The Place of Immune Reconstitution Therapy in the Management of Relapsing Multiple Sclerosis in France: An Expert Consensus.

The treatment strategy in relapsing multiple sclerosis (RMS) is a complex decision requiring individualization of treatment sequences to maximize clinical outcomes. Current local and international guidelines do not provide specific recommendation on the use of immune reconstitution therapy (IRT) as alternative to continuous immunosuppression in the management of RMS. The objective of the program was to provide consensus-based expert opinion on the optimal use of IRT in the management of RMS. A Delphi method was performed from May 2022 to July 2022. Nineteen clinical assertions were developed by a scientific committee and sent to 14 French clinical experts in MS alongside published literature. Two consecutive reproducible anonymous votes were conducted. Consensus on recommendations was achieved when more than 75% of the respondents agreed or disagreed with the clinical assertions. After the second round, consensus was achieved amongst 16 out of 19 propositions: 13 clinical assertions had a 100% consensus, 3 clinical assertions a consensus above 75% and 3 without consensus. Expert-agreed consensus is provided on topics related to the benefit of the early use of IRT from immunological and clinical perspectives, profiles of patients who may benefit most from the IRT strategy (e.g. patients with family planning, patient preference and lifestyle requirements). These French expert consensuses provide up-to-date relevant guidance on the use of IRT in clinical practice. The current program reflects status of knowledge in 2022 and should be updated in timely manner when further clinical data in IRT become available.

Identification of Patient Profiles with High Risk of Hospital Re-Admissions for Acute COPD Exacerbations (AECOPD) in France Using a Machine Learning Model.

Purpose: To characterise patients with chronic obstructive pulmonary disease (COPD) who are rehospitalised for an acute exacerbation, to estimate the cost of these hospitalisations, to characterise high risk patient sub groups and to identify factors potentially associated with the risk of rehospitalisation. Patients and Methods: This was a retrospective study using the French National Hospital Discharge Database. All patients aged ≥40 years hospitalised for an acute exacerbation of COPD between 2015 and 2016 were identified and followed for six months. Patients with at least one rehospitalisation for acute exacerbation of COPD constituted the rehospitalisation analysis population. A machine learning model was built to study the factors associated with the risk of rehospitalisation using decision tree analysis. A direct cost analysis was performed from the perspective of national health insurance. Results: A total of 143,006 eligible patients were hospitalised for an acute exacerbation of COPD (AECOPD) in 2015-2016 (mean age: 74 years; 62.1% men). 25,090 (18.8%) were rehospitalised for another exacerbation within six months. In this study, 8.5% of patients died during or immediately following the index hospitalisation and 10.5% died during or immediately after rehospitalisation (p <0.001). The specific cost of these rehospitalisations was € 5304. The overall total cost per patient of all AECOPD-related stays was € 9623, being significantly higher in patients who were rehospitalised (€ 16,275) compared to those who were not (€ 8208). In decision tree analysis, the most important driver of rehospitalisation was hospitalisation in the previous two years (contributing 85% of the information). Conclusion: Rehospitalisations for acute exacerbations of COPD carry a high epidemiological and economic burden. Since hospitalisation for an acute exacerbation is the most important determinant of future rehospitalisations, management of COPD needs to focus on interventions aimed at decreasing the rehospitalisation risk of in order to lower the burden of disease.

Treatment sequence of first and second generation tyrosine kinase inhibitor followed by osimertinib in EGFR-mutated non-small-cell lung cancer: a real life study.

Background: We aimed to assess the effectiveness and cost of patients with first line tyrosine kinase inhibitors (TKIs) sequence of first (1G) and second generation (2G) followed by osimertinib. Materials & methods: Using the French nationwide claims and hospitalization database, we analyzed non-small-cell lung cancer patients who had been treated with osimertinib between April 2015 and December 2017, after a first line treatment with a TKI-1G/2G. Results: The median time on treatment for sequential TKI-1G/2G followed by osimertinib was 34 months (95% CI: 31-46); 13 and 12months, respectively for TKI 1G or 2G and TKI 3G, respectively. The median overall survival for sequential TKI 1G or 2G followed by osimertinib was 37 months (95% CI: 34-42). The mean monthly costs per patient was €5162. Conclusion: These results, in line with those observed during clinical trials, confirm the effectiveness of the sequence TKI-1G/2G followed by osimertinib in EGFR-mutated non-small-cell lung cancer.

