An adapted neural-fuzzy inference system model using preprocessed balance data to improve the predictive accuracy of warfarin maintenance dosing in patients after heart valve replacement

Background Tailoring warfarin use poses a challenge for physicians and pharmacists due to its narrow therapeutic window and huge inter-individual variability. This study aimed to create an adapted neural-fuzzy inference system (ANFIS) model using preprocessed balance data to improve the predictive accuracy of warfarin maintenance dosing in Chinese patients undergoing heart valve replacement (HVR). Methods This retrospective study enrolled patients who underwent HVR between June 1, 2012 and June 1, 2016 from 35 centers in China. The primary outcomes were the mean difference between predicted warfarin dose by ANFIS models and actual dose, and the models’ predictive accuracy, including the ideal predicted percentage, the mean absolute error (MAE), and the mean squared error (MSE). The eligible cases were divided into training, internal validation, and external validation groups. We explored input variables by univariate analysis of a general liner model and created two ANFIS models using imbalanced and balanced training sets. We finally compared the primary outcomes between the imbalanced and balanced ANFIS models in both internal and external validation sets. Stratified analyses were conducted across warfarin doses (low, medium, and high doses). Results A total of 15,108 patients were included and grouped as follows: 12,086 in the imbalanced training set; 2,820 in the balanced training set; 1,511 in the internal validation set; and 1,511 in the external validation set. Eight variables were explored as predictors related to warfarin maintenance doses, and imbalanced and balanced ANFIS models with multi-fuzzy rules were developed. The results showed a low mean difference between predicted and actual doses (< 0.3 mg/d for each model) and an accurate prediction property in both the imbalanced model (ideal prediction percentage: 74.39–78.16%, MAE: 0.37 mg/daily, MSE: 0.39 mg/daily) and the balanced model (ideal prediction percentage: 73.46–75.31%, MAE: 0.42 mg/daily; MSE, 0.43 mg/daily). Compared to the imbalanced model, the balanced model had a significantly higher prediction accuracy in the low-dose (14.46% vs. 3.01%; P < 0.001) and the high-dose warfarin groups (34.71% vs. 23.14%; P = 0.047). The results from the external validation cohort confirmed this finding. Conclusions The ANFIS model can accurately predict the warfarin maintenance dose in patients after HVR. Through data preprocessing, the balanced model contributed to improved prediction ability in the low- and high-dose warfarin groups.

The Comparison of Therapeutic Efficacy Between Dabigatran Versus Warfarin in Patients With Nonvalvular Atrial Fibrillation

Background Novel oral anticoagulants and warfarin are widely used for stroke prevention in patients with atrial fibrillation. The anticoagulation status of patients receiving warfarin or rivaroxaban has been studied. In this study, we aimed to evaluate the effect of dabigatran and warfarin on preventing thrombin generation (TG). Methods This retrospective study enrolled 237 nonvalvular atrial fibrillation (NVAF) subjects treated with 110 mg dabigatran etexilate twice daily and 224 NVAF patients received adjusted-dose warfarin (international normalized ratio [INR] of 2 to 3)). Coagulation assays, prothrombin fragment 1 + 2 (F1+2), calibrated automated thrombogram, and thrombin–antithrombin complex (TAT) were detected at the steady state. Results Activated partial thromboplastin time (APTT), antithrombin III activity, fibrinogen, and lag time showed no difference between the two groups. Compared to the dabigatran group, prothrombin time and INR values were higher in the warfarin group (all P < .001). Thrombin time, endogenous thrombin potential, peak TG (Cmax), F1+2, and TAT were lower in the warfarin group. The inhibition of TG was still stronger in the warfarin group when the patients were divided into subgroups. Conclusion Conventional coagulation assays are suboptimal for assessing the coagulation status of dabigatran. TG could be used as supplementary assays to evaluate the anticoagulation effect of oral anticoagulants. Our results suggest that warfarin may inhibit TG more aggressively than dabigatran in patients regardless of age and kidney function.

Low-dose warfarin combined with low-dose aspirin associated Spinal intramedullary hemorrhage: a case report

Background:Spinal intramedullary hemorrhage is a rare event, the disease still has not received enough attention and many characteristics of the disease have not been sufficiently explored. Due to its rarity, it can easily be forgotten or misdiagnosed. Case presentation:We report a case of 72-year-old male patient with a medical history of coronary heart disease, atrial fibrillation (AF), hypertension, cervical spondylosis, carotid and vertebral artery stenosis with low-dose anticoagulation combined with low-dose antiplatelet therapy who suffered from sudden posterior neck and back pain for 3 hours visited our emergency department (ED). The International Normalization Ratio (INR) were controlled well, and other laboratory tests were within normal limits or only slightly abnormal. However, the patient was diagnosed with spinal intramedullary hemorrhage and died finally. Conclusion:Anticoagulation combined with antiplatelet-associated rare and life-threatening complications should be paid more attention.

