Geriatrics

Barriers to Translating Evidence into Clinical Care: the Zoster Vaccine

October 10, 2013

By Zachary Elkin

Faculty Peer Reviewed

There are more than a million cases of herpes zoster (HZ) in the US annually [1-3]. The incidence of HZ, or shingles, has been rising in the US since the 1990s [2,4-7]. One third of all people in the US will get HZ, with the highest incidence in people aged 50 to 79 [2,5]. As a result of the Shingles Prevention Study (SPS), the U.S. Food and Drug Administration (FDA) and Advisory Committee on Immunization Practices (ACIP) approved the Zostavax vaccine (Merck & Co Inc, Whitehouse Station, New Jersey) for the prevention of HZ in 2006 for immunocompetent patients aged 60 and above [8]. The FDA extended the approval to patients aged 50 to 59 in March 2011 [9].

Despite strong evidence of efficacy, the uptake of zoster vaccination among eligible patients has been significantly less than other standard adult vaccines [1,10-13]. CDC estimates show that only 15.8% of eligible patients received the vaccine in 2011, up from 14.4% in 2010, 10% in 2009, and 6.7% in 2008 [13,14]. The 2011 rates were even lower in African Americans (7.9%) and Hispanics (8.0%). Our 2011 survey at NYU found that that only 66% of general internal medicine physicians responded that HZ vaccination was an important clinical priority, and 48% reported that less than 10% of their patients received the HZ vaccine [15]. Why has this evidence-based medicine not been translated into standard clinical care?

Evidence behind the efficacy of the HZ vaccine

Published in 2005, the Shingles Prevention Study demonstrated that HZ vaccine reduced the burden of illness by 61%, the incidence of post-herpetic neuralgia by 66.5%, and incidence of zoster by 51.3% [16]. Since then, the HZ vaccine has repeatedly been shown to be safe and efficacious. A 2012 study reported the efficacy of preventing HZ in persons 50-59 to be 69.8% [17] and another found the hazard ratio of recurrent HZ in patients under 70 to be 0.39 among vaccinated patients compared with unvaccinated patients [18]. A Cochrane Review of 3 randomized controlled studies of HZ vaccination efficacy found a risk ratio for HZ to be 0.49 in all vaccinated patients [19]. Furthermore, the 4-year follow-up to the SPS showed continued reductions in burden of illness of 50.1% [20].

Current barriers to the use of the HZ vaccine

Most of the barriers to HZ vaccination use are related to difficulties distributing the vaccine and a lack of physician recommendation. Hurley and colleagues identified the top barriers for physicians to be the perceived cost to patients, reimbursement difficulties, and the up-front cost of stocking the vaccine [11]. Patients with Medicaid (which covers the vaccine) and those without insurance have overall lower HZ coverage and greater difficulty accessing adult vaccines [1,21].

Additional studies have described a lack of strong physician recommendation as a major barrier to patient adherence with national guidelines [11,12]. Hurley reported that only 41 percent of physicians strongly recommended the zoster vaccine [11]. A study in the Netherlands by Opstelten and colleagues found that a lack of strong physician recommendations accounted for an odds ratio of 4.0 for patients refusing the HZ vaccine when offered free with a yearly influenza vaccine [12]. Correspondingly, a study estimated that 95.1% of unvaccinated patients had at least one missed opportunity to be offered the zoster vaccine at an outpatient visit [1]. Even when the HZ vaccine was offered for free by ophthalmologists at the Bellevue Eye Clinic during regularly scheduled appointments, 47% of patients who refused the vaccine reported wanting to speak to their primary care physician [22]. None returned to receive the vaccine.

Framework to overcome barriers in translating evidenced-based medicine into clinical practice

Cabana and colleagues described that to overcome barriers to physician adherence to evidence-based practice, there must first be a change in knowledge, then attitude [23]. Knowledge can be limited by lack of awareness of the published guidelines. Attitude can be affected by disagreement with guidelines, a lack of clinical priority, or insecurity in performing the task. Finally, physician behaviors can be affected by patient adherence and structural barriers within the health system.

