Benefits and Harms of Prescription Drugs and Supplements for Treatment of Clinical Alzheimer-Type Dementia: A Systematic Review and Meta-analysisFREE
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Abstract
Background:
Effects of drug treatment of clinical Alzheimer-type dementia (CATD) are uncertain.
Purpose:
To summarize evidence on the effects of prescription drugs and supplements for CATD treatment.
Data Sources:
Electronic bibliographic databases (inception to November 2019), ClinicalTrials.gov (to November 2019), and systematic review bibliographies.
Study Selection:
English-language trials of prescription drug and supplement treatment in older adults with CATD that report cognition, function, global measures, behavioral and psychological symptoms of dementia (BPSD), or harms. Minimum treatment was 24 weeks (≥2 weeks for selected BPSD).
Data Extraction:
Studies with low or medium risk of bias (ROB) were analyzed. Two reviewers rated ROB. One reviewer extracted data; another verified extraction accuracy.
Data Synthesis:
Fifty-five studies reporting non-BPSD outcomes (most ≤26 weeks) and 12 reporting BPSD (most ≤12 weeks) were analyzed. Across CATD severity, mostly low-strength evidence suggested that, compared with placebo, cholinesterase inhibitors produced small average improvements in cognition (median standardized mean difference [SMD], 0.30 [range, 0.24 to 0.52]), no difference to small improvement in function (median SMD, 0.19 [range, −0.10 to 0.22]), no difference in the likelihood of at least moderate improvement in global clinical impression (median absolute risk difference, 4% [range, 2% to 4%]), and increased withdrawals due to adverse events. In adults with moderate to severe CATD receiving cholinesterase inhibitors, low- to insufficient-strength evidence suggested that, compared with placebo, add-on memantine inconsistently improved cognition and improved global clinical impression but not function. Evidence was mostly insufficient about prescription drugs for BPSD and about supplements for all outcomes.
Limitation:
Most drugs had few trials without high ROB, especially for supplements, active drug comparisons, BPSD, and longer trials.
Conclusion:
Cholinesterase inhibitors and memantine slightly reduced short-term cognitive decline, and cholinesterase inhibitors slightly reduced reported functional decline, but differences versus placebo were of uncertain clinical importance. Evidence was mostly insufficient on drug treatment of BPSD and on supplements for all outcomes.
Primary Funding Source:
Agency for Healthcare Research and Quality. (PROSPERO: CRD42018117897)
Dementia, a clinical syndrome in which acquired cognitive deficits interfere with independence in daily activities (1), affects about 10% of older U.S. adults (2, 3). In most persons, Alzheimer disease (AD) is the primary cause of dementia. Clinical Alzheimer-type dementia (CATD) impairs cognition and function, lowers quality of life, burdens caregivers, and increases institutionalization (4). Behavioral and psychological symptoms of dementia (BPSD) (such as agitation and psychosis) are common in advanced CATD (5).
A 2008 evidence synthesis (6) and a guideline from the American Academy of Family Physicians (AAFP) and American College of Physicians (7) concluded that cholinesterase inhibitors and memantine improve cognition versus placebo. However, the authors further concluded that the average magnitude of effect was not clinically important and that evidence was limited about whether these drugs increase the likelihood of clinically important improvements in cognition or function. The review did not address prescription drugs for treatment of CATD-associated BPSD or the effects of supplements in CATD. However, off-label use of prescription drugs for BPSD is common, and many supplements are promoted for CATD treatment, including for BPSD, despite uncertainty about their benefits and harms (8–13). In addition, CATD-associated BPSD is a common qualifying condition for state medical marijuana programs (14), although effects of cannabinoids in CATD are also unclear.
To address uncertainties regarding CATD drug treatment and provide an updated evidence base for a new AAFP guideline on CATD management, this systematic review examined 2 questions. First, what are the effects of prescription drugs and supplements for treatment of patients with CATD, including those with BPSD? Second, do treatment effects of CATD drugs vary by patient or drug characteristics?
