| BackgroundAll patients that receive such mechanical valves generally need to be treated via anticoagulant therapy for the remainder of their lives,with vitamin K antagonists(VKA)being the only effective orally deliverable options,among which warfarin is the most frequently used.It is necessary to develop a reasonable individualized anticoagulant therapy for warfarin,due to its safety range is narrow,and the factors affecting the anticoagulantion of warfarin is numerous.The oral anticoagulant therapy intensity of warfarin including the following three aspects:the optimal INR,subtherapeutic INR and excessive anticoagulation.There is no guideline for warfarin anticoagulantion in China and the only expert consensus is based on Western guidelines.It is inappropriate to apply Western anticoagulant guidelines to Chinese people,because the optimal INR of Chinese people is lower than that of Westerner.It remains controversial as to what this optimal intensity level and best therapeutic treatment of excessive anticoagulation is among Chinese patients with bileaflet mechanical valves.Chapter 1 Optimal oral anticoagulant therapy in patients with mechanical heart valvesObjective:By reviewing the actual anticoagulant strength data and calculating the incidence of adverse events in different ranges of anticoagulant strength,we sought to better determine what the ideal oral anticoagulant therapy intensity is in a Chinese population of patients implanted with mechanical valves.Methods:This is a prospective follow-up,retrospective data study.We observed the outcomes of eligible enrolled Chinese patients that had been implanted with St.Jude Medical prosthetic valves and who had been treated at our institution from 2013 onwards.All enrolled patients were followed from one to six years by outpatient visits or telephone interviews following discharge.Prothrombin time was monitored a minimum of once every 56 days,given that we were unable to assume that linear changes would occur between temporally distant follow-up time points.Study endpoints included instances of thromboembolism and major hemorrhage.We calculated the international normalized ratio(INR)-specific incidence of such adverse events as a means of determining optimal anticoagulant therapeutic intensity in Han patients with these bileaflet mechanical valve prostheses.We further assessed optimal VKA dosing intensity in patients as a function of patient valve site and thromboembolism risk via separating patients according to their valve sites or risk level(high or low)and then conducting subgroup analyses.Results:In total this study enrolled 3176 patients,of whom 3017 were followed for 12,746.08 total person-years(4.22 mean years per patient),while the remaining 159 patients(5%)were lost during follow-up.A total of 185 patients suffered from adverse events,with a roughly 1.45%annual incidence rate of such adverse events(95%confidence interval[CI],1.22-1.64).Of these,54 patients suffered from episodes of major bleeding(0.42%per patient-year,95%CI,0.31-0.53),while 131 suffered from thromboembolism(1.03%per patient-year,95%CI,0.85-1.21).Based on these analyses,we determined that the ideal low-intensity anticoagulant treatment regimen for patients with bileaflet mechanical heart valve prostheses was an INR between 1.5 and 2.5.In those patients that had undergone aortic valve replacement(AVR),the optimal INR was between 1.5 and 2.0 regardless of any thromboembolism risk factors in these patients.In contrast,in patients that had undergone mitral valve replacement(MVR)who were not at risk for thromboembolism,the optimal INR was between 1.5 and 2.0,whereas in those at risk of thromboembolism the optimal INR was between 2.0 and 2.5.The ideal anticoagulant intensity in patients undergoing both AVR and MVR(DVR)was the same as in patients undergoing MVR alone.Due to the small number of patients with TVR,the ideal intensity of anticoagulation has not been determined in our study.However,according to the particularity of tricuspid valve location,it is more prone to thrombosis.We recommend that the intensity of anticoagulation should reach INR 2.0-2.5 at least.Conclusion:In order to achieve optimal outcomes by maintaining effective anticoagulant dosing while entailing minimal risk in Chinese patients that have undergone a bileaflet mechanical valve replacement,the target INR range should be between 1.5 and 2.5,with the final intensity of this anticoagulant regimen being determined based on a given patient’s risk of thromboembolism.Chapter 2 The treatment strategies for excessive anticoagulation in patients with mechanical heart valvesObjective:This trial aimed to determine the safety and efficacy of using low-dose vitamin K1(different administration routes)or Placebo to lower international normalized ratio(INR)values