Pierre Charles

Single-Center Trials Show Larger Treatment Effects Than Multicenter Trials: Evidence From a Meta-epidemiologic Study

BACKGROUNDnA recent study suggested that results of single-center trials are frequently contradicted when similar trials are performed in multicenter settings.nnnPURPOSEnTo perform a meta-epidemiologic study to evaluate whether estimates of treatment effect differ between single-center and multicenter randomized, controlled trials (RCTs).nnnDATA SOURCESnMEDLINE was searched via PubMed for meta-analyses of RCTs with binary outcomes that were published between August 2008 and January 2009 and in the first 6 months of 2010 in the 10 leading journals of each medical specialty. One issue of the Cochrane Database of Systematic Reviews was also searched.nnnSTUDY SELECTIONnAll individual RCTs included in the meta-analyses were selected.nnnDATA EXTRACTIONnData were extracted and their quality was assessed by use of the risk of bias tool of the Cochrane Collaboration.nnnDATA SYNTHESISnThe primary outcome was the ratio of odds ratios (ROR), used to quantify the difference in estimated intervention effect between single-center and multicenter RCTs. An ROR less than 1 would indicate larger estimates of the intervention effect in single-center trials. Sensitivity analyses were performed with adjustment for sample size, risk of bias within RCTs, and variance of the log odds ratio to take publication bias into account. Forty-eight meta-analyses were selected, including 421 RCTs (223 were single-center and 198 were multicenter). Single-center RCTs showed a larger intervention effect than did multicenter RCTs (combined ROR, 0.73 [95% CI, 0.64 to 0.83]), with low heterogeneity across individual meta-analyses (I(2) = 12.0%; P = 0.24). Adjustment for sample size yielded consistent results (ROR, 0.85 [CI, 0.74 to 0.97]), as did adjustment for risk of bias within RCTs, such as allocation concealment (ROR, 0.76 [CI, 0.67 to 0.86]), and variance of log odds ratio (ROR, 0.83 [CI, 0.72 to 0.96]).nnnLIMITATIONnDespite sensitivity analyses, meta-confounding cannot be fully excluded.nnnCONCLUSIONnSingle-center RCTs showed larger treatment effects than did multicenter RCTs, a finding that was consistent in all sensitivity analyses. These results suggest that this item should be considered when the results of RCTs and meta-analyses are interpreted.nnnPRIMARY FUNDING SOURCEnAcademic grant Recherche sur la Recherche from the Délégation Interrégionale à la Recherche Clinique (DIRC), Ile de France, Assistance Publique-Hôpitaux de Paris (APHP).

Reporting of sample size calculation in randomised controlled trials: review

Objectives To assess quality of reporting of sample size calculation, ascertain accuracy of calculations, and determine the relevance of assumptions made when calculating sample size in randomised controlled trials. Design Review. Data sources We searched MEDLINE for all primary reports of two arm parallel group randomised controlled trials of superiority with a single primary outcome published in six high impact factor general medical journals between 1 January 2005 and 31 December 2006. All extra material related to design of trials (other articles, online material, online trial registration) was systematically assessed. Data extracted by use of a standardised form included parameters required for sample size calculation and corresponding data reported in results sections of articles. We checked completeness of reporting of the sample size calculation, systematically replicated the sample size calculation to assess its accuracy, then quantified discrepancies between a priori hypothesised parameters necessary for calculation and a posteriori estimates. Results Of the 215 selected articles, 10 (5%) did not report any sample size calculation and 92 (43%) did not report all the required parameters. The difference between the sample size reported in the article and the replicated sample size calculation was greater than 10% in 47 (30%) of the 157 reports that gave enough data to recalculate the sample size. The difference between the assumptions for the control group and the observed data was greater than 30% in 31% (n=45) of articles and greater than 50% in 17% (n=24). Only 73 trials (34%) reported all data required to calculate the sample size, had an accurate calculation, and used accurate assumptions for the control group. Conclusions Sample size calculation is still inadequately reported, often erroneous, and based on assumptions that are frequently inaccurate. Such a situation raises questions about how sample size is calculated in randomised controlled trials.

