Effects of Medications With Anti-Cholinergic Properties
This is the first systematic review to assess the effects of medications with anti-cholinergic properties on delirium and physical function, and an important update on cognitive function and mortality. The findings indicate that medicines with anti-cholinergic properties have a negative effect on cognitive function. The results also indicated no significant association between anti-cholinergic load and either mortality or delirium. Single- or limited-drug studies in the past have supported the relationship between these medicines and delirium. Using anti-cholinergic drug scales to identify all medications with anti-cholinergic properties did not appear to confirm such an association. Finally, this review identified that the use of medications with anti-cholinergic properties may be associated with a deterioration in physical function.
The negative effect of increased anti-cholinergic load on adverse cognitive outcomes revealed the strongest association throughout the evidence-base. This is in keeping with previous literature reviews which have examined the effect of anti-cholinergic burden on cognition. A previous review noted that the effect of anti-cholinergic drugs on cognition is not always due to one anti-cholinergic drug alone, but instead an accumulation of a number of drugs with anti-cholinergic properties is an important consideration. Therefore, in this systematic review, it was decided to only include studies which quantified this load; either through dosage of the drug used in an RCT, or through using scales to quantify ACB.
Of those studies which did not report a negative effect of increased anti-cholinergic load on cognitive function, three of the five studies had relatively shorter follow-up periods (<2 years) or were cross-sectional studies. As studies included in the review had a highly variable follow-up period, ranging from a few weeks to 12 years, it was difficult to interpret whether the studies with short follow-ups would have progressed to report a significant association with cognitive decline should they have included a longer follow-up period.
There is little support that anti-cholinergic medications increase the risk of mild cognitive impairment, which then presents a risk of developing dementia. In addition, there is little, if any, evidence for a non-reversible impact of anti-cholinergics on cognition. Consequently, the findings of this review on cognition should be interpreted with caution until the evidence-base develops in this area.
In contrast to the continued evidence supporting anti-cholinergic burden and its effect on cognitive function, its effect on developing the more acute form of cognitive impairment, delirium, was less coherent. Once again these studies were heterogeneous in their quantification of anti-cholinergic load and reporting the outcome. Not all studies used the Confusion Assessment Method which is thought to be the most accurate and currently recommended diagnostic tool for delirium by the National Institute of Clinical Excellence guidance in the UK. This review did not find an association between anti-cholinergic load with delirium as reported in previous reviews, although this review was based on a larger, more contemporary literature dataset. One reason for this may be the improvement in characterising delirium not used in more historic studies. In addition what may have been seen in previous studies is the miscoding of delirium for cognitive impairment, therefore the diagnosis of delirium may not have been made, rather the term 'dementia' used to categorise all participants with cognitive impairment.
The majority of studies which reported the effect of anti-cholinergic medications on physical function reported a significant inverse relationship; the higher the anti-cholinergic burden the lower the physical functioning. Yet again there were different methods of quantifying anti-cholinergic load used and different methods of measuring physical function. Avoiding anti-cholinergic medications may therefore preserve and maximise function and prevent acute adverse events such as falls.
The effect of anti-cholinergic burden on mortality present inconclusive findings. The majority of studies reported no statistical association between these variables. However, in a large prospective cohort study undertaken by Fox et al., an adjusted statistically significant negative effect of increased anti-cholinergic load with increased mortality was reported. Whilst this difference in results may be due to the heterogenic nature of studies available, further research should be conducted in this area. Furthermore, these mortality figures should be viewed with caution given that the follow-up periods for these studies were insufficient, ranging from 8.9 weeks to 3.3 years.
This paper is the first systematic review to examine the effect of anti-cholinergic medication load (excluding those measured by serum anti-cholinergic alone) on cognitive function, physical function, delirium and mortality over a large time frame spanning decades of research from published and unpublished sources. However, the included articles contained a number of limitations. First, due to the data available, the analysis focused on estimating the presence or absence of significant associations in drug response rather than estimating effect size which was not possible in this instance. Secondly, the MMSE was the major measure of cognitive change. This could be argued as an inappropriate tool for this means in its sensitivity and scope, whilst mortality, given the multi-factorial cause of this end-point, may have been insensitive to evaluation specifically against anti-cholinergeric agents. The approach in accounting for covariates, both confounders and effect modifiers, varied considerably across the included studies. There was variability in age and seriousness of medical morbidity for which the various drugs were prescribed; these factors are critical. Studies did not consider sub-clinical disease, which may have confounded any associations, but medication use was associated with health status, so despite adjusting for many health-related factors, the possibility of residual confounders between health status and outcome could not be excluded. Indication bias may have limited this review in those participants with, for example, cognitive impairment may have been more likely to be exposed to anti-cholinergic medications because of the presence of cognitive impairment. The ratings of anti-cholinergic exposure varied considerably across the included studies. In some studies, this was presented on a standard scale, in others as a dichotomous (yes/no) scale. Additionally, the reliability of these ratings across studies was difficult to establish. Managing these confounders should be considered when designing future studies in this area. Finally, the principle limitation to this review is the variability in study designs. This may be a contributing factor to the different effects being reported on physical function, delirium and mortality. However, by managing these studies separately during the analysis, and considering the appraisal of study quality, the distinction between higher and lower quality evidence was made during the interpretation of findings.
