Mitchell Levine

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

Drug-herb interaction among commonly used conventional medicines: a compendium for health care professionals.

The objective of the review was to consolidate the clinical and pharmacologic aspects of drug–herb interactions to develop a compendium of information to provide prescribers with a measure of the risk of interactions, a description of the clinical consequences, and an assessment of the quality (ie, validity) of evidence. A variety of electronic databases and hand-searched references were used to identify documentation of interactions between herbal products and drugs from the most commonly used therapeutic classes. MEDLINE, Allied and Complementary Medicine Database, CINHAL, HealthSTAR, and EMBASE were searched from 1966 to the present. One hundred sixty-two citations were identified. Only 22 citations met the inclusion criteria. Using a matrix of 165 possible drug–herb interaction pairs (15 therapeutic drug classes by 11 herbal products), we identified 51 (31%) interactions discussed in the literature. Twenty-two of these 51 drug–herb pairs (43%) were supported by randomized clinical trials, case–control studies, cohort studies, case series, or case studies. The remaining interaction pairs reflected theoretic reasoning in the absence of clinical data. Most interactions were pharmacokinetic, with most actually or theoretically affecting the metabolism of the affected product by way of the cytochrome P450 enzymes. In this review, warfarin was the most common drug and St. Johns wort was the most common herbal product reported in drug–herb interactions. To create a comprehensive and valid list of herb-drug interactions would require a substantial increase in research activities in this area. Improvements in the quality of methodology used are also necessary.

A systematic review of the literature examining the diagnostic efficacy of measurement of fractionated plasma free metanephrines in the biochemical diagnosis of pheochromocytoma

BackgroundFractionated plasma metanephrine measurements are commonly used in biochemical testing in search of pheochromocytoma.MethodsWe aimed to critically appraise the diagnostic efficacy of fractionated plasma free metanephrine measurements in detecting pheochromocytoma. Nine electronic databases, meeting abstracts, and the Science Citation Index were searched and supplemented with previously unpublished data. Methodologic and reporting quality was independently assessed by two endocrinologists using a checklist developed by the Standards for Reporting of Diagnostic Studies Accuracy Group and data were independently abstracted.ResultsLimitations in methodologic quality were noted in all studies. In all subjects (including those with genetic predisposition): the sensitivities for detection of pheochromocytoma were 96%–100% (95% CI ranged from 82% to 100%), whereas the specificities were 85%–100% (95% CI ranged from 78% to 100%). Statistical heterogeneity was noted upon pooling positive likelihood ratios when those with predisposition to disease were included (p < 0.001). However, upon pooling the positive or negative likelihood ratios for patients with sporadic pheochromocytoma (n = 191) or those at risk for sporadic pheochromocytoma (n = 718), no statistical heterogeneity was noted (p = 0.4). For sporadic subjects, the pooled positive likelihood ratio was 5.77 (95% CI = 4.90, 6.81) and the pooled negative likelihood ratio was 0.02 (95% CI = 0.01, 0.07).ConclusionNegative plasma fractionated free metanephrine measurements are effective in ruling out pheochromocytoma. However, a positive test result only moderately increases suspicion of disease, particularly when screening for sporadic pheochromocytoma.

Measurement of fractionated plasma metanephrines for exclusion of pheochromocytoma: Can specificity be improved by adjustment for age?

BackgroundBiochemical testing for pheochromocytoma by measurement of fractionated plasma metanephrines is limited by false positive rates of up to 18% in people without known genetic predisposition to the disease. The plasma normetanephrine fraction is responsible for most false positives and plasma normetanephrine increases with age. The objective of this study was to determine if we could improve the specificity of fractionated plasma measurements, by statistically adjusting for age.MethodsAn age-adjusted metanephrine score was derived using logistic regression from 343 subjects (including 33 people with pheochromocytoma) who underwent fractionated plasma metanephrine measurements as part of investigations for suspected pheochromocytoma at Mayo Clinic Rochester (derivation set). The performance of the age-adjusted score was validated in a dataset of 158 subjects (including patients 23 with pheochromocytoma) that underwent measurements of fractionated plasma metanephrines at Mayo Clinic the following year (validation dataset). None of the participants in the validation dataset had known genetic predisposition to pheochromocytoma.ResultsThe sensitivity of the age-adjusted metanephrine score was the same as that of traditional interpretation of fractionated plasma metanephrine measurements, yielding a sensitivity of 100% (23/23, 95% confidence interval [CI] 85.7%, 100%). However, the false positive rate with traditional interpretation of fractionated plasma metanephrine measurements was 16.3% (22/135, 95% CI, 11.0%, 23.4%) and that of the age-adjusted score was significantly lower at 3.0% (4/135, 95% CI, 1.2%, 7.4%) (p < 0.001 using McNemars test).ConclusionAn adjustment for age in the interpretation of results of fractionated plasma metanephrines may significantly decrease false positives when using this test to exclude sporadic pheochromocytoma. Such improvements in false positive rate may result in savings of expenditures related to confirmatory imaging.

Sex differences in hospital admissions from emergency departments in asthmatic adults: a population-based study

BACKGROUND Women represent the majority of adult patients hospitalized for asthma. Analyzing the course of emergency department (ED) visits before hospital admission can help understanding of the mechanisms behind the excess of hospitalizations in women. OBJECTIVE To investigate sex differences in hospital admission rates in adult patients with asthma visiting EDs in Ontario. METHODS Asthmatic patients 18 to 55 years old who visited Ontario EDs between April 1, 2003, and March 31, 2004, were identified using the Canadian Institute for Health Informations National Ambulatory Care Reporting System. The generalized estimating equations for binary outcome were used to model rates of hospital admission with sex, age, and triage (severity) score as covariates. Analysis was further stratified by the ED volume. RESULTS Women represented 62.2% of all ED visits. They were on average older than men, but both groups had similar distributions of triage scores. Female patients accounted for more hospital admissions than male patients (7.4% vs 4.5%). After adjusting for age and triage score, women were more likely to be admitted than men (odds ratio, 1.64; 95% confidence interval, 1.41-1.90). The interaction found between sex and triage level indicates that hospitalized women may have less severe asthma than hospitalized men. Analysis by ED volume did not significantly alter the results. CONCLUSION The higher admission rates in women may be related to sex differences in the subjective perception of dyspnea, management of asthma by ED physician, or inadequate ambulatory care strategies in women and thus merit further investigation.

Cost-utility of Intravenous Immunoglobulin (IVIG) compared with corticosteroids for the treatment of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in Canada.

ObjectivesIntravenous immunoglobulin (IVIG) has demonstrated improvement in chronic inflammatory demyelinating polyneuropathy (CIDP) patients in placebo controlled trials. However, IVIG is also much more expensive than alternative treatments such as corticosteroids. The objective of the paper is to evaluate, from a Canadian perspective, the cost-effectiveness of IVIG compared to corticosteroid treatment of CIDP.MethodsA markov model was used to evaluate the costs and QALYs for IVIG and corticosteroids over 5 years of treatment for CIDP. Patients initially responding to IVIG could remain a responder or relapse every 12 week model cycle. Non-responding IVIG patients were assumed to be switched to corticosteroids. Patients on corticosteroids were at risk of a number of adverse events (fracture, diabetes, glaucoma, cataract, serious infection) in each cycle.ResultsOver the 5 year time horizon, the model estimated the incremental costs and QALYs of IVIG treatment compared to corticosteroid treatment to be

Potential Interactions Between Pharmaceuticals and Natural Health Products in Canada

124,065 and 0.177 respectively. The incremental cost per QALY gained of IVIG was estimated to be

Efficacy of angiotensin II receptor antagonists in preventing headache: a systematic overview and meta-analysis

687,287. The cost per QALY of IVIG was sensitive to the assumptions regarding frequency and dosing of maintenance IVIG.ConclusionsBased on common willingness to pay thresholds, IVIG would not be perceived as a cost effective treatment for CIDP.

Outcomes of Dosage Adjustments Used to Manage Antiretroviral Drug Interactions

This study sought to measure the extent to which potentially interacting combinations of natural health products (NHPs) and drugs are used in the Canadian adult population. Data were obtained from the Statistics Canada 2000–2001 National Population Health Survey. A total of 11 424 adults completed the survey. Of the survey participants, 9.3% reported the use of at least 1 natural health product in the prior 2 days. Among natural health product users, 57% also used a conventional medicine with systemic exposure in the same time period. A minimum of 1 potential drug‐NHP interaction was identified in 28.4% of such combination users. Most interactions (90%) were of unknown clinical significance. Female gender, older age, lower education, and the presence of diabetes and high blood pressure were associated with a higher risk of having at least 1 potential interaction. Health professionals need to maintain a working knowledge of common potential drug‐NHP interactions, to dialogue with all patients regarding the use of natural health products, and to remain vigilant in reporting all suspected interactions and adverse events involving natural health products. Regulatory agencies should also capture and assess reports of drug‐NHP interactions more effectively.

Health-related quality of life in patients with major depression who are treated with moclobemide.

PURPOSE To determine whether angiotensin II receptor antagonists prevent headaches. METHODS We systematically searched MEDLINE, EMBASE, the Cochrane Library, and International Pharmaceutical Abstracts for studies in which participants were randomly assigned to an angiotensin II receptor antagonist or placebo. We also contacted experts and manually reviewed all references to identify additional articles. Two reviewers independently extracted data from the studies. Discrepancies were resolved by discussion. We estimated the pooled relative risk (RR) for headache using the random-effects model and examined dose response using random-effects Bayesian logistic regression. RESULTS Data from 27 studies involving 12,110 patients were included in the meta-analysis. The risk of headache was about one third lower in patients taking an angiotensin II receptor antagonist than in those taking placebo (RR = 0.69; 95% confidence interval [CI]: 0.62 to 0.76; the test of heterogeneity was negative, P = 0.2). The odds ratio for having a headache per unit dose of the reference drug losartan was 0.81 (95% CI: 0.68 to 0.93). CONCLUSION Angiotensin II receptor antagonists appear to be effective in preventing headaches, but the mechanism of this benefit and the types of headaches that are prevented are not known. Randomized trials are warranted.