Are Anticholinergic Symptoms a Risk Factor for Falls in Older General Practice Patients With Polypharmacy? Study Protocol for the Development and Validation of a Prognostic Model

Dinh, Truc Sophia; González‐González, Ana Isabel; Meid, Andreas D.; Snell, Kym I E; Rudolf, Henrik; Brueckle, Maria-Sophie; Blom, Jeanet W.; Thiem, Ulrich; Trampisch, Hans–Joachim; Elders, Petra; Donner-Banzhoff, Norbert; Gerlach, Ferdinand M.; Harder, Sebastian; Akker, Marjan van den; Glasziou, Paul; Haefeli, Walter E.; Muth, Christiane

doi:10.3389/fphar.2020.577747

Cited by 5 publications

(5 citation statements)

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“…The second limitation is that the average age of the study participants was very young (at around 40 years) limiting the generalizability of our results to older people. This is because older people are generally more sensitive to anticholinergic effects [ 70 ], and known to be at risk of certain harms, such as cognitive decline and falls [ 70 , 71 ], which were not reported in the RCTs included in our review.…”

Section: Discussionmentioning

confidence: 99%

Amitriptyline’s anticholinergic adverse drug reactions–A systematic multiple-indication review and meta-analysis

Brueckle

Thomas²,

Seide³

et al. 2023

PLoS ONE

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Background Half the US population uses drugs with anticholinergic properties. Their potential harms may outweigh their benefits. Amitriptyline is among the most frequently prescribed anticholinergic medicinal products, is used for multiple indications, and rated as strongly anticholinergic. Our objective was to explore and quantify (anticholinergic) adverse drug reactions (ADRs) in patients taking amitriptyline vs. placebo in randomized controlled trials (RCTs) involving adults and healthy individuals. Methods We searched electronic databases from their inception until 09/2022, and clinical trial registries from their inception until 09/2022. We also performed manual reference searches. Two independent reviewers selected RCTs with ≥100 participants of ≥18 years, that compared amitriptyline (taken orally) versus placebo for all indications. No language restrictions were applied. One reviewer extracted study data, ADRs, and assessed study quality, which two others verified. The primary outcome was frequency of anticholinergic ADRs as a binary outcome (absolute number of patients with/without anticholinergic ADRs) in amitriptyline vs. placebo groups. Results Twenty-three RCTs (mean dosage 5mg to 300mg amitriptyline/day) and 4217 patients (mean age 40.3 years) were included. The most frequently reported anticholinergic ADRs were dry mouth, drowsiness, somnolence, sedation, fatigue, constitutional, and unspecific anticholinergic ADRs. Random-effects meta-analyses showed anticholinergic ADRs had a higher odd’s ratio for amitriptyline versus placebo (OR = 7.41; [95% CI, 4.54 to 12.12]). Non-anticholinergic ADRs were as frequent for amitriptyline as placebo. Meta-regression analysis showed anticholinergic ADRs were not dose-dependent. Discussion The large OR in our analysis shows that ADRs indicative of anticholinergic activities can be attributed to amitriptyline. The low average age of participants in our study may limit the generalizability of the frequency of anticholinergic ADRs in older patients. A lack of dose-dependency may reflect limited reporting of the daily dosage when the ADRs occurred. The exclusion of small studies (<100 participants) decreased heterogeneity between studies, but may also have reduced our ability to detect rare events. Future studies should focus on older people, as they are more susceptible to anticholinergic ADRs. Registration PROSPERO: CRD42020111970.

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Section: Discussionmentioning

confidence: 99%

Amitriptyline’s anticholinergic adverse drug reactions–A systematic multiple-indication review and meta-analysis

Brueckle

Thomas²,

Seide³

et al. 2023

PLoS ONE

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“…The rationale behind and methodology used in this study have been described in detail in a study protocol [ 29 ]. We therefore provide only a brief summary here, in which we also describe necessary adaptions (a summary of adaptions to the study protocol is included in the S1 Text ).…”

Section: Methodsmentioning

confidence: 99%

“…For this study, candidate predictors were pre-selected based on a literature review, predictor availability, and clinical reasoning [ 29 ]. Candidate predictors were collected at baseline and included variables associated with:…”