Methods
We developed and followed a standard protocol that is registered in PROSPERO (CRD42018117897) and available at https://effectivehealthcare.ahrq.gov/topics/alzheimers-type-dementia/protocol. The full technical report contains search strategies, flow diagrams, evidence tables, study quality assessment tables, and detailed results (https://effectivehealthcare.ahrq.gov/products/alzheimers-type-dementia/research).
Data Sources and Searches
We searched MEDLINE, the Cochrane Library, EMBASE, and PsycINFO from inception to November 2019 using search terms for AD or dementia. We searched ClinicalTrials.gov to November 2019 and bibliographies of relevant systematic reviews published since 2013 for additional studies.
Study Selection
We included English-language trials of adults with CATD that compared drug treatment versus placebo, inactive control, or active treatment (drug or nondrug) and reported efficacy or harms. Studies were excluded if participants had dementia attributed solely to a non-AD cause. Cholinesterase inhibitors, memantine, and all supplements were eligible drugs for assessment of non-BPSD efficacy outcomes (cognition, function, global measures of clinical impression, CATD stage, level of independence, and quality of life). Cholinesterase inhibitors; memantine; antipsychotic, antidepressant, anxiolytic, and antiseizure drugs; hormones; supplements; and cannabinoids were eligible drugs for assessment of BPSD efficacy outcomes (patient aggression, agitation, psychosis, disinhibited sexual behavior, general behavior, depression, anxiety, and quality of life, and caregiver depression, distress, burden, and quality of life). All of these drugs were eligible for assessment of the following harms: serious adverse events, withdrawals due to adverse events, somnolence, confusion, falls, extrapyramidal symptoms, stroke, and mortality. Caregiver efficacy and BPSD were evaluated only in participants with both CATD and BPSD at baseline. Minimum study duration was 2 weeks for agitation, aggression, psychosis, and disinhibited sexual behavior and 24 weeks for all other BPSD and non-BPSD efficacy outcomes.
Studies considered possibly eligible by at least 1 of 2 independent reviewers (among P.J.D., M.A.M., P.C.S., M. Brasure, R.M., V.A.N., and M. Butler) after title and abstract review were forwarded for full-text screening. Two reviewers (among P.J.D., M.A.M., P.C.S., M.L.F., M. Brasure, M. Butler, V.A.N., and R.M.) independently screened full-text articles and resolved discrepancies in eligibility decisions by consensus.
Data Extraction and Quality Assessment
For each eligible study, 2 reviewers (among E.J.L., P.J.D., P.C.S., M.L.F., W.N., M. Brasure, M. Butler, K.M.S., K.M.C.T., V.A.N., and R.M.) rated risk of bias (ROB) as low, medium, or high on the basis of guidance from the Agency for Healthcare Research and Quality (AHRQ) (selection, attrition, performance, detection, and reporting bias) (15). High-ROB studies were excluded from further analyses. For studies with low or medium ROB, 1 reviewer (E.J.L., P.J.D., P.C.S., M.L.F., K.M.S., R.M., V.A.N., or M. Brasure) extracted details on study design, inclusion criteria, participant characteristics, drug treatment and control interventions, treatment duration, and efficacy and harms outcomes. A second reviewer (E.J.L., P.C.S., W.N., M. Butler, K.M.C.T., R.M., V.A.N., or M. Brasure) verified extraction accuracy. For each treatment comparison and outcome of interest that was evaluated by at least 2 studies with low or medium ROB or 1 study with low or medium ROB and at least 100 participants, 2 reviewers (among E.J.L., P.J.D., P.C.S., M.L.F., W.N., M. Butler, K.M.S., K.M.C.T., R.M., V.A.N., and M. Brasure) graded strength of evidence (SOE) as insufficient, low, moderate, or high on the basis of study limitations, directness, consistency, and precision (16). When there was only 1 study with low or medium ROB and fewer than 100 participants, SOE was considered insufficient. We confirmed ROB and SOE assessments by consensus.
Data Synthesis and Analysis
For individual studies with low or medium ROB, we used Comprehensive Meta-Analysis, version 3 (Biostat), to calculate standardized mean differences (SMDs) with corresponding 95% CIs for continuous outcomes and risk ratios or Peto odds ratios (the latter for mortality, given few events) with corresponding 95% CIs for binary outcomes.
