. Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomised trials. PLoS Med. 2007 Nov 27;4(11):e338. PubMed.

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  1. A systematic review collects all relevant studies on a subject, integrates findings, and allows readers to do their own assessments based on all available evidence. Inferences from systematic reviews stand in sharp contrast to picking and choosing individual studies from which to make decisions such as treatment.

    Mild cognitive impairment (MCI) has been controversial both in terms of clinical validity and treatment. Many physicians choose to treat patients they diagnose with MCI with cholinesterase inhibitors.

    Raschetti and colleagues did a systematic review of randomized, placebo-controlled MCI trials of the marketed cholinesterase inhibitors. They identified eight such trials, including two in which data were unavailable. The authors neatly summarized characteristics and outcomes of the trials and made a number of observations:

    1. Although the trials used the Petersen or Mayo Clinic criteria for MCI, each trial operationalized the criteria differently.

    2. The outcomes and scales used, especially cognitive scales, varied widely beyond the omnipresent the ADAS-cog. The reviewers arranged these in a matrix by MCI trial and showed a forest plot of the outcomes of the trials.

    3. Their most remarkable observation is the distinct lack of evidence for cognitive, ADL, behavior, or global effects on any of the measures over the 2- to 4-year courses of the trials. The one exception was a significant effect on the 13-item ADAS-cog in favor of donepezil in the one short-term, 6-month long trial. (It is notable that the ADCS donepezil and vitamin E trial showed a similar effect at 6 months that was lost after 18 months).

    The reviewers discuss the thorny issue of making inferences about treatment when the condition being treated, MCI in this case, is so heterogeneous. They cite important work by Visser and colleagues, who applied the protocol-specified MCI criteria used by Janssen, Novartis, and the ADCS to their clinic patients and found differing prevalences of 51 percent, 21 percent, and 17 percent, depending on the criteria.

    Finally, they voiced the ethical specter that the uncertainty of currently applied MCI diagnostic criteria prompts questions about the scientific validity and ethical value of the trials. They quote from Jason Karlawish’s paper that the “logic of clinical purpose” of clinical trials is they be “logically grounded in, and ethically justified by, the way they reflect and contribute in clinical practice.” The authors opine that MCI may be an example of a “risk factor conceptualized as a clinical condition,” and caution that “when there is controversy surrounding the definition of a condition or disease, even inconclusive results from RCTs can be used to suggest treatment.” They estimate that in Italy, 27 percent of patients diagnosed with MCI are prescribed cholinesterase inhibitors, and needless to say, they don’t think this is a good thing.

    References:

    . Alzheimer's disease--clinical trials and the logic of clinical purpose. N Engl J Med. 2006 Oct 12;355(15):1604-6. PubMed.

    . Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005 Jun 9;352(23):2379-88. Epub 2005 Apr 13 PubMed.

    . Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomised trials. PLoS Med. 2007 Nov 27;4(11):e338. PubMed.

    . Do MCI criteria in drug trials accurately identify subjects with predementia Alzheimer's disease?. J Neurol Neurosurg Psychiatry. 2005 Oct;76(10):1348-54. PubMed.

    View all comments by Lon Schneider