Laure Huot

Ranibizumab versus Bevacizumab for Neovascular Age-related Macular Degeneration: Results from the GEFAL Noninferiority Randomized Trial.

OBJECTIVE To evaluate the relative efficacy and safety profile of bevacizumab versus ranibizumab intravitreal injections for the treatment of neovascular age-related macular degeneration (AMD). DESIGN Multicenter, prospective, noninferiority, double-masked, randomized clinical trial performed in 38 French ophthalmology centers. The noninferiority limit was 5 letters. PARTICIPANTS Patients aged ≥50 years were eligible if they presented with subfoveal neovascular AMD, with best-corrected visual acuity (BVCA) in the study eye of between 20/32 and 20/320 measured on the Early Treatment of Diabetic Retinopathy Study chart and a lesion area of less than 12 optic disc areas (DA). METHODS Patients were randomly assigned to intravitreal administration of bevacizumab (1.25 mg) or ranibizumab (0.50 mg). Hospital pharmacies were responsible for preparing, blinding, and dispensing treatments. Patients were followed for 1 year, with a loading dose of 3 monthly intravitreal injections, followed by an as-needed regimen (1 injection in case of active disease) for the remaining 9 months with monthly follow-up. MAIN OUTCOME MEASURES Mean change in visual acuity at 1 year. RESULTS Between June 2009 and November 2011, 501 patients were randomized. In the per protocol analysis, bevacizumab was noninferior to ranibizumab (bevacizumab minus ranibizumab +1.89 letters; 95% confidence interval [CI], -1.16 to +4.93, P < 0.0001). The intention-to-treat analysis was concordant. The mean number of injections was 6.8 in the bevacizumab group and 6.5 in the ranibizumab group (P = 0.39). Both drugs reduced the central subfield macular thickness, with a mean decrease of 95 μm for bevacizumab and 107 μm for ranibizumab (P = 0.27). There were no significant differences in the presence of subretinal or intraretinal fluid at final evaluation, dye leakage on angiogram, or change in choroidal neovascular area. The proportion of patients with serious adverse events was 12.6% in the bevacizumab group and 12.1% in the ranibizumab group (P = 0.88). The proportion of patients with serious systemic or ocular adverse events was similar in both groups. CONCLUSIONS Bevacizumab was noninferior to ranibizumab for visual acuity at 1 year with similar safety profiles. Ranibizumab tended to have a better anatomic outcome. The results are similar to those of previous head-to-head studies.

Cultured autologous oral mucosal epithelial cell sheet (CAOMECS) transplantation for the treatment of corneal limbal epithelial stem cell deficiency.

PURPOSE Total bilateral corneal limbal epithelial stem cell deficiency (LSCD) cannot be treated with the surgical transplantation of autologous limbus or cultured autologous limbal epithelium. Transplantation of allogenic limbal epithelium is possible but requires immunosuppressive treatments. Cultured autologous oral mucosal epithelial cell sheet (CAOMECS) is a transparent, resistant, viable, and rapidly bioadhesive cell sheet, cultured with the UpCell-Insert technology (CellSeed, Inc., Tokyo, Japan), which allows for grafting onto the patients corneal stroma without suturing. It has therefore been proposed as an alternative treatment for LSCD. METHODS The objectives were to assess the safety and efficacy of CAOMECS, using a prospective Gehans design. Safety was measured in terms of ocular adverse events during the study period, and efficacy was measured using a composite criterion based on epithelial defect, punctate epithelial keratopathy, conjunctival epithelium on the cornea, number of vascular pediculi, and vessel activity. RESULTS CAOMECS was found to be safe and effective. In total, 26 eyes of 25 patients received a graft. Two patients experienced serious adverse events classified as not product related. Twenty-five patients were included in the efficacy analysis, as one patient was lost to follow-up. The treatment was found to be effective in 16 of 25 patients at 360 days after grafting. Of the 23 patients who completed follow-up at 360 days, 22 had no ulcers, and 19 showed a decrease in the severity of the punctate epithelial keratopathy. CONCLUSIONS CAOMECS is a well-tolerated and safe tissue-engineered product. These results suggest its efficacy for reconstructing the ocular surface in patients with total bilateral corneal LSCD.

Prognostic factors of recurrent respiratory papillomatosis from a registry of 72 patients

Conclusions: The database revealed severity factors relating to human papillomavirus (HPV) type and age at diagnosis. While not exhaustive, the database is easy to use and could serve for a European multicentre epidemiological study. Objectives: To propose a database as a starting point for a national registry and to estimate prognostic factors in recurrent respiratory papillomatosis (RRP). Materials and methods: This was a retrospective study carried out in a tertiary care teaching hospital. From January 2005 to July 2007, epidemiological, clinical and treatment information on patients undergoing endoscopy for RRP in the department was entered in a database. Data were collected on three forms: the first comprised information about disease history before assessment in the department, the second about the disease and its treatment in the department, and the third about evolution after treatment. Results: Data on 72 patients were entered into an RRP database between January 2005 and July 2007. In all, 82% had already been treated for RRP in a different centre; 24 had juvenile-onset (JORRP) and 48 adult-onset (AORRP) papillomatosis. Cidovir injections had been administered to 91% of the patients. Histology found nine cases of dysplasia, one of carcinoma in situ and one of invasive carcinoma. Subglottic and tracheal locations were significantly more frequent in JORRP than in AORRP, as were the maximum Derkay scores and annual numbers of endoscopies. Patients with type 11 HPV had significantly more endoscopies per year than those with type 6.

