Objective: Sudden cardiac death (SCD) is at the first rank of cardiovascular death causes in patients with type 2 diabetes (T2D). ACEIs and statins, but not antidiabetic agents were known to be effective in preventing this accident in these patients, until the EMPAREG OUTCOME trial. This study reported a significant protective effect on SCD by empagliflozin, a hypoglycemic drug inhibiting sodium–glucose cotransporter. We aimed here to estimate the public health impact of this tri-therapy in preventing SCD in a French type 2 diabetic virtual realistic population (VRP).Design and method: The steps of our approach were (i) developing a refined scoring scheme for calculating the risk of SCD in T2D, using logistic regression model on individual data of 21 036 men and 9 524 women (age ranged from 35 to 98 years) from 7 RCTs (INDANA database and DIABHYCAR trial); (ii) estimating the risk reduction on SCD in T2D by ACEI and statin through existing meta-analyses and by gliflozin from EMPAREG OUTCOME trial; and finally (iii) integrating the results obtained on a VRP generated from real French cohorts with risk-based patient selection and different therapeutic strategies. Results: A French diabetic RVP of 176 187 was generated from a 8 995-patient sample, giving median of SCD risk of 1.7% at a 5-year time horizon. A simulation of public health impact in this platform estimated the numbers needed to treat (NNTs) of 110 people when whole population was treated and of 52 people when treatment was focused in 10% of patients with highest estimated SCD risk, simultaneously by statin, ACEI and empagliflozin for one year (Tab 1). Conclusions: Our results suggested that the largest strategy by this tri-therapy would prevent 1 SCD every year among 110 patients at possible SCD risk. However, interaction between concerned drugs should be further verified. On the other hand, we confirmed here the feasibility of our approach to simulate impact of various drugs strategies. This could be an innovative tool to base public health strategies and help individual decision-making.

L’épilepsie est une maladie chronique qui a de nombreuses conséquences sociales et psychologiques. La recherche sur la qualité de vie des patients épileptiques se caractérise par de nombreuses méthodes d’évaluation. La qualité de vie des patients épileptiques est moins bonne que celle de la population générale. Elle est comparable ou moins bonne que celle des patients souffrant d’autres maladies chroniques. Mais la qualité de vie des patients dont les crises sont bien contrôlées est comparable à celle des personnes en bonne santé. La fréquence des crises est un des facteurs déterminants de la qualité de vie. Être libre de crises est une condition nécessaire mais non suffisante pour avoir une bonne qualité de vie. La qualité de vie est moins bonne s’il existe une co-morbidité comme la dépression. L’impact du traitement chirurgical sur la qualité de vie est positif quelque soit l’âge, si les crises cessent. Il est difficile d’analyser l’impact des traitements médicaux sur la qualité de vie. A cause du manque d’approche standardisée, synthétiser la littérature dans ce domaine demeure un exercice difficile.Epilepsy is a chronic condition with numerous social and psychological consequences. Research on quality of life in epilepsy is characterized by different kind of methodology.Quality of life is worse in epileptic patients than in the general population. Quality of life is also comparable or worse in epileptic patients than in patients with other chronic conditions. But quality of life in well-controlled epileptic patients is similar to quality of life in healthy persons. Frequency of seizures seems to be one of the most relevant determinants of poor quality-of-life scores. Being seizure free is a necessary but not sufficient condition to have a good quality of life. Quality of life is worsened by the co-existence of depression. The impact of surgical treatment on quality of life is positive, in all ages, in correlation with seizure control. It is difficult to analyze the impact of drug therapy on quality of life. Because of the lack of a standardized approach summarizing the literature in the field remains extremely difficult.

