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Bleeding Risk in Patients With Atrial Fibrillation The AMADEUS Study

CHEST 2011年第1期140卷 146-155页

作者： Lane, Deirdre A. Kamphuisen, Pieter W. Minini, Pascal Buller, Harry R. Lip, Gregory Y. H. Univ Birmingham City Hosp Ctr Cardiovasc Sci Birmingham B18 7QH W Midlands England Univ Amsterdam Acad Med Ctr Dept Vasc Med NL-1105 AZ Amsterdam Netherlands Sanofi Aventis Res & Dev Biostat & Programming Chilly Mazarin France

Objective: This study aimed to assess the impact of combination antithrombotic therapy on stroke and bleeding risk compared with anticoagulation therapy only in patients with atrial fibrillation (AF). Methods: Post hoc analysis of 4,576 patients with AF (mean +/- SD age, 70.1 +/- 9.1 years;men, 66.5%) enrolled in the Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation (AMADEUS) trial were randomized to receive either subcutaneous idraparinux (2.5 mg weekly) (n = 2,283) or dose-adjusted vitamin K antagonists (VKAs) (international normalized ratio, 2.0-3.0) (n = 2,293). Of these patients, 848 (18.5%) received antiplatelet therapy (aspirin, clopidogrel, ticlopidine, etc) in addition to anticoagulation treatment (combination antithrombotic therapy). Results: A total of 572 (15.3% per year) clinically relevant bleeding and 103 (2.6% per year) major bleeding events occurred. Patients receiving combination antithrombotic therapy had a 2.3- to 2.5-fold increased risk of clinically relevant bleeding events and major bleeding events, respectively, compared with those receiving anticoagulation therapy only. Multivariate analyses (hazard ratio, 95% CI) revealed that the risk of clinically relevant bleeding was significantly increased by age 65 to 74 years (1.44, 1.14-1.82) and >= 75 years (1.59, 1.24-2.04, P = .001) and by combination antithrombotic therapy (2.47, 2.07-2.96, P < .0001). The same held true for major bleeding events, with analogous figures for age 65 to 74 years (2.26, 1.08-4.71) and >= 75 years (4.19, 1.98-8.87, P = .0004) and for combination antithrombotic therapy (2.23, 1.49-3.34, P < .0001). Combination antithrombotic therapy was not associated with a decrease in ischemic stroke risk compared with anticoagulation therapy only (11 [1.4% per year] vs 22 [0.7% per year];adjusted hazard ratio, 2.01;95% CI, 0.94-4.30;P = .07). Conclusions: Combination antithrombotic therapy increases the risk of clinically relev

关键词： Aged Anticoagulants/adverse effects Anticoagulants/therapeutic use Atrial Fibrillation/complications Dose-Response Relationship, Drug Drug Therapy, Combination England/epidemiology England/epidemiology Female Hemorrhage/chemically induced Hemorrhage/epidemiology Humans Incidence Injections, Subcutaneous Male Oligosaccharides/administration & dosage Oligosaccharides/adverse effects Platelet Aggregation Inhibitors/administration & dosage Platelet Aggregation Inhibitors/adverse effects Prognosis Risk Assessment/methods Risk Factors Stroke/etiology Stroke/prevention & control Warfarin/adverse effects Warfarin/therapeutic use

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Clinical and Statistical Assessment of Suicidal Ideation and Behavior in Pharmaceutical Trials

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CLINICAL PHARMACOLOGY & THERAPEUTICS 2011年第4期90卷 554-560页

作者： Gassmann-Mayer, C. Jiang, K. McSorley, P. Arani, R. DuBrava, S. Suryawanshi, S. Webb, D. M. Nilsson, M. Johnson & Johnson Pharmaceut Res & Dev LLC Clin Biostat Raritan NJ USA Sanofi Aventis Biostat & Programming Bridgewater NJ USA GlaxoSmithKline Neurosci Med Dev Ctr Stat & Programming Res Triangle Pk NC USA Bristol Myers Squibb Co Global Biometr Sci Pennington NJ USA Pfizer Inc Clin Stat New London CT USA Merck & Co Inc Late Dev Stat Rahway NJ 07065 USA Eli Lilly & Co Global Med Commun Indianapolis IN 46285 USA Eli Lilly & Co Global Stat Sci Steamboat Springs CO USA

