Afisi Ismaila

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

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

OBJECTIVEnThis 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.nnnSTUDY DESIGN AND SETTINGnWe 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.nnnRESULTSnWe 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.nnnCONCLUSIONnQuantitative 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.

AHRQ Series Paper 4: Assessing harms when comparing medical interventions: AHRQ and the Effective Health-Care Program

Comparative effectiveness reviews (CERs) are systematic reviews that evaluate evidence on alternative interventions to help clinicians, policy makers, and patients make informed treatment choices. Reviews should assess harms and benefits to provide balanced assessments of alternative interventions. Identifying important harms of treatment and quantifying the magnitude of any risks require CER authors to consider a broad range of data sources, including randomized controlled trials (RCTs) and observational studies. This may require evaluation of unpublished data in addition to published reports. Appropriate synthesis of harms data must also consider issues related to evaluation of rare or uncommon events, assessments of equivalence or noninferiority, and use of indirect comparisons. This article presents guidance for evaluating harms when conducting and reporting CERs. We include suggestions for prioritizing harms to be evaluated, use of terminology related to reporting of harms, selection of sources of evidence on harms, assessment of risk of bias (quality) of harms reporting, synthesis of evidence on harms, and reporting of evidence on harms.

Screening for hypoglycemia at the bedside in the neonatal intensive care unit (NICU) with the Abbott PCx glucose meter

BackgroundPoint of care (POC) glucose meters are routinely used as a screening tool for hypoglycemia in a neonatal setting. Glucose meters however, lack the same accuracy as laboratory instruments for glucose measurement. In this study we investigated potential reasons for this inaccuracy and established a cut off value for confirmatory testing.MethodsIn this prospective study, all patients in the neonatal intensive care unit who had a plasma glucose test ordered were eligible to participate. Demographic information, sample collection information (nine variables) and a recent hematocrit value were recorded for each sample. Glucose measurements were taken at the bedside on the glucose meter (RN PCx) as well as in the laboratory on both the glucose meter (LAB PCx) and the laboratory analyzer (PG). Data were analyzed by simple and mixed-effects regression analysis and by analysis of a receiver operator characteristics (ROC) curve.ResultsThere were 475 samples analyzed from 132 patients. RN PCx values were higher than PG values (mean = 4.9%), while LAB PCx results were lower (mean = -5.2%) than PG values. Only 31% of the difference between RN PCx – PG and 46% of the difference for LAB PCx – PG could be accounted for by the variables tested. The largest proportion of variance between PCx and PG measurements was explained by hematocrit (about 30%) with a greater effect seen at glucose concentrations ≤4.0 mmol/L (≤72 mg/dL)(48% and 40% for RN PCx and LAB PCx, respectively). The ROC analysis showed that for detection of all cases of hypoglycemia (PG < 2.6 mmol/L)(PG < 47 mg/dL) the PCx screening cut off value would need to be set at 3.8 mmol/L (68 mg/dL) requiring 20% of all samples to have confirmatory analysis by the laboratory method.ConclusionThe large difference between glucose results obtained by PCx glucose meter compared to the laboratory analyzer can be explained in part by hematocrit and low glucose concentration. These results emphasize that the glucose meter is useful only as a screening device for neonatal hypoglycemia and that a screening cut off value must be established.

Health and economic impact of PHiD-CV in Canada and the UK: a Markov modelling exercise

Abstract Objective: The spectrum of diseases caused by Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) represents a large burden on healthcare systems around the world. Meningitis, bacteraemia, community-acquired pneumonia (CAP), and acute otitis media (AOM) are vaccine-preventable infectious diseases that can have severe consequences. The health economic model presented here is intended to estimate the clinical and economic impact of vaccinating birth cohorts in Canada and the UK with the 10-valent, pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) compared with the newly licensed 13-valent pneumococcal conjugate vaccine (PCV-13). Methods: The model described herein is a Markov cohort model built to simulate the epidemiological burden of pneumococcal- and NTHi-related diseases within birth cohorts in the UK and Canada. Base-case assumptions include estimates of vaccine efficacy and NTHi infection rates that are based on published literature. Results: The model predicts that the two vaccines will provide a broadly similar impact on all-cause invasive disease and CAP under base-case assumptions. However, PHiD-CV is expected to provide a substantially greater reduction in AOM compared with PCV-13, offering additional savings of Canadian

Cost-effectiveness evaluation of quadrivalent influenza vaccines for seasonal influenza prevention: a dynamic modeling study of Canada and the United Kingdom

9.0 million and £4.9 million in discounted direct medical costs in Canada and the UK, respectively. Limitations: The main limitations of the study are the difficulties in modelling indirect vaccine effects (herd effect and serotype replacement), the absence of PHiD-CV- and PCV-13-specific efficacy data and a lack of comprehensive NTHi surveillance data. Additional limitations relate to the fact that the transmission dynamics of pneumococcal serotypes have not been modelled, nor has antibiotic resistance been accounted for in this paper. Conclusion: This cost-effectiveness analysis suggests that, in Canada and the UK, PHiD-CV’s potential to protect against NTHi infections could provide a greater impact on overall disease burden than the additional serotypes contained in PCV-13.

Statistical issues in the design and analysis of expertise‐based randomized clinical trials

BackgroundThe adoption of quadrivalent influenza vaccine (QIV) to replace trivalent influenza vaccine (TIV) in immunization programs is growing worldwide, thus helping to address the problem of influenza B lineage mismatch. However, the price per dose of QIV is higher than that of TIV. In such circumstances, cost-effectiveness analyses provide important and relevant information to inform national health recommendations and implementation decisions. This analysis assessed potential vaccine impacts and cost-effectiveness of a country-wide switch from TIV to QIV, in Canada and the UK, from a third-party payer perspective.MethodsAn age-stratified, dynamic four-strain transmission model which incorporates strain interaction, transmission-rate seasonality and age-specific mixing in the population was used. Model input data were obtained from published literature and online databases. In Canada, we evaluated a switch from TIV to QIV in the entire population. For the UK, we considered two strategies: Children aged 2–17 years who receive the live-attenuated influenza vaccine (LAIV) switch to the quadrivalent formulation (QLAIV), while individuals agedu2009>u200918xa0years switch from TIV to QIV. Two different vaccination uptake scenarios in children (UK1 and UK2, which differ in the vaccine uptake level) were considered. Health and cost outcomes for both vaccination strategies, and the cost-effectiveness of switching from TIV/LAIV to QIV/QLAIV, were estimated from the payer perspective. For Canada and the UK, cost and outcomes were discounted using 5xa0% and 3.5xa0% per year, respectively.ResultsOverall, in an average influenza season, our model predicts that a nationwide switch from TIV to QIV would prevent 4.6xa0% influenza cases, 4.9xa0% general practitioner (GP) visits, 5.7xa0% each of emergency room (ER) visits and hospitalizations, and 6.8xa0% deaths in Canada. In the UK (UK1/UK2), implementing QIV would prevent 1.4xa0%/1.8xa0% of influenza cases, 1.6xa0%/2.0xa0% each of GP and ER visits, 1.5xa0%/1.9xa0% of hospitalizations and 4.3xa0%/4.9xa0% of deaths. Discounted incremental cost-utility ratios of

Brain type carnosinase in dementia: a pilot study

7,961 and £7,989/£7,234 per quality-adjusted life-year (QALY) gained are estimated for Canada and the UK (UK1/UK2), both of which are well within their respective cost-effectiveness threshold values.ConclusionsSwitching from TIV to QIV is expected to be a cost-effective strategy to further reduce the burden of influenza in both countries.

Comparison of Bayesian and frequentist approaches in modelling risk of preterm birth near the Sydney Tar Ponds, Nova Scotia, Canada

In order to avoid certain difficulties with the conventional randomized clinical trial design, the expertise-based design has been proposed as an alternative. In the expertise-based design, patients are randomized to clinicians (e.g. surgeons), who then treat all their patients with their preferred intervention. This design recognizes individual clinical preferences and so may reduce the rates of procedural crossovers compared with the conventional design. It may also facilitate recruitment of clinicians, because they are always allowed to deliver their therapy of choice, a feature that may also be attractive to patients.The expertise-based design avoids the possibility of so-called differential expertise bias. If a standard treatment is generally more familiar to clinicians than a new experimental treatment, then in the conventional design, more patients randomized to the standard treatment will have an expert clinician, compared with patients randomized to the experimental treatment. If expertise affects the study outcome, then a biased comparison of the treatment groups will occur.We examined the relative efficiency of estimating the treatment effect in the expertise-based and conventional designs. We recognize that expected patient outcomes may be better in the expertise-based design, which in turn may modify the estimated treatment effect. In particular, a larger treatment effect in the expertise-based design can sometimes offset a higher standard error arising from the confounding of clinician effects with treatments.These concepts are illustrated with data taken from a randomized trial of two alternative surgical techniques for tibial fractures.

Ratings of counterproductive performance: the effect of source and rater behavior

BackgroundThe pathological processes underlying dementia are poorly understood and so are the markers which identify them. Carnosinase is a dipeptidase found almost exclusively in brain and serum. Carnosinase and its substrate carnosine have been linked to neuropathophysiological processes.MethodsCarnosinase activity was measured by a flourometric method in 37 patients attending a Geriatric Outpatient Clinic. There were 17 patients without dementia, 13 had Alzheimers disease (AD) and 7 had mixed dementia (MD).ResultsThe range of serum carnosinase activity for patients without dementia was 14.5 – 78.5 μmol/ml/h. There was no difference in carnosinase activity between patients without dementia (40.3 ± 15.2 μmol/ml/h) and patients with AD (44.4 ± 12.4 μmol/ml/h) or MD (26.6 ± 15 μmol/ml/h). However, levels in the MD group were significantly lower than the AD group (p = 0.01). This difference remained significant after adjusting for gender, MMSE score, exercise, but not age, one at a time and all combined. The effect of other medical conditions did not remove the significance between the AD and MD groups. The MD group, but not the AD group, demonstrated a significant trend with carnosinase activity decreasing with duration of disease (from first recorded date of diagnosis to date of blood collection) (r = -0.76, p = 0.049). There was no association with carnosinase activity and MMSE score in the AD or MD group. Both AD and MD patients on any dementia medication (donepezil, galantamine, memantine) had higher carnosinase activity compared to those not taking a dementia medication. Carnosinase activity was higher in patients who regularly exercised (n = 20) compared to those who did not exercise regularly (n = 17)(p = 0.006).ConclusionThis exploratory study has shown altered activities of the enzyme carnosinase in patients with dementia.