Long-Term Combination Alzheimer's Therapy Slows Decline CME

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Continuing Medical Education course

Release Date: September 30, 2008; Valid for credit through September 30, 2009
Credits Available
Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™ for physicians;
Family Physicians - up to 0.25 AAFP Prescribed credit(s) for physicians

All other healthcare professionals completing continuing education credit for this activity will be issued a certificate of participation.
Physicians should only claim credit commensurate with the extent of their participation in the activity.

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September 30, 2008 — Long-term combination therapy with memantine and cholinesterase inhibitors significantly slows the rate of cognitive and functional decline in patients with Alzheimer's disease (AD), new research suggests.

In the first long-term real-world study of Alzheimer's drugs, investigators at Massachusetts General Hospital, Boston, found that extended combination therapy slowed disease progression and helped patients maintain their ability to perform activities of daily living.

"Based on these results, we believe combination therapy should be strongly considered for first-line treatment in patients with Alzheimer's disease, as it appears this regimen helps individuals maintain their cognitive and functional abilities for a longer period of time," principal investigator Alireza Atri, MD, PhD, told Medscape Psychiatry.

The study is published in the July/September issue of Alzheimer Disease and Associated Disorders.

Real-World, All-Comers Study

According to Dr. Atri, to date, the majority of AD drug studies have been randomized, placebo-controlled trials of limited duration — usually 6 months — conducted in highly selected cohorts.

The findings of such studies, said Dr. Atri, give the impression that AD medications only work in a limited number of patients and only for a short period.

"There's almost a myth that has developed that [AD] drugs only work for some people and that if you respond early, you don't respond later. But the fact is this assertion is not backed up by any data," he said.

He added that long-term effectiveness data for monotherapy or combination therapy in a real-world setting that includes a heterogeneous all-comers population is lacking.

To gather such data, researchers conducted a prospective study of patients treated at the Massachusetts General Hospital's Memory Disorders Unit from 1990 to 2005 who were subsequently enrolled in the Massachusetts Alzheimer's Disease Research Center Patient Registry Database.

All study participants had a clinical diagnosis of probable AD; had at least 3 examinations in the memory disorders unit, with completed assessments of their cognitive and functional capacities; and were categorized according to the type of treatment they received.

Maintenance of Functional Status

Individuals were evaluated using the Information-Memory-Concentration subscale of the Blessed Dementia scale (BDS) and the Weintraub Activities of Daily Living (ADL) scale.

Of 382 subjects, 144 received no AD treatment with either cholinesterase inhibitor or memantine. A total of 122 were treated with cholinesterase inhibitors alone, and 116 received both a cholinesterase inhibitor and memantine.

Subjects in the no-therapy group were enrolled between 1990 and 1995, when cholinesterase inhibitors and memantine were not routinely used. Those receiving cholinesterase inhibitor and combination therapy were enrolled after 1997, when widespread use of cholinesterase inhibitors began in the United States.

All subjects received standard care and treatment for AD during the study. The practice was to prescribe cholinesterase inhibitors at initial diagnosis of AD. Memantine was added on an individual basis.

As a whole, the entire group declined. However, the researchers found significant differences in the rate of symptom progression among the 3 study groups. With a mean follow up of 2.5 years, the lowest rate of decline was seen in patients receiving combination therapy, particularly with respect to maintenance of functional status.

Furthermore, using a statistical model to predict probability outcomes out to 4 years, the investigators predicted that the longer patients received combination therapy, the smaller the rate of decline would become.

Disease-Modifying Effect?

"My gut feeling is these are mostly symptomatic drugs, but there was an indication that the combination therapy may actually be disease modifying. However, we need more research before we can draw any firm conclusions with respect to this," Dr. Atri said.

According to Dr. Atri, the study's main take-home point is that taking AD medication for a longer period slows decline and symptom progression. Giving medication for 6 months, he said, is not an accurate measure of effectiveness because the effects are quite small even for patients who do respond in this short period.

"It appears we need to give these drugs over a much longer period of time in order for them to demonstrate their full effect. So in some ways this study debunks the theory that if you don't respond early, you're never going to respond," said Dr. Atri.

In light of the sheer numbers of patients that are likely to develop AD during the next 20 years, the findings have important global health implications. It is estimated there are currently 5 million individuals in the United States alone with AD. In the absence of preventive therapies, within the next 30 to 40 years the number of cases is expected to triple to 15 million.

