Clinical Question: Does donepezil provide clinically meaningful benefits in typical patients with Alzheimer’s disease?

Setting: Population-based

Study Design: Randomized controlled trial (double-blinded)

Allocation: Concealed

Synopsis: This relatively complex study had multiple phases designed to evaluate community-dwelling elderly adults with mild to moderate Alzheimer’s disease (based on criteria from the Diagnostic and Statistical Manual of Mental Disorders, 4th ed.). To start, 565 patients were randomized to receive 12 weeks of donepezil in a dosage of 5 mg daily or placebo. Following this initial treatment, 486 of these patients were randomized once more to receive 48 weeks of donepezil (5 or 10 mg daily) or placebo, followed by a six-week washout period. During phase 2, the patients remained in the same groups for an additional 48 weeks, followed by a four-week washout period. This pattern continued until four phases were completed. The number of patients who were able to move on to the next phase steadily declined as the trial continued; only seven patients entered phase 4. The authors chose this design to minimize long-term bias from patients dropping out during the first 12 weeks.

The authors evaluated the effect of treatment on the rate of entry to institutional care and progression of disability, defined as a loss of either two of four basic activities or six of 11 instrumental activities on the Bristol Activities of Daily Living Scale (range = zero to 60). In addition to several secondary outcomes, the authors also performed an economic evaluation using a societal perspective. The authors did not state whether they analyzed the outcomes by intention to treat. Although they hoped to enroll 3,000 patients, the final enrollment number of 565 patients had 90 percent power to detect clinically relevant differences in the main outcomes.

The patients taking donepezil achieved no significant reduction in institutionalization (42 versus 44 percent for placebo) or progression of disability (58 versus 59 percent). However, at the end of two years, the patients taking donepezil scored an average of 0.8 points higher on the Mini-Mental State Examination (on a 30-point scale) than those taking placebo (95 percent confidence interval [CI], 0.5 to 1.2; P < .0001). Patients taking donepezil also scored 1 point higher (95 percent CI, 0.5 to 1.6; P < .0001) on the Bristol Activities of Daily Living Scale during the first two years. This study did not demonstrate any meaningful benefits on economic factors or caregiver stress.

Bottom Line: Long-term use of donepezil provides minimal improvement in cognition and no benefit in preventing institutionalization. Donepezil also provides no meaningful long-term protection against functional decline. (Level of Evidence: 2b)