Anticholinergic drugs and incident dementia, mild cognitive impairment and cognitive decline: a meta-analysis

Abstract

Background: the long-term effect of the use of drugs with anticholinergic activity on cognitive function remains unclear.

Methods: we conducted a systematic review and meta-analysis of the relationship between anticholinergic drugs and risk of dementia, mild cognitive impairment (MCI) and cognitive decline in the older population. We identified studies published between January 2002 and April 2018 with ≥12 weeks follow-up between strongly anticholinergic drug exposure and the study outcome measurement. We pooled adjusted odds ratios (OR) for studies reporting any, and at least short-term (90+ days) or long-term (365+ days) anticholinergic use for dementia and MCI outcomes, and standardised mean differences (SMD) in global cognition test scores for cognitive decline outcomes. Statistical heterogeneity was measured using the I2 statistic and risk of bias using ROBINS-I.

Results: twenty-six studies (including 621,548 participants) met our inclusion criteria. 'Any' anticholinergic use was associated with incident dementia (OR 1.20, 95% confidence interval [CI] 1.09-1.32, I2 = 86%). Short-term and long-term use were also associated with incident dementia (OR 1.23, 95% CI 1.17-1.29, I2 = 2%; and OR 1.50, 95% CI 1.22-1.85, I2 = 90%). 'Any' anticholinergic use was associated with cognitive decline (SMD 0.15; 95% CI 0.09-0.21, I2 = 3%) but showed no statistically significant difference for MCI (OR 1.24, 95% CI 0.97-1.59, I2 = 0%).

Conclusions: anticholinergic drug use is associated with increased dementia incidence and cognitive decline in observational studies. However, a causal link cannot yet be inferred, as studies were observational with considerable risk of bias. Stronger evidence from high-quality studies is needed to guide the management of long-term use.

Keywords: anticholinergics; cognition; dementia; meta-analysis; older people; systematic review.

Figure 1

Meta-analysis of odds ratios for dementia by any, at least short-term and long-term definite anticholinergic use versus no use. ^OR (95% CI) estimated as the inverse variance weighted average of the published adjusted ORs for exposures of 1–90, 91–365, 366–1095 and >1095 daily doses for any use, of 91–365, 366–1095 and >1095 daily doses for short-term use (90+ days) and of 366–1095 and >1095 daily doses for long-term use (365+ days). ǂOR (95% CI) estimated as the inverse variance weighted average of the published adjusted ORs for exposures of 90–364, 365–1459 and >1460 daily doses for short-term use (90+ days) and of 365–1459 and >1460 daily doses for long-term use (365+ days). ^*The Cai 2013 estimate is for 60+ days use versus <60 days, Ancelin 2006 estimated long-term use (365+ days) as use at baseline and at 1-year follow-up and Gomm 2016 estimated long-term use (365+ days) as a prescription every quarter for 6 consecutive quarters. ^**OR (95% CI) estimated as the inverse variance weighted average of the published adjusted ORs for exposures of oxybutynin, solifenacin and tolterodine. Abbreviations: n, number of dementia cases; N, number of participants.

Figure 2

Meta-analysis of odds ratios for mild cognitive impairment by any, at least short-term and long-term definite anticholinergic use versus no use. ^*Campbell 2010 estimated long-term use (365+ days) as use at all participating waves (baseline, 3-year and 6-year follow-up).

Figure 3

Meta-analysis of standardised mean differences in global cognitive decline by any definite anticholinergic use versus no use. ^*Standardised mean difference (95% CI) estimated as the inverse variance weighted average of the estimated standardised mean difference for prevalent and incident users. Decline in global cognition was defined as the change in mean z-score across 19 cognitive tests. Abbreviations: d, standardised mean difference.