The study published yesterday has made the headlines across the media;

” The study they funded, led by Professor Robert Howard from the Institute of Psychiatry at Kings College London, and published in the New England Journal of Medicine, has concluded that the drugs carry on working in people whose illness has become severe.

“For the first time, we have robust and compelling evidence that treatment with these drugs can continue to help patients at the later, more severe stages of the disease,” he said. “We observed that patients who continued taking donepezil were better able to remember, understand, communicate and perform daily tasks for at least a year longer than those who stopped taking the drugs. These improvements were noticeable to patients, their caregivers and doctors.”

I’m not quite so sure. The trial took 295 patients living in the community who had moderate to severe Alzheimers disease and who were already on donepezil. They were divided into groups;

treated with donepezil,

discontinue donepezil,

discontinue donepezil and start memantine,

continue donepezil and start memantine.

They were followed for a year. At the start, in the ‘methods’ section, the researchers say

” The minimum clinically important differences were 1.4 points on the SMMSE and 3.5 points on the BADLS.”

These are the’standardised mini mental state examination’, and ‘Bristol Activities of Daily Living’. The latter is a functional assessment and a better guide for useful improvements.

The important bits in the results are in a box that I can’t manage to cut and paste, but the relevant bits are

BALDS – Difference between scores for continued vs discontinued donepezil, which were -2.9 at 52 weeks, with an ‘overall difference’ of -3.0.

Active versus placebo memantine scores were different by -1.5.

The BALDs score is a 60 point scale. The authors told us in the discussion that a 3.5 point difference would be clinically significant, but the difference in the results is a points score on this scale of 3. What does this mean? I am not sure, because small improvements in function may be very clinically meaningful (eg the ability to keep up with personal hygiene).

The other thing that bothers me is this.

“The study was overseen by King’s College London and was funded by the U.K. Medical Research Council (MRC) and the Alzheimer’s Society.”

and ”

Recruitment was slower than anticipated, and it was not possible to extend the recruitment period, since the public funder of the study (MRC) believed that the disadvantages of a delay in reporting results outweighed the benefits of increasing the power of the study.”

This is quite unusual, because a better powered study usually means more definitive results. Around 50 patients in each of the 4  groups who completed the study. I’m not sure this is definitive enough evidence to make a large change in practice. Additionally, patients were excluded who were felt unable to “adhere to the study regimens”. This may have produced a bias – the cognitively best or most socially supported may have been over-represented and may not reflect normal practice.

The other note is the amount of potential conflicts of interest.

“Dr. McShane reports receiving payment for work as the local principal investigator for commercial trials from Abbott, Novartis, i3 Innovus, and Medivation; Dr. Lindesay, receiving consulting fees from Novartis NEURONET and lecture fees from Janssen, Novartis, Eisai, and Pfizer; Dr. Ritchie, receiving consulting and lecture fees from Pfizer and Eisai and grant support and reimbursement for travel expenses from Eisai; Dr. Barber, receiving royalties from Arnold Press; Dr. Burns, receiving royalties from John Wiley; Dr. Findlay, receiving lecture fees and reimbursement for meeting expenses from Eisai, Pfizer, and Lundbeck; Dr. Jones, receiving consulting fees from Merz Pharmaceuticals and Janssen, grant support from Eisai, Lundbeck, and Merz Pharmaceuticals, and lecture fees from Lundbeck, Merz Pharmaceuticals, Eisai, Pfizer, and Novartis and being a board member of Merz Pharmaceuticals, Lundbeck, Eisai, Pfizer, and Lilly; Dr. McKeith, receiving lecture fees from Novartis; Dr. O’Brien, receiving consulting fees from GE Healthcare, Bayer Healthcare, and Servier and lecture fees from Pfizer, Eisai, Novartis, Lundbeck, Eli Lilly, Shire, and GE Healthcare; Dr. Passmore, receiving consulting fees from Pfizer, Lundbeck, Novartis, Shire, and Johnson & Johnson and lecture fees and reimbursement for travel expenses from Lundbeck and Pfizer; Dr. Katona, receiving consulting fees from Lundbeck and Eli Lilly, grant support from Lundbeck, lecture fees from Lundbeck, Lilly, Shire, and Pfizer, payment for development of educational presentations from Lundbeck, and reimbursement for travel expenses from Pfizer and being a board member of Lundbeck; Dr. Ballard, receiving consulting and lecture fees from Lundbeck, Eisai, Bristol-Myers Squibb, Janssen, Acadia, and Novartis and grant support from Lundbeck and Acadia; Dr. Brown, receiving lecture fees from UCB Pharma, GlaxoSmithKline, Solvay, and Lundbeck; Dr. Banerjee, receiving grant support from Pfizer, lecture fees from Lundbeck, and reimbursement for travel expenses from Pfizer and Eisai; and Dr. Bentham, receiving consulting fees from TauRx Therapeutics.”

This work is interesting, but it didn’t achieve the level of functional benefit the authors had said would be clinically significant. I’m wary of false hope being generated.