Lynda Booker

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

Systematic reviews and meta-analyses on treatment of asthma: Critical evaluation

Abstract Objective: To evaluate the clinical, methodological, and reporting aspects of systematic reviews and meta-analyses on the treatment of asthma and to compare those published by the Cochrane Collaboration with those published in paper based journals. Design: Analysis of studies identified from Medline, CINAHL, HealthSTAR, EMBASE, Cochrane Library, personal collections, and reference lists. Studies: Articles describing a systematic review or a meta-analysis of the treatment of asthma that were published as a full report, in any language or format, in a peer reviewed journal or the Cochrane Library. Main outcome measures: General characteristics of studies reviewed and methodological characteristics (sources of articles; language restrictions; format, design, and publication status of studies included; type of data synthesis; and methodological quality). Results: 50 systematic reviews and meta-analyses were included. More than half were published in the past two years. Twelve reviews were published in the Cochrane Library and 38 were published in 22 peer reviewed journals. Forced expiratory volume in one second was the most frequently used outcome, but few reviews evaluated the effect of treatment on costs or patient preferences. Forty reviews were judged to have serious or extensive flaws. All six reviews associated with industry were in this group. Seven of the 10 most rigorous reviews were published in the Cochrane Library. Conclusions: Most reviews published in peer reviewed journals or funded by industry have serious methodological flaws that limit their value to guide decisions. Cochrane reviews are more rigorous and better reported than those published in peer reviewed journals.

Reproducibility of impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) classification: a systematic review

Abstract Background: The classifications of impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) represent glucose levels above normal, but below the decision threshold for diabetes. We sought to determine what the reproducibility of these classifications was when repeat tests were performed by conducting a systematic review of the literature. Methods: All primary studies published in English of any study design were included. Studies were excluded if they did not follow the World Health Organization or American Diabetes Association diagnostic criteria, used whole blood as the specimen type, a glucose meter for analysis, or performed repeat testing greater than 8 weeks apart. Results: Five papers had reproducibility data for IGT or IFG, two of which where from the same population but sampled differently. The κ coefficients, indicating agreement between repeat tests that exceeded chance, indicated poor to fair agreement for IGT (0.04, 0.22, 0.38, 0.42) and moderate agreement for IFG (0.44 and 0.56). Similarly, the observed reproducibility was slightly lower for IGT (33%, 44%, 47%, 48%) compared to IFG (51%, 64%). In two studies for which data were available for both IGT and IFG, the average reproducibility was lower (49%) for the prediabetes group compared to the diabetes group (73%) or the normal group (93%). Conclusions: Poor reproducibility of IGT and IFG classification suggests caution should be exercised when interpreting a single test result. Clin Chem Lab Med 2007;45:1180–5.

The treatment of attention-deficit hyperactivity disorder: an annotated bibliography and critical appraisal of published systematic reviews and metaanalyses.

Context: The Agency for Health Care Policy and Research charged the McMaster Evidence-based Practice Center with conducting a comprehensive systematic review of the literature on the treatment of attention-deficit hyperactivity disorder (ADHD), with input from various groups of stakeholders. One strategy used to avoid duplication of work included a critical appraisal of existing systematic reviews and metaanalyses. Objective: To identify and appraise published metaanalyses and systematic reviews on the treatment of ADHD and to produce an annotated bibliography. Data Sources: Medline, Cumulative Index in Nursing and Allied Health (CINAHL), Healthstar, Psycinfo, and Embase were searched to September 1998; the Cochrane Database (1998 issue 3), selected Internet sites, and the files of investigators were also reviewed. Study Selection: Review articles described as systematic reviews or metaanalyses or including a Methods section were identified independently by 3 reviewers. Data Extraction: Two reviewers extracted, by consensus, relevant information on the name, methodological quality, ADHD-related aspects (comorbid disorders, family characteristics) of those reviews; data on the population, study setting, interventions, and outcomes evaluated by the reviews were also retrieved. Results: Thirteen reviews, published from 1982 to 1998, were included. Eight included metaanalysis and 5 a qualitative review. Non-pharmacological treatments were mentioned in 6 reviews and combination therapies in 3. One review focused on the treatment of adults. Forty-seven drugs and 20 adverse effects were mentioned. Most reviews had major methodological flaws. Conclusions: Most published systematic reviews and metaanalyses on the treatment of ADHD have limited value for guiding clinical, policy, and research decisions. A rigorous, systematic review following established methodological criteria is warranted.

