The Whiteley-Martin Research Centre, Discipline of Surgery, Nepean Hospital, The University of Sydney, Level 3, Clinical Building, PO Box 63, Penrith, NSW, 2751, Australia.
CNS Drugs. 2018 Jun;32(6):485-497. doi: 10.1007/s40263-018-0535-3.
Benzodiazepine use is highly prevalent in elderly and late middle-aged populations and may be associated with an increased risk of dementia. Observational studies have suggested that benzodiazepine use may increase the risk of dementia, however there have been significant concerns regarding protopathic bias in these studies, precluding conclusive findings.
The aim of our study was to investigate the risk of dementia associated with the use of benzodiazepines in elderly patients, after controlling for protopathic bias.
We identified observational studies with more than 50 cases, adequate assessment of benzodiazepine exposure, and reliable dementia diagnosis ascertainment, from the MEDLINE, PubMed, EMBASE, CINAHL, LILACS and CENTRAL electronic databases through to 5 June 2018, with no language limits. The association of any current or former use of short- or long-acting benzodiazepines with incident dementia was analysed. A subgroup analysis was performed by the introduction of lag time to assess the effect of protopathic bias. We also performed analyses considering the effect of higher benzodiazepine cumulative doses and adjustment for psychiatric covariates. Study quality was investigated using the Newcastle-Ottawa Scale.
We identified 15 studies reported in 14 articles, involving 159,090 cases. Ever use of benzodiazepines was associated with a significantly increased risk of dementia [odds ratio (OR) 1.39, 95% confidence interval (CI) 1.21-1.59]. Those studies that implemented the longest lag times of ≥ 5 years, and hence most likely to overcome protopathic bias, found a risk estimate that was marginally attenuated, but still significant (OR 1.30, 95% CI 1.14-1.48). Long-acting benzodiazepines were associated with a marginally higher magnitude risk (OR 1.21, 95% CI 0.99-1.49) than short-acting benzodiazepines (OR 1.13, 95% CI 1.02-1.26), although the former failed to reach statistical significance (p = 0.059).
Our findings indicate that the association between benzodiazepine use and dementia incidence is not purely an artefact due to protopathic bias. Reduction of inappropriate benzodiazepine prescription is likely to attenuate dementia risk.
苯二氮䓬类药物在老年和中老年人群中广泛使用，可能与痴呆风险增加有关。观察性研究表明，苯二氮䓬类药物的使用可能会增加痴呆的风险，但这些研究存在明显的前驱偏倚问题，无法得出明确的结论。
我们的研究旨在调查在控制前驱偏倚后，老年患者使用苯二氮䓬类药物与痴呆风险之间的关系。
我们从 MEDLINE、PubMed、EMBASE、CINAHL、LILACS 和 CENTRAL 电子数据库中检索了超过 50 例病例、充分评估苯二氮䓬类药物暴露情况和可靠的痴呆诊断确定的观察性研究，检索截至 2018 年 6 月 5 日，无语言限制。分析了任何当前或过去使用短效或长效苯二氮䓬类药物与新发痴呆之间的关联。通过引入滞后时间进行亚组分析，以评估前驱偏倚的影响。我们还进行了考虑更高累积苯二氮䓬类药物剂量和调整精神科协变量影响的分析。使用纽卡斯尔-渥太华量表评估研究质量。
我们确定了 15 项研究，共涉及 159090 例病例，这些研究发表在 14 篇文章中。使用苯二氮䓬类药物与痴呆风险显著增加相关[比值比（OR）1.39，95%置信区间（CI）1.21-1.59]。那些实施最长滞后时间≥5 年的研究，最有可能克服前驱偏倚，发现风险估计略有减弱，但仍有统计学意义（OR 1.30，95% CI 1.14-1.48）。长效苯二氮䓬类药物与痴呆风险增加幅度略高（OR 1.21，95% CI 0.99-1.49），而短效苯二氮䓬类药物（OR 1.13，95% CI 1.02-1.26）则无统计学意义（p=0.059）。
我们的研究结果表明，苯二氮䓬类药物使用与痴呆发生率之间的关联并非仅仅是前驱偏倚的一种假象。减少不适当的苯二氮䓬类药物处方可能会降低痴呆风险。