Il n'y a pas de bonne définition de l'innovation thérapeutique. Dans le domaine du cancer du poumon, il semble bien que ce soit la quantité de vie gagnée qui définisse le mieux l'innovation thérapeutique pour le grand public comme pour les professionnels de santé. Les médicaments doivent subir un développement long et multi-étape pour arriver jusqu'à leur autorisation de mise sur le marché (AMM). Ce développement est très coûteux pour les industriels, et l'innovation thérapeutique pèse lourd économiquement pour la société, du fait du remboursement des traitements. Le concept de thérapeutique ciblée couplée à son biomarqueur prédictif a permis de rationaliser et de raccourcir les délais d'obtention des AMM, mais le nivolumab, anticorps anti-PD1, a obtenu très rapidement son AMM dans le traitement des carcinomes épidermoïdes, sans la nécessité d'un biomarqueur prédictif. Les agences de régulation ont également mis en place des procédures d'évaluation accélérée des molécules, comme les AMM conditionnelles. L'explosion des techniques de biologie moléculaire a aussi permis de découvrir un grand nombre d'addictions oncogéniques rares, mais parfois partagées par différents cancers, menant à de nouvelles sortes d'essais thérapeutiques de type basket, afin d'en évaluer l'efficacité. Finalement, la France propose des dispositifs réglementaires uniques à travers ses autorisations temporaires d'utilisation (ATU) et recommandations temporaires d'utilisation (RTU) pour offrir à tous – ou presque – un accès aux innovations thérapeutiques.There is no good definition of therapeutic innovation. In the field of lung cancer, it seems that it is the amount of life gained that best defines therapeutic innovation for the public and for healthcare professionals. The drugs must undergo a long and multi steps development to reach their marketing authorization. Such development is very costly for industrial and therapeutic innovation weighs heavily on societal expenses, due to reimbursement of treatment. The concept of targeted therapy coupled with its predictive biomarker has streamlined and shorten delays in obtaining marketing authorization, but nivolumab – an anti-PD1 antibody, got rapidly its authorization in the treatment of squamous cell carcinoma, without any predictive biomarker. Regulatory agencies have also introduced accelerated assessment procedures, such as conditional marketing authorization. The explosion of molecular biology techniques has also uncovered a large number of rare oncogenic addictions, but sometimes shared by different cancers, leading to new types of therapeutic trials, such as "basket" trials, to evaluate their efficacy. Finally, France offers a unique regulatory system through their autorisations temporaires d'utilisation (ATU) and recommandations temporaires d'utilisation (RTU) to provide for all – or nearly all – access to therapeutic innovations.

L'information tirée de données obtenues à partir des empreintes de pieds est une composante utile, fiable et objective de l'évaluation des patients présentant une pathologie musculosquelettique. Les paramètres spatiaux habituels extrapolés à partir de telles données incluent l'angle (angulation) et l'appui de la marche. Une recherche antérieure a décrit une méthode fiable d'analyse des données obtenues à partir des empreintes de pieds dynamiques. Bien que ces dernières demeurent fondamentales, peu ou pas d'études ont documenté la comparaison des empreintes de pieds dynamiques et des empreintes de pieds statiques. L'objet de cette étude était d'établir les différences entre l'angle et l'appui de la marche tirées de données obtenues à partir d'empreintes de pieds dynamiques ou statiques. Vingt-cinq sujets ont fourni trois empreintes de pieds dynamiques (analyse de la demi-marche) et trois empreintes de pieds statiques. La fiabilité intrinsèque de la technique de mesure de l'angle et de l'appui de la marche s'est avérée excellente (p > 0,001) pour les deux états (dynamique et statique). Les comparaisons entre l'état dynamique et l'état statique ont révélé qu'il n'y avait pas de différences significatives (p < 0,0001) en ce qui concernait l'angle de marche alors que l'on pouvait remarquer des différences significatives entre l'état statique et l'état dynamique en ce qui concernait l'appui de la marche. Une analyse plus poussée utilisant une régression linéaire a montré que l'angle de la marche pour le pied gauche et pour le pied droit prédisait une situation dynamique à 67 et 60 % ; une prédiction légèrement plus faible de 54 % a été remarquée pour l'appui de la marche. Ces résultats suggèrent que les empreintes de pieds statiques montrent une certaine prédiction de la fonction dynamique lorsque l'on évalue l'angle et l'appui de la marche chez les sujets normaux.Information derived from footprint data serves as a useful, reliable and objective component to the assessment of patients with musculoskeletal pathology. Common spatial parameters extrapolated from such data include the angle and base of gait. Previous research has described a reliable method for analysing dynamic footprint data. While this data remains fundamental, few studies, if any have documented the comparisons of dynamic and static footprints. The purpose of this study was to ascertain the differences between the angle and base of gait from dynamic and static footprint data. Twenty-five subjects provided three dynamic (mid-gait analysis) and three static footprints. Intra-rater reliability of the measurement technique for both the angle and base of gait was found to be excellent (P >0.001) for each of the two conditions (dynamic and static). Comparisons between the dynamic and static condition revealed no significant differences (P <0.0001) for the angle of gait, whilst significant differences were noted between the static and dynamic condition for the base of gait. Further analysis using linear regression identified that the angle of gait for the left and right foot predicted a 67 and 60% of that of a dynamic situation; a slightly lower prediction of 54% was noted for base of gait. These results suggest that static footprints do demonstrate some prediction of dynamic function when assessing the angle and base of gait in normal subjects.

