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Within the life-cycle assessment of health technologies, real-world data (RWD) have until now been of secondary importance to clinical trial data. The availability of massive, better quality RWD, particularly with the emergence of connected devices, the improvement of methods for characterizing populations, make it possible to have a better insight into the effects of treatment, sometimes on a national scale the importance of RWD is likely to progress in the eyes of health technology assessors, going from being traditionally complementary to possibly replacing clinical trial data. This is the fundamental question that the round table, involving experts from the academic and/or hospital, institutional, and industrial worlds, set out to answer. This work served first to establish the current role of RWD in health technology assessment, by distinguishing the main purposes of RWD, the timing of the evaluation in relation to the life cycle of the technology, and then according to the party commissioning or receiving the outcomes of RWD-based studies. Secondly, the round table proposed six general recommendations for more intensive and decisive use of RWD in the assessment and decision-making process.

Resume Introduction Le recours aux cones en metal poreux pour combler les pertes de substance osseuse au cours des arthroplasties du genou est croissant, mais ces dispositifs ne sont pas rembourses en sus des groupes homogenes de sejour (GHS). L’impact economique des cones en metal poreux pourrait etre important pour les hopitaux. Materiel et methodes Etude bicentrique observationnelle incluant tout patient ayant beneficie d’une prothese totale du genou avec reconstruction osseuse par cones en metal poreux entre juin 2014 et juin 2019, dans deux hopitaux universitaires francais. Les couts ont ete evalues a l’aide de l’etude nationale des couts a methodologie commune. Les depenses engagees par les hopitaux ont ete comparees aux montants des groupes homogenes de malades (GHM) et aux recettes percues au titre des GHS. Resultats 96 patients (103 sejours) ont beneficie de l’implantation de 195 cones. Les etablissements ont percu en moyenne 10 970 ± 1401€ /sejour. Les depenses associees aux cones representaient en moyenne 35 % des GHM et 44 % des GHS. Le surcout moyen lie aux cones etait de 2709 ± 1138€ /sejour. Si les reconstructions avaient ete realisees par allogreffe, le gain moyen pour les hopitaux aurait ete de 108€ /sejour. Conclusion Les cones semblent presenter des avantages cliniques pour les chirurgiens en diminuant l’incidence des reprises. Cette etude montre l’inadequation actuelle du financement de ces dispositifs pour les hopitaux francais, suggerant la necessite d’elargir les possibilites de prise en charge des technologies innovantes.

Objectives This study aimed to identify a subset of patients based on echocardiographic parameters who might have benefited from transcatheter correction using the Mitraclip system in the MITRA-FR (Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation) trial. Background It has been suggested that differences in the degree of mitral regurgitation (MR) and left ventricular (LV) remodeling may explain the conflicting results between the MITRA-FR and the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trials. Methods In a post hoc analysis, we evaluated the interaction between the intervention and subsets of patients defined based on MR severity (effective regurgitant orifice [ERO], regurgitant volume [RVOL] and regurgitant fraction [RF]), LV remodeling (end-diastolic and end-systolic diameters and volumes) and combination of these parameters with respect to the composite of death from any cause or unplanned hospitalization for heart failure at 24 months. Results We observed a neutral impact of the intervention in subsets with the highest MR degree (ERO ≥30 mm2, RVOL ≥45 ml or RF ≥50%) as in patients with milder MR degree. The same was seen in subsets with the milder LV remodeling using either diastolic or systolic diameters or volumes. When parameters of MR severity and LV remodeling were combined, there was still no benefit of the intervention including in the subset of patients with an ERO/end-diastolic volume ratio ≥ 0.15 despite similar ERO and LV end-diastolic volume compared with COAPT patients. Conclusions In the MITRA-FR trial, we could not identify a subset of patients defined based on the degree of the regurgitation, LV remodeling or on their combination, including those deemed as having disproportionate MR, that might have benefited from transcatheter correction using the Mitraclip system. (Multicentre Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients With Severe Secondary Mitral Regurgitation [MITRA-FR]; NCT01920698).

ObjectiveTo review the survival modelling used in cost-effectiveness studies evaluating an interventional procedure and to discuss implications for decision-makers.DesignA case study of three economic evaluations that each used immature data from the EVEREST II High Surgical Risk (HSR) Study of transcatheter edge-to-edge repair (TEER) for patients with severe mitral regurgitation (MR) who were at high risk of surgery.SettingEstimation of patient survival in cost-effectiveness studies.ParticipantsThe EVEREST II HSR Study included 78 patients who had TEER of the mitral valve using the MitraClip device and a retrospectively identified control group of 36 patients who received medical management and were followed up for 12 months. Observed survival (TEER arm only) was updated at 5 years.ResultsTwo studies used 12-month observed mortality from EVEREST II HSR to model survival over lifetime horizons. Observed and modelled survival were associated with considerable uncertainty due to short follow-up and small numbers of participants. Modelling control patients’ survival required an approximate 10-fold extrapolation based on 12-month observation of only 38 patients. Observed 5-year survival in the TEER group differed from that less mature follow-up suggesting that survival modelling based on shorter follow-up was unsatisfactory. No public domain data for the control group are available beyond 12-month follow-up so meaningful estimates using mature data for both arms are currently not possible. A third study developed survival models using incompletely reported transitions between MR grades in EVEREST II HSR and mortality rates observed for different MR grades derived from a study in an unrelated population.ConclusionsModelling survival in such small samples followed up for only 12 months is associated with great uncertainty, and cost-effectiveness results based on these analyses should be viewed as premature and used cautiously in reimbursement decisions.

