Warfarin is one of the most frequently prescribed oral anticoagulant. Many researches have shown that the cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex 1 (VKORC1) genotypes have been strongly associated with warfarin maintenance doses. Warfarin maintenance doses can be accurately predicted by use of dosing algorithms including genetic and clinical information. Although several clinical trials demonstrated mixed results, calling into question the utility of this approach. The present data do not support genetic testing to guide warfarin maintenance doses, but in the setting where genotype data are available, use of this approach is reasonable. Ongoing trials are expected to provide more data, and more work is needed to define dosing algorithms that include appropriate variables in minority populations. All these work will further improve the clinical application of genotype-guided warfarin maintenance doses.
ObjectiveTo compare the cost-effectiveness of warfarin and enoxaparin overlapping treatment for the prevention of venous thromboembolism (VTE) or pulmonary embolism (PE) in patients with nephrotic syndrome (NS). MethodsA decision tree model was constructed. The efficacy data applied in our decision tree were from clinical data, and the cost data was based on the hospitalization cost of 103 patients with nephrotic syndrome in Guangdong Provincial People's Hospital from 2013 to 2014, State Development and Reform Commission pricing and literature report. The one-way sensitivity analyses was conducted to analyze the stability of test. ResultsIn base case, the cost and cost-effective ratio of warfarin and enoxaparin overlapped treatment for 3 days were 10305.49 yuan and 31607.15, respectively. While those overlapped treatment for 4 days were 8849.36 yuan and 20896.46, overlapped treatment for 5 days and above were 9494.29 yuan and 21659.95, respectively. The incremental cost-effectiveness ratio of 4 days versus 5 days and above was 5600.96. The cost-effective ratio of 4 days was lower but the incremental cost-effectiveness ratio of it was higher. The sensitivity analysis showed the test result was stable. ConclusionCost-effectiveness analysis shows that warfarin and enoxaparin overlapping treatment for 4 days in patients with nephrotic syndrome has cost-effective advantage. Due to the limited sample size of our study, the above conclusion should be proved by more large-scale high-quality clinical studies.
Warfarin, a classic oral anticoagulant, is characterized by a narrow therapeutic window and considerable interindividual variability in dosing requirements. This makes precise dose adjustment challenging in clinical practice and increases the risk of bleeding or thrombosis. To improve dose prediction, this study developed a streamlined multilayer perceptron (MLP) model using real-world data from the International Warfarin Pharmacogenomics Consortium (IWPC) database. The LASSO-proj algorithm was applied for high-precision feature selection prior to model construction. The resulting model demonstrated strong predictive performance on the test set, achieving a coefficient of determination (R2) of 0.456, a mean absolute error (MAE) of 8.92 mg/week, and 48.522% of its predictions falling within ±20% of the actual stable therapeutic dose. Through SHAP-based interpretation using DeepExplainer, key features influencing warfarin dosing were identified, including the VKORC1 genotype, body weight, age, and ethnicity. The interpretable MLP framework incorporating LASSO-proj not only maintains high predictive accuracy, but also significantly enhances model transparency, providing a valuable tool for guiding warfarin therapy.
Objective To investigate the role of clinical pharmacists in warfarin therapy. Methods A total of 134 patients underwent prosthetic heart valve replacement and had warfarin for life from March 2013 to October 2013 in Fujian Medical University Union Hospital. All patients were equally divided into two groups (an intervention and a non-intervention group) crosswise by sequence. There were 67 patients in each group. The anticoagulant effects of the two groups were compared. Results There was no statistical difference in the patients' demographic information between the two groups. However, the time for the patients to reach the target international normalized ratio(INR) values for the first time (7.1±3.3 dvs. 10.5±5.0 d,P=0.000) and time of INR in the therapy range (46.3%±18.8%vs.19.0%±16.2%,P=0.000) during their hospitalization, proportion of time of under anticoagulation (47.5%±19.5%vs. 71.2%±22.9%,P=0.000), proportion of time of anticoagulation overdose (5.3%±8.2%vs. 9.9%±16.7%,P=0.002) were significantly different. While there was no statistical difference in postoperative hospitalization time between the two groups (19.9±6.6 dvs. 18.1±7.0 d,P=0.137). There were 4 patients (6.0%) with minor hemorrhage and no severe complication was found in the intervention group. There were seven patients (10.4%) with mild hemorrhage, two patients with stroke, one patient with mild pulmonary embolism, and severe complication rate of 4.5% in the non-intervention group. Conclusion With clinical pharmacists involved in the whole anticoagulation therapy progress of patients after mechanical heart valve replacement, the time to achieve the therapeutic window for the first time is effectively shorten, and the time of the INR value controlled in therapeutic range is highly improved during hospitalization time. Moreover, the patients' risk of thrombosis and bleeding is eventually reduced.