When data were appropriate for pooling (that is, minimal clinical heterogeneity of participants, interventions, and outcomes), we synthesized data in R (R Foundation) (17, 18). We applied the Hartung–Knapp–Sidik–Jonkman method for random-effects models to calculate SMD for continuous outcomes and relative measures of effect for categorical outcomes with corresponding 95% CIs (19). However, when there were fewer than 5 trials and no between-study variance (τ2 at or near 0), data were meta-analyzed with a fixed-effects model (20). When a treatment group had no events, we used the treatment group continuity correction. For continuous outcomes, we followed existing conventions (21) to characterize SMDs as small (≥0.2 to <0.5), medium (≥0.5 to <0.8), or large (≥0.8). Absolute risk differences (ARDs) were calculated for binary outcomes.
We measured the magnitude of statistical heterogeneity with the I 2 statistic (22). When results suggested substantial heterogeneity (that is, I 2 ≥ 75%) (22), we stratified results by participant or study characteristics or explored sensitivity analyses. When data allowed, we evaluated whether treatment outcomes varied by participant age, sex, race/ethnicity, living setting, prevalence of depression, cognition, function, or study-defined severity of CATD or BPSD, or by drug dose, delivery route, or treatment duration.
Role of the Funding Source
This review was funded by AHRQ. The AAFP, AHRQ staff, and a key informant panel helped refine the project scope. The draft report was reviewed by a technical expert panel, peer and public reviewers, and AHRQ staff. The authors are solely responsible for the content of this article.
Results
We identified 6550 publications from electronic bibliographic databases and hand-searching, of which 66 unique studies met eligibility criteria, had low or medium ROB, and were analyzed (Appendix Figure 1). Only 8 of these trials reported efficacy outcomes beyond 26 weeks (23–30), and just 2 reported BPSD efficacy outcomes beyond 12 weeks (27, 31).
Appendix Figure 1. Evidence search and selection.
BPSD = behavioral and psychological symptoms of dementia; ROB = risk of bias.
* Because 1 eligible trial with low to medium ROB of persons with BPSD reported both non-BPSD and BPSD outcomes, the total numbers of eligible references and unique studies are smaller than the sums of eligible references and unique studies for the non-BPSD and BPSD outcome groups, and the total number of eligible unique studies with low or medium ROB is lower than the sum of eligible studies with low to medium ROB for the non-BPSD and BPSD outcome groups.
† The total number of studies reporting non-BPSD outcomes is smaller than the sum for the separately listed drug classes because individual studies may have included comparisons of drug treatment with placebo, a different formulation or dose of the same drug, a different drug in the same class, or a different drug class.
Studies most frequently reported between-group differences in mean score change from baseline. Less often, they reported the proportion of participants who had a categorical outcome, including a change of at least 4 points on the Alzheimer's Disease Assessment Scale–Cognitive Subscale and minimal, moderate, or marked improvement on measures of global clinical impression (for example, Alzheimer's Disease Cooperative Study–Clinical Global Impression of Change). Data for some categorical outcomes, including for specific harms, were sparse.
Non-BPSD Outcomes
Cholinesterase Inhibitors
Cholinesterase inhibitors were compared with placebo in 25 trials (n = 9476) (32–56), including 18 of donepezil, 5 of rivastigmine, and 2 of galantamine. Eleven trials (n = 5893) compared different dosages or formulations of the same cholinesterase inhibitor (35, 39, 44, 51–53, 56–60). All trial results were based on 24 to 26 weeks of follow-up. Mean participant age was 75 years; 65% of participants were female; 64% had mild or moderate CATD; baseline Mini-Mental State Examination score was 15; and, in the 17 trials reporting race/ethnicity, 66% of participants were white.
Trials provided mostly low-strength evidence favoring standard dosages of cholinesterase inhibitors (that is, donepezil, 10 mg/d; rivastigmine, 12 mg/d oral or 9.5 mg/d patch; or galantamine, 32 mg/d) over placebo for cognition, function, and global clinical impression (Table 1; Appendix Figures 2 and 3).
