Evaluating the Safety of an Educational Deprescribing Intervention: Lessons from the Optimize Trial.

BACKGROUND: Patients, family members, and clinicians express concerns about potential adverse drug withdrawal events (ADWEs) following medication discontinuation or fears of upsetting a stable medical equilibrium as key barriers to deprescribing. Currently, there are limited methods to pragmatically assess the safety of deprescribing and ascertain ADWEs. We report the methods and results of safety monitoring for the OPTIMIZE trial of deprescribing education for patients, family members, and clinicians. METHODS: This was a pragmatic cluster randomized trial with multivariable Poisson regression comparing outcome rates between study arms. We conducted clinical record review and adjudication of sampled records to assess potential causal relationships between medication discontinuation and outcomes. This study included adults aged 65+ with dementia or mild cognitive impairment, one or more additional chronic conditions, and prescribed 5+ chronic medications. The intervention included an educational brochure on deprescribing that was mailed to patients prior to primary care visits, a clinician notification about individual brochure mailings, and an educational tip sheets was provided monthly to primary care clinicians. The outcomes of the safety monitoring were rates of hospitalizations and mortality during the 4 months following brochure mailings and results of record review and adjudication. The adjudication process was conducted throughout the trial and included classifications: likely, possibly, and unlikely. RESULTS: There was a total of 3012 (1433 intervention and 1579 control) participants. There were 420 total hospitalizations involving 269 (18.8%) people in the intervention versus 517 total hospitalizations involving 317 (20.1%) people in the control groups. Adjusted risk ratios comparing intervention to control groups were 0.92 [95% confidence interval (CI) 0.72, 1.16] for hospitalization and 1.19 (95% CI 0.67, 2.11) for mortality. Both groups had zero deaths "likely" attributed to a medication change prior to the event. A total of 3 out of 30 (10%) intervention group hospitalizations and 7 out of 35 (20%) control group hospitalizations were considered "likely" due to a medication change. CONCLUSIONS: Population-based deprescribing education is safe in the older adult population with cognitive impairment in our study. Pragmatic methods for safety monitoring are needed to further inform deprescribing interventions. TRIAL REGISTRATION: NCT03984396. Registered on 13 June 2019.

Intervention design in cognitively impaired populations-Lessons learned from the OPTIMIZE deprescribing pragmatic trial.

BACKGROUND: Polypharmacy is common in older adults with cognitive impairment and multiple chronic conditions, increasing risks of adverse drug events, hospitalization, and death. Deprescribing, the process of reducing or stopping potentially inappropriate medications, may improve outcomes. The OPTIMIZE pragmatic trial examined whether educating and activating patients, family members and clinicians about deprescribing reduces number of chronic medications and potentially inappropriate medications. Acceptability and challenges of intervention delivery in cognitively impaired older adults are not well understood. METHODS: We explored mechanisms of intervention implementation through post hoc qualitative interviews and surveys with stakeholder groups of 15 patients, 7 caregivers, and 28 clinicians. We assessed the context in which the intervention was delivered, its implementation, and mechanisms of impact. RESULTS: Acceptance of the intervention was affected by contextual factors including cognition, prior knowledge of deprescribing, communication, and time constraints. All stakeholder groups endorsed the acceptability, importance, and delivery of the intervention. Positive mechanisms of impact included patients scheduling specific appointments to discuss deprescribing and providers being prompted to consider deprescribing. Recollection of intervention materials was inconsistent but most likely shortly after intervention delivery. Short visit times remained the largest provider barrier to deprescribing. CONCLUSIONS: Our work identifies key learnings in intervention delivery that can guide future scaling of deprescribing interventions in this population. We highlight the critical roles of timing and repetition in intervention delivery to cognitively impaired populations and the barrier posed by short consultation times. The acceptability of the intervention to patients and family members highlights the potential to incorporate deprescribing education into routine clinical practice and expand proven interventions to other vulnerable populations.

Deprescribing Education vs Usual Care for Patients With Cognitive Impairment and Primary Care Clinicians: The OPTIMIZE Pragmatic Cluster Randomized Trial.

Background: Individuals with dementia or mild cognitive impairment frequently have multiple chronic conditions (defined as ≥2 chronic medical conditions) and take multiple medications, increasing their risk for adverse outcomes. Deprescribing (reducing or stopping medications for which potential harms outweigh potential benefits) may decrease their risk of adverse outcomes. Objective: To examine the effectiveness of increasing patient and clinician awareness about the potential to deprescribe unnecessary or risky medications among patients with dementia or mild cognitive impairment. Design, Setting, and Participants: This pragmatic, patient-centered, 12-month cluster randomized clinical trial was conducted from April 1, 2019, to March 31, 2020, at 18 primary care clinics in a not-for-profit integrated health care delivery system. The study included 3012 adults aged 65 years or older with dementia or mild cognitive impairment who had 1 or more additional chronic medical conditions and were taking 5 or more long-term medications. Interventions: An educational brochure and a questionnaire on attitudes toward deprescribing were mailed to patients prior to a primary care visit, clinicians were notified about the mailing, and deprescribing tip sheets were distributed to clinicians at monthly clinic meetings. Main Outcomes and Measures: The number of prescribed long-term medications and the percentage of individuals prescribed 1 or more potentially inappropriate medications (PIMs). Analysis was performed on an intention-to-treat basis. Results: This study comprised 1433 individuals (806 women [56.2%]; mean [SD] age, 80.1 [7.2] years) in 9 intervention clinics and 1579 individuals (874 women [55.4%]; mean [SD] age, 79.9 [7.5] years) in 9 control clinics who met the eligibility criteria. At baseline, both groups were prescribed a similar mean (SD) number of long-term medications (7.0 [2.1] in the intervention group and 7.0 [2.2] in the control group), and a similar proportion of individuals in both groups were taking 1 or more PIMs (437 of 1433 individuals [30.5%] in the intervention group and 467 of 1579 individuals [29.6%] in the control group). At 6 months, the adjusted mean number of long-term medications was similar in the intervention and control groups (6.4 [95% CI, 6.3-6.5] vs 6.5 [95% CI, 6.4-6.6]; P = .14). The estimated percentages of patients in the intervention and control groups taking 1 or more PIMs were similar (17.8% [95% CI, 15.4%-20.5%] vs 20.9% [95% CI, 18.4%-23.6%]; P = .08). In preplanned subgroup analyses, adjusted differences between the intervention and control groups were -0.16 (95% CI, -0.34 to 0.01) for individuals prescribed 7 or more long-term medications at baseline (n = 1434) and -0.03 (95% CI, -0.20 to 0.13) for those prescribed 5 to 6 medications (n = 1578) (P = .28 for interaction; P = .19 for subgroup interaction for PIMs). Conclusions and Relevance: This large-scale educational deprescribing intervention for older adults with cognitive impairment taking 5 or more long-term medications and their primary care clinicians demonstrated small effect sizes and did not significantly reduce the number of long-term medications and PIMs. Such interventions should target older adults taking relatively more medications. Trial Registration: ClinicalTrials.gov Identifier: NCT03984396.

Designing a Primary Care-Based Deprescribing Intervention for Patients with Dementia and Multiple Chronic Conditions: a Qualitative Study.

BACKGROUND: Patients with dementia and multiple chronic conditions (MCC) frequently experience polypharmacy, increasing their risk of adverse drug events. OBJECTIVES: To elucidate patient, family, and physician perspectives on medication discontinuation and recommended language for deprescribing discussions in order to inform an intervention to increase awareness of deprescribing among individuals with dementia and MCC, family caregivers and primary care physicians. We also explored participant views on culturally competent approaches to deprescribing. DESIGN: Qualitative approach based on semi-structured interviews with patients, caregivers, and physicians. PARTICIPANTS: Patients aged ≥ 65 years with claims-based diagnosis of dementia, ≥ 1 additional chronic condition, and ≥ 5 chronic medications were recruited from an integrated delivery system in Colorado and an academic medical center in Maryland. We included caregivers when present or if patients were unable to participate due to severe cognitive impairment. Physicians were recruited within the same systems and through snowball sampling, targeting areas with large African American and Hispanic populations. APPROACH: We used constant comparison to identify and compare themes between patients, caregivers, and physicians. KEY RESULTS: We conducted interviews with 17 patients, 16 caregivers, and 16 physicians. All groups said it was important to earn trust before deprescribing, frame deprescribing as routine and positive, align deprescribing with goals of dementia care, and respect caregivers' expertise. As in other areas of medicine, racial, ethnic, and language concordance was important to patients and caregivers from minority cultural backgrounds. Participants favored direct-to-patient educational materials, support from pharmacists and other team members, and close follow-up during deprescribing. Patients and caregivers favored language that explained deprescribing in terms of altered physiology with aging. Physicians desired communication tips addressing specific clinical situations. CONCLUSIONS: Culturally sensitive communication within a trusted patient-physician relationship supplemented by pharmacists, and language tailored to specific clinical situations may support deprescribing in primary care for patients with dementia and MCC.

Drugs Contributing to Anticholinergic Burden and Risk of Fall or Fall-Related Injury among Older Adults with Mild Cognitive Impairment, Dementia and Multiple Chronic Conditions: A Retrospective Cohort Study.

BACKGROUND: It is not known whether drugs with different anticholinergic ratings contribute proportionately to overall anticholinergic score. OBJECTIVES: Our objective was to assess the risk of falls or fall-related injuries as a function of the overall anticholinergic score resulting from drugs with different anticholinergic ratings among people with impaired cognition. METHODS: This was a retrospective cohort study of adults aged ≥ 65 years with mild cognitive impairment (MCI) or dementia and two or more additional chronic conditions (N = 10,698) in an integrated delivery system. Electronic health record data, including pharmacy fills and diagnosis claims, were used to assess anticholinergic medication use, quantified using the anticholinergic cognitive burden (ACB) scale, falls and fall-related injuries. RESULTS: During a median follow-up of 366 days, 63% of the cohort used one or more ACB drug; 2015 (18.8%) people experienced a fall or fall-related injury. Among patients with a daily ACB score of 5, the greatest increase in risk of falls or fall-related injuries was seen when level 2 and level 3 drugs were used in combination [hazard ratio (HR) 2.06; 95% confidence interval (CI) 1.51-2.83]. Multiple ACB level 1 drugs taken together also increased the hazard of a fall or fall-related injury (HR 1.16; 95% CI 1.03-1.32). The risk of fall or fall-related injury as a function of exposure to ACB level 2 drugs (HR 1.56; 95% CI 1.16-2.10) was higher than that for ACB level 1 or 3 drugs. CONCLUSIONS: The same daily ACB score was associated with a different degree of risk, depending on the ACB ratings of the individual drugs comprising the score. Combinations of level 2 and level 3 drugs had the greatest risk of fall or fall-related injury relative to other individuals with the same daily ACB score. Low-potency anticholinergic drugs taken together modestly increased the hazard of a fall or fall-related injury.

Medication Profiles of Patients with Cognitive Impairment and High Anticholinergic Burden.

BACKGROUND: Drugs with anticholinergic properties are considered potentially inappropriate in patients with cognitive impairment because harms-including delirium, falls, and fractures-may outweigh benefits. OBJECTIVE: To highlight opportunities to improve clinical decision making and care for patients with cognitive impairment and multiple chronic conditions, we identified distinct subgroups of patients with mild cognitive impairment (MCI) and dementia who had high cumulative anticholinergic burden and specific patterns of anticholinergic use. PATIENTS AND METHODS: We conducted a retrospective cohort study in a not-for-profit, integrated delivery system. Participants included community-dwelling adults aged 65 years and older (n = 13,627) with MCI or dementia and at least two other chronic diseases. We calculated the Anticholinergic Cognitive Burden (ACB) score for each participant from pharmacy and electronic health record (EHR) data. Among individuals with a mean 12-month ACB score ≥ 2, we used agglomerative hierarchical clustering to identify groups or clusters of individuals with similar anticholinergic prescription patterns. RESULTS: Twenty-four percent (3257 participants) had high anticholinergic burden, defined as an ACB score ≥ 2. Clinically meaningful clusters based upon anchoring medications or drug classes included a cluster of cardiovascular medications (n = 1497; 46%); two clusters of antidepressant medications (n = 633; 20%); and a cluster based on use of bladder antimuscarinics (n = 431; 13%). Several clusters comprised multiple central nervous system (CNS)-active drugs. CONCLUSIONS: Cardiovascular and CNS-active medications comprise a substantial portion of anticholinergic burden in people with cognitive impairment and multiple chronic conditions. Antidepressants were highly prevalent. Clinical profiles elucidated by these clusters of anticholinergic medications can inform targeted approaches to care.

Myopathy associated with atorvastatin-ezetimibe combination therapy.

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) play a prominent role in the treatment of dyslipidemia. Overall, statins are well tolerated, with a low occurrence of adverse effects. More serious reactions to statins have been reported, although they are rare (e.g., rhabdomyolysis 0.3-13.5 cases/million statin prescriptions). Combination therapy to treat dyslipidemia has become common in many patients; however, it can also increase the risk of serious adverse effects. We report the case of a patient who experienced muscle pain and elevated creatine kinase levels 16 days after the addition of ezetimibe to his atorvastatin therapy for hypercholesterolemia. Twelve days after stopping the ezetimibe, his muscle pain resolved and his serum creatine kinase level returned to baseline. This case report raises questions regarding the safety of high-dose atorvastatin and ezetimibe combination therapy and suggests that caution and careful monitoring may be warranted.