INTRODUCTION:Equivalence trials are actually frequently used to prove non-inferiority in anticoagulant therapy. Equivalence trials consist to demonstrate that two treatments are not too much different. This difference has to be under a margin previously determined. The margin corresponds to an efficacy loss that is defined to be acceptable, in accordance to the advantages due to the new treatment. The aim of this work is to explore the equivalence trial published in the thromboembolic disease by focus on the non-inferiority margin used.METHODS:We identified published equivalence trials in the venous thromboembolic disease, by a systematic search in Medline. We calculated the efficacy loss by reference with the value of the smallest effect size of the standard treatment compared to placebo.RESULTS:We found 9 equivalence trials used in venous thromboembolic disease. The mean value of the efficacy loss was 434%, and the median value was 357%. Eighty-five percent of the values of the efficacy loss were above 100%.DISCUSSION:Eighty-five percent of the equivalence trials conclude to equivalence despite a complete efficacy loss of the effect of the standard treatment compared to placebo. The results of equivalence trials should be interpreted warily. The corresponding non-inferiority margin should be chosen more rigorously and by reference with the value of the smallest effect size of the standard treatment compared to placebo.

Introduction. - Equivalence trials are actually frequently used to prove non-inferiority in anticoagulant therapy. Equivalence trials consist to demonstrate that two treatments are not too much different. This difference has to be under a margin previously determined. The margin correspends to an efficacy loss that is defined to be acceptable, in accordance to the advantages due to the new treatment. The aim of this work is to explore the equivalence trial published in the thromboembolic disease by focus on the non-inferiority margin used.Methods. - We identified published equivalence trials in the venous thromboembolic disease, by a systematic search in Medline. We calculated the efficacy loss by reference with the value of the smallest effect size of the standard treatment compared to placebo.Results. - We found 9 equivalence trials used in venous thromboembolic disease. The mean value of the efficacy loss was 434%, and the median value was 357%. Eighty-five percent of the values of the efficacy loss were above 100%.Discussion. - Eighty-five percent of the equivalence trials conclude to equivalence despite a complete efficacy loss of the effect of the standard treatment compared to placebo. The results of equivalence trials should be interpreted warily. The corresponding non-inferiority margin should be chosen more rigorously and by reference with the value of the smallest effect size of the standard treatment compared to placebo. (c) 2007 Elsevier Masson SAS. Tous droits reserves.

With the aim of inhibiting cancer growth and reducing the risk of metastasis, pharmaceutical companies in the early 1990s developed anti-metastatic agents called inhibitors of metalloproteinases (MMPi). Despite the promising results obtained in pre-clinical studies, results of Phase III trials have been somewhat disappointing for late stage cancer patients. With the aim of mathematically investigating this therapeutic failure, we developed a mechanistically based model which integrates cell cycle regulation and macroscopic tumor dynamics. By simulating the model, we evaluated the efficacy of MMPi therapy. Simulation results predict the lack of efficacy of MMPi in advanced cancer patients. The theoretical model may aid in evaluating the efficacy of anti-metastatic therapies, thus benefiting the design of prospective clinical trials.

1Service de Biostatistique, Hospices Civils de Lyon, Lyon, France 2EA3736 Universite Claude Bernard Lyon I, Lyon, France 3Medical Statistics Unit, London School of Hygiene and Tropical Medicine, London, UK

1Service de Biostatistique, Hospices Civils de Lyon, Lyon, France 2EA3736 Universite Claude Bernard Lyon I, Lyon, France 3Medical Statistics Unit, London School of Hygiene and Tropical Medicine, London, UK

Population pharmacokinetic analysis is being increasingly applied to individual data collected in different studies and pooled in a single database. However, individual pharmacokinetic parameters may change randomly from one study to another. In this article, we show by simulation that neglecting inter-study variability (ISV) does not introduce any bias for the fixed parameters or for the residual variability but may result in an overestimation of inter-individual (IIV) variability, depending on the magnitude of the ISV. Two random study-effect (RSE) estimation methods were investigated: (i) estimation, in a single step, of the three-nested random effects (inter-study, inter-individual and residual variability); (ii) estimation of residual variability and a mixture of ISV and IIV in the first step, then separation of ISV from IIV in the second. The one-stage RSE model performed well for population parameter assessment, whereas, the two-stage model yielded good estimates of IIV only with a rich sampling design. Finally, irrespective of the method used, ISV estimates were valid only when a large number of studies was pooled. The analysis of one real data set illustrated the use of an ISV model. It showed that the fixed parameter estimates were not modified, whether an RSE model was used or not, probably because of the homogeneity of the experimental designs of the studies, and suggest no study-effect in this example.