Appendix Figure 2. Forest plots for drug treatment: donepezil vs. placebo.
ADAS-Cog = Alzheimer's Disease Assessment Scale–Cognitive Subscale; CATD = clinical Alzheimer-type dementia; MMSE = Mini-Mental State Examination; OR = odds ratio; RR = risk ratio; SMD = standardized mean difference.
Appendix Figure 3. Forest plots for drug treatment: rivastigmine vs. placebo.
ADAS-Cog = Alzheimer's Disease Assessment Scale–Cognitive Subscale; CATD = clinical Alzheimer-type dementia; MMSE = Mini-Mental State Examination; OR = odds ratio; RR = risk ratio; SMD = standardized mean difference.
* Two other trials of rivastigmine vs. placebo in patients with mild to moderate CATD did not report on the Progressive Deterioration Scale. Instead, Winblad and colleagues (52) reported on the Alzheimer's Disease Cooperative Study–Activities of Daily Living, and Nakamura and colleagues (53) reported on the Disability Assessment for Dementia.
Average benefits versus placebo were small for mean change in cognitive test score (median pooled drug-specific SMD, 0.30 [range, 0.24 to 0.52]) (32–35, 37, 38, 40–42, 44–54, 56) and ranged from no difference to a small benefit for mean change in function (median pooled drug-specific SMD, 0.19 [range, −0.10 to 0.22]) (34, 37–39, 49–53, 56).
Results for the likelihood of improvement from baseline favored cholinesterase inhibitors over placebo for cognition (≥4-point change in Alzheimer's Disease Assessment Scale–Cognitive Subscale) (median ARD, 16% [range, 8% to 19%]) (45, 50–52, 56). Similarly, results favored cholinesterase inhibitors for the proportion of participants with minimal or greater improvement in global clinical impression (median ARD, 10% [range, 8% to 13%]) (37–41, 44, 45, 48, 50–52, 54). However, moderate or marked improvement in global clinical impression was uncommon and did not differ between treatments (median ARD, 4% [range, 2% to 4%]) (37, 39, 40, 48, 50, 52, 53). Quality of life was reported in only 2 trials (44, 45), and evidence was insufficient.
Compared with placebo, standard doses of donepezil and rivastigmine increased withdrawals due to adverse events (32–48, 51–56) and inconsistently increased serious adverse events (34–37, 39, 41–46, 48, 51–54, 56) (Table 2; Appendix Figures 2 and 3). Low doses of cholinesterase inhibitors did not differ from placebo for these harms (39, 44, 45, 51, 53).
Evidence conflicted about whether the efficacy of cholinesterase inhibitors versus placebo varied by baseline cognitive level (34, 48–50), and no trials reported whether efficacy varied by other participant characteristics. On the basis of direct and indirect comparisons, we found mostly low- to moderate-strength evidence that efficacy did not differ by donepezil dose, that standard rivastigmine doses had greater efficacy than placebo but low doses did not, and that evidence on efficacy by galantamine dosing was mostly insufficient. For harms, compared with 10 mg of donepezil per day, higher dosing increased withdrawals due to adverse events (moderate SOE) (57, 58) and lower dosing reduced serious adverse events (low SOE) and withdrawals due to adverse events (moderate SOE). Evidence was insufficient about differences in harms between galantamine doses (59) or rivastigmine doses or formulations (51–53, 60).
Memantine
Six trials (n = 2227) compared memantine versus placebo, of which 5 evaluated dosages up to 20 mg/d (23, 61–64) and 1 evaluated 28 mg/d (65). Follow-up results were available through 30 weeks for 1 trial (23) and 24 weeks for the others. Mean participant age was 77 years; 64% of participants were female; 63% had moderate to severe CATD; mean baseline score on the Mini-Mental State Examination was 13; and, in 4 trials reporting race/ethnicity, 93% of participants were white.
