As Alzheimer's disease (AD) progresses into the advanced stage, physicians and families often grapple with how to adjust a patient's treatment regimen. In the U.S., patients already on an acetylcholinesterase inhibitor such as donepezil may continue, discontinue, replace the drug, or add another such as the NMDA receptor antagonist memantine. In the U.K., however, the National Institute for Health and Clinical Excellence (NICE), which sets clinical guidelines for the National Health Service, does not recommend donepezil for advanced AD or approve memantine as an add-on. What is the best course of action? According to a paper in the March 8 New England Journal of Medicine, a trial designed to address this question, led by Robert Howard, Kings College London, U.K., found that continuing donepezil treatment into the advanced stage of AD is better for cognition than discontinuing it. The trial data also indicate that substituting memantine offers less benefit than donepezil, and that adding memantine may be no better than continuing donepezil alone, though that latter finding is being challenged. "What was most surprising was the size of the effect of donepezil on cognition," Howard told ARF. "The implication of our study is that far more patients should receive the drug for longer."
In this multicenter, double-blind, randomized, placebo-controlled withdrawal trial, dubbed DOMINO (Donepezil and Memantine in Moderate to Severe Alzheimer's Disease), Howard and colleagues enrolled 295 community-dwelling adults with moderate to severe Alzheimer's disease who scored between 5 and 13 on the Standardized Mini-Mental State Examination (SMMSE). All had been treated with donepezil for at least three months (though many had taken the drug longer, some upwards of five years), and their physicians were considering a change in their therapeutic regimen. Controlling for length of previous donepezil treatment, age, baseline SMMSE score, and center, the team randomly assigned volunteers to stay on the drug, discontinue it (first halving the dose and then starting placebo), swap it for memantine, or add memantine. Patients were tested at six, 18, 30, and finally at 52 weeks with the SMMSE, caregiver-rated Bristol Activities of Daily Living Scale (BADLS), and other tests including the Neuropsychiatric Inventory (NPI).
Patients who stayed on donepezil showed a 32 percent cognitive improvement over those who were taken off the drug at 52 weeks, with an average 1.9-point better score on the SMMSE. Scores on the BADLS were better by about three points (though they fell just short of the authors' pre-specified minimum clinically important difference of 3.5), which amounts to 23 percent behavioral improvement. Patients with higher baseline SMMSE scores benefited the most from continued donepezil.
This study confirms that doctors in the U.S. may be on the right track in terms of prescribing these drugs into advanced stages of the disease, Howard said. He hopes the National Health Service will look upon this as useful evidence in formulating its recommendations. The finding coincides with donepezil's patent expiration, Howard pointed out, so it will become cheaper to keep patients on generic forms for longer. Cost and health economics figure prominently in the NICE’s deliberations.
DOMINO confirms what Andrew Budson, Boston University Alzheimer's Disease Center in Massachusetts, has concluded from his own clinical experience—that donepezil seems to turn back the clock six to 12 months in AD patients, whereas removal is like turning the clock forward by the same amount. "The bottom line is that cholinesterase inhibitors should be started in the earliest stage of Alzheimer's disease and continued throughout the majority of [the patient’s] life," Budson told ARF. "If you can keep someone at a higher level of function, even for six to 12 months, that can be an enormous savings to society at all levels."
In the British study, patients who swapped donepezil for memantine showed some cognitive and functional improvement over the discontinuation group, though neither met the pre-specified clinically important difference. However, memantine appears to help the patient come off of donepezil, said Howard. Adding memantine to continued donepezil treatment showed no added cognitive or functional improvement, but all patients on memantine had better behavioral scores on the NPI than those not on the drug, regardless of donepezil treatment. "The hint of an effect on behavioral symptoms is interesting and could provide a rationale for carrying out further research regarding the combination in this patient population," Douglas Galasko, University of California, San Diego, told ARF in an e-mail.
In 2004, Pierre Tariot, then at the University of Rochester Medical Center, New York, and colleagues reported that, in a larger, six-month study of 404 patients with moderate to severe AD, memantine as adjunctive therapy to donepezil led to significant cognitive, functional, and behavioral improvements over donepezil alone (see ARF related news story). The new results may not contradict that previous study, said Lon Schneider, University of Southern California, Los Angeles, who authored an accompanying NEJM editorial. DOMINO data show an additive benefit at six months that fades by 12 months, he pointed out. Still, further research is needed on whether the two drugs together are better than one, he said in his editorial. At the same time, he cautioned that the dramatically lower SMMSE scores in patients who discontinued donepezil could result from withdrawal, even though the dose was cut in half first. "It might turn out that, if the taper were slower, there would be no difference in those scores," Schneider told ARF. "That needs to be tested."
