3 April 2006. 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.
Winblad B, Kilander L, Eriksson S, Minthon L, Båtsman S, Wetterholm A-L, Jansson-Blixt C, Haglund A. Donepezil in patients with severe Alzheimer’s disease: double-blind, parallel-group, placebo-controled study. The Lancet. March 23, 2006. Online publication. Abstract
Hogan DB. Donepezil for severe Alzheimer’s disease. The Lancet. March 23, 2006. Online publication.