Sunday, August 11, 2013

Current Alzheimer's Medications: Effective Treatments or Expensive Bottles of Hope?

I am not a medical researcher, nor am I a medical doctor.  I am, however, a spouse caregiver for my wife, who is now in moderate stages of Alzheimer’s Disease (AD).  While admittedly lacking an M.D. degree, my reading of the AD literature, my listening to other spouse caregivers, my observations of more than a dozen people with Alzheimer's ,and my research on the effectiveness of current AD medications all tell me that doctors too often recommend that Alzheimer’s patients continue taking ineffective “treatment medications.”  Well after the time period when even the pharmaceutical manufacturers claim that their products are effective, many doctors continue to prescribe these same ineffective AD medications for their patients. 

History
My wife took two of the most commonly prescribed AD medications, donepezil (Aricept) and memantine (Namenda).  Along with galantamine (Razadyne) and rivastigmine (Exelon), these are four of the five prescription medications that have been approved by the U.S. Food and Drug Administration to treat people diagnosed with AD.  A fifth medication, tacrine (Cognex), was also approved by the FDA, but it is now rarely prescribed due to safety concerns. 1  All but memantine are termed “cholinesterase inhibitors”  that “prevent the breakdown of acetylcholine, a brain chemical believed to be important for memory and thinking.” 1  Memantine works differently by regulating glutamate, a brain chemical that, “when produced in excessive amounts, may lead to brain cell death.” 1 Each of these medications carries the possibility for side effects such as nausea, vomiting, or diarrhea, to name a few.1

Research
Although there is absolutely no research to indicate that any of these medications will stop or cure Alzheimer’s, there is some research to indicate that, for some patients, these medications may slow the rate of decline for a brief  period of time.  However, this research is based on only a few clinical trials of very short duration, and this research is badly flawed in two major respects.

The first research flaw is that the “significant positive outcomes” obtained in clinical trials cited by drug manufacturers as “evidence” of the effectiveness of their medications are usually based upon results obtained on the MMSE or ADAS-Cog tests.  The MMSE, a commonly used AD screening test, is an instrument that was never designed to diagnose Alzheimer’s and cognitive declines in some people with early to moderate stage AD score may not be accurately measured. 2  The ADAS-Cog, according to two studies reported in 2012, is a test instrument “not subtle enough to properly track changes in the early stages of Alzheimer’s. 3   A major study conducted by Consumer Reports in 2012 concluded that the differences in scores on the ADAS-Cog for patients taking any of the FDA approved medications, when compared to placebo groups, are “smaller than 4 points, which is so small, it is not considered meaningful.”  Consumer Reports also concluded that the “small improvements” showing slower rates of decline in activities of daily living as measured by various instruments “would not be considered clinically meaningful by most doctors.” 4

The second research flaw is that clinical trials cited as evidence of the effectiveness of these medications are few, and of very brief duration with absolutely no data supporting any positive outcomes beyond that clinical trial duration.  I would think that if any pharmaceutical manufacturer had any evidence of its medication having any positive effects beyond the duration of their brief clinical trials, that evidence would be made public ... in a heartbeat!

I went to the website of each medication to learn about the clinical trials in support of their effectiveness and found similar results for each medication.  All had clinical trials of short duration, all of the positive effects were leveling off or slowing down by the end of the trials, and all testing was with instruments that are not necessarily the best measurements of cognitive performance.

The website of Ortho-McNeil Neurologics, a division of Ortho-McNeil-Janssen Pharmaceuticals, Inc., cites only 4 randomized, double blind, placebo controlled clinical investigations for galantamine in patients with probable Alzheimer’s. 5  Using the ADAS-Cog to assess cognitive performance, the 4 trials lasted 21, 26, 26, and 13 weeks, respectively.  At the end of these short duration trials, results had already either leveled off or begun to decline, even for the groups demonstrating initial improvement.
There is not even one study demonstrating that galantamine is effective to any degree whatsoever beyond 26 weeks. 5

On the Novartis website, one finds data from five clinical trials with AD patients that lasted 12, 24 and 48 weeks using rivastigmine in oral or “patch” form, and all relied upon the ADAS-Cog and MMSE to measure outcomes.  All trial results show that even for the groups demonstrating improvement on the medication, declines in scores appear after 24 weeks.  There is not even one study demonstrating that rivastigmine is effective to any degree whatsoever beyond 48 weeks.  6