Misrepresentation of randomized controlled trials in press releases and news coverage: a cohort study.

A study conducted by Amélie Yavchitz and colleagues examines the factors associated with “spin” (specific reporting strategies, intentional or unintentional, that emphasize the beneficial effect of treatments) in press releases of clinical trials.

Rituximab for induction and maintenance treatment of ANCA-associated vasculitides: a multicentre retrospective study on 80 patients

OBJECTIVESnRituximab has been shown to induce remission of ANCA-associated vasculitides (AAVs). Our study was undertaken to describe AAV clinical responses to rituximab used for remission-induction and/or maintenance therapy, assess rituximabs safety profile and evaluate French clinical practices.nnnMETHODSnThis retrospective study concerned AAV patients who had received one or more rituximab infusion between 2002 and January 2011 and had follow-up lasting ≥12 months.nnnRESULTSnEighty patients were included, most with refractory or relapsing AAV: 70 (88%) with granulomatosis with polyangiitis (GPA), 9 (11%) with microscopic polyangiitis and 1 (1%) with eosinophilic GPA. Rituximab was the first agent used to induce remission in 73 patients. The two most commonly administered regimens were an infusion of 375 mg/m(2)/week for 4 weeks (54 patients) and an infusion of 1 g every 2 weeks for a month (16 patients). Rituximab was first prescribed to maintain remission in seven patients. Respective 1-, 2-, and 3-year relapse-free survival rates after the first infusion were 80% (95% CI 72, 89), 63% (51, 77) and 52% (39, 70). Relapse-free survival was longer for patients receiving rituximab maintenance therapy (P = 0.002). Among 22 (28%) rituximab-treated patients experiencing severe adverse events, 12 (15%) had infectious complications leading to 4 (5%) deaths. Only 15 (19%) patients had received anti-pneumococcal vaccine before rituximab.nnnCONCLUSIONnRituximab was able to induce AAV remission and seemed to maintain remission better than other agents, but caution is needed concerning its safety, especially regarding bacterial infections, in this population.

Rituximab: Recommendations of the French Vasculitis Study Group (FVSG) for induction and maintenance treatments of adult, antineutrophil cytoplasm antibody- associated necrotizing vasculitides

Increasing rituximab prescription for ANCA-associated necrotizing vasculitides justifies the publication of recommendations for clinicians. Rituximab is approved in the United States to induce and maintain remission. In Europe, rituximab was recently approved for remission induction. However, governmental agencies approvals cannot replace clinical practice guidelines. Herein, the French Vasculitis Study Group Recommendations Committee, comprised of physicians with extensive experience in the treatment of vasculitides, presents its consensus guidelines based on literature analysis, the results of prospective therapeutic trials and personal experience.

Suffering among carers working in critical care can be reduced by an intensive communication strategy on end-of-life practices

PurposeBurnout syndrome (BOS) has frequently been reported in healthcare workers, and precipitating factors include communication problems in the workplace and stress related to end-of-life situations. We evaluated the effect of an intensive communication strategy on BOS among caregivers working in intensive care (ICU).MethodsLongitudinal, monocentric, before-and-after, interventional study. BOS was evaluated using the Maslach Burnout Inventory (MBI) and depression using the Centre for Epidemiologic Studies Depression Scale (CES-D) in 2007 (period 1) and 2009 (period 2). Between periods, an intensive communication strategy on end-of-life practices was implemented, based on improved organisation, better communication, and regular staff meetings.ResultsAmong 62 caregivers in the ICU, 53 (85%) responded to both questionnaires in period 1 and 49 (79%) in period 2. We observed a significant difference between periods in all three components of the MBI (emotional exhaustion, pxa0=xa00.04; depersonalization pxa0=xa00.04; personal accomplishment, pxa0=xa00.01). MBI classified burnout as severe in 15 (28%) caregivers in period 1 versus 7 (14%) in period 2, pxa0<xa00.01, corresponding to a 50% risk reduction. Symptoms of depression as evaluated by the CES-D were present in 9 (17%) caregivers in period 1 versus 3 (6%) in period 2, pxa0<xa00.05, corresponding to a risk reduction of almost 60%.ConclusionThe implementation of an active, intensive communication strategy regarding end-of-life care in the ICU was associated with a significant reduction in the rate of burnout syndrome and depression in a stable population of caregiving staff.

