Alzheimer's Disease: Epidemiology and Clinical Progression.

Alzheimer's disease (AD) is prevalent throughout the world and is the leading cause of dementia in older individuals (aged ≥ 65 years). To gain a deeper understanding of the recent literature on the epidemiology of AD and its progression, we conducted a review of the PubMed-indexed literature (2014-2021) in North America, Europe, and Asia. The worldwide toll of AD is evidenced by rising prevalence, incidence, and mortality due to AD-estimates which are low because of underdiagnosis of AD. Mild cognitive impairment (MCI) due to AD can ultimately progress to AD dementia; estimates of AD dementia etiology among patients with MCI range from 40% to 75% depending on the populations studied and whether the MCI diagnosis was made clinically or in combination with biomarkers. The risk of AD dementia increases with progression from normal cognition with no amyloid-beta (Aß) accumulation to early neurodegeneration and subsequently to MCI. For patients with Aß accumulation and neurodegeneration, lifetime risk of AD dementia has been estimated to be 41.9% among women and 33.6% among men. Data on progression from preclinical AD to MCI are sparse, but an analysis of progression across the three preclinical National Institute on Aging and Alzheimer's Association (NIA-AA) stages suggests that NIA-AA stage 3 (subtle cognitive decline with AD biomarker positivity) could be useful in combination with other tools for treatment decision-making. Factors shown to increase risk include lower Mini-Mental State Examination (MMSE) score, higher Alzheimer's Disease Assessment Scale (ADAS-cog) score, positive APOE4 status, white matter hyperintensities volume, entorhinal cortex atrophy, cerebrospinal fluid (CSF) total tau, CSF neurogranin levels, dependency in instrumental activities of daily living (IADL), and being female. Results suggest that use of biomarkers alongside neurocognitive tests will become an important part of clinical practice as new disease-modifying therapies are introduced.

The Humanistic and Economic Burden of Alzheimer's Disease.

Alzheimer's disease (AD) is the leading cause of cognitive impairment and dementia in older individuals (aged ≥ 65 years) throughout the world. As a result of these progressive deficits in cognitive, emotional, and physical function, AD dementia can cause functional disability and loss of independence. To gain a deeper understanding of the recent literature on the burden of AD, including that of mild cognitive impairment (MCI) due to AD, we conducted a comprehensive targeted review of the PubMed-indexed literature (2014 to 2021) to examine the humanistic and economic burden of AD (including MCI) in North America, Europe, and Asia. Our literature review identified a range of factors associated with quality of life (QoL): some factors were positively associated with QoL, including caregiver relationship, religiosity, social engagement, and ability to engage in activities of daily living (ADL), whereas other factors such as neuropsychiatric symptoms were associated with poorer QoL. While patient- and proxy-rated QoL are highly correlated in patients with early AD dementia, proxy-rated QoL declines more substantially as severity worsens. The maintenance of self-reported QoL in patients with more severe AD dementia may be due to lack of awareness or to adaptation to circumstances. Compared to persons with normal cognition, MCI is associated with a greater cost burden, and individuals with MCI exhibit worse QoL. Key drivers of the societal economic burden of AD include disease severity, dependence level, institutionalization, and comorbidity burden. Evaluation of the impact of a hypothetical disease-modifying treatment delaying the progression from MCI to AD has suggested that such a treatment may result in cost savings.

Item response theory analysis of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised in the Pooled Resource Open-Access ALS Clinical Trials Database.

