse patient populations, is needed before the role of a pharmacogenomic approach to oral anticoagulation therapy in clinical practice can be established.

The population pharmacokinetics of R- and S-warfarin: effect of genetic and clinical factors.

BACKGROUND: Warfarin is a drug with a narrow therapeutic index and large interindividual variability in daily dosing requirements. Patients commencing warfarin treatment are at risk of bleeding due to excessive anticoagulation caused by overdosing. The interindividual variability in dose requirements is influenced by a number of factors, including polymorphisms in genes mediating warfarin pharmacology, co-medication, age, sex, body size and diet. AIMS: To develop population pharmacokinetic models of both R- and S-warfarin using clinical and genetic factors and to identify the covariates which influence the interindividual variability in the pharmacokinetic parameters of clearance and volume of distribution in patients on long-term warfarin therapy. METHODS: Patients commencing warfarin therapy were followed up for 26 weeks. Plasma warfarin enantiomer concentrations were determined in 306 patients for S-warfarin and in 309 patients for R-warfarin at 1, 8 and 26 weeks. Patients were also genotyped for CYP2C9 variants (CYP2C9*1,*2 and *3), two single-nucleotide polymorphisms (SNPs) in CYP1A2, one SNP in CYP3A4 and six SNPs in CYP2C19. A base pharmacokinetic model was developed using NONMEM software to determine the warfarin clearance and volume of distribution. The model was extended to include covariates that influenced the between-subject variability. RESULTS: Bodyweight, age, sex and CYP2C9 genotype significantly influenced S-warfarin clearance. The S-warfarin clearance was estimated to be 0.144 l h⁻¹ (95% confidence interval 0.131, 0.157) in a 70 kg woman aged 69.8 years with the wild-type CYP2C9 genotype, and the volume of distribution was 16.6 l (95% confidence interval 13.5, 19.7). Bodyweight and age, along with the SNPs rs3814637 (in CYP2C19) and rs2242480 (in CYP3A4), significantly influenced R-warfarin clearance. The R-warfarin clearance was estimated to be 0.125 l h⁻¹ (95% confidence interval 0.115, 0.135) in a 70 kg individual aged 69.8 years with the wild-type CYP2C19 and CYP3A4 genotypes, and the volume of distribution was 10.9 l (95% confidence interval 8.63, 13.2). CONCLUSIONS: Our analysis, based on exposure rather than dose, provides quantitative estimates of the clinical and genetic factors impacting on the clearance of both the S- and R-enantiomers of warfarin, which can be used in developing improved dosing algorithms.

Vitamin K deficiency amplifies anticoagulation response to ximelagatran: possible implications for direct thrombin inhibitors and their clinical safety.

Dietary vitamin K is known to influence the anticoagulation response to warfarin. It is possible that dietary vitamin K availability also influences the pharmacological activity of other oral anticoagulants, which target the vitamin-K dependent clotting proteins in the coagulation cascade. This study examined whether vitamin K insufficiency affected anticoagulation response to the direct thrombin inhibitor, ximelagatran. Anticoagulation response to ximelagatran and warfarin in rats on a normal diet was compared to those on a vitamin K deficient diet. Ximelagatran and warfarin increased prothrombin time (PT) by 1.4- and 1.3-fold, activated partial thromboplastin time (APTT) by 1.8- and 1.4-fold and ecarin clotting time (ECT) by 6.8- and 1.2-fold, respectively, in rats on normal diet. Vitamin K deficient diet alone caused modest increases in PT, APTT and ECT. The anticoagulant activity of both ximelagatran and warfarin was significantly greater in rats on vitamin K deficient diet (6.1- and 12.3-fold for PT, 2.6- and 5.1-fold for APTT and 2.9- and 1.6-fold for ECT, respectively) compared to those on normal diet. Factor II activity was reduced by both ximelagatran (58%) and warfarin (44%) in rats on normal diet. However, factor II activity was virtually abolished (<0.1%) by both drugs in rats on vitamin K deficient diet. The results suggest that oral anticoagulant drugs, whose primary site of action is not within the vitamin K cycle, may also exhibit variability in clinical response due to dietary variation as the established coumarin drugs such as warfarin.