Re: TREAD

In the September issue of this journal, several articles reviewed and endorsed the use of cholinesterase inhibitors in the treatment of Alzheimer disease. These included a report of a consensus conference (TREAD)[1] attended by numerous local leaders in the field. Some clinicians, including notable academics, will no doubt argue that cholinesterase inhibitors have not proven their worth. To support their view, they may cite the AD2000 reported earlier this year.[2] While this study had one point in its favor—namely that it was not supported by pharmaceutical companies—I believe that it was flawed in numerous ways, and that its results should be viewed with skepticism. Consider the following points. (1) Donepezil (the drug under study) was already available and considered by many to be the standard of care in AD. The investigators therefore enrolled only patients whose clinicians were “substantially uncertain that the individual would obtain a worthwhile clinical benefit from donepezil.” This enrollment criterion may have introduced substantial selection bias against responders. (2) Of those patients randomized to donepezil, half received only 5 mg per day, a dose known to be less effective. (3) For unknown reasons, the investigators used drug washouts of 4 to 6 weeks’ duration throughout the study. It has already been established that washouts cause loss of accrued benefits. (4) The study sought to enroll 3000 subjects but experienced recruitment problems and settled for 565. As others have pointed out, this study may have been significantly underpowered.[3] (5) The results of this study are inconsistent with an impressive number of pivotal trials, all of which show a remarkable degree of consistency with each other.

Like the many good clinicians who participated in the TREAD conference, I believe that cholinesterase inhibitors offer evidence-based (as opposed to hope-based) efficacy. Acknowledging that the magnitude of benefit is modest, we eagerly await the arrival of more potent therapeutic strategies.

—Douglas C. Drummond, MD
New Westminster

The authors respond

We are grateful for the interest that our theme issue, “The new era of treatable Alzheimer disease,” September 2004 [1] has generated and for the opportunity to respond to the letters to the editor that have been written.

Dr Rees has asked[2] that a recently published study in Lancet be commented on in our consideration of the acetylcholinesterase inhibitors (AchEIs) as therapy for AD. We agree with Dr Rees that the results of the AD2000 should be considered with the other trials that have been done with AchEIs and feel that the evidence needs to be considered in its aggregate. The value of the TREAD conference is that it specifically set out to address this aggregate of all of published RCTs through January 2003. There was, however, no provision within TREAD for an ongoing process to review articles that might be subsequently published such as the AD 2000 study in Lancet by Courtney and colleagues.[3] As the consensus process of the TREAD involved presentation, debate, and then voting by participants, we did not feel that we could add this paper into the TREAD consensus proceedings. In turn we can only respond to Dr Rees with our own opinion of the AD2000 study, a study that had very substantial design and methodological limitations and whose conclusions must be read with considerable caution.

The AD2000 study set out to determine the long-term benefits of donepezil treatment. The study called for an a priori sample of 3000 subjects yet recruited only 15% of its intended sample. At 1 year it reported a 40% dropout rate and at 2 years a 77% dropout, making the likelihood of a type II error quite high. The authors designed the study to include patients around a principle of uncertainty of response to treatment. As well, they washed patients from treatment at the end of each year of therapy, an effect which Dr Drummond points out in his letter would on average remove the symptomatic benefit and set the patients backwards. Neither of these maneuvers are consistent with usual care, which was to be the guiding basis for conducting the study. The bias that these decisions exerted on the results was likely important though remains difficult to determine. Dr Drummond posits in his letter that the uncertainty principle likely biased the study against donepezil responders being included.

On the positive side of this study, the 2-year placebo-controlled results within the small remaining sample indicated that there were small but statistically significant symptomatic benefits on both cognition (MMSE) and ADLs (Bristol ADL). This extends our understanding of the symptomatic efficacy of donepezil to 2 years from the previous longest 1-year placebo study.[4]

It remains our opinion that these small symptomatic benefits in AD of the AchEIs are indeed meaningful to patients, caregivers, and the community and ought not to be overlooked or marginalized as being unimportant. We do not see the withholding of such treatments on the grounds that the benefits should be greater, as being in the interest of our patients.

— H. Feldman, MD
B.L. Beattie, MD
Vancouver

References

1. Feldman H, Beattie BL. The new era of treatable Alzheimer disease: Ending a dark age in British Columbia. BCMJ 2004; 46:332-333. Full Text
2. Rees P. Re: Alzheimer dementia, cholinesterase inhibitors, and impartiality. BCMJ 2004;46:500. Full Text
3. Courtney C, Farrell D, Gray R, et al. Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): Randomized double blind trial. Lancet 2004;363:2105-2115. PubMed Abstract Full Text
4. Winblad B, Engedal K, Soininen H, et al. A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology 2001; 57:489-495. PubMed Abstract Full Text