High-Resolution Manometry Improves the Diagnosis of Esophageal Motility Disorders in Patients With Dysphagia: A Randomized Multicenter Study

Objectives:High-resolution manometry (HRM) might be superior to conventional manometry (CM) to diagnose esophageal motility disorders. We aimed to compare the diagnosis performed with HRM and CM and confirmed at 6 months in a multicenter randomized trial.Methods:Patients with unexplained dysphagia were randomized to undergo either CM or HRM. Motility disorders were diagnosed using the Castell and Spechler classification for CM and the Chicago classification for HRM. Diagnosis confirmation was based on clinical outcome and response to treatment after 6-month follow-up. The initial diagnosis and percentage of confirmed diagnoses were compared between the two arms (CM and HRM).Results:In total, 247 patients were randomized and 245 analyzed: 122 in the CM arm and 123 in the HRM arm. A manometric diagnosis was more frequently initially achieved with HRM than with CM (97% vs. 84%; P<0.01). Achalasia was more frequent in the HRM arm (26% vs. 12% in the CM arm; P<0.01) while normal examinations were more frequent in the CM arm (52% vs. 28% in the HRM arm; P<0.05). After follow-up, the initial diagnosis was confirmed in 89% of patients in the HRM arm vs. 81% in the CM arm (P=0.07). Finally, overall procedure tolerance was better with CM than with HRM (P<0.01).Conclusions:This randomized trial demonstrated an improved diagnostic yield for achalasia with HRM compared with CM. Diagnoses tended to be more frequently confirmed in patients who underwent HRM, suggesting that esophageal motility disorders could be identified earlier with HRM than with CM (ClinicalTrial.gov, NCT01284894).

Visibility of retractions: a cross-sectional one-year study

BackgroundRetraction in Medline medical literature experienced a tenfold increase between 1999 and 2009, however retraction remains a rare event since it represents 0.02% of publications. Retractions used to be handled following informal practices until they were formalized in 2009 by the Committee on Publication Ethics (COPE). The objective of our study was to describe the compliance to these guidelines.MethodsAll retractions published in 2008 were identified using the Medline publication type “retraction of publication”. The notices of retraction and the original articles were retrieved. For each retraction, we identified the reason for retraction, the country of affiliation of the first author, the time to retraction, the impact factor of the journal and the mention of retraction on the original article.ResultsOverall, 244 retractions were considered for analysis. Formal retraction notices could not be retrieved for 9. Of the 235 retractions available (96%), the reason was not detailed for 21 articles (9%). The most cited reasons were mistakes (28%), plagiarism (20%), fraud (14%) and overlap (11%). The original paper or its location was found for 233 retractions (95%). Of these, 22% were available with no mention of the retraction.ConclusionA standard retraction form could be helpful, with a check list of major reason, leaving the editor free to provide the reader with any further information. Original articles should remain available with a clear mention of the retraction.

Evolution of costs of care for cystic fibrosis patients after clinical guidelines implementation in a French network

OBJECTIVES The aim of this study was to evaluate how advances in CF management in France between 2000 and 2003 impacted CF-related costs. METHODS The analysis of direct medical costs was done in 2000 and 2003 from the perspective of the French national healthcare insurance system. The patients, 65 in 2000 and 64 in 2003, were followed-up in one pediatric and one adult CF reference center (CFRC). We quantified and valued CF-related home and hospital care costs. RESULTS We found an average cost of euro16474/patient/year in 2000, and euro22725 in 2003 (based on the 2003 euro value). Hospital care increased from 15% of the total cost in 2000 to 22% in 2003. Medications accounted for 45% of the total cost for the two periods, with an average cost of euro7229/patient/year in 2000 and euro10336 in 2003. Home intravenous antibiotic therapy accounted for 20% of the total cost for the two periods. CONCLUSIONS We highlighted an increase in CF care costs between 2000 and 2003, which might be related to the changes in practice patterns that followed guidelines implementation, such as the use of new medications (dornase alpha and tobramycin) and more frequent follow-up in the CFRC.

Safety and efficacy of flow-diverter stents in endovascular treatment of intracranial aneurysm: interest of the prospective DIVERSION observational study.

Journal of Neuroradiology - In Press.Proof corrected by the author Available online since mardi 1 avril 2014

Medical device assessment: scientific evidence examined by the French national agency for health - a descriptive study.

