Effects of rivastigmine on cognitive function in patients with traumatic brain injury
James M.Noble, M.D., Gertrude H. Sergievsky Center, Department of Neurology, Columbia University Medical Center, New York, 710 W 168th St, New York NY 10032jnoble@neuro.columbia.edu
W. Allen Hauser, M.D.
Submitted December 03, 2006
Efforts to identify treatments for traumatic brain injury (TBI)
should be commended since the condition often removes the young from
social and functional independence. However, in attempting to identify novel
treatments, inappropriate conclusions should not be drawn when the study rigor
does not warrant them. We are concerned by the potentially misleading abstract
conclusions regarding rivastigmine and TBI reported by Silver et al. [1]
As
described in the abstract and manuscript results sections, the primary
cognitive outcome measures showed no difference compared to placebo at any
time. The final statement "rivastigmine shows promising results in the
subgroup of patients with traumatic brain injury with moderate to severe
memory deficits" seems inconsistent with the results presented in the
paper.
The abstract conclusion reflects what the authors described as
"additional analyses…planned to identify subgroups more likely to benefit
from treatment." Referring to the corresponding clinical trial identifier
# NCT00171795 (and the open-label 26 week extension, CTI #NCT00219245)[2],
there were no planned secondary analyses based on pre-treatment severity
of illness. That these patients with moderate to severe memory deficits
had greater improvement hinges upon post-hoc analysis of 81 patients with
relatively worse baseline scores on two of twelve reported tests. Several
concerns arise from these analyses.
First, the characterization of people
meeting "moderate to severe impairment" would not be clinically possible;
for clinical usefulness, these criteria are crucial. The results of the
other ten tests in this group, including several others testing aspects of
memory, are not discussed. Given no difference overall,
improvement on selected tests in severely impaired patients begs the
question of impact on mildly impaired patients. Was there a subgroup that
actually did worse while on treatment? How many different cuts were made
before a "severely affected" subgroup became defined? Wide variances,
small sample sizes, and use of a single direction standard-error bar chart
for data presentation, make p-value interpretations of the reported tests
dubious. A table listing results of each test performance relative to a
defined pre-study cognitive function (mild vs. moderate-severe) would be
more informative to the reader.
Given that TBI phenotype and recovery periods widely vary, perhaps
future study design should include a lead-in period of serial
neuropsychological tests to establish pre-treatment cognitive trends, pre-
determined post-treatment analyses, and standard neuropsychological test
cutoffs and clinical criteria for degree of cognitive impairment.
References
1. Silver JM, Koumaras B, Chen M, et al. Neurology.
2006;67:748-755.
2. http://www.clinicaltrials.gov, using search terms "Rivastigmine"
or "Traumatic Brain Injury"
Disclosure: The authors report no conflicts of interest.
Efforts to identify treatments for traumatic brain injury (TBI) should be commended since the condition often removes the young from social and functional independence. However, in attempting to identify novel treatments, inappropriate conclusions should not be drawn when the study rigor does not warrant them. We are concerned by the potentially misleading abstract conclusions regarding rivastigmine and TBI reported by Silver et al. [1]
As described in the abstract and manuscript results sections, the primary cognitive outcome measures showed no difference compared to placebo at any time. The final statement "rivastigmine shows promising results in the subgroup of patients with traumatic brain injury with moderate to severe memory deficits" seems inconsistent with the results presented in the paper.
The abstract conclusion reflects what the authors described as "additional analyses…planned to identify subgroups more likely to benefit from treatment." Referring to the corresponding clinical trial identifier # NCT00171795 (and the open-label 26 week extension, CTI #NCT00219245)[2], there were no planned secondary analyses based on pre-treatment severity of illness. That these patients with moderate to severe memory deficits had greater improvement hinges upon post-hoc analysis of 81 patients with relatively worse baseline scores on two of twelve reported tests. Several concerns arise from these analyses.
First, the characterization of people meeting "moderate to severe impairment" would not be clinically possible; for clinical usefulness, these criteria are crucial. The results of the other ten tests in this group, including several others testing aspects of memory, are not discussed. Given no difference overall, improvement on selected tests in severely impaired patients begs the question of impact on mildly impaired patients. Was there a subgroup that actually did worse while on treatment? How many different cuts were made before a "severely affected" subgroup became defined? Wide variances, small sample sizes, and use of a single direction standard-error bar chart for data presentation, make p-value interpretations of the reported tests dubious. A table listing results of each test performance relative to a defined pre-study cognitive function (mild vs. moderate-severe) would be more informative to the reader.
Given that TBI phenotype and recovery periods widely vary, perhaps future study design should include a lead-in period of serial neuropsychological tests to establish pre-treatment cognitive trends, pre- determined post-treatment analyses, and standard neuropsychological test cutoffs and clinical criteria for degree of cognitive impairment.
References
1. Silver JM, Koumaras B, Chen M, et al. Neurology. 2006;67:748-755.
2. http://www.clinicaltrials.gov, using search terms "Rivastigmine" or "Traumatic Brain Injury"
Disclosure: The authors report no conflicts of interest.