All of these issues must be addressed through interventions to increase adherence to national vaccination guidelines. System supports can be implemented to improve physician attitudes towards HZ vaccination. Chaudhry and colleagues evaluated clinical decision support software as part of the electronic medical record at the Mayo Clinic and found an increase in vaccine utilization of 43% and 54% at two clinics [24]. Loo and colleagues described a statistical increase in pneumococcal vaccination and influenza vaccination at Beth Israel Deaconess following implementation of EMR reminders [25]. Physician reminders can be more successful when combined with patient reminders [26] or nurse-initiated reminders [27].

However, time and general changes in the healthcare system are also needed to increase utilization. For example, in 2011, 62.3% of eligible patients in the US received the pneumococcal vaccine [14]. Interventions to increase use of that vaccine started in 1981 with Medicare covering it, but by 1989 only 14.1% of eligible adults 65 and older were vaccinated [28]. The HZ vaccine was only approved for immunocompetent patients 60 and older in 2006, and healthcare system-wide changes have only begun. New York State began to allow certified pharmacists to administer the HZ vaccine with a prescription in October 2012, and Merck began a marketing campaign about shingles that year as well. More time may be needed to see overall changes in patient and provider behaviors.

In a commentary in 2003 in the New England Journal of Medicine, Lenfant described how healthcare providers and the public were not applying the vast wealth of clinical knowledge gained in the 20th century to clinical practice [29]. He explained that there were structural, economic, and motivational barriers to the adoption of evidence-based medicine; however, a major problem is that research rarely focuses on translating knowledge to public use. Simple interventions like the ones described and demonstration of cost effectiveness can go a long way to improving physician and patient adherence. More operational research is needed to describe which interventions work best in varied clinical settings. This may be the best approach to increase use of the HZ vaccine.

Commentary by Dr. Michael Simberkoff

There were specific problems with the shingles vaccine that hampered initial enthusiasm for its use. These include the cost of the vaccine compared to others that are commonly available, the mechanism that was set up for reimbursement (Medicare Part D), the difficulty of shipment and storage of the vaccine in a frozen state until it is used, and the shortages of vaccine due to production problems that led to shortages of the vaccine at a time when its use should have been promoted. Many of these issues have been resolved, but they slowed acceptance of an otherwise useful vaccine. The author suggests that more widespread use of the EMR will improve adherence to guidelines. I would agree that the EMR can provide reminders about good clinical practices, but remain skeptical that these will translate into sustainable improvements unless they are coupled with incentives for providers.

Dr. Zachary Elkin is a 4th year medical student at NYU School of Medicine

Peer reviewed by Michael Simberkoff, MD, Chief of Staff, Deparment of Veterans Affairs, New York Harbor Healthcare System, Professor of Medicine (Infectious Diseases), NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References

1. Lu PJ, Euler GL, Harpaz R. Herpes zoster vaccination among adults aged 60 years and older, in the U.S., 2008. Am J Prev Med. 2011;40(2):e1-6.  http://www.ncbi.nlm.nih.gov/pubmed/21238856

2. Rimland D, Moanna A. Increasing incidence of herpes zoster among Veterans. Clin Infect Dis. 2010;50(7):1000-1005.

3. Tseng HF, Smith N, Harpaz R, Bialek SR, Sy LS, Jacobsen SJ. Herpes zoster vaccine in older adults and the risk of subsequent herpes zoster disease. JAMA. 2011;305(2):160-166.

4. Yawn BP, Saddier P, Wollan PC, St Sauver JL, Kurland MJ, Sy LS. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction. Mayo Clin Proc. 2007;82(11):1341-1349.  http://www.ncbi.nlm.nih.gov/pubmed/17976353

5. Insinga RP, Itzler RF, Pellissier JM, Saddier P, Nikas AA. The incidence of herpes zoster in a United States administrative database. J Gen Intern Med. 2005;20(8):748-753.

6. Ghaznawi N, Virdi A, Dayan A, et al. Herpes zoster ophthalmicus: comparison of disease in patients 60 years and older versus younger than 60 years. Ophthalmology. 2011;118(11):2242-2250.