International audience; BACKGROUND: In the MITRA-FR trial, transcatheter mitral valve repair (TMVR) was not associated with a 2-year clinical benefit in patients with secondary mitral regurgitation (SMR). AIMS: This landmark analysis aimed at investigating a potential reduction of the hospitalisation rate for heart failure (HF) between 12 and 24 months after inclusion in the MITRA-FR trial in patients randomised to the intervention group (TMVR with the MitraClip device), as compared with patients randomised to the control group (guideline-directed medical therapy [GDMT]). METHODS: The MITRA-FR trial randomised 307 patients with SMR for TMVR on top of GDMT (TMVR group; n=152) or for GDMT alone (control group; n=155). We conducted a 12-month landmark analysis in surviving patients who were not hospitalised for HF within the first 12 months of follow-up. The primary endpoint was the 1-year cumulative number of HF hospitalisations. RESULTS: A total of 140 patients (TMVR group: 67; GDMT group: 73) were selected for this landmark analysis with similar characteristics at inclusion in the trial. The primary endpoint was 28 events per 100 patient-years in the TMVR group, as compared with 60 events per 100 patient-years in the GDMT group (hazard ratio [HR] 0.46, 95% confidence interval [CI]: 0.20-1.02; p=0.057). CONCLUSIONS: In this landmark analysis of the MITRA-FR trial, the cumulative rate of HF hospitalisation between 12 and 24 months among patients treated with TMVR on top of GDMT was approximately half as many as those of patients treated with GDMT alone, a difference which did not reach statistical significance in the setting of a low number of events.

Several low-impact laparoscopic strategies have been developed to improve the safety of pneumoperitoneum. We conducted a systematic review to establish the current evidence base for the use of the AIRSEAL® insufflation device for low-pressure pneumoperitoneum in laparoscopic surgery. We searched the literature using several electronic databases, for studies with comparative design published in the English language from January 2010 to April 2020. The population of interest included patients with any type of health condition who underwent laparoscopic surgery using the AIRSEAL® insufflation system or a standard CO2 insufflator. Ten studies (four randomized clinical trials/six non-randomized clinical trials), that enrolled 1394 participants in total who underwent urology, gynaecology or abdominal surgeries, were included. Total complication rates were similar between groups. Only three studies evaluated the impact of the insufflation system on post-operative pain, and showed inconsistent benefit of AIRSEAL® (significant decrease in pain in two studies, no difference in one). The same was observed in the two sole studies in which pain killers consumption was measured (significant decrease in morphine consumption 24 h after surgery in one study, no difference in the other). Operative duration was significantly shorter with AIRSEAL® in three studies. For both post-operative room and total length of stay, there was no difference between groups. No studies reported economic outcomes. Current literature supports the feasibility of the AIRSEAL® system during laparoscopic surgery but more studies are required to establish the added clinical benefit and to explore the preferences of physicians and patients.

International audience; BACKGROUND AND AIM OF THE STUDY: Acute cardiovascular failure remains a leading cause of death in severe poisonings. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) has been increasingly used as a rescue therapeutic option for those cases refractory to optimal conventional treatment. We sought to evaluate the outcomes after VA-ECMO used for drug intoxications in a single-center experience. METHODS: We performed an observational analysis of our prospective institutional database. The primary endpoint was survival to hospital discharge. RESULTS: Between January 2007 and December 2020, 32 patients (mean age: 45.4 ± 15.8 years; 62.5% female) received VA-ECMO for drug intoxication-induced refractory cardiogenic shock (n = 25) or cardiac arrest (n = 7). Seven (21.8%) patients developed lower limb ischemia during VA-ECMO support. Twenty-six (81.2%) patients were successfully weaned after a mean VA-ECMO support of 2.9 ± 1.3 days. One (3.1%) patient died after VA-ECMO weaning for multiorgan failure and survival to hospital discharge was 78.1% (n = 25). In-hospital survivors were discharged from hospital with a good neurological status. Survival to hospital discharge was not statistically different according to sex (male = 75.0% vs. female = 80.0%; p = .535), type of intoxication (single drug = 81.8% vs. multiple drugs = 76.1%; p = .544) and location of VA-ECMO implantation (within our center = 75% vs. peripheral hospital using our Mobile Unit of Mechanical Circulatory Support = 100%; p = .352). Survival to hospital discharge was significantly lower in patients receiving VA-ECMO during on-going cardiopulmonary resuscitation (42.8% vs. 88.0%; p = .026). CONCLUSIONS: VA-ECMO appears to be a feasible therapeutic option with a satisfactory survival rate and acceptable complications rate in poisonings complicated by refractory cardiogenic shock or cardiac arrest.

Objectives Whether the effects of therapies may wane over time is a matter of debate, especially when considering their long-term cost-effectiveness. Here, we examined how the assumption of the waning of treatment effect was applied across the National Institute for Health and Care Excellence (NICE) appraisals for disease-modifying therapies (DMTs) used in multiple sclerosis. Methods We undertook a document analysis following a search of the NICE website. The inclusion criteria of the study were as follows: all publicly available documents related to completed appraisals for DMTs (period: January 2000 to July 2021). The exclusion criteria of the study were as follows: all documents that did not meet the inclusion criteria, especially pertaining to drugs used in other disease areas. We extracted information about the waning of treatment effect assumption as considered by companies, assessment groups, and appraisal committees, and we analyzed trends over time. Results We reviewed fifteen appraisals that reported guidance on sixteen DMTs. Irrespective of the drugs’ mechanism of action or their pharmaceutical nature, there was substantial variation in the modalities when the assumption of waning was implemented. We noted the recent preference to use all-cause discontinuation as a proxy. This heterogeneity did not appear to affect acceptance of the DMTs (all but one were recommended for use across the National Health System (NHS)). Conclusions Modeling the long-term effect of therapies is challenging, especially given the limited follow-up duration of related trials. This generates recurrent debates on the presence of waning of treatment efficacy and heterogeneity across appraisals. More refined recommendations obtained by consensus among stakeholders could help to achieve greater consistency in decision making.