Our objective was to examine dimensionality and item-level performance of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) across time using classical and modern test theory approaches. Confirmatory factor analysis (CFA) and Item Response Theory (IRT) analyses were conducted using data from patients with amyotrophic lateral sclerosis (ALS) Pooled Resources Open-Access ALS Clinical Trials (PRO-ACT) database with complete ALSFRS-R data (n = 888) at three time-points (Time 0, Time 1 (6-months), Time 2 (1-year)). Results demonstrated that in this population of 888 patients, mean age was 54.6 years, 64.4% were male, and 93.7% were Caucasian. The CFA supported a 4* individual-domain structure (bulbar, gross motor, fine motor, and respiratory domains). IRT analysis within each domain revealed misfitting items and overlapping item response category thresholds at all time-points, particularly in the gross motor and respiratory domain items. Results indicate that many of the items of the ALSFRS-R may sub-optimally distinguish among varying levels of disability assessed by each domain, particularly in patients with less severe disability. Measure performance improved across time as patient disability severity increased. In conclusion, modifications to select ALSFRS-R items may improve the instrument's specificity to disability level and sensitivity to treatment effects.

Cost-effectiveness of injectable disease-modifying therapies for the treatment of relapsing forms of multiple sclerosis in Spain.

OBJECTIVE: To compare the cost-effectiveness of injectable disease-modifying therapies (DMTs) for the first-line treatment of relapsing-remitting multiple sclerosis (RRMS) in Spain. METHODS: A Markov model was developed to estimate the cost-effectiveness of intramuscular interferon beta-1a (IM IFNß-1a), subcutaneous interferon beta-1a (SC IFNß-1a), interferon beta-1b (IFNß-1b) and glatiramer acetate (GA) relative to best supportive care in a hypothetical cohort of 1,000 RRMS patients in Spain. The model was developed from a societal perspective with a time horizon of 30 years. Natural history and clinical trial data were used to model relapse rates and disease progression. Cost and utility data were obtained from a published survey of multiple sclerosis patients in Spain. The primary outcome measure was cost per quality-adjusted life year (QALY) gained. Univariate and probabilistic sensitivity analyses were performed. RESULTS: Compared to best supportive care, the base case cost-effectiveness was 168,629 per QALY gained for IM IFNß-1a, 231,853 per QALY gained for IFNß-1b, 295,638 per QALY gained for SC IFNß-1a, and 318,818 per QALY gained for GA. Results were most sensitive to changes in DMT cost, utility values and treatment effect. CONCLUSIONS: In our cost-effectiveness analysis of first-line injectable DMTs in Spain, we found IM IFNß-1a to be more cost-effective than SC IFNß-1a, IFNß-1b or GA. Sensitivity analyses confirmed the robustness of these results.

Narrative review of the literature on adherence to disease-modifying therapies among patients with multiple sclerosis.

While no curative treatment exists for multiple sclerosis (MS), several disease-modifying therapies (DMTs) have been developed to reduce relapse rates, slow disability progression, and modify the overall disease course. However, because of the chronic nature of the disease, long-term therapy adherence can be challenging for some patients with MS. Low adherence to DMTs has been shown to be associated with higher rates of disease relapses and progression as well as with an increase in medical resource utilization. As new MS treatments are developed, a comprehensive understanding of current adherence rates and the impact of adherence on clinical and economic outcomes is of particular interest. Our objective was to conduct a review of the published literature to evaluate rates of adherence to DMTs in MS and the impact of adherence on both clinical and economic outcomes from the patient and payer perspectives. Systematic literature searches were conducted using MEDLINE, EMBASE, and the Cochrane Central Register for Controlled Trials. Studies were limited to those completed on human subjects, written in the English language, and published between May 1, 2001, and May 1, 2011. Additional inclusion criteria required that studies involve a population of patients with MS, utilize the administration of DMTs, and report a measurement of adherence. Studies reporting persistence measures (e.g., treatment discontinuation rates) or rates of switching between DMTs (with no other measure of adherence reported) were excluded if they did not also assess adherence. Among the 24 studies meeting inclusion criteria, adherence to DMTs ranged from 41% to 88%. Weighted mean adherence rates were higher for intramuscular (IM) interferon beta-1a (IFNß-1a) administered once a week (69.4%), and subcutaneous (SC) IFNß-1b administered every other day (63.8%) than for SC IFNß-1a administered 3 times a week (58.4%) and glatiramer acetate administered daily (56.8%). There was a numerically greater risk of MS relapse or disease progression among patients nonadherent to therapy versus adherent patients, with findings statistically significant in 2 of 4 studies. Additionally, 2 studies showed statistically significant reductions in inpatient or emergency room utilization and total MS-related medical costs among patients adherent to therapy compared with nonadherent patients. Higher patient out-of-pocket copayments and coinsurance were significantly associated with lower adherence to DMTs, while the use of interventional or disease therapy management programs were associated with improved adherence. Lack of medication adherence remains a problem among patients with MS. Improvements in adherence have the potential to improve patient and payer burden in terms of improved clinical outcomes and lower nonpharmacy medical resource utilization.  