Long-term cost-effectiveness of the fixed-dose combination of tiotropium plus olodaterol based on the DYNAGITO trial results.

PURPOSE: Combinations of long-acting bronchodilators are recommended to reduce the rate of COPD exacerbations. Evidence from the DYNAGITO trial showed that the fixed-dose combination of tiotropium + olodaterol reduced the annual rate of total exacerbations (P<0.05) compared with tiotropium monotherapy. This study aimed to estimate the cost-effectiveness of the fixed-dose combination of tiotropium + olodaterol vs tiotropium monotherapy in COPD patients in the French setting. PATIENTS AND METHODS: A recently developed COPD patient-level simulation model was used to simulate the lifetime effects and costs for 15,000 patients receiving either tiotropium + olodaterol or tiotropium monotherapy by applying the reduction in annual exacerbation rate as observed in the DYNAGITO trial. The model was adapted to the French setting by including French unit costs for treatment medication, COPD maintenance treatment, COPD exacerbations (moderate or severe), and pneumonia. The main outcomes were the annual (severe) exacerbation rate, the number of quality-adjusted life-years (QALYs), and total lifetime costs. RESULTS: The number of QALYs for treatment with tiotropium + olodaterol was 0.042 higher compared with tiotropium monotherapy. Using a societal perspective, tiotropium + olodaterol resulted in a cost increase of +€123 and an incremental cost-effectiveness ratio (ICER) of €2,900 per QALY compared with tiotropium monotherapy. From a French National Sickness Fund perspective, total lifetime costs were reduced by €272 with tiotropium + olodaterol, resulting in tiotropium + olodaterol being the dominant treatment option, that is, more effects with less costs. Sensitivity analyses showed that reducing the cost of exacerbations by 34% increased the ICER to €15,400, which could still be considered cost-effective in the French setting. CONCLUSION: Treatment with tiotropium + olodaterol resulted in a gain in QALYs and savings in costs compared with tiotropium monotherapy using a National Sickness Fund perspective in France. From the societal perspective, tiotropium + olodaterol was found to be cost-effective with a low cost per QALY.

Patient preference for chronic obstructive pulmonary disease (COPD) treatment inhalers: a discrete choice experiment in France.

OBJECTIVES: Understanding inhaler preferences may contribute to improving adherence in COPD patients and improving long-term outcomes. This study aims to identify and quantify preferences for convenience-related inhaler attributes in French moderate-to-severe COPD patients, with discrete choice experiment (DCE) methodology. METHODS: Attributes were defined from a literature search, clinician and patient interviews: shape, dose insertion, dose preparation, dose release, dose confirmation, dose counter and reusability. An online DCE was conducted in respondents with self-reported COPD stage 2-4 recruited through a panel. The study questionnaire included twelve choice scenarios per respondent and questions on patient characteristics, treatment and disease severity. Statistical analyses used a mixed logit regression model with random effects. Utility scores were estimated for four types of inhalers: Inhaler A - soft mist inhaler; Inhaler B - reusable soft mist inhaler; Inhaler C - multi-dose dry powder inhaler; and Inhaler D - single dose dry powder inhaler. RESULTS: The study was completed by 153 patients (50 females); respondents were 50.4 years old on average; 13 different inhaler devices were reported. The most preferred inhaler is L-shaped, has dose preparation with capsule insertion and a dose counter, and is reusable. Inhaler profiles A and B had the highest utilities (mean of 1.2533 and 0.9578 respectively) compared to inhaler C (0.6315) and D (0.2200). CONCLUSIONS: This study showed statistically significant results that the strongest drivers of preference in French users of inhalation devices for COPD are shape, dose counter and reusability. Convenience-related characteristics are important to patients and should be taken into account by clinicians prescribing these devices.