Abstract: Objective To investigate the anticoagulation effect of warfarin on pregnant women with prosthetic mechanical heart valves during the whole course of pregnancy and their fetuses. Methods Followup survey was carried out on 103 pregnant women with prosthetic mechanical heart valves treated in the Second Xiangya Hospital of Central South University from April 1998 to June 2010. Their age ranged from 19 and 38 years (26.4±3.8 years). All the 103 pregnant women were given oral administration of warfarin during the whole course of pregnancy. The average dose of domestic warfarin was 3.30±0.43 mg/d (87 cases), while the average dose of imported warfarin was 2.90±1.05 mg/d (16 cases). Results None of the patients suffered from serious embolic events. One patient suffered from spontaneous peritoneal hemorrhage. There were 4 cases of intrauterine deaths, and 5 cases of fetal malformation including 1 case of Down’s syndrome and 4 cases of hydrocephalus. Six cases of low birth weight infants and 1 case of ABO hemolytic disease were also found. All the other neonates were healthy with normal weight. No pregnant women suffered from postpartum hemorrhage. Conclusion Oral administration of low dose warfarin (lt;5 mg/d) during the whole course of pregnancy is a relative safe and effective anticoagulation protocol.
ObjectiveTo clarify the relationship between the G/C polymorphism of inflammatory gene matrix metalloproteinase-2 (MMP2) and warfarin therapy after cardiac valve replacement (CVR). MethodsWe finally identified 96 patients who received additional warfarin therapy after CVR as a trial group and 78 patients without the warfarin therapy as a control group. Gene sequencing techniques were adopted to determine single nucleotide polymorphism allele. We analyzed genotype and clinical features of the two groups and explored the relationship between the different MMP2 geno-types and warfarin therapy after CVR. Logistic regression was used to analyze the correlation between genotypes and risk factors after CVR and Kaplan-Meier survival curves were performed to analyze the survival time and efficacy of patients carrying MMP2 GC and GG genotypes. ResultsThe distribution of MMP2 genotype in patients receiving warfarin therapy after surgery was different from that in patients without warfarin therapy. The results of multivariate logistic regression analysis showed that GC and GG genotypes were risk factors of complications of CVR. The proportion of GG genotype was higher in the patients with postoperative complications compared with those without. The survival time of patients carrying genotype MMP2 GG was shorter than those carrying GC genotype (P < 0.05), which reveals that the level of MMP2 GG genotype was associated with the prognosis. ConclusionG allele of MMP2 is a risk factor of complications following CVR. GG genotype is relevant to CVR and prognosis, which can be regarded as a risk factor post CVR.
ObjectiveTo explore the anticoagulant strategy of adjusting the dose of warfarin at different stages after mechanical valve replacement of mitral valve.MethodsClinical data of a total of 302 patients, including 76 males and 226 females, with an average age of 50.1±10.1 years, who underwent mechanical mitral valve replacement in the Chinese adult cardiac surgery database from 2013 to 2017 were retrospectively analyzed. According to the dose adjustment strategy of taking warfarin, the patients were divided into a D group (adjusting warfarin dose in days) and a W group (adjusting warfarin dose in weeks) to evaluate the anti-coagulation effect of warfarin.ResultsThe total follow-up time was 423277 d (1159.7 years). There was no significant difference in the overall anticoagulant strength, and the warfarin dose adjusted in days was better in the early postoperative period (P<0.05), especially in patients over 60 years. It was better to adjust warfarin dose in weeks in the middle and long periods (P<0.05), especially in patients ≤40 years. In terms of the stability of anticoagulation, it was better to adjust the dosage of warfarin in weeks (P<0.05). It was better to adjust the dosage of warfarin in weeks for early, middle- and long-term anticoagulant therapy after operation (P<0.05), especially in the females aged >40 and ≤50 years.ConclusionWithin the target range of international normalized ratio (1.5-2.5), the anticoagulant strategy of adjusting warfarin dose in days after mechanical valve replacement of mitral valve can achieve a better anticoagulant strength, and adjusting the dosage of warfarin in weeks is better in the middle- and long-term after operation. In general, the anticoagulant effect is more stable in the short term when warfarin dose is adjusted on a weekly basis.
