Nalmefene in alcohol dependence treatment

Le nalméfène représente une option nouvelle dans le traitement de l’alcoolodépendance. Cette molécule a reçu une AMM européenne en 2013 pour réduire la consommation d’alcool des patients adultes ayant une consommation à risque élevé selon la classification de l’OMS (i.e. plus de 60 g d'alcool par jour pour les hommes, ou plus de 40 g par jour pour les femmes). Toutefois, les avis dans la littérature divergent quant à son intérêt. Nous avons donc souhaité réévaluer le rapport bénéfice-risque de cette molécule en appliquant des méthodes appartenant au domaine de la méta-recherche. Une première méta-analyse des essais randomisés contrôlés comparant le nalméfène par voie orale à un placebo nous a permis de mettre en évidence des tailles d’effet faibles sur les critères de consommation, avec un possible biais d’attrition dans les études. Dans une seconde méta-analyse en réseau évaluant l’efficacité, dans l’indication de réduction des consommations, du nalméfène à d’autres traitements également utilisés dans la prise en charge de l’alcoolodépendance, nous avons conclu à l’absence de preuve de haut niveau de l’efficacité des traitements pharmacologiques pour contrôler la consommation d'alcool chez les patients non abstinents souffrant de troubles liés à l’usage. Enfin, nous avons montré, à travers la réalisation d’un grand nombre de méta analyses, que les choix méthodologiques faits dans les essais randomisés contrôlés évaluant le nalméfène et la naltrexone dans la prise en charge de l’addiction à l’alcool entraînaient une variation substantielle de l’estimation de l’efficacité de ces deux traitements, phénomène également appelé « vibration de l’effet » des traitements.Nalmefene is a new option in the treatment of alcohol dependence. It was approved by the European Medicines Agency to help reduce alcohol consumption in adults who consume more than 60 g of alcohol per day (for men) or more than 40 g per day (for women). However, researchers’ opinions on the interest of the drug are divided. We therefore planned direct and network meta-analyses to enable an objective reappraisal of the efficacy of nalmefene. A first meta-analysis of randomized controlled trials comparing oral nalmefene with placebo showed small effect sizes on consumption criteria with a possible attrition bias in the studies. In a second network meta-analysis evaluating the comparative efficacy of nalmefene to control drinking with other treatments also used in the management of alcohol dependence, we concluded that there was no high-grade evidence for pharmacological treatment to control drinking in non-abstinent patients with alcohol use disorders. Finally, we explored the vibration of effects in a large number of overlapping indirect meta-analyses comparing nalmefene versus naltrexone to reduce alcohol consumption. We demonstrated that the methodological choices made in randomized controlled trials resulted in a substantial variation in the effect sizes of these two treatments

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Vibration of effects resulting from network geometry in mixed-treatment comparisons: a case study in network meta-analyses of antidepressants in major depressive disorde

Nalmefene in alcohol-dependent patients with a high drinking risk a limited efficacy in reducing alcohol consumption

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The Accuracy of Temperature Measurements Provided by the Edwards Lifesciences Pulmonary Artery Catheter

International audienceBACKGROUND: Pulmonary artery catheters (PACs) are frequently used for monitoring patient temperatures in the intensive care unit. Nevertheless, data regarding the accuracy of these measurements are lacking, and few data testify to the accuracy of temperatures recorded after the PAC has been in place for several days. The absolute values of such measurements are relevant for critical care because patient temperatures are often used as diagnostic criteria for sepsis and antibiotic therapy. We thus hypothesized that the Edwards Lifesciences PAC would accurately measure blood temperature. To test our hypothesis, we compared temperature measurements obtained from PACs inserted in patients for different lengths of time with measurements of a reference platinum resistance thermometer (PRT). METHODS: PACs were removed and analyzed in 39 patients in whom PACs were inserted for 0 to 5 days. The PACs were placed in calibration baths, and 10 consecutive measurements at each of 7 different temperatures were obtained (36°C, 36.5°C, 37°C, 38°C, 38.3°C, 39°C, and 40°C). The temperature measurements obtained using PACs were compared with measurements obtained using a PRT. Bland-Altman statistical analyses were performed. Outliers, defined as PAC temperature measurements that varied more than ±0.3°C from PRT measurements, were identified. We considered a catheter unfit for clinical diagnostic or therapeutic use if ≥15% of data pairs were outliers. RESULTS: A total of 2730 data pairs were analyzed. Overall, the bias was -0.15°C; the precision was +0.13°C; and the limits of agreement were -0.45°C to +0.13°C. The bias and limits of agreement did not differ according to the age of the catheter or the temperature tested. One hundred fourteen data pairs (4.2% [95% confidence interval, 2.0%-6.4%]), involving 13 PACs and mostly from 4 PACs, were outliers. CONCLUSIONS: We conclude that temperature measurements obtained using the Edwards Lifesciences PACs are thus sufficiently accurate to be used for clinical temperature monitoring in critically ill patient

