Rule-Based Identification of Individuals with Mild Cognitive Impairment or Alzheimer's Disease Using Clinical Notes from the United States Veterans Affairs Healthcare System.

BACKGROUND: Early identification of individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD) is a clinical and research imperative. Use of diagnostic codes for MCI and AD identification has limitations. We used clinical notes to supplement diagnostic codes in the Veterans Affairs Healthcare System (VAHS) electronic health records (EHR) to identify and establish cohorts of Veterans recorded with MCI or AD. METHODS: Targeted keyword searches for MCI ("Mild cognitive impairment;" "MCI") and AD ("Alz*") were used to extract clinical notes from the VAHS EHR from fiscal year (FY) 2010 through FY 2019. Iterative steps of inclusion and exclusion were applied until searches achieved a positive predictive value ≥ 80%. MCI and AD cohorts were identified via clinical notes and/or diagnostic codes (i.e., including Veterans recorded by "Notes Only," "Notes + Code," or "Codes Only"). RESULTS: A total of 2,134,661 clinical notes from 339,007 Veterans met the iterative search criteria for MCI due to any cause and 4,231,933 notes from 572,063 Veterans met the iterative search criteria for AD. Over the 10-year study period, the number of clinical notes recording AD was generally stable, whereas the number for MCI more than doubled. More Veterans were identified for the MCI or AD cohorts via clinical notes than by diagnostic codes, particularly in the AD cohort. Among Veterans identified by having "Notes + Code" for MCI, the number first recorded by a code was lower than the number first recorded by a note until FY 2015 and then gradually became comparable after FY 2015. Among Veterans identified by having "Notes + Code" for AD, the number first recorded by a note was more than double the number first recorded by a code AD in each of the FYs. CONCLUSIONS: Clinical note-based identification captured more Veterans recorded with MCI and AD than diagnostic code-based identification.

Assessing out-of-pocket expenses and indirect costs for the Alzheimer disease continuum in the United States.

BACKGROUND: The societal costs of Alzheimer disease (AD) are considerable. Cost data stratified by cost category (direct and indirect) and AD severity in the United States are limited. OBJECTIVE: To describe out-of-pocket (OOP) expenses and indirect costs from unpaid caregiving and work impairment among patients with AD by severity and among patients with mild cognitive impairment (MCI) in a representative sample of the US population. METHODS: Data from the Health and Retirement Study (HRS) were used. HRS respondents were included if they reported an AD diagnosis or were considered as having MCI based on their cognitive performance. MCI and AD severity staging was performed using a crosswalk from results of the modified Telephone Interview of Cognitive Status to the Mini-Mental State Examination. OOP expenses were assessed along with indirect costs (costs to caregivers from providing unpaid help and costs to employers). Sensitivity analyses were performed by varying assumptions of caregiver employment, missed workdays, and early retirement. Patients with AD were stratified by nursing home status, type of insurance, and income level. All cost calculations applied sampling weights. RESULTS: A total of 18,786 patients were analyzed. Patients with MCI (n = 17,885) and AD (n = 901) were aged 67.8 ± 10.7 and 80.9 ± 9.3 years, were 55.7% and 63.3% female, and were 28.3% and 0.9% employed, respectively. OOP expenses per patient per month increased with AD severity, ranging from $420 in mild to $903 in severe AD but were higher in MCI ($554) than in mild AD. Indirect costs to employers were similar across the AD continuum ($197-$242). Costs from unpaid caregiving generally increased by disease severity, from $72 (MCI) to $1,298 (severe AD). Total OOP and indirect costs increased by disease severity, from $869 (MCI) to $2,398 (severe AD). Sensitivity analysis assuming nonworking caregivers and zero costs to employers decreased the total OOP and indirect costs by 32%-53%. OOP expenses were higher for patients with AD who had private insurance (P < 0.01), had higher incomes (P < 0.01), or were in nursing homes (P < 0.01). Indirect costs to caregivers were lower for patients with AD in nursing homes ($600 vs $1,372, P < 0.01). Total indirect costs were higher for patients with AD with lower incomes ($1,498 vs $1,136, P < 0.01) and for those not in nursing homes ($1,571 vs $799, P < 0.01). CONCLUSIONS: This study shows that OOP expenses and indirect costs increase with AD severity, OOP expenses increase with higher income, subscription of private insurance, and nursing home residency, and total indirect costs decrease with higher income and nursing home residency in the United States. DISCLOSURES This study was financially sponsored by Eisai. Drs Zhang and Tahami are employees of Eisai. Drs Chandak, Khachatryan, and Hummel are employees of Certara; Certara is a paid consultant to Eisai. The views expressed here are those of the authors and are not to be attributed to their respective affiliations. Laura De Benedetti, BSc, provided medical writing support to the manuscript; she is an employee of Certara.

