A new paper by British investigators that assesses the benefits of cholinesterase inhibitors in moderate to severe Alzheimer disease (AD) has elicited impassioned debate among AD experts in the United States. They generally agree with the trial's primary outcomes — on the benefits of donepezil — but question the study design and the authors' interpretation of secondary data about whether adding memantine is beneficial.
Known as DOMINO [for the Donepezil and Memantine in Moderate to Severe Alzheimer's Disease] trial, the study randomized 295 patients who were taking donepezil (Aricept) from the time of diagnosis to one of four study groups: to continue taking donepezil only; discontinue donepezil; discontinue donepezil and start memantine (Namenda); or take both donepezil and memantine. Patients received the study treatment for 52 weeks.
The patients who continued receiving donepezil performed significantly better on both the Standardized Mini-Mental State Exam (SMMSE) and the Bristol Activities of Daily Living Scale (BADLS) — both primary outcomes — than those who discontinued treatment, the investigators reported in the March 8 New England Journal of Medicine. The donepezil group scored higher by an average of 1.9 points (95% confidence interval [CI], 1.3 to 2.5) on SMMSE, and lower (indicating less impairment in function) on the BADLS by 3.0 points — 95% CI, 1.8 to 4.3 (p<0.001 for both comparisons).
The authors concluded, on the other hand, that the scores on the Neuropsychiatric Inventory and other tests measuring behavioral and psychological symptoms — secondary outcomes — did not show significant benefits with combination donepezil and memantine over memantine alone — something that many neurologists say is inconsistent with their clinical experience and the preponderance of data from previous clinical trials and long-term observational clinical cohort studies.
WAS THE STUDY UNDERPOWERED?
Some experts, who were not involved with the study, claim the study might have been underpowered. DOMINO was plagued with recruitment problems from the beginning, the study authors, led by Robert Howard, MD, professor of old age psychiatry and psychopathology at the Institute of Psychiatry of King's College London, acknowledged. They had originally planned to recruit 800 participants; when that proved impossible, they adjusted their sample size to 430, anticipating that such a group would still have sufficient power to detect outcome differences. Even that number proved difficult to attain.
“Recruitment was slower than anticipated, and it was not possible to extend the recruitment period, since the public funder of the study (MRC) [the UK Medical Research Council] believed that the disadvantages of a delay in reporting results outweighed the benefits of increasing the power of the study,” they wrote.
Alireza Atri, MD, PhD, who was not involved with the study, said he was disturbed by the decision to move forward with the trial and the subsequent interpretation of the data. Dr. Atri, assistant in neurology at the Harvard Medical School Massachusetts General Hospital Memory Disorders Unit, and clinical director of the Geriatric Research Education Clinical Center Outpatient Memory Disorders & Dementia Units at the Edith Nourse Rogers Memorial VA Bedford Hospital, co-authored a long-term cohort study — published in 2008 in the journal Alzheimer Disease and Associated Disorders — that concluded that combination therapy for AD slows functional and cognitive decline compared with cholinesterase-inhibitor monotherapy and to standard care without anti-AD medications.
“With low statistical power, you can't overreach,” he said. “I do applaud the authors for trying to do a difficult and important study that's long term and assesses established anti-AD medications we all use in the US, but one cannot be blind to the realities — for well-known reasons, such long-term placebo-controlled studies are impractical if not impossible to do in developed countries.”
Dr. Atri said the authors should have acknowledged that their results on the secondary outcomes were inconclusive, as opposed to conflating failure to find statistical significance with the absence of an effect or even evidence for such absence. “The study only achieved 37 percent of their a priori specified initial target enrollment and 68 percent of a revised target enrollment,” he pointed out.
Dr. Atri noted that an unusually high dropout rate — 59 percent overall —disproportionately focused within one group, further handicapped the results. “They started with 291 subjects taking study medications and ended up with 119 — there was a 72 percent dropout rate for placebo, 63 percent for memantine, and 53 percent for donepezil,” he said. “Worse yet, the dropouts were disproportionately concentrated in the placebo arm followed by the arms taking fewer active medications (one versus two), a pattern of missing data that is not ignorable — no amount of sensitivity analysis is going to make up for that since there is bias in the data.”
Responding to the criticism, study author Dr. Howard said: “It is true to say that the trial was underpowered to detect differences between the donepezil and donepezil plus memantine subgroups — if those differences were smaller than the minimum clinically important differences that we had determined and published before we analyzed the data.”
“But I don't accept that this disproportionately disadvantaged particular arms — particularly the donepezil plus memantine arm where dropouts were low. The study was not underpowered to detect statistically significant advantages for both donepezil and memantine on the co-primary outcomes of cognition and function, and the sizes of these advantages were not influenced by whether the participants were also taking the other drug.”