"We didn't measure this in our study, but it would make sense that by delaying the decline in patients' cognitive and functional status, even a small difference would translate into major benefits for patients, their families, and healthcare systems not only in the United States but globally," he said.

The study was supported by the National Institutes on Aging. The authors have disclosed no relevant financial relationships.

Alzheimer Dis Assoc Disord. 2008;22:209-221.
Learning Objectives for This Educational Activity
Upon completion of this activity, participants will be able to:

1. Compare the clinical effectiveness of cholinesterase inhibitors with memantine vs that of placebo on clinical outcomes of Alzheimer's disease.
2. Compare the clinical effectiveness of cholinesterase inhibitors with memantine vs that of the inhibitors alone on clinical outcomes of Alzheimer's disease.

Clinical Context

AD will affect more than 6 million Americans by 2050, and treatment currently consists of cholinesterase inhibitors and memantine, which have modest symptomatic but not curative effects. However, long-term, real-time effectiveness data on combination therapy with both cholinesterase inhibitors and memantine (combination therapy) and cholinesterase inhibitors alone on cognition and functional ability are limited.

This is an observational longitudinal study conducted since 1990 to examine and compare the effects of the combination cholinesterase inhibitors and memantine with placebo and cholinesterase inhibitor therapy alone during 30 months of follow-up.

Study Highlights

* Included were 382 patients attending a memory disorders clinic with a known diagnosis of AD who had completed at least 3 examinations showing functional and cognitive impairment.
* Patients were assigned to the cholinesterase inhibitor group if they received any cholinesterase inhibitors for any duration but did not receive memantine (n = 122).
* Patients were assigned to the cholinesterase inhibitors with memantine group (combination therapy) if they were treated with cholinesterase inhibitors and memantine for any duration (n = 116).
* Cholinesterase inhibitors used were donezepil, glantamine, and rivastigmine-tacrine.
* The control group consisted of patients who received neither treatment.
* Because memantine was always added to cholinesterase inhibitor therapy, there was no group for memantine alone.
* All subjects underwent a comprehensive clinical dementia evaluation.
* Instruments used included the Information-Memory-Concentration subscale of the BDS and the Weintraub ADL.
* The ADL was a 31-question questionnaire completed by a family member or caretaker.
* Assessments were performed every 6 months.
* The start date of medication was the day of the prescription.
* Subjects in the combination therapy group were younger and had lower BDS scores than the other groups.
* The cumulative duration of medication treatment for those in the cholinesterase inhibitor and combination therapy groups was at least 6 months.
* The median duration of medication use was 1.9 years for the cholinesterase inhibitors and 1.55 years for the combination therapy group.
* Mean cumulative duration of treatment time was 22.5 months.
* 90% of patients in the cholinesterase inhibitors and combination therapy groups had a cumulative duration of treatment of 1 or more years.
* The dropout rate (those who did not have follow-up data) was 18% for the control, 34% for the cholinesterase inhibitors, and 25% for the combination therapy groups, respectively.
* The combination therapy group was superior to both the cholinesterase inhibitor and control groups in decreasing the rate of progression of cognitive impairment.
* The annualized rates of deterioration of BDS and ADL scores was significantly lower in the combination therapy group compared with the other 2 groups.
* The cholinesterase inhibitor group was superior to the control group for cognitive function with slower rate of decline.
* The combination therapy group had a lower rate of decline of ADL than the control and cholinesterase inhibitor groups, which did not differ significantly from one another.
* The authors concluded that the effect of combination therapy was superior to cholinesterase inhibitor monotherapy or no therapy and that the effects persisted for years.

Pearls for Practice

* Use of combination cholinesterase inhibitor and memantine therapy for patients with AD over time is associated with a greater reduced rate of decline of cognitive and ADL function than cholinesterase inhibitor therapy alone.
* Use of combination cholinesterase inhibitor and memantine therapy for patients with AD over time is associated with a greater reduced rate of decline of cognitive and ADL function than no therapy.

Medscape Medical News 2008. ©2008 Medscape

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News Author: Caroline Cassels
CME Author: Désirée Lie, MD, MSEd

The study was supported by the National Institutes on Aging. The authors have disclosed no relevant financial relationships.

Alzheimer Dis Assoc Disord. 2008;22:209-221.