International audience; No abstract available

International audience; Introduction: Given the complexity of the therapeutic management of irritable bowel syndrome (IBS), alternative non-pharmacological therapies are frequently offered to patients. The aim of this study was to conduct a systematic review in order to establish the current evidence base for non-pharmacological interventions (body-directed and mind-body therapies) in the management of IBS.Materials and methods: The literature was searched in several electronic databases (PubMed (including Medline), Web of Science (Clarivate Analytics), Scopus (Elsevier), ScienceDirect (Elsevier), Cochrane Library (Wiley), and Wiley Online Library (Wiley)) for randomized controlled trials (RCTs) published in the English language from 1990 to 2020. Effectiveness outcomes were examined through the change in overall IBS symptoms or abdominal pain up to 12 months after treatment.Results: 11 studies (parallel-group RCTs) were identified that enrolled 1590 participants in total. Body-directed therapies (acupuncture and osteopathic medicine) showed a beneficial effect compared with standard medical treatment for overall IBS symptoms at 6 months follow-up, while no study found any difference between body-directed and sham therapies for abdominal pain or overall IBS symptoms. It was not possible to conclude whether hypnotherapy was superior to standard medical treatment or supportive therapy for overall IBS symptoms or abdominal pain due to discordant results.Conclusions: Although body-directed therapies such as acupuncture and osteopathic medicine may be beneficial for overall IBS symptoms, higher-quality RCTs are needed to establish the clinical benefit of non-pharmacological interventions for IBS. An important challenge will be the definition of the optimal control groups to be used in non-pharmacological trials.

Aims The MITRA-FR trial showed that among symptomatic patients with severe secondary mitral regurgitation, percutaneous repair did not reduce the risk of death or hospitalization for heart failure at 12 months compared with guideline-directed medical treatment alone. We report the 24-month outcome from this trial. Methods and results At 37 centres, we randomly assigned 304 symptomatic heart failure patients with severe secondary mitral regurgitation (effective regurgitant orifice area >20 mm2 or regurgitant volume >30 mL), and left ventricular ejection fraction between 15% and 40% to undergo percutaneous valve repair plus medical treatment (intervention group, n = 152) or medical treatment alone (control group, n = 152). The primary efficacy outcome was the composite of all-cause death and unplanned hospitalization for heart failure at 12 months. At 24 months, all-cause death and unplanned hospitalization for heart failure occurred in 63.8% of patients (97/152) in the intervention group and 67.1% (102/152) in the control group [hazard ratio (HR) 1.01, 95% confidence interval (CI) 0.77-1.34]. All-cause mortality occurred in 34.9% of patients (53/152) in the intervention group and 34.2% (52/152) in the control group (HR 1.02, 95% CI 0.70-1.50). Unplanned hospitalization for heart failure occurred in 55.9% of patients (85/152) in the intervention group and 61.8% (94/152) in the control group (HR 0.97, 95% CI 0.72-1.30). Conclusions In patients with severe secondary mitral regurgitation, percutaneous repair added to medical treatment did not significantly reduce the risk of death or hospitalization for heart failure at 2 years compared with medical treatment alone.