On the Eisai/Pfizer website, one finds data from 4 clinical trials with AD patients taking donepezil.  Two trials were for patients with mild to moderate AD, one for 15 weeks and one for 30 weeks.  Two trials were for patients with moderate to severe AD, for 24 weeks in Japan and six months in Sweden.  Once again, even for groups demonstrating improvement on this medication, declines in scores begin at or before the 24 week stage as measured by the ADAS-Cog and other instruments. There is not even one study demonstrating that donepezil (Aricept) is effective to any degree whatsoever beyond 30 weeks. 7

Discussion
What do all clinical trials using cholinesterase inhibitors tell us?  Very simply, we learn that of the 11 clinical trials for these three medications, 9 of them lasted for 26 weeks or less.  We also learn that in every study, even patients showing initial evidence of improvement started to decline after 24 weeks, if not sooner. 

And, finally, we learn that there is absolutely no evidence indicating that patients continuing to take these medications beyond a very limited period of time, one year or less, will continue to demonstrate any positive effects these medications may have had.   If there were such evidence in any clinical trial of any cholinesterase inhibitor, this clinical trial data would be heralded by both the pharmaceutical company and by the FDA as the greatest breakthrough ever in Alzheimer's treatment.

And what do we learn from clinical trials about the evidence of effectiveness of memantine?  On the Forest Laboratories, Inc. website, two studies are reported, one lasting 24 weeks and one for 28 weeks.  Outcomes were measured using two instruments, one to measure activities of daily living and one to measure cognitive function.  In the 28 week study, after four weeks, the group receiving a placebo started to decline; the group receiving memantine showed a slight improvement for 12 weeks, and then started to decline.  In the 24 week study, the treatment groups were different.  One group received memantine and donepezil, while the other group received memantine and a placebo.  After 4 weeks, the group receiving memantine and the placebo started to decline, whereas the group receiving memantine and donepezil didn’t show declines until the 8 week point.  There is not even one study demonstrating that memantine (Namenda), given with or without donepezil, is effective to any degree whatsoever beyond 28 weeks. 8

Despite there being no research to support the effectiveness of these AD medications beyond a few months, at best, many doctors continue prescribing these medications for years and years.  Not only can these AD meds no longer be helping their patients, but they may actually be causing some harm.  Maintaining patients on these medications long term may provide false hope to patients and their caregivers.  I refer to these medications as “bottles of hope” because as I watch my wife decline, I know that the medications cannot possibly be helping anymore, if they ever did at all. 

For many patients and caregivers, the high costs of AD medications present an economic hardship.  Money spent on AD medications is money that might otherwise be spent on day care programs, companions, home health aides, or other services that would actually improve the quality of their lives.   

Another problem with continuing to take these medications for many years may be long term negative side effects.  Negative side effects were reported to some degree in all of the short duration clinical trials, but there is no data on long term negative side effects.  Side effects not initially apparent may surface after continuing to take these medications year after year.

Doctors frequently place patients on AD medications shortly after diagnosis and that's a good option to try to slow down the initial rate of decline.  Adding memantine when the patient advances to moderate stages is also a worthwhile option to sty to slow the rate od decline.  despite an absence of any supportive research, perhaps residual positive effects may even last a year or two for some patients, not just a few months.  But is there any point in continuing these medications beyond two years?  Doctors must be realistic and honest with both patient and caregiver.  Absent research to the contrary, doctors should recommend that their patients discontinue taking these medications after a year or two at the most.

The “Best Buy Drugs Report “ issued by Consumers Union in May, 2012 was not given much publicity until excerpts appeared in the Washington Post on January 7, 2013. 9  Consumers Union, which reviewed more than 1100 research studies and articles on AD meds, begins the recommendations section of their comprehensive 2012 report with this statement: “The medications used to treat mental decline in people with Alzheimer’s disease are not particularly effective.  When compared to a placebo, most people who take one will not experience a meaningful benefit.  And it is the rare person who has a significant delay in the worsening of their symptoms over time.” 10  The recommendations page concludes with these words, “if the person taking the drugs does not show signs of improvement within three months, it is unlikely they ever will, so the drug should then be stopped.” 10

The Research Center of the Alzheimer’s Association provides much information about treatments for Alzheimer’s.  Their conclusion with respect to current medication is this: “On average, the five approved Alzheimer’s drugs are effective for about six - 12 months for about half of the individuals who take them.” 11

The National Institutes of Health (NIH) also recently affirmed that these AD medications are largely ineffective beyond a limited period of time.  The executive summary of its comprehensive “Alzheimer’s Disease Progress Report,” 2011-2012, concludes that the current FDA approved AD meds “may help some people” ... but even for those it does help, it is ”only for months to a couple of years.” 12   

Conclusion
Doctors should definitely prescribe AD medications for several months and even up to a year or two if they or their patients or caregivers see positive effects.  But doctors should not recommend that patients continue taking these medications once they are obviously ineffective.  This practice must stop. 