Health economic evaluation in idiopathic pulmonary fibrosis in France.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive, fibrosing interstitial pneumonia of unknown cause. To date, there is no specific cure for IPF, and only two treatments (pirfenidone and nintedanib) have marketing authorizations and recommendations in international and French guidelines. OBJECTIVES: A cost-utility analysis (CUA) has been conducted to evaluate the efficiency of nintedanib, in comparison to all available alternatives, in a French setting using the official methodological guidelines. METHODS: A previously developed lifetime Markov model was adapted to the French setting by simulating the progression of IPF patients in terms of lung function decline, incidence of acute exacerbations, and death. Considering the effect of IPF on patients' quality-of-life, a CUA integrating quality adjusted life years (QALY) was chosen as the primary outcome measure in the main analysis. One-way, probabilistic, and scenario sensitivity analyses were performed to evaluate the robustness of the model. RESULTS: Treatment with nintedanib resulted in an estimated total cost of €76,414 (vs €82,665 for pirfenidone). In comparison with all other available options, nintedanib was predicted to provide the most QALY gained (3.34 vs 3.29). This analysis suggests that nintedanib has a 59.0% chance of being more effective than pirfenidone and s 77.3% chance of being cheaper than pirfenidone. Sensitivity analyses showed the results of the CUA to be robust. CONCLUSIONS: In conclusion, this CUA has found that nintedanib appears to be a more cost-effective therapeutic option than pirfenidone in a French setting, due to fewer acute exacerbations and a better tolerability profile.

Evaluating the cost-effectiveness of afatinib after platinum-based therapy for the treatment of squamous non-small-cell lung cancer in France.

BACKGROUND AND AIMS: Lung cancer has the highest mortality rate of all cancers worldwide. Non-small-cell lung cancer (NSCLC) accounts for 85% of all lung cancers and has an extremely poor prognosis. Afatinib is an irreversible ErbB family blocker designed to suppress cellular signaling and inhibit cellular growth and is approved in Europe after platinum-based therapy for squamous NSCLC. The objective of the present analysis was to evaluate the cost-effectiveness of afatinib after platinum-based therapy for squamous NSCLC in France. METHODS: The study population was based on the LUX-Lung 8 trial that compared afatinib with erlotinib in patients with squamous NSCLC. The analysis was performed from the perspective of all health care funders and affected patients. A partitioned survival model was developed to evaluate cost-effectiveness based on progression-free survival and overall survival in the trial. Life expectancy, quality-adjusted life expectancy and direct costs were evaluated over a 10-year time horizon. Future costs and clinical benefits were discounted at 4% annually. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: Model projections indicated that afatinib was associated with greater life expectancy (0.16 years) and quality-adjusted life expectancy (0.094 quality-adjusted life years [QALYs]) than that projected for erlotinib. The total cost of treatment over a 10-year time horizon was higher for afatinib than erlotinib, EUR12,364 versus EUR9,510, leading to an incremental cost-effectiveness ratio of EUR30,277 per QALY gained for afatinib versus erlotinib. Sensitivity analyses showed that the base case findings were stable under variation of a range of model inputs. CONCLUSION: Based on data from the LUX-Lung 8 trial, afatinib was projected to improve clinical outcomes versus erlotinib, with a 97% probability of being cost-effective assuming a willingness to pay of EUR70,000 per QALY gained, after platinum-based therapy in patients with squamous NSCLC in France.

Cost-Effectiveness Analysis of Afatinib versus Gefitinib for First-Line Treatment of Advanced EGFR-Mutated Advanced Non-Small Cell Lung Cancers.

INTRODUCTION: The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib were compared in the multicenter, international, randomized, head-to-head phase 2b LUX-Lung 7 trial for first-line treatment of advanced EGFR mutation-positive NSCLCs. Afatinib and gefitinib costs and patients' outcomes in France were assessed. METHODS: A partitioned survival model was designed to assess the cost-effectiveness of afatinib versus gefitinib for EGFR mutation-positive NSCLCs. Outcomes and safety were taken primarily from the LUX-Lung 7 trial. Resource use and utilities were derived from that trial, an expert-panel questionnaire, and published literature, limiting expenditures to direct costs. Incremental cost-effectiveness ratios (ICERs) were calculated over a 10-year time horizon for the entire population, and EGFR exon 19 deletion or exon 21 L858R mutation (L858R) subgroups. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: For all EGFR mutation-positive NSCLCs, the afatinib-versus-gefitinib ICER of was €45,211 per quality-adjusted life-year (QALY) (0.170 QALY gain for an incremental cost of €7697). ICERs for EGFR exon 19 deletion and L858R populations were €38,970 and €52,518, respectively. Afatinib had 100% probability to be cost-effective at a willingness-to-pay threshold of €70,000/QALY for patients with common EGFR mutations. CONCLUSION: First-line afatinib appears cost-effective compared with gefitinib for patients with EGFR mutation-positive NSCLCs.

Implementación de una iniciativa para promover un entorno laboral saludable en un Servicio de Medicina Familiar de un Hospital Universitario: investigación-acción participativa / Implementation of an initiative to promote a healthy working environment in a Division of Family Medicine at a University Hospital: participatory action research

Objetivos: describir el proceso y los resultados de la implementación de un proyecto para la promoción de un entorno laboral saludable (ELS) en el Servicio de Medicina Familiar y Comunitaria de un Hospital Universitario. Métodos: investigación con enfoque cualitativo, diseño investigación-acción participativa desarrollada entre marzo de 2011 y marzo de 2012. La intervención incluyó tres ejes de trabajo (alimentación, actividad física y estrategias comunicacionales) y estuvo dirigida a 60 profesionales médicos y a los cuatro empleados administrativos de dicho servicio. Se proveyeron cuestionarios (adaptados del "STEP" propuesto por la Organización Mundial de la Salud) antes de iniciar el proyecto y al año de la intervención. Se realizaron entrevistas semiestructuradas y se aplicaron técnicas de observación-participante. Resultados: el proyecto se institucionalizó y se destacó su repercusión positiva en el clima laboral. Se instauró dentro del Servicio, durante el horario de trabajo, el consumo de frutas y las pausas activas, se generaron espacios de actividad física y de recreación deportiva en horarios extralaborales y se difundió su existencia a otros sectores del hospital. Se documentó un aumento estadísticamente significativo en el consumo semanal promedio de frutas (+3,04 porciones semanales; IC 95% 0,86 a 5,21; p < 0,01) y un aumento estadísticamente no significativo en el consumo semanal de hortalizas (+0,8 porciones semanales; IC 95%: -1,84 a 3,45; p = 0,55) y en la práctica semanal de ejercicio (+101 minutos; -78,7 a 281,55; p = 0,27). Conclusiones: una intervención sencilla y sustentable contribuyó a instalar el consumo de frutas durante el horario laboral y la posibilidad de la pausa activa; asimismo generó en las redes sociales un espacio de intercambio para propuestas saludables. Esperamos que estos resultados motiven a otros grupos de trabajo a avanzar en programas que promuevan un ELS. (AU)

Objectives: To describe the process and the results of the implementation of a project to promote a healthy working environment (HWE) in the Division of Family and Community Medicine at a University Hospital. Methods: Qualitative research using part of a participatory action research conducted between March 2011 and March 2012. The intervention included three working areas (food, physical activity and communication strategies) and was directed to 60 medical professionals and four administrative employees that were working in that service. Questionnaires (adapted from "STEP" proposed by the World Health Organization) have been administered before starting the project and a year of intervention. Semi-structured interviews and participant observation techniques were performed. Results: the project was institutionalized, what highlights its positive impact on the working environment. Consumption of fruits and active breaks during working hours was installed and physical activity/recreative sports spaces during extra-working hours were generated and spread to other divisions of the hospital. After the program a statistically significant increase (+3,04 portions weekly; 95% CI 0.86 to 5.21; p < 0.01) in the weekly average fruit consumption was documented and a no statistically significant increase in the weekly consumption of vegetables (+0.8 weekly servings, 95%CI -1.84 to 3.45; p = 0.55) and in weekly exercise (+101 min; -78.7 to 281.55; p = 0.27). Conclusions: A simple and sustainable intervention contributed to installed fruit consumption during working hours, the possibility of active pause and generates a social networking space for healthy exchange proposals. We hope these results will encourage other working groups to implement programs that promote HWE. (AU)

Potentiation of adrenaline vasoconstrictor response by sub-threshold concentrations of U-46619 in human umbilical vein: involvement of smooth muscle prostanoid TP(alpha) receptor isoform.