Diagnostic Accuracy of Inflammatory Markers As Early Predictors of Infection After Elective Colorectal Surgery: Results From the IMACORS Study.

Background:Intra-abdominal infections are frequent and life-threatening complications after colorectal surgery. An early detection could diminish their clinical impact and permit safe early discharge. Objective:This study aimed to find the most accurate marker for the detection of postoperative intra-abdominal infection and the appropriate moment to measure it. Methods:A prospective, observational study was conducted in 3 centers. Consecutive patients undergoing elective colorectal surgery with anastomosis were included. C-reactive protein and procalcitonin were measured daily until the fourth postoperative day. Postoperative infections were recorded according to the definitions of the Centres for Diseases Control. The areas under the receiver operating characteristic curve were analyzed and compared to assess the diagnostic accuracy of each marker. Results: :Five-hundred and one patients were analyzed. The incidence of intra-abdominal infection was 11.8%, with 24.6% of patients presenting at least one infectious complication. Overall mortality was 1.2%. At the fourth postoperative day, C-reactive protein was more discriminating than procalcitonin for the detection of intra-abdominal infection (areas under the ROC curve: 0.775 vs 0.689, respectively, P = 0.03). Procalcitonin levels showed wide dispersion. For the detection of all infectious complications, C-reactive protein was also significantly more accurate than procalcitonin on the fourth postoperative day (areas under the ROC curve: 0.783 vs 0.671, P = 0.0002). Conclusions:C-reactive protein is more accurate than procalcitonin for the detection of infectious complications and should be systematically measured at the fourth postoperative day. It is a useful tool to ensure a safe early discharge after elective colorectal surgery.

Rituximab for induction and maintenance therapy in granulomatosis with polyangiitis (Wegener's). Results of a single-center cohort study on 66 patients

The aim of this study was to evaluate the efficacy and safety of rituximab (RTX) associated with glucocorticoid treatment based on disease severity, as a remission induction treatment for granulomatosis with polyangiitis (GPA) (Wegeners) and to analyze the results of long-term maintenance therapy with low doses of RTX in a routine time-based protocol. This single-center retrospective study used standardized data collection from all GPA patients receiving RTX between 2002 and 2013. The remission induction regimen consisted of RTX and glucocorticoids, adapted according to disease severity. Once remission was achieved, patients received RTX maintenance treatment (500xa0mg every 6 months) for 18 months. Sixty-six GPA patients received RTX for remission induction. After six months, a response had been achieved in 78.8% of these patients, with a moderate oral prednisone regimen (mean dose at baseline, 32.8xa0±xa023.4xa0mg/day). Subglottic stenosis increased the risk of treatment failure (ORxa0=xa031.2, Pxa0=xa00.0104). RTX maintenance treatment was continued for 18 months in 92% of the GPA patients, who were followed for 34.2xa0±xa026.2 months (mean total cumulative RTX dose of 4.6xa0±xa01.7xa0g). The relapse rate was 11.2/100 patient-years. The relapses occur a mean of 13.5xa0±xa014.7 months after the last RTX infusion. Twenty-one severe adverse events were recorded; 13.6% patients had severe infections. We conclude that in this single-center cohort, RTX associated with glucocorticoid treatment adapted for disease severity appeared to induce remission effectively in GPA patients. Maintenance treatment with low doses of RTX in a routine time-based protocol was safe and associated with low rates of relapse on treatment.