The economic burden of advanced liver disease among patients with hepatitis C virus: a large state Medicaid perspective.

BACKGROUND: Chronic hepatitis C virus (HCV) may progress to advanced liver disease (ALD), including decompensated cirrhosis and/or hepatocellular carcinoma (HCC). ALD can lead to significant clinical and economic consequences, including liver transplantation. This study evaluated the health care costs associated with ALD among HCV infected patients in a Medicaid population. METHODS: Using Florida Medicaid claims data, cases were patients with at least 1 diagnosis of HCV or prescription therapy for HCV (ribavirin plus interferon, peginterferon, or interferon alfacon-1) prior to an incident ALD-related diagnosis ("index event") between 1999 and 2007. ALD-related conditions included decompensated cirrhosis, HCC, or liver transplant. A cohort of HCV patients without ALD (comparison group subjects) were matched 1-to-1 based on age, sex, and race. Baseline and follow-up were the 12 months prior to and following index, respectively; with both periods allowing for a maximum one month gap in eligibility. For both case and comparison patient cohorts, per-patient-per-eligible month (PPPM) costs were calculated as total Medicaid paid amount for each patient over their observed number of eligible months in follow-up, divided by the patient's total number of eligible months. A generalized linear model (GLM) was constructed controlling for age, race, Charlson score, alcoholic cirrhosis, and hepatitis B to explore all-cause PPPM costs between study groups. The final study group included 1,193 cases and matched comparison patients (mean age: 49 years; 45% female; 54% white, 23% black, 23% other). RESULTS: The majority of ALD-related diagnoses were for decompensated cirrhosis (92%), followed by HCC (6%) and liver transplant (2%). Cases had greater comorbidity (mean Charlson score: 3.1 vs. 2.3, P < 0.001). All-cause inpatient use up to 1-year following incident ALD diagnosis was significantly greater among cases with ALD (74% vs. 27%, P < 0.001). In the GLM, cases had 2.39 times greater total adjusted mean all-cause PPPM costs compared to the comparison group ($4,956 vs. $1,735 respectively; P < 0.001). Among cases, mean total unadjusted ALD-related costs were $1,356 PPPM, which were largely driven by inpatient costs ($1,272). CONCLUSIONS: Our results suggest that among patients diagnosed with HCV, the incremental costs of developing ALD are substantial, with inpatient stays as the main driver of these increased costs.

The cost offsets and cost-effectiveness associated with pegylated drugs: a review of the literature.

Pegylation (PEG) is used as both a drug-delivery and a drug-modification technology in ten drugs approved by the US FDA. Benefits of PEG drugs can include increased plasma half-life, longer absorption, improved tumor targeting and less antigenicity and immunogenicity. Clinical benefits of PEG drugs over non-PEG drugs may include reduced administration, improved efficacy, improved tolerability, and decreased severity and incidence of adverse events. This study reviews 37 economic literature publications featuring PEG drugs versus non-PEG versions. PEG drugs showed some reductions in overall costs resulting from various offsets including fewer administrations, lower adverse event treatment costs, reduced disease complication costs or reduced inpatient/outpatient costs. Of the 18 cost-effectiveness studies reviewed, 17 of them found PEG drugs to be cost effective versus the non-PEG drugs. Cost offsets and cost-effectiveness of PEG drugs have been demonstrated in multiple studies across various therapies, indications and country settings, and the results have been found to be stable when key parameters were varied in analyses. Further studies are needed to assess the potential for cost savings and cost-effectiveness for new PEG therapies in development.