The epidemiology of mild cognitive impairment, Alzheimer's disease and related dementia in U.S. veterans.

INTRODUCTION: US veterans have a unique dementia risk profile that may be evolving over time. METHODS: Age-standardized incidence and prevalence of Alzheimer's disease (AD), AD and related dementias (ADRD), and mild cognitive impairment (MCI) was estimated from electronic health records (EHR) data for all veterans aged 50 years and older receiving Veterans Health Administration (VHA) care from 2000 to 2019. RESULTS: The annual prevalence and incidence of AD declined, as did ADRD incidence. ADRD prevalence increased from 1.07% in 2000 to 1.50% in 2019, primarily due to an increase in the prevalence of dementia not otherwise specified. The prevalence and incidence of MCI increased sharply, especially after 2010. The prevalence and incidence of AD, ADRD, and MCI were highest in the oldest veterans, in female veterans, and in African American and Hispanic veterans. DISCUSSION: We observed 20-year trends of declining prevalence and incidence of AD, increasing prevalence of ADRD, and sharply increasing prevalence and incidence of MCI.

Therapeutic preference for Alzheimer's disease treatments: a discrete choice experiment with caregivers and neurologists.

BACKGROUND: Alzheimer's disease (AD) is a major global health crisis in need of more effective therapies. However, difficult choices to optimize value-based care will need to be made. While identifying preferred therapeutic attributes of new AD therapies is necessary, few studies have explored how preferences may vary between the stakeholders. In this study, the trade-offs among key attributes of amyloid plaque-lowering therapies for AD were assessed using a discrete choice experiment (DCE) and compared between caregivers and neurologists. METHODS: An initial pilot study was conducted to identify the potentially relevant features of a new therapy. The DCE evaluated seven drug attributes: clinical effects in terms of delay in AD progression over the standard of care (SOC), variation in clinical effects, biomarker response (achieving amyloid plaque clearance on PET scan), amyloid-related imaging abnormalities-edema (ARIA-E), duration of therapy, need for treatment titration as well as route, and frequency of drug administration. Respondents were then randomly presented with 12 choice sets of treatment options and asked to select their preferred option in each choice set. Hierarchical Bayesian regression modeling was used to estimate weighted preference attributes, which were presented as mean partial utility scores (pUS), with higher scores suggesting an increased preference. RESULTS: Both caregivers (n = 137) and neurologists (n = 161) considered clinical effects (mean pUS = 0.47 and 0.82) and a 5% incremental in ARIA-E (mean pUS = - 0.26 and - 0.52) to be highly impactful determinants of therapeutic choice. In contrast, variation in clinical effects (mean pUS = 0.12 and 0.14) and treatment duration (mean pUS = - 0.02 and - 0.13) were the least important characteristics of any new treatment. Neurologists' also indicated that subcutaneous drug delivery (mean pUS = 0.42 vs. 0.07) and administration every 4 weeks (mean pUS = 1.0 vs. 0.20) are highly desirable therapeutic features. Respondents were willing to accept up to a 9% increment in ARIA-E for one additional year of delayed progression. CONCLUSIONS: Caregivers and neurologists considered incremental clinical benefit over SOC and safety to be highly desirable qualities for a new drug that could clear amyloid plaques and delay clinical progression and indicated a willingness to accept incremental ARIA-E to achieve additional clinical benefits.

Comparative efficacy of lemborexant and other insomnia treatments: a network meta-analysis.

BACKGROUND: Insomnia is a common disorder associated with a substantial burden of illness, particularly in older adults. OBJECTIVE: To compare the efficacy and safety of lemborexant with specified other insomnia treatments through a systematic literature review and network meta-analysis (NMA). METHODS: Medline and Embase were systematically searched from inception to February 2019 and updated with a targeted search of PubMed for pivotal trials in March 2021. Randomized controlled trials in adults with primary insomnia were included if they reported results following at least 1 week of treatment. Interventions of interest were specified as lemborexant, suvorexant, benzodiazepines, benzodiazepine receptor agonists (also called Z-drugs [zolpidem, eszopiclone, zaleplon, zopiclone]), trazodone, and ramelteon. Efficacy outcomes included wake after sleep onset (WASO), sleep efficiency (SE), latency to persistent sleep (LPS)/sleep onset latency (SOL), total sleep time (TST) and Insomnia Severity Index (ISI). Bayesian NMA were performed at predetermined time intervals approximating 4 weeks, 3 months, and 6 months. Safety outcomes included serious adverse events (SAEs), withdrawals due to adverse events (AEs), and specified AEs (dizziness, somnolence, and falls). Subgroup analysis was conducted in the older population. RESULTS: 45 studies were included in the NMA. At 4 weeks, lemborexant had the highest probability of being the best treatment for 3 of the 4 outcomes measured objectively by polysomnography-TST, LPS, and SE-and was ranked second to suvorexant on WASO. Eszopiclone was highly ranked for subjectively measured SOL and ISI at 4 weeks, 3 months, and 6 months. Lemborexant was rated more highly than suvorexant in subjective measures of WASO, TST, and SOL at 4 weeks (the differences were not statistically significant). No statistically significant interactions between treatment effect and older subpopulations were found, indicating that the treatment effect was similar in older and adult populations. The safety profile of lemborexant was broadly similar to the other treatments for SAEs and withdrawals due to AEs. A limitation is the age of some of the included studies (3 were published in 1990 or earlier). A further limitation is the lack of stratification of recommended doses. If the doses used in the study publications do not reflect doses used in clinical practice, this could potentially bias the results. CONCLUSIONS: Lemborexant was ranked highest of the treatments studied on 3 out of the 4 objectively measured insomnia efficacy outcomes, with a safety profile broadly similar to other insomnia treatments. DISCLOSURES: This work was funded by Eisai Inc., which was involved with all stages of the study and analysis. McElroy, O'Leary, and Adena are consultants with Datalytics Pty Ltd., which was paid by Eisai Inc. for conducting the literature review and analysis. They were not financially compensated for collaborative efforts on publication-related activities. Campbell, Tahami Monfared, and Meier are employed by Eisai Inc. This study was presented as a poster at AMCP Nexus Virtual, October 20-23, 2020 and at the AGS Virtual Annual Scientific Meeting 2021, May 13-15, 2021.

Economic Evaluation of Nivolumab Plus Ipilimumab Combination as First-Line Treatment for Patients with Advanced Melanoma in Canada.

OBJECTIVE: Our objective was to evaluate the cost effectiveness of the combination of nivolumab and ipilimumab, referred to as "Regimen", as a first-line treatment for patients with advanced melanoma from the perspective of Canada's public healthcare system. METHODS: We developed a partitioned-survival model (progression-free survival, post-progression survival, and death) to determine the clinical and economic outcomes of immunotherapy for advanced melanoma over a 20-year time horizon. Regimen was compared with nivolumab, ipilimumab, and pembrolizumab. Two treatment durations for pembrolizumab were considered: (1) maximum of 24 months or until progression or (2) no maximum duration, until progression. The model used data from CheckMate-067 (28 months' follow-up) for treatments involving nivolumab and ipilimumab. The efficacy of pembrolizumab was estimated using indirect comparisons. A scenario looking at the cost of subsequent treatments following disease progression was examined. RESULTS: Regimen had better outcomes and was cost effective compared with all other immunotherapies at a threshold of $CAN100,000 per quality-adjusted life-year (QALY) gained. Compared with nivolumab and ipilimumab, the incremental cost-effectiveness ratios (ICERs) were $CAN47,119 and 66,750 per QALY, respectively. Compared with pembrolizumab with a treatment duration cap, the ICER was $CAN85,436. When assuming no duration cap, Regimen dominated pembrolizumab. With the inclusion of subsequent treatment costs following progression, Regimen's ICER improved compared with all other comparators. CONCLUSIONS: Despite the advent of effective new therapies for advanced melanoma, prognosis remains poor for some patients. Compared with other immunotherapies, Regimen offers marked benefit and may be a cost-effective treatment option.

The concept of the 'percent wasted patients' in preventive health strategies.

PURPOSE: To better communicate the impact of poor persistence when preventive therapies are initiated, we propose a new measure that is intuitively understandable for clinicians. This measure is the percent wasted patients (PWP). METHODS: The PWP is the percentage of patients, out of the new users of a given preventive treatment, who have discontinued therapy before the time point at which clinical benefits become apparent on the cumulative incidence curves in randomized controlled trials (RCTs) comparing active treatment to placebo. To calculate the PWP, the RCTs that demonstrated the efficacy of the therapy under study must be identified from a MEDLINE search. The point at which the cumulative incidence curves for the main outcome in the experimental and placebo group start diverging is identified and is called the point of visual divergence (PVD). Then, using pharmaceutical claims databases, the percent persistence at the PVD in new users of the therapy is determined. The PWP is then calculated as 100% persistence at PVD. RESULTS: For primary prevention with statins, in the province of Quebec, the PWP is 44%. Of 100 patients starting statins for the primary prevention of coronary events, 44 will represent a waste in health resources because they will have discontinued therapy before any clinical benefit can be expected. CONCLUSIONS: The PWP is a simple measure that can be used by clinicians to select the therapies that need the most reinforcement concerning the importance of persistence.

Accuracy and validity of using medical claims data to identify episodes of hospitalizations in patients with COPD.

PURPOSE: In Quebec, MED-ECHO database can be used to estimate inhospital length of stay (LOS) and number of hospitalizations (NOH) both accurately and reliably. However, access to MED-ECHO database is time-consuming. Quebec medical claims database (RAMQ) can be used as an alternative source to estimate these measures. Considering MED-ECHO as the 'gold standard,' this study examined the validity of using RAMQ medical claims to estimate LOS and NOH. METHODS: We used a cohort of 3768 elderly patients with chronic obstructive pulmonary disease (COPD) between 1990 and 1996 and identified those with inhospital claims. Inhospital LOS was defined as the total number of days with inhospital claims. Various grace periods (1-15 days) between consecutive claims were considered for the estimation of LOS and NOH. RAMQ and MED-ECHO databases were linked using unique patient identifiers. Estimates obtained from RAMQ data were compared to those from MED-ECHO using various measures of central tendency and predictive error estimates. RESULTS: Overall, 32.7% of patients were hospitalized at least once during the study period based on RAMQ claims, as compared to 32.0% in MED-ECHO ( p-value = 0.51). The best estimates [mean (p-value)] were found to be those obtained when using a 7-day grace period. RAMQ versus MED-ECHO estimates were: 12.2 versus 13.5 days (< 0.001) for LOS and 3.6 versus 3.7 times (0.36) for NOH. CONCLUSIONS: RAMQ medical claims can be used as a reliable source to estimate LOS and NOH, particularly when time and resources are restricted. RAMQ, however, should be used with caution since slight underestimations may occur.

Pain and quality of life assessment after endovascular versus open repair of abdominal aortic aneurysms in patients at low risk.

PURPOSE: To compare functional autonomy, quality of life (QOL), and pain control after endovascular and open repair (OR) of abdominal aortic aneurysms. MATERIALS AND METHODS: Forty patients with a low surgical risk profile and anatomic compatibility for stent-graft therapy were randomized to receive OR or endovascular aneurysm repair (EVAR). Technical and clinical success as well as mortality were assessed in both groups and compared by Kaplan-Meier analysis. Functional autonomy and QOL were assessed by Karnofsky score and Short Form 36 (SF-36) questionnaire. Pain control was assessed by a numeric rating scale and Brief Pain Inventory questionnaire. QOL outcomes by means of the SF-36 and pain questionnaires were compared with use of mixed-effects models for repeated-measures analysis. RESULTS: All procedures were technically successful in both groups. Three late clinical failures requiring surgical conversion or repeated intervention were observed in the EVAR group and one was observed in the OR group. There was no significant difference between groups in terms of functional autonomy or QOL. No difference in pain level was evident during the early postoperative period, whereas the pain level was lower in the OR group after 1 month. Opioid analgesic drug consumption was significantly greater in the OR group during the postoperative period. Mean hospitalization duration was shorter in the EVAR group than in the OR group (4.5 days +/- 2.4 vs 11.5 days +/- 8.1; P= .001). CONCLUSION: EVAR has no advantage over OR in patients at low risk in terms of functional autonomy, QOL, and pain control. However, EVAR was associated with shorter hospitalization durations compared with OR.

A comparison between persistence to therapy in ALLHAT and in everyday clinical practice: a generalizability issue.

BACKGROUND: Persistence to therapy was very high in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) and was similar between treatment arms. Most patients were already on antihypertensive therapy before the trial began. Clinically, the results from this trial are more likely to be applied when antihypertensive therapy is initiated. OBJECTIVES: To assess whether the conclusions drawn from ALLHAT could be applied to the initiation of antihypertensive therapy. METHODS: A MEDLINE literature search was performed using the key words 'persistence', 'persistence to therapy', 'compliance' and 'adherence', and these were each linked with 'hypertension'. Studies from pharmaceutical databases were selected when they reported persistence to any antihypertensive therapy at one year according to which initial drug class (calcium channel blockers, angiotensin-converting enzyme inhibitors and thiazides) was initially prescribed. From the reported persistence rates, the number of patients was determined in whom treatment of hypertension results in a waste of health resources when each initial drug class was prescribed. RESULTS: Persistence to antihypertensive therapy at one year reported in the pharmaceutical databases varies from 5% to 75%. It was lower when the initial drug that was prescribed was a diuretic versus an angiotensin-converting enzyme inhibitor or a calcium channel blocker. The number of patients in whom treatment of hypertension resulted in a waste of resource was also higher when a diuretic was initially prescribed. CONCLUSION: Persistence to antihypertensive therapy is low for all the agents initiated and the lowest with diuretics. This should be considered as a word of caution when the ALLHAT conclusions are applied to the clinical setting.