In the past two decades, the potential association between the risk of suicidal ideation and behavior and the clinical use of pharmaceutical products has been debated among industry, regulators, and academia. A better understanding of the possible effects-favorable, unfavorable, or neutral-of pharmaceuticals on the risk of suicidal ideation and behavior may be required, especially for trials typically designed for other primary objectives. Here, a cross-industry statistical team provides recommendations that address the assessment, statistical analysis, interpretation, and utility of suicide-related data in pharmaceutical clinical trials. These recommendations are to evaluate suicidal ideation, suicidal behavior, and the two combined as end points;utilize standard scales to collect data prospectively;and analyze the data using several statistical methods. A more accurate assessment of the potential association between the use of pharmaceutical products and risk of suicide-related events will contribute to estimating the benefit/risk ratio and result in safer medicines for patients.

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Sample size considerations for Japanese patients in a multi-regional trial based on MHLW guidance

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PHARMACEUTICAL STATISTICS 2010年第2期9卷 100-112页

作者： Quan, Hui Zhao, Peng-Liang Zhang, Ji Roessner, Martin Aizawa, Kyo Sanofi Aventis Biostat & Programming Bridgewater NJ 08807 USA

Since the publication of the International Conference on Harmonization E5 guideline, new drug approvals in Japan based on the bridging strategy have been increasing. To further streamline and expedite new drug development in Japan, the Ministry of Health, Labour and Welfare, the Japanese regulatory authority, recently issued the 'Basic Principles on Global Clinical Trials' guidance to promote Japan's participation in multi-regional trials. The guidance, in a Q&A format, provides two methods as examples for recommending the number of Japanese patients in a multi-regional trial. Method l in the guidance is the focus of this paper. We derive formulas for the sample size calculations for normal, binary and survival endpoints. Computations and simulation results are provided to compare different approaches. Trial examples are used to illustrate the applications of the approaches. Copyright (C) 2009 John Wiley & Sons, Ltd.

关键词： bridging study ethnic effect delta method survival endpoint risk reduction

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Use of the Average Baseline Versus the Time-Matched Baseline in Parallel Group Thorough QT/QTc Studies

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JOURNAL OF BIOPHARMACEUTICAL STATISTICS 2010年第3期20卷 665-682页

作者： Meng, Zhaoling Quan, Hui Fan, Li Kringle, Robert Sun, Gordon Sanofi Aventis Biostat & Programming Bridgewater NJ 08807 USA

Using historical studies, we compared the impact of using the average baseline or time-matched baseline on diurnal effect correction, treatment effect estimation, and analysis of variance/covariance (ANOVA/ANCOVA) efficiency in a parallel thorough QT/QTc (TQT) study. Under a multivariate normal distribution assumption, we derived conditions for achieving unbiasness and better efficiency when using the average baseline, and confirmed these conditions using historical TQT studies. Furthermore, simulations were conducted under the randomized trial with and without observed imbalanced baseline settings. We conclude that the analyses using average baseline yield better efficiency and unbiased or less biased results under our TQT study conditions.