Risks and benefits of Nalmefene in the treatment of adult alcohol dependence: a systematic literature review and meta-analysis of published and unpublished double-blind randomized controlled trials.

Nalmefene is a recent option in alcohol dependence treatment. Its approval was controversial. We conducted a systematic review and meta-analysis of the aggregated data (registered as PROSPERO 2014:CRD42014014853) to compare the harm/benefit of nalmefene versus placebo or active comparator in this indication.Three reviewers searched for published and unpublished studies in Medline, the Cochrane Library, Embase, ClinicalTrials.gov, Current Controlled Trials, and bibliographies and by mailing pharmaceutical companies, the European Medicines Agency (EMA), and the US Food and Drug Administration. Double-blind randomized clinical trials evaluating nalmefene to treat adult alcohol dependence, irrespective of the comparator, were included if they reported (1) health outcomes (mortality, accidents/injuries, quality of life, somatic complications), (2) alcohol consumption outcomes, (3) biological outcomes, or (4) treatment safety outcomes, at 6 mo and/or 1 y. Three authors independently screened the titles and abstracts of the trials identified. Relevant trials were evaluated in full text. The reviewers independently assessed the included trials for methodological quality using the Cochrane Collaboration tool for assessing risk of bias. On the basis of the I2 index or the Cochrane's Q test, fixed or random effect models were used to estimate risk ratios (RRs), mean differences (MDs), or standardized mean differences (SMDs) with 95% CIs. In sensitivity analyses, outcomes for participants who were lost to follow-up were included using baseline observation carried forward (BOCF); for binary measures, patients lost to follow-up were considered equal to failures (i.e., non-assessed patients were recorded as not having responded in both groups). Five randomized controlled trials (RCTs) versus placebo, with a total of 2,567 randomized participants, were included in the main analysis. None of these studies was performed in the specific population defined by the EMA approval of nalmefene, i.e., adults with alcohol dependence who consume more than 60 g of alcohol per day (for men) or more than 40 g per day (for women). No RCT compared nalmefene with another medication. Mortality at 6 mo (RR = 0.39, 95% CI [0.08; 2.01]) and 1 y (RR = 0.98, 95% CI [0.04; 23.95]) and quality of life at 6 mo (SF-36 physical component summary score: MD = 0.85, 95% CI [-0.32; 2.01]; SF-36 mental component summary score: MD = 1.01, 95% CI [-1.33; 3.34]) were not different across groups. Other health outcomes were not reported. Differences were encountered for alcohol consumption outcomes such as monthly number of heavy drinking days at 6 mo (MD = -1.65, 95% CI [-2.41; -0.89]) and at 1 y (MD = -1.60, 95% CI [-2.85; -0.35]) and total alcohol consumption at 6 mo (SMD = -0.20, 95% CI [-0.30; -0.10]). An attrition bias could not be excluded, with more withdrawals for nalmefene than for placebo, including more withdrawals for safety reasons at both 6 mo (RR = 3.65, 95% CI [2.02; 6.63]) and 1 y (RR = 7.01, 95% CI [1.72; 28.63]). Sensitivity analyses showed no differences for alcohol consumption outcomes between nalmefene and placebo, but the weight of these results should not be overestimated, as the BOCF approach to managing withdrawals was used.The value of nalmefene for treatment of alcohol addiction is not established. At best, nalmefene has limited efficacy in reducing alcohol consumption

Specific and non-specific effects of psychotherapeutic interventions for depression: Results from a meta-analysis of 84 studies