OBJECTIVE:To review the effectiveness of diuretic or beta-blocker-based treatment of hypertension in diabetic patients.RESEARCH DESIGN AND METHODS:A meta-analysis on individual patient data was performed on four trials of the treatment of hypertension in which diabetic patients were included and treated with first-line diuretics or beta-blockers. The main outcomes were the relative risk of death, fatal or nonfatal stroke, fatal or nonfatal coronary events, and major cardiovascular events.RESULTS:There were 92 diabetic patients who received first-line beta-blockers and 1,008 who received diuretics. In the control groups, diabetic patients had nearly twice the risk of any outcome when compared with nondiabetic patients. The same blood pressure reduction was achieved under treatment in the diabetic and nondiabetic patients, except for systolic pressure, which decreased more in the nondiabetic patients at 1 year. In the 15,843 nondiabetic patients, the risk of all four outcomes was reduced significantly in the treated group. In the 2,254 diabetic patients, the risk reduction was significant only for fatal and nonfatal stroke (36%, P = 0.011) and major cardiovascular events (20%, P = 0.032), but not for death (5%, P = 0.65) and fatal or nonfatal coronary events (15%, P = 0.23). However, no heterogeneity was detected between diabetic patients and nondiabetic patients for any outcome. The numbers of outcomes avoided for 1,000 patients treated for 5 years were higher in diabetic patients (e.g., 38 major cardiovascular events) than with nondiabetic patients (e.g., 28 major cardiovascular events).CONCLUSIONS:These results show that hypertensive diabetic patients benefit from first-line treatment with diuretics. No conclusion can be drawn for beta-blockers, owing to the small sample size.

BackgroundPrevious meta-analyses of fluoxetine as an antidepressant have many methodological problems, including diagnosis of major depression, validity of outcome measures and lack of intention-to-treat analyses.AimsTo provide an estimate of the effect of fluoxetine compared with placebo and tricyclic antidepressants (TCAs), and to investigate reasons for early discontinuation from acute treatment.MethodRandomised trials were analysed using both intention-to-treat, efficacy and end-point.ResultsFluoxetine was superior to placebo but effect size was low. In trials comparing fluoxetine v. TCA, the results for all trials and for the USA trials showed a trend in favour of fluoxetine. Those for the non-USA trials showed a trend in favour of TCA. When combined, the results showed that significantly fewer patients on fluoxetine discontinued treatment because of adverse events.ConclusionFluoxetine is superior to placebo, irrespective of the analytical approach use, whereas the results obtained v. TCAs depend on the approach used. Hence, the results should be interpreted in this light.

The optimal duration of oral anticoagulant therapy after a first episode of venous thromboembolism (VTE) is still a matter of debate. It is essential to balance the desired effect of the anticoagulants in reducing recurrences against the risk of major bleeding. The aims of this paper are to describe the current concepts in this field. Recent data, based on randomized controlled trials, suggest that it is necessary to tailor the duration of anticoagulation individually according to the topography of VTE and the presence of risk factors. A 6-week treatment for patients with isolated calf vein thrombosis is sufficient. For proximal thrombosis and/or pulmonary embolism, a short anticoagulant course is sufficient in patients with temporary risk factors (3 months), and a longer anticoagulant course (6 months at least) is recommended for cases with permanent risk factors or idiopathic VTE. For these high-risk of recurrence patients, an assessment of low- or fixed-dose oral anticoagulation is necessary in order to reduce the bleeding risk. It is not possible to precisely determine the optimal duration with the available data. We have already performed a meta-analysis on summary data that suggests a long course of oral anticoagulant therapy is superior to a short course. An individual meta-analytic approach is needed to draw more precise conclusions on an interesting and important clinical topic.

Objective: To establish, using a systematic review and meta-analysis, whether there is any evidence from randomised controlled clinical trials of the efficacy of homeopathic treatment in patients with any disease.