Section: Methodsmentioning

confidence: 99%

Anticholinergic burden measures, symptoms, and fall-associated risk in older adults with polypharmacy: Development and validation of a prognostic model

et al. 2023

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Background Anticholinergic burden has been associated with adverse outcomes such as falls. To date, no gold standard measure has been identified to assess anticholinergic burden, and no conclusion has been drawn on which of the different measure algorithms best predicts falls in older patients from general practice. This study compared the ability of five measures of anticholinergic burden to predict falls. To account for patients’ individual susceptibility to medications, the added predictive value of typical anticholinergic symptoms was further quantified in this context. Methods and findings To predict falls, models were developed and validated based on logistic regression models created using data from two German cluster-randomized controlled trials. The outcome was defined as “≥ 1 fall” vs. “no fall” within a 6-month follow-up period. Data from the RIME study (n = 1,197) were used in model development, and from PRIMUM (n = 502) for external validation. The models were developed step-wise in order to quantify the predictive ability of anticholinergic burden measures, and anticholinergic symptoms. In the development set, 1,015 patients had complete data and 188 (18.5%) experienced ≥ 1 fall within the 6-month follow-up period. The overall predictive value of the five anticholinergic measures was limited, with neither the employed anticholinergic variable (binary / count / burden), nor dose-dependent or dose-independent measures differing significantly in their ability to predict falls. The highest c-statistic was obtained using the German Anticholinergic Burden Score (0.73), whereby the optimism-corrected c-statistic was 0.71 after interval validation using bootstrapping and 0.63 in the external validation. Previous falls and dizziness / vertigo had the strongest prognostic value in all models. Conclusions The ability of anticholinergic burden measures to predict falls does not appear to differ significantly, and the added value they contribute to risk classification in fall-prediction models is limited. Previous falls and dizziness / vertigo contributed most to model performance.

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“…Drugs with anticholinergic effects are associated with a variety of side effects and negative health outcomes, especially falls, loss of quality of life, cognitive impairment, and loss of functional status [26][27][28]. Falls are the leading cause of disability and death in older age and are associated with increases in mortality, morbidity, hospital admissions, and treatment costs [29].…”

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confidence: 99%

Multimedication in Family Doctor Practices: The German Evidence-Based Guidelines on Multimedication

Schubert

Fessler²,

Harder

et al. 2022

Pharmacoepidemiology

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Patients with multimorbidity and multimedication require special attention from their treating physicians, as the risks of drug interactions and negative effects on adherence increase with the number of drugs. Most guidelines aim for the treatment of a single disease and do not take potential problems due to multimedication into account. In 2021, updates and evidence-based upgrades of the first version (2012) of the German Guidelines on Multimedication were issued. The aim of the article is to introduce the framework of these evidence-based guidelines, which follows the medication process in six steps: (1) inventory and medication assessment; (2) coordination with the patient; (3) prescription proposal and communication; (4) dispensing of medicines; (5) medication application and self-management; and (6) monitoring. For each step, recommendations and practice tips are presented. The central feature is a structured medication review. The target group is patients with multimorbidity and the concurrent use of five or more drugs. The Medication Appropriateness Index has been modified, and the guiding questions are recommended as guidance for the structured medication review. Overuse and undertreatment are taken into account. The guidelines were consented to in a formal process with 15 medical societies, a patient representative, and experts, as well as piloted in general practices.

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Are Anticholinergic Symptoms a Risk Factor for Falls in Older General Practice Patients With Polypharmacy? Study Protocol for the Development and Validation of a Prognostic Model

Cited by 5 publications

References 64 publications

Amitriptyline’s anticholinergic adverse drug reactions–A systematic multiple-indication review and meta-analysis

Amitriptyline’s anticholinergic adverse drug reactions–A systematic multiple-indication review and meta-analysis

Anticholinergic burden measures, symptoms, and fall-associated risk in older adults with polypharmacy: Development and validation of a prognostic model

Multimedication in Family Doctor Practices: The German Evidence-Based Guidelines on Multimedication

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