In 2 trials in adults with mild to moderate CATD, memantine and placebo did not differ for mean change in function (low SOE) and evidence was insufficient for mean change in cognition (Table 1). Results for measures of global clinical impression were inconsistent. In 1 trial in which participants did not receive a cholinesterase inhibitor, those assigned memantine had a small improvement in mean change in global clinical impression and were more likely to experience a composite outcome of no change or any improvement (low SOE) (61). By comparison, in 1 trial in patients who received a cholinesterase inhibitor, mean change in global clinical impression did not differ between memantine and placebo (low SOE) (63).
In 4 trials in adults with moderate to severe CATD, all of whom were receiving a cholinesterase inhibitor, add-on memantine did not differ from placebo for mean change in function (low SOE), there was a small benefit with memantine in mean change in global clinical impression (low SOE), and evidence for memantine benefit in continuous cognition measures varied by type of cognitive measure (23, 62, 64, 65) (Table 1).
No memantine trials reported data on the likelihood that persons improved in cognition, function, or global measures, let alone whether they had moderate or marked improvement.
Memantine and placebo did not differ for serious adverse events (61, 63, 65) or withdrawals due to adverse events (61, 63–65) (Table 2; Appendix Figure 4). Somnolence was higher with memantine than placebo (4.4% vs. 1.1%; risk ratio, 3.75 [95% CI, 1.36 to 10.30]) (61, 65), but treatment groups did not statistically differ for confusion (61, 63–65), falls (23, 61, 63–65), stroke (23, 65), or mortality (23, 61, 63, 65). No studies reported data on extrapyramidal symptoms.
Appendix Figure 4. Forest plots for drug treatment: memantine plus cholinesterase inhibitor vs. placebo plus cholinesterase inhibitor.
CATD = clinical Alzheimer-type dementia; OR = odds ratio; RR = risk ratio.
Other than the possible effect modification by CATD severity detailed earlier, no studies reported whether differences in efficacy between memantine and placebo vary by other participant characteristics.
Supplements
Twelve trials of supplements versus placebo (n = 2214) and 4 of supplements versus prescription drugs (n = 258) reported effects on cognition, function, or harms in persons with CATD.
Two 24-week trials (n = 786) reported no difference between Souvenaid (Nutricia Advanced Medical Nutrition) and placebo for function, serious adverse events, or withdrawals due to adverse events (all low SOE), but evidence was insufficient for cognition (66–68) (Tables 1 and 2; Appendix Figure 5). Two trials (n = 230) that studied omega-3 fatty acids versus placebo for 6 and 12 months reported no difference for cognition (low SOE) and insufficient evidence about function, other efficacy outcomes, and harms (24, 69, 70). One trial (n = 210) reported low-strength evidence that oral vitamin D3, 800 IU/d, versus placebo for 12 months improved mean change in cognition but found insufficient evidence about other outcomes (30).
Appendix Figure 5. Forest plots for drug treatment: Souvenaid vs. placebo.
CATD = clinical Alzheimer-type dementia; OR = odds ratio; RR = risk ratio.
By comparison, evidence was insufficient for all evaluated outcomes for the following supplements compared with placebo: omega-3 fatty acids combined with α-lipoic acid (n = 26) (24), an antioxidant combination (n = 52) (71), choline alfoscerate (n = 261) (72), prolonged-release melatonin (n = 80) (73), sodium selenite (n = 40) (74), soy isoflavones (n = 65) (75), copper (n = 68) (28), and folic acid combined with vitamin B (n = 409) (29).
Prescription Drugs Versus Prescription Drug or Supplement
Seven trials compared prescription drugs with each other or supplements. All provided insufficient-strength evidence for between-treatment differences in all reported efficacy and harms outcomes. These comparisons were donepezil versus galantamine (n = 188) (25), memantine (n = 67) (76), ginkgo biloba (n = 50) (47), vitamin E (n = 40) (77), or Huannao Yicong formula (Beijing CMages Pharmaceutical) (n = 60) (78); memantine versus continued antipsychotic drug therapy (n = 199) (31) or saffron (n = 68) (26); and vitamin E versus rivastigmine (n = 40) (77).