Schneider cautioned that DOMINO does not provide evidence that indefinite treatment with donepezil is warranted. This was not an efficacy trial, but a withdrawal trial, he said, and hence supports only limited interpretation of drug effects. As previous trials have suggested, donepezil improves cognition and delays functional decline in severely demented, donepezil-naive AD patients (see ARF related news story). Donepezil treatment also improved cognition and global function, but not activities of daily living, for patients with severe AD who were not donepezil naive but had been untreated for at least three months (see ARF related news story).
Tariot, now at Banner Alzheimer's Institute in Phoenix, Arizona, pointed out that enrollment into the DOMINO study fell far short of the 800 volunteers originally sought. The resulting small sample sizes, as well as unequal dropout rates and baseline differences between the groups, may not allow the study to determine whether or not added memantine had benefits beyond donepezil. "The failure to demonstrate a 'statistically significant' effect in this study does not mean or even imply that there is no effect," he wrote in an e-mail to Alzforum. Tariot points to a multicenter trial that did confirm his 2004 study (ClinicalTrials.gov). He further raises the question of how the placebo-treated patients whose cognition dropped off steeply were monitored and protected by the study’s data safety monitoring board (see full comment below).
About half the patients assigned to continue on donepezil stopped taking it during the course of the trial, suggesting that patients experienced side effects or perceived the drug to be ineffective. Even so, said Howard, those who stayed on it had the advantage. "The advice I would give to doctors is, carry on with donepezil so long as the patient is tolerating it and the patients and their caregivers want to go on," said Howard.—Gwyneth Dickey Zakaib
- Trial of Memantine/Donepezil Paves the Way for Combination Therapy
- Donepezil—Relief for Patients with Severe AD?
- Donepezil—Trial Data Show Some Benefit for Patients with Severe AD
- Feldman H, Gauthier S, Hecker J, Vellas B, Hux M, Xu Y, Schwam EM, Shah S, Mastey V, Donepezil MSAD Study Investigators Group. Economic evaluation of donepezil in moderate to severe Alzheimer disease. Neurology. 2004 Aug 24;63(4):644-50. PubMed.
- Jones R, Sheehan B, Phillips P, Juszczak E, Adams J, Baldwin A, Ballard C, Banerjee S, Barber B, Bentham P, Brown R, Burns A, Dening T, Findlay D, Gray R, Griffin M, Holmes C, Hughes A, Jacoby R, Johnson T, Knapp M, Lindesay J, McKeith I, McShane R, Macharouthu A, O'brien J, Onions C, Passmore P, Raftery J, Ritchie C, Howard R, . DOMINO-AD protocol: donepezil and memantine in moderate to severe Alzheimer's disease - a multicentre RCT. Trials. 2009;10:57. PubMed.
- Feldman H, Gauthier S, Hecker J, Vellas B, Xu Y, Ieni JR, Schwam EM, . Efficacy and safety of donepezil in patients with more severe Alzheimer's disease: a subgroup analysis from a randomized, placebo-controlled trial. Int J Geriatr Psychiatry. 2005 Jun;20(6):559-69. PubMed.
- Winblad B, Black SE, Homma A, Schwam EM, Moline M, Xu Y, Perdomo CA, Swartz J, Albert K. Donepezil treatment in severe Alzheimer's disease: a pooled analysis of three clinical trials. Curr Med Res Opin. 2009 Nov;25(11):2577-87. PubMed.
- Howard R, McShane R, Lindesay J, Ritchie C, Baldwin A, Barber R, Burns A, Dening T, Findlay D, Holmes C, Hughes A, Jacoby R, Jones R, McKeith I, Macharouthu A, O'brien J, Passmore P, Sheehan B, Juszczak E, Katona C, Hills R, Knapp M, Ballard C, Brown R, Banerjee S, Onions C, Griffin M, Adams J, Gray R, Johnson T, Bentham P, Phillips P. Donepezil and memantine for moderate-to-severe Alzheimer's disease. N Engl J Med. 2012 Mar 8;366(10):893-903. PubMed.
- Schneider LS. Discontinuing donepezil or starting memantine for Alzheimer's disease. N Engl J Med. 2012 Mar 8;366(10):957-9. PubMed.