Parminder Raina

Effectiveness of Cholinesterase Inhibitors and Memantine for Treating Dementia: Evidence Review for a Clinical Practice Guideline

Dementias have become a major public health concern because of their increasing prevalence, chronicity, caregiver burden, and high personal and financial costs of care. Currently, there are no cures for most dementias. For the most common types (Alzheimer disease, vascular dementia, and mixed dementias), clinicians often prescribe pharmacotherapy to alleviate symptoms and delay disease progression. The pharmacotherapeutic agents available to treat problems associated with dementias (for example, psychosis) have varying levels of evidence to support their efficacy and have been reviewed elsewhere (1). Some drugs, although not approved, are being used in populations with mild cognitive impairment; in such patients, the rate of conversion to dementias is 0.3 to 2.3 per 100 person-years (2). Currently, 5 drugs have U.S. Food and Drug Administration (FDA) approval for managing dementias. The cholinesterase inhibitors (donepezil, galantamine, rivastigmine, and tacrine) degrade acetylcholinesterase, allowing levels of acetylcholine (a neurotransmitter critical to the neurons involved in cognition) to increase. Memantine partially blocks the N-methyl-d-aspartic acid receptor and prevents excess stimulation of the glutamate system, which influences memory and learning. Although FDA approval specifies use of these 5 drugs for Alzheimer disease, in clinical practice the drugs are also prescribed for other dementias. This review systematically evaluates the evidence for the effectiveness of these 5 drugs in improving outcomes in cognition, global function, behavior, and quality of life among patients with dementia. Methods Search and Selection We searched the Cochrane Central Register of Controlled Trials, MEDLINE, PREMEDLINE, EMBASE, Allied and Complementary Medicine Database, CINAHL, AgeLine, and PsycINFO for relevant evidence published in English from January 1986 through November 2006. We also reviewed the bibliographies of retrieved papers. All populations with major dementias (including Alzheimer disease, vascular dementia, and Parkinson dementia) and mild cognitive impairment were included. Only parallel randomized, controlled trials that compared a cholinesterase inhibitor or memantine with placebo or another drug were eligible. We excluded crossover trials because of potential bias due to period effects or period-by-treatment interaction. Our content-expert panel reached consensus and established that eligible studies also had to have a minimum modified Jadad score of 3 of 5 (original scale), indicating moderate study quality. Study outcomes primarily encompassed 4 broad domains: cognition, global function, behavior, and quality of life (including activities of daily living [ADLs] and caregiver burden). We classified most clinical outcomes within these 4 domains; other outcomes were rate of institutionalization, mortality, or adverse events. Two independent reviewers evaluated each study for eligibility. Appendix Table 1 describes the eligibility criteria in detail. Appendix Table 1. Detailed Eligibility Criteria for Systematic Review This systematic review was done in the context of an Agency for Healthcare Research and Qualityfunded review that evaluated 92 pharmacologic agents for dementias (1). Data Abstraction and Quality Assessment Two independent reviewers abstracted data from and assessed the quality of all studies that met the eligibility criteria. The modified Jadad scale (which includes additional domains that concern collection of adverse events, description of statistical analysis, and reporting of eligibility criteria) (3) and a checklist for the quality of reporting of adverse events were used to evaluate methodological quality; the latter measures included questions on frequency of reporting harms, withdrawals, and method of collection (1). Data Synthesis and Statistical Analysis Evaluation of benefit was based on reported changes in the principal outcome within the domains of interest. Although we did not restrict studies by the type of outcome, we did anticipate that some outcomes would be more commonly used in these drug studies. We searched the literature to establish the magnitude of change considered to be clinically important in key outcomes. Specifically, within the domain of cognition, we considered the Alzheimers Disease Assessment Scale (ADAS)consisting of the cognitive subscale (ADAS-cog), noncognitive subscale (ADAS-noncog), and total ADAS score (ADAS-tot)the Mini-Mental State Examination (MMSE) (or the standardized MMSE version), and the Severe Impairment Battery (SIB) to be commonly used measures that have established properties and are scored by a trained evaluator or clinician. The ADAS-cog is a validated psychometric assessment scale for the domains of attention, memory, orientation, language ability, and praxis in Alzheimer disease (4). Scores range from 0 to 70, with higher scores indicating greater