I distinctly remember the day I attended a “drug lunch” (as a PM&R resident in New York City) to learn about the value of donepezil (Aricept) for the treatment of dementia. I was surprised by the drug’s lack of efficacy – the graph displayed in the PowerPoint show demonstrated a 2-point improvement on the Mini Mental State Exam (MMSE), an effect that began after 6 months of donepezil use, and persisted for only 6 months after that. A 2-point difference on the MMSE has no clinical relevance of which I’m aware. The drug’s common side effects include: nausea, vomiting, diarrhea, loss of appetite, tiredness, drowsiness, trouble sleeping, or muscle cramps. That day I realized that the risk-benefit profile did not support its use.
Nonetheless, I was perplexed by the number of patients who came to the hospital already on the medication. Over and over again I heard the same story: “Mom is becoming forgetful so our doctor started her on this medication to help her memory.”
When I asked the family if they thought the medicine helped, the response was equally predictable: a shrug and then “What else can we do?”
Here we have a classic example of a medical problem with no satisfactory treatment or cure – and a desperate desire on the part of patients and family members to do something – anything – about it. Many times people in these predicaments turn to alternative medicines, herbal supplements and faith –based remedies. And sometimes they turn to FDA-approved drugs.
Donepezil is approved for the treatment of mild to moderate dementia of the Alzheimers type. Although the benefits are modest, the drug can delay progression of symptoms for about six months.
Mild cognitive impairment (MCI) is mild memory difficulty severe enough to be noticed but not to affect activities of daily living. About 20% of people over 70 have MCI, and they are more likely to go on to develop dementia, even though many patients with MCI do not progress. Although donepezil is not indicated for MCI it is commonly used to treat it. The Cochrane Collaboration has reviewed the scientific literature on the use of donepezil in mild cognitive impairment, and has found:
There is no evidence to support the use of donepezil for patients with mild cognitive impairment (MCI). The putative benefits are minor, short lived and associated with significant side effects.
So how did this drug get approved? Well, there do seem to be some small improvements (of dubious clinical significance in my opinion) in measures of cognitive impairment in patients with Alzheimer’s dementia in particular.
The Agency for Healthcare Research and Quality (AHRQ) states:
The evidence is mixed, however, about the effects of cholinesterase inhibitors on functional measures such as instrumental activities of daily living (i.e., ability to use the telephone, mode of transportation, responsibility for medication, and ability to handle finances). In general, the studies show little or no effect on functional decline after 6 months of treatment and a small but statistically significant difference from placebo after 12 months of treatment.
Research has found no clinically important differences between people taking cholinesterase inhibitors and those taking placebo in the development of behavioral and psychological symptoms… Studies rarely addressed other important health outcomes such as utilization of health care services, injuries, and caregiver burden.
Pfizer’s press release (when they received FDA approval to market Aricept in 1996) noted:
Alzheimer’s disease is a family tragedy. Aricept will benefit patients and families alike by improving or maintaining patient function, which in turn may help ease the burden for caregivers and help maintain personal dignity… Aricept represents a significant step forward in addressing the therapeutic needs of the Alzheimer’s disease community…This therapy will help to change the approach to the management of Alzheimer’s disease.
Global sales of Aricept were approximately $1.1 billion for 2008 alone.
Me-too cholinesterase inhibitors have seen similar global profits, with sales of rivastigmine at close to $1 billion in 2008. All this while the AHRQ can find no clinically relevant difference between the drugs in this class, and the effects they have are small and short lived.
There are pharmaceutical innovations that have changed the course of history (imagine where we’d be without the polio or smallpox vaccines), while others leverage the tiniest statistically-significant effects to drive global drug empires driven by public feelings of helplessness in the face of currently incurable diseases.
It’s no wonder that the public has a mistrust of Pharma – their marketing engines drive sales of drugs that have vastly different clinical value. That means it’s up to physicians and scientists to tease out the legitimate enthusiasm from the marketing hype. And judging from all the patients with mild dementia that I see on cholinesterase inhibitors, I think most of us deserve a failing grade.
Note: This article was updated on 01/25/2010