BPSD Outcomes in Persons With CATD and BPSD
We found no eligible trials that enrolled adults with CATD and BPSD, had low or medium ROB, and reported BPSD outcomes with antianxiety drugs, hormones, or cannabinoids.
Antipsychotic Drugs
Four trials (n = 522) compared antipsychotic drugs (haloperidol [79], quetiapine [80], aripiprazole [81], and pimavanserin [82, 83]) versus placebo. Two comprised community-dwelling adults (n = 279) (79, 81), and 2 were limited to nursing home residents (n = 243) (80, 82, 83). One trial enrolled participants with agitation, 2 enrolled those with psychosis, and 1 required agitation or psychosis. Study durations were 6 to 12 weeks.
Evidence was insufficient about differences between antipsychotics and placebo for agitation and aggression (79, 80, 82, 83). Although antipsychotics were statistically significantly better than placebo for a few of many reported psychosis outcomes (79, 81–83), evidence for psychosis was also deemed insufficient, primarily because of imprecision and inconsistency of results within trials (Table 3). No trials reported data on disinhibited sexual behavior, and none reported data at 24 weeks or later for depression, anxiety, general behavior, or caregiver outcomes.
Evidence was insufficient about differences between antipsychotics and placebo for serious adverse events or withdrawals due to adverse events (Table 4; Appendix Figure 6). Falls seemed similar between groups in 1 trial (23% vs. 23%) (82, 83). In a second trial, both injurious falls (8% vs. 1%) and somnolence (8% vs. 1%) seemed more common with antipsychotics than placebo (81). Two trials (n = 279) reported that changes in extrapyramidal symptoms and abnormal movements did not statistically differ between placebo and standard-dose haloperidol (79) or aripiprazole (81). In 3 trials reporting it (n = 451), mortality over 6 to 12 weeks was 4.4% in the antipsychotic group and 1.8% with placebo (ARD, 2.6% [CI, −0.6% to 5.8%]) (80–83). No trials reported data on confusion or stroke.
Appendix Figure 6. Forest plots for drug treatment: antipsychotic drugs vs. placebo.
OR = odds ratio; RR = risk ratio.
Antidepressant Drugs
Four trials (n = 836) compared antidepressant drugs (citalopram [84–86], sertraline [27, 87], and mirtazapine [27]) versus placebo. Two were restricted to participants with agitation or aggression (84–86), 1 to those with depression (27), and 1 to those with increased neuropsychiatric symptom scores (87). Eighty-nine percent of participants were community-dwelling. Both citalopram trials used 30-mg/d dosing, exceeding the maximum currently recommended dose for patients older than 60 years (88). Study durations were 8 to 39 weeks.
Evidence was insufficient about differences between antidepressants and placebo for treatment of BPSD. Among persons with agitation or aggression (n = 430), results for psychosis were insufficient, and no data were reported for disinhibited sexual behavior (Table 3). Although high-dose citalopram was statistically significantly better than placebo for some reported agitation outcomes, results were not consistent, and evidence was considered insufficient. Citalopram was associated with statistically significantly more improvement in caregiver distress than placebo (84–86), but sertraline and placebo did not statistically differ for change in caregiver burden (87). Among persons with depression (n = 326), low-strength evidence showed no difference between antidepressants and placebo for participant depression, general behavior, or quality of life (27). No studies reported data on participant anxiety or caregiver depression.
Evidence was insufficient to draw conclusions about differences between antidepressants and placebo for serious adverse events or withdrawals due to adverse events (Table 4; Appendix Figure 7). In 1 trial reporting confusion, falls, and somnolence (n = 176), citalopram and placebo did not seem to differ for these outcomes (84, 85). In 2 trials reporting mortality (n = 404), citalopram and placebo also did not seem to differ (27, 84, 85). No studies reported data on extrapyramidal symptoms or stroke.
Appendix Figure 7. Forest plots for drug treatment: antidepressant drugs vs. placebo.
OR = odds ratio; RR = risk ratio.
