Previously submitted to: JMIR Aging (no longer under consideration since Jun 05, 2025)
Date Submitted: Feb 12, 2025
Open Peer Review Period: Feb 20, 2025 - Apr 17, 2025
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Risk of Bradycardia and Syncope Associated with the Use of Cholinesterase Inhibitors in Patients with Alzheimer's Disease and Related Dementias: A Systematic Review and Meta-Analysis
ABSTRACT
Background:
In some cases, cholinesterase inhibitors (ChEIs) can amplify the effect of acetylcholine on vagal stimulation of the heart, which may lead to syncope and bradycardia. Available evidence does not definitively establish this association, and therefore clinicians may be unaware of it.
Objective:
To systematically review and perform a meta-analysis of the risk of bradycardia and syncope in patients with Alzheimer's Disease and Related Dementias (ADRD) treated with ChEIs.
Methods:
Our data sources were PubMed, EMBASE, Cochrane Library, and reference lists of relevant articles. Databases were searched from inception to June 15, 2024. We included randomized controlled trials and observational studies (cohort and case-control studies). Three reviewers independently extracted data per PRISMA recommendations and assessed the quality of each study with the National Heart, Lung, and Blood Institute quality assessment tools. We used random-effects modeling to estimate pooled relative risks (RRs) and their 95% confidence intervals (CIs). The outcomes examined were bradycardia and syncope.
Results:
Twenty-five independent studies (sixteen RCTs, seven cohorts, one case-control, one pragmatic trial; n=258,388) were included in the systematic review and meta-analysis out of the original 310 studies identified. The median reported age in the studies included was 76.3 years (range from 70 to 89.2). In most studies (18 out of 25), more than half of the individuals were female. Additionally, 18 (72%) of the studies included patients with Alzheimer’s disease. The overall absolute risk of bradycardia was 4.63% (95% CI, 1.80-8.55%; 16 studies, n=97,165), and that of syncope was 2.31% (95% CI, 1.18-3.77%; 16 studies, n= 134,162). Use of ChEIs in patients with ADRD was significantly associated with increased risk of bradycardia (RR: 1.23 [95% CI: 1.14-1.33]; 6 studies, n=97,396) and syncope (RR: 1.40 [95% CI: 1.20-1.64]; 9 studies, n=85,169) compared to non-use.
Conclusions:
This systematic review and meta-analysis suggest that patients with ADRD treated with ChEIs have an increased risk of bradycardia and syncope. Therefore, clinicians should consider the risk of bradycardia and syncope against the benefits of ChEIs when treating patients with ADRD.
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