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Risks and benefits of nalmefene in the treatment of adult alcohol dependence: systematic literature review and meta-analysis of published and unpublished double blind randomised controlled trials

Title - Risks and benefits of nalmefene in the treatment of adult alcohol dependence: systematic literature review and meta-analysis of published and unpublished double blind randomised controlled trials Objective – To compare harm/benefit of nalmefene versus placebo or active comparator in the treatment of adult alcohol dependence. Design – Systematic review with meta-analyses on aggregated data. Data sources – Three reviewers searched for published and unpublished studies on Medline, the Cochrane Library, Embase, clinicaltrials.gov, Current Controlled Trial, in bibliographies, and by mailing industrialists, EMA, FDA and relevant key researchers. Trial selection – Double-blind randomised clinical trials evaluating nalmefene to treat adult alcohol dependence, irrespective of comparator, were included if they reported 1/ health outcomes (mortality, accident/injury, somatic complications, quality-of-life), 2/ clinical (such as consumption) outcomes, 3/ biological outcomes or 4/ safety outcomes, at 6 months and 1 year. Data extraction – Three authors independently screened titles and abstracts of trials identified. Relevant trials were evaluated in full text. The reviewers independently assessed trials included for methods, interventions, outcomes, and bias. Fixed effects models or, when appropriate, random effects models were used to estimate risk ratios (RR), mean differences (MD) or standardised differences in means (SMD) with 95% confidence intervals. Sensitivity analyses were performed using conservative approaches (‘Baseline Observation Carried Forward’ or ‘lost-to-follow-up = failure’). Results – Five RCTs versus placebo including 2567 randomised participants were included in the main analysis. None of these studies was performed in the specific population defined by EMA approval. No RCT compared Nalmefene with another medication. Mortality at 6 months (0.39 [0.08; 2.01]) and 1 year (0.98 [0.04; 23.95]), quality-of-life at 6 months (MD for SF−36 physical component summary score: 0.85 [−0.32; 2.01] and mental component summary score: 1.01 [−1.33; 3.34]) were not different across groups. Other health outcomes were not reported. Differences were encountered for consumption outcomes such as monthly number of heavy drinking days at 6 months (MD -1.65 [−2.41; −0.89]) and at 1 year (MD -1.60 [−2.85; −0.35]) and total alcohol consumption at 6 months (SMD of −0.20 [−0.30; −0.10]). An attrition bias could not be excluded, with more withdrawal for nalmefene than for placebo including more withdrawals for safety reasons at both 6 months (RR = 3.65 [2.02; 6.63]) and 1 year (RR=7.01 [1.72; 28.63]). The sensitivity analyses using conservative approaches found no differences for consumption outcomes. Conclusions – The interest of nalmefene is currently not unequivocally established. At best, the proven efficacy of nalmefene is small in improving alcohol consumption outcomes. Systematic review registration – PROSPERO 2014:CRD42014014853