into the target range in a cohort of Chinese patients with mechanical heart valves.We sought to determine what the ideal treatment strategies for excessive anticoagulation are in a Chinese population of patients implanted with mechanical valves.Methods:This study was a single-center prospective randomized controlled trial which was divided into three randomized controls.The three parts are as follows:oral Vitamin K1 vs placebo,oral vs intravenous Vitamin K1,oral vs intramuscular Vitamin K1.Patients receiving warfarin after mechanical valve replacement in our institution,who had an INR value between 4.0 and 10.0,were enrolled in the study between January 2018 and January 2021.Randomized controlled trials were conducted according to the experimental scheme.The dose of vitamin K1 or placebo was 2.5mg.The INR values were monitored for all subjects at 4,8,12 and 24h after administration.The INR values were then monitored every 24 hours until the target range was reached.All subjects were followed up and INR values were measured at 3 days,7 days,1 month,2 months and 3 months after warfarin adjustment.Vitamin K-dependent coagulation factors were monitored for ten patients who were selected from the oral,intravenous,intramuscular injection of Vitamin K groups and placebo group.Thromboembolism,bleeding,Vitamin K1 anaphylaxis,warfarin resistance and other adverse events were recorded in all patients over the period studied.Results:The patients of 236 were screened in the study between in January 2018 and January 2021,of whom 220 participated in the study.The patients of 10(5%)were lost during follow-up.All patients did not have vitamin K1 hypersensitivity reaction and warfarin resistance.1.Oral Vitamin K vs Placebo:Forty patients were included in the placebo group and the vitamin K group respectively.The placebo group took significantly longer for normalisation of their INR(INR≤2.5)than the vitamin K group(3.45±1.34 vs 1.15±0.36 day,P<0.001)after treatment.The percentage of patients who received vitamin K1 had INR values of 1.5-2.5 was significantly higher than those who received placebo the day after the study drug(72.5%vs 0%,P<0.001).The placebo group exhibited significantly higher average of values of INR relative to the vitamin K1 group on first 8-72 hours following treatment(P<0.05).When all 80 patients were incorporated into the safety analysis,we observed a significantly reduced bleeding incidence in patients of vitamin K group relative to the placebo group(p=0.025;OR 0.33,95%CI 0.11-0.88).2.Oral vs Intravenous Vitamin K:38 patients were included in the oral administration of Vitamin K1 group and 37 patients in the intravenous Vitamin K1 administration.The percentage of patients who received oral vitamin K1 had INR values of 1.5-2.5 was significantly higher than those who received intravenous Vitamin K1 on 24 hours after taking the drug(71.95%vs 35.14%,P<0.001).56.76%of the patients had INR values less than 1.5 after intravenous administration and 13.16%after oral administration(P<0.001).The percentage of patients with the values of INR≤2.5 within 12 hours after treatment was considerably higher for the intravenous group relative to oral group(P<0.05).At the same time,The percentage of patients with the values of INR<1.5 on 12-72 hours after treatment was considerably higher for the intravenous group relative to oral group.The oral group exhibited significantly higher average of values of INR relative to the intravenous group on 4-72 hour following treatment(P<0.05).There was no significant difference in thromboembolic events and bleeding events between the two groups.3.Oral vs Intramuscular Vitamin K:33 patients were included in the oral administration of Vitamin K1 group and 32 patients in the intramuscular Vitamin K1 administration.The duration of warfarin withdrawal in the oral vitamin K1 group and the intramuscular injection vitamin K1 group were 1.15±0.44 day and 2.31±0.90 day respectively(P<0.001).The percentage of patients who received oral vitamin K1 had INR values of 1.5-2.5 was significantly higher than those who received Intramuscular Vitamin K1 on 24 hours after administration of Vitamin K1(78.79%vs 18.75%,<0.001).However,At 24 hours,26/32(81.25%)patients had an INR greater than 2.5 and 10(31.25%)patients failure to respond to Vitamin K1(INR>4.0 at 24 hours)in the Intramuscular Vitamin K1 group.At 12 to 48 hours after taking vitamin Kl,the percentage of patients in the oral administration of Vitamin K group had INR values less than or equal 2.5 was significantly higher than those in the Intramuscular Vitamin K group.The bleeding events significantly higher in the intramuscular injection vitamin K1 group than and the oral vitamin K1 group.But there was no significant difference in thromboembolic events between the two