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1. Letter to the Editor

   • Theresa Rowe, MD
   • Thomas Finucane

   Johns Hopkins Bayview Campus

   The clinical practice guideline on pharmacologic treatment of dementia (1) is ambiguous and misleading. Does Recommendation 1, “Clinicians should base the decision to initiate a trial of therapy …” mean that there is such a decision to initiate? In our opinion, this could be stated more clearly as, “the decision whether to initiate therapy”. The studies of cholinesterase inhibitors (ChEIs) have shown consistent small improvements in cognition and global assessments, and none have shown consistent improvement in quality of life or behavior. Comparing placebo to donepezil on the Alzheimer Disease Assessment Scale- cognitive subscale, for example, the accompanying evidence review states that “no group achieved a change of 4 points (the change considered clinically significant),” and concludes “Treatment of dementia with cholinesterase inhibitors and memantine can result in statistically significant but clinically marginal improvement in measures of cognition and global assessment of dementia.”(2) The 2001 American Academy of Neurology practice guideline on the same subject concludes that studies of cholinesterase inhibitors “suggest a small average degree of benefit.”(3).

   Recommendation 1 continues that the decision to initiate a trial of therapy should be based on an individualized assessment. What are we to assess? Might there be a particular subgroup that would benefit? If so, what are the characteristics of this group?

   Recommendation 3 notes “an urgent need for further research on the clinical effectiveness of current pharmacological treatment for dementia”. According to the article 59 unique trials of at least moderate quality have been published that study current treatment. The authors could say that research is needed to determine whether there is a subset of patients who might realize meaningful benefit from these drugs. These studies have not been done. They could also say that there is an urgent need for pharmacological treatment that can provide meaningful help to patients suffering from this terrible illness.

   The multibillion dollar sales of drugs whose actual clinical effectiveness has not really been shown is based in part on guidelines like these.

   Theresa A. Rowe, MD Thomas E. Finucane, MD Johns Hopkin Bayview Medical Center Baltimore, MD 21224

   Reference List

   (1) Qaseem A, Snow V, Cross JT, et al. Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2008 March 4; 148(5):370-8.

   (2) Parminder R, Pasqualina S, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med. 2008 March 4; 148(5):379-97.

   (3) Doody RS, Stevens JC, et al. Practice parameter: management of dementia (an evidence-based review). Report of the quality standards subcommittee of the American Academy of Neurology. Neurology. 2001 May 8; 56(9):1154-66.

   Conflict of Interest:

   None declared

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   Published April 18, 2008
2. In Response

   • Ben Seltzer, MD

   Harvard Medical School

   As a neurologist/investigator who participated in clinical trials of all 5 FDA-approved drugs for Alzheimer’s disease (AD), I read with consternation the recommendations of Qaseem et al for the treatment of dementia. I fear they will set back for many years efforts of AD specialists, the Alzheimer Association, and others to improve the lot of AD patients.

   If we had strongly effective, disease-modifying therapies for AD, there would be no argument about treatment. But such therapies are not available and may not be for a long time. In the meantime we have an ever growing number of AD patients and family members who are in great distress.

   Qaseem et al have decided to accept only certain psychometric changes, e.g. improvement of 4 or more points on the ADAS-cog scale, as evidence of clinically significant benefit from therapy. But such a decision is purely arbitrary. The FDA set up many other well-thought out criteria, which also have validity as indicators of improvement and were in fact met by all currently available drugs.

   Qaseem et al. admit that many AD patients do meet their high standard for clinically important improvement with current therapies. Predicting who will respond in such a way is a topic of intense interest, but still unresolved. In the absence of such information, it seems reasonable to give most patients with AD the opportunity to benefit from anti-AD medications. The recommendation of Qaseem et al. to base treatment on an “individualized assessment” is ambiguous because they do not present any information on how to decide whom to treat. Rather than guide the physician, they cause further confusion.

   Their guidelines are also at substantial variance with those of the American Academy of Neurology (Doody et al., Neurology 2001;56:1154-1166) and the American Psychiatric Association (available at www.psych.org).

   Conflict of Interest:

   Past Research support, honoraria for speaking: Eisai/Pfizer; Janssen; Novartis; Forest

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   Published April 3, 2008