Attention-deficit hyperactivity disorder: Critical appraisal of extended treatment studies

We undertook a systematic review of the literature on the long-term treatment of attention-deficit hyperactivity disorder (ADHD). We used systematic strategies to identify randomized treatment studies in which treatment was administered for 12 weeks or more. We included 14 studies involving 1379 subjects. Because of the limited number of high-quality studies and the heterogeneity of outcome measures, we did not perform metaanalysis. We rated 5 studies as adequate for methodological quality. Five studies followed children for more than 26 weeks. Pharmacologic interventions were studied more frequently than non-pharmacologic ones. Six studies permitted evaluation of the effects of combined drug and behavioural intervention. Twenty-five different outcomes were measured using 26 different tests. Stimulant medication appears to reduce ADHD (7 studies), dysfunctional social behaviour (6 studies), and internalizing symptoms (2 studies). Available studies provide little evidence for improved academic performance with stimulants (3 studies). Medications other than stimulants have not been studied extensively (3 studies). Only 1 study showed that combination therapy adds to the effects of medication. Rigorous treatment research among representative samples of ADHD individuals is needed.

Utility of monitoring mycophenolic acid in solid organ transplant patients.

OBJECTIVES To investigate whether monitoring concentrations of mycophenolic acid (MPA) in the serum or plasma of persons who receive a solid organ transplant will result in a lower incidence of transplant rejections and adverse events versus no monitoring of MPA. To investigate whether the incidence of rejection or adverse events differs according to MPA dose or frequency, type of MPA, the form of MPA monitored, the method of MPA monitoring, or sample characteristics. To assess whether monitoring is cost-effective versus no monitoring. DATA SOURCES The following databases were searched from their dates of inception (in brackets) until October 2007: MEDLINE (1966); BIOSIS Previews (1976); EMBASE (1980); Cochrane Database of Systematic Reviews (1995); and Cochrane Central Register of Controlled Trials (1995). REVIEW METHODS Studies identified from the data sources went through two levels of screening (i.e., title and abstract, full text) and the ones that passed were abstracted. Criteria for abstraction included publication in the English language, study design (i.e., randomized controlled trial [RCT], observational study with comparison group, case series), and patient receipt of allograft solid organ transplant. Additionally, any form of MPA had to be measured at least once in the plasma or serum using any method of measurement (e.g., AUC0-12, C0). Furthermore, these measures had to be linked to a health outcome (e.g., transplant rejection). Certain biomarkers (e.g., serum creatinine, glomular filtration rate) and all adverse events were also considered health outcomes. RESULTS The published evidence on MPA monitoring is inconclusive. Direct, head-to-head comparison of monitoring versus no monitoring is limited to one RCT in adult, kidney transplant patients. Inferences about monitoring can be made from some observational studies, although the evidence is equivocal for MPA dose and dose frequency, nonexistent for type of MPA, inconclusive for form of MPA monitored or method of monitoring, and nonexistent for cost-effectiveness. Some studies suggest gender and concomitant use of calcineurin inhibitors will affect pharmacokinetic parameters, but the impact of these findings has not been assessed in relation to monitoring versus no monitoring. CONCLUSIONS The state of knowledge about therapeutic drug monitoring of MPA in solid organ transplants is still in its infancy. Until there is more evidence on the utility of routine MPA monitoring in solid organ transplant recipients, patients, clinicians, and other stakeholders (e.g., public and private insurers) will have to decide on a case by case basis whether the possible but uncertain benefits are worth the extra time and expense of monitoring.

