In our meta-analysis of randomized controlled trials, cholinesterase inhibitor use appear to increase the risk of syncope, but have no statistically significant effect on falls, fracture, and accidental injury. We found that memantine use had no statistically significant effect on falls, syncope, and accidental injury, but appeared to reduce the risk of fracture. Subgroup analyses did not suggest that the risk of falls and fall-related adverse events differed by type and severity of cognitive impairment, residential status, or length of follow-up.
Our finding that cholinesterase inhibitors increase the risk of syncope can be explained by the known effect of these drugs on cardioinhibition and bradyarrhythmia through augmentation of parasympathetic activity.89
Neurocardiovascular instability, including bradyarrhythmia and hypotension, is prevalent among older adults with dementia and cognitive impairment and may lead to falls, syncope, and cerebral microvascular pathology.90
These responses can be exacerbated by cholinesterase inhibitors. The pooled estimate from our meta-analysis is consistent with a large population-based Canadian study that found cholinesterase inhibitor use was associated with a 1.76-fold increase in the rate of hospitalization for syncope.25
Although the product label of cholinesterase inhibitors includes a potential risk of bradycardia and syncope, these medications are often continued following hospitalization for syncope or bradycardia. Given that syncope can result in other adverse consequences, such as falls, fracture, accidental injury, and car accidents, clinicians should not overlook a significant increase in the risk of syncope that was suggested in observational studies and confirmed in our meta-analysis.
We did not find a statistically significant effect of cholinesterase inhibitors on falls, fracture, or accidental injury. However, due to small number and possible underreporting of events, we cannot exclude the possibility of small benefits or harms. Previous studies have suggested that cholinesterase inhibitors are associated with improved gait speed and variability in patients with AD.19;20
A double-blind, placebo-controlled, randomized trial (NCT00934531) is underway to evaluate the effect of donepezil on gait velocity, variability, and balance in older adults with MCI. Similarly, we did not find any statistically significant increase in fractures associated with cholinesterase inhibitor use. However, this is consistent with 1.18-fold increase in the rate of hip fracture from a previously reported population-based cohort study.25
Although the direct effects of cholinesterase inhibitors on bone mineral density or falls are not known, it is possible that the risk of fractures may increase as a consequence of syncopal events. In addition, there was moderate between-study heterogeneity on accidental injury for cholinesterase inhibitors, indicating that more variations exist in the study results than would be expected by chance alone. The heterogeneity was not explained by the difference in study population and design characteristics that were considered.
Our finding that memantine is associated with a large reduction in fractures is intriguing. Glutamate is a major excitatory neurotransmitter found in the central nervous system as well as in non-neural peripheral tissues, including bone. The role of glutamate in bone formation and remodeling is not fully understood, but animal and experimental studies have demonstrated that NMDA-receptor agonists promote osteoblast differentiation and osteoclastogenesis, and that NMDA-receptor antagonists inhibit osteoclast formation.91;92
To date, we are not aware of any studies that have examined the effect of memantine on markers of bone turnover, bone mineral density, or fracture. Given that the data were extracted from three small unpublished studies, our finding should be viewed as hypothesis-generating, rather than confirmatory. Future studies should be conducted to replicate our findings. While we did not find any harmful effects of memantine on falls or fall-related adverse events, we cannot eliminate the possibility of any small benefits or harms. Memantine can cause dizziness and elevated blood pressure due to its dopaminergic and antimuscarinic properties. Other cardiovascular effects of memantine have not been studied in humans. Studies in rats have shown that NMDA receptors are present in cardiovascular tissues and produce positive inotropic and negative chronotropic effects.93;94
Adverse cardiac events, including bradycardia, orthostatic hypotension with fall, fainting, heart failure, and sudden death have been reported in a pharmacovigilance study, but a causal relationship could not be established due to its descriptive design, underreporting, and concurrent use of other agents that are well-known to induce bradycardia.23
Strengths and Limitations
Our meta-analysis has several strengths. First, we manually searched various sources to identify unpublished sources and complement published studies. There was no evidence of publication bias. Therefore, our work contributes to the literature by providing a more comprehensive, unbiased view on the safety of cholinesterase inhibitors and memantine in relation to falls and related adverse events that are associated with adverse health outcomes and substantial health care expenditure in older adults. Second, we conducted sensitivity analyses to test the robustness of our findings by repeating our analysis including studies with complete follow-up and studies with larger sample size. We also examined the influence of individual studies on the pooled estimates. Our results remained consistent under different assumptions. Third, since our findings came from randomized controlled trials, residual confounding is unlikely.