Vitamin K Tissue Distribution Is Modified by Large-Dose Warfarin and Menaquinone-4 Content of the Diet

Objectives Investigate the influence of large-dose warfarin (W) on tissue K1 and MK-4 distribution in rats fed a standard K1 diet, or enriched with MK4. Methods Male Wistar rats were fed a regular K1 (750 mcg K1/kg/diet; WK1) or enriched MK-4 (100 mg MK-4/kg/diet; WK1 + MK4) diet for 1 week after which they were administered 14 mg W/kg/day (in drinking water) and subcutaneous K1 (94 mg/kg, 3X/week; to maintain coagulation), for 12 weeks; diets were maintained throughout the experimental period. Respective diet controls (C and C + MK4) received subcutaneous saline and regular water. K1 and M-4 quinone and their epoxide forms (K1O and MK-4O) were assessed in serum, liver, heart, kidney, pancreas, adipose tissue and brain, by HPLC. Group differences were tested by one-way ANOVA, and by t-test for each K vitamer. Results In C group, K1 was the predominant K vitamer in serum, liver and heart, whereas MK-4 was found in relative higher concentrations in kidney, pancreas, brain, and adipose tissue. In MK-4 containing organs, W treatment was associated with significantly lower MK-4 concentration in pancreas, brain, and heart (P &lt; 0.05) despite the local presence of K1, which suggests that W may block the production of MK-4 by UBIAD1. Compared to C group, K1 concentrations were significantly higher in all organs and serum in WK1 and WK1 + MK4 groups as a result of the subcutaneous administration. Interestingly, in WK1 animals who had received a MK-4 enriched diet (WK1 + MK4), K1 concentrations in naturally K1 rich tissues (i.e., liver, heart and serum) were significantly increased when compared to those from the WK1 group (P &lt; 0.05), suggesting that dietary MK-4 may play a role in modulating the uptake of K1 in these tissues. Except in liver, W administration (WK1 and WK1 + MK4) was associated with higher tissue concentrations of K1 and MK-4 epoxide when compared to C group (P &lt; 0.05). Noteworthy, in WK1 animals who had received a MK-4 enriched diet (WK1 + MK4), naturally rich MK-4 containing organs (i.e., kidney, pancreas, adipose tissue and brain) presented significantly higher concentration of MK-4 epoxide (relative to K1 epoxide), suggesting a preferential use of MK4 by these organs when available from the diet. Conclusions In conclusion, results from this study point to modulatory roles of W and dietary MK-4 on tissue distribution of K1 and MK-4 in what appears to be a tissue specific manner. Funding Sources CIHR.

P168 Non-bacterial endocarditis in patients with antiphospholipid syndrome treated with direct oral anticoagulants

Introduction Primary antiphospholipid syndrome (APS) is a hypercoagulability state of autoimmune origin. Vitamin K- antagonists remain the mainstay therapy though the difficulties in maintaining target therapeutic range contributed to prescriptions of direct oral anticoagulants (ACOD). A recent randomized trial reported an excess in thromboembolic events in patients under rivaroxaban therapy compared with warfarin. Purpose Description of two cases of Libman-Sacks endocarditis in APS patients on therapy with rivaroxaban due to poor control with coumadin. Methods and results. Case 1 is a 47-year-old woman and case 2 a 69-yo man with APS with high antibody titers of 3 classes and previous thrombotic events (pulmonary embolism in case 1 and acute coronary syndrome in case 2). In both cases, coumadin was switched to rivaroxaban because of poor control. During follow-up the diagnosis of blood culture-negative endocarditis was stablished in both cases. Echo examinations in case 1 revealed a 12 mm mobile vegetation in the ventricular face of the non-coronary aortic cusp, which resolved after 2 months high-dose warfarin therapy. Case 2 was admitted to hospital because of heart failure. TTE and TOE revealed a 26 mm mass attached to the atrial face of posterior mitral leaflet and moderate mitral regurgitation. He underwent mitral valve replacement with a mechanical prosthesis and the final pathologic diagnosis was Libman-Sacks endocarditis. Conclusions Libman-Sacks endocarditis as a thrombotic feature of high-risk APS patients can occur under rivaroxaban therapy. In one of our 2 cases, high-dose coumadin therapy resolved this complication Abstract P168 Figure. Cases

Lack of effect of Imrecoxib, an innovative and moderate COX-2 inhibitor, on pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers

Imrecoxib is a registered treatment for osteoarthritis pain symptoms in China. This study aims to assess the effect of imrecoxib on the pharmacodynamics and pharmacokinetics of warfarin. 12 healthy male volunteers with CYP2C9*3 AA and VKORC1 AA genotypes took a 5 mg dose of warfarin both alone and concomitantly with steady-state imrecoxib. Both warfarin alone and concomitantly with imrecoxib have safey and good tolerance across the trial. Following warfarin and imrecoxib co-administration, neither Cmax, AUC0-t and t1/2 of warfarin enantiomers nor AUC of international normalized ratio (INR) were markedly different from those of warfarin alone. The geometric mean ratios (GMRs) (warfarin + imrecoxib: warfarin alone) of INR(AUC) was 1 (0.99, 1.01). The GMRs of warfarin AUC0-∞ (90% confidence interval, CIs) for warfarin + imrecoxib: warfarin alone were 1.12 (1.08, 1.16) for R-warfarin and 1.13 (1.07, 1.18) for S- warfarin. The 90% CIs of the GMRs of AUC0-∞, Cmax and INR (AUC) were all within a 0.8–1.25 interval. The combination of warfarin and imrecoxib did not impact the pharmacodynamics and pharmacokinetics of single-dose warfarin; therefore, when treating a patient with imrecoxib and warfarin, it is not required to adjust the dosage of warfarin.