| BackgroundWarfarin is the oldest oral anticoagulants, widely used in a variety of thrombus embolism in the anticoagulant treatment, mainly including treatment and prevention of deep vein thrombosis or pulmonary embolism or prevention of systemic embolism or stroke in patients with prosthetic heart valves or atrial fibrillation. But there are some problems exist in the clinical use of warfarin:narrow therapeutic index, frequent blood tests, dose requirement varies widely among patients, influenced by many factors and so on. How to achieve the stable dose safely and quickly has always been the hot spot of the anticoagulant research.With the progress of pharmacogenomics research in warfarin, in order to apply individualization and to reduce the occurrence of adverse reactions, more and more researchers had involved into the stable warfarin dose prediction model study. Many kinds of prediction models had published till now. The variables of these models, which can explain about 40%～70% of warfarin dose differences, include genetic information and non-genetic information (gender, age, height, weight, race, and drug combination, etc.).Vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 isoenzyme 2C9 (CYP2C9) gene polymorphism are the two major genetic factors which influence the stable dose of warfarin.At present, there are few warfarin dose prediction models for Chinese patients, but the sample size is small and without large scale validation. We (key laboratory of clinical trial research in cardiovascular drugs, clinical pharmacology center, Fuwai hospital) had established an model named Fu-Hua2 algorithm to predict the warfarin maintenance dose in Chinese population and had been preliminarily validated.This study is to compare the performance of. Fu-Hua2 algorithm with other models in Chinese patients with heart valvular replacementPurpose:1. To validate the performance of our Fu-Hua2 algorithm, compare the predict dose with the stable average daily dose of warfarin in Chinese patients undergoing heart valve replacement (HVR).2. To compare the performance of our Fu-Hua2 algorithm with previously published warfarin dose algorithms in Chinese patients with heart valve replacement (HVR).Methods:From September in 2014 to September in 2015, one thousand two hundred and thirty four inpatients in Fuwai hospital with prosthetic heart valves were enrolled who had achieved stable warfarin dose and accept the treatment of warfarin for at least 2 months.Validate the accuracy of Fu-Hua2 algorithm by comparing the predicted dose with actual stable average daily dose. A search was made in the Pubmed, Medline and Embase database for previously published warfarin dosing algorithms after 2004. Performance of each of the selected algorithms was determined using mean absolute error (MAE) and percentages of under, ideal and over predictions.Trial registration:Identifier NCT01855737.Results:There were 1234 subjects included in this trial. All the patients have reached stable warfarin dose, including 613 male patients (48.6%) and 621 female patients (49.2%). The average age of all patients is of 53.9±1.379 years old. Warfarin daily dose was 3.17±1.24 mg/d.This study shows that:VKORC1-1639 AA, GA, GG genotype frequency are 83.310%,15.64% and 1.05% respectively; at least more than 83.31% patients carried CYP2C9* 3 genotype; CYP4F2 CC, CT and TT genotype frequency of patients were 54.05%,37.76% and 8.18% respectively. The above results are similar to genotype distribution, frequency of Chinese population in other literature.The gene polymorphism of VKORC1 and CYP2C9 is the main factors affecting warfarin stable average daily dose of patients after heart valve replacement in our country, and the influence degree of the VKORC1 gene polymorphism is greater than the CYP2C9. Without considering the effects of CYP2C9 gene polymorphism, the patieants who carry at least one VKORC1-1639 G allel mutation can increase about 82.7% warfarin stable daily dose than VKORC1-1639AA. And without considering the effects of VKORC1 gene polymorphism, the patieants who carry at least one CYP2C9* 3 gene variant can lower 28%. warfarin stable average daily dose than wild type CYP2C9*1/* genotype patients.A total of 13 previously published stable warfarin dosing algorithms were enrolled in this trial. The lowest absolute MAE value were calculated from IWPC、 Ohno and Fu-Hua2 model,0.06 mg/d,0.07 mg/d and 0.13, mg/d respectively, which indicate the predict dose of these models are close to the actual stable warfarin dose. The percentages of ideal prediction calculated from Fu-Hua2(61.02%,)、Gage (59.56%)、Huang (59.56%)、IWPC(57.86%)and Ohno(57.46%) algorithm were higher than others. And.the percentage of under prediction is less than its percentage of over prediction in most of the prediction model of warfarin. was undervalued predicted its overestimate predicted percentage, that’s to say,the predict dose computed from these algorithms are more likely to be higher than actual stable dosage.Conclusions:1. The predict dose of Fu-Hua2 algorithm is close to actually stable dose of warfarin;2. Compared with other algorithms, Fu-Hua2 have a good value in predicting warfarin dose for Chinese patients who underwent heart valve replacement.BackgroundHeart rate (HR) is an important treatment target for chronic stable angina pectoris (CSAP).The effect of beta-blocking agents on prognosis can be largely accounted for by HR reduction. In addition to lowering HR, anti-angina drugs such as β-blockers can produce side effects of affecting the atrioventricular conduction and potential induced asthma.Ivabradine (Iva), member of a novel class of HR-slowing drugs, has highly specific inhibitory action on the If channel. In a double-blind, placebo-controlled trial, Iva (2.5,5, or 10 mg BID) produced a dose-dependent HR reduction and improved exercise tolerance. Iva has also been demonstrated to exert equivalent dose-dependent anti-anginal efficacy compared with Atenolol (Aten) and Amlodipine, and can produce additional efficacy when combined with Aten.Iva was approved by the European Medicines Evaluation Agency (EMEA) to trea CSAP in patients with a normal heart rhythm. This medicine is used when beta-blockers are unsuitable, or cause unacceptable side effects.The brand drug is not available in china. Domestic pharmaceutical companies had synthesized to produce waiting to be approved. This can significantly reduce costs provide more choices for patients. Our trial is registered in China Food and Drug Administration (CFDA) for the drug to come into market aim to demonstrate non-inferiority in efficacy and safety of Iva compared with Aten in Chinese CSAP patients.Purpose:To assess whether the efficacy and safety of Iva (5,7.5 mg) non-inferiority to Aten (12.5,25mg) in Chinese patients with chronic stable angina pectoris.Methods:This is a randomized, double-blind, double-dummy, multicentered, active-controlled, parallel-arm phase Ⅱ clinical trial, conducted between October 2009 and July 2012.Patients with symptomatic angina pectoris and positive exercise tolerance test (ETT) were randomized into the Iva (5 mg BID) or Aten group (12.5 mg BID) according to computer-generated random numbers for 4 weeks.Adjusted the dose according to ETT test results and heart rate after 4 weeks, either continued to use the original dose (Iva group,5 mg bid; Atenl group,12.5 mg bid) or increased the dose (Iva group,7.5 mg bid; Aten group,25 mg bid) and then continue the treatment for 8 weeks.Results:Actually there were 332 patients (Iva group n=166; Aten group n=166) included in the final statistics.In full analysis set, increases in the total exercise duration (TED) were 54.3±120.1 s with Iva 5 mg and 58.8±114.7 s with Aten 12.5 mg at fourth week, and, at 12th week, TED improved by 84.1±130.5s with Iva and 77.8±126.6 s with Aten (95% CI:-21.4～ 34.1s, p=0.0011 for non-inferiority). The analysis of per protocol set yielded similar results (95% CI:-31.4～33.0 s,p=0.0131 for non-inferiority)..No significant differences were found in time to 1 mm ST depression (TST) between the two groups. The depression of maximal HR and rate-pressure product (RPP) at week 12 presented marked changes within groups comparing with baseline (no significant difference between groups). The number of angina attacks and consumption of nitroglycerin both showed a general trend of reduction (p>0.05). HR was reduced in both groups at rest and during peak exercise.There were small, non-significant differences in the number of adverse events between the two groups (66 in Iva,73 in Aten, p> 0.05). Nine patients (5.42%) were reported to develop phosphenes/luminous phenomena and blurred vision in Iva group (p = 0.0035). And the incidence of moderate bronchospasm was 0.6% in Aten group.Iva had no significant impact on blood pressure and the corrected QT interval (QTc)Conclusions:Iva is effective in reducing heart rates and coronary patients can enjoy a number of clinical benefits from pure heart rate reduction. The efficacy of Iva is non-inferior to Aten Chinese patients with CSAP, as reported previously. Iva is well tolerated and safeTrial registration:Identifier ACTRN12613000354785. |
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