Table 1.
Characteristics of Included Trials
| Study | Total n | Patients | Diagnosis | Duration | Age (mean ± SD) | Male % | Race (%) | Drug | n | Dose (dose mg/day) | With ChEI % (mean or median dose, ± SD mg) | Outcomes |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Tariot 2004 (USA) industry | 404 | AD: Outpatient (NR) Inclusions: age ≥50 y, MMSE 5–14, MRI or CT consistent with a diagnosis of probable AD (within 12 mo), ongoing DON therapy for >6 mo before entrance into the trial and at a stable dose (5–10mg/d) for at least 3 months, caregiver to accompany the patient to research visits and oversee the administration of the investigational agent during the trial, residence in the community, ambulatory or ambulatory-aided ability, stable medical condition, permitted to continue receiving stable doses of concomitant medication (including antidepressants, antihypertensive, antiinflammatory drugs, atypical antipsychotics, antiparkinsonian drugs, laxatives, diuretics, and sedatives/hypnotics.), Exclusions: B12 or folate deficiency, active disease (pulmonary, gastrointestinal, renal, hepatic, endocrine, or cardiovascular disease.), other psychiatric or central nervous system disorders, dementia complicated by other organic disease, modified HIS 4 <. | probable AD: NINCDS-ADRDA criteria | 24 wk | MEM (75.5 ± 8.45); PLA (75.5 ± 8.73) | MEM, 37; PLA, 33 | MEM: White (90.1); PLA: White (92.5) | MEM | 203 | MEM 20mg, [fixed] | DON 100 % (9.25±1.79) | MEM>PLA: SIB, ADCS-ADL, CIBIC-Plus, NPI, BGP |
| PLA | 201 | PLA | DON 100 % (9.49±1.88) | |||||||||
| Porsteinsson 2008 (USA) industry | 433 | AD: Outpatient (NR) Inclusions: age ≥50 years, MMSE 10–22, MRI or CT consistent with a diagnosis (within 12 mo), treatment with a ChEI for 6 mo or longer, and a stable dosing regimen for 3 mo or longer (DON 5 or 10mg/d, RIV 6,9, or 12mg/d, GAL 16 or 24mg/d), caregiver to accompany the participant to all study visits and supervise administration of the study drug, ability to ambulate, vision and hearing sufficient to permit compliance with assessments, MADRS <22, medical stability. Exclusions: B12 or folate deficiency, clinically significant and active disease (pulmonary, gastrointestinal, renal, hepatic, endocrine, or cardiovascular disease.), other psychiatric or central nervous system disorders, dementia complicated by other organic disease or AD with delusions or delirium, undergoing treatment for an oncology diagnosis, or completion of treatment within 6 mo of screening, modified HIS 4 <, poorly controlled hypertension, substance abuse, participation in an investigational drug study or use of an investigational drug within 30 d (or 5 half-lives, whichever is longer) of screening, depot neuroleptic use within 6 mo of screening, positive urine drug test, likely institutionalization during the trial, previous MEM treatment or participation in an investigational study of MEM, and likely cessation of ChEI treatment during the trial. | probable AD: NINCDS-ADRDA criteria | 24 wk | MEM (74.9 ± 7.64); PLA (76.0 ± 8.43) | MEM, 46.1; PLA, 49.5 | NR | MEM | 217 | MEM 20mg, (dose adjustments were permitted) | DON 71 % (9.5 ± 1.5); RIV 15.2 % (9.2 ± 2.8); GAL 13.8 % (19.7 ± 4.6) | MEM=PLA: ADAS-cog, CIBIC-Plus, ADCS-ADL, NPI, MMSE |
| PLA | 216 | PLA | DON 63.4 % (8.9 ± 2 .1); RIV 20.4 % (10.0 ± 2.6); GAL 16.2 % (19.4 ± 5.2) | |||||||||