Cholinesterase Inhibitors
In a 12-week trial (n = 272) in persons with agitation who were living in a residential care facility and were unresponsive to psychosocial interventions, donepezil and placebo did not differ for change in agitation (low SOE) (Table 3) (89). Falls (1.6% with donepezil and 1.5% with placebo) and stroke (0.8% with donepezil and 0% with placebo) were rare. Mortality was 2.3% and 3.1% in the donepezil and placebo groups, respectively. Results for other efficacy and harms outcomes either were of high ROB and were not analyzed or were not reported (Tables 3 and 4).
Antiseizure Drugs
In a 6-week trial (n = 153) of divalproex versus placebo in nursing home residents with agitation, evidence was insufficient about between-treatment differences in change in agitation from baseline (Table 3) (90). No data were reported on other participant BPSD outcomes, caregiver outcomes, serious adverse events, or withdrawals due to adverse events (Table 4). Falls occurred in 21% of the divalproex group and 17% of the placebo group, and 1 divalproex participant died. No studies reported data on confusion, somnolence, stroke, or extrapyramidal symptoms.
Supplements
Discussion
This systematic review summarized the evidence on the efficacy and harms of prescription drugs and supplements for CATD, including effects on non-BPSD outcomes (such as cognition, function, and global clinical impression), BPSD outcomes (such as agitation, aggression, psychosis, depression, and anxiety), and caregiver outcomes.
We found that cholinesterase inhibitors compared with placebo were associated with small reductions in the average amount of worsening in cognition and function over about 6 months. Although likelihood of at least minimal improvement in global measures was greater with cholinesterase inhibitors than placebo, at least moderate improvement was uncommon and no more likely with treatment than placebo. Data were mixed regarding differences in efficacy by cholinesterase inhibitor dose, but standard doses more consistently increased harms versus placebo, whereas low doses did not. Memantine generally did not differ from placebo in patients with mild to moderate CATD but had inconsistent benefits and few harms when added to a cholinesterase inhibitor in those with moderate to severe CATD. Evidence for the effects of supplements on cognition and function was mostly insufficient. For treatment of BPSD, despite isolated statistically significant findings favoring antipsychotics over placebo for psychosis and high-dose citalopram over placebo for agitation, findings were insufficient because of few studies, small sample sizes, and inconsistent results within and between trials. Antipsychotic trials were small and short and reported relatively few total deaths, but findings were not inconsistent with warnings from the U.S. Food and Drug Administration about increased risk (9, 10). Evidence on efficacy and harms of BPSD treatment with other antidepressants, antiseizure drugs, antianxiety drugs, hormones, cannabinoids, and supplements was insufficient or absent. Among trials that directly compared drug treatments, no 2 with low or medium ROB evaluated the same treatment comparison, and all provided insufficient evidence to conclude anything about relative benefits and harms.
Our findings have several clinical implications. They suggest that cholinesterase inhibitors may have symptomatic benefits in cognition, function, and global measures compared with placebo. Only 1 small trial (n = 67) directly compared a cholinesterase inhibitor versus memantine, but evidence of benefit versus placebo seems weaker for memantine than for cholinesterase inhibitors. However, the clinical importance of these treatment differences versus placebo is unclear. Based on conventional interpretations of effect size (21), the average differences in efficacy of cholinesterase inhibitors and memantine versus placebo as estimated by SMD are small. Although cholinesterase inhibitors were more likely than placebo to produce a change of at least 4 points in the Alzheimer's Disease Assessment Scale–Cognitive Subscale, this commonly cited metric for clinically important change in cognition is based on U.S. Food and Drug Administration expert opinion (92) and has not been adequately validated on the basis of patient and caregiver values and preferences (93). Although cholinesterase inhibitors were more likely than placebo to at least minimally improve global clinical impression, this threshold probably correlates with a minimal detectable difference (93). The outcome of at least moderate improvement in global clinical impression is more likely to meet or exceed the minimal clinically important difference, but this outcome occurred no more frequently in participants assigned cholinesterase inhibitors than placebo. We also found no trial data on the effects of drug treatments on function at home or delay in the need for higher-level care (for example, transfer from independent to assisted living)—outcomes that are important to participants. Current data do not provide clear guidance on whether any prescription drugs improve BPSD outcomes in patients with CATD, let alone whether benefits outweigh harms, overall or in any patient subgroups. Finally, from trials included in this review and rated as having low or medium ROB, we could not establish whether any supplements or cannabinoids have clinically important benefits for any outcome that would support their use in persons with CATD, including those with BPSD.