For metastatic colorectal cancer a series of novel therapies has emerged during the last decade but their use in routine clinical practice and their costs are not well documented.This study evaluated the clinical effectiveness of metastatic colorectal cancer patients in Lebanese oncologic units and estimated the costs.A prospective cohort study was conducted on metastatic colorectal cancer patients during 2008-2013. The type of medical management, overall survival and total costs from diagnosis to death were described. Cost analysis was performed using tariffs from 2013 in US dollars.One hundred and seventy-nine metastatic patients were selected among which 84.9% had colorectal cancer involvement. The average follow-up from diagnosis until death or the latest news was 34.8 months. Around 49.7% were still alive at last follow-up date. Three lines of treatment accounted for 4.5%, 39.6% and 55.9% with an average duration of 14.5, 11.4 and 14.6 months respectively. A 73.2% of patients benefited from targeted therapy. The median overall survival was 20.8 months. The mean total costs of drugs was $22 256 in patients with standard therapy alone whereas the cost increased to $80 396 after the addition of targeted therapy. The mean global total cost was estimated at $64 805 per patient (min $3703; max $304 086).Targeted therapy associated to standard therapy is highly prevalent in Lebanon in metastatic disease and the associated medical cost substantial. This study is the first to show the clinical effectiveness and costs of targeted therapy in patients with metastatic colorectal cancer.علاج مرضى سرطان القولون المستقيمي النقيلي في المستشفيات اللبنانية والتكلفة المباشرة المرتبطة بها: دراسة أترابية متعددة المراكز.أنا ماريا حنين، جرجس شاهين، مارسيل مسعود، باسكال سلامة، سناء عوادة، ناتالي لحود، إدوارد إلياس، منصور سالم، سهير بالوت، دانيل هارتمان، جيل أولانيير، كزافيير أرمواري.بالنسبة لمرض السرطان القولوني المستقيمي النقيلي، ظهرت سلسلة من العلاجات الجديدة في العقد الأخير ولكن لم يُوثق استخدامها في الممارسات السريرية الروتينية وتكاليفها بشكل كافٍ.قيَّمت هذه الدراسة الفعالية السريرية لعلاج مرضى سرطان القولون المستقيمي النقيلي في وحدات علاج الأورام اللبنانية، وقدَّرت تكاليف هذا العلاج.أُجريت دراسة أترابية استباقية على مرضى سرطان القولون المستقيمي النقيلي في الفترة بين عامي 2008 و 2013. وجرى توضيح نوع العلاج الطبي والمعدل الإجمالي للبقاء وإجمالي التكاليف بداية من التشخيص حتى الوفاة. وأُجري تحليل للتكاليف باستخدام التسعيرات بالدولار الأمريكي من عام 2013.تم اختيار 179 مريضًا بالأمراض النقيلية حيث وُجد أن 84.9% منهم مصابين بسرطان القولون المستقيمي. وبلغ متوسط مدة المتابعة بداية من التشخيص حتى الوفاة أو الحصول على أحدث المستجدات 34.8 شهرًا. وكان حوالي 49.7% لا زالوا على قيد الحياة في آخر موعد للمتابعة. وتم استخدام ثلاثة خطوط للعلاج مع 4.5% و 39.6% و 55.9% حيث بلغ متوسط مدة المتابعة 14.5 و 11.4 و 14.6 شهرًا على التوالي. واستفاد 73.2% من المرضى من العلاج المستهدف. وبلغ متوسط المعدل الإجمالي للبقاء 20.8 شهرًا. وبلغ متوسط إجمالي تكاليف الأدوية 22256 دولارًا أمريكيًا مع المرضى الذين يحصلون على علاج معياري فقط، بينما ارتفعت التكاليف إلى 80396 دولارًا أمريكيًا بعد إضافة العلاج المستهدف. وقُدِّر متوسط إجمالي التكلفة العالمية 64805 دولارًا أمريكيًا لكل مريض (بحد أدنى 3703 دولارًا أمريكيًا؛ بحد أقصى 304086 دولارًا أمريكيًا).يعد العلاج المستهدف المرتبط بالعلاج المعياري شائعًا بكثرة في لبنان بين المرضى بالأمراض النقيلية، وتعد التكلفة الطبية للعلاج مرتفعة. وتعد هذه الدراسة هي الأولى من نوعها التي توضح الفعالية السريرية وتكاليف العلاج المستهدف بين مرضى سرطان القولون المستقيمي النقيلي.Prise en charge des patients atteints d’un cancer colorectal métastatique dans les hôpitaux libanais et coût direct associé : étude de cohorte multicentrique.Pour le cancer colorectal métastatique, une série de nouveaux traitements sont apparus durant la dernière décennie, mais leur utilisation dans la pratique clinique courante et leurs coûts ne sont pas bien documentés.La présente étude a évalué l’efficacité clinique de ce type de traitements sur les patients atteints de cancer colorectal métastatique dans les unités oncologiques libanaises et en a estimé les coûts.Une étude de cohorte prospective a été menée sur des patients atteints de cancer colorectal métastatique au cours de la période 2008-2013. Le type de prise en charge médicale, la survie globale et les coûts totaux des traitements du diagnostic jusqu’au au décès ont été décrits. L’analyse des coûts a été réalisée sur la base des tarifs de 2013 en dollars US.Cent soixante-dix-neuf patients métastatiques ont été sélectionnés, dont 84,9 % présentaient une atteinte de type cancer colorectal métastatique. Le suivi moyen entre le diagnostic et le décès ou le dernier contact avec le patient était de 34,8 mois. Environ 49,7 % étaient encore en vie à la dernière date de suivi. Trois lignes de traitement représentaient 4,5 %, 39,6 % et 55,9 % des cas, avec une durée moyenne de 14,5, 11,4 et 14,6 mois respectivement ; 73,2 % des patients ont bénéficié d’un traitement ciblé. La survie globale médiane était de 20,8 mois. Le coût total moyen des médicaments s’élevait à USD 22 256 chez les patients recevant un traitement standard seulement, alors que le coût passait à USD 80 396 après l’ajout du traitement ciblé. Le coût total moyen global a été estimé à USD 64 805 par patient (min. USD 3 703 ; max. USD 304 086).Le traitement ciblé associé au traitement standard est très répandu au Liban pour les maladies métastatiques et le coût médical associé est substantiel. Cette étude est la première à montrer l’efficacité clinique et les coûts d’un traitement ciblé chez des patients atteints de cancer colorectal métastatique.

cited By 1; Background: A review of therapies for advanced cancers licenced by the EMA between 2009 and 2013 concluded that for more than half of these drugs there was little evidence of overall survival or quality of life benefit. Recent years have witnessed a growing number of licensed second-line pharmacotherapies for advanced/metastatic non-small cell lung cancer (NSCLC). With the aim of gauging patient survival benefit, we conducted a systematic review of randomised controlled trials (RCT) and compared survival outcomes from available licensed treatments for patients with advanced/metastatic NSCLC. Methods: RCTs of second/third line treatments in participants with advanced/metastatic NSCLC and negative/low expression of Anaplastic Lymphoma Kinase (ALK) and of Epidermal Growth Factor Receptor (EGFR) were included. We searched electronic databases (MEDLINE; EMBASE; Web of Science) from January, 2000 up to July, 2017. Two or more independent reviewers screened bibliographic records, extracted data, and assessed risk of bias of studies. Published Kaplan Meier plots for OS and PFS along with restricted-mean-survival methods and parametric modelling were used to estimate the survival outcomes as mean number of months of survival. Network meta-analysis was undertaken to rank interventions and to make indirect comparisons. Results: We included 11 RCTs with data for 7581 participants that compared nine different drugs. In studies of patients regardless of histology groups, targeted drugs (ramucirumab and nintedanib) yielded small overall survival gains of < 2.5 months over docetaxel, erlotinib provided no benefit, while immunotherapies (atezolizumab and pembrolizumab) delivered 5 to 6 months gain. Studies with patients stratified by histology confirmed the apparent superiority of immunotherapy (nivolumab and atezolizumab) over targeted treatments (ramucirumab, nintedanib, afatinib) providing between about 4 to 8 months OS gain over docetaxel. In network analysis immunotherapies consistently ranked higher than alternatives irrespective of population histology and outcome measure. Conclusion: Our review indicates that nivolumab, pembrolizumab and atezolizumab provide superior survival benefits compared to other licensed drugs for late stage NSCLC. Patient gains from these immunotherapies are substantial compared to the expected average survival with chemotherapy (docetaxel) of < 1 year for people with squamous histology and about 1.25 year for those with non-squamous histology. © 2019 The Author(s).