Considering the potential physiological, pharmacological and therapeutic relevance of synergistic interaction of thromboxane A(2) with adrenaline at postjunctional receptor sites, we examined whether sub-threshold concentrations of thromboxane A(2) mimetic U-46619 (9,11-dideoxy-9alpha, 11alpha-methanoepoxy prostaglandin F(2alpha)) could amplify adrenaline-induced contraction in human umbilical vein. The receptor involved in U-46619-induced potentiation of adrenaline contractility was also investigated. Umbilical cords (n=125) from healthy patients after full-term vaginal or caesarean deliveries were employed. The vein was dissected out of cords and rings used for isolated organ bath experiments or reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. Presence of endothelium did not modify U-46619-induced contraction in human umbilical vein. Prostanoid TP-selective receptor antagonist, SQ-29548 (7-[3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-[1S(1alpha,2alpha(Z),3alpha,4alpha)]-5-Heptenoic acid), inhibited U-46619-induced contraction (pA(2)=8.22+/-0.11). U-46619 sub-threshold concentrations (0.1-0.3 nM) potentiated adrenaline-vasoconstriction response in a concentration-dependent manner. SQ-29548 (0.1 microM) abolished this potentiation. Using RT-PCR, we found that human umbilical vein rings with or without endothelium express the prostanoid TP(alpha), but not the prostanoid TP(beta) receptor isoform. Western blot allowed the identification of proteins with an electrophoretic mobility (47- and 55-kDa) indistinguishable from human platelet prostanoid TP receptor, a rich source of prostanoid TP(alpha) receptor isoform. Collectively, present results demonstrate that prostanoid TP(alpha) is the major receptor isoform localized on smooth muscle cells which participate in both direct vasoconstriction and potentiating effects of U-46619 on adrenaline contractions in human umbilical vein. These results suggest that thromboxane A(2) may interact synergistically with adrenaline in pathophysiological situations that lead to an increase of its umbilical venous levels (e.g. preeclampsia associated with fetal distress) raising the possibility of vasoconstriction affecting fetal blood flow.

Human umbilical vein vasoconstriction induced by epinephrine acting on alpha1B-adrenoceptor subtype.

OBJECTIVE: Our purpose was to determine the presence of alpha(1)-adrenoceptor messenger RNA subtypes and extend the pharmacologic characterization of alpha(1)-adrenoceptors involved in human umbilical vein (HUV) contraction. STUDY DESIGN: Cords (n=124) from healthy patients after term vaginal or cesarean deliveries were used. The vein was carefully dissected out of cords and used for reverse transcription combined with polymerase chain reaction (RT-PCR) to amplify alpha(1)-adrenoceptor transcripts. In isolated organ baths, HUV rings were mounted and cumulative concentration-response curves were constructed either for epinephrine or the selective alpha(1A)-adrenoceptor agonist, A-61603. In other series of experiments, the effects of the selective alpha(1A)- and alpha(1B)-adrenoceptor antagonists (RS-100329 or B8805-033 or spiperone, AH11110A and cyclazosin, respectively) were evaluated to estimate its blocking potencies on epinephrine concentration-response curves. RESULTS: By means of RT-PCR technique alpha(1a)- and alpha(1b)-adrenoceptor transcripts were detected in the HUV. The blocking potency values of RS-100329 or B8805-033 against responses mediated by epinephrine were not consistent with the activation of an alpha(1A)-adrenoceptor population. Moreover, the low potency of the agonist A-61603 was not in accordance with an alpha(1A)-adrenoceptor interaction. On the other hand, the antagonist potencies of spiperone, AH11110A and cyclazosin were in agreement with an interaction on alpha(1B)-adrenoceptor subtype. CONCLUSION: Although alpha(1a)- and alpha(1b)-adrenoceptor messenger RNAs are detected in the HUV, only alpha(1B)-adrenoceptors are involved in epinephrine vasoconstrictor action.