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Abstract Background Macular edema (ME) results from hyperpermeability of retinal vessels, leading to chronic extravasation of plasma components into the retina and hence potentially severe visual acuity loss. Current standard of care consists in using intravitreal injections (IVI), which results in a significant medical and economic burden. During diabetic retinopathy (DR) or retinal vein occlusion (RVO), it has recently been shown that focal vascular anomalies (capillary macro-aneurysms, also termed TelCaps) for telangiectatic capillaries may play a central role in the onset, early recurrence, and/or persistence of ME. Since targeted photocoagulation of TelCaps may improve vision, identification, and photocoagulation of TelCaps, it may represent a way to improve management of ME. Objective The Targeted Laser in (Diabetic) Macular Edema (TalaDME) study aims to evaluate whether ICG-guided targeted laser (IGTL), in association with standard of care by IVI, allows reducing the number of injections during the first year of treatment compared with IVI only, while remaining non-inferior for visual acuity. Methods TalaDME is a French, multicentric, two-arms, randomized, sham laser-controlled, double-masked trial evaluating the effect of photocoagulation of TelCaps combined to IVI in patients with ME associated with TelCaps. Patients with vision loss related to center involved ME secondary to RVO or DR and presenting TelCaps are eligible. Two hundred and seventy eyes of 270 patients are randomized in a 1:1 ratio to standard care, i.e., IVI of anti-VEGF solely (control group) or combined with IGTL therapy (experimental group). Stratification is done on the cause of ME (i.e., RVO versus diabetes). Anti-VEGF IVI are administered to both groups monthly for 3 months (loading dose) and then with a pro re nata regimen with a monthly follow-up for 12 months. The primary endpoint will be the number of IVI and the change in visual acuity from baseline to 12 months. Secondary endpoints will be the changes in central macular thickness, impact on quality of life, cost of treatment, and incremental cost-utility ratio in each groups. Key safety Rare but severe AE linked to the use of IVI and laser, and previously described, are expected. In the sham group, rescue laser photocoagulation may be administered by the unmasked investigator if deemed necessary at month 3. Discussion The best management of ME associated with TelCaps is debated, and there have been no randomized study designed to answer this question. Given the fact that TelCaps may affect 30 to 60% of patients with chronic ME due to DR or RVO, a large number of patients could benefit from a specific management of TelCaps. TalaDME aims to establish the clinical and medico-economic benefits of additional targeted laser. The results of TalaDME may raise new recommendations for managing ME and impact healthcare costs. Trial registration EudraCT: 2018-A00800-55/ NCT03751501. Registration date: Nov. 23, 2018.

Abstract Background With 11,558 deaths and 200,000 suicide attempts in 2019, France is among the European countries most affected. The aim of this study was to determine the costs and burden of suicides and suicide attempts in France (population 67 million). Methods We estimated direct costs, comprising healthcare, as well as post-mortem costs including autopsy, body removal, funeral expenses, police intervention and support groups; indirect costs comprised lost productivity, daily allowances; the burden of disease calculations used a monetary value for death and disability based on incidence data. Data was obtained from the national statistics, health and social care database, registries, global burden of disease, supplemented by expert opinion. We combined top down and bottom up approaches. Results The total costs and burden of suicides and suicide attempts was estimated at €18.5 billion and €5.4 billion, respectively. Direct costs were €566 million and €75 million; indirect costs were €3.8 billion and €3.5 billion; monetary value for death and disability was €14.6 billion and €1.3. The monetary value for death and disability represented 79.1% and 24.8% of total costs for suicide and suicide attempt respectively. Some costs were based upon expert opinion, caregivers’ burden was not counted and pre COVID data only is reported. Conclusions In France, the total cost and burden of suicides and suicide attempts was several billion €, suggesting major potential savings from public health interventions.

Background In patients with distal bifurcation left main stem lesions requiring intervention, the European Bifurcation Club Left Main Coronary Stent Study trial found a non-significant difference in major adverse cardiac events (MACEs, composite of all-cause death, non-fatal myocardial infarction and target lesion revascularisation) favouring the stepwise provisional strategy, compared with the systematic dual stenting.Aims To estimate the 1-year cost-effectiveness of stepwise provisional versus systematic dual stenting strategies.Methods Costs in France and the UK, and MACE were calculated in both groups to estimate the incremental cost-effectiveness ratio (ICER). Uncertainty was explored by probabilistic bootstrapping. The analysis was conducted from the perspective of the healthcare provider with a time horizon of 1 year.Results The cost difference between the two groups was €−755 (€5700 in the stepwise provisional group and €6455 in the systematic dual stenting group, p value

Abstract Background The aim of this trial-based economic evaluation was to assess the incremental costs and cost-effectiveness of the modified diagnostic strategy combining the YEARS rule and age-adjusted D-dimer threshold compared with the control (which used the age-adjusted D-dimer threshold only) for the diagnosis of pulmonary embolism (PE) in the Emergency Department (ED). Methods Economic evaluation from a healthcare system perspective alongside a non-inferiority, crossover, and cluster-randomized trial conducted in 16 EDs in France and two in Spain with three months of follow-up. The primary endpoint was the additional cost of a patient without failure of the diagnostic strategy, defined as venous thromboembolism (VTE) diagnosis at 3months after exclusion of PE during the initial ED visit. Mean differences in 3-month failure and costs were estimated using separate generalized linear-regression mixed models, adjusted for strategy type, period, and the interaction between strategy and period as fixed effects and the hospital as a random effect. The incremental cost-effectiveness ratio (ICER) was obtained by dividing the incremental costs by the incremental frequency of VTE. Results Of the 1,414 included patients, 1,217 (86%) were analyzed in the per-protocol analysis (648 in the intervention group and 623 in the control group). At three months, there were no statistically significant differences in total costs (€-46; 95% CI: €-93 to €0.2), and the failure rate was non inferior in the intervention group (-0.64%, one-sided 97.5% CI: -∞ to 0.21%, non-inferiority margin 1.5%) between groups. The point estimate of the incremental cost-effectiveness ratio (ICER) indicating that each undetected VTE averted in the intervention group is associated with cost savings of €7,142 in comparison with the control group. There was a 93% probability that the intervention was dominant. Similar results were found in the as randomized population. Conclusions Given the observed cost decrease of borderline significance, and according to the 95% confidence ellipses, the intervention strategy has a potential to lead to cost savings as a result of a reduction in the use of chest imaging and of the number of undetected VTE averted. Policy-makers should investigate how these monetary benefits can be distributed across stakeholders. Clinicaltrials Trial registration number ClinicalTrials.gov Identifier: NCT04032769; July 25, 2019.

Abstract Objective Prognostic models in patients living with diabetes allow physicians to estimate individual risk based on medical records and biological results. Clinical risk factors are not always all available to evaluate these models so that they may be complemented with models from claims databases. The objective of this study was to develop, validate and compare models predicting the annual risk of severe complications and mortality in patients living with type 2 diabetes (T2D) from a national claims data. Research design and methods Adult patients with T2D were identified in a national medical claims database through their history of treatments or hospitalizations. Prognostic models were developed using logistic regression (LR), random forest (RF) and neural network (NN) to predict annual risk of outcome: severe cardiovascular (CV) complications, other severe T2D-related complications, and all-cause mortality. Risk factors included demographics, comorbidities, the adjusted Diabetes Severity and Comorbidity Index (aDSCI) and diabetes medications. Model performance was assessed using discrimination (C-statistics), balanced accuracy, sensibility and specificity. Results A total of 22,708 patients with T2D were identified, with mean age of 68 years and average duration of T2D of 9.7 years. Age, aDSCI, disease duration, diabetes medications and chronic cardiovascular disease were the most important predictors for all outcomes. Discrimination with C-statistic ranged from 0.715 to 0.786 for severe CV complications, from 0.670 to 0.847 for other severe complications and from 0.814 to 0.860 for all-cause mortality, with RF having consistently the highest discrimination. Conclusion The proposed models reliably predict severe complications and mortality in patients with T2D, without requiring medical records or biological measures. These predictions could be used by payers to alert primary care providers and high-risk patients living with T2D.

Introduction The surveillance of hepatocellular carcinoma (HCC) using semi-annual liver ultrasound (US) is justified in patients with cirrhosis. In this context, US has a low sensitivity (3% per year) could increase the rates of patients with a tumour detected at an early stage accessible to curative-intent treatment, and demonstrate its cost-effectiveness in this population.Methods and analysis The FASTRAK trial is a multicentre, randomised controlled trial with two parallel arms, aiming for superiority and conducted on patients at high risk for HCC (yearly HCC incidence >3%). Randomisation will be conducted on an individual basis with a centralised approach and stratification by centre. After inclusion in the trial, each patient will be randomly assigned to the experimental group (semi-annual US and AMRI) or the control group (semi-annual US alone). The main objective is to assess the cost/quality-adjusted life year and cost/patient detected with a BCLC 0 HCC in both arms. A total of 944 patients will be recruited in 37 tertiary French centres during a 36-month period and will be followed-up during 36 months.Ethics and dissemination The FASTRAK trial received ethical approval on 4 April 2022. Results will be disseminated via publication in peer-reviewed journals as well as presentation at international conferences.Trial registration number Clinical trial number (ClinicaTrials.gov) NCT05095714.