Cost-effectiveness analyses of treatments for glioblastoma multiforme (GBM) have mostly used state transition Markov models with time invariant transition probabilities (TIMMs). In three case studies of GBM treatments, we compared Partitioned Survival model (PSM) results with published outputs from TIMMs. PSMs used the same RCT data sources, utility values, time horizons, cycle times and annual discounting used in published TIMMs. Reported overall survival and progression-free survival plots were digitised and fitted with a range of parametric models. Economic model outputs were generated in the same form as reported for the TIMMs. PSM output uncertainty was explored in univariate and in multivariate sensitivity analyses. PSMs generated incremental cost-effectiveness ratios that were different to the published TIMMs. The magnitude of difference was substantial in two cases. The PSMs were reasonably robust and in sensitivity analyses were sensitive to variations in the same model inputs as were the TIMMs. When compared to the RCT data, the TIMMs tended to generate underestimates of the likely overall survival gain. TIMM estimates for depletion of individuals from the stable disease state and for accumulation in the dead state had relatively poor resemblance to the source RCT data. TIMMs delivered different cost-effectiveness estimates to PSMs; in two cases, TIMMs produced substantially lower ICER values than PSMs. Model output differences appear attributable to less realistic cost-and-benefit estimates generated in TIMMs due to rapid depletion from the stable disease state and/or accumulation in the dead state.

Ocrelizumab is the first approved drug for primary progressive multiple sclerosis. Following appraisal by health technology assessment (HTA) bodies, this medicine has not been widely covered across European countries. We have compared the HTA process in England and France.We undertook an analysis of relevant documents that were published by the two HTA bodies. We analyzed patients' availability of Ocrelizumab at the different stages of the process.We identified differences in the assessment, one being the use of a different population of the pivotal trial, which has resulted in the consideration of distinct clinical effectiveness estimates. Ocrelizumab became available earlier in France as part of an early access program. However, rapid access was discontinued for newly eligible patients following an opinion concluding that Ocrelizumab yielded no additional benefit over placebo. This opinion was not compatible with the criteria allowing reimbursement in France.In England, there was no early access program and following an appraisal that included cost-effectiveness evaluation combined with pricing agreements, medicine was finally recommended. In conclusion, differences in the HTA process may result in appreciable differences in timing and outcome from marketing authorization to the adoption of newly licensed drugs.

International audience; OBJECTIVE: To analyze the impact of the modification of the authors' institutional protocol on outcomes after extracorporeal cardiopulmonary resuscitation (ECPR) for out-of-hospital cardiac arrest (OHCA). DESIGN: An observational analysis. The protocol complied with national recommendations. A further eligibility criterion was added since January 2015: the presence of sustained shockable rhythm at extracorporeal life support (ECLS) implantation. To assess the impact of this change, patients were divided into two groups: (1) from January 2010 to December 2014 (group A) and (2) from January 2015 to December 2019 (group B). The primary endpoint was survival to hospital discharge with good neurologic outcome. Predictors of survival were searched with multivariate analyses. SETTING: University hospital. PARTICIPANTS: Adult patients supported with ECPR for refractory OHCA. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: From January 2010 to December 2019, 85 patients had ECLS for OHCA (group A, n = 68, 80%; group B, n = 17, 20%). The mean age was 42.4 years, 78.8% were male. The rate of implantation of ECLS was significantly lower in group B (p = 0.01). Mortality during ECLS support was significantly lower (58.8 v 86.8%; p = 0.008), and the weaning rate was significantly higher (41.2 v 13.2%; p = 0.008) in group B. Survival to discharge with good neurologic outcome was significantly improved (23.5 v 4.4%; p = 0.027) in group B. A sustained shockable rhythm was the only independent predictor of survival to hospital discharge with good neurologic outcome. CONCLUSIONS: The modification of the authors' institutional protocol throughout the further criterion of sustained shockable rhythm yielded a favorable impact on outcomes after ECPR for OHCA.

International audience; BACKGROUND AND AIM OF THE STUDY: Data about the beating heart (BH) technique for isolated tricuspid valve (TV) surgery compared to the arrested heart (AH) technique are sparse. We compared the outcomes of isolated TV surgery between BH and AH technique. METHODS: We performed an observational analysis of our database of isolated TV surgery. Patients were divided into two groups according to whether surgery was performed without (BH group) or with (AH group) aortic cross-clamping and cardioplegic arrest. The primary endpoint was survival to hospital discharge. Risk factors for in-hospital mortality were searched with multivariate analyses. We undertook further comparisons after propensity-score matching. RESULTS: From January 2007 to December 2017, we performed 82 isolated TV surgery (BH group, n = 47, 57.3%; AH group, n = 35, 42.7%). The mean age was 59.1 years, 56.1% were female. BH group patients were older (61.8 vs. 55.4 years; p = .035), had greater impaired renal function (glomerular filtration rate, 61.1 vs. 74.6 ml/min; p = .012), were more frequently operated for secondary TR (61.7 vs. 31.4%; p = .008), underwent more frequently a reoperation (53.2 vs. 28.6%; p = .042) and exhibited a higher surgical risk (EuroSCORE II, 3.92 vs. 2.50%; p = .013). In-hospital mortality was not different between both groups, either considering unmatched (BH = 10.6 vs. AH = 5.7%; OR = 1.96, 95% confidence interval [CI] = 0.36-10.77) or matched populations (BH = 10.6 vs. AH = 6.4%; OR = 1.89, 95% CI = 0.36-9.97). Age was the only predictor of in-hospital mortality. CONCLUSIONS: The BH technique showed comparable outcomes to the AH technique for isolated TV surgery despite a higher risk profile.

