Long-term course and effectiveness of combination therapy in Alzheimer disease

Abstract

Objective: To compare the real-world clinical effectiveness and long-term clinical trajectory in patients with Alzheimer disease (AD) treated with combination (COMBO) therapy consisting of cholinesterase-inhibitor (CI) plus memantine (MEM) versus CI alone versus no treatment with either.

Methods: Three hundred eighty-two subjects with probable AD underwent serial clinical evaluations at a memory disorders unit. Cognition was assessed by the Information-Memory-Concentration subscale of the Blessed Dementia Scale (BDS) and function was assessed by the Weintraub Activities of Daily Living Scale (ADL) at 6-month intervals. One hundred forty-four subjects received standard care without CI or MEM (NO-RX), 122 received CI monotherapy, and 116 received COMBO therapy with CI plus MEM. Mean follow-up was 30 months (4.1 visits) and mean cumulative medication treatment time was 22.5 months. Rates of decline were analyzed using mixed-effects regression models, and Cohen's d effect sizes were calculated annually for years 1 to 4.

Results: Covarying for baseline scores, age, education, and duration of illness, the COMBO group had significantly lower mean annualized rates of deterioration in BDS and ADL scores compared with the CI (P<0.001; Cohen's dBDS=0.10-0.34 and dADL=0.23-0.46 at 1 to 2 y) and NO-RX groups (P<0.001; Cohen's dBDS=0.56-0.73 and dADL=0.32-0.48 at 1 to 2 y). For the COMBO group, Cohen's d effect sizes increased with treatment duration. Similar comparisons significantly favored the CI over the NO-RX group on the BDS.

Conclusions: COMBO therapy slows cognitive and functional decline in AD compared with CI monotherapy and no treatment. These benefits had small-to-medium effect sizes that increased with time on treatment and were sustained for years.

Conflict of interest statement

Disclosure: Dr. Atri has received remuneration for lectures or consulting from Eisai, Forest, Merck and Pfizer, and Investigator-Initiated research grant support from Forest. He has also participated in conducting clinical trials in association with the Alzheimer’s Disease Cooperative Study (ADCS), Elan, Neurochem and Wyeth. There was no sponsorship or involvement by the pharmaceutical industry, including the motivation, design, execution, interpretation, presentation and costs associated with any part of this study. Ms. Shaughnessy, Dr. Locascio and Dr. Growdon have no potential conflicts to disclose.

Figures

Fig 1

Raw data for BDS versus Duration of Illness (symptoms) for A) NO-RX group (no medications), B) CI group, and C) COMBO group of subjects. Thin lines connect data for an individual (subject), while the thick line is the best fitting ordinary least square (OLS) regression line for the data. There is progressive shallowing of the slope for the OLS regression lines going from NO-RX to CI to COMBO that is consistent with a respective slower rate of cognitive decline with use of medication(s).

Fig 2

Raw data for ADL versus Duration of Illness (symptoms) for A) NO-RX group (no medications), B) CI group, and C) COMBO group of subjects. Thin lines connect data for an individual (subject), while the thick line is the best fitting OLS regression line for the data. There is shallowing of the slope for the OLS regression lines going from NO-RX and CI to COMBO that is consistent with a slower rate of functional decline in the COMBO group.

Fig 3

Illustrative mean BDS values predicted by best fitting longitudinal model for patients in the different medication regimens. Baseline scores of 0, 10 and 20 are given as arbitrary examples. (Square = No Meds; X = CI Only; dot = COMBO).

Fig 4

Illustrative mean ADL values predicted by best fitting longitudinal model for patients in the different medication regimens. Baseline scores of 0, 25% and 50% dependent are given as arbitrary examples. (Square = No Meds; X = CI Only; dot = COMBO).

Fig 5

Confidence bands around illustrative mean (A) BDS and (B) ADL trajectories. Confidence bands (dashed lines) corresponding to 95% confidence interval around the predicted model trajectories (solid lines) for patients in different medication regimens who start out in the study with mild-to-moderate stage dementia severity corresponding to a baseline BDS score of 10 and a baseline ADL score of 25% dependent. (Square = No Meds; X = CI Only; dot = COMBO).