Sickle cell disease (SCD) is a genetic disorder of the hemoglobin resulting in chronic anemia, hemolysis, and vaso-occlusions. Its treatment mostly relies on hydroxycarbamide, transfusions, and stem cell transplantation. This study aimed at describing the epidemiology and management of SCD in adolescent and adult patients in France. This was a retrospective study performed among SCD patients aged ≥12 years between 2016 and 2018 and controls. SCD patients were matched on a 1:3 ratio with a group of individuals with no diagnosis of SCD, referred as control group. The matching of SCD patients and controls was a direct matching based on age, sex, CMU-c status (which corresponds to free-of-charge complementary coverage for people with low resources) and geographical region of residence. SCD patients and their matched controls were followed-up for the same amount of time by adjusting controls’ follow-up period to that of the associated patients. This study used claims data from the French representative 1/97th sample of health data system. The main outcomes were the patients’ characteristics and treatments received, healthcare consumptions and related costs among SCD cases and controls. Between 2016 and 2018, 151 patients with ≥6 months of follow-up were identified out of the total population of 732,164 individuals. SCD prevalence extrapolated to the entire population [95% CI] was 19,502 [19,230, 19,778] in 2018. The median (Q1–Q3) age at inclusion date was 37.0 (25.0–48.0) years, with 69.5% of patients being female. The mean (SD) reimbursed cost over follow-up was €24,310 (89,167), mostly represented by hospitalization costs accounting for €21,156 (86,402). A switch in SCD management was observed with age, as younger patients presented more frequent hospitalizations and acute procedures, while older ones had more frequent medical visits and paramedical care. Mean (SD) annual costs were €25,680 (91,843) and vs. €3,227 (23,372) for patients and controls, respectively (p

The objective of this study was to assess the clinical impact and financial costs of next-generation sequencing (NGS) in 5 categories of pediatric and adult hematological cancers. NGS prescriptions were prospectively collected from 26 laboratories, with varied technical and reporting practice (all or only significant targets). Impact was defined by the identification of (1) an actionable mutation, (2) a mutation with prognostic and/or theranostic value, and/or (3) a mutation allowing nosological refinement, reported by local investigators. A microcosting study was undertaken in 4 laboratories, identifying the types and volumes of resources required for each procedural step. Individual index prescriptions for 3961 patients were available for impact analysis on the management of myeloid disorders (two thirds) and, mainly mature B, lymphoid disorders (one third). NGS results were considered to impact the management for 73.4% of prescriptions: useful for evaluation of prognostic risk in 34.9% and necessary for treatment adaptation (actionable) in 19.6%, but having no immediate individual therapeutic impact in 18.9%. The average overall cost per sample was 191 € for the restricted mature lymphoid amplicon panel. Capture panel costs varied from 369 € to 513 €. Unit costs varied from 0.5 € to 5.7 € per kb sequenced, from 3.6 € to 11.3 € per target gene/hot-spot sequenced and from 4.3 € to 73.8 € per target gene/hot-spot reported. Comparable costs for the Amplicon panels were 5–8 € per kb and 10.5–14.7 € per target gene/hot-spot sequenced and reported, demonstrating comparable costs with greater informativity/flexibility for capture strategies. Sustainable funding of precision medicine requires a transparent discussion of its impact on care pathways and its financial aspects.

Abstract Background 82-Rubidium-Positron emission tomography myocardial perfusion imaging (Rb-PET-MPI) offers higher diagnostic performance for the detection of myocardial ischemia compared to Tc-SPECT-MPI. The aim of this economic evaluation was to perform a cost-effectiveness analysis of Rb-PET-MPI versus Tc-SPECT-MPI in patients with suspected myocardial ischemia according to pretest probabilities (PTP) of obstructive coronary artery disease based on the results of the RUBIS Trial. Methods Costs and effectiveness were calculated for all patients over 1 year and an incremental analysis of differences in costs and effectiveness in terms of diagnostic accuracy was performed. The uncertainty of the results was estimated using bootstrap. The analysis was conducted from the perspective of the French health care system with a time horizon of 12 months. Results The average cost of a Rb-PET-MPI-based strategy for the detection of myocardial ischemia was €219 lower than a SPECT-MPI-based strategy (€1192 (± 1834) vs €973 (± 1939), p 15% for the Rb-PET-MPI vs. Tc-SPECT-MPI strategy. Analysis of the joint distribution of costs and outcomes found that the Rb-PET-MPI strategy had a 92% probability to be dominant (cost-saving and outcome-improving). Conclusions Rb-PET-MPI is cost-effective compared to Tc-SPECT-MPI for the detection of myocardial ischemia in patients with PTP > 15% of obstructive coronary artery disease. Trial registration RUBIS Trial registration: NCT01679886, Registered 03 September 2012, https://clinicaltrials.gov/ct2/show/NCT01679886 .

Abstract Objective The GERONTACCESS trial evaluated the utility and cost-effectiveness of a gerontological telemedicine (TLM) programme for preventing unplanned hospitalisation of residents living in nursing homes (NHs) in regions lacking medical facilities and/or qualified medical providers (“medical deserts”). Design GERONTACCESS was a 12-month, multicentre, prospective cluster-randomised trial conducted in NHs. The intervention group underwent TLM assessments every 3 months. The control group received the usual care. In both groups, comprehensive on-site assessments were conducted at baseline and the final visit. Care requirements were documented throughout the study. Setting and participants NH residents aged ≥ 60 years with multiple chronic diseases. Methods The study outcomes were the proportion of patients who experienced avoidable and unplanned hospitalisation, and the incremental cost savings per quality-adjusted life years from baseline to the 12-month follow-up. Results Of the 426 randomised participants (mean ± standard deviation age, 87.2 ± 7.6 years; 311 [73.0%] women), 23.4% in the intervention group and 32.5% in the control group experienced unplanned hospitalisation (odds ratio [OR] = 0.73, 95% confidence interval [CI] 0.43 to 0.97; p = 0.034). Each avoided hospitalisation in the intervention group saved $US 3,846. Conclusions and implications The results of GERONTACCESS revealed that our gerontological, preventative TLM program significantly reduced unplanned hospitalisations. This innovative intervention limited disease progression and promoted a healthy lifestyle among NH residents. Trial registration Clinicaltrials.gov, NCT02816177, registered June 28, 2016.

Abstract Background Spread of resistant bacteria causes severe morbidity and mortality. Stringent control measures can be expensive and disrupt hospital organization. In the present study, we assessed the effectiveness and cost-effectiveness of control strategies to prevent the spread of Carbapenemase-producing Enterobacterales (CPE) in a general hospital ward (GW). Methods A dynamic, stochastic model simulated the transmission of CPE by the hands of healthcare workers (HCWs) and the environment in a hypothetical 25-bed GW. Input parameters were based on published data; we assumed the prevalence at admission of 0.1%. 12 strategies were compared to the baseline (no control) and combined different prevention and control interventions: targeted or universal screening at admission (TS or US), contact precautions (CP), isolation in a single room, dedicated nursing staff (DNS) for carriers and weekly screening of contact patients (WSC). Time horizon was one year. Outcomes were the number of CPE acquisitions, costs, and incremental cost-effectiveness ratios (ICER). A hospital perspective was adopted to estimate costs, which included laboratory costs, single room, contact precautions, staff time, i.e. infection control nurse and/or dedicated nursing staff, and lost bed-days due to prolonged hospital stay of identified carriers. The model was calibrated on actual datasets. Sensitivity analyses were performed. Results The baseline scenario resulted in 0.93 CPE acquisitions/1000 admissions and costs 32,050 €/1000 admissions. All control strategies increased costs and improved the outcome. The efficiency frontier was represented by: (1) TS with DNS at a 17,407 €/avoided CPE case, (2) TS + DNS + WSC at a 30,700 €/avoided CPE case and (3) US + DNS + WSC at 181,472 €/avoided CPE case. Other strategies were dominated. Sensitivity analyses showed that TS + CP might be cost-effective if CPE carriers are identified upon admission or if the cases have a short hospital stay. However, CP were effective only when high level of compliance with hand hygiene was obtained. Conclusions Targeted screening at admission combined with DNS for identified CPE carriers with or without weekly screening were the most cost-effective options to limit the spread of CPE. These results support current recommendations from several high-income countries.

