The use of ChEIs in persons with MCI, for periods ranging from less than 4 mo to 3 y, was not associated with any delay in the onset of AD or dementia. Furthermore, according to the 38 surrogate measures used in the trials, and after appropriate adjustment for multiple comparisons, only neuroimaging showed a significant difference in favour of the drug being studied; the clinical implications of this finding are unclear [32
]. Moreover, the safety profile showed that the risks associated with ChEIs are not negligible.
These results confirm for the all class of ChEIs those reported by two Cochrane systematic reviews. The first review was on the effect of galantamine in patient with MCI or AD; the authors concluded that the clinical benefit was marginal but “galantamine use in MCI is not recommended due to its association with an excess death rate” [20
]. The second review [21
] included two trials on donepezil, one that showed some promise for certain outcomes [36
], and the other that showed side effects and no evidence of efficacy [37
]. The authors' conclusion was “there is no evidence to support the use of donepezil for patient with MCI. The putative benefits are minor, short lived and associated with significant side effects” [21
A recent meta-analysis on four trials using progression to dementia as the major parameter of efficacy found an approximate 24% reduction of risk of conversion to dementia and an increase of more than 50% in adverse events [38
]. This pooled effect estimate was obtained notwithstanding the substantial heterogeneity of populations enrolled nor the methods of assessment. Moreover, the relative risk of conversion could not be calculated for the two trials on galantamine, as original data were necessary to apply a Cox proportional hazard ratio model.
Our revision of all the trials on the three drugs permits an overall comparison across the studies with respect to design, objective, and definition of MCI.
The primary end point of prevention trials should be the time to development of dementia or AD; this measure was used in only four of the trials included in this review [31
]. The efficacy of the study drugs was also assessed on cognitive and/or functional domains applying a number of surrogate measures: 38 different instruments were used, considering simultaneously a wide range of hypotheses. Moreover, most of these measures have been developed for AD trials and transposed to MCI trials without first having been validated. However, it has already been claimed that the validation process is not simple, given that it is subordinate to the definition of MCI as a clinical entity, which itself is controversial [10
A first important consequence of this uncertainty is that the trial populations were not homogeneous, even if the same criteria proposed by Petersen and colleagues were used [9
]. Petersen and colleagues, in fact, did not specify which neuropsychological tests or instrument should be used to operazionalise MCI criteria. The predictable consequence of this flexibility is that operationalisation of the MCI diagnostic criteria differed widely among the trials, giving rise to quite different populations.
This was confirmed in a recent study in which the authors applied the enrolment criteria used in the GAL-INT-11, InDDEX, and Petersen et al. trial to the same cohort of 150 participants sampled in a memory clinic [15
]. The study found that MCI was diagnosed in 51.3%, 21.3%, and 16.7% of the participants when applying, respectively, the criteria of GAL-INT-11, InDDEX, and Petersen's trial. This wide clinical heterogeneity among the study populations is the main reason for not combining the included studies in a pooled analysis.
In general, the uncertainty regarding MCI as a clinical entity raises the question as to the scientific validity and ethical value of these trials [39
]. In fact, the requirement of scientific validity regards not only the mere technical domain of the correct design and conduct of a clinical trial. It is also a criterion to apply to the soundness of the clinical question approached by the experimentation. In a recent New England Journal of Medicine
editorial, Karlawish used the concept of the “logic of clinical purpose” in discussing the role of clinical trials in AD [40
]. According to this idea, ”Clinical trials are logically grounded in and ethically justified by the way they reflect and contribute to clinical practice.” As some participants in a 2006 workshop dedicated to MCI have reported, no agreement emerged during the conference as to the clinical utility of MCI, in that there was no consensus on the nature of MCI (is it a syndrome, a risk state, a new diagnosis?) [13
Moreover, there is epidemiological evidence that the diagnosis of MCI is often unstable, and many persons labelled as having MCI may revert over time to normal cognition [16
]. Since none of the trials provided information on this phenomenon, it cannot be excluded that some participants may have received the treatment despite having reverted to normal cognition.
A possible limitation of our review was that there was no information on the results of two trials: one of the trials was suspended for unknown reasons [35
], and the other was completed in September 2004, yet the results are not yet available [30
]. Nonetheless, this probably did not bias the risk–benefit profile of ChEIs for MCI patients, given that publication bias usually works in favour of the study drugs.
With regard to the quality of reporting of the trials, a common shortcoming was the inadequate description of the randomization and blinding procedures. Other important weaknesses were the very poor description of dropouts and of harm-related issues (e.g., only one trial reported all of the causes of death for each study arm). Our review was not blinded to the trials. This may have influenced our assessments of the quality of primary studies, although, given the simplicity of the Jadad scale, distorted judgements are very unlikely.
On average, the maximum dosage of ChEIs was used in all trials, which probably contributed to the high frequency of dropout and discontinuation for AEs. Mortality was higher among persons receiving donepezil or galantamine, compared to placebo recipients, and this excess in mortality seems to have been prevalently due to cardio- and cerebrovascular diseases. In GAL-INT-11 [32
] and GAL-INT-18 [33
], the regulatory authorities considered the increased mortality as noteworthy and stressed that ChEIs are not indicated for MCI patients; they also recommended that ChEIs be used with caution in AD patients with cardiovascular risk factors [22
Recently, some authors have suggested the rating of medial temporal atrophy, performed using magnetic resonance imaging, as a routine clinical evaluation to identify “individuals with MCI who are destined to progress to dementia within 3 years” [43
MCI seems to be an example of a risk factor conceptualised as a clinical condition, and it is surely still too heterogeneous and unpredictable as a clinical entity to enable researchers to establish its exact role in the progression toward dementia. From a public health point of view, it seems reasonable to affirm that additional research for clearly defining MCI is needed before testing new pharmacological treatments. When there is controversy surrounding the definition of a condition or disease, even inconclusive results from RCTs can be used to suggest treatment for persons tagged with some “pre-disease” condition. For example, in Italy an extimated 27% of patients diagnosed with MCI are prescribed cholinesterase inhibitors off-label [44
]; it is likely that this situation is not limited to Italy.
The philosophy of widening the boundaries of treatable illness corresponds to the strategy of expanding the market for new products. This has been recently described as “disease mongering” [45
]. This issue was also recently addressed by Britain's House of Commons Health Committee: “[…] There has been a trend towards categorising more and more individuals as ‘abnormal' or in need of drug treatment […]. Where disease awareness campaigns end and disease mongering begins is a very indistinct line” [47
This review shows that the diagnosis of MCI is uncertain and variable, and whatever criteria are adopted, ChEIs are not effective in either preventing AD or improving cognitive functions in persons with MCI. These drugs may even be harmful in some people. Thus the alleged clinical implications of the trials, as claimed by some of the authors, are not justified by the data.