Several low-impact laparoscopic strategies have been developed to improve the safety of pneumoperitoneum. We conducted a systematic review to establish the current evidence base for the use of the AIRSEAL

Background Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) has been increasingly used over the last decade in patients with refractory cardiogenic shock. ECMO weaning can, however, be challenging and lead to circulatory failure and death. Recent data suggest a potential benefit of levosimendan for ECMO weaning. We sought to further investigate whether the use of levosimendan could decrease the rate of ECMO weaning failure in adult patients with refractory cardiogenic shock. Methods We performed an observational single-center cohort study. All patients undergoing VA-ECMO from January 2012 to December 2018 were eligible and divided into two groups: group levosimendan and group control (without levosimendan). The primary endpoint was VA-ECMO weaning failure defined as death during VA-ECMO treatment or within 24 h after VA-ECMO removal. Secondary outcomes were mortality at day 28 and at 6 months. The two groups were compared after propensity score matching. P

This study aimed to identify a subset of patients based on echocardiographic parameters who might have benefited from transcatheter correction using the MitraClip system in the MITRA-FR (Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation) trial.It has been suggested that differences in the degree of mitral regurgitation (MR) and left ventricular (LV) remodeling may explain the conflicting results between the MITRA-FR and the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trials.In a post hoc analysis, we evaluated the interaction between the intervention and subsets of patients defined based on MR severity (effective regurgitant orifice [ERO], regurgitant volume [RVOL] and regurgitant fraction [RF]), LV remodeling (end-diastolic and end-systolic diameters and volumes) and combination of these parameters with respect to the composite of death from any cause or unplanned hospitalization for heart failure at 24 months.We observed a neutral impact of the intervention in subsets with the highest MR degree (ERO ≥30 mmIn the MITRA-FR trial, we could not identify a subset of patients defined based on the degree of the regurgitation, LV remodeling or on their combination, including those deemed as having disproportionate MR, that might have benefited from transcatheter correction using the MitraClip system. (Multicentre Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients With Severe Secondary Mitral Regurgitation [MITRA-FR]; NCT01920698).

International audience; OBJECTIVES: The objective of the study is to evaluate the performance of high-dimensional propensity scores (hdPSs) for controlling indication bias as compared with propensity scores (PSs) in surgical comparative effectiveness studies. STUDY DESIGN AND SETTING: Patients who underwent interventional transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (SAVR) between 2013 and 2017 were included from the French nationwide hospitals. At each hospital level, matched pairs of patients who underwent TAVI and SAVR were formed using PSs, considering 20 patient baseline characteristics, and hdPSs, considering the same patient characteristics and 300 additional variables from procedure and diagnosis codes the year before surgery. We compared death, reoperation, and stroke up to 3 years between TAVI and SAVR using Cox or Fine and Gray models. RESULTS: Before matching, 12 of 20 patient characteristics were imbalanced between the included patients who underwent TAVI and SAVR. No significant imbalance persisted after matching with both methods. Hazard ratio of 1-year death, reoperation, and stroke was 1.3 [1.1; 1.4], 1.6 [1.1; 2.4], and 1.4 [1.2; 1.7] for TAVI relative to SAVR with PSs (n = 9,498 pairs) and 1.1 [1.0; 1.3], 1.3 [0.8; 2.0], and 1.3 [1.0; 1.6] with hdPSs (n = 7,157). CONCLUSION: HdPS estimations were more consistent with results seen in randomized controlled trials. The HdPS is a promising alternative for the PS to control indication bias in comparative studies of surgical procedures.

Cost-effectiveness analyses of treatments for glioblastoma multiforme (GBM) have mostly used state transition Markov models with time invariant transition probabilities (TIMMs). In three case studies of GBM treatments, we compared Partitioned Survival model (PSM) results with published outputs from TIMMs.PSMs used the same RCT data sources, utility values, time horizons, cycle times and annual discounting used in published TIMMs. Reported overall survival and progression-free survival plots were digitised and fitted with a range of parametric models. Economic model outputs were generated in the same form as reported for the TIMMs. PSM output uncertainty was explored in univariate and in multivariate sensitivity analyses.PSMs generated incremental cost-effectiveness ratios that were different to the published TIMMs. The magnitude of difference was substantial in two cases. The PSMs were reasonably robust and in sensitivity analyses were sensitive to variations in the same model inputs as were the TIMMs. When compared to the RCT data, the TIMMs tended to generate underestimates of the likely overall survival gain. TIMM estimates for depletion of individuals from the stable disease state and for accumulation in the dead state had relatively poor resemblance to the source RCT data.TIMMs delivered different cost-effectiveness estimates to PSMs; in two cases, TIMMs produced substantially lower ICER values than PSMs. Model output differences appear attributable to less realistic cost-and-benefit estimates generated in TIMMs due to rapid depletion from the stable disease state and/or accumulation in the dead state.

Objectives\ud \ud Nusinersen (Spinraza®, Biogen) and onasemnogene abeparvosec (Zolgensma®, Novartis) are novel gene-based therapies for the orphan disease Spinal Muscular Atrophy. Onasemnogene abeparvosec has been allocated an acquisition cost of up to US$5 million per patient. We undertook a rapid inquiry to evaluate if onasemnogene abeparvosec is likely to be cost effective for the UK NHS.\ud \ud Methods\ud \ud We used publicly available cost effectiveness data and recommended methodology to perform cost utility evaluation of onasemnogene abeparvosec versus best supportive care and nusinersen.\ud \ud Results\ud \ud Our evaluations highlight wide variations in cost and benefit estimates of nusinersen and indicate that onasemnogene abeparvosec is unlikely to represent value for money according to current standards of reimbursement. Results are discussed in the context of reimbursement decisions for orphan diseases.\ud \ud Conclusion\ud \ud Commonly implemented commercial confidentiality practices combined with uncertain data obscure scrutiny and justification of past and present reimbursement decisions for orphan drugs. Future cutting edge expensive therapies will be numerous, they will entail very substantial economic strains. We conclude that there is an urgent and increasing need for the development of improved procedures that can lead to equitable, consistent and transparent decision making.

Ocrelizumab is indicated for relapsing remitting and primary progressive multiple sclerosis (RRMS and PPMS, respectively). In an appraisal undertaken by the National Institute for Health and Care Excellence (NICE), the company Roche presented the evidence for ocrelizumab used in patients with PPMS, which came from one single randomised controlled trial (RCT) comparing ocrelizumab versus placebo. Based on results from this trial, the licensed indication was restricted to patients with early PPMS in terms of disease duration and level of disability, and with imaging features characteristic of inflammatory activity. Overall, the Evidence Review Group (ERG) found that the RCT had a low risk of bias. In the post-hoc defined magnetic resonance imaging (MRI) active subgroup, matching the label indication, the risk of confirmed disability progression sustained for 12 weeks (CDP-12) was significantly delayed in the ocrelizumab group compared to placebo. However, considering the same risk with progression sustained for 24 weeks (CDP-24), which was deemed the most clinically relevant, the benefit from ocrelizumab did not reach statistical significance. In the same MRI active subgroup, benefits from ocrelizumab on functional outcomes and on health-related quality of life were not clearly demonstrated. A de novo Markov model was used to estimate the cost-effectiveness of ocrelizumab versus best supportive care (BSC) for treating patients with PPMS. Health states were defined by the Expanded Disability Status Scale (EDSS), ranging from 0 to 9. Disability progression was based on the MSBase natural history cohort that exhibited disease progression in the absence of disease-modifying therapy. Treatment with ocrelizumab delayed disability progression, with evidence of its clinical effectiveness obtained from the RCT. The economic analysis was undertaken from the National Health Service and Personal Social Services perspective, and the outcomes were reported in terms of life years gained and quality-adjusted life years (QALYs), with the overall results reported in terms of an incremental cost-effectiveness ratio (ICER), expressed as cost per QALY gained over a 50-year time horizon. Both costs and effects were discounted at 3.5% per annum. The company undertook deterministic one-way sensitivity analyses and scenario analyses, including probabilistic sensitivity analysis (PSA). The ERG raised several concerns, which were discussed at the appraisal committee meetings, resulting in the committee’s preferences being applied and a revised economic analysis from the company. Under an approved patient access scheme with appraisal committee preferences applied, analyses yielded an ICER of approximately £78,300 per QALY. Sensitivity analysis results indicated that the treatment effect on CDP-12 had the greatest impact. Results for the PSA showed that at a willingness-to-pay threshold of £30,000 per QALY gained, ocrelizumab versus BSC had a zero probability of being cost-effective. Following new analyses submitted by the company, with a revised confidential patient access scheme, NICE recommended ocrelizumab in the treatment of early PPMS in adults with imaging features characteristic of inflammatory activity.

High-risk pulmonary embolism (PE) requires hemodynamic and respiratory support along with reperfusion strategies. Recently updated European guidelines assign a low class of recommendation to extracorporeal membrane oxygenation (ECMO) for high-risk PE. This systematic review assessed clinical outcomes after ECMO in high-risk PE. We searched electronic databases including PubMed, Embase and Web of Science from January 2000 to April 2020. Efficacy outcomes included in-hospital survival with good neurological outcome and survival at follow-up. Safety outcomes included lower limb ischemia and hemorrhagic and ischemic stroke. Where possible (absence of high heterogeneity), meta-analyses of outcomes were undertaken using a random-effects model. We included 16 uncontrolled case-series (533 participants). In-hospital survival with good neurological outcome ranged between 50% and 95% while overall survival at follow-up ranged from 35% to 95%, both with a major degree of heterogeneity (I2 > 70%). The prevalence of lower limb ischemia was 8% (95% CI 3% to 15%). The prevalence of stroke (either hemorrhagic or ischemic) was 11% (95% CI 3% to 23%), with notable heterogeneity (I² = 63.35%). Based on currently available literature, it is not possible to draw definite conclusions on the usefulness of ECMO for high-risk PE. Prospective, multicenter, large-scale studies or nationwide registries are needed to best define the role of ECMO for high-risk PE. PROSPERO registration ID: CRD42019136282.

Background We systematically reviewed the comparative effectiveness of injectable beta-interferons (IFN-β) and glatiramer acetate (GA) on annualised relapse rate (ARR), progression and discontinuation due to adverse events (AEs) in RRMS, using evidence from within the drugs’ recommended dosages. Methods We updated prior comprehensive reviews, checked references of included studies, contacted experts in the field, and screened websites for relevant publications to locate randomised trials of IFN-β and GA with recommended dosages in RRMS populations, compared against placebo or other recommended dosages. Abstracts were screened and assessed for inclusion in duplicate and independently. Studies were appraised using the Cochrane risk of bias tool. Rate ratios for ARR, hazard ratios for time to progression, and risk ratios for discontinuation due to AEs were synthesised in separate models using random effects network meta-analysis. Results We identified 24 studies reported in 42 publications. Most studies were at high risk of bias in at least one domain. All drugs had a beneficial effect on ARR as compared to placebo, but not compared to each other, and findings were robust to sensitivity analysis. We considered time to progression confirmed at 3 months and confirmed at 6 months in separate models; while both models suggested that the included drugs were effective, findings were not consistent between models. Discontinuation due to AEs did not appear to be different between drugs. Conclusions Meta-analyses confirmed that IFN-β and GA reduce ARR and generally delay progression as defined in these trials, though there was no clear ‘winner’ across outcomes. Findings are additionally tempered by the high risk of bias across studies, and the use of an impairment/mobility scale to measure disease progression. Future research should consider more relevant measures of disability and, given that most trials have been short-term, consider a longitudinal approach to comparative effectiveness. Review registration PROSPERO CRD42016043278. Electronic supplementary material The online version of this article (10.1186/s12883-018-1162-9) contains supplementary material, which is available to authorized users.

Background\ud Non-small cell lung cancer (NSCLC) is one of the most commonly diagnosed cancers. There are many published studies of cost-effectiveness analyses of licensed treatments, but no study has compared these studies or their approaches simultaneously.\ud \ud Objective\ud To investigate the methodology used in published economic analyses of licensed interventions for previously treated advanced/metastatic NSCLC in patients without anaplastic lymphoma kinase or epidermal growth factor receptor expression.\ud \ud Methods\ud A systematic review was performed, including a systematic search of key databases (e.g. MEDLINE, EMBASE, Web of Knowledge, Cost-effectiveness Registry) limited to the period from 01 January 2001 to 26 July 2019. Two reviewers independently screened, extracted data and quality appraised identified studies. The reporting quality of the studies was assessed by using the Consolidated Health Economic Evaluation Reporting Standards and the Philips’ checklists.\ud \ud Results\ud Thirty-one published records met the inclusion criteria, which corresponded to 30 individual cost-effectiveness analyses. Analytical approaches included partitioned survival models (n = 14), state-transition models (n = 7) and retrospective analyses of new or published data (n = 8). Model structure was generally consistent, with pre-progression, post-progression and death health states used most commonly. Other characteristics varied more widely, including the perspective of analysis, discounting, time horizon, usually to align with the country that the analysis was set in.\ud Conclusions\ud There are a wide range of approaches in the modelling of treatments for advanced NSCLC; however, the model structures are consistent. There is variation in the exploration of sensitivity analyses, with considerable uncertainty remaining in most evaluations. Improved reporting is necessary to ensure transparency in future analyses.

Pembrolizumab is an intravenously administered monoclonal antibody licensed for locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy. This summary presents the perspective of Warwick Evidence, the Evidence Review Group (ERG) appointed by the National Institute of Health and Care Excellence (NICE) for the single technology appraisal of pembrolizumab for this indication. Pembrolizumab is manufactured by Merck, Sharp and Dohme (MSD). The major source of clinical effectiveness was the KEYNOTE-045 trial, where 542 patients received either pembrolizumab or clinician’s choice of docetaxel, paclitaxel or vinflunine as a second-line treatment. No indirect treatment comparison was performed. The clinical effectiveness was assessed using hazard ratios for overall survival (OS) and progression-free survival (PFS) of the intention-to-treat (ITT) population, together with the subpopulations positive for programmed cell death 1 ligand 1 (PD-L1) expression (combined positive score [CPS] ≥ 1%) and strongly positive for PD-L1 expression (CPS ≥ 10%). In the ITT population, OS improved with pembrolizumab (HR 0.73, 95% CI 0.59–0.91) while PFS outcomes showed no difference (HR 0.98, 95% CI 0.81–1.19). Pembrolizumab demonstrated a better safety profile than its combined comparators, with fewer patients experiencing adverse events (60.9 vs 90.2%). Similar results were observed in populations expressing PD-L1. MSD estimated the cost effectiveness of pembrolizumab using a de novo partitioned survival model. The model had three health states: pre-progression, post-progression and death, where OS and PFS estimates excluded patients who received vinflunine. The largest uncertainty was over the selection of the parametric models used to extrapolate OS and PFS and the time point for when to begin their extrapolation. The company preferences for extrapolation were not well supported and the ERG disagreed with their selection for OS. Utility values were also contentious, with the company preferring to use pooled time-to-death–based utilities pooled across treatment arms, whilst the ERG preferred pooled progression-based utilities. The company preferred to use data from patients receiving vinflunine when calculating the utility values, which the ERG disagreed with as this is not recommended treatment within the UK. The company assumed a lifetime treatment effect for their model; however, the lack of evidence made it difficult to confidently provide a realistic estimate of treatment effect duration. Various durations were explored (3, 5 and 10 years). The first appraisal committee meeting concluded that pembrolizumab was not cost effective, largely due to uncertainty in the OS and PFS extrapolations. The company’s second submission included an additional 4 months follow-up to survival data. The company in this new submission maintained their original assumptions in their base-case analysis, changing only the choice of parametric curve for PFS. This change resulted in the OS and PFS curves intersecting at 6 years in the pembrolizumab arm, at which point PFS identically followed OS. This resulted in no patients in the post-progression health state beyond this time point, and therefore, the majority of pembrolizumab’s benefit came from pre-progression survival. Given the unclear PFS benefit, the ERG found this implausible and maintained their original base-case model assumptions. Considerable uncertainty remained over the specification of the extrapolations and the duration of treatment effect. Based on a new-value proposition submitted by the company, the appraisal committee concluded that pembrolizumab had plausible potential to be cost effective. Pembrolizumab was referred for funding through the Cancer Drugs Fund, so that further data could be collected with the aim of diminishing the outstanding uncertainties pertaining to its clinical effectiveness.\ud \ud

The Evidence Review Group members that contributed to this editorial are funded by the UK NIHR HTA Programme. The views and opinions expressed are those of the authors and do not necessarily reflect those of the UK Department of Health and the NIHR.