Summary: Background: Prostatic artery embolisation (PAE) is a minimally invasive treatment of symptomatic benign prostatic hyperplasia (BPH). Our aim was to compare patient's symptoms improvement after PAE and medical treatment. Methods: A randomised, open-label, superiority trial was set in 10 French hospitals. Patients with bothersome lower urinary tract symptoms (LUTS) defined by International Prostatic Symptom Score (IPSS) > 11 and quality of life (QoL) > 3, and BPH ≥50 ml resistant to alpha-blocker monotherapy were randomly assigned (1:1) to PAE or Combined Therapy ([CT], oral dutasteride 0.5 mg/tamsulosin hydrochloride 0.4 mg per day). Randomisation was stratified by centre, IPSS and prostate volume with a minimisation procedure. The primary outcome was the 9-month IPSS change. Primary and safety analysis were done according to the intention-to-treat (ITT) principle among patients with an evaluable primary outcome. ClinicalTrials.gov Identifier: NCT02869971. Findings: Ninety patients were randomised from September 2016 to February 2020, and 44 and 43 patients assessed for primary endpoint in PAE and CT groups, respectively. The 9-month change of IPSS was −10.0 (95% confidence interval [CI]: −11.8 to −8.3) and −5.7 (95% CI: −7.5 to −3.8) in the PAE and CT groups, respectively. This reduction was significantly greater in the PAE group than in the CT group (−4.4 [95% CI: −6.9 to −1.9], p = 0.0008). The IIEF-15 score change was 8.2 (95% CI: 2.9–13.5) and −2.8 (95% CI: −8.4 to 2.8) in the PAE and CT groups, respectively. No treatment-related AE or hospitalisation was noticed. After 9 months, 5 and 18 patients had invasive prostate re-treatment in the PAE and CT group, respectively. Interpretation: In patients with BPH ≥50 ml and bothersome LUTS resistant to alpha-blocker monotherapy, PAE provides more urinary and sexual symptoms benefit than CT up to 24 months. Funding: French Ministry of Health and a complementary grant from Merit Medical.

BackgroundCovidom was a telemonitoring solution for home monitoring of patients with mild to moderate COVID-19, deployed in March 2020 in the Greater Paris area in France to alleviate the burden on the health care system. The Covidom solution included a free mobile application with daily monitoring questionnaires and a regional control center to quickly handle patient alerts, including dispatching emergency medical services when necessary. ObjectiveThis study aimed to provide an overall evaluation of the Covidom solution 18 months after its inception in terms of effectiveness, safety, and cost. MethodsOur primary outcome was to measure effectiveness using the number of handled alerts, response escalation, and patient-reported medical contacts outside of Covidom. Then, we analyzed the safety of Covidom by assessing its ability to detect clinical worsening, defined as hospitalization or death, and the number of patients with clinical worsening without any preceding alert. We evaluated the cost of Covidom and compared the cost of hospitalization for Covidom and non-Covidom patients with mild COVID-19 cases seen in the emergency departments of the largest network of hospitals in the Greater Paris area (Assistance Publique-Hôpitaux de Paris). Finally, we reported on user satisfaction. ResultsOf the 60,073 patients monitored by Covidom, the regional control center handled 285,496 alerts and dispatched emergency medical services 518 times. Of the 13,204 respondents who responded to either of the follow-up questionnaires, 65.8% (n=8690) reported having sought medical care outside the Covidom solution during their monitoring period. Of the 947 patients who experienced clinical worsening while adhering to daily monitoring, only 35 (3.7%) did not previously trigger alerts (35 were hospitalized, including 1 who died). The average cost of Covidom was €54 (US $1=€0.8614) per patient, and the cost of hospitalization for COVID-19 worsening was significantly lower in Covidom than in non-Covidom patients with mild COVID-19 cases seen in the emergency departments of Assistance Publique-Hôpitaux de Paris. The patients who responded to the satisfaction questionnaire had a median rating of 9 (out of 10) for the likelihood of recommending Covidom. ConclusionsCovidom may have contributed to alleviating the pressure on the health care system in the initial months of the pandemic, although its impact was lower than anticipated, with a substantial number of patients having consulted outside of Covidom. Covidom seems to be safe for home monitoring of patients with mild to moderate COVID-19.

Introduction End-stage renal disease (ESRD) affects 84 000 persons in France and costs an estimated €4.2 billion. Education about their disease empowers patients and allows improved management of their disease and better health outcomes. This study aims to explore whether the addition of an interactive web-based platform to patient education is effective and cost-effective and additionally whether complementing the platform with social functions and features improves its performance.Methods and analysis Patients with severe, ESRD or post-transplant will be randomised 1:1:1 to either standard therapeutic education; or education using a specific application; or the enhanced interactive app with social features. The total follow-up duration is 18 months. Primary endpoint is the cost utility of using app-based therapeutic intervention; secondary endpoints are: compliance with treatment guidelines, app use (professionals and patients), patients’ satisfaction, budget impact analysis.Ethics and dissemination The findings will inform the deployment and reimbursement of the application. The study has ethical approval by the Ile de France ethics committee. Dissemination of the results will be presented at conferences and in peer-reviewed publications.Trial registration number NCT03090828.

Introduction Lung cancer screening (LCS) using low-dose CT has been demonstrated to reduce lung cancer-related mortality in large randomised controlled trials. Moving from trials to practice requires answering practical questions about the level of expertise of CT readers, the need for double reading as in trials and the potential role of artificial intelligence (AI). In addition, most LCS studies have predominantly included male participants with women being under-represented, even though the benefit of screening is greater for them. Thus, this study aims to compare the performance of a single CT reading by general radiologists trained in LCS using AI as a second reader to that of a double reading by expert thoracic radiologists, in a campaign for low-dose CT screening in high-risk women.Methods and analysis This observational cohort study will recruit 2400 asymptomatic women aged between 50 and 74 years, current or former smokers with at least a 20 pack-year smoking history, in 4 different French district areas. Assistance with smoking cessation will be offered to current smokers. An initial low-dose CT scan will be performed, with subsequent follow-ups at 1 year and 2 years. The primary objective is to compare CT scan readings by a single LCS-trained, AI-assisted radiologist to that of an expert double reading. The secondary objectives are: to evaluate the performance of AI as a stand-alone reader; the adherence to screening of female participants; the influence on smoking cessation; the psychological consequences of screening; the detection of chronic obstructive pulmonary disease (COPD), coronary artery disease and osteoporosis on low-dose CT scans and the costs incurred by screening.Ethics and dissemination Ethics approval was obtained from the Comité de Protection des Personnes Sud-Est 1 (ethics approval number: 2021-A02265-36 with an amendment on 15 July 2022). Trial results will be disseminated at conferences, through relevant patient groups and published in peer-reviewed journals.Trial registration number NCT05195385.

Background: HTA guidance has generally been driven by situations where innovative and usually more expensive technologies are compared to the prevailing standards of care. Cheaper and less efficacious interventions have received scarce attention, although strategies with minimal individual efficacy losses might produce collective health gains when savings are redistributed.Purpose: This systematic review of health economic evaluations identified interventions that are both cost and outcome reducing to procure a list of candidate decrementally cost-effective technologies.Data Sources: English language searches were performed in PubMed, EMBASE and ClinicalTrials.gov covering 2005 to September 2021.Study Selection: Full economic evaluations reporting in English decrementally cost-effective health technologies based on RCT data, modelling or mixed methods.Data Synthesis: After filtering 4,975 studies found through the systematic database search, 107 decrementally cost-effective health technologies (HTs) were identified. Nearly a third were services (n = 29) and similarly for drugs (n = 31). For over half of the studies (n = 54) health outcomes were measured in QALYs and the cost-utility ratios varied from €140 to €5 million saved per QALY lost, albeit with time horizons varying from 4 days of follow-up to lifetime extrapolations. Less than a quarter of the studies were carried out from the societal perspective.Limitations: Despite including ClinicalTrials.gov as data source, unpublished studies may have been missed.Conclusions: Our results show a growth in recent years in the number of economic publications demonstrating decrementally cost-effective HTs. Economic tools are needed to facilitate the adoption of such HTs by policy-makers at the national level to maximise health outcomes at the population level.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=95504, identifier CRD42018095504.

The annual incidence of rabies deaths has been estimated in Cambodia at nearly 5.8/100,000 person-years. The cost of post exposure prophylaxis (PEP) and travel is potentially a significant barrier for exposed patients and their families, although safety nets are in place to provide the prophylaxis at no cost for low-income families. A decision-tree model was built to estimate changes in the costs from the patients' perspective and the survival outcomes of the Institut Pasteur du Cambodge (IPC) rabies PEP regimen after the switch from the Thai Red Cross (TRC) rabies PEP regimen in patients exposed to WHO category II or III bites by dogs. Derived from the IPC database, data included the trajectory of 203,497 patients, 1412 called-back patients and economic data on 201 patients. Uncertainty was addressed using one-way and probabilistic sensitivity analyses. Compared to the TRC regimen, the IPC regimen was cheaper and equally effective in patients with category II bites. In patients with category III bites, the IPC regimen was cheaper and its modeled probability of survival was 0.04% (95% CI, −0.12%; 0%) lower than the TRC regimen. However, the mortality rate was very low and the causes of death were uncertain. The data available may have lacked power to be able to statistically significantly tell apart the difference between genuine PEP failure and incorrect PEP administration, in the three versus the four-PEP sessions.