| Choi 2011 (South Korea) industry | 172 | AD: Outpatient (NR) Inclusions: age 50–90 y, ambulatory or ambulatory-aided, MMSE 10–20, had MRI or CT showing no clinical evidence of other diseases capable of producing a dementia syndrome, and had a reliable caregiver who met the patient at least once a week and was sufficiently familiar with the patient to provide the investigator with accurate information. Exclusions: any primary neurodegenerative disorder or psychiatric disorder other than AD, clinically significant laboratory abnormalities (such as thyroid function, B12, folate, venereal disease), any history of drug or alcohol addiction for the past 10 y, any severe or unstable medical disease, bradycardia with <50 beats/min, sick sinus syndrome, sinoatrial block, second or third degree atrioventricular block, any hearing or visual impairment that could disturb the efficient evaluation of the patient, any active skin lesion, a history of allergy to topical products containing any of the constitution of the patches, known hypersensitivity to ChEI, and an involvement in other clinical trials or treated by any experimental drug within 4wk. | probable AD: NINCDS-ADRDA criteria | 16 wk | MEM (75.0 ± 7.3); UC (74.7 ± 7.7) | MEM, 25; UC, 15.7 | NR | MEM | 88 | MEM 20mg, (dose adjustments were permitted) | RIV patch 100 % (9.77±1.041cm2) | MEM=UC: ADAS-cog, MMSE, FAB, NPI, ADCS-ADL, CDR MEM<UC: CMAI |
| UC | 84 | UC | RIV patch 100 % (9.64±1.280cm2) | |||||||||
| Howard 2012 (UK) non-industry | 146 | AD: Outpatient (NR) Inclusions: community residents who had caregivers who either lived with them or visited them at least daily, continuously treatment with DON for at least 3 mo (treatment with DON 10mg for at least the previous 6wk), SMMSE 5–13, each eligible patient’s prescribing clinician was considering a change in drug treatment on the basis of NICE guidelines at the time, discussions with the patient and caregivers, and the physician’s clinical judgment. Exclusions: severe or unstable medical conditions, current prescription of MEM, contra-indications or previous adverse or allergic reactions to trial drugs, involvement in another trial or concerns over the patient’s compliance. | probable or possible AD: NINCDS-ADRDA criteria | 52 wk | MEM (77.5 ± 9.0); PLA (77.2 ± 7.5) | MEM, 33; PLA, 30 | MEM: White (92) Black (5) Other (3)PLA: White (95) Black (1) Other (4) | MEM | 73 | DON 10mg, MEM 20 mg | DON 100 % (10) | MEM>PLA: NPI MEM=PLA: SMMSE, BADLS, DEMQOL-proxy, GHQ-12 |
| PLA | 73 | DON 10mg, PLA | DON 100 % (10) | |||||||||
| Creţu 2008 (Romania) NR | 43 | AD: Outpatient (NR) Inclusions: age ≥50 y, MMSE 10–17, MRI or CT consistent with a diagnosis of probable AD (within 12 mo), under current treatment with DON 10mg for at least 6 mo, have a caregiver in the family who could give information about their health. Exclusions: VD, severe depressive disorder, HIS 4 <, unstable or severe somatic diseases, chronic treatment with BZD, hypnotics, anticholinergics, anxiolytics. |
AD: DSM-Ⅳ-TR | 24 wk | 72.5 | MEM, 38; UC, 37 | NR | MEM UC |
22 21 |
MEM 20 mg | DON 100 % (10) | statistical results were unknown. Favorable add-on MEM: MMSE, ADAS-cog, NPI, CMAI |