关键词： ANCOVA ANOVA Bias Diurnal effect correction Efficiency

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Multiple Comparisons in Microarray Data Analysis

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STATISTICS IN BIOPHARMACEUTICAL RESEARCH 2010年第3期2卷 368-382页

作者： Zhang, Donghui Liu, Li Sanofi Aventis Biostat & Programming Bridgewater NJ 08807 USA

Multiplicity is a challenging statistical issue in drug discovery, and a particular example is microarray study. The traditional approach of controlling of the family-wise error rate (FWER) is conservative when the number of tests is large. A more appropriate approach is to control the false discovery rate (FDR). Since the development of the Benjamini and Hochberg (BH) FDR procedure in 1995, many modifications have been proposed aimed at relaxing the requirement for independent test statistics or improving the power of the BH FDR procedure. Comparisons of these procedures in the current literature are not comprehensive and the conclusions on performances are inconsistent. The objectives of this article are three-fold: (a) to perform a more comprehensive comparison of extant multiple testing procedures using two real microarray datasets and various simulated data sets;(b) to explore potential reasons for the inconsistencies in published simulation results;and (c) to identify suitable FDR procedures under different scenarios according to covariance structure, percent of true null hypotheses among multiple tests, and sample size.

关键词： False discovery rate Family-wise error rate Multiple testing

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Letter to the Editor: Revisit the Combination Validation Test of Tsong et al. for Thorough QT/QTc Clinical Trials

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JOURNAL OF BIOPHARMACEUTICAL STATISTICS 2010年第3期20卷 683-687页

作者： Sun, Guowen (Gordon) Quan, Hui Sanofi Aventis Biostat & Programming Bridgewater NJ 08807 USA

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关键词： Editors letter aluminium Clinical Trial Proof testing

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Benefit-Risk Assessments in Dose-Finding Trials

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STATISTICS IN BIOPHARMACEUTICAL RESEARCH 2010年第2期2卷 153-164页

作者： Quan, Hui Wu, Yujun Ren, Haobo Seko, Noriko Bizet, Florence Koch, Gary Sanofi Aventis Biostat & Programming Bridgewater NJ 08807 USA Regeneron Pharmaceut Inc Biostat & Data Management Bridgewater NJ 08807 USA Sanofi Aventis Biostat & Programming Shinjuku Ku Tokyo 1631488 Japan Sanofi Aventis Biostat & Programming F-92165 Antony France Univ N Carolina Chapel Hill NC 27599 USA

The objective of dose-finding trials is to identify the doses that are sufficiently effective and safe for either future late-phase trials or the ultimate patients. Most methodologies for analyzing data from Phase II dose-finding trials mainly focus on finding the effective doses or minimum effective dose through hypothesis testing, while Phase I studies focus on finding the maximum tolerated dose. In this article, we focus on benefit-risk assessment through both hypothesis testing and point estimation. For purposes of efficiency, monotone dose-response relationships will be assumed for the safety parameter. However, the monotone assumption cannot be made directly for the benefit-risk measure. This consideration can limit the use of downward or upward sequential procedures for multiplicity adjustment for benefit-risk assessment. Several different approaches will be discussed and evaluated. Numerical and data examples will be used to illustrate the properties of these approaches.

关键词： Confidence interval Monotone assumption Multiplicity Restricted estimate

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Assessing consistent treatment effect in a multi-regional clinical trial: a systematic review

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PHARMACEUTICAL STATISTICS 2010年第3期9卷 242-253页

作者： Chen, Joshua Quan, Hui Binkowitz, Bruce Ouyang, S. Peter Tanaka, Yoko Li, Gang Menjoge, Shailendra Ibia, Ekopimo Merck Res Labs N Wales PA USA Sanofi Aventis Biostat & Programming Bridgewater NJ USA Celgene Summit NJ USA Eli Lilly Indiapolis IN USA Johnson & Johnson Raritan NJ USA Boehringer Ingelheim GmbH & Co KG Ridgefield CT USA