Abstract Background Currently, oral targeted therapies are known to be effective and are frequently used to treat metastatic cancer patients, but fatigue is a frequently reported early side effect of these treatments. This fatigue may impact the patient’s treatment adherence and result in a negative impact on quality of life. Physical exercise significantly improved the general well-being and quality of life of advanced cancer patients. However, there is no specific physical activity program adapted for patients with advanced disease. Methods QUALIOR is a two-part, randomized, open-label, and multicenter with two arms phase II/III trial. Patients (phase II: n = 120; phase III: n = 312) with metastatic cancer (breast cancer, kidney cancer, lung cancer, and other cancers [including but not limited to colon cancer, melanoma, sarcoma, or hepatocarcinoma]) treated with a first- or second-line oral targeted therapy without chemotherapy will be included. Patients will be randomized (2:1) to a 3-month supervised home-based standardized physical activity program or to a recommended adapted physical activity (via a booklet). The primary objective of the phase II is to evaluate the feasibility of the supervised program. The primary objective of the phase III is the evaluation of the benefit of the supervised home-based program compare to the recommended program in terms of fatigue and quality of life at 3 months. The secondary objectives aim to evaluate the impact of the supervised program on fatigue over time, pain, physical capacities, psychosocial and cognitive functions, general quality of life, frequency of dose reduction and patients’ adherence to the targeted therapy, overall survival, and progression-free survival. This study will also evaluate the medico-economic impact of supervised program compared to the recommended adapted physical activity program. Discussion The aim of this study is to evaluate home-based physical exercise program for metastatic cancer patients treated with oral targeted therapies to help patients to cope with fatigue and improve quality of life. Trial registration This trial was registered in ClinicalTrials.gov since May 2017 ( NCT03169075 ).

Abstract Introduction In the work-up strategy for pulmonary embolism (PE) in the ED, the recently introduced YEARS rule allows the raising of the D-dimer threshold to 1000 ng/ml in patients with no signs of deep venous thrombosis and no hemoptysis and in whom PE is not the most likely diagnosis. However, this decision rule has never been prospectively compared to the usual strategy. Furthermore, it is unclear if the YEARS rule can be used on top of the Pulmonary Embolism Rule-out Criteria (PERC). We aim to assess the non-inferiority of YEARS compared to current guidelines to rule out PE among PERC-positive ED patients with suspicion of PE. Methods/design The MODIGLIANI study is a multicenter, European, non-inferiority, cluster-randomized, two periods cross-over, controlled trial. Each center will be randomized for the sequence of two 4-month periods: intervention (MOdified Diagnostic Strategy: MODS) followed by control (usual care), or control followed by intervention with 1 month of “wash-out” between the two periods. In the control period, the threshold will be as usual (500 ng/ml for patients aged 50 years or younger and age × 10 for older patients). In the MODS period, the threshold of D-dimers to rule out PE will be raised to 1000 ng/ml if no item of the YEARS score is present or will remain unchanged otherwise. Patients will be included if they have a suspicion of PE, defined as chest pain, dyspnea, or syncope. Non-inclusion criteria comprise a high clinical probability of PE or PERC-negative patients with low clinical probability. Ethics and dissemination The study has received the following approvals: Comité de protection des personnes Ile de France XI (France) and Comité de Ética de la Investigación con medicamentos del Hospital Clínic de Barcelona (Spain). Results will be made available to all included participants and other researchers. Trial registration ClinicalTrials.gov, NCT04032769 . Registered on 24 July 2019.

Abstract Background A utility value is a health-related quality of life metric (HRQoL) metric used in a cost-effectiveness analysis. While utilities as outcomes in the treatment of advanced Parkinson’s disease (PD) with deep brain stimulation (DBS) are available, they do not currently exist for PD with early motor complications. The objectives of this study were to predict utilities from observed disease-specific HRQoL data using two mapping algorithms, and investigate their performance in terms of longitudinal changes within and between treatment groups, and distribution by PD severity. Methods This is a post hoc analysis of data from the EARLYSTIM trial of DBS compared with best medical therapy (BMT) in PD patients with early motor complications We used two published algorithms comprising ordinal and multinomial regression models to map EQ-5D-3L utilities from observed PD-specific 39 item Questionnaire (PDQ-39) scores in EARLYSTIM. Utilities were calculated using the predicted functioning levels of EQ-5D-3L dimensions and the established EQ-5D-3L UK tariffs. Statistical analyses (analysis of variance, two-tailed Student’s t-test) were used to test the change from baseline within groups and difference in change from baseline between groups in utilities. Boxplots were developed to investigate the distribution of predicted utilities by PD severity, measured using the Hoehn and Yahr scale. Results The change from baseline in predicted mean utilities was statistically significant at all visits up to 24 months for the DBS group (p

Abstract Background The diagnostic performance of 18F-sodium fluoride positron emission tomography/computed tomography (PET/CT) (NaF), 18F-fluorocholine PET/CT (FCH) and diffusion-weighted whole-body magnetic resonance imaging (DW-MRI) in detecting bone metastases in prostate cancer (PCa) patients with first biochemical recurrence (BCR) has already been published, but their cost-effectiveness in this indication have never been compared. Methods We performed trial-based and model-based economic evaluations. In the trial, PCa patients with first BCR after previous definitive treatment were prospectively included. Imaging readings were performed both on-site by local specialists and centrally by experts. The economic evaluation extrapolated the diagnostic performances of the imaging techniques using a combination of a decision tree and Markov model based on the natural history of PCa. The health states were non-metastatic and metastatic BCR, non-metastatic and metastatic castration-resistant prostate cancer and death. The state-transition probabilities and utilities associated with each health state were derived from the literature. Real costs were extracted from the National Cost Study of hospital costs and the social health insurance cost schedule. Results There was no significant difference in diagnostic performance among the 3 imaging modalities in detecting bone metastases. FCH was the most cost-effective imaging modality above a threshold incremental cost-effectiveness ratio of 3000€/QALY when imaging was interpreted by local specialists and 9000€/QALY when imaging was interpreted by experts. Conclusions FCH had a better incremental effect on QALY, independent of imaging reading and should be preferred for detecting bone metastases in patients with biochemical recurrence of prostate cancer. Trial registration NCT01501630 . Registered 29 December 2011.

Abstract Background Non-medical data, such as the amount of time that patients and caregivers spend managing their condition, may be relevant when assessing therapeutic strategies. For chronic pediatric conditions, the time that patients and caregivers spend in seeking and providing care (which are the indirect costs in an economic evaluation) can be significantly different depending on the treatment arm. To explore methods for collecting information on the care burden for caregivers and patients, we investigated whether a patient diary provided additional information compared to retrospective investigator-led interviews and whether a diary that was completed intermittently produced more or less information than a diary completed continually. The main objective of this study was to identify which type of data collection was most effective for measuring the time spent by caregivers and for estimating indirect treatment costs over 9 months. Methods Start-In! is a randomized controlled trial comparing the efficacy of three strategies of real-time continuous glucose monitoring for 12 months in children and adolescents with type 1 diabetes. We designed an ancillary study to assess methods of collecting information on the time spent by patients and caregivers in managing their condition (indirect costs). Data were entered retrospectively in case report forms (CRFs) by investigators during quarterly follow-up visits, which were supplemented with diaries completed prospectively by children or caregivers either continuously or intermittently. Data about absences from school and work as well as the time that caregivers spent on diabetes care were collected and the three collection methods were compared. Results At the end of the 9-month study, 42% of the study participants failed to return their diary. For the diaries that were received, less than 10% of expected data were collected versus 82% during investigators'interviews. Based on all the information collected, we calculated that over 9 months, caregivers lost on average 3.9 days of working time (€786) and 4 days of personal time, i.e. the equivalent of €526, and spent around 15 min of time on care per day, i.e. the equivalent of €1700. Conclusions The CRFs completed by investigators during quarterly visits cannot be replaced by a diary. Completing the diaries appeared to represent an important additional burden to children and their caregivers, and the diaries provided little additional information compared to investigators’ entries in the CRF. Trial registration ClinicalTrials.gov, NCT00949221. Registered on 30 July 2009. Registry name: Study of Insulin Therapy Augmented by Real Time Sensor in Type 1 Children and Adolescents (START-IN!).

Background and objectives: Venous thromboembolism (VTE) represents a health and economic burden with consequent healthcare resource utilization. Direct oral anticoagulants (DOACs) have emerged as the mainstay option for VTE treatment but few data exist on their cost-effectiveness as compared to the standard therapy (vitamin K antagonists (VKAs)). This study aimed to assess the cost-effectiveness of rivaroxaban compared to VKAs in VTE treatment by calculating the incremental cost effectiveness ratio (ICER). Materials and methods: We conducted a prospective observational study based on the REMOTEV registry, including patients hospitalized for VTE from 23 October 2013 to 31 July 2015, to evaluate the impact of the anticoagulant treatment (DOACs versus VKAs) on 6-month complications: major or clinically relevant non-major bleeding, VTE recurrence and all-cause death. Rivaroxaban was the only DOAC prescribed in this study. The ICER was calculated as the difference in costs divided by the difference in effectiveness. Results: Among the 373 patients included, 279 were treated with rivaroxaban (63.1 ± 17.9 years old; 49% men) and 94 with VKAs (71.3 ± 16.6 years old; 46% men). The mean cost was EUR 5662 [95% CI 6606; 9060] for rivaroxaban and EUR 7721 [95% CI 5130; 6304] for VKAs, while effectiveness was 0.0586 95% CI [0.0114; 0.126] for DOACs and 0.0638 [95% CI 0.0208; 0.109] for VKAs. The rivaroxaban treatment strategy was dominant with costs per patient EUR 2059 lower [95% CI −3582; −817] and a higher effectiveness of 0.00527 [95% CI −0.0606; 0.0761] compared to VKAs. Conclusions: This study provides real-world evidence that rivaroxaban is not only an efficient and safe alternative to VKAs for eligible VTE patients, but also cost-saving.

