The R2D2 (Reducing the Risk of Dementia by Deprescribing) trial is underway to evaluate the effectiveness of an anticholinergic deprescribing intervention on cognitive function in older adults. This cluster randomized trial, published in Trials Journal, is designed to determine if reducing the use of strong anticholinergic medications can preserve brain health and improve quality of life in this population.
Study Design and Objectives
The R2D2 trial utilizes a cluster randomized, superiority design, with primary care providers as the unit of randomization. This approach aims to minimize contamination between the intervention and control groups. The trial spans 24 months, a duration chosen to capture long-term trends in cognitive outcomes. The primary objective is to assess the impact of the deprescribing intervention on cognition compared to usual care. Secondary objectives include examining the effects on quality of life and evaluating the safety profile of deprescribing.
The study also seeks to identify demographic, genetic (APOE Ɛ4 status), and clinical characteristics that may moderate the effect of the deprescribing intervention. This personalized approach could help tailor interventions to those most likely to benefit.
Recruitment and Eligibility
Participants are being recruited from primary care practices within health systems in central Indiana, including Indiana University Health and the Community Health Network. Eligible individuals are community-dwelling older adults aged 65 years and older without a prior diagnosis of Alzheimer's disease and related dementias (ADRD). Participants must have had at least one office visit to their primary care physician within the previous 12 months and be using at least one strong anticholinergic medication.
Key exclusion criteria include permanent residency in an extended care facility, a diagnosis of schizophrenia, bipolar disorder, or schizoaffective disorder, and a diagnosis of ADRD. The study design initially required the presence of subjective cognitive dysfunction, but this criterion was later modified to enhance recruitment.
Deprescribing Intervention
The deprescribing intervention is implemented by trained clinical pharmacists, referred to as deprescribing care coordinators (DCCs). These pharmacists work with patients, caregivers, and providers to clarify the indication for the anticholinergic medication, educate about the risks of cognitive impairment, and make shared decisions about deprescribing. The DCCs also identify appropriate alternatives, communicate the deprescribing plan, and monitor the patient's progress.
The deprescribing process involves several steps: (1) clarifying the indication for the anticholinergic; (2) educating about the risks of cognitive impairment; (3) making a shared decision to deprescribe; (4) identifying an appropriate alternative; (5) communicating the deprescribing plan; and (6) monitoring and revising the plan as needed. Tapering schedules are individualized and follow established recommendations, with modifications based on clinical judgment and symptom monitoring.
Outcome Measures
The primary outcome measure is cognitive performance, assessed using a composite score derived from several cognitive tests. These tests evaluate information processing speed, memory, and executive function. Specific tests include the Symbol Digit Modalities Test, Hopkins Verbal Learning Test, Oral Trails Making Test, and Controlled Oral Word Association and Semantic Fluency tests. Cognitive assessments are conducted at baseline, 6, 12, 18, and 24 months.
Secondary outcome measures include patient-reported outcomes related to depression, anxiety, sleep disturbance, and pain, as measured by the PROMIS profile-29. Health-related quality of life is assessed using the Health Utility Index (HUI). Adverse events are monitored through self-reporting and analysis of acute care utilization data.
Statistical Analysis
The study will employ an intention-to-treat approach, with mixed effects models used to analyze the primary outcome variables. These models will account for the cluster randomized design and adjust for potential confounding factors. Additional analyses will explore the role of anticholinergic exposure and potential moderation effects of genetic and clinical characteristics.
Significance
Anticholinergic medications are commonly prescribed to older adults for various conditions, including overactive bladder, depression, and insomnia. However, these medications have been linked to cognitive impairment and an increased risk of dementia. The R2D2 trial addresses a critical need to evaluate the effectiveness of deprescribing interventions in preserving cognitive health in this vulnerable population. The results of this trial could inform clinical practice and public health strategies aimed at reducing the burden of dementia.