impairment. A change of 4 points is considered clinically significant for patients with mild to moderate dementia, but the ADAS-cog is not uniformly sensitive to change over the course of the disease (5). The ADAS-noncog evaluates behavioral changes. The MMSE is a widely used measure of cognitive function validated in dementia populations (6). Scores range from 0 to 30, with lower scores indicating greater impairment. The MMSE measures orientation, attention, recall, and language, but it does not evaluate mood or disordered forms of thinking. The SIB is a validated measure of cognitive function for moderate to severe dementias in the areas of orientation, attention, language, and praxis (7). Scores on the SIB range from 0 to 100, with lower scores indicating greater deficits. There are no established clinically important differences for the MMSE or SIB. For the domain of global function, a commonly used outcome is the clinician-based impression of change (CIBIC), with caregiver input (CIBIC-plus) and other modified versions (New York UniversityCIBIC-plus, clinicians global impression of change [CGIC], Alzheimers Disease Cooperative Study CGIC, and clinician interviewbased impression). The CIBIC-plus is a validated measure of change that requires a clinician to judge global patient function in 4 areas: general, cognitive, behavioral, and ADLs (8). This measure is scored on a 7-point scale, with 1 reflecting marked improvement, 4 indicating no change, and 7 denoting marked worsening. Because the CIBIC-plus is a global rating by clinicians, any change in score is considered clinically significant. Most other measures commonly used in clinical settings do not have established effect sizes that reflect clinically important differences. To evaluate adverse effects, we used a standardized instrument that assessed rates of withdrawals due to adverse effects, the method (active vs. passive and standardized vs. nonstandardized approaches) and frequency of collection of harms, and the definition and collection of serious and severe harms. A priori, we selected specific events (nausea, diarrhea, dizziness, accidental injury, agitation, urinary disorder, serious adverse events) and expressed these as a percentage for each study. Where 2 or more studies provided sufficient information, we calculated the summary estimate for the specific adverse event evaluated. We used standard meta-analytic techniques to estimate effect sizes for each drug in studies with the same outcomes. The effect measure selected varied according to the manner in which the outcome was reported and included change scores or, for dichotomous data, relative risks (RRs). Reasonableness of pooling was assessed on clinical and biological grounds in terms of clinical heterogeneity (drugs, similarity of populations, and outcomes); therefore, meta-analysis was not appropriate for all outcomes. We did not include summary estimates when studies provided only end point scores. Similarly, we excluded studies that did not provide a measure of variance for outcomes when computing summary estimates. When meta-analyses were undertaken, the weighted mean difference (WMD) was selected as the pooled estimate instead of the standardized mean difference. When only the proportions of patients whose condition improved or worsened were reported, the RR was used as a measure of the summary effect size. In all meta-analyses, a random-effects model was used; tests for statistical heterogeneity were based on the chi-square statistic and the I 2 statistic. In some cases (912), estimates of mean changes in the study outcomes used for the meta-analyses were based on best estimates derived from figures in the citations. Results Figure 1 shows the process of study selection. Of the papers in the larger review, 127 evaluated donepezil, galantamine, rivastigmine, tacrine, and memantine. We excluded 22 of these that scored less than 3 on the Jadad scale, 8 that were crossover trials, and 1 that administered tacrine to both study groups. The Appendix lists all excluded studies. The remaining 96 reports included 59 unique study cohorts. Seventy-five different outcomes were measured across the domains of interest. Cognition and global function were the domains from which efficacy was most frequently determined. Figure 1. Study flow diagram. The term companion refers to multiple reports from a single study. The authors considered the first published study as the main paper and referred to all associated reports as companion papers. DSM = Diagnostic and Statistical Manual of Mental Disorders; ICD = International Classification of Diseases; NINCDS = National Institute of Neurological and Communicative Disorders and Stroke. Donepezil versus Placebo Twenty-four unique studies (9, 10, 1233) from 34 different reports evaluating donepezil versus placebo (or vitamin E) were eligible for this systematic review. Three additional studies (4 reports) directly compared donepezil with galantamine (34, 35) and rivastigmine (36, 37) and are discussed in the section on compara

Vitamin D, cognition, and dementia A systematic review and meta-analysis

Objective: To examine the association between cognitive function and dementia with vitamin D concentration in adults. Methods: Five databases were searched for English-language studies up to August 2010, and included all study designs with a comparative group. Cognitive function or impairment was defined by tests of global or domain-specific cognitive performance and dementia was diagnosed according to recognized criteria. A vitamin D measurement was required. Two authors independently extracted data and assessed study quality using predefined criteria. The Q statistic and I2 methods were used to test for heterogeneity. We conducted meta-analyses using random effects models for the weighted mean difference (WMD) and Hedges g. Results: Thirty-seven studies were included; 8 contained data allowing mean Mini-Mental State Examination (MMSE) scores to be compared between participants with vitamin D <50 nmol/L to those with values ≥50 nmol/L. There was significant heterogeneity among the studies that compared the WMD for MMSE but an overall positive effect for the higher vitamin D group (1.2, 95% confidence interval [CI] 0.5 to 1.9; I2 = 0.65; p = 0.002). The small positive effect persisted despite several sensitivity analyses. Six studies presented data comparing Alzheimer disease (AD) to controls but 2 utilized a method withdrawn from commercial use. For the remaining 4 studies the AD group had a lower vitamin D concentration compared to the control group (WMD = −6.2 nmol/L, 95% CI −10.6 to −1.8) with no heterogeneity (I2 < 0.01; p = 0.53). Conclusion: These results suggest that lower vitamin D concentrations are associated with poorer cognitive function and a higher risk of AD. Further studies are required to determine the significance and potential public health benefit of this association.

Conducting quantitative synthesis when comparing medical interventions: AHRQ and the Effective Health Care Program

OBJECTIVE This article is to establish recommendations for conducting quantitative synthesis, or meta-analysis, using study-level data in comparative effectiveness reviews (CERs) for the Evidence-based Practice Center (EPC) program of the Agency for Healthcare Research and Quality. STUDY DESIGN AND SETTING We focused on recurrent issues in the EPC program and the recommendations were developed using group discussion and consensus based on current knowledge in the literature. RESULTS We first discussed considerations for deciding whether to combine studies, followed by discussions on indirect comparison and incorporation of indirect evidence. Then, we described our recommendations on choosing effect measures and statistical models, giving special attention to combining studies with rare events; and on testing and exploring heterogeneity. Finally, we briefly presented recommendations on combining studies of mixed design and on sensitivity analysis. CONCLUSION Quantitative synthesis should be conducted in a transparent and consistent way. Inclusion of multiple alternative interventions in CERs increases the complexity of quantitative synthesis, whereas the basic issues in quantitative synthesis remain crucial considerations in quantitative synthesis for a CER. We will cover more issues in future versions and update and improve recommendations with the accumulation of new research to advance the goal for transparency and consistency.

Health status of school-aged children with cerebral palsy: information from a population-based sample.

In this study parents’systematic accounts of the health status of 408 school‐aged children with cerebral palsy (CP) are reported (221 males, 187 females; mean age 8 years 5 months, SD 1 year 11 months; range 5 to 13 years), as are relations between severity of functional motor impairment and eight functional health status domains. Data were collected as part of a longitudinal study of the motor development of a population‐based, stratified, random sample of children with CP from across Ontario, Canada. The Gross Motor Function Classification System (GMFCS) was used to classify severity of CP and functional health status was described with the eight‐level Health Utilities Index ‐ Mark 3. Rates of functional limitations in Mobility, Dexterity, Speech, and Vision were statistically significantly associated with GMFCS levels (all p<0.01), with correlation values (tau‐b) of 0.82,0.58,0.46, and 0.36, respectively. Functional limitations in hearing (tau‐b=0.16; p=0.04) and cognition (tau‐b=0.27;p<0.01) were both statistically significantly associated with GMFCS levels, though correlations were low. Neither emotion (tau‐b=0.03;p=0.24) nor pain (tau‐b=0.07;p=0.37) was associated with degree of functional limitation as described by the GMFCS. Clinical and epidemiological implications of findings are discussed.

Agreement between Self-reported and Routinely Collected Health-care Utilization Data among Seniors

OBJECTIVE To examine the agreement between self-reported and routinely collected administrative health-care utilization data, and the factors associated with agreement between these two data sources. DATA SOURCES/STUDY SETTING A representative sample of seniors living in an Ontario county within Canada was identified using the Ontario Ministry of Healths Registered Persons Data Base in 1992. Health professional billing information and hospitalization data were obtained from the Ontario Ministry of Health and Long-Term Care (OMH) and the Ontario Health Insurance Plan (OHIP). STUDY DESIGN A cross-sectional survey was carried out to assess any contact and frequency of contacts with health professionals and hospital admissions. Similar information was obtained from routinely collected administrative data. The level of agreement was assessed using the proportion of absolute agreement, Cohens kappa statistic (kappa), and the intraclass correlation coefficient (ICC). Logistic and linear regressions were used to identify factors that were associated with the magnitude and direction of disagreement respectively. DATA COLLECTION/EXTRACTION METHODS Telephone interviews were conducted on 1,054 seniors, and complete data were available for 1,038 seniors. Each respondents personal health number was used to electronically link survey data with health professional billing and hospitalization databases. PRINCIPAL FINDINGS Substantial to almost perfect agreement was found for the contact utilization measures, while agreement on volume utilization measures varied from poor to almost perfect. In surveys, seniors overreported contact with general practitioners and physiotherapists or chiropractors, and underreported contact with other medical specialists. Seniors also underreported the number of contacts with general practitioners and other medical specialists. The odds of agreement decreased if respondents were male, aged 75 years and older, had incomes of less than

Rasch analysis of the gross Motor Function Measure: Validating the assumptions of the Rasch model to create an interval-level Measure

25,000, had poor/fair/good self-assessed health status, or had two or more chronic conditions. CONCLUSION The findings of this study indicate that there are substantial discrepancies between self-reported and administrative data among older adults. Researchers seeking to examine health-care use among older adults need to consider these discrepancies in the interpretation of their results. Failure to recognize these discrepancies between survey and administrative data among older adults may lead to the establishment of inappropriate health-care policies.

Should meta-analysts search Embase in addition to Medline?

OBJECTIVES To describe the Rasch analysis of the Gross Motor Function Measure (GMFM-88) and to demonstrate how the assumptions of unidimensionality, sample-free measurement, and test-free measurement were validated to create an interval level measure. DESIGN Cross-sectional and longitudinal (12-mo) data from a prospective study of motor development in children with cerebral palsy (CP) were used for the analysis. SETTING Motor assessments were completed at 18 childrens ambulatory rehabilitation centers in Ontario, Canada, by pediatric physical therapists trained in the use of the GMFM-88. PARTICIPANTS The first 537 of 682 children enrolled into a longitudinal study of motor development in children with CP. Children had a mean age of 6.43+/-2.75 years (range, 11mo-12y) with varying types and severity of CP. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURE The GMFM-88. RESULTS The Rasch analysis, in conjunction with clinical decisions, identified 66 items from the GMFM-88 that formed a unidimensional measure (GMFM-66). Assumptions of sample-free and test-free measurement were confirmed, and a user-friendly scoring program was developed. CONCLUSIONS The GMFM-66 is an interval-level measure of gross motor function for children with CP; it should improve the scoring, interpretation, and overall clinical and research utility over the original GMFM.

Systematic Review: Family History in Risk Assessment for Common Diseases

It is widely accepted that meta-analysts should search multiple databases. The selection of databases is ideally based on the potential contribution of each database to the project or on the potential for bias if a database is excluded, as supported by research evidence. We explore whether searching Embase yields additional trials that influence a meta-analysis. We identified meta-analyses that searched Medline and Embase. A random-effects weighted mean method was used to estimate the intervention effect in articles indexed only in Embase compared with those indexed elsewhere. On average, Embase-unique trials yielded significantly smaller estimates by 29% (ratio of odds ratio [ROR] 0.71, 95% confidence interval [CI] 0.56-0.90) but influenced the pooled estimate by an average of only 6% (ROR 0.94, 95% CI 0.88-0.99). Searching Medline but not Embase risks biasing a meta-analysis by finding studies that show larger estimates, but their prevalence seems low enough that the risk may be slight, provided the rest of the search is comprehensive.

Population attributable risk for functional disability associated with chronic conditions in Canadian older adults

Wilson and associates reviewed evidence about the potential beneficial and harmful effects of routinely collecting family history information in primary care settings. They also reviewed studies th...

A systematic review of studies evaluating diffusion and dissemination of selected cancer control interventions.

OBJECTIVES to investigate the population impact on functional disability of chronic conditions individually and in combination. METHODS data from 9,008 community-dwelling individuals aged 65 and older from the Canadian Study of Health and Aging (CSHA) were used to estimate the population attributable risk (PAR) for chronic conditions after adjusting for confounding variables. Functional disability was measured using activity of daily living (ADL) and instrumental activity of daily living (IADL). RESULTS five chronic conditions (foot problems, arthritis, cognitive impairment, heart problems and vision) made the largest contribution to ADL- and IADL-related functional disabilities. There was variation in magnitude and ranking of population attributable risk (PAR) by age, sex and definition of disability. All chronic conditions taken simultaneously accounted for about 66% of the ADL-related disability and almost 50% of the IADL-related disability. CONCLUSIONS in community-dwelling older adults, foot problems, arthritis, cognitive impairment, heart problems and vision were the major determinants of disability. Attempts to reduce disability burden in older Canadians should target these chronic conditions; however, preventive interventions will be most efficient if they recognize the differences in the drivers of PAR by sex, age group and type of functional disability being targeted.