Doctors must accept that AD medications eventually become expensive “bottles of hope” that will not slow down the inevitable degenerative progression of Alzheimer’s.  Doctors must also accept that, by continuing to prescribe these medications year after year long after they can possibly still be helpful, they may unintentionally be doing their patients and caregivers more harm than good.
 
1.  “Alzheimer’s Disease Medications Fact Sheet.”  NIH, U.S. Department of Health and Human Services.  Accessed online at www.nia.nih.gov/alzheimers/publication/alzheimers-disease-medications-fact-sheet , p. 1. Accessed January 15, 2013, pp. 1-5.

2.  A. Vann.  “Listen More Carefully to Alzheimer’s Caregivers.”  Journal of the American Geriatrics Society, October, 2012, No. 60, p. 2000.

3.  “Cognitive Test in Alzheimer’s Drug Trial May Be Flawed.”  Medical News Today.  Accessed online at www.sciencedaily.com/releases/2012/12/121216200803.htm.
Accessed on December 26, 2012.

4.  “Evaluating Prescription Drugs Used to Treat: Alzheimer’s Disease.”  Consumer Reports, May, 2012, p. 8.  Accessed online at www.consumerreports.org/health/best-buy-drugs/alzheimers.htm.  Accessed on January 15, 2013.   

5.  Razadyne ... “Full U.S. Prescribing Information.”  Accessed online at www.razadyneer.com/sites/default/files/shared/pi/razadyne_er.pdf, pp.2-4.  Accessed on January 15, 2013

6. “Exelon ... “Highlights of Prescribing Information.”  Accessed online at www.pharma.us.novartis.com/product/pi/pdf/exelon.pdf, pp. 13-16.  Accessed on January 15, 2013.

7. “Aricept ... Highlights of Prescribing Information.” Accessed online at www.aricept.com/assets/pdf/AriceptComboFullPIFebruary2012.pdf, pp. 7-11.  Accessed on February 5, 2013.

8. “Namenda Full Prescribing Information.”  Accessed online at www.frx.com/pi/namenda_pi.pdf,  pp.3-8.  Accessed on January 15, 2013.

9.  “Alzheimer’s drugs are expensive and don’t work very well for most people.”  Accessed online at www.washingtonpost.com/national/health-science/alzheimers-drugs-are-expensive-and-they-dont-work-very-well-for-most-people Accessed on January 7, 2013.

10.  “Evaluating Prescription Drugs Used to Treat: Alzheimer’s Disease.”  Consumer Reports, May, 2012, p. 3.

11.  “Five FDA Approved Alzheimer’s Drugs.”  Research Center, Science & Progress Treatment Horizon section.  Accessed online at www.alz.org/research/science/alzheimers_disease_treatments.asp. Accessed on January 15, 2013.

12.  “A Primer on Alzheimer’s Disease and the Brain.”  NIH Alzheimer’s Disease Progress Report, 2011-2012, p. 9.  Accessed online at www.nia.nih.gov/alzheimers/publication/2011-2012-alzheimers-disease-progress-report/primer-alzheimers-disease-and.   Accessed on January 15, 2013.

Published in JAMDA, Journal of the American Medical Association, July, 2013, Vol. 14, No. 7 pp. 525-527.  Access at: www.jamda.com/article/S1525-8610(13)00167-9/fulltext
 

3 comments:

  1. Hi, Alan. There is a big difference between a clinical trial designed to obtain FDA approval for marketing for a specific patient population, and a study designed to evaluate benefits of long-term use. Every study on long-term use that I've found concluded that, for the average patient, these drugs were beneficial over the entire period of the study -- as long as 10 years. I'd suggest you go to the research literature itself, instead of using news reports.

    See, e.g. the list of publications under "Further reading" at:

    http://www.alzcompend.info/?p=244

    Regards,
    Sunshyne

    ReplyDelete
  2. Thanks for the info. These will really help everyone who read this understand that AD makes it difficult for seniors to convey the whatever physical changes or discomfort they feel. People around older adults, especially those with Alzheimer's disease, should be more sensitive to the changes and needs of these seniors.

    Alzheimer specialist

    ReplyDelete