| Grossberg 2013 (Argentina, USA, Mexico, Chile), industry | 677 | AD: Outpatient (100%) Inclusions: age ≥50 y, MMSE 3–14, results of a MRI or CT consistent with a diagnosis (within the past 12 mo), ongoing CHEI therapy (stable dosage for at least 3 mo), normal (or clinically nonsignificant) results on physical examination, laboratory evaluations, and ECG. Exclusions: clinically significant and active pulmonary, gastrointestinal, renal, hepatic, endocrine, or cardiovascular system disease or cancer, a neurologic disorder or dementia complicated by other organic disease or predominant delusions, DSM-IV Axis I disorder other than AD, evidence of clinically significant disease involving the central nervous system, systolic hypertension or hypotension, HIS 4 <, and current or prior exposure to any unapproved concomitant medication that could not be discontinued or switched to an allowable alternative medication before baseline. | probable AD: NINCDS-ADRDA and DSM-IV-TR criteria | 24 wk | MEM (76.2 ± 8.4); PLA (76.8 ± 7.8) | MEM, 28.4; PLA, 27.5 | MEM: White (95) Hispanic (68.3) PLA: White (93.1) Hispanic (69.6) | MEM | 342 | MEM (28mg, extended-release) | DON 69.2 %, (8.0±2.8); RIV 9.4 %, (6.8±2.6); GAL 21.1 %, (13.5±5.7) | MEM>PLA: SIB, CIBIC-Plus, NPI, VFT MEM=PLA: ADCS-ADL |
| PLA | 335 | DON 68.1 %, (7.8±2.6); RIV 12.2 %, (6.8±2.9); GAL 20.3 %, (13.5±5.4) | ||||||||||
| Dysken 2014 (USA) non-industry | 307 | AD: Outpatient (NR) Inclusions: MMSE 12–26, presence of a caregiver who can assume responsibility for medication compliance, can accompany the patient to all visits, and rate patient’s condition, written informed consent from both the patient and caregiver, administration of maintenance dosage of a ChEI for at least 4wk. Exclusions: other psychiatric disorders, presence of any uncontrolled illness, pregnant or intention to became pregnant, use of WAR, VitE (past 2wk), MEM (past 4wk), and AMA (past 2wk), creatinine clearance 5 < mL/min. |
probable or possible AD: NINCDS-ADRDA criteria | 6 mo to 4 y | MEM (78.8 ± 7.2); PLA (79.4 ± 7.0) | MEM, 96; PLA, 98 | MEM: White (85) Black (14) Other (1)PLA: White (86) Black (13) Other (1) | MEM | 155 | MEM 20mg, (dose adjustments were permitted) | DON 65 %, (NR); RIV 5 %, (NR); GAL 30 %, (NR)DON 63 %, (NR); RIV 1 %, (NR); GAL 36 %, (NR) | MEM=PLA: ADCS-ADL, ADAS-cog, NPI, MMSE, CAS |
| PLA | 152 |
AD, Alzheimer’s Disease, ADAS-cog, Alzheimer’s Disease Assessment Scale cognitive subscale, ADCS-ADL, Alzheimer’s Disease Cooperative Study–Activities of Daily Living, ADL, activities of daily living, AMA, amantadine, BADLS, Bristol Activities of Daily Living Scale, BGP, Behavioral Rating Scale for Geriatric Patients, BZD, benzodiazepine, CAS, Caregiver Activity Survey, CDR, Clinical Dementia Rating scale, CIBIC-Plus, Clinician’s Interview-Based Impression of Change Plus Caregiver Input, ChEI, cholinesterase inhibitors, CMAI, Cohen Mansfield Agitation Inventory, CT, computed tomographic scan, d, days, DON, donepezil, DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders-4th edition-text revision, ECG, electrocardiogram, FAB, Frontal Assessment Battery, GAL, galantamine, GHQ-12, General Health Questionnaire 12, HIS, Hachinski Ischaemic Score, MADRS, Montgomery-Asberg Depression Rating Scale, MMSE, Mini-Mental State Examination, MRI, magnetic resonance imaging, m, months, NICE, National Institute for Health and Clinical Excellence, NINCDS-ADRDA, National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association, NPI, neuro-psychiatric inventory, NR, Not report, RIV, rivastigmine, SIB, Severe Impairment Battery, SMMSE, Standardized Mini–Mental State Examination, UC, usual care, VD, vascular dementia, VFT, verbal fluency test, VitE, vitamin E, WAR, warfarin, y, years.