Evidence for this review was limited in several ways. Although more than half of the analyzed studies were published after the search date for the 2008 evidence synthesis and guideline from the AAFP and American College of Physicians (6, 7), substantially augmenting the evidence base (including for supplements and treatment of BPSD), the general findings of our review are similar, and significant evidence gaps remain. We identified few eligible trials for many individual drug treatments. Among eligible trials, many had high ROB due to attrition, especially longer trials and trials of supplements, active drug comparisons, and treatments for BPSD. We found no trials that compared drug versus nondrug treatments. By design, this review did not examine the effects of drug treatment on cognition or function for less than 24 weeks or drug treatment of BPSD for less than 2 weeks. By design, this review also did not examine risk for many individual harms defined by trials as nonserious and not associated with study withdrawals. Because few trials evaluating cognition or function exceeded 26 weeks and few for BPSD exceeded 12 weeks, longer-term drug effects were unclear—although patients generally live with CATD for years (94, 95). Most trials had small sample sizes, and treatment effects were inconsistent within and between trials. This limited statistical power to detect potentially meaningful differences between treatments in both efficacy and harms. In addition, some trials analyzed results using methods of accounting for missing data that may overestimate treatment benefit in a progressive disease like CATD (such as last observation carried forward). Few trials reported data on participant quality of life or caregiver outcomes, and none with low or medium ROB reported data on disinhibited sexual behavior. Harms reporting was poor. Last, few trials evaluated whether treatment efficacy or harms vary by participant characteristics, and none evaluated whether they vary by accuracy of CATD diagnosis.
Future trials of CATD drug treatment should be large enough to detect the likelihood of treatment response as defined for validated, clinically important outcomes related to cognition, function, global function, and BPSD. Future trials should investigate treatment efficacy and harms beyond 6 months. They should enroll more diverse participants, including nonwhite persons, and prespecify analyses to examine whether treatment effects are modified by participant characteristics, including age, sex, race/ethnicity, CATD and BPSD severity, and living setting. In addition to agitation, aggression, and psychosis, BPSD treatment trials should routinely report data on participant depression, anxiety, disinhibited sexual behavior, and quality of life and caregiver outcomes. Future trials should examine prescription drug treatments for which data, although currently insufficient, raise questions about possible benefit. For example, high-dose citalopram data suggest that lower-dose citalopram for agitation warrants investigation. Future trials also should rigorously evaluate nonprescription drug treatments (such as supplements and cannabinoids) for which claims of efficacy have been made in comparison with both placebo and prescription drugs approved by the U.S. Food and Drug Administration. Last, future BPSD trials should directly compare benefits and harms of drug treatments with nondrug treatment strategies.
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Published In
Annals of Internal Medicine
Volume 172 • Number 10 • 19 May 2020
Pages: 656 - 668
History
Published online: 28 April 2020
Published in issue: 19 May 2020
Keywords
- Adverse events
- Antipsychotics
- Biochemistry
- Cognition
- Cognitive psychology
- Dementia
- Drugs
- Enzyme inhibitors
- Enzymology
- Epidemiology
- Health care
- Health care providers
- Odds ratio
- Pharmacology
- Prevention, policy, and public health
- Psychiatry and mental health
- Psychology
- Research and reporting methods
- Research design
- Statistical methods
Authors
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Benefits and Harms of Prescription Drugs and Supplements for Treatment of Clinical Alzheimer-Type Dementia: A Systematic Review and Meta-analysis. Ann Intern Med.2020;172:656-668. [Epub 28 April 2020]. doi:10.7326/M19-3887
Benefits and Harms of Prescription Drugs and Supplements for Treatment of Clinical Alzheimer-Type Dementia: A Systematic Review and Meta-analysis. Ann Intern Med.2020;172:656-668. [Epub 28 April 2020]. doi:10.7326/M19-3887
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