7. Yawn BP, Wollan PC, Kurland MJ, St Sauver JL, Saddier P. Herpes zoster recurrences more frequent than previously reported. Mayo Clin Proc. 2011;86(2):88-93.  http://www.ncbi.nlm.nih.gov/pubmed/21220354

8. Harpaz R, Ortega-Sanchez IR, Seward JF. Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57(RR-5):1-30.  http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5705a1.htm

9. Harpaz R, Hales CM, Bialek SR. Update on herpes zoster vaccine: licensure for persons aged 50 through 59 years. MMWR Morb Mortal Wkly Rep. 2011;60(44):1528.  http://www.ncbi.nlm.nih.gov/pubmed/22071592

10. Freed GL, Clark SJ, Cowan AE, Coleman MS. Primary care physician perspectives on providing adult vaccines. Vaccine. 2011;29(9):1850-1854.

11. Hurley LP, Lindley MC, Harpaz R, et al. Barriers to the use of herpes zoster vaccine. Ann Intern Med. 2010;152(9):555-560.

12. Opstelten W, van Essen GA, Hak E. Determinants of non-compliance with herpes zoster vaccination in the community-dwelling elderly. Vaccine. 2009;27(2):192-196.  http://www.cabdirect.org/abstracts/20093090353.html;jsessionid=9CFCCF3008A615DD6B3D63AEA35E874A?freeview=true

13. Williams WW, Peng-Jun L, Singleton JA, etal. Adult vaccination coverage-United States, 2010. MMWR. 2012;61(04):66-72.  http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6104a2.htm

14. Williams WW, Peng-Jun L, Greby S, et al. Noninfluenza vaccination coverage among adults–United States, 2011. MMWR. 2013;62(04):66-72.

15. Elkin Z, Cohen E, Goldberg J, et al. Studying physician knowledge, attitudes, and practices regarding the herpes zoster vaccine to address perceived barriers to vaccination. Cornea. 2013;32(7):976-981.

16. Oxman MN, Levin MJ, Johnson GR, et al; Shingles Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352(22):2271-2284.

17. Schmader KE, Levin MJ, Gnann JW, et al. Efficacy, safety, and tolerability of herpes zoster vaccine in persons aged 50-59 years. Clin Infect Dis. 2012;54(7):922-928.  http://cid.oxfordjournals.org/content/54/7/922.abstract

18. Tseng HF, Chi M, Smith N, Marcy SM, Sy LS, Jacobsen SJ. Herpes zoster vaccine and the incidence of recurrent herpes zoster in an immunocompetent elderly population. J Infect Dis. 2012;206(2):190-196.

19. Gagliardi AM, Gomes Silva BN, Torloni MR, Soares BG. Vaccines for preventing herpes zoster in older adults. Cochrane Database Syst Rev. 2012;10:CD008858.

20. Schmader KE, Oxman MN, Levin MJ, et al. Persistence of the efficacy of zoster vaccine in the shingles prevention study and the short-term persistence substudy. Clin Infect Dis. 2012;55(10):1320-1328.

21. Orenstein WA, Mootrey GT, Pazol K, Hinman AR. Financing immunization of adults in the United States. Clin Pharmacol Ther. 2007;82(6):764-768.

22. Jung JJ, Elkin ZP, Li X, et al. Increasing use of the vaccine against zoster through recommendation and administration by ophthalmologists at a city hospital. Am J Ophthalmol. 2013;155(5):787-795.

23. Cabana MD, Rand CS, Powe NR, et al. Why don’t physicians follow clinical practice guidelines? A framework for improvement. JAMA. 1999;282(15):1458-1465.

24. Chaudhry R, Schietel SM, North F, Dejesus R, Kesman RL, Stroebel RJ. Improving rates of herpes zoster vaccination with a clinical decision support system in a primary care practice. J Eval Clin Pract. 2013;19(2):263-266.  http://www.ncbi.nlm.nih.gov/pubmed/22304668

25. Loo TS, Davis RB, Lipsitz LA, et al. Electronic medical record reminders and panel management to improve primary care of elderly patients. Arch Intern Med. 2011;171(17):1552-1558.