Inhibition of DNA synthesis by cytosine arabinoside: Relation to response of acute non-lymphocytic leukemia to remission induction therapy and to stage of the disease

The sensitivity of leukemic marrow cell DNA synthesis to cytosine arabinoside (araC) exposure in vitro was studied in specimens obtained from patients with acute non-lymphocytic leukemia. Cells from patients who had been treated with araC in the past were more likely to be resistant to the effect of araC on DNA synthesis than cells obtained from patients who had not been so-treated previously. Resistance to the effects of araC on DNA synthesis was associated with the failure of high-dose araC therapy to induce remissions in relapsed patients, whereas remission induction failure in previously untreated patients was not associated with araC resistance.

Differential calcium leucovorin protection of human lymphoid cell lines from methotrexate

SummaryHuman lymphoid cell lines were studied for leucovorin requirements to protect from methotrexate (MTX)-induced growth suppression. Over a 72h continuous exposure leucovorin provided better protection to the cell lines LAZ-007 and RAJI than to the cell lines CCRF-CEM and MOLT-4. The lower leucovorin requirement for LAZ-007 protection versus CCRF-CEM was also seen over a 3h exposure period in which leucovorin protection was assessed by measuring its effect on MTX-induced suppression of 3H-deoxyuridine incorporation into acid-precipitable material. Growth experiments with addition of hypoxanthine or thymidine did not abolish differential protection, suggesting that the phenomenon is not related to selective differences in the tolerance of these cells to an MTX-induced purineless or thymineless state. Preloading of cells with calcium leucovorin caused an identical shift of the CCRF-CEM and LAZ-007 MTX dose-response curves, suggesting that differential catabolism of leucovorin does not contribute to differential protection. The same degree of differential protection was observed for 5-methyltetrahydrofolate as for leucovorin, suggesting that differences in the metabolism of leucovorin do not contribute to differential protection. To elucidate the mechanism of differential protection the influence of leucovorin on [3H]MTX transport and polyglutamylation were studied. Although the Km(MTX) influx and the Ki(leucovorin) for MTX uptake were lower in CCRF-CEM compared with LAZ-007 cells, the size of the difference does not seem adequate to explain differential protection. The extent of MTX polyglutamylation in CCRF-CEM and LAZ-007 cells was identical and the influence of leucovorin on MTX polyglutamylation was the same in both cell lines.

Comparison of leucovorin protection from variety of antifolates in human lymphoid cell lines

SummaryLeucovorin requirements for protection of the T cell line CCRF-CEM and the B cell line LAZ-007 against the cytotoxic effects of a variety of antifolates were studied. Differential leucovorin protection for DDMP-induced growth suppression occurred in the opposite direction to that for MTX, with CCRF-CEM requiring less leucovorin than LAZ-007 for equivalent protection. A pattern of differential protection from DDMP different from that of protection from MTX was also seen for the cell lines RAJI and MOLT-4. Differential leucovorin protection was observed for the chain-extended MTX analogue PT441. The degree of differential protection was similar to that seen for MTX, and transport studies showed that PT441 was a weak inhibitor of tritiated MTX uptake into CCRF-CEM cells. Differential leucovorin protection was observed for the lipophilic antifolate trimetrexate glucoronate (TMQ) but the degree of differential protection was smaller than that seen for PT441 or for MTX. Since TMQ is not transported into cells by the reduced folate system, while PT441 is a weak competitive inhibitor of [3H]MTX transport, and since neither is polyglutamylated, these results support the conclusion reached in previous experiments that differential leucovorin protection of MTX is unlikely to be a transport-related phenomenon and is not due to an effect on polyglutamylation. In addition, the different patterns of relative leucovorin requirements for DDMP and MTX protection suggest that differential metabolism or catabolism of leucovorin does not account for differential protection.