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Question 2: Does Pharmacotherapy Delay Cognitive Deterioration or Delay Disease Onset of Dementia Syndromes?
Delay of Onset of Dementia
The concept of "delay onset" was operationalized to imply conversion from a state of cognitive impairment, classified as MCI, CLoND or CIND, to a true dementia state. No studies with this population met the final eligibility criteria, although four trials109-112 advanced to the full text screening stage. The lack of studies eligible for evaluation in this systematic review points to a gap in the literature for pharmacological interventions (attempting to demonstrate a delay in disease onset) in MCI-type populations.
Delay of Progression of Dementia
The need for good evaluation of disease progression in trials was also identified. In general, few studies evaluated subjects in more severe states of the disease. This suggests that a bias exists towards evaluating mild to moderate disease in the trials eligible in this systematic review; this may reflect an underlying assumption that the less severe groups are most likely to benefit from drug trials. Since so few studies have evaluated the more severe groups, this assumption may require some empirical justification in future research. A consensus is required regarding the diagnostic criteria to be used to establish levels of severity.
Three studies evaluating cerebrolysin, selegiline and vitamin E, and donepezil have shown statistically significant effects in delaying disease progress in mild to moderate and moderately severe disease in patients with AD. This delay in progress was expressed in terms of delay in days to primary event or statistical differences between placebo at a specified time interval. Although these trials coincidentally evaluated dementia patients over the longest time interval, their protocol did not withdraw the drug at the end of the study. Theoretically, conclusive evidence of disease delay would be demonstrated if the treatment groups did not return to the level of the placebo. Thus, distinguishing between symptomatic and disease modifying effects is not possible unless the drug is withdrawn and the treatment groups are observed for these changes.
When studies attempted to evaluate disease progression, long-term (1 year or greater) trials continued in an "open-label fashion," where blinding was no longer maintained. This limits the confidence that bias did not affect the subsequent changes in the outcomes. It was observed that increasing levels of dropout (for a variety of reasons) also plagued these open-label phases of evaluation. From a practical perspective, maintaining adherence in longer-term trials in dementia patients is challenging, particularly for those in the placebo arm or for those with interventions that have a high proportion of adverse events. Although this practical challenge exists, the findings of this review suggest that there is a gap in the literature showing delay of the disease process of dementia related disorders.
Question 3: Are Certain Drugs, Including Alternative Medicines (Non-pharmaceutical) More Effective Than Others?
Head-to-head Comparisons of Drugs in the Treatment of Dementia
A total of 2618,39,47,60,61,65,66,68,69,73,113-128 studies compared efficacy of the two or more pharmacological agents relative to each other. In general, few drugs showed statistically significant differences relative to each other. Those that did include (listed in declining order of performance):
- Sulphomucopolysaccharides versus CDP-choline:117 Statistically significant differences were seen in favor of sulphomucopolysaccharides in measures of behavior and global assessment in 30 institutionalized patients with mild to moderate MID.
- Donepezil and vitamin E:18 Statistically significant differences were seen in favor of donepezil in general cognitive function 54 patients with mild AD.
- Antagonic stress versus nicergoline:39 Statistically significant differences were seen in favor of antagonic stress in cognition as well as a global assessments in 62 subjects with mild to moderate AD.
- Antagonic stress versus meclofenate:124 Statistically significant differences were seen in favor of antagonic stress in measures of cognition and global assessment in 63 patients with mild to moderate AD.
- Posatirelin versus citicoline:47 Statistically significant differences were seen in favor of posatirelin in general cognitive measure and mood in 222 community living patients with mild to moderate AD.
- Pyritinol versus hydergine:125 A significant difference in favor of pyritinol in a global assessment measure in 102 Hispanic patients with mild to moderate AD.
- Idebenone61 versus tacrine: Mixed results were observed; the Efficacy Index Score showing a statistically significant benefit over tacrine, while the global assessment showed no difference in 203 individuals with AD, 44 of whom completed the study.
Current Drugs Approved in the United States for the Treatment of Dementia
What may be most relevant to clinicians are head to head comparison of the cholinergic modifying neurotransmitter pharmacological agents, particularly those currently approved for the treatment of dementia (tacrine, rivastigmine, galantamine, donepezil) in the United States. The evidence for each of these drugs has been extensively detailed, and the relative merits and handicaps of each are outlined in the results section of the full report (Chapter 3). Relative effectiveness as demonstrated by effect sizes for the ADAS-cog and the CIBIC are also compared in Chapter 3. Although the psychometric properties of these two outcomes are commonly accepted, comparison across the populations in these pooled estimates may not lend themselves to direct comparison across these four different specific drugs; populations may be different and reporting of adverse events is not consistent. Inferences about the relative efficacy of these four medications specific for the treatment of dementia should be made cautiously as head to head comparisons were not undertaken.
Question 4: Do Certain Patient Populations Benefit More from Pharmacotherapy Than Others?
In general, very few trials examined the efficacy of dementia drugs across different populations or described the population characteristics in sufficient detail. From the 15 studies 2,3,8,10-12,23-24,61,84,93,129-132 that reported stratified analyses, eight different variables were identified, which included age, gender, Apolipoprotein E gene (APOE) genotype, disease type, disease severity (as determined by MMSE/ ADAS-cog threshold levels), treatment center, care dependence, and presence of depression. Additionally, three trials were identified that evaluated efficacy in:
- Patients with Down's syndrome and dementia.
- Different races as a function of treatment center of a multicenter trial.
- Depressed patients.
Given the relatively small number of trials evaluating these variables within different populations and different pharmacological interventions, the findings of this review are inconclusive with respect to these variables. A significant gap in the literature has been identified.
Question 5: What Is the Evidence-base for the Treatment of Ischemic Vascular Dementia?
A total of 20 pharmacological interventions in 29 studies 17,36,38,44,46,70-72,81,92,96,98,102-104,106-107,117,126,128,133-141 were applied specifically to VaD classified dementias. The majority of these pharmacological interventions (n=14) were represented by single trials, limiting the ability to judge the evidence; these interventions included:
- Sulphomucopolysaccharides (CDP choline).
- Ginkgo biloba.
- 5-THF (trazodone).
Six interventions had more than a single trial, and these included:
- Choto-san (n=2).
- Memantine (n=3).
- Nicergoline (n=2).
- Pentoxifylline (n=4).
- Posatirelin (n=2).
- Propentofylline (n=2).
In general, when the drug interventions were shown to be effective, it was in the domains of cognitive function (both general and specific) and global assessment. Other domains were less frequently evaluated. Several trials attempted to test for differences between VaD groups and other dementia types.
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The findings of this report suggest several important areas for future research using pharmacological treatments for dementia and these include:
Analytic Framework of the Intended Aim of the Therapy on the Disease
- Better conceptualization and research design to capture "delay in progression."
- Clearer consensus on defining efficacy (benefits and clinically important change).
- Longer term studies (> 12 months).
Potential for Bias
- Clarification of the role of industry sponsorship; one recommendation should be that all studies are required to disclose such information in future, including who analyzed the results.
- More concerted effort to incorporate unpublished studies and negative trials in future reviews.
- Inclusion of the spectrum of severity in the patient populations (nothing to suggest that severe patients may not benefit from pharmacotherapy aimed at cognitive function improvement).
- The need for validation of trials and testing processes within cultures other than the traditional white population.
- Examining the efficacy of interventions in different sub-populations (age, disease severity levels, etc.).
- Better measurement and reporting of important patient characteristics (including baseline cognition scores, co-morbid conditions, the use of other medications, etc.).
- Inclusion of MCI type groups of subjects to evaluate "delay of onset" (studies in progress).
- Expansion of outcomes collected to include more than just cognitive function, and especially include caregiver burden and quality of life/ADL.
- Clear operational definitions for determining critical outcomes (delay to onset, delay to progression, important effect size, etc.).
- Understanding of how therapies are addressed and what outcomes are produced in different cultures.
- Production of other testing tools to detect both onset and responses to therapies across varied cultural groups.
- Improvement in the reporting of adverse events to evaluate harm and risk vs. benefit.
- Improvement in detailing adverse events associated with the duration period and those occurring following this period.
- Appropriate analytical strategies that take into account intention to treat (ITT)/last observation carried forward (LOCF) analyses; where possible both observed case and ITT/LOCF analyses should be presented.
- Sufficient data to estimate effect size, taking into account variability in both treated and control populations on the primary measures.
- Reporting the power of the study when findings are statistically non-significant.
- Undertake more studies with direct comparison of drugs to determine the relative efficacy of agents.
- Improved description of the titration process.
- Improved collection of adverse events undertaken in a systematic fashion with standardized instruments.
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Availability of Full Report
The full evidence report from which this summary was taken was prepared for the Agency for Healthcare Research and Quality (AHRQ) by mcmacepc.htm">McMaster University Evidence-based Practice Center under Contract No. 290-02-0020. It is expected to be available in April 2004. At that time, printed copies may be obtained free of charge from the AHRQ Publications Clearinghouse by calling 800-358-9295. Requesters should ask for Evidence Report/Technology Assessment No. 97, Pharmacological Treatment of Dementia.
The Evidence Report is also online on the National Library of Medicine Bookshelf, or can be downloaded as a PDF File (PDF File, 13 MB). Plugin Software Help.
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AHRQ Publication Number 04-E018-1
Current as of April 2004