ObjectiveTo investigate the influence of high activity of CYP2C9 (Cytochrome P450 proteins 2C9)and VKORC (Vitamin K epoxide reductase C)on warfarin anticoagulation of patients after heart valve replacement (HVR). MethodsFrom February 2010 to May 2013, 40 patients with high activity of CYP2C9 and VKORC underwent HVR in the Department of Cardiac Surgery, the First Affiliated Hospital of Zhengzhou University. There were 18 male and 22 female patients with their age of 40-51 (45.18±2.93)years. There were18 patients receiving mitral valve replacement (MVR), 14 patients receiving MVR and tricuspid valvuloplasty (TVP), and 8 patients receiving double valve replacement (DVR). Depen-ding on whether they received preoperative genetic polymorphism detection of CYP2C9 and VKORC1, all the patients were divided into 2 groups with 20 patients in each group. Patients in group A didn't receive preoperative genetic polymorphism detection of CYP2C9 and VKORC1, while patients in group B received preoperative genetic polymorphism detection of CYP2C9 and VKORC1. Postoperatively, periodic examination of international normalized ratio (INR)was performed to adjust warfarin dosage. Time to reach expected INR value and morbidity were collected. All the patients were followed up for 3-12 months after discharge. Monthly telephone follow-up was performed to record INR values, morbidity and general recovery. ResultsPostoperatively, in group A, 2 patients had cerebral infarction, 2 patients had popliteal artery throm-bosis, 1 patient had pulmonary embolism, and 1 patient had thrombosis in the annulus. Expected INR was achieved 15-20 days after warfarin treatment among the other 14 patients without thromboembolism. Three months after surgery, CYP2C9 and VKORC1 gene polymorphism was examined to find 17 patients with positive CYP2C9*1/*1 (*2CC/*3AA)and positive VKORC1-1639 GA, and 3 patients with positive CYP2C9*1/*1 (*2CC/*3AA)and positive VKORC1-1639 GG. In Group B, patients received aspirin (100 mg/d)and low molecular heparin (0.4 ml/d)in addition to warfarin since the second posto-perative day. Expected INR was achieved 5-9 days after warfarin treatment, and then aspirin and low molecular heparin were discontinued. During the 6 months follow-up period, no obvious thromboembolism was found, and only 1 patient had epistaxis who was cured with nasal tamponade. ConclusionPreoperative detection of genetic polymorphisms of CYP2C9 and VKORC1 can provide important guidance for warfarin anticoagulation after HVR.
Objective To systematically review the effect of discontinuous warfarin on the risk of postoperative bleeding complications after tooth extractions. Methods PubMed, EMbase, The Cochrane Library (Issue 9, 2016), CNKI, VIP, WanFang Data, China Food and Drug Administration and the ADR supervision system of FDA were electronically searched to collect randomized controlled trials (RCTs) and cohort studies about the effect of discontinuous warfarin on risk of postoperative bleeding complications after tooth extractions in patients until September 30th, 2016. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies. Then, meta-analysis was performed using RevMan 5.3 software. Results A total of 8 studies were included, involving 3 RCTs and 5 cohort studies. The results of meta-analysis showed that: there was no significant difference between the discontinuous or reduced warfarin group and the continuous warfarin group (RCTs: RR=0.86, 95%CI 0.49 to 1.51,P=0.60; cohort studies: RR=0.67, 95%CI 0.45 to 1.01,P=0.06). Conclusions Current evidence indicates that there is no statistically significant correlation between whether discontinuous warfarin and the risk of postoperative bleeding complications after tooth extractions. Due to the limited quantity and quality of included studies, the above conclusions are needed to be further verified by more high quality studies.
Warfarin is one of the most frequently prescribed oral anticoagulant. Many researches have shown that the genotypes have been strongly associated with warfarin maintenance doses. Especially, it has been accepted in academia that cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex 1 subunit (VKORC1) could affect the warfarin maintenance doses. There are also many other genotypes that were reported to be related to warfarin doses, but the results have been in controversial so far. The studies found that the dose formula which contained the genetic factors and clinical information could accurately predict the maintenance dose of warfarin, however, its usefulness is suspected due to the inconsistent results of clinical trials. Large-sample and multi-center studies are necessary to verify the specific effects of gene and non-gene factors to warfarin dose; at the same time, testing constructed models or building new models help to improve the explained percentages of individual differences.