Questioning the evidence
========================

* Alan Cassels

I am writing about a recent article in the CMA Leadership Series on Elder Care, distributed with the Nov. 8, 2005, issue of *CMAJ*.1

As one who has been studying the research and marketing related to Alzheimer's disease (AD) treatments for nearly a decade, I found the article disturbing. The discussion on the benefits of the AD drugs are nearly opposite to what the best evidence says.

The writer states that “In numerous randomized clinical trials (RCTs), cholinesterase inhibitors (ChEIs) have consistently been shown to improve or delay the decline of cognitive functioning, delay the emergence of challenging behaviours and slow the loss of activities of daily living. In RCTs, benefits have been shown to last over a period of up to 2 years, with data from open-label trials suggesting a longer benefit.”1

However, the company-sponsored trials upon which this statement relies are problematic and overstate the case for the role of these drugs in managing AD. The latest meta-analyses find that the effects of ChEIs are marginal to non-existent.2

I found the discussion of side effects almost laughable: “Before initiating treatment, physicians should discuss reasonable expectations with the patient and their caregiver. Patients should be warned of possible side effects, noting that they are often mild and fleeting.”1

When I have read the monographs of the key AD drugs, the effects such as nausea, vomiting, anorexia and stomach upset are as high as 30%. In fact some commentators have joked that these drugs are more effective as weight-loss pills than altering the rate of cognitive decline. Here is an example of some of the side effects related to an AD drug, rivastigmine (taken from the product monograph):

Exelon's use is associated with significant gastrointestinal adverse reactions, including nausea and vomiting, anorexia, and weight loss. In the controlled clinical trials, 47% of the patients treated with an Exelon dose in the therapeutic range of 6 to 12 mg/day developed nausea (compared with 12% in placebo). A total of 31% of Exelon-treated patients developed at least one episode of vomiting (compared with 6% for placebo). The rate of vomiting was higher during the titration phase … than in the maintenance phase … Five percent of patients discontinued for vomiting, compared to less than 1% for patients on placebo.3 

I don't know any physician who would dismiss these effects as “mild and fleeting.”

I would echo the words of one researcher, Jason Karlawish, who remarked on a flawed study on donepezil with: “Would it be churlish to wonder out loud how this paper is different from an advertisement?”4 I have to admit I am on the verge of losing a lot of respect for the *CMAJ* unless it stops distributing this kind of clearly biased and non–evidence-based fluff. I cannot see how it is in the best interests of physicians to have such articles published under the banner of *CMAJ*.

## REFERENCES

1.  1. Keren R. Managing Alzheimer's disease. *Elder care: issues and options for Canadian physicians 2005*. CMA Leadership Series; 2005.
    
    

2.  2. Kaduszkiewicz H, Zimmermann T, Beck-Bornholdt HP, et al. Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials. BMJ 2005;331(7512):321-7.
    
    [Abstract/FREE Full Text](http://www.cmaj.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MzoiYm1qIjtzOjU6InJlc2lkIjtzOjEyOiIzMzEvNzUxMi8zMjEiO3M6NDoiYXRvbSI7czoyMzoiL2NtYWovMTc0LzkvMTMwNC4xLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

3.  3. Exelon (rivastigmine tartrate) [product monograph]. East Hanover (NJ): Novartis Pharmaceutical Corporation; 2006.
    
    

4.  4. Karlawish JH. Donepezil delay to nursing home placement study is flawed. J Am Geri Soc 2004;52:845.
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=15086676&link_type=MED&atom=%2Fcmaj%2F174%2F9%2F1304.1.atom)