Conducting a systematic review that evaluates harms of an intervention is often challenged with difficulty in finding such data.26
First, underreporting of falls, syncope, and related events was common. Our systematic search identified 156 potentially eligible randomized controlled trials, but only 54 reported data on at least one type of fall-related adverse event and 16 reported data on three or more types of adverse events. Despite our best efforts to identify both published and unpublished safety data from various sources, the number of fall-related events reported was much lower than the rates estimated from previous observational studies, even after considering the difference in follow-up duration. This suggests that falls, syncope, and related events may have been systematically underreported or that participants in randomized controlled trials are generally healthier than cognitively impaired adults who did not participate. In addition, if those assigned to cholinesterase inhibitors or memantine were more likely to drop out than those assigned to placebo during the study, the reported number of events could be smaller in the active treatment arm due to shorter follow-up time. Both scenarios would lead to underestimation of the potentially important risks of fall-related adverse events associated with these medications. Nonetheless, this limitation does not reduce the importance of our review. Our findings were consistent with those from observational studies. Furthermore, the absence of publication bias further supports the validity of our findings.
Second, trials did not provide detailed information on how falls, syncope, and related events were defined, monitored, and reported. Although falls can be recorded more accurately by using fall calendars, it is often not practical in the setting of clinical trials in which falls are not the main outcome of interest. As a result, a non-differential misclassification of the events might occur and bias the results toward the null. In addition, we recognize that we evaluated the quality of overall adverse events monitoring and reporting, rather than focusing on specific fall-related adverse events, which might have caused misclassification in assessing study quality. However, in our sensitivity analysis, the results were similar between trials that indicated the use of standardized definitions of adverse events and trials that did not.
Third, there are few quality assessment tools for reporting harms.27
We assessed the rigorousness of monitoring and the quality of reporting by adopting previously suggested criteria,60
in addition to commonly used quality criteria. We were not able to find a set of quality criteria that were uniformly associated with either exaggerated or attenuated effect. Further efforts are needed to develop appropriate tools for reporting harm.
Furthermore, the number of included trials for a certain outcome of interest, in particular, fracture, was small. As a result, we were not able to detect any meaningful variations in the effects of treatment by subgroups and quality criteria. Although we found significant variations by type of cognitive impairment in the effect of cholinesterase inhibitors on syncope, the variation was mostly driven by imprecise estimates from studies of PDD or DLB and MCI. Finally, the majority of participants in randomized controlled trials had mild or mild-to-moderate degree of cognitive impairment and were living in the community, thereby limiting generalizability of our findings to a broader population of severely cognitively impaired, institutionalized older adults. If the true effect of cholinesterase inhibitors on syncope were larger in those with severe cognitive impairment and other multiple comorbidities, our results would underestimate the causal effect at a population level.
Conclusions and Implications
Our meta-analysis of randomized controlled trials provides further support and complements existing evidence from observational studies, by showing that cholinesterase inhibitors may increase the risk of syncope. We observed that cholinesterase inhibitors have little effect on falls, fracture, or accidental injury, and memantine appears to have little effect on fall, syncope, or accidental injury. Nonetheless, our review does not exclude a potentially significant risk due to underreporting and small number of outcome events. In addition, whether memantine reduces the risk of fracture needs to be confirmed in future prospective studies.
Considering the public health impact of fall-related adverse events and the potential causal role of medications in such events among older adults with cognitive impairment, these events should be routinely included in trial reports. Furthermore, more high-quality observational research is warranted to evaluate the impact of these agents on fall-related adverse events in a more representative population.