With the exception of the glutamate antagonist memantine, the only drug treatments currently approved by the U.S. Food and Drug Administration for treating Alzheimer disease are cholinesterase inhibitors, such as donepezil. But because these drugs are only approved for mild to moderate AD, doctors and caregivers face a difficult decision: Do you take your patient, or family member, off the drug once the disease has progressed to the severe stage, or do you keep them on the drug in the hope that it continues to do some good. Those who opt for the latter might find some solace from a study reported in this week’s Lancet online. The study does not address the question directly, though, because it was designed to test the cholinesterase inhibitor donepezil in patients with severe AD who were donepezil “naïve.” In other words, it was not designed to address the benefit of continuing treatment in those already on the drug once dementia becomes severe.

Nevertheless, the study found that the cholinesterase inhibitor improved cognition and delayed functional decline in patients with severe AD. Bengt Winblad, Karolinska Institute, Stockholm, and colleagues from the Severe Alzheimer’s Disease Study Group, a Swedish-based consortium that includes employees of Pfizer, the pharmaceutical company that markets the drug, tested donepezil in a double-blind, placebo-controlled study that lasted 6 months. At the beginning, middle and end of the trial, the Group scored patients in tests of cognition (the severe impairment battery or SIB) and ability to perform daily living tasks (the Alzheimer’s Disease Cooperative Study activities of daily living for severe AD, or ADCS-ADL-severe). The researchers found that though SIB scores continued to decline in the placebo group, with patients losing two points on average over 6 months, SIB scores actually increased in those on donepezil—patients taking the drug had SIB scores that were about four points higher at the end of the trial. Similarly, ADCS-ADL scores in the drug group declined at a much slower rate than in the placebo group. While the latter lost an average of three points by the end of the trial, patients on the drug only scored about one point lower. “Our findings indicate that donepezil can improve cognition and preserves function in patients with severe Alzheimer’s disease,” write the authors.

But many, including David Hogan, a clinician at the University of Calgary Health Sciences Center, Alberta, Canada, may see a cloud in the silver lining. On the larger issue of whether or not cholinesterase inhibitors should be prescribed for those with severe AD, “for various reasons, I believe such treatment might be a case of too little, too late,” Hogan writes in an accompanying Lancet editorial.

Hogan suggests that even by their own criteria, the Study Group has failed to demonstrate that the drug’s impact is large. While Winblad and colleagues sized the study in order to detect minimum differences of 3.6 on the ADCS-ADL scale and 7 on the SIB scale—values that they believed would be statistically significant—they only detected differences of 1.7 and 5.7, respectively. “Although statistically significant, are these differences clinically important?” Hogan asks. When the SIB scores are broken down, for example, patients on the drug performed significantly better on only three measures out of nine: language, praxis, and visuospatial ability. Similarly, significant improvements were seen in only two of six basic measures of daily living: bowel/bladder function (cholinesterase inhibitors are commonly used to treat incontinence unrelated to Alzheimer disease) and getting dressed. What is desperately required in dementia trials is a way to achieve more meaningful outcomes, Hogan suggests.

Though doctors and family may grasp at even a modest, temporary improvement in patients with severe AD, there could be a downside. While offering modest benefit, cholinesterase inhibitors could potentially increase the length of time patients have the disease. Winblad and colleagues contend that there is no increase in survival on sustained cholinesterase inhibitors (see, for example, Lopez et al., 2002), but Hogan disagrees (see Gasper et al., 2005). And while the debate over this is often framed in terms of healthcare cost, another important consideration is whether a minor benefit for severe AD patients may be offset by a protracted illness further down the road (the benefit and cost-effectiveness of prescribing cholinesterase inhibitors to people with mild to severe AD is contentious, as well—see ARF related news story).