Discussion
This is the first systematic review to assess the effects of medications with anti-cholinergic properties on delirium and physical function, and an important update on cognitive function and mortality. The findings indicate that medicines with anti-cholinergic properties have a negative effect on cognitive function. The results also indicated no significant association between anti-cholinergic load and either mortality or delirium. Single- or limited-drug studies in the past have supported the relationship between these medicines and delirium. Using anti-cholinergic drug scales to identify all medications with anti-cholinergic properties did not appear to confirm such an association. Finally, this review identified that the use of medications with anti-cholinergic properties may be associated with a deterioration in physical function.
The negative effect of increased anti-cholinergic load on adverse cognitive outcomes revealed the strongest association throughout the evidence-base. This is in keeping with previous literature reviews which have examined the effect of anti-cholinergic burden on cognition. A previous review noted that the effect of anti-cholinergic drugs on cognition is not always due to one anti-cholinergic drug alone, but instead an accumulation of a number of drugs with anti-cholinergic properties is an important consideration. Therefore, in this systematic review, it was decided to only include studies which quantified this load; either through dosage of the drug used in an RCT, or through using scales to quantify ACB.
Of those studies which did not report a negative effect of increased anti-cholinergic load on cognitive function, three of the five studies had relatively shorter follow-up periods (<2 years) or were cross-sectional studies. As studies included in the review had a highly variable follow-up period, ranging from a few weeks to 12 years, it was difficult to interpret whether the studies with short follow-ups would have progressed to report a significant association with cognitive decline should they have included a longer follow-up period.
There is little support that anti-cholinergic medications increase the risk of mild cognitive impairment, which then presents a risk of developing dementia. In addition, there is little, if any, evidence for a non-reversible impact of anti-cholinergics on cognition. Consequently, the findings of this review on cognition should be interpreted with caution until the evidence-base develops in this area.
In contrast to the continued evidence supporting anti-cholinergic burden and its effect on cognitive function, its effect on developing the more acute form of cognitive impairment, delirium, was less coherent. Once again these studies were heterogeneous in their quantification of anti-cholinergic load and reporting the outcome. Not all studies used the Confusion Assessment Method which is thought to be the most accurate and currently recommended diagnostic tool for delirium by the National Institute of Clinical Excellence guidance in the UK. This review did not find an association between anti-cholinergic load with delirium as reported in previous reviews, although this review was based on a larger, more contemporary literature dataset. One reason for this may be the improvement in characterising delirium not used in more historic studies. In addition what may have been seen in previous studies is the miscoding of delirium for cognitive impairment, therefore the diagnosis of delirium may not have been made, rather the term 'dementia' used to categorise all participants with cognitive impairment.
The majority of studies which reported the effect of anti-cholinergic medications on physical function reported a significant inverse relationship; the higher the anti-cholinergic burden the lower the physical functioning. Yet again there were different methods of quantifying anti-cholinergic load used and different methods of measuring physical function. Avoiding anti-cholinergic medications may therefore preserve and maximise function and prevent acute adverse events such as falls.
The effect of anti-cholinergic burden on mortality present inconclusive findings. The majority of studies reported no statistical association between these variables. However, in a large prospective cohort study undertaken by Fox et al., an adjusted statistically significant negative effect of increased anti-cholinergic load with increased mortality was reported. Whilst this difference in results may be due to the heterogenic nature of studies available, further research should be conducted in this area. Furthermore, these mortality figures should be viewed with caution given that the follow-up periods for these studies were insufficient, ranging from 8.9 weeks to 3.3 years.
This paper is the first systematic review to examine the effect of anti-cholinergic medication load (excluding those measured by serum anti-cholinergic alone) on cognitive function, physical function, delirium and mortality over a large time frame spanning decades of research from published and unpublished sources. However, the included articles contained a number of limitations. First, due to the data available, the analysis focused on estimating the presence or absence of significant associations in drug response rather than estimating effect size which was not possible in this instance. Secondly, the MMSE was the major measure of cognitive change. This could be argued as an inappropriate tool for this means in its sensitivity and scope, whilst mortality, given the multi-factorial cause of this end-point, may have been insensitive to evaluation specifically against anti-cholinergeric agents. The approach in accounting for covariates, both confounders and effect modifiers, varied considerably across the included studies. There was variability in age and seriousness of medical morbidity for which the various drugs were prescribed; these factors are critical. Studies did not consider sub-clinical disease, which may have confounded any associations, but medication use was associated with health status, so despite adjusting for many health-related factors, the possibility of residual confounders between health status and outcome could not be excluded. Indication bias may have limited this review in those participants with, for example, cognitive impairment may have been more likely to be exposed to anti-cholinergic medications because of the presence of cognitive impairment. The ratings of anti-cholinergic exposure varied considerably across the included studies. In some studies, this was presented on a standard scale, in others as a dichotomous (yes/no) scale. Additionally, the reliability of these ratings across studies was difficult to establish. Managing these confounders should be considered when designing future studies in this area. Finally, the principle limitation to this review is the variability in study designs. This may be a contributing factor to the different effects being reported on physical function, delirium and mortality. However, by managing these studies separately during the analysis, and considering the appraisal of study quality, the distinction between higher and lower quality evidence was made during the interpretation of findings.
Source...