Clinical trials of pharmaceutical products, including drugs for AD, are often biased, according to senior study author Alizera Atri, MD, PhD, Memory Disorders Unit, Massachusetts General Hospital, Boston, tending to have “stringent inclusion and exclusion criteria that are intended to select a homogeneous and highly leveraged subpopulation of patients, in order to maximize the likelihood of finding significant drug-treatment effects and to minimize the potential for adverse effects.”

To assess the clinical effectiveness of combination therapy with cholinesterase inhibitor and memantine (Namenda, Forest) for the treatment of AD in a real-world setting, Dr. Atri and colleagues analyzed longitudinal data from 521 patients with AD (mean age, 74.6 years) who underwent serial clinical evaluations at the Memory Disorders Unit. The combination therapy was given to 117 patients; 404 patients were either untreated or had been treated with a cholinesterase inhibitor only.

An analysis of changes in various indexes of AD severity during a mean follow-up of 30 months showed that patients in the memantine-plus-cholinesterase inhibitor group experienced significantly less annual deterioration in cognitive abilities than did those in the cholinesterase inhibitor-only or the untreated groups.

According to Dr. Atri, these results provide strong support for the notion that the combination therapy has significant long-term clinical benefits in real-world patients with AD. “In this large, well-characterized and prospectively assessed cohort of patients with AD, who received clinical care at our Memory Disorders Unit, the benefits of such combined therapy were significant, with small to medium effect sizes that were sustained for years,” he said.

“The results also raise the intriguing possibility that combined therapy with memantine and a cholinesterase inhibitor may actually modestly modify the long-term clinical course of AD,” Dr. Atri said. He also pointed out that the study employed conservative bias in the methods and analyses, aimed toward minimizing potential drug-treatment benefits, and that it was not sponsored or supported by the pharmaceutical industry.

According to Martin R. Farlow, MD, professor and vice chairman for research in neurology, Department of Neurology, Indiana University School of Medicine, Indianapolis, the study by Dr. Atri and colleagues is important because there is a general lack of knowledge regarding whether combination therapy with cholinesterase inhibitors and memantine provide merely short-term symptomatic effects or whether these drugs continue to be symptomatically effective in the long term.

“There also is a dearth of data regarding whether either of these drugs affects disease progression and whether the combination continues to provide symptomatic benefits beyond six to 12 months,” he said. “Also, data from former clinical trials may not accurately reflect how effective drugs may be in real-world use.”

The study by Dr. Atri’s team addresses some of these concerns, and it has a number of strengths, such as the long-term follow-up and the use of an unselected, real-world population of patients with AD, Dr. Farlow said. He also noted, however, that the study does have some weaknesses, including the lack of a double-blind placebo-controlled group and possible selection biases regarding who is on which treatment.

Another “major issue,” according to Dr. Farlow, is that the different groups were treated at different time periods. “It has been found in recent clinical AD trials that placebo-treated patients are not progressing nearly as rapidly today as they did in the early 1990s,” Dr. Farlow said. “As the untreated group in this trial was elevated during the period when patients were progressing more rapidly, this phenomenon could seriously bias the results.”

The study results were presented at the recent 2007 annual meeting of the American Academy of Neurology.