BackgroundScientific evidence supports decision-making on the use of implantable medical devices (IMDs) in clinical practice, but IMDs are thought to be far less investigated than drugs. In the USA, studies have shown that approval process of high-risk medical devices was often based on insufficiently robust studies, suggesting that evidence prior to marketing may not be adequate. This study aimed to ascertain level of evidence available for IMDs access to reimbursement in France.MethodsThe objective was to examine the scientific evidence used for IMDs assessment by the French National Authority for Health. We collected all public documents summarising supportive clinical data and opinions concerning IMDs issued in 2008. An opinion qualifies the expected benefit (EB) of the IMD assessed as sufficient or insufficient, and if sufficient, the level of improvement of the expected benefit (IEB) on a scale from major (level I) to no improvement (level V). For each opinion, the study with the highest level of evidence of efficacy data, and its design were collected, or, where no studies were available, any other data sources used to establish the opinion.ResultsOne hundred and two opinions were analysed, with 72 reporting at least one study used for assessment (70.6%). When considering the study with the highest level of evidence: 34 were clinical non-comparative studies (47.2%); 29 were clinical comparative studies of which 25 randomised controlled trials (40.3%); 5 were meta-analyses of randomised controlled trials (6.9%); and 4 were systematic literature reviews (5.6%). The opinions were significantly different according to the study design (p < 0.001). The most frequent design for insufficient EB, IEB level V and IEB level IV was a non-comparative study (10/19, 52.6%; 15/24, 62.5%; and 8/15, 53.3%; respectively). For the 30 opinions with no supporting clinical study, 16 (53.3%) were based on an expert-based process, 9 (30.0%) were based on the conclusions of a previous opinion (all concluding IEB level V), and 5 (16.7%) reported no data (concluding insufficient EB for 4 and IEB level V for 1).ConclusionsThis study confirmed that level of evidence of clinical evaluation of IMDs is low and needs to be improved.

Fate of protocols submitted to a French national funding scheme: a cohort study.

Background The fate of clinical research projects funded by a grant has been investigated, but there is no information on the projects which did not receive funding. The fate of these projects is not known: do they apply for and/or receive funding from other sources or are they carried out without specific funding? Purpose The aim of the study was to describe all clinical research projects submitted to a French national funding scheme (PHRC 2000) and to assess project initiation, completion and publication status taking into account whether or not they received funding. Methods This study is a retrospective cohort. The initial project characteristics were retrieved from the submission files and follow-up information was collected from the primary investigator. The percentages of projects started, completed and published were studied. Results A total of 481 projects were studied. Follow-up information was obtained for 366. Overall, 185 projects were initiated (51%); 139 of them were funded by the PHRC 2000 or other sources. The most commonly cited reason for not initiating a project was a lack of funding. Subsequently, 121 of the projects initiated were completed (65%). Accrual difficulties were the main reason cited to explain why studies were stopped prematurely or were still ongoing. Finally, 88 of the completed projects were published (73%). Amongst the completed projects, the only factor explaining publication was the statistical significance of the results. Conclusions Obtainment of funding was a determining factor for project initiation. However, once initiated, the funding did not influence completion or publication.

Serious Adverse Events with Bevacizumab or Ranibizumab for Age-Related Macular Degeneration: Meta-analysis of Individual Patient Data

TOPIC A comparison between ranibizumab and bevacizumab of the incidence of systemic serious adverse events (SAEs) among patients with neovascular age-related macular degeneration (nAMD) who participated in a large-scale randomized trial. Use of individual patient data, rather than aggregate data, allowed adjustment for strong predictors of SAEs. CLINICAL RELEVANCE Relative safety of ranibizumab and bevacizumab is important in choosing an anti-VEGF drug for the hundreds of thousands of patients with nAMD treated each year worldwide. METHODS Results of a Cochrane aggregate meta-analysis of the relative efficacy and safety of bevacizumab and ranibizumab that used searches of bibliographic databases and clinical trial registries as of March 14, 2014 and hand searching were reviewed to identify 6 large-scale, multicenter clinical trials. Individual patient data on SAEs, assigned drug and dosing regimen, and baseline prognostic factors were requested from the leaders of the 6 trials. A two-stage approach was used to estimate relative risks and 95% confidence intervals (CIs) from Cox proportional hazards models adjusting for baseline prognostic factors. The primary outcome measure was development of ≥1 SAE; secondary outcome measures were death, arteriothrombotic events, events associated with systemic anti-VEGF therapy, and events not associated with systemic anti-VEGF therapy. RESULTS Individual patient data were received from 5 trials to provide information on 3052 patients. There were no large imbalances between drug groups on baseline factors. The adjusted relative risk (95% CI) for bevacizumab relative to ranibizumab was 1.06 [(0.84, 1.35); p=0.61] for ≥1 SAEs. For secondary outcomes, adjusted relative risks were 0.99 [ (0.69, 1.43); p=0.97] for death, 0.89 [ (0.62, 1.28); p=0.53] for arteriothrombotic events, 1.10 [ (0.81, 1.50); p=0.54] for events related to anti-VEGF treatment, and 1.11 [ (0.87, 1.40); p=0.40] for events not related to anti-VEGF treatment. CONCLUSION Our findings support the absence of large differences in risk of systemic serious adverse events between these two anti-VEGF drugs; i.e., relative risks of ≥1.5 are unlikely. Because additional head-to-head trials are unlikely, any further investigation of differential risk between anti-VEGF agents will only be achieved though post-marketing surveillance or through the interrogation of healthcare databases.