Medical care costs and survival associated with hepatocellular carcinoma among the elderly.

BACKGROUND & AIMS: We assessed the burden of hepatocellular carcinoma (HCC), in terms of mortality and medical care costs, based on analysis of the Surveillance, Epidemiology and End Results (SEER)-Medicare database. METHODS: We analyzed data from the SEER-Medicare database on patients 66 years or older who were diagnosed with primary HCC from 1991 to 2007, entitled for Medicare Parts A and B, and not enrolled in health maintenance organizations (n = 5712). Controls were individuals without HCC, identified from a 5% sample of Medicare beneficiaries residing in SEER areas; they were matched 1:1 with individuals with HCC (cases) for age, sex, race, and geographic region (average age, 75 y; 34.7% female). Kaplan-Meier analysis was used to estimate survival distributions. Costs were reported in 2009 dollars; per-patient-per-month (PPPM) costs were compared between cases and controls using the Wilcoxon rank sum test. RESULTS: The largest proportion of cases had localized disease (38.2%), followed by regional (24.0%), unstaged (20.4%), and distant (17.3%) disease. The median survival times were 5 months for cases and 60 months for controls; they were 3 months for patients with distant disease, 4 months for patients with regional disease, and 9 months for those with localized disease. The mean PPPM costs were $7863 for cases and $1243 for controls (P < .001). These costs were primarily driven by inpatient (mean, $5439 vs $682 without HCC; P < .001) and hospice (mean $554 vs $42 without HCC; P < .001) care. Mean PPPM costs by stage were $7265 for localized disease, $8072 for regional disease, and $9585 for distant disease (P < .001 for trend). CONCLUSIONS: Based on analysis of the SEER-Medicare database, costs for patients with HCC are approximately 6- to 8-fold higher than for those without this cancer. Patients with distant HCC had the greatest costs. These findings highlight that HCC is a substantial medical cost burden for elderly patients.

A framework for assessing the value of diagnostic imaging in the era of comparative effectiveness research.

In June 2009, the Federal Coordinating Council for Comparative Effectiveness Research submitted a report to the President and Congress in which the Council described the purpose of comparative effectiveness research (CER) as developing evidence-based information for interventions and determining under what circumstances an intervention is effective (1). With the enactment of the Patient Protection and Affordable Care Act, a Patient-centered Outcomes Research Institute (PCORI) was established to assist decision makers in making evidence-based health decisions through synthesis and dissemination of clinical CER of health interventions (2). Its founding has underscored a heightened need for health policy makers to consider the impact of health care technologies on final outcomes of interest--for example, functional status, quality of life, disability, major clinical events, and mortality (3-5).

Biologic disease-modifying drug treatment patterns and associated costs for patients with rheumatoid Arthritis.

OBJECTIVE: To assess the influence of biologic treatment patterns on healthcare costs for patients with rheumatoid arthritis (RA) initiating tumor necrosis factor-α (TNF-α) antagonist therapy. METHODS: Patients with 2 RA diagnoses (International Classification of Diseases, 9th ed, 714.xx), and without psoriasis or Crohn's disease, were identified in a US employer-based insurance claims database. A sample of 2545 was constructed based on an index event of initiating TNF-α antagonist therapy and 30 months of continuous enrollment. Baseline characteristics were assessed in the 6-month pre-index period and treatment patterns were determined during the 12-month post-index period. Medical service and prescription drug costs were analyzed for Months 13-24 using multivariate regression analysis to control for baseline characteristics and time-varying confounding associated with treatment and disease severity. RESULTS: In the first year after TNF-α initiation, 89% used a single TNF-α antagonist; only 9% and 2% had switched TNF-α antagonists or received non-TNF biologic disease-modifying antirheumatic drugs, respectively. Descriptive analyses revealed pairwise differences between groups (p < 0.05) in baseline characteristics (comorbidities, RA-related procedure use, and prescription drug use). Controlling for observed baseline characteristics, costs were greater for those treated with multiple vs single TNF-α antagonists: annual RA-related prescription drug costs ($8,340 vs $7,058; p = 0.012), RA-related healthcare costs ($15,048 vs $13,312; p = 0.008), and total healthcare costs ($26,697 vs $21,381; p < 0.001). CONCLUSION: In this sample, the majority of patients with RA were treated with a single TNF-α antagonist over the first year on therapy. For those who switched therapy, Year 2 RA-related and total direct healthcare costs were higher, adjusting for claims-based measures of RA disease severity.

Comparison of health care use and costs in newly diagnosed and established patients with fibromyalgia.

UNLABELLED: In 2004, the American Pain Society (APS) issued evidence-based fibromyalgia treatment recommendations. The objective of this claims database analysis is to describe prescription and medical use in patients with newly diagnosed and established fibromyalgia. Privately insured patients with 2+ myalgia/myositis claims (1999 to 2005) were categorized as newly diagnosed or established; this dichotomy involves comparisons between prediagnosis (S1) and postdiagnosis (S2) stages in the newly diagnosed and between newly diagnosed (S2) and established patients (S3). Use of APS guideline medications increased across stages: selective serotonin reuptake inhibitors (SSRIs) (S1, S2, S3: 20.6%, 22.9%, 25.3%), serotonin norepinephrine reuptake inhibitors (SNRIs) (4.5%, 6.4%, 8.9%), pregabalin/gabapentin (5.4%, 7.4%, 8.8%), benzodiazepines (19.0%, 21.1%, 24.2%), non-benzodiazepine sedatives (9.1%, 11.5%, 13.7%) (all P < .0001), and opioids (39.5%, 43.3%, 43.9%; S1 vs S2, P < .0001; S2 vs S3, P = .2835). Use of multiple therapeutic classes also increased across stages: 3+ classes (7.1%, 9.6%, 11.8%) (all P < .0001). Office visits to providers increased, on average, after diagnosis: primary care (70.9%, 78.3%, 76.3%; all P < .0001), chiropractors (28.8%, 51.1%, 53.3%; all P < .0001), rheumatologists (4.2%, 9.9%, 10.5%; S1 vs S2, P < .0001; S2 vs S3, P = .0595), mental health (6.4%, 7.3%, 8.3%; S1 vs S2, P < .0001, S2 vs S3, P = .0003). Average health care costs rose after diagnosis in the newly diagnosed group (S1: $6555 vs S2: $8654, P < .0001). PERSPECTIVE: This paper investigates prescription drug and medical care use with respect to stages of fibromyalgia diagnosis. Established fibromyalgia patients use more medical resources and have higher rates of concomitant medication use than newly diagnosed fibromyalgia patients. Findings can help educate providers regarding optimal drug treatment patterns in this population.

Costs associated with cardiovascular events in patients with hypertension in US managed care settings.

Study quantified incremental cost of cardiovascular (CV) events in 6 high-risk and compelling indication subgroups: post-myocardial infarction (MI), diabetes, diabetic nephropathy, elderly, chronic kidney disease, and prior stroke. Based on claims data from privately insured individuals with 2+ hypertension (HTN) diagnoses in 2004-2006, we estimated regression-adjusted per-member-per-month healthcare costs after CVE. Costs were compared between patients with and without a CV events, and before and after CV events in each subgroup. The following CVevents were studied: acute MI, acute coronary syndrome, angina, ventricular arrhythmia, atrial arrhythmia, heart failure, coronary artery disease, left ventricular hypertrophy, stroke, and sinus tachycardia. Of 1,598,890 HTN patients, 510,118 had >/=1 CV event. Compared with controls, healthcare costs among patients with events were significantly greater across all cost components (inpatient, outpatient, and prescription drug). Acute MI and congestive heart failure generally had the largest incremental total healthcare costs. First-quarter post-event costs were attributable to inpatient costs. CV events are costly sequelae of hypertension in high-risk and CI subgroups.

Comparative and interactive effects of depression relative to other health problems on work performance in the workforce of a large employer.

OBJECTIVES: To present data on the comparative and interactive workplace costs of depression relative to other health problems in the workforce of a large employer. METHODS: The World Health Organization Health and Work Performance Questionnaire was used to assess self-reported health problems and work performance. Survey data were linked to medical-pharmacy claims data. Regression analysis was used to assess comparative effects of depression in the absence and presence of comorbidities on Health and Work Performance Questionnaire measures of work performance. RESULTS: Depression had the largest individual-level effect on work performance of any condition examined. Several comorbid conditions exacerbated the effect of depression, but had no effects in the absence of depression. CONCLUSIONS: Depression is a strong predictor of decrements in work performance. Other conditions that often co-occur with depression, including anxiety and fatigue-sleep disturbance, exacerbate the adverse effect of depression.

Management of anaemia: a critical and systematic review of the cost effectiveness of erythropoiesis-stimulating agents.

Erythropoiesis-stimulating agents (ESAs) are genetically engineered forms of erythropoietin that are used in the treatment of anaemia. Their successful use in the treatment of anaemia associated with renal disease, cancer and other diseases, as well as the development of multiple agents, has increased the visibility of these agents in the clinical and health economics literature. The circumstances under which the use of ESAs is cost effective, or indeed, whether it is cost effective, is of central concern for clinicians and payers who must make informed decisions regarding the management of these costly resources. Much of the recent literature on ESAs in the treatment of anaemia associated with chronic kidney disease and cancer, the two major therapeutic areas for ESA treatment, has focused on comparisons between individual ESAs, particularly epoetin alfa and darbepoetin alfa. While there have been some studies of cost effectiveness, many studies in these treatment areas have employed a cost-minimization approach and have relied on published prices rather than actual market prices. In general, this review of the literature suggests a cost advantage for epoetin alfa relative to darbepoetin alfa in the treatment of anaemia in renal and oncology indications. For other indications in which the literature is less developed, such as anaemia induced by antiviral therapy and blood management in surgery, small prospective studies or decision-analytic models comparing ESA therapy and standard care have been most common. Few conclusions can be drawn about the overall and relative costs or cost effectiveness of ESAs in these treatment areas. With the recent concerns about the safety of ESAs, especially when used outside the approved product labelling, future evaluations of epoetin alfa and darbepoetin alfa should factor their safety profiles into estimates of cost effectiveness. Moreover, additional studies are needed to evaluate whether the treatment of anaemia with ESAs is cost effective compared with no treatment or minimal blood transfusions, and whether the cost effectiveness of ESAs would be improved if ESA doses and durations were reduced. With the introduction of new longer-acting ESAs, such as the continuous erythropoietin receptor activator, the relative cost effectiveness among the different ESAs will continue to be an important question for public and private payers, policy makers and clinicians who must consider the emergence of new data and changing dosing patterns when making decisions about the use of these important but costly agents.

Employees with fibromyalgia: medical comorbidity, healthcare costs, and work loss.

OBJECTIVES: To compare 2005 health care resources among matched samples of employees with fibromyalgia (FM), osteoarthritis (OA), and controls. METHODS: Using a claims database of privately insured individuals, FM and OA samples were derived from those with two or more disease-specific claims in 1999 to 2005 (> or =1 in 2002 to 2005). RESULTS: Total costs for employees with FM ($10,199) approached OA costs ($10,861, P = 0.3758) and were significantly higher than controls ($5274, P < 0.0001). Cost components varied across disease-specific samples (direct medical: FM $7286 vs OA $8325, P < 0.0287; pharmacy: FM $1630 vs OA $1341; indirect: FM $2913 vs OA $2537, P < 0.0001). Employees with FM had more claims than OA for psychiatric diagnoses, chronic fatigue, and most pain conditions. Use of multiple prescription drug classes was common in both samples. CONCLUSIONS: FM imposes significant economic burden. Work loss contributes substantially to the impact.