Objective To assess different anticoagulant regimens in pregnant women with mechanical heart valves: taking oral warfarin throughout the pregnancy, or heparin in the 1st trimester and oral warfarin for the other trimesters. The main outcome measures were major maternal complications and perinatal outcomes. Methods The MEDLINE, EMbase, CBM and CNKI were searched. The quality of the included studies was evaluated and data were extracted by two reviewers independently. Meta-analyses were performed on the results of homogeneous studies. Result Seven studies involving 629 pregnancies in 469 patients met the inclusion criteria for this review, all of which were retrospective surveys. The comparison between the administration of heparin in the 1st trimester plus oral warfarin for the other trimesters and warfarin throughout the pregnancy showed that, there are not significant different in the incidence of major maternal complications and the incidence of adverse perinatal outcomes. Conclusion Compared with the administration of warfarin throughout the pregnancy, the administration of heparin in the 1st trimester and oral warfarin for the other trimesters might increase the incidence of major maternal complications, but with a similar incidence of adverse perinatal outcomes.
Objective To investigate the influence of CYP2C9 3，VKORC1-1639 G＞A and CYP4F2 rs2108622 genetic polymorphisms on warfarin dosages of patients after heart valve replacement. Methods A total of 133 patients undergoing heart valve replacement in the Department of Cardiovascular Surgery of Fujian Provincial Hospital from November 2011 to August 2012 were included in this study. Polymerase chain reaction（PCR）gene sequencing was performed to detect CYP2C9 3，VKORC1-1639 G＞A and CYP4F2 rs2108622 genetic polymorphism of these 133 patients. Patients were grouped according to their genotypes，and average warfarin dosages were compared between different genotype groups. Results The frequencies of CYP2C9 3 AA，AC and CC were 127 patients，6 patients and 0 patient respectively，and average daily warfarin dosages were 3.75 mg and 2.13 mg respectively which were statistically different between differentCYP2C9 3 genotypes （P＜0.05）. The frequencies of VKORC1-1639 G＞A GG，GA and AA were 3 patients，32 patientsand 98 patients respectively，and average daily warfarin dosages were 6.00 mg，4.50 mg and 3.00 mg respectively which were statistically different between different VKORC1-1639 G＞A genotypes （P＜0.05）. The frequencies of CYP4F2 rs 2108622 CC，CT and TT were 67 patients，59 patients and 7 patients respectively，and average daily warfarin dosages were 3.00 mg，3.75 mg and 4.50 mg respectively which were statistically different between different CYP4F2 rs2108622 genotypes（P＜0.05）. Conclusion CYP2C9 3，VKORC1-1639 G＞A and CYP4F2 rs2108622 genetic polymorphisms are associated with individual difference of warfarin dosages of patients after heart valve replacement.
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.
Objective To explore the impact of the women taking warfarin throughout pregnancy after mechanical valve replacement on the children’s physical and mental development.Methods A total of 12 children whose mothers had taken mechanical valve replacement before pregnancy were enrolled in the experimental group in this study, for determination of their physical and mental development. The following indicators were measured: a) Physical development indexes: height, weight, sitting height, head circumference, chest circumference; b) Mental development indexes: intelligence quotient (IQ), and development quotient (DQ) which included adaptability, big movement, fine motor, language, and individual-society. According to the 1?∶?2 matching ratio, 24 children of the healthy women were selected in the control group, and then the difference of each index between the two groups was analyzed. Results In the aspects of both physical development indexes and mental development indexes, there were no significant differences in the children aged 0 to 3 yrs, 4 to 6 yrs, and 6 to 12 yrs in the two groups (Pgt;0.05). Conclusion After mechanical valve replacement, women taking oral anticoagulant warfarin in daily dose not exceeding 5mg are safe, and there are no negative effects on children’s physical and mental development.
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.
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.
ObjectivesTo investigate the correlation of warfarin dose genetic and polymorphism of Han-patients after heart valve replacement, to forecast the anticoagulation therapy with warfarin reasonable dosage, and to realize individualized management of anticoagulation monitoring. MethodsWe selected 103 patients between January 1, 2011 and December 31, 2012 in West China Hospital of Sichuan University who were treated by oral warfarin after heart valve replacement with monitoring anticoagulation by international normalized ratio (INR) in Anticoagulation Therapy Database of Chinese Patients after Heart Valve Replacement. There were 32 males and 71 female at age of 21-85 (48.64± 11.66) years. All the patients' CYP2C9 and VKORC1 genetic polymorphisms were detected by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RELP) method and gene sequencing technology. Warfarin concentration in plasma was determined by high performance liquid chromatography (HPLC) method. The activity of coagulation factorⅡ, Ⅶ, Ⅸ, Ⅹwas determined by Sysmex CA7000 analyzer. ResultsThe multivariate linear regression analysis showed that age, body surface area, and coagulation factor activity had no significant effect on warfarin dosage. While the gene polymor-phisms of CYP2C9 and VKORC1, warfarin concentration, and age had significant contributions to the overall variability in warfarin dose with decisive coefficients at 1.2%, 26.5%, 43.4%, and 5.0% respectively. The final equation was:Y=1.963-0.986× (CYP2C9* 3) +0.893× (VKORC1-1639) +0.002× (warfarin concentration)-0.019× (age). ConclusionMultiple regression equation including gene polymorphisms of CYP2C9 and VKORC1, non-genetic factors of coagulation factor activity, warfarin concentration, age, and body surface area can predict reasonable dosage of warfarin for anticoagulation to achieve individualized management of anticoagulation monitoring and reduce the anticoagulation complications.
ObjectiveTo systematically review therapy-related complications incidences of warfarin with different anticoagulation intensity in Chinese after mechanical heart valve replacement, and to explore the suitable anticoagulation intensity of warfarin. MethodsWe electronically searched The Cochrane Library (Issue 2, 2013), EMbase, PubMed, CNKI, CBM, WanFang Data and VIP for studies about therapy-related complications rates of warfarin with different anticoagulation intensity in Chinese after mechanical heart valve replacement from inception to March 2013. Two reviewers independently screened literature according to inclusion and exclusion criteria, extracted data, and assessed methodological quality of included studies. Then meta-analysis was performed using RevMan 5.2. ResultsA total of 7 studies involving 3 787 cases were finally included, 2 985 cases in Group A (targeted INR≤2.3) and 802 cases in Group B (targeted INR > 2.3). The results of meta-analysis showed that, compared with Group B, the total therapy-related complications incidence of warfarin with different anticoagulation intensity significantly decreased in Group A (OR=0.35, 95%CI 0.28 to 0.44, P < 0.000 01). The incidence of hemorrhage in Group A (OR=0.15, 95%CI 0.08 to 0.27, P < 0.000 01) was lower than that in Group B. However, the incidence of embolism in Group A was higher than that in Group B (OR=2.77, 95%CI 1.54 to 4.98, P=0.000 7). ConclusionApplying low-intensity anticoagulation for Chinese patients after mechanical heart valve replacement could reduce the overall incidences of anticoagulation-related complications and hemorrhage, but it could also significantly increase the incidence of thrombosis.
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.
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.