Nalmefene in alcohol‐dependent patients with a high drinking risk: A limited efficacy in reducing alcohol consumption

Abstract

Nalmefene authorization in Europe for reducing alcohol consumption in alcohol-dependent patients with high or very high drinking risk level and maintaining a high drinking risk level 2 weeks after initial assessment was granted on the grounds of controversial data. There had been no randomized controlled trial (RCT) conducted in the target population at that point. The market authorization was based on data from subgroup analyses of the pivotal studies: ESENSE1 (NCT00811720), ESENSE2 (NCT00812461), and SENSE (NCT00811941). However, subgroup analyses are only exploratory. It is therefore reasonable to question if the new RCT assessing the efficacy of nalmefene in patients with a high drinking risk can add to the previous body of evidence. We argue that this study shares the weaknesses of the previous phase 3 trials that led to questioning the efficacy of nalmefene in reducing alcohol consumption. Overall, although the effect sizes observed on the consumption outcomes were higher than in the previous studies, the clinical relevance of such differences remains questionable. Regarding total alcohol consumption, the difference in the adjusted change from baseline between nalmefene 20 mg and placebo (expressed in least square mean) at 6 months was −11 g of alcohol/day (i.e., about a 100-mL glass of wine). It is also not known how much these differences were due to attrition bias. Compared to placebo (89.4%), the treatment completion rates were significantly lower in the nalmefene 20-mg (76.2%, P < 0.001) and nalmefene 10-mg (75.5%, P < 0.001) groups. Whereas a loss to follow-up of 5% or lower is usually of little concern, such a loss of >20% prevents good-quality intention-to-treat analysis and can cause biased estimates of the treatment effect. The rate of discontinuation due to adverse events was higher in the groups receiving nalmefene than in the placebo group (18.1%, 18.5%, and 4.5%, respectively, for nalmefene 20-mg, nalmefene 10-mg, and placebo). These characteristics were already observed in a meta-analysis of the initial trials submitted to the European Medicine Agency. In addition, a primary outcome assessed at 12 weeks and a follow-up ending at 24 weeks is too short to evaluate a drug intending to reduce harm. No RCT has assessed the efficacy of nalmefene in the long term. Only one RCT has assessed the efficacy of nalmefene after 1 year of treatment, and showed limited and inconsistent efficacy on consumption outcomes. Currently, the harm-reduction approach is based on models that are basically an extrapolation of the results from subgroup analyses of the previous pivotal RCT beyond the trial time horizon. Moreover, it is unlikely that a slight reduction in consumption, even if sustained, could be clinically relevant considering that the model is dealing with patients who had experienced high consumption for a long time, which is different to subjects with excessive use. None of the previous trials demonstrated any benefit of nalmefene on harm related to alcohol use, and the current study failed to show significant effect of nalmefene on health-related quality of life (i.e., Alcohol Quality of Life Scale, Short Form – 36 Health Survey, and EuroQol 5 Dimension) at 24 weeks. In several European countries, such as in Germany, agencies for efficiency in health care have concluded that studies of nalmefene showed no additional benefit for alcohol dependence compared to naltrexone, another opioid antagonist that was an earlier and less costly comparator therapy. A recent independent indirect comparison concluded a lack of advantage of nalmefene versus naltrexone. Long-term psychosocial interventions by trained professionals remain the cornerstone of successful care. Further, treatment would be a Sisyphean task and would demonize vulnerable people who cannot stop their problem drinking if no comprehensive public health policy for alcohol control is implemented. Finally, readers must be aware that a Californian winery, Ridge Vineyards Inc., is a subsidiary company of Otsuka Holdings Co., Ltd. In conclusion, it should be recalled that the clinical significance of a statistically significant difference on a surrogate outcome should be critically appraised.