While the debate about cholinesterase inhibitors and survival continues, it is worth noting that in a recent clinical trial for donepezil in vascular dementia, there were more deaths in the treatment group than among those on placebo. Out of 648 patients enrolled to take the drug for 24 weeks, 11 died, while none of 326 patients in the placebo group did. The latter number appears to be smaller than expected in the placebo group, while the death rate in the treatment group (1.7 percent) is similar to that observed in other studies of vascular dementia, according to news reports. Eisai Company, the manufacturer of the drug, has apparently relayed the safety data to regulatory authorities worldwide.—Tom Fagan


  1. This Swedish nursing home trial demonstrates the practical utility of donepezil in severely impaired Alzheimer patients and provides support for its use. It shows that more patients with severe illness actually improve their cognitive functioning and to a relatively marked extent over their baselines. By comparison, patients with mild to moderate AD generally only maintain their function with the drug over a 6-month trial. The overall group effect on the Severe Impairment Battery was a mean improvement of three or four points above baseline in the donepezil group and did not depend on the placebo group continuing to decline in order to gain statistical significance. More than half of the treated patients showed overall clinical improvement compared to about one-third of placebo patients on the CIBIC+, that is, 53-59 percent versus 36-38 percent.

    This trial demonstrates again the realistic limitations of these medications, that they can improve intellectual functioning, communication, and general clinical state, while not actually improving activities of daily living but attenuate their worsening.

    To a large extent, the trial contradicts the claims by manufacturers that these drugs must be used early in the course of illness and continued indefinitely, and undermines claims that the drugs alter the course of the illness. The fact that donepezil shows this robust an effect in severe dementia demonstrates the potential that many patients will show improvements at various times throughout their illness.

    Many physicians have been using cholinesterase inhibitors in patients with severe dementia even though the labeling is for mild to moderate AD. So the results support donepezil use here, provided there are no medical contraindications such as significant cardiovascular or pulmonary disease, syncope, gastrointestinal disease, seizures, etc.

    David Hogan, in an accompanying editorial, correctly questions aspects of the clinical significance of donepezil because this and nearly all other cholinesterase inhibitor trials were not designed to measure the number of individual patients who actually gain worthwhile benefits. (The way the CIBIC+ clinical global rating is used doesn’t quite do this). The study reports mainly average changes on test scales that don’t translate into the numbers of individuals who uniquely benefit from treatment. Yet the overall clinical impression from the CIBIC+ of 53-59 percent improving with donepezil versus 36-38 percent with placebo reported in the trial (a statistically “moderate” effect size implying that the number needed to treat for one patient to benefit could be about 5 or 6) would be quite clinically significant if those particular patients also could be shown to have sustained their improvements and to have improved their cognitive function. Without the use of appropriate individual patient outcomes, the clinical meaning of the statistical effects of cholinesterase inhibitors and memantine will continue to be elusive.

    There is no evidence, one way or another, that prescribing a cholinesterase inhibitor—or memantine for that matter—would either increase or decrease overall costs for nursing home patients. (No doubt we will soon see such claims after “economic” analyses are bootstrapped on to this trial). Regardless, and more importantly, there is nothing wrong with paying for a treatment that really improves patients’ function and quality of life. Moreover, people with severe dementia who live in nursing homes can and do have meaningful quality of life, and there is nothing wrong with prolonging their survival even if it costs more. There is no credible evidence, however, that these drugs prolong survival, just that they improve symptoms. (There is also no credible evidence that they delay nursing home placement in more mildly impaired patients).

    It is a bit of an overstatement for David Hogan to describe the effect in this study as “too little, too late,” as some patients can meaningfully benefit, probably even some who may have received cholinesterase inhibitors previously and had not benefited from them then. It could be that cholinesterase inhibitors have their best and most pronounced effects in people who are further along in their illness with more severe cholinergic deficits. This, however, might run counter to the interests of some who want the medications to be started early in the course and continued indefinitely. The political climate may not allow us to accept these trial results with as much enthusiasm as they deserve.

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News Citations

  1. Cholinesterase Inhibitors Not What They're Cracked Up To Be?

Paper Citations

  1. . Cholinesterase inhibitor treatment alters the natural history of Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2002 Mar;72(3):310-4. PubMed.
  2. . Is donepezil therapy associated with reduced mortality in nursing home residents with dementia?. Am J Geriatr Pharmacother. 2005 Mar;3(1):1-7. PubMed.

Further Reading

Primary Papers

  1. . Donepezil in patients with severe Alzheimer's disease: double-blind, parallel-group, placebo-controlled study. Lancet. 2006 Apr 1;367(9516):1057-65. PubMed.