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Third Congress of the International Society for Vascular and Cognitive Disorders

San Antonio, Texas / July 11-14, 2007

The growing population of older adults inevitably will lead to a higher prevalence of Alzheimer’s disease (AD), vascular dementia and mixed dementia. Consequently, the demand will increase for treatment that can maintain or improve cognitive, functional and behavioural parameters. To that end, the cholinesterase inhibitor (ChEI) galantamine was evaluated in a six-month, randomized, placebo-controlled clinical trial involving patients with probable vascular dementia and mixed dementia.

After a four-week placebo run-in phase, patients were randomized 2:1 to galantamine 24 mg/day or placebo and followed for six months, reported Dr. Timo Erkinjuntti, Helsinki University, Finland, and colleagues. Patients were assessed at baseline and at study end by means of multiple assessment scales: 11-item Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog/11); Clinician’s Interview-Based Impression of Change with caregiver input (CIBIC+); Neuropsychiatric Inventory (NPI); and Disability Assessment in Dementia (DAD) scale.

Response to treatment was defined for each of the assessment tools: ADAS-cog/11 at ³0-point, ³4-point, and ³7-point change; CIBIC+ at £4-point change; DAD-total score ³0 and subscale items with ³0-point change, indicating stability or improvement; and NPI ³0 change.

Study Results

Investigators randomized 285 patients, 188 to active treatment and 97 to placebo. At the end of the study, 154 (81.9%) of actively-treated patients and 87 (89.7%) placebo patients had complete data for responder analyses. At baseline, the groups did not differ with respect to age (76 to 77 years), proportion with cardiovascular disease (65% to 70%) or scores on assessments of cognitive function (MMSE, ADAS-cog/11, DAD and NPI).

Investigators reported that responder rates for the ADAS-cog/11 were significantly better for the ChEI vs. placebo for all definitions of response (Table 1). The percentage of patients who improved on the ADAS-cog/11 by 7 points or more in the galantamine group was almost three times that of the placebo group. Investigators considered this an exceptional clinical response rate.

Table 1. Responder Analyses: Efficacy Measures

Patients randomized to the ChEI had significantly higher response rates for three of the four outcome measures and demonstrated a trend to better response in the fourth measure. Results of the CIBIC+ assessment showed that 74.8% of this patient cohort were stable or improved vs. 53.6% of the placebo group (P=0.0006). Actively-treated patients had a response rate of 64.9% on the NPI compared with 56.6% in the placebo group (P=0.024). By the DAD assessment, 51% of patients on active treatment and 39.5% of placebo patients had responses (P=0.105).

“Although this was a small sample size, we showed a clinically meaningful effect of galantamine in patients with AD and clinically significant cerebrovascular disease,” remarked Dr. Erkinjuntti. “We observed improvement in cognition, global impression and activities of daily living, as well as a trend toward improvement in the behavioural measure. The effect size is as good or even better than what has been observed in uncomplicated AD. This was a clinically, as well as statistically, meaningful effect.”

Although the difference in treatment response on the DAD scale did not differ, the mean change in total DAD was clinically and statistically (P=0.003) significant for galantamine vs. placebo, according to investigators.

Three types of adverse events occurred more often with the ChEI than with placebo: nausea (20% vs. 10%), vomiting (12% vs. 7%) and dizziness (12% vs. 7%). Other adverse events, such as abdominal pain, diarrhea, headache and fatigue, occurred in a similar proportion of patients in each group.

The results of the trial suggest that the agent could have a meaningful impact on the lives of many older adults. “AD with concomitant cerebrovascular disease is frequent in older populations,” noted Dr. Erkinjuntti. “In the future, this might be the largest single subset of patients with dementia. However, AD with cerebrovascular disease is too often misdiagnosed as vascular dementia and not treated in the absence of vascular dementia.”

He continued, “This is the first and only randomized controlled trial of a ChEI in this patient population. The current responder analysis, as well as the original study report [Lancet 2002;359:1283-90], show clear-cut, meaningful treatment effects with galantamine in patients with AD and concomitant cerebrovascular disease. The challenge is to recognize these too often-misdiagnosed patients and offer them this treatment.”

Dementia Diagnostic Assessment Methods

One of the unmet needs of dementia management relates to early and accurate diagnostic assessment. Earlier intervention with effective therapies might lead to further improvement in response and outcome for patients with AD, vascular dementia and mixed dementia.

At a VAS-COG workshop, Dr. Earle DeCoteau, Department of Clinical Gerontology, University of Saskatchewan, Saskatoon, and the 25-item Executive Interview (EXIT25) developer Dr. Donald Royall, University of Texas Health Science Center, San Antonio, discussed the use of this assessment tool in clinical practice. It has shown promise for evaluation of patients with mild dementia and is used to assess executive function. Dr. DeCoteau has used this assessment tool to evaluate several hundred patients.

The test allows clinicians to identify patients with evidence of dementia that other tests might miss, he explained. The EXIT25 has proven especially useful in evaluating patients with small-vessel cerebrovascular disease, which can lead to a variety of behavioural disorders, including dementia. Small-vessel disease in the brain appears to affect executive function to a greater degree compared with other aspects of cognitive function.

Dr. DeCoteau and colleagues reported findings from a study of patients with cerebrovascular disease and well-preserved MMSE scores. The investigators noted that the EXIT25 has been found to elicit subtle evidence of abnormality in patients who have high MMSE scores.

In comparing EXIT25 results with those of the Cognitive Competency Test (CCT), they have found that patients with a low EXIT25 score (indicative of good executive function) have high CCT scores. Conversely, patients with a high EXIT25 score usually have low CCT scores. The cumulative data from the Saskatchewan group showed that the EXIT25 at all levels correlated very well with the CCT and further substantiates the value of the EXIT25 as a test of cognitive function.

In Saskatoon, the EXIT25 has gone from being something of a curiosity to an invaluable aid in the assessment of patients with suspected dementia.“Practically every patient we see is evaluated with the EXIT25,” Dr. DeCoteau told delegates. “Initially, our occupational therapists were very unimpressed; now they wouldn’t be without it. It has opened up a whole new world as far as assessment of dementia is concerned.”