[The author responds:]
Mr. Cassels raises 2 major objections relating to comments I made about the treatment of AD with ChEIs.1 His first objection refers to the quality of the evidence supporting the use of these medications. The second objection relates to the tolerability of these drugs, specifically, addressing the issue of gastrointestinal side effects.
With regards to the evidence supporting the use of ChEIs, to date there are 22 RCTs with ChEIs published in leading peer-reviewed journals, including the New England Journal of Medicine, the Journal of the American Medical Association, the Lancet, Neurology and JAGS, that have consistently shown a modest benefit for patients with AD. All these trials were carried out under Good Clinical Practice and International Conference of Harmonization guidelines.2 Based on a systemic review of these trials, the Canadian Consensus Conference on Dementia guidelines1 unequivocally recommended that all patients with mild to moderate AD be offered a trial of one of these drugs. Mr. Cassels argues that a recently published systematic review by Kaduszkewicz in BMJ3 is “best evidence” and, in his view, this review not only negates the evidence from the aforementioned published clinical drug trials but also 4 previously published meta-analyses of ChEIs4–7 and the Cochrane reviews,8–10 all of which have concluded that ChEIs offer a modest benefit to patients with AD in the domains of cognition, behaviour, function and caregiver burden. In September 2005 the Canadian Coordinating Office for Health Technology Assessment (CCOHTA) published a systematic review of this class of drugs claiming a modest impact on functional performance and global outcomes.11 Lastly, in a recent survey conducted in the UK in 2295 patients with AD treated with ChEIs and the caregivers, 1569 (68%) of people who had been treated with at least one of the ChEIs stated that the treatment had worked. The 10 most frequently reported benefits included being more aware and more active, calmer, taking more interest in things, improved conversation, better quality of life and increased confidence, in addition to the improvements usually evaluated in clinical trials.12 No study is without its flaws, but to write off all of the evidence supporting the use of ChEIs in the treatment of AD based on one critical review seems unreasonable. The Health Protection Branch of Health Canada has weighed the evidence and approved the use of these drugs for the treatment of mild to moderate AD, and most provincial and private drug benefit programs provide financial coverage for their use.
ChEIs are considered to be safe and well tolerated. The CCOHTA report concluded that these drugs have not shown an increased risk of serious adverse events or death. With regard to side effects, Mr. Cassels bases his comments on one of the drug's (rivastigmine) product monograph, citing a high incidence of gastrointestinal side effects and compares the drugs to “weight loss pills.” Gastrointestinal side effects are known to occur in this class of drugs, but their prevalence as reported in product monographs is based on data from clinical drug trials, which is greater than what is seen in clinical practice. This is for two reasons: first, in clinical drug trials a side effect is reported regardless of its frequency and severity: second, dosages are increased using forced titration schedules. In clinical practice, physicians can reduce the impact of side effects through slower titration and dose adjustments. Also, they can address the patient's treatment expectations and potential side effects by providing education and support. Having personally treated hundreds of patients with these drugs, nausea, vomiting and weight loss have been infrequent complaints that have rarely necessitated discontinuation of treatment, and when treatment is stopped these side effects generally resolve quickly.
Mr. Cassels' comments echo a number of recent critical reviews of ChEIs, including the preliminary report from the UK's National Institute of Clinical Excellence and the University of British Columbia's Therapeutics Initiative. These reports question the cost effectiveness of treating patients with ChEIs, claiming that the drugs, at best, have a modest effect and do not delay milestones such as time to institutionalization. As your readers know, AD is a progressive neurodegenerative disease for which there is no cure. It affects over 300 000 Canadians, robbing them of their self, stripping the, of their independence, leading them to institutionalization and death. In doing so, AD places a huge burden on patients, their caregivers and society at large. Taking this into consideration, treatments that offer even modest benefits can have an important impact on the quality of life of patients and caregivers affected by this disease.