A key issue in multi-regional clinical trials (MRCTs) is how to assess the consistency of treatment effect across regions, although there is no a priori reason to believe that the treatment effect should vary across the regions. In this article, we define the research question as an assessment of overall consistency across all regions for which all regions are considered equally important. This is different from the region/country-specific analyses (e. g. US vs Non-US), which are frequently requested by local regulatory agencies and usually performed for multiple agencies. We provide a systematic review of methods that may potentially be used for assessing consistency across regions, including commonly used quantitative/qualitative interaction tests, Japanese Pharmaceutical Medical Device Agency (PMDA) Methods 1 & 2, and those proposed for different purposes (e. g. bridging studies, meta-analysis, and vaccine lot consistency, among others). These methods are classified into three groups: global methods, multivariate quantitative methods, and multivariate qualitative methods. A case study is used to illustrate these methods. We also provide recommendations on how to choose appropriate methods and incorporate them in the study design. Copy right (C) 2010 John Wiley & Sons, Ltd.

关键词： multi-regional clinical trial consistency heterogeneity quantitative qualitative

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Assessment of Consistency of Treatment Effects in Multiregional Clinical Trials

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DRUG INFORMATION JOURNAL 2010年第5期44卷 617-632页

作者： Quan, Hui Li, Mingyu Chen, Joshua Gallo, Paul Binkowitz, Bruce Ibia, Ekopimo Tanaka, Yoko Ouyang, Soo Peter Luo, Xiaolong Li, Gang Menjoge, Shailendra Talerico, Steven Ikeda, Kimitoshi Sanofi Aventis Biostat & Programming Bridgewater NJ 08807 USA Boehringer Ingelheim GmbH & Co KG Ingelheim Germany

Multiregional clinical trials (MRCTs) present great opportunities but also challenges to the trial community. To address the challenges and fully realize the opportunities, a PhRMA MRCT Cross-Functional Key Issue Team (KIT) was formed in 2008. One of the work streams within the KIT particularly focuses on the assessment of consistency of treatment effects across regions. As the main objective of this work stream, this research explores a number of definitions for consistency assessments. We address the issues primarily for superiority trials with continuous endpoints, then extend briefly to noninferiority trials, random effect models, binary endpoints, and survival endpoints. Computations and simulations are used to study the properties of the proposed definitions, particularly the power for showing consistency. To illustrate applications of the methods, we use a trial example with a continuous endpoint. We discuss considerations for trial design as well as for data analysis. The consistency assessment relies heavily on the definition of regions and the number of regions. We recommend working with health authorities to define region in a manner that is sensible from a practical interpretation standpoint and also makes region consistency assessment a feasible undertaking.

关键词： Ethnic effect Sample size Power Noninferiority Interaction Random effect model

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Multiplicity Adjustment for Clinical Trials With Two Doses of an Active Treatment and Multiple Primary and Secondary Endpoints

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STATISTICS IN BIOPHARMACEUTICAL RESEARCH 2009年第3期1卷 258-267页

作者： Quan, Hui Capizzi, Thomas Zhang, Ji Sanofi Aventis Biostat & Programming Bridgewater NJ 08807 USA Schering Plough Corp Biostat & Data Management Kenilworth NJ 07033 USA Sanofi Aventis Int Clin Operat Bridgewater NJ 08807 USA

Frequently, two doses of an active treatment, multiple primary and secondary endpoints are simultaneously considered in Phase III confirmatory clinical trials. For these trials, many traditional multiplicity adjustment procedures do not take into account the possible dose effect on each endpoint and the priority order of the primary and secondary endpoints, and therefore may have lower power. To gain power, we consider the problem as a three-dimensional multiplicity problem: one dimension concerns the multiple doses, one dimension concerns the priority order of the primary and secondary endpoints, and another dimension concerns the multiple endpoints in each priority category. We propose procedures that consider the dose order and the priorities of the endpoints to form closed procedures and therefore control the family-wise error rate. Furthermore, we consider procedures that provide control of type I error rates in clinically relevant subfamilies of comparisons, providing a pragmatic approach to maintain study power as compared to the traditional approaches for the ultimate overall strong control. Simulation results and a real data example show that the procedures proposed in this article in general are easy to use and have improved power.

关键词： Closed procedure Family-wise error rate Gatekeeping procedure Strong control

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