International audienceThere is a long-standing and very active debate regarding which psychotherapeutic intervention should be used in depressive disorders. However, the effects of psychotherapies may result majorly from non-specific factors rather than from specific factors related to the type of psychotherapeutic intervention. We performed a systematic review and meta-analysis on aggregated data to understand how the effects of different psychotherapies are impacted by non-specific factors. We included randomized controlled trials that assessed the efficacy of psychotherapeutic interventions in the treatment of adult depressive disorders. The primary outcome was the change in depression score from baseline to the latest follow-up visit (i.e. response). A meta-regression was performed to predict response according to the type of intervention and non-specific factors (e.g. number of treatment sessions, length of follow-up, therapeutic allegiance of the investigator). The main analysis included 214 study arms from 84 trials. The effects of psychotherapies compared to the waiting list control condition failed to remain significant after adjusting for non-specific factors. Response increased with the number of treatment sessions (β = 0.03, 95% CI [0.01; 0.04]) and the length of follow-up (β = 0.01, 95% CI [0.00; 0.02]). Response also improved in case of presumed therapeutic allegiances among investigators (β = 0.29, 95% CI [0.07; 0.52]). Response to psychotherapies seems to be closely related to non-specific effects. The development of a well-designed trial that controls for non-specific factors might help disentangle the effects of psychotherapies

Understanding the Antidepressant Debate in the Treatment of Major Depressive Disorder

There is a long-standing polemic concerning the usefulness of antidepressants in the treatment of major depressive disorder. In this paper, we propose to highlight some aspects of this controversy by exploring the mutual influence of psychopharmacology and trial methodologies. Indeed, antidepressant efficacy, if not proved, was accepted before antidepressant randomised controlled trials (RCTs) were run. While RCTs became a gold standard to meet the requirements of the regulatory bodies, methodological tools were required to measure outcomes and to test whether antidepressants provide statistically significant benefits as compared with a placebo. All these methodological options have nonetheless introduced fuzziness in our interpretation of study results, in terms of clinical meaningfulness and in terms of transposability to a real life settings. Additionally, selective publication raises concerns about the published literature, and results in many paradoxes. Instead of providing easy answers, the application of the RCT paradigm in MDD raises numerous questions. This is probably in the nature of all scientific studies, but it can be in contradiction with clinicians’ expectations, who want to be sure that the treatment will (or will not) work for their individual patients

Vibration of effects from diverse inclusion/exclusion criteria and analytical choices 9216 different ways to perform an indirect comparison meta-analysis

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Non-menopausal Status, High Nuclear Grade, Tumor Size \textgreater30 mm and Positive Resection Margins Are Predictors of Residual Tumor After Lumpectomy for Ductal Carcinoma In Situ of the Breast

International audienceAIM: Breast-conserving surgery with radiation therapy is the primary treatment for ductal carcinoma in situ (DCIS). Re-excision is indicated when clear resection margins have not been achieved, although in some cases the procedure may be unnecessary as there is no residual tumor. The purpose of our three-Center retrospective study was to identify predictors of positive re-excision findings following breast-conserving surgery for DCIS. PATIENTS AND METHODS: A total of 285 patients underwent re-excision following conservative treatment for DCIS between 01/01/08 and 12/31/13 at three breast-cancer referral Centers. We conducted a retrospective, comparative review of the factors that differentiated patients with a residual tumor from those without. The study was based on clinical, radiological, surgical and pathological criteria. RESULTS: A total of 180 patients (63%) had residual tumor after conservative treatment. Six factors were predictive on univariate analysis: young age (p=0.025), non-menopausal status (p=0.016), absence of preoperative biopsy (p=0.0029), high nuclear grade (p=0.0181), lesion size \textgreater30 mm (p=0.032), and positive surgical margins (p=0.0016). Four factors remained independently predictive on multivariate analysis: non-menopausal status (p=0.0017), high nuclear grade (p=0.0031), lesion size \textgreater30 mm (p=0.012) and positive surgical margins (p=0.0013). We calculated a 93% probability of positive re-excision findings if all four factors were combined. On the other hand, if none of the factors were present, the rate fell to 18%. CONCLUSION: In cases of DCIS, where risk factors for both involved lumpectomy margins and recurrence are carefully studied, knowledge of the risk factors for residual tumor can help guide therapeutic choice

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<p>FDA, US Food and Drug Administration.</p