Neurology -- Correspondence for Rockwood et al., 68 (14) 1116-1121

Correspondence published:

Effect of galantamine on verbal repetition in AD: A secondary analysis of the VISTA trial: Victoria S.S. Wong (23 May 2007)

Reply from the authors: Kenneth Rockwood, Elissa Asp (23 May 2007)

Effect of galantamine on verbal repetition in AD: A secondary analysis of the VISTA trial 23 May 2007

Victoria S.S. Wong,
University of Hawaii John A Burns School of Medicine
PO Box 23377, Honolulu, HI 96823-3377
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Re: Effect of galantamine on verbal repetition in AD: A secondary analysis of the VISTA trial

wongvict{at}hawaii.edu Victoria S.S. Wong

Rockwood et al report the reduction of verbal repetition in patients with Alzheimer Disease (AD) after treatment with galantamine.[1] They stated that Goal Attainment Scaling (GAS) was appropriately used as the primary outcome measure. Although GAS had been used by the original VISTA trial as an outcome measure,[2] it should not be recommended for use as the primary outcome measure in this research context where the goal of treatment is the reduction of repetitive speech. The potential risks of galantamine use outweighed the benefit of reduced repetitive speech for the patient.
Repetitive speech is hypothesized to be a result of compromised memory or executive function.[1] It is then likely that the goal of diminution of repetitive speech was set by the caregiver rather than the patient in the “patient GAS.” To my knowledge, repetitive speech has not been studied as a correlate to patient quality of life. The presence of other neuropsychiatric symptoms such as apathy and irritability have been correlated with a reduced patient quality of life using proxy ratings by caregivers.[3] These symptoms also correlated with a reduced caregiver quality of life. However, the symptoms did not correlate with the patient’s own quality of life rating.
Thus, the use of GAS and the primary outcome measure of verbal repetition was not appropriate in this study. The benefit of reduced verbal repetition to the patient is not clear, while the use of galantamine does carry some risk. The adverse effect profile revealed that 53.1% of patients in the galantamine group experienced the most common adverse effects of nausea, vomiting, and upper respiratory tract infection compared to 12.1% in the placebo group.[2]
Future standalone studies that use GAS as a primary outcome measure should correlate the caretaker and clinician goals of treatment with the patient quality of life.
References
1. Rockwood K, Fay S, Jarrett P, Asp E. Effect of galantamine on verbal repetition in AD: A secondary analysis of the VISTA trial. Neurology 2007; 68: 1116-1121.
2. Rockwood K, Fay S, Song X, MacKnight C, Gorman M. Attainment of treatment goals by people with Alzheimer’s disease receiving galantamine: a randomized control trial. CMAJ 2006; 174: 1099-1105.
3. Hoe J, Katona C, Orrell M, Livingston G. Quality of life in dementia: care recipient and caregiver perceptions of quality of life in dementia: the LASER-AD study. Int J Geriatr Psychiatry. In press.
Disclosure: The author reports no conflicts of interest.

Reply from the authors 23 May 2007

Kenneth Rockwood,
Divisions of Geriatric Mediicne & Neurology, Dalhousie University
1421-5955 Veterans Memorial Lane, Halifax NS Canada, B3H 2E1,
Elissa Asp
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Re: Reply from the authors

Kenneth.Rockwood{at}Dal.ca Kenneth Rockwood, et al.

We thank Dr. Wong for her interest in our report of the impact of galantamine on verbal repetition in people with AD,[1] but we do not follow her argument against Goal Attainment Scaling. On the contrary, we see it as informative in the debate about the clinical meaningfulness of the statistically significant differences in standardized cognitive tests that have been observed in randomized controlled trials of cholinesterase inhibitors.
Dr. Wong comments that patients with verbal repetition might have had poor insight, they might not have realized the extent of their problem and therefore might not have had a better quality of life as a result of this unrecognized problem. This is possible but it is not the analysis that we reported. The phrase “quality of life” is not mentioned. There is reason to be skeptical that current quality of life measurement adds much to the question of the clinical meaningfulness of treatment.[4]
Dr. Wong’s calculation of the risk of galantamine is incorrect. She appears to have calculated a 53.1% adverse event (AE) rate for galantamine-treated patients by adding the original report’s occurrence of each symptom individually. It is important to recall, however, that patients could have had more than one symptom so that an AE rate cannot be inferred from the sum of individual symptoms. As reported in the original paper, any AE occurred in 84% of patients on galantamine and 62% on placebo; drug-related AEs occurred in 28% on galantamine and 15% on placebo. AEs that resulted in withdrawal in the double-blind phase occurred in five patients on galantamine and three (including one death) on placebo.[2] This burden is too high for the benefit described.
Individualized measures such as Goal Attainment Scaling allow patients and caregivers a voice in discussions about whether any treatment is clinically meaningful. Note that although it is a very important problem, verbal repetition has been little studied in dementia. It turned out to be a useful marker of a worthwhile treatment response. It is unlikely to be the only one, but to find out more, we need a systematic way to hear people who are affected by the disease. That is why we view Goal Attainment Scaling to be useful and appropriate.
References
4. Rockwood K. Quality of life outcomes, in Rockwood K, Gauthier S (eds.) Trial Design and Outcomes in Dementia Therapeutics Research. London: Taylor & Francis, 2006.
Disclosure: The study to which this Correspondence refers was cofunded by Janssen-Ortho Inc. and by the Canadian Institutes of Health Research, through a CIHR Rx & D operating grant, DCT-49981. Janssen-Ortho Inc. provided all medications and matching placebos, conducted on-site monitoring, and gathered and electronically coded the case report forms. All data are held by the Principal Investigator (K.R.), who initiated and supervised all analyses. Janssen-Ortho received a draft of the paper to which this Correspondence refers 45 days before submission to verify protocol details and review results, but publication decision rested with the Principal Investigator. Kenneth Rockwood receives career support from the Canadian Institutes of Health Research through Investigator awards and is also supported by the Dalhousie Medical Research Foundation as the Kathryn Allen Weldon Professor of Alzheimer Research. Kenneth Rockwood has undertaken consultancies and received honoraria from Janssen Ortho, the study’s cosponsor, and from Pfizer, Novartis, and Merck. He is also part owner of DementiaGuide, which is developing a Web site to aid in goal setting for people with dementia. Pamela Jarrett, an author on the original study, has received honoraria from Janssen Ortho Inc. Sherri Fay and Elissa Asp report no conflicts of interest.