Willingness of older people living with dementia and mild cognitive impairment and their caregivers to have medications deprescribed.

BACKGROUND: people living with cognitive impairment commonly take multiple medications including potentially inappropriate medications (PIMs), which puts them at risk of medication related harms. AIMS: to explore willingness to have a medication deprescribed of older people living with cognitive impairment (dementia or mild cognitive impairment) and multiple chronic conditions and assess the relationship between willingness, patient characteristics and belief about medications. METHODS: cross-sectional study using results from the revised Patients' Attitudes Towards Deprescribing questionnaire (rPATDcog) collected as baseline data in the OPTIMIZE study, a pragmatic, cluster-randomised trial educating patients and clinicians about deprescribing. Eligible participants were 65+, diagnosed with dementia or mild cognitive impairment, and prescribed at least five-long-term medications. RESULTS: the questionnaire was mailed to 1,409 intervention patients and 553 (39%) were returned and included in analysis. Participants had a mean age of 80.1 (SD 7.4) and 52.4% were female. About 78.5% (431/549) of participants said that they would be willing to have one of their medications stopped if their doctor said it was possible. Willingness to deprescribe was negatively associated with getting stressed when changes are made and with previously having a bad experience with stopping a medication (P < 0.001 for both). CONCLUSION: most older people living with cognitive impairment are willing to deprescribe. Addressing previous bad experiences with stopping a medication and stress when changes are made to medications may be key points to discuss during deprescribing conversations.

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.

Defining Clinical Trial Estimands: A Practical Guide for Study Teams with Examples Based on a Psychiatric Disorder.

While the ICH E9(R1) Addendum on "Estimands and Sensitivity Analysis in Clinical Trials" was released in late 2019, the widespread implementation of defining and reporting estimands across clinical trials is still in progress and the engagement of non-statistical functions in this process is also in progress. Case studies are sought after, especially those with documented clinical and regulatory feedback. This paper describes an interdisciplinary process for implementing the estimand framework, devised by the Estimands and Missing Data Working Group (a group with clinical, statistical, and regulatory representation) of the International Society for CNS Clinical Trials and Methodology. This process is illustrated by specific examples using various types of hypothetical trials evaluating a treatment for major depressive disorder. Each of the estimand examples follows the same template and features all steps of the proposed process, including identifying the trial stakeholder(s), the decisions they need to make about the investigated treatment in their specific role and the questions that would support their decision making. Each of the five strategies for handling intercurrent events are addressed in at least one example; the featured endpoints are also diverse, including continuous, binary and time to event. Several examples are presented that include specifications for a potential trial design, key trial implementation elements needed to address the estimand, and main and sensitivity estimator specifications. Ultimately this paper highlights the need to incorporate multi-disciplinary collaborations into implementing the ICH E9(R1) framework.

Ethical Aspects of Physician Decision-Making for Deprescribing Among Older Adults With Dementia.

Importance: Physicians endorse deprescribing of risky or unnecessary medications for older adults (aged ≥65 years) with dementia, but there is a lack of information on what influences decisions to deprescribe in this population. Objective: To understand how physicians make decisions to deprescribe for older adults with moderate dementia and ethical and pragmatic concerns influencing those decisions. Design, Setting, and Participants: A cross-sectional national mailed survey study of a random sample of 3000 primary care physicians from the American Medical Association Physician Masterfile who care for older adults was conducted from January 15 to December 31, 2021. Main Outcomes and Measures: The study randomized participants to consider 2 clinical scenarios in which a physician may decide to deprescribe a medication for older adults with moderate dementia: 1 in which the medication could cause an adverse drug event if continued and the other in which there is no evidence of benefit. Participants ranked 9 factors related to possible ethical and pragmatic concerns through best-worst scaling methods (from greatest barrier to smallest barrier to deprescribing). Conditional logit regression quantified the relative importance for each factor as a barrier to deprescribing. Results: A total of 890 physicians (35.0%) returned surveys; 511 (57.4%) were male, and the mean (SD) years since graduation was 26.0 (11.7). Most physicians had a primary specialty in family practice (50.4% [449 of 890]) and internal medicine (43.5% [387 of 890]). A total of 689 surveys were sufficiently complete to analyze. In both clinical scenarios, the 2 greatest barriers to deprescribing were (1) the patient or family reporting symptomatic benefit from the medication (beneficence and autonomy) and (2) the medication having been prescribed by another physician (autonomy and nonmaleficence). The least influential factor was ease of paying for the medication (justice). Conclusions and Relevance: Findings from this national survey study of primary care physicians suggests that understanding ethical aspects of physician decision-making can inform clinician education about medication management and deprescribing decisions for older adults with moderate dementia.

Skilled home healthcare clinicians' experiences in communicating with physicians: A national survey.

BACKGROUND: Effective communication between skilled home healthcare (SHHC) clinicians and physicians is critical to care coordination. No studies have examined this from the point of view of SHHC clinicians at the national level. The objective is to determine in national sample issues related to how SHHC agency clinicians communicate with physicians. DESIGN: Mailed survey. METHODS: Mailed survey to a national representative random sample of SHHC agencies. The survey measured the experiences of SHHC clinicians in communicating with physicians. Multilevel logistic regression models examining odds of adverse patient outcomes associated with communication failures. RESULTS: A total of 265 surveys from 168 SHHC agencies were returned for a response rate of 13.3% at the individual respondent level and 16.8% at the SHHC agency level. Agency-level characteristics were similar between responding and nonresponding agencies. The most common method of contacting physicians during routine SHHC visits was telephone; communication via the electronic health record was uncommon. Nearly 40% of SHHC clinicians report never or rarely being able to reach a physician. SHHC clinicians rate the Center for Medicare and Medicaid Services Home Health Certification and Plan of Care (CMS-485) as a useful means of communication 6.3 (SD, 2.5) scale of 1 (least useful) to 10 (most useful); only 14% could have SHHC orders signed electronically. In multilevel logistic models, compared to SHHC clinicians who could reach a physician nearly every time or always, the odds of an SHHC clinician sending someone to the emergency department were 3.66 (95% confidence interval 1.16-11.5) for SHHC clinicians who were sometimes or often able to reach a physician and 5.43 (95% CI 1.56-18.9) for those who never or rarely reached a physician. CONCLUSIONS: In this exploratory study, SHHC clinicians experience significant communication barriers with physicians who order SHHC services. Strategies to enhance meaningful communication between SHHC clinicians and physicians must be developed.

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.

Skilled Home Healthcare Clinician and Staff Perspectives on Communication With Physicians: A Multisite Qualitative Study.

Communication between physicians who order, and clinicians who provide skilled home healthcare (SHHC), is critical to well-coordinated care. The views of SHHC staff on communication with physicians have not been well studied. The objective of this study was to explore how SHHC staff view the communication processes with physicians who order SHHC services. Using purposive and snowball sampling, we conducted semistructured interviews with 22 SHHC staff across multiple regions of the United States. Qualitative thematic content analysis was used to analyze the data. SHHC staff experienced significant barriers to effective communication with physicians, including not being able to communicate in a timely manner when necessary for patient care, and challenges identifying the correct physician to coordinate care and sign SHHC orders. Key strategies to enhance communication focused on creating standardized processes to streamline communication, setting expectations for response times in communication, and improving the Centers for Medicare & Medicaid Services Home Health Certification and Plan of Care form (commonly referred to as the "CMS-485"/Plan of Care). SHHC staff experience significant communication challenges with physicians who order SHHC services that can compromise care coordination and delivery. Modifications to workflows are urgently needed to improve efficiency and quality of communication, care coordination, and quality of care.

Absorbing and transferring risk: assessing the impact of a statewide high-risk-pregnancy telemedical program on VLBW maternal transports.

BACKGROUND: Prior research has shown that resources have an impact on birth outcomes. In this paper we ask how combinations of telemedical and hospital-level resources impact transports of mothers expecting very low birth weight (VLBW) babies in Arkansas. METHODS: Using de-identified birth certificate data from the Arkansas Department of Health, data were gathered on transports of women carrying VLBW babies for two six-month periods: a period just before the start of ANGELS (12/02-05/03), a telemedical outreach program for high-risk pregnancies, and a period after the program had been running for six months (12/03-05/04). For each maternal transport, the following information was recorded: maternal race-ethnicity, maternal age, and the birth weight of the infant. Logistic regression was used to assess the relationship between the predictors (telemedicine, hospital level, maternal characteristics) and the probability of a transport. RESULTS: Having a telemedical site available increases the probability of a mother carrying a VLBW baby being transported to a level III facility either before or during birth. Having at least a level II nursery also increases the chance of a maternal transport. Where both level II nurseries and telemedical access are available, the odds of VLBW maternal transports are only modestly increased in comparison to the case where neither is present. At the individual level, Hispanic mothers were less likely to be transported than other mothers, and teenaged mothers were more likely to be transported than those 18 and over. A mother's being Black or being over 35 did not have an impact on the odds of being transported to a level III facility. CONCLUSION: Combinations of resources have an impact on physician decisions regarding VLBW transports and are interpretable in terms of the capacity to diagnose and absorb risk. We suggest a collegial review of transport patterns and birth outcomes from areas with different levels of resources as a vehicle for moving the entire system of care forward over time. With such an evidence-based review in place, the collegial relations among level III specialists and obstetricians from around the state can, over time, develop workable protocols for when and how level III facilities should be involved.

Equity in the development of telemedicine sites in an Arkansas high-risk pregnancy programme.

We investigated where telemedicine sites were placed in a telemedicine network to assist high-risk pregnancies in Arkansas. There were 14 telemedicine sites in 75 counties, excluding the central site in Pulaski county. Logistic regression was used to examine site placement. Five potential predictors of site placement were examined: (1) the logarithm of the number of births in the county (LOGBIRTHS); (2) an indicator of whether a county had an abnormal rate of low birthweight babies (HIGHLBW); (3) the proportion of the county population below the government's poverty level; (4) the ratio of black to white births; (5) an indicator of whether the county bordered the telemedicine hub site county. The results suggested that telemedicine sites were placed where there were more births (LOGBIRTHS, P = 0.001) and more low birthweight babies (HIGHLBW, P = 0.004). After controlling for these variables, the county poverty level did not reduce the likelihood of site placement. Thus telemedicine sites had been established in those areas where the need was great both in terms of immediate risk (rate of low birthweight babies) and in terms of the continuing pressure of large numbers of births. This is significant in view of the concentration of poor minorities in certain areas, which historically have not been matched by past distribution of resources.

Phase 1 Dose Escalation Study of MEDI-565, a Bispecific T-Cell Engager that Targets Human Carcinoembryonic Antigen, in Patients With Advanced Gastrointestinal Adenocarcinomas.

INTRODUCTION: MEDI-565, a bispecific, single-chain antibody targeting human carcinoembryonic antigen on tumor cells and the CD3 epsilon subunit of the human T-cell receptor complex, showed antitumor activity in carcinoembryonic antigen-expressing tumors in murine models. PATIENTS AND METHODS: This phase I, multicenter, open-label dose escalation study enrolled adults with gastrointestinal adenocarcinomas. MEDI-565 was given intravenously over 3 hours on days 1 through 5 in 28-day cycles, with 4 single-patient (0.75-20 µg) and 5 standard 3 + 3 escalation (60 µg-3 mg; 1.5-7.5 mg with dexamethasone) cohorts. Primary objective was determining maximum tolerated dose; secondary objectives were evaluating pharmacokinetics, antidrug antibodies, and antitumor activity. RESULTS: Thirty-nine patients were enrolled (mean age, 59 years; 56% male; 72% colorectal cancer). Four patients experienced dose-limiting toxicities (2 at 3 mg; 2 at 7.5 mg + dexamethasone): hypoxia (n = 2), diarrhea, and cytokine release syndrome (CRS). Five patients reported grade 3 treatment-related adverse events: diarrhea, CRS, increased alanine aminotransferase, hypertension (all, n = 1), and hypoxia (n = 2); 6 experienced treatment-related serious adverse events: diarrhea, vomiting, pyrexia, CRS (all, n = 1), and hypoxia (n = 2). MEDI-565 pharmacokinetics was linear and dose-proportional, with fast clearance and short half-life. Nineteen patients (48.7%) had antidrug antibodies; 5 (12.8%) had high titers, 2 with decreased MEDI-565 concentrations. No objective responses occurred; 11 (28%) had stable disease as best response. CONCLUSIONS: The maximum tolerated dose of MEDI-565 in this patient population was 5 mg administered over 3 hours on days 1 through 5 every 28 days, with dexamethasone. Pharmacokinetics were linear. No objective responses were observed.

A simple wavelet-based test for evoked responses.

Statistically valid detection of evoked responses from magnetoencephalographic (MEG) sensors is complicated by temporal autocorrelation. By decorrelating time series and transforming them toward normality, the discrete wavelet transform (DWT) allows the analyst to test for an association between stimulus and sensor time series with appropriate degrees of freedom. Eswaran et al. (Neurosci. Lett. 2002a;331:128-32) used a 151-channel fetal MEG system to obtain serial recordings from 10 pregnant subjects. There were 3-8 recordings per subject. In each recording session, the fetus was stimulated by 500Hz and 1KHz tones with a relative frequency of 80-20%, respectively. In this new analysis of the same data, the fetal MEG signals were compared to two different stimulus waveforms: the frequent tone and the Novel stimulus, defined as a change in pitch. WaveDetect was developed to determine whether there was a significant association between the stimuli and the MEG traces. This test is performed by taking the DWT of each series and then computing the Spearman correlation between the wavelet coefficients for an appropriate scale. A significant response (i.e., correlated stimulus-sensor pair) was detected from each patient. This result suggests that the combination of serial recordings and WaveDetect may ensure reliable detection of auditory evoked responses.

A two-period assessment of changes in specialist contact in a high-risk pregnancy telemedical program.

The purpose was to examine the organizational impact of a state-wide high-risk pregnancy telemedical system, Antenatal and Neonatal Guidelines, Education and Learning System (ANGELS), after the first year of its roll out. The focus is on several aspects of system organization, including the volume and diversity of patient-based telemedical consultations and weekly telemedical case discussions, telephone consultations, and changes in the pattern of birth-related patient transports. Individual data on patient transports and associated hospital days, provider-specialist telephone calls, and telemedical consultations were collected for two time periods: December 2002-May 2003 (prior to initiation of ANGELS), and December 2003-May 2004 (postinitiation of ANGELS). Different statistical tests were constructed to compare the two periods as appropriate. Significant increases were observed in the volume and geographic diversity of telemedical consultations and the volume of telephone consultations. There was a moderate, but nonsignificant decrease in the number of maternal transports to University of Arkansas School of Medical Sciences (UAMS), and the average length of stay decreased. The type of specialist-provider and specialist-patient contact has changed as the ANGELS high-risk pregnancy telemedical system has evolved over the first year. We conclude that the rollout of the ANGELS program is changing the shape of high-risk patient care in Arkansas, and we attribute that to an evolving collegial network between specialists and generalists.