Introduction At the time of the worrying emergence and spread of bacterial resistance, reducing the selection pressure by reducing the exposure to antibiotics in patients with community-acquired pneumonia (CAP) is a public health issue. In this context, the combined use of molecular tests and biomarkers for guiding antibiotics discontinuation is attractive. Therefore, we have designed a trial comparing an integrated approach of diagnosis and treatment of severe CAP to usual care.Methods and analysis The multiplex PCR and procalcitonin to reduce duration of antibiotics exposure in patients with severe-CAP (MULTI-CAP) trial is a multicentre (n=20), parallel-group, superiority, open-label, randomised trial. Patients are included if adult admitted to intensive care unit for a CAP. Diagnosis of pneumonia is based on clinical criteria and a newly appeared parenchymal infiltrate. Immunocompromised patients are excluded. Subjects are randomised (1:1 ratio) to either the intervention arm (experimental strategy) or the control arm (usual strategy). In the intervention arm, the microbiological diagnosis combines a respiratory multiplex PCR (mPCR) and conventional microbiological investigations. An algorithm of early antibiotic de-escalation or discontinuation is recommended, based on mPCR results and the procalcitonin value. In the control arm, only conventional microbiological investigations are performed and antibiotics de-escalation remains at the clinician’s discretion. The primary endpoint is the number of days alive without any antibiotic from the randomisation to day 28. Based on our hypothesis of 2 days gain in the intervention arm, we aim to enrol a total of 450 patients over a 30-month period.Ethics and dissemination The MULTI-CAP trial is conducted according to the principles of the Declaration of Helsinki, is registered in Clinical Trials and has been approved by the Committee for Protection of Persons and the National French Drug Safety Agency. Written informed consents are obtained from all the patients (or representatives). The results will be disseminated through educational institutions, submitted to peer-reviewed journals for publication and presented at medical congresses.Trial registration number NCT03452826; Pre-results.

Abstract Background The transplantation process usually takes place without transplant teams being able to use imaging data to assess graft quality. The decision of whether to go get the graft or not is therefore limited and suboptimal. “Cristal images” is a teleimaging project allowing real-time visualization of images of the organs of the donor. The objective of our study is to assess whether the use of a secure teleimaging can improve the effectiveness and efficiency of the procurement and transplantation processes. Methods We will use the exhaustive national registry of organ allocation and transplantation, and compare outcomes before the deployment of “Cristal images” (years 2015–2016) and after it becomes operational (years 2018–2019) for heart, lung, liver and kidney transplant in a before-after study, combined with a preference elicitation study. The primary endpoint will be the number of successful organ transplantations. Secondary endpoints will be related to the efficiency of the transplant process (decision making, transportation, cost) and a preference elicitation study will determine the relative preferences of transplant teams towards few “Cristal images”’ components or potential developments, which are yet to be determined through a qualitative analysis based on interviews with professionals. Discussion This study will provide stakeholders data on the efficiency of real-time visualization for transplant teams and identify the levers likely to influence the technology use among these teams. Trial registration clinicaltrials.gov: NCT03201224, 13 June 2017, retrospectively registered.

Abstract Background The determination of foetal Rhesus D (RHD) status allows appropriate use of IgRh prophylaxis by restricting its use to cases of RHD feto-maternal incompatibilities. There is a degree of uncertainty about the cost-effectiveness of foetal RHD determination, yet screening programs are being introduced into clinical practice in many countries. This paper evaluates the impact of non-invasive foetal Rhesus D (RHD) status determination on the costs of managing RHD-negative pregnant women and on the appropriate use of anti-D prophylaxis in a large sample of RHD-negative pregnant women using individual prospectively collected clinical and economic data. Methods A prospective two-armed trial of RHD negative pregnant women was performed in 11 French Obstetric Departments. Non-invasive foetal RHD genotyping was performed before 26 weeks' gestation in the experimental arm whereas the control arm participants received usual care. The costs associated with patient management in relation to their RHD negative status (biological tests, anti-D prophylaxis and visits) were calculated from inclusion to the end of the postpartum period. The costs of hospital admissions during pregnancy and delivery were also determined. Results A total of 949 patients were included by 11 centres between 2009 and 2012, and 850 completed follow-up, including medical and biological monitoring. Patients were separated into two groups: the genotyping group (n=515) and the control group (n=335). The cost of the genotyping was estimated at 140 euros per test. The total mean cost per patient was estimated at €3,259 (SD ± 1,120) and €3,004 (SD ± 1,004) in the genotyping and control groups respectively. The cost of delivery represented three quarters of the total cost in both groups. The performance of managing appropriately RHD negative anti-D prophylaxis was 88% in the genotyping group, versus 65% in the control group. Using the costs related to RHD status (biological tests, anti-D immunoglobulin injections and visits) the incremental cost-effectiveness ratio (ICER) was calculated to be €578 for each percentage gain in women receiving appropriate management. Conclusion Early knowledge of the RHD status of the foetus using non-invasive foetal RHD genotyping significantly improved the management of RHD negative pregnancies with a small increase in cost. Trial registration Clinical trials registry-NCT00832962–13 January 2009 - retrospectively registered.

Objective To assess trends in the average costs and effectiveness of the French ultrasound screening programme for birth defects.Design A population-based study.Setting National Public Health Insurance claim database.Participants All pregnant women in the ‘Echantillon Généraliste des Bénéficiaires’, a permanent representative sample of 1/97 of the individuals covered by the French Health Insurance System.Main outcomes measures Trends in the costs and in the average cost-effectiveness ratio (ACER) of the screening programme (in € per case detected antenatally), per year, between 2006 and 2014. incremental cost-effectiveness ratio (ICER) from 1 year to another were also estimated. We assessed costs related to the ultrasound screening programme of birth defects excluding the specific screening of Down’s syndrome. The outcome for effectiveness was the prenatal detection rate of birth defects, assessed in a previous study. Linear and logistic regressions were used to analyse time trends.Results During the study period, there was a slight decrease in prenatal detection rates (from 58.2% in 2006 to 55.2% in 2014; p=0.015). The cost of ultrasound screening increased from €168 in 2006 to €258 per pregnancy in 2014 (p=0.001). We found a 61% increase in the ACER for ultrasound screening during the study period. ACERs increased from €9050 per case detected in 2006 to €14 580 per case detected in 2014 (p=0.001). ICERs had an erratic pattern, with a strong tendency to show that any increment in the cost of screening was highly cost ineffective.Conclusion Even if the increase in costs may be partly justified, we observed a diminishing returns for costs associated with the prenatal ultrasound screening of birth defects, in France, between 2006 and 2014.

Abstract Background Territorial differences in the access to innovative anticancer drugs have been reported from many countries. The objectives of this study were to evaluate access to innovative treatments for metastatic lung cancer in France, and to assess whether socioeconomic indicators were predictors of access at the level of the municipality of residence. Methods All incident cases of metastatic lung cancer hospitalised for a chemotherapy in public hospitals in 2011 were identified from the French National Hospital discharge database. Information on prescription of innovative drugs from an associated database (FICHCOMP) was crossed with the population density of the municipality and a social deprivation index based on national census data. Results Overall, 21,974 incident cases of metastatic lung cancer were identified, all of whom were followed for 2 years. Of the 11,486 analysable patients receiving chemotherapy in the public sector, 6959 were treated with a FICHCOMP drug at least once, principally pemetrexed. In multivariate analysis, prescription of FICHCOMP drugs was less frequent in patients ≥66 years compared to those ≤55 years (odds ratio: 0.49 [0.44–0.55]), in men compared to women (0.86 [0.79–0.94]) and in patients with renal insufficiency (0.55 [0.41–0.73]) and other comorbidities. Prescription rates were also associated with social deprivation, being lowest in the most deprived municipalities compared to the most privileged municipalities (odds ratio: 0.82 [0.72–0.92]). No association was observed between the population density of the municipality and access to innovative drugs. Conclusion Although access to innovative medication in France seems to be relatively equitable, social deprivation is associated with poorer access. The reasons for this need to be investigated and addressed.

Abstract Background The REVOLENS study compared lung volume reduction coil treatment to usual care in patients with severe emphysema at 1 year, resulting in improved quality-adjusted life-year (QALY) and higher costs. Durability of the coil treatment benefit and its cost-effectiveness at 2 years are now assessed. Methods After one year, the REVOLENS trial’s usual care group patients received coil treatment (second-line coil treatment group). Costs and QALYs were assessed in both arms at 2 years and an incremental cost-effectiveness ratio in cost per QALY gained was calculated. The uncertainty of the results was estimated by probabilistic bootstrapping. Results The average cost of coil treatment in both groups was estimated at €24,356. The average total cost at 2 years was €9655 higher in the first-line coil treatment group (p = 0.07) and the difference in QALY between the two groups was 0.127 (p = 0.12) in favor of first-line coil treatment group. The 2-year incremental cost-effectiveness ratio (ICER) was €75,978 / QALY. The scatter plot of the probabilistic bootstrapping had 92% of the replications in the top right-hand quadrant. Conclusion First-line coil treatment was more expensive but also more effective than second-line coil treatment at 2 years, with a 2-year ICER of €75,978 / QALY. Trial registration ClinicalTrials.gov Identifier NCT01822795.

Whilst much uncertainty exists as to the efficacy of renal denervation (RDN), the positive results of the DENERHTN study in France confirmed the interest of an economic evaluation in order to assess efficiency of RDN and inform local decision makers about the costs and benefits of this intervention. The uncertainty surrounding both the outcomes and the costs can be described using health economic methods such as the non-parametric bootstrap. Internationally, numerous health economic studies using a cost-effectiveness model to assess the impact of RDN in terms of cost and effectiveness compared to antihypertensive medical treatment have been conducted. The DENERHTN cost-effectiveness study was the first health economic evaluation specifically designed to assess the cost-effectiveness of RDN using individual data. Using the DENERHTN results as an example, we provide here a summary of the principle methods used to perform a cost-effectiveness analysis.

Abstract Background Patient characteristics and survival outcomes in randomized trials may be different from those in real-life clinical practice. The objective of this study was to describe treatment pathways, safety, drug costs and survival in patients with metastatic Renal Cell Carcinoma (mRCC) in a real world setting. Methods A retrospective analysis was performed using IQVIA real world oncology cross-sectional survey data, a retrospective treatment database collecting anonymized patient-level data in Europe. Data on treatment naïve patients with mRCC who received a first-line targeted therapy in France were extracted for the period 2005–2015. Descriptive analyses were performed on treatment patterns, patient characteristics and safety profiles. Progression Free Survival (PFS) was determined using Kaplan-Meier survival analysis. Results One thousand three hundred thirty-one patients with mRCC who received a first-line targeted therapy were included. The male/female sex ratio was 2.5 and 66% of patients were aged > 60 years. 83% of patients had clear cell adenocarcinoma. 83% of patients underwent a surgical procedure, 10% had radiotherapy. In patients who received a first-line targeted therapy, 73% received sunitinib. The mean time from diagnosis to first-line treatment by targeted therapies in patients initially diagnosed with metastatic disease was 3.3 months [95% CI:2.5–4.1]. In patients who received second-line targeted therapy n = 257 (19%), the most frequently observed treatment sequences were sunitinib-everolimus (33%) and sunitinib-sorafenib (27%). Adverse events data were available for 501 patients and adverse events were documented in 70% of patients, most frequently diarrhoea. The overall median PFS was 13 months [95% CI:11.5–16]. Conclusion Patient characteristics were consistent with the literature. Treatment patterns appeared to follow current practice guidelines. Despite some variations, PFS in our study seems to be consistent with findings from other real world studies. Nevertheless, PFS results were higher than those observed in clinical trials. Due to the use of cross-sectional data, PFS in our study should be interpreted with caution.

Abstract Background Cytomegalovirus (CMV) infection and disease (CMV episodes) are global concerns after allogeneic hematopoietic stem cell transplantation (HSCT). They affect survival, both by direct and indirect effects. Due to safety issues of current anti-CMV antivirals, long-term CMV prophylaxis is poorly tolerated and the most common strategy to decrease the incidence of CMV disease is preemptive. New, less toxic, molecules are currently being assessed for CMV prophylaxis which should replace or considerably decrease the preemptive approach. The aim of this study was to assess the economic burden of CMV episodes after HSCT with a preemptive approach. Methods We analyzed data from 208 consecutive adults transplanted in our institution, between 2008 and 2013. Hospital resource utilization was retrieved via the linked hospital admissions and Diagnostic Related Groups for the period of conditioning to 12 months after transplant. Results CMV episodes occurred in 70 patients (34%) over the first 12 months following HSCT, after a mean of 75 days (median: 46 (7–334)). The mean total length of stay was significantly associated with the occurrence of a CMV episode (113.9 vs. 87.5 days, p = 0.0002) but was associated neither with the pre-transplant CMV serology of donors/recipients nor with survival. The mean cost of transplant was €104,016 (SD = €37,281) after 12 months. Bivariate and multivariate analyses indicated that the occurrence of >1 CMV episode increased the costs of allogeneic HSCT by 25–30% (p

Abstract Background Cooling may reduce infarct size and improve neurological outcomes in patients with ischaemic stroke. In phase II trials, cooling awake patients with ischaemic stroke has been shown to be feasible and safe, but the effects in functional outcomes has not yet been investigated in an adequately sized randomised clinical trial. Methods/design The EuroHYP-1 trial is a multinational, randomised, superiority phase III clinical trial with masked outcome assessment testing the benefits and harms of therapeutic cooling in awake adult patients with acute ischaemic stroke. The outcomes dealt with here include the primary outcome the Rankin score (mRS) at day 91 +/-14 days after randomisation. The secondary and exploratory outcomes at day 91 +/-14 days unless otherwise stated encompassing: (1) death or dependency, defined as mRS score > 2; (2) death; (3) National Institutes of Health Stroke Score; (4) brain infarct size at 48 +/-24 hours; (5) EQ-5D-5 L score, and (6) WHODAS 2.0 score. Other outcomes are: the primary safety outcome serious adverse events; and the incremental cost-effectiveness, and cost utility ratios. The analysis sets include (1) the intention-to-treat population, and (2) the per protocol population. The sample size is estimated to 800 patients (5% type 1 and 20% type 2 errors). All analyses are adjusted for the protocol-specified stratification variables (nationality of centre), and the minimisation variables. In the analysis, we use ordinal regression (the primary outcome), logistic regression (binary outcomes), general linear model (continuous outcomes), and the Poisson or negative binomial model (rate outcomes). Discussion Major adjustments compared with the original statistical analysis plan encompass: (1) adjustment of analyses by nationality; (2) power calculations for the secondary outcomes; (3) to address the multiplicity problem using of a fixed-sequence testing procedure starting with the primary outcome followed by the secondary outcomes ordered according to falling power; (4) assignment of worst possible score to patients who are not alive at the planned date of measurement of the continuous scores; (5) improved imputations; (6) outline of a supplementary exploratory analysis of the temperature measurements and time to death; and (7) substantial reduction of sample size. Trial registration Clinicaltrials.gov, identifier: NCT01833312 . 4 April 2013.

Introduction Fractures of the tibial plateau are in constant progression. They affect an elderly population suffering from a number of comorbidities, but also a young population increasingly practicing high-risk sports. The conventional open surgical technique used for tibial plateau fractures has several pitfalls: bone and skin devascularisation, increased risks of infection and functional rehabilitation difficulties. Since 2011, Poitiers University Hospital is offering to its patients a new minimally invasive technique for the reduction and stabilisation of tibial plateau fractures, named ‘tibial tuberoplasty’. This technique involves expansion of the tibial plateau through inflation using a kyphoplasty balloon, filling of the fracture cavity with cement and percutaneous screw fixation. We designed a study to evaluate the quality of fracture reduction offered by percutaneous tuberoplasty versus conventional open surgery for tibial plateau fracture and its impact on clinical outcome.Methods and analysis This is a multicentre randomised controlled trial comparing two surgical techniques in the treatment of tibial plateau fractures. 140 patients with a Schatzker II or III tibial plateau fracture will be recruited in France. They will be randomised either in tibial tuberoplasty arm or in conventional surgery arm. The primary outcome is the postoperative radiological step-off reduction blindly measured on CT scan (within 48 hours post-op). Additional outcomes include other radiological endpoints, pain, functional abilities, quality of life assessment and health-economic endpoints. Outcomes assessment will be performed at baseline (before surgery), at day 0 (surgery), at 2, 21, 45 days, 3, 6, 12 and 24 months postsurgery.Ethics and dissemination This study has been approved by the ethics committee Ile-De-France X and will be conducted in accordance with current Good Clinical Practice (GCP) guidelines, Declaration of Helsinki and standard operating procedures. The results will be disseminated through presentation at scientific conferences and publication in peer-reviewed journals.Trial registration number Clinicaltrial.gov:NCT03444779.

ObjectiveTo assess the cost-effectiveness of acupuncture for pelvic girdle and low back pain (PGLBP) during pregnancy.DesignPragmatic-open-label randomised controlled trial.SettingFive maternity hospitals.PopulationPregnant women with PGLBP.Method1:1 randomization to standard care or standard care plus acupuncture (5 sessions by an acupuncturist midwife).Main outcome measureEfficacy: proportion of days with self-assessed pain by numerical rating scale (NRS) ≤ 4/10. Cost effectiveness (societal viewpoint, time horizon: pregnancy): incremental cost per days with NRS ≤ 4/10. Indirect non-healthcare costs included daily compensations for sick leave and productivity loss caused by absenteeism or presenteeism.Results96 women were allocated to acupuncture and 103 to standard care (total 199). The proportion of days with NRS ≤ 4/10 was greater in the acupuncture group than in the standard care group (61% vs 48%, p = 0.007). The mean Oswestry disability score was lower in the acupuncture group than with standard care alone (33 versus 38, Δ = 5, 95% CI: 0.8 to 9, p = 0.02). Average total costs were higher in the control group (€2947) than in the acupuncture group (€2635, Δ = -€312, 95% CI: -966 to +325), resulting from the higher indirect costs of absenteeism and presenteeism. Acupuncture was a dominant strategy when both healthcare and non-healthcare costs were included. Costs for the health system (employer and out-of-pocket costs excluded) were slightly higher for acupuncture (€1512 versus €1452, Δ = €60, 95% CI: -272 to +470).ConclusionAcupuncture was a dominant strategy when accounting for employer costs. A 100% probability of cost-effectiveness was obtained for a willingness to pay of €100 per days with pain NRS ≤ 4.

In France, secondary care hospitals encounter difficulties to adhere to retinopathy of prematurity (ROP) screening guidelines. Our objective was to assess the effectiveness and efficacy of a tele-expertise program for ROP screening in neonatal intensive care units without on-site ophthalmologists. We evaluated the impact of a tele-expertise program funded by the Paris Region Health Authority in a secondary care center general hospital of the Paris Region (CHSF), where there was previously no on-site ophthalmologist. We performed an observational, controlled before-after study, with a university tertiary care center with on-site ophthalmologists (Port-Royal) as the control group. Recruitment and data collection for both periods took place from 1 January 2012 to 31 December 31 2012, and from 1 January 2014 to 31 March 2015. The primary endpoint was the percentage of compliance with screening guidelines, secondary endpoints included pain scores and costs. Over the two periods, at total of 351 infants were recruited in the CHSF. Implementation of the tele-expertise resulted in an absolute +57.3% increase in the proportion of examinations realized in accordance with guidelines (3.8% during the "before" period and 61.1% during the "after" period, p

To assess the cost-effectiveness of the elbasvir/grazoprevir (EBR/GZR) regimen in patients with genotype 1 chronic hepatitis C virus (HCV) infection with severe and end-stage renal disease compared to no treatment.This study uses a health economic model to estimate the cost-effectiveness of treating previously untreated and treatment experienced chronic hepatitis C patients who have severe and end stage renal disease with the elbasvir-grazoprevir regimen versus no treatment in the French context. The lifetime homogeneous markovian model comprises of forty combined health states including hepatitis C virus and chronic kidney disease. The model parameters were from a multicentre randomized controlled trial, ANRS CO22 HEPATHER French cohort and literature. 1000 Monte Carlo simulations of patient health states for each treatment strategy are used for probabilistic sensitivity analysis and 95% confidence intervals calculations. The results were expressed in cost per quality-adjusted life year (QALY) gained.The mean age of patients in the HEPATHER French cohort was 59.6 years and 56% of them were men. 22.3% of patients had a F0 fibrosis stage (no fibrosis), 24.1% a F1 stage (portal fibrosis without septa), 7.1% a F2 stage (portal fibrosis with few septa), 21.4% a F3 stage (numerous septa without fibrosis) and 25% a F4 fibrosis stage (compensated cirrhosis). Among these HCV genotype 1 patients, 30% had severe renal impairment stage 4, 33% had a severe renal insufficiency stage 5 and 37% had terminal severe renal impairment stage 5 treated by dialysis.Fixed-dose combination of direct-acting antiviral agents elbasvir and grazoprevir compared to no-treatment.EBR/GZR increased the number of life years (6.3 years) compared to no treatment (5.1 years) on a lifetime horizon. The total number of QALYs was higher for the new treatment because of better utility on health conditions (6.2 versus 3.7 QALYs). The incremental cost-utility ratio (ICUR) was of €15,212 per QALY gained for the base case analysis.This cost-utility model is an innovative approach that simultaneously looks at the disease evolution of chronic hepatitis C and chronic kidney disease. EBR/GZR without interferon and ribavirin, produced the greatest benefit in terms of life expectancy and quality-adjusted life years (QALY) in treatment-naïve or experienced patients with chronic hepatitis C genotype 1 and stage 4-5 chronic kidney disease including dialysis patients. Based on shape of the acceptability curve, EBR/GZR can be considered cost-effective at a willingness to pay of €20,000 /QALY for patients with renal insufficiency with severe and end-stage renal disease compared to no treatment.

CONTEXT:The prevalence of skin diseases among prisoners is higher than in the general population. Diagnosing and treating these lesions require a dermatologic advice. A tele-expertise network in dermatology for prisoners including 8 health facilities in prison and 2 hospital dermatological departments was developed to improve access to dermatologists' expertise in correctional facilities. Our objective was to evaluate the effectiveness and costs of tele-expertise in dermatology for prisoners. METHODS:We carried out a retrospective cohort study on data collected by the information system of the tele-expertise network. We used the MAST (Model for ASsessment of Telemedicine) model to perform a multidimensional assessment including the proportion of patients with a completed treatment plan for the skin lesions, the proportion of technical problems, the quality of the pictures, the investment and operating costs and the satisfaction of the professionals. RESULTS:Mean patient age was 34.2 years with 90% men. 511 requests for 450 patients were initiated. The delay from the connection to the tele-expertise software to the validation of the request was inferior to 7 min for 50% of the requests and inferior to 30 min for 85% of the requests. Overall, with tele-expertise, 82% of the patients had a completed treatment plan for the skin lesions, with 2.9% of all patients requiring a later face-to-face appointment or hospitalization, to be compared to a proportion of 35% of patients with a completed treatment plan when tele-expertise was not available. The most frequent lesions were acnea (22%) and atopic dermatitis (18%). The mean cost for one completed treatment plan was €184 by tele-expertise and €315 without tele-expertise. Tele-expertise was well accepted among physicians with all responders (n = 9) willing to continue using it. CONCLUSION:Tele-expertise is a dominant intervention in comparison to a face-to face consultation taking into account the cost of transportation and the proportion of canceled appointments and is acceptable for physicians. TRIAL REGISTRATION:NCT02309905.

Background: We evaluated first the feasibility of endoscopic small-bowel polypectomy and second, the economic aspects, by comparing the cost of endoscopic and surgical polyp resection. Methods: A prospective, observational, multicenter study included 494 patients with positive capsule endoscopy (CE) before double-balloon enteroscopy (DBE). We selected only CE with at least one polyp. The retrospective economic evaluation compared patients treated by DBE or surgery for small-bowel polypectomy. Hospital readmission because of repeat polyp resection or complication-related interventions was noted. The 1-year cost was estimated from the viewpoint of the healthcare system and included procedures, hospital admissions and follow up. Results: CE indicated one or more polyps in 62 (12.5%) patients (32 males, 49 ± 5 years), all of whom underwent a successful DBE exploration. The DBE polyp diagnostic yield was 58%. There were no major complications. A total of 26 (42%) patients in the DBE group and 19 (39%) in the control group required hospital readmission. All readmissions in the DBE group were for repeat procedures to remove all polyps, and in the control group, for surgical complications. The total cost of the initial hospitalization (€4014 ± 2239 DBE versus €11,620 ± 7183 surgery, p < 0.0001) and the 1-year total cost (€8438 ± 9227 DBE versus €13,402 ± 7919 surgery, p < 0.0001) were lower in the DBE group. Conclusions: Endoscopic polypectomy was efficient and safe. The total cost at 1 year was less for endoscopy than surgery. DBE should be proposed as the first-line treatment for small-bowel polyp resection.

The French healthcare system is a universal healthcare system with no financial barrier to access to health services and cancer drugs. The objective of the study is to investigate associations between, on the one hand, incidence and survival of patients diagnosed with lung cancer in France and, on the other, the socioeconomic deprivation and population density of their municipality of residence. A national, longitudinal analysis using data from the French National Hospital database crossed with the population density of the municipality and a social deprivation index based on census data aggregated at the municipality level. For lung cancer diagnosed at the metastatic stage, one-year and two-year survival was not associated with the population density of the municipality of residence. In contrast, mortality was higher for people living in very deprived, deprived and privileged areas compared to very privileged areas (hazard ratios at two years: 1.19 [1.13-1.25], 1.14 [1.08-1.20] and 1.10 [1.04-1.16] respectively). Similar associations are also observed in patients diagnosed with non-metastatic disease (hazard ratios at two years: 1.21 [1.13-1.30], 1.15 [1.08-1.23] and 1.10 [1.03-1.18] for people living in very deprived, deprived and privileged areas compared to very privileged areas). Despite a universal healthcare coverage, survival inequalities in patients with lung cancer can be observed in France with respect to certain socioeconomic indicators.

CONTEXT:In France more than 70,000 deaths from diseases related to smoking are recorded each year, and since 2005 prevalence of tobacco has increased. Providing free access to smoking cessation treatment would reduce this burden. The aim of our study was to estimate the incremental cost-effectiveness ratios (ICER) of providing free access to cessation treatment taking into account the cost offsets associated with the reduction of the three main diseases related to smoking: lung cancer, chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD). To measure the financial impact of such a measure we also conducted a probabilistic budget impact analysis. METHODS AND FINDINGS:We performed a cost-effectiveness analysis using a Markov state-transition model that compared free access to cessation treatment to the existing coverage of €50 provided by the French statutory health insurance, taking into account the cost offsets among current French smokers aged 15-75 years. Our results were expressed by the incremental cost-effectiveness ratio in 2009 Euros per life year gained (LYG) at the lifetime horizon. We estimated a base case scenario and carried out a Monte Carlo sensitivity analysis to account for uncertainty. Assuming a participation rate of 7.3%, the ICER value for free access to cessation treatment was €3,868 per LYG in the base case. The variation of parameters provided a range of ICER values from -€736 to €15,715 per LYG. In 99% of cases, the ICER for full coverage was lower than €11,187 per LYG. The probabilistic budget impact analysis showed that the potential cost saving for lung cancer, COPD and CVD ranges from €15 million to €215 million at the five-year horizon for an initial cessation treatment cost of €125 million to €421 million. CONCLUSION:The results suggest that providing medical support to smokers in their attempts to quit is very cost-effective and may even result in cost savings.

BACKGROUND & OBJECTIVES:The aim of this study was to assess the economic burden of hospitalisations for metastatic renal cell carcinoma (mRCC), to describe the patterns of prescribing expensive drugs and to explore the impact of geographic and socio-demographic factors on the use of these drugs. METHODS:We performed a retrospective analysis from the French national hospitals database. Hospital stays for mRCC between 2008 and 2013 were identified by combining the 10th revision of the International Classification of Diseases (ICD-10) codes for renal cell carcinoma (C64) and codes for metastases (C77 to C79). Incident cases were identified out of all hospital stays and followed till December 2013. Descriptive analyses were performed with a focus on hospital stays and patient characteristics. Costs were assessed from the perspective of the French National Health Insurance and were obtained from official diagnosis-related group tariffs for public and private hospitals. RESULTS:A total of 15,752 adult patients were hospitalised for mRCC, corresponding to 102,613 hospital stays. Of those patients, 68% were men and the median age at first hospitalisation was 69 years [Min-Max: 18-102]. Over the study period, the hospital mortality rate reached 37%. The annual cost of managing mRCC at hospital varied between 28M€ in 2008 and 42M€ in 2012 and was mainly driven by inpatient costs. The mean annual per capita cost of hospital management of mRCC varied across the study period from 8,993€ (SD: €8,906) in 2008 to 10,216€ (SD: €10,527) in 2012. Analysis of the determinants of prescribing expensive drugs at hospital did not show social or territorial differences in the use of these drugs. CONCLUSION:This study is the first to investigate the in-hospital economic burden of mRCC in France. Results showed that in-hospital costs of managing mRCC are mainly driven by expensive drugs and inpatient costs.

OBJECTIVES: To estimate annual direct costs of early RA by resource component in an inception cohort, with reference to four distinct treatment strategies: no disease modifying antirheumatic drugs (DMARDs), synthetic DMARDs only, biologic DMARDs in the first year ('first-year biologic', FYB), and biologic DMARDs from the second year after inclusion ('later-year biologic', LYB); to determine predictors of total and non-DMARD related costs. METHODS: The ESPOIR cohort is a French multicentric, prospective study of 813 patients with early arthritis. Data assessing RA-related resource utilisation and disease characteristics were collected at baseline, biannually during the first two years and annually thereafter. Costs predictors were determined by generalised linear mixed analyses. RESULTS: Over the 4-year follow-up, mean annual direct total costs per treatment strategy group were €3,612 for all patients and €998, €1,922, €14,791, €8,477 respectively for no DMARDs, synthetic DMARDs only, FYB and LYB users. The main predictors of higher costs were biologic use and higher Health Assessment Questionnaire (HAQ) scores at baseline. Being a biologic user led to a higher total cost (FYB Rate Ratio (RR) 7.22, [95% CI 5.59-9.31]; LYB RR 4.39, [95% CI 3.58-5.39]) compared to non-biologic users. Only LYB increased non-DMARD related costs compared to all other patients by 60%. CONCLUSIONS: FYB users incurred the highest levels of total costs, while their non-DMARD related costs remained similar to non-biologic users, possibly reflecting better RA control.

Rapid advances in the understanding of cancer biology have transformed drug development thus leading to the approval of targeted therapies and to the development of molecular tests to select patients that will respond to treatments. KRAS status has emerged as a negative predictor of clinical benefit from anti-EGFR antibodies in colorectal cancer, and anti-EGFR antibodies use was limited to KRAS wild type tumors. In order to ensure wide access to tumor molecular profiling, the French National Cancer Institute (INCa) has set up a national network of 28 regional molecular genetics centers. Concurrently, a nationwide external quality assessment for KRAS testing (MOKAECM) was granted to analyze reproducibility and costs.96 cell-line DNAs and 24 DNA samples from paraffin embedded tumor tissues were sent to 40 French laboratories. A total of 5448 KRAS results were collected and analyzed and a micro-costing study was performed on sites for 5 common methods by an independent team of health economists.This work provided a baseline picture of the accuracy and reliability of KRAS analysis in routine testing conditions at a nationwide level. Inter-laboratory Kappa values were >0.8 for KRAS results despite differences detection methods and the use of in-house technologies. Specificity was excellent with only one false positive in 1128 FFPE data, and sensitivity was higher for targeted techniques as compared to Sanger sequencing based methods that were dependent upon local expertise. Estimated reagent costs per patient ranged from €5.5 to €19.0.The INCa has set-up a network of public laboratories dedicated to molecular oncology tests. Our results showed almost perfect agreements in KRAS testing at a nationwide level despite different testing methods ensuring a cost-effective equal access to personalized colorectal cancer treatment.

BACKGROUND: Peer review is the most widely used method for evaluating grant applications in clinical research. Criticisms of peer review include lack of equity, suspicion of biases, and conflicts of interest (CoI). CoIs raise questions of fairness, transparency, and trust in grant allocation. Few observational studies have assessed these issues. We report the results of a qualitative study on reviewers' and applicants' perceptions and experiences of CoIs in reviews of French academic grant applications. METHODOLOGY AND PRINCIPAL FINDINGS: We designed a qualitative study using semi-structured interviews and direct observation. We asked members of assessment panels, external reviewers, and applicants to participate in semi-structured interviews. Two independent researchers conducted in-depth reviews and line-by-line coding of all transcribed interviews, which were also subjected to Tropes® software text analysis, to detect and qualify themes associated with CoIs. Most participants (73/98) spontaneously reported that non-financial CoIs predominated over financial CoIs. Non-financial CoIs mainly involved rivalry among disciplines, cronyism, and geographic and academic biases. However, none of the participants challenged the validity of peer review. Reviewers who felt they might be affected by CoIs said they reacted in a variety of ways: routine refusal to review, routine attempt to conduct an impartial review, or decision on a case-by-case basis. Multiple means of managing non-financial CoIs were suggested, including increased transparency throughout the review process, with public disclosure of non-financial CoIs, and careful selection of independent reviewers, including foreign experts and methodologists. CONCLUSIONS: Our study underscores the importance of considering non-financial CoIs when reviewing research grant applications, in addition to financial CoIs. Specific measures are needed to prevent a negative impact of non-financial CoIs on the fairness of resource allocation. Whether and how public disclosure of non-financial CoIs should be accomplished remains debatable.

BACKGROUND: Peer review of grant applications has been criticized as lacking reliability. Studies showing poor agreement among reviewers supported this possibility but usually focused on reviewers' scores and failed to investigate reasons for disagreement. Here, our goal was to determine how reviewers rate applications, by investigating reviewer practices and grant assessment criteria. METHODS AND FINDINGS: We first collected and analyzed a convenience sample of French and international calls for proposals and assessment guidelines, from which we created an overall typology of assessment criteria comprising nine domains relevance to the call for proposals, usefulness, originality, innovativeness, methodology, feasibility, funding, ethical aspects, and writing of the grant application. We then performed a qualitative study of reviewer practices, particularly regarding the use of assessment criteria, among reviewers of the French Academic Hospital Research Grant Agencies (Programmes Hospitaliers de Recherche Clinique, PHRCs). Semi-structured interviews and observation sessions were conducted. Both the time spent assessing each grant application and the assessment methods varied across reviewers. The assessment criteria recommended by the PHRCs were listed by all reviewers as frequently evaluated and useful. However, use of the PHRC criteria was subjective and varied across reviewers. Some reviewers gave the same weight to each assessment criterion, whereas others considered originality to be the most important criterion (12/34), followed by methodology (10/34) and feasibility (4/34). Conceivably, this variability might adversely affect the reliability of the review process, and studies evaluating this hypothesis would be of interest. CONCLUSIONS: Variability across reviewers may result in mistrust among grant applicants about the review process. Consequently, ensuring transparency is of the utmost importance. Consistency in the review process could also be improved by providing common definitions for each assessment criterion and uniform requirements for grant application submissions. Further research is needed to assess the feasibility and acceptability of these measures.