Dr. Howard noted that both donepezil and memantine, singly or in combination, had the effects (1.9 MMSE points and 3.0 BADLS points for donepezil and 1.2 MMSE points and 1.5 BADLS points for memantine) that the trial authors reported. “However, because the memantine effects were small compared with those of donepezil and because of the lack of power, we were not able to demonstrate a significant difference between the donepezil alone and combination subgroups,” he said. “If we had recruited many more participants it is likely that we would have demonstrated statistically significant differences but these would certainly have been smaller than minimum clinically important differences. We think that there's an important distinction.”
HUMAN SUBJECT CONCERNS
Rachelle Doody, MD, PhD, professor of neurology, Effie Marie Cain Chair in Alzheimer's Disease Research, and director of the Alzheimer's Disease and Memory Disorders Center at Baylor College of Medicine, contends, however, that such a trial would never have been approved in the United States in the first place. “You're taking a group of already undertreated dementia patients who had reached a moderate to severe level of decline, and then either keeping them on their under-treatment, taking them off all treatment, giving them a different treatment which also constitutes under-treatment, or giving them a second drug,” she said. “In the US, almost all of these patients would have been on a second drug to start with.”
“Although they anticipated adverse events among treated patients that did not occur,” she continued, “the safety monitoring board did not stop the study early although one group was doing worse than the others.”
Dr. Howard acknowledged that the board was aware, from early on in the study, of a trend for the patients who were randomized from donepezil to not fare as well. “They weren't aware that it was significantly worse until quite later on in the trial,” he explained. “And withdrawing donepezil as the disease advances is actually standard, approved treatment in many places outside the US, so they didn't feel the need to terminate the trial urgently.”
But, according to Dr. Atri, memantine alone and the combination got short shrifted. “They never had an arm with memantine by itself that didn't put it at a disadvantage; the patients that went on memantine were the ones who went off donepezil,” he said. “We know what happens to those people — they get worse!”
THE PERSISTENCE OF TREATMENT
Dr. Doody suggested that it is the persistence of treatment that has the most impact on the course of Alzheimer disease. “Our research shows that what matters is the percentage of your disease span that you spend on treatment,” she said, referring to a 2009 paper in the journal Alzheimer's Research & Therapy. “That predicts what your level of cognitive and day-to-day function will be for the rest of your life. There's a convergence of data saying that you do better for the many years you live if you're treated.”
In 2009, a first-of-its kind study published in the Journal of Neurology, Neurosurgery & Psychiatry, led by the University of Pittsburgh's Oscar Lopez, MD, found that combination therapy with memantine and a cholinesterase inhibitor kept people with AD out of a nursing home longer, and indicated that the benefits of the combination therapy were most evident in the long term. In that study, patients on combination therapy were seven times less likely to be placed in a nursing home compared with patients who received a cholinesterase inhibitor alone.
Stephen Salloway, MD, director of Neurology and the Memory and Aging Program at Butler Hospital in Providence, RI, and professor of clinical neurosciences and psychiatry at Brown Medical School, said: “I think that some of the findings are probably correct. The principal finding, that there is benefit from continuing donepezil in moderate to severe patients, is borne out by other studies and my clinical experience. But I think if they had had more subjects, used a more sensitive cognitive outcome measure such as the severe impairment battery, and a higher dose of donepezil, it would have been an even more robust finding.”
His reservations notwithstanding, Dr. Atri thinks there is utility in some of the data. “I still think it's a valuable study; it supports and extends the preponderance of clinical evidence and clinical wisdom that these medications produce real benefits in slowing clinical decline: that donepezil and memantine monotherapy are both superior to placebo for at least one year. It also supports that at least up to about 30 weeks, the combination of memantine and donepezil is superior to donepezil,” Dr. Atri said.
Dr. Atri noted that one of the study figures — see figure on page 12 — shows a clear pattern on both panels regarding the different arms of the study, and an overall advantage for the combination arm in experiencing less decline in cognition and function. “The paths for the cognitive measure converge only after 30 weeks, when most subjects have dropped out and so few subjects remain on study medications — 27, 34, and 38 subjects per anti-AD medication arm — that the study loses its ability to detect differences.”
He advises clinicians to show AD patients and their family members the same figure. “Ask them which path they'd like to take their chances to be on?”
But, Dr. Howard countered, donepezil does not have a license for the treatment of severe Alzheimer's disease in the UK. He stressed that standard clinical practice there and in many other parts of the world involves stopping these drugs when patients progress to severe AD. “The results of DOMINO, which were reported as early as possible and at the expense of collecting additional potential power, will open up the future prospect of approved treatment for many severe AD patients,” he said.
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