groups.4.Coagulation factor monitoring:The trends of coagulation factor had strong correlation with the INR change.At 24 hours after treatment,the order of clotting factor levels is as follows:Intravenous Vitamin K1>Oral Vitamin K1>Intramuscular Vitamin K1>Oral Placebo.Conclusion:1.Chinese patients treated with warfarin anticoagulation after mechanical valve replacement with INR values of 4.0 to 10.0 without bleeding should be actively given vitamin K1 treatment.2.Low dose vitamin K1 is effective to reverse Excessive Anticoagulation;however,the safety of drug application needs to expand sample size in future studies.3.Intravenous administration has the fastest effect and definite curative effect,followed by oral,and the effect of oral administration is similar to that of intravenous administration after 24 hours of treatment.Intramuscular vitamin K was the least effective owing to the irregular and unpredictable absorption.Chapter 3 Genetic factors of excessive anticoagulation in patients with mechanical valve replacementObjective:To compared the differences of genetic factors between patients of excessive anticoagulation and stable anticoagulation,we sought to determine the genetic underpinnings for rational medicine use of warfarin in Chinese patients with excessive anticoagulation.Methods:This study was a retrospective,non-randomized controlled trial,which was divided into excessive anticoagulation and stable anticoagulation group.Patients receiving warfarin after mechanical valve replacement in our institution,who had an INR value between 4.0 and 10.0 of unknown cause,were enrolled in the excessive anticoagulation group.Patients with mechanical heart valves,who take orally warfarin anticoagulant therapy got two times stable INR(INR1.5-2.5)at least and with no need to adjust VKA dosing at least 3 months were recruited in stable anticoagulation group.Polymerase Chain Reaction-Restricted Fragment Length Polymorphisms(PCR-RFLP)was used to test the polymorphisms of VKORCI and CYP2C9genes.The mutations of the above polymorphism sites,the differences of gene and warfarin dose were compared between the two groups.Patients in the excessive anticoagulation group were followed up until the patients reached a stable anticoagulantion.Warfarin dose was recorded after anticoagulant stabilization in these patients.Results:According to inclusion and exclusion criteria,the patients of 128 and 130 were enrolled in the excessive anticoagulation group and the stable anticoagulantion group,respectively,from July 2015 to December 2020.There was a significant positive correlation between height,weight,BSA and daily warfarin maintenance dose in both groups.However,the linear regression analysis showed that the fitting degree(R2)and linear slope of the linear regression equation in the excessive anticoagulation group were lower than those in the stable anticoagulantion group.The proportion of wild-type patients with CYP2C9 gene in the excessive anticoagulation group was significantly lower than that in the stable anticoagulantion group(72.66%vs 90.00%,OR 0.30,95%CI 0.15-0.58,P<0.001).And CYP2C9*3 heterozygous mutation in the excessive anticoagulation group were significantly higher than those in the stable anticoagulantion group(24.22%vs 9.23%,OR 3.01,95%CI 1.49-6.09,P<0.001).Percentage of patients carrying VKORC1-1639 AA and CYP2C9*1*3 in the excessive anticoagulation group was significantly higher than that in the stable anticoagulantion group(21.88%vs 9.23%,P=0.02).In contrast,Percentage of patients carrying VKORC1-1639 A A and CYP2C9*1*1 in the excessive anticoagulation group was significantly lower than that in the stable anticoagulantion group(50.78%vs 90.00%,P<0.001).Mutations at VKORC1-1639 were associated with high doses of warfarin.Mutations at CYP2C9 were associated with low doses of warfarin.The mean daily warfarin dosage of patients with wild-type patients with VKORC1-1639 in the excessive anticoagulation group was significantly lower than that in the stable anticoagulantion group(2.65±0.92 mg/d,3.01±1.22 mg/d,P=0.02).Conclusion:1.The mutation rate of polymorphic sites of CYP2C9*3 in Chinese Han patients with excessive anticoagulation was significantly higher than those with stable anticoagulantion,in turn,lead to the average daily requirement for warfarin in the excessive anticoagulation population is reduced.Finally,the effect of non-genetic factors on warfarin dose was weakened.2.This study found the genetic basis of excessive anticoagulation,which provides a new idea for the precise treatment of patients with excessive anticoagulation.At the same time,it provides the basis for future prospective validation test and Randomized,Controlled trial of Genotype-guided Warfarin Prescribing for patients with excessive anticoagulation. |
PDF Full Text Request