Central nervous system involvement of granulomatosis with polyangiitis: clinical–radiological presentation distinguishes different outcomes

OBJECTIVEnThe aim of this study was to describe the presentation and outcomes of patients with granulomatosis with polyangiitis (GPA) presenting with CNS involvement.nnnMETHODSnPatients were included in this nationwide retrospective study if they had GPA according to ACR criteria and/or the European Medicines Agency algorithm and CNS involvement.nnnRESULTSnThirty-five patients were included in the study. CNS involvement was observed in 51% of patients at GPA diagnosis. Headache (66%) was the main symptom, followed by sensory (43%) and motor impairment (31%). CNS involvement was characterized by pachymeningitis in 20, cerebral ischaemic lesions in 15 and haemorrhagic lesions in 2, with hypophyseal involvement in 2 patients. According to the clinical-radiological presentation, we distinguished granulomatous (G-CNS) and vasculitic (V-CNS) phenotypes. G-CNS patients more frequently had headaches, while V-CNS patients more frequently had motor impairment and renal involvement. Induction therapy produced clinical responses in 86% of patients. Baseline modified Rankin scale was higher for V-CNS than G-CNS patients (3 vs 2, P = 0.002). Initial spinal cord pachymeningitis was significantly associated with the need for a new induction regimen for relapsing/refractory disease (P = 0.01). Long-term neurological sequelae were noted in 51% of patients, including 35% with G-CNS and 69% with V-CNS (P = 0.08). Neurological sequelae were mainly noted in cases of spinal cord pachymeningitis (100%) and ischaemic or haemorrhagic lesions (73%).nnnCONCLUSIONnThe clinical-radiological phenotype distinguished different long-term outcomes in patients with GPA and CNS involvement. Long-term neurological sequelae persisted in half of patients, mainly those with spinal cord pachymeningitis and vasculitic lesions.

Empirical Micafungin Treatment and Survival Without Invasive Fungal Infection in Adults With ICU-Acquired Sepsis, Candida Colonization, and Multiple Organ Failure: The EMPIRICUS Randomized Clinical Trial

ImportancenAlthough frequently used in treating intensive care unit (ICU) patients with sepsis, empirical antifungal therapy, initiated for suspected fungal infection, has not been shown to improve outcome.nnnObjectivenTo determine whether empirical micafungin reduces invasive fungal infection (IFI)-free survival at day 28.nnnDesign, Setting, and ParticipantsnMulticenter double-blind placebo-controlled study of 260 nonneutropenic, nontransplanted, critically ill patients with ICU-acquired sepsis, multiple Candida colonization, multiple organ failure, exposed to broad-spectrum antibacterial agents, and enrolled between July 2012 and February 2015 in 19 French ICUs.nnnInterventionsnEmpirical treatment with micafungin (100 mg, once daily, for 14 days) (nu2009=u2009131) vs placebo (nu2009=u2009129).nnnMain Outcomes and MeasuresnThe primary end point was survival without proven IFI 28 days after randomization. Key secondary end points included new proven fungal infections, survival at day 28 and day 90, organ failure, serum (1-3)-β-D-glucan level evolution, and incidence of ventilator-associated bacterial pneumonia.nnnResultsnAmong 260 patients (mean age 63 years; 91 [35%] women), 251 (128, micafungin group; 123, placebo group) were included in the modified intent-to-treat analysis. Median values were 8 for Sequential Organ Failure Assessment (SOFA) score, 3 for number of Candida-colonized sites, and 99 pg/mL for level of (1-3)-β-D-glucan. On day 28, there were 82 (68%) patients in the micafungin group vs 79 (60.2%) in the placebo group who were alive and IFI free (hazard ratio [HR], 1.35 [95% CI, 0.87-2.08]). Results were similar among patients with a (1-3)-β-D-glucan level of greater than 80 pg/mL (nu2009=u2009175; HR, 1.41 [95% CI, 0.85-2.33]). Day-28 IFI-free survival in patients with a high SOFA score (>8) was not significantly different when compared between the micafungin vs placebo groups (HR, 1.69 [95% CI, 0.96-2.94]). Use of empirical micafungin decreased the rate of new invasive fungal infection in 4 of 128 patients (3%) in the micafungin group vs placebo (15/123 patients [12%]) (Pu2009=u2009.008).nnnConclusions and RelevancenAmong nonneutropenic critically ill patients with ICU-acquired sepsis, Candida species colonization at multiple sites, and multiple organ failure, empirical treatment with micafungin, compared with placebo, did not increase fungal infection-free survival at day 28.nnnTrial Registrationnclinicaltrials.gov Idenitfier: NCT01773876.