Jonathan M.Silver, New York University School of Medicine, 40 East 83rd Street, Suite 1E, New York, NY 10028jonsilver@aol.com
Philip D. Harvey
Submitted December 03, 2006
We thank Drs. Noble and Hauser for their comments on our article and
the opportunity to clarify the subgroup analysis. We agree that the
statistically significant results are from a post-hoc analysis; therefore,
all of the caveats associated with post-hoc analyses apply. Currently, there
are no treatments effective for TBI so we think that the
use of "promising" to describe treatment with rivastigmine was suitable. While categorization of the severity of the initial traumatic
brain injury has been standardized, the characterization of the severity
of impairments is difficult.
With respect to specific questions about study design, the patients
were assessed twice during the run-in phase and so it is unlikely that our
results are a random retest artifact. The primary endpoint of the study
was the percentage of responders on memory tests and so the post-hoc
analysis reported the results of assessments of memory. Although not
statistically significant, all of the neuropsychological (NP) tests
administered (12 in total), except for CANTAB-RVIP A’, showed greater
improvement in the severely impaired patients for rivastigmine versus
placebo.
In some tests, the severely impaired patients receiving
rivastigmine showed improvement at week 12 compared with the patients
receiving placebo, who showed deterioration on some indices (eg, CANTAB
reaction time, CANTAB-RVIP mean latency, HVLT retention, and WAIS digit
span). Thus, other NP tests showed a trend for similar results of greater
improvement with rivastigmine for the more impaired patients, but these
results were not reported in the paper.
Only two subgroups were analyzed: patients with greater than 25% impairment
and patients with less than 25% impairment from baseline. For the less impaired
patients (N=62), the percent responders with at least a 4-point
improvement on HVLT total trials 1–3 was greater for those receiving
rivastigmine versus those receiving placebo; however, this post-hoc result
was not statistically significant.
For the other NP tests, patients
receiving placebo showed more improvement than those receiving
rivastigmine. For Trails B, the improvement for patients with less than 25%
impairment was statistically better for treatment with placebo versus
rivastigmine.
We agree with most of the points made by Drs. Noble and Hauser.
However, rivastigmine offers at least a hint that it might be beneficial
in more severely impaired patients with TBI. Further clinical trials are needed to further elaborate on these results.
Disclosure: Disclosure: The article to which this correspondence refers supported by Novartis Pharmaceuticals Corporation. J. Silver has received honoraria from Novartis for consulting services. P. Harvey has received honoraria from Novartis.
Disclaimer: The views expressed in the article to which this Correspondence refers are those of the author and do not reflect the official policy of the Department of the Army, Department of Defense, or US Government.
We thank Drs. Noble and Hauser for their comments on our article and the opportunity to clarify the subgroup analysis. We agree that the statistically significant results are from a post-hoc analysis; therefore, all of the caveats associated with post-hoc analyses apply. Currently, there are no treatments effective for TBI so we think that the use of "promising" to describe treatment with rivastigmine was suitable. While categorization of the severity of the initial traumatic brain injury has been standardized, the characterization of the severity of impairments is difficult.
With respect to specific questions about study design, the patients were assessed twice during the run-in phase and so it is unlikely that our results are a random retest artifact. The primary endpoint of the study was the percentage of responders on memory tests and so the post-hoc analysis reported the results of assessments of memory. Although not statistically significant, all of the neuropsychological (NP) tests administered (12 in total), except for CANTAB-RVIP A’, showed greater improvement in the severely impaired patients for rivastigmine versus placebo.
In some tests, the severely impaired patients receiving rivastigmine showed improvement at week 12 compared with the patients receiving placebo, who showed deterioration on some indices (eg, CANTAB reaction time, CANTAB-RVIP mean latency, HVLT retention, and WAIS digit span). Thus, other NP tests showed a trend for similar results of greater improvement with rivastigmine for the more impaired patients, but these results were not reported in the paper.
Only two subgroups were analyzed: patients with greater than 25% impairment and patients with less than 25% impairment from baseline. For the less impaired patients (N=62), the percent responders with at least a 4-point improvement on HVLT total trials 1–3 was greater for those receiving rivastigmine versus those receiving placebo; however, this post-hoc result was not statistically significant.
For the other NP tests, patients receiving placebo showed more improvement than those receiving rivastigmine. For Trails B, the improvement for patients with less than 25% impairment was statistically better for treatment with placebo versus rivastigmine.
We agree with most of the points made by Drs. Noble and Hauser. However, rivastigmine offers at least a hint that it might be beneficial in more severely impaired patients with TBI. Further clinical trials are needed to further elaborate on these results.
Disclosure: Disclosure: The article to which this correspondence refers supported by Novartis Pharmaceuticals Corporation. J. Silver has received honoraria from Novartis for consulting services. P. Harvey has received honoraria from Novartis. Disclaimer: The views expressed in the article to which this Correspondence refers are those of the author and do not reflect the official policy of the Department of the Army, Department of Defense, or US Government.