26. Thomas RE, Russell M, Lorenzetti D. Interventions to increase influenza vaccination rates of those 60 years and older in the community. Cochrane Database Syst Rev. 2010(9):CD005188.

27. Rhew DC, Glassman PA, Goetz MB. Improving pneumococcal vaccine rates. Nurse protocols versus clinical reminders. J Gen Intern Med. 1999;14(6):351-356.  http://www.ncbi.nlm.nih.gov/pubmed/10354255

28. Koch JA. Strategies to overcome barriers to pneumococcal vaccination in older adults: an integrative review. J Gerontol Nurs. 2012;38(2):31-39.

29. Lenfant C. Clinical research to clinical practice–lost in translation? New Engl J Med. 2003;349(9):868-874.

 

 

 

From The Archives – Evolution and Medicine: Why do we age?

July 19, 2012

Please enjoy this post from the archives dated January 30, 2010.

Mark D. Schwartz and Julia Hyland Bruno

Jeanne Calment rode her bicycle until age 100, quit smoking at 117, and died in 1977 at 122 years of age in Arles, France. This news-worthy story raises some questions: Why do we age at all? Why don’t we live forever? And many of us are asked by our patients, is old age a disease we can cure?

First, some useful distinctions: Aging is getting chronologically older, while senescence is physiologic degeneration that diminishes our function and vitality and makes us more vulnerable to disease and death. Lifespan is the average age at death for a population and varies widely by species, while longevity is that for an individual and depends on its unique interactions of genes, environment, and chance. Extrinsic mortality is the stochastic death rate due to environmental factors like earthquakes, starvation, and predation. Most species in the wild do not live long enough to grow old. Intrinsic mortality is the death rate absent environmental factors, resulting from how the species allocates limited resources over its biological functions like growth, tissue repair, and reproduction.

As discussed in the previous column in this series [1], biological questions of causality like these are of two types. In medicine we typically ask proximate “how” questions about mechanisms (pathophysiology) or development (ontogeny) over an individual’s lifetime. We less commonly ask evolutionary “why” questions about function (adaptation) or development of a trait in species over millennia (phylogeny).

In human history, average life expectancy has increased (Figure) but our maximal longevity has not.[2] Our lifespan expanded thanks to changes we made in our environment that reduced our extrinsic mortality. Most important of these were the agricultural and industrial revolutions, and more recent advances in public health and the development of antibiotics. However, while we now have more centenarians, it remains exceedingly rare for anyone to live beyond 115 years, suggesting we have a biological limit due to intrinsic mortality.

So why do we senesce and die? Proximate answers about mechanisms are emerging but remain controversial. Damage-based theories propose that injury to DNA, telomeres, and tissues due to normal toxic by-products of metabolism (e.g. free radicals) or inefficient repair or defense accumulates throughout the lifespan and causes senescence.[3] Circulating levels of superoxide dismutase, uric acid, and other antioxidants are linked to lifespan across species. An alternative theory is that senescence is driven by a genetically regulated, programmed process with hormonal mechanisms as its pacemaker. Recent work has focused on neuroendocrine signaling that may account for increased longevity associated with caloric restriction.[4]

From an evolutionary perspective, individuals that do not senesce would have a tremendous reproductive advantage. So why hasn’t natural selection eliminated senescence? Why don’t we live and reproduce indefinitely?

Evolutionary answers to the problem of aging reflect the range of thinking about evolutionary processes.[5] Weissman and others proposed death as an adaptation for the good of the species-an idea that has been discounted on the grounds that natural selection is far stronger at the individual than at the group level.[6] Three more contemporary theories of why we senesce offer complementary explanations that account for natural selection and may also illuminate proximate explanations of aging.

In 1952 Peter Medawar proposed that we senesce because the force of natural selection decreases as we age (mutation accumulation theory).[7] Since most organisms die of extrinsic causes, genes beneficial early in life are favored by natural selection over genes beneficial late in life. By an age when few organisms survive, the force of selection is too weak to oppose the genetic drift and mutation accumulation that can lead to the loss of late acting beneficial genes or to the expression of late acting harmful genes.

George Williams (1957) expanded this idea and posed the theory of antagonistic pleiotropy, in which genes that increase reproductive fitness in younger organisms will be favored by selection, even if they have adverse effects post reproductive age.[8] An example of such a tradeoff is testosterone in males, promoting reproductive fitness in youth, but increasing risk of prostate cancer and heart disease later in life.

Tom Kirkwood (1977) further specified that senescence results from the inevitable tradeoffs in the allocation of resources between reproduction and somatic maintenance (disposable soma theory).[9] Maintenance requires resources (DNA repair, immune system surveillance) at the expense of fecundity. Genes will be favored that shift the balance toward investing scarce resources in mechanisms that promote reproductive fitness and maintenance of the germ line versus the soma.

The strongest driver of the evolution of longevity is the force of extrinsic mortality. When high, life expectancy is short, harmful gene effects accrue earlier, and selection for somatic maintenance is weaker. When extrinsic mortality is lower as in humans, selection against senescence attenuates more slowly, and selection for investing in somatic maintenance is stronger.

Therefore, senescence is the price we pay for vigor and reproductive fitness in our youth. The humbling takeaway is that natural selection optimizes our reproductive fitness, not our health or lifespan.[10] As physicians we cannot cure our aging patients of senescence but we can endeavor to postpone its effects. Biologically, we are here to transmit our genes, so living well beyond 100 years is likely to remain news.

Please also see the Proceedings of the National Academy of Sciences Supplement on Evolution in Health and Medicine

Mark Schwartz is an Associate Professor of Medicine at NYU Langone Medical Center

Julia Hyland-Bruno is now a doctoral student of biology at CUNY

References:

1. Schwartz MD. Evolution and Medicine: Practicing medicine with only half of biology?” Clinical Correlations, Evolution and Medicine Column 1, August 5, 2009. Available at: https://www.clinicalcorrelations.org/?p=1670 .

2. Oeppen J and Vaupel JW. Broken limits to life expectancy. Science 2002;296(5570):1029-1031. Available at: http://www.sciencemag.org/cgi/content/full/296/5570/1029/DC1.

3. Beckman K B and Ames BN. The free radical theory of aging matures. Physiol Rev 1998;78(2):547-581.

4. Berner YN and Stern F. Energy restriction controls aging through neuroendocrine signal transduction. Ageing Res Rev 2004;3(2):189-198. Available at: http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6X1H-4BMTCGM3&_user=142623&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_searchStrId=1129451275&_rerunOrigin=google&_acct=C000000333&_version=1&_urlVersion=0&_userid=142623&md5=5bb24de576b23e0dbe97135d7f70d7e0.

5. Kirkwood TB and Austad SN. Why do we age? Nature 2000;408(6809):233-238. Available at: http://www.nature.com/nature/journal/v408/n6809/full/408233a0.html.

6. Weismann himself abandoned the idea. See Rose MR, Evolutionary Biology of Aging, New York: Oxford University Press, 1994.

7. Medawar P B. An Unsolved Problem of Biology. H. K. Lewis, London, 1952.

8. Williams GC. Pleiotropy, natural selection, and the evolution of senescence. Evolution 1975;11:398-411.

9. Kirkwood TB. Evolution of ageing. Nature 1977;270(5635):301-304

10. Gluckman P, Beedle A, Hanson M. Principles of Evolutionary Medicine, Chapter 5. New York: Oxford University Press, 2009.

Use it or Lose it- Do cognitive leisure activities protect against the development of Alzheimer’s?

March 30, 2012

By Courtney Cunningham, MD

Faculty Peer Reviewed

As the world population ages, enormous resources will be required to adequately care for persons suffering from Alzheimer’s disease. The disease is the fifth leading cause of death for adults aged 65 years and older, and is estimated to affect 1 in 8 persons in this age group.[1,2] Despite recent advances, the cause of Alzheimer’s disease is not well understood. The FDA-approved medications in common use—donepezil (Aricept), galantamine (Razadyne), rivastigmine (Exelon), and memantine (Namenda)–help to manage symptoms; however there are no treatments available shown to stop or reverse the progression of the disease.

In addition to medical therapy, researchers have begun to explore the utility of behavioral interventions in preventing and slowing the progression of dementia. Emerging evidence from observational studies suggest that participating in cognitive leisure activities may have a protective effect on the development of Alzheimer’s disease and other dementias.[3] Activities considered to require mental effort include reading books or newspapers, writing for pleasure, doing crossword puzzles, playing board games, and playing musical instruments. Studies suggest that increased participation in such activities in middle and late life is associated with slower rates of cognitive decline.[3]

Although the evidence is convincing, a causal relationship between participation in cognitive leisure activities and dementia has not been firmly established. A systematic review by Wilson and colleagues from 2010 included 13 observational studies that were grouped by the stage of adult life when cognitive interventions were taken. Results of this analysis showed that 5 out of 6 middle-adulthood and 6 out of 7 late-life interventions were significantly associated with a reduced risk of developing Alzheimer’s and other dementias. However, it is possible that reduced participation in leisure activities is itself an early maker of dementia that precedes decline on cognitive tests.[4]

In attempt to eliminate this important confounding factor, a study from the New England Journal of Medicine recruited 469 subjects over the age of 75 years who did not have dementia at baseline and evaluated the risk of dementia according to the baseline level of participation in leisure activities.[5] Advantages of this study include its prospective design and long (median 5.1 years) period of observation. The investigators found that participation in leisure activities conferred a protective effect that persisted after excluding from the analysis persons with possible early symptoms of dementia and adjusting for age, sex, educational level, and chronic medical illnesses. The protective effects were restricted to those activities requiring mental effort; activities involving mere physical activity did not show a significant effect. Nevertheless, controlled trials are still needed to establish causality in the observed association between cognitive stimulation and dementia.

If there is a causal role, two competing theories have been proposed to offer an explanation. The first is that is that of the “cognitive reserve.”[6] This theory suggests that individuals with higher educational or occupational attainment may compensate for early pathological changes of dementia by utilizing cognitive strategies or brain networks associated with increased reserve.[6] A cognitive reserve improved through cognitive enrichment would therefore delay the onset of symptoms without altering the biologic progression of dementia.[6,7] An alternative hypothesis is that participation in cognitive activities slows the pathological processes of the disease during the preclinical phase of dementia.[5] This view emphasizes the remarkable plasticity of the brain, and suggests that cognitive stimulation may play a role in strengthening existing synaptic connections as well as in generating new ones.[8,9] It has also been theorized that cognitive activities may stimulate neurogenesis, even during middle- or late-adult life.[7] The role of such biologic mechanisms underlying cognitive stimulation would have major implications for behavioral intervention in preventing dementia.

A few studies have employed neuroimaging techniques to unravel the brain mechanisms involved in cognitive stimulation interventions. A study by Belleville and colleagues was the first to use functional magnetic resonance imaging to measure the effect of memory training on brain activation in adults with mild cognitive impairment.[8] The aim of the study was to assess whether memory training can reverse brain changes seen in mild cognitive impairment, a precursor state to dementia. The patients participated in a memory-training program where they learned to use memory devices like mnemonics and word lists. Comparison of imaging before and after training revealed an increase in activation and new recruitment of brain regions typically implicated in memory. Furthermore, the majority of areas recruited after training in subjects with mild cognitive impairment were normal prior to training. These results indicate that the older brain is highly plastic and remains so even during the early stages of neurodegenerative disease.

The relative contribution of factors like effortful mental activity to the pathogenesis of dementia remains incompletely understood. A growing body of literature suggests that persistent engagement by the elderly in effortful mental activities may promote plastic changes in the brain that alter the clinical progression of dementia. However, further investigation is needed establish a causal relationship between participation in cognitive leisure activities and a slowed progression of disease. For the time being, elderly patients should nonetheless be encouraged to challenge themselves through crossword puzzles, card games, and stimulating social interactions.

References

1. Centers for Disease Control and Prevention Web site. Alzheimer’s Disease Statistics.http://www.cdc.gov/mentalhealth/data_stats/alzheimers.htm.  July 1, 2011.  Accessed November 15, 2011.

2. Alzheimer’s Association Web site. 2011 Alzheimer’s Disease Facts and Figures. www.alz.org/downloads/Facts_Figures_2011.pdf. Accessed November 15, 2011.

3. Stern C and Munn Z. Cognitive leisure activities and their role in preventing dementia: a systematic review. Int J Evid Based Healthc. 2010; 8(1): p. 2-17.  http://onlinelibrary.wiley.com/doi/10.1111/j.1744-1609.2010.00150.x/pdf

4. Wilson RS, Mendes De Leon CF, Barnes LL, et al. Participation in cognitively stimulating activities and risk of incident Alzheimer disease. JAMA. 2002; 287(6): p. 742-8.

5. Verghese J, Lipton RB, Katz MJ, et al. Leisure activities and the risk of dementia in the elderly. N Engl J Med. 2003; 348(25): p. 2508-16. http://www.nejm.org/doi/full/10.1056/NEJMoa022252

6. Stern Y, Albert S, Tang MX, and Tsai WY. Rate of memory decline in AD is related to education and occupation: cognitive reserve? Neurology. 1999; 53(9): p. 1942-7.  http://www.ncbi.nlm.nih.gov/pubmed/10599762

7. Milgram NW, Siwak-Tapp CT, Araujo J, and Head E. Neuroprotective effects of cognitive enrichment. Ageing Res Rev. 2006; 5(3): p. 354-69.

8. Belleville S, Clement F, Mellah S, Gilbert B, Fontaine F, and Gauthier S. Training-related brain plasticity in subjects at risk of developing Alzheimer’s disease. Brain. 2011; 134(Pt 6): p. 1623-34.

9. Coyle, JT. Use it or lose it-do effortful mental activities protect against dementia? N Engl J Med. 2003; 348(25): p. 2489-2490.

 

Commentary by David Sutin, MD

In April 2011 the National Institute of Aging and the Alzheimer’s Association workgroup published new criteria for Alzheimer’s diagnosis, the major difference being the recognition that clinical symptomatology may significantly lag behind pathological changes.

–The preclinical stage, for which the guidelines only apply in research settings.

–The mild cognitive impairment (MCI) stage, marked by memory problems severe enough to be noticed and measured, but not compromising a person’s independence. People with MCI may or may not progress to Alzheimer’s dementia.

–Alzheimer’s dementia. These criteria apply to the final stage of the disease.

As those of us who work with the elderly have realized, Alzheimer’s disease is not only catastrophic for the patient, but also has tremendous impacts on the family. Preventive strategies must start in the preclinical stage, well before the onset of dementia. While we wait for the availability of disease-modifying therapy and the development of risk stratification tools, it seems prudent to continue to recommend cognitively engaging activities to all.[2]

1. Alzheimer’s diagnostic guidelines updated for first time in decades, National Institute of Aging, last accessed December 9, 2011 at http://www.nia.nih.gov/NewsAndEvents/PressReleases/PR20110419guidelines.htm

2. Williams JW, Plassman BL, Burke J, et al. Preventing Alzheimer’s Disease and Cognitive Decline. Evidence Report/Technology Assessment no. 193. (prepared by the Duke Evidence-based Practice Center under Contract No. HHSA 290-2007-10066-1) AHRQ Publication No. 10-E005. Rockville, MD: Agency for Healthcare Research and Quality. April 2010.

Dr. Courtney Cunningham is a student at NYU School of Medicine

Peer reviewed by David Sutin, MD, Clinical Associate Professor, Section Chief Geriatrics, Bellevue Hospital Center

Image courtesy of Wikimedia Commons (Alois Alzheimