Biomedical subjects

Michel Cucherat

Publications and source records attributed to Michel Cucherat.

29 records · Page 2Linked to original sources

PubMed2003

The assessment of deep vein thromboses for therapeutic trials.

In the current paper, we provide recommendations for the assessment of deep vein thromboses for the purpose of therapeutic trials evaluating antithrombotic drugs in the prevention of deep venous thrombosis. We have reviewed recently published articles on diagnostic and therapeutic studies, and we have evaluated methods of assessments. Ascending venography has been considered as the reference test for the confirmation of DVT. A roentgenographic image is subsequently available for review and allows classification by blinded, objective observers. However, venography poses substantial clinical and methodological limitations, particularly in the setting of systematic screening for all patients enrolled in a randomized clinical trial. Compression ultrasonography may replace venography for systematic screening of DVT in clinical trials, provided that specific methodological details are specified in the protocol and are fulfilled to ensure high and comparable sensitivity and specificity from all participating centers. This non-invasive technique has virtually no contraindications, and therefore more patients can be enrolled and evaluated. Furthermore, the compression ultrasonograph can be videotaped for central reading. Compression ultrasonography has already been adopted as the principal method for evaluating DVT in several ongoing large scale prevention trials with the approval of major drug agencies.

Clinical Trials as Topic↗

PubMed2003

Pharmacogenetics and responders to a therapy: theoretical background and practical problems.

In a narrow meaning, responders to a therapy are all those who will react as expected following the administration of this therapy. However, a wider definition is worth considering: all those for whom the administration of the therapy will be beneficial. Innovative therapies are increasingly expensive and hazardous, and limiting prescriptions to responders is both economically and ethically compulsory. The theoretical basis for such an approach exists. The process of defining the profile of responders consists of identifying the characteristics of the patients that interact with the size of the effect and integrating them quantitatively in a predictive model. The effect model, which is the relation between the risks of the event with and without the treatment, can be used for the prediction. It can integrate interactions of the efficacy with risk factors and/or genes. The data to be used to achieve both the identification of the interactions and the building of the predictive model are those from the studied population, the set of patients enrolled in clinical trials. Hence, the process of defining the therapy is an extrapolation from the studied population. To carry out the extrapolation process one can use various available techniques, of which none fully fits the purpose. No method is currently both fully adequate and validated. Finally, the predictive models, which we need to identify responders, do not exist in practice. Fortunately, new research approaches have been developed recently.

Humans↗

PubMed2003

Getting evidence to prescribers and patients or how to make EBM a reality.

Bringing all available evidence on therapy efficacy to users is a necessary step in the evidence-based medicine paradigm. Today, the needs of physicians in medical information, including therapeutic information, are not met. Further, the information reaching the doctors is rarely consistent with the available evidence. The growth rate of emerging evidence and its increasing complexity make the doctors unable to cope with it within the current medical information system. So, there is a real need to sort out a new way for transferring therapeutic information to doctors and patients. We conceived a new paradigm and designed an Internet process based on it by which unbiased evidence is brought to doctors in such a format that it can be accessed and used during the visit.

Decision Support Systems, Clinical↗

PubMed2002

Pooling, meta-analysis, and the evaluation of drug safety.

BACKGROUND: The "integrated safety report" of the drug registration files submitted to health authorities usually summarizes the rates of adverse events observed for a new drug, placebo or active control drugs by pooling the safety data across the trials. Pooling consists of adding the numbers of events observed in a given treatment group across the trials and dividing the results by the total number of patients included in this group. Because it considers treatment groups rather than studies, pooling ignores validity of the comparisons and is subject to a particular kind of bias, termed "Simpson's paradox." In contrast, meta-analysis and other stratified analyses are less susceptible to bias. METHODS: We use a hypothetical, but not atypical, application to demonstrate that the results of a meta-analysis can differ greatly from those obtained by pooling the same data. In our hypothetical model, a new drug is compared to 1) a placebo in 4 relatively small trials in patients at high risk for a certain adverse event and 2) an active reference drug in 2 larger trials of patients at low risk for this event. RESULTS: Using meta-analysis, the relative risk of experiencing the adverse event with the new drug was 1.78 (95% confidence interval [1.02; 3.12]) compared to placebo and 2.20 [0.76; 6.32] compared to active control. By pooling the data, the results were, respectively, 1.00 [0.59; 1.70] and 5.20 [2.07; 13.08]. CONCLUSIONS: Because these findings could mislead health authorities and doctors, regulatory agencies should require meta-analyses or stratified analyses of safety data in drug registration files.

Editorial↗

PubMed2002

Which coding system for therapeutic information in evidence-based medicine.

The coding of information in the computer representation of clinical trials is essential both for the rationalisation of the activities involved in the production of therapeutic information for evidence-based decision support and for the integration of the messages produced by these activities with clinical information and electronic patient record systems. There is no standard coding system available, however, so building on existing evaluations, we performed a simple semi-quantitative evaluation of ICD-10, CDAM, MEDDRA, MESH, READ, SNOMED and UMLS to provide objective criteria for the choice of a coding system. Inclusion and exclusion criteria for four clinical trials recorded in TriSum constituted the corpus of evaluation texts. Criteria included coding coverage, size, integration and language coverage. The results of the comparison lead us to choose SNOMED as the most appropriate coding system for our needs. The absence of a European Medical Language System project is observed, as is the need for combinatorial as opposed to enumerative systems.

Clinical Trials as Topic↗

PubMed2002

Bisoprolol for the treatment of chronic heart failure: a meta-analysis on individual data of two placebo-controlled studies--CIBIS and CIBIS II. Cardiac Insufficiency Bisoprolol Study.

BACKGROUND: Despite the available evidence from randomized clinical trials, beta-blockers are often not used optimally in patients with congestive heart failure (CHF). This meta-analysis aims at providing a precise and quantitative estimate of the benefit and risks of long-term bisoprolol on major clinical events in patients with CHF, both overall and in selected subgroups. This may help clinicians in their decisions as to whether to prescribe bisoprolol for their individual patients. METHODS: Meta-analysis was performed of results from the 2 randomized, controlled clinical studies in which bisoprolol was compared with placebo (Cardiac Insufficiency Bisoprolol Study [CIBIS and CIBIS II]), which included 3288 patients with proven CHF. The main outcomes were total death, cardiovascular death, sudden death, hospitalization for heart failure, and myocardial infarction. RESULTS: A highly significant 29.3% relative reduction of death (17%, 40%; P =.00003) was observed, as well as significant risk reduction in cardiovascular death and sudden death in favor of bisoprolol. Also, a highly significant relative reduction of 18.4% (25%, 11%; P =.00001) in hospital admission or death was observed. A similar relative reduction of death was consistently observed in selected subgroups of patients. CONCLUSIONS: Bisoprolol prevents major cardiovascular events in patients with CHF with a high benefit-to-risk ratio and can be recommended for these patients.

Adrenergic beta-Antagonists↗

PubMed2002

Physiologically based model of acute ischemic stroke.

In the treatment of acute ischemic stroke most of the clinical trials have failed, contrasting with promising results in the preclinical stages. This continuing discrepancy suggests some misconceptions in the understanding of acute ischemic stroke. One possible method for identifying the shortcomings of present-day approaches is to integrate all the available knowledge into a single mathematical model and to subject that model to challenges via simulations with available experimental data. As a first stage, then, the authors developed a simplified model, defining the structure and the different parameters that represent the phenomena that occur during the hyperacute phase of ischemic stroke. First, the different critical points of the evolution of ischemic stroke, based on the available evidence on the pathophysiology of stroke, were identified. Those key steps were then related to the quantitative data obtained by magnetic resonance imaging and positron emission tomography scan. These two techniques allow the measurement of diverse key markers of cerebral metabolism: cerebral blood flow (CBF), oxygen extraction factor, cerebral metabolism rate of oxygen, and the apparent diffusion coefficient of water, among others. Those markers were organized together through mathematical equations, and changed over time in order to describe the evolution of an acute ischemic stroke. At each time during the evolution of stroke those parameters are summarized in a parameter called survival delay. This parameter made possible the definition of three different states for tissues-functional, infarcted, salvageable-as end point. Once the model was designed, simulations were performed to explore its internal validity. Simulation results were consistent with the reality of acute ischemic stroke and did not reveal any major drawbacks in the use of the model. The more rapid the decrease in CBF, the larger is the final infarcted area. The model also allowed for the characterization of two types of tissue in the penumbra: tissues with an initial metabolic impairment and tissues altered owing to the closeness of the ischemic area. The results of this experiment were consistent with what is known of acute ischemic stroke. The model integrated different markers of acute ischemic stroke into a single entity in order to mimic acute ischemic stroke, and has been shown to have a reasonable degree of internal validity.

Animals↗

PubMed2002

Questionnaire color and response rates to mailed surveys. A randomized trial and a meta-analysis.

The authors conducted a randomized trial in Geneva, Switzerland, to assess whether response rates to a mailed survey could be increased by printing the questionnaire on green paper. The authors also conducted a meta-analysis of 10 experimental studies that tested the effect of colored questionnaires on response rates. The randomized trial showed no effect (relative risk of responding [RR] = 1.00). The meta-analysis showed that mailing questionnaires on pink paper increased response rates by 12% (RR = 1.12, 95% confidence interval = 1.01 to 1.25, p = 0.04). Other colors had no statistically significant effect (blue: RR = 1.03, p = 0.49; green: RR = 1.02, p = 0.23; yellow: RR = 0.96, p = 0.30). Overall, using colored instead of white paper had no effect (RR = 1.02, p = 0.17). Thus, printing questionnaires on colored paper does not substantially increase response rates in surveys, except for pink paper.

Adult↗

PubMed2002

Effects of L-carnitine supplementation in maintenance hemodialysis patients: a systematic review.

There are many causes for carnitine depletion during maintenance hemodialysis. Supplementation with L-carnitine in animals has been associated with improvement in some abnormalities also present in chronic renal failure. However, it is still controversial whether restoring plasma or tissue carnitine will correct clinical or biologic symptoms observed in maintenance hemodialysis. A systematic review is here performed to determine the effects of L-carnitine in maintenance hemodialysis patients. Eighty-three prospective trials were identified from 1978 to 1999 in which L-carnitine was randomly allocated in 21 trials. Change in serum triglycerides, cholesterol fractions, hemoglobin levels, erythropoietin dose, and other symptoms (muscle function, exercise capacity, and quality of life) were examined. A total of 482 patients in 18 trials were considered for analysis. There was no effect of L-carnitine on triglycerides, total cholesterol, or any of its fractions. Before the erythropoietin (EPO) era, L-carnitine treatment was associated with improved hemoglobin (P < 0.01) and with a decreased EPO dose (P < 0.01) and improved resistance to EPO when patients routinely received EPO. Muscle function, exercise capacity, and quality of life could not be reliably assessed because of the noncombinable nature of end points and the limited number of trials. In conclusion, L-carnitine cannot be recommended for treating the dyslipidemia of maintenance hemodialysis patients. By contrast, this review suggests a promising effect of L-carnitine on anemia management. The route of L-carnitine administration should be evaluated because there is no evidence as to the most efficient method of administration in maintenance hemodialysis.

Anemia↗

PubMedDate not supplied

Clinical trial simulation in drug development.

The simulation of therapeutic models and clinical trial simulation have recently attracted attention as emerging techniques for developing new active molecules and the exploration of possible clinical trial results. Such approaches have benefited from fundamental progress in the development of 'in silico' models, as well as progress in nonlinear mixed-effect pharmacokinetic-pharmacodynamic models. Mixing the two approaches allows simulation of 'virtual' patients, who receive virtual treatments or placebo. These have various uses, such as proof of concept, decision analysis or experimental design optimisation. Also, the effect of departures from protocol on clinical trial results can easily be evaluated by the use of simulation. This technique is now implemented by the pharmaceutical industry for optimising phase II and III experimental designs when a good biomarker or a clinical outcome model is available, but the use of an in silico therapeutic model as a proof of concept is only just beginning. In order to see such methodologies used more widely in drug development, multidisciplinary efforts need to be initiated, new modelling and simulation tools developed, and sound modelling and simulation practice documents need to be adopted. A reduction in the number of failed clinical development projects, the number of negative phase II and III clinical trials, or in just their cost and duration, are among the expected benefits of modelling and simulation in clinical drug development.

Clinical Trials as Topic↗

PubMedDate not supplied

[New approaches in pharmacology: numerical modelling and simulation].

The complexity of pathophysiological mechanisms is beyond the capabilities of traditional approaches. Many of the decision-making problems in public health, such as initiating mass screening, are complex. Progress in genomics and proteomics, and the resulting extraordinary increase in knowledge with regard to interactions between gene expression, the environment and behaviour, the customisation of risk factors and the need to combine therapies that individually have minimal though well documented efficacy, has led doctors to raise new questions: how to optimise choice and the application of therapeutic strategies at the individual rather than the group level, while taking into account all the available evidence? This is essentially a problem of complexity with dimensions similar to the previous ones: multiple parameters with nonlinear relationships between them, varying time scales that cannot be ignored etc. Numerical modelling and simulation (in silico investigations) have the potential to meet these challenges. Such approaches are considered in drug innovation and development. They require a multidisciplinary approach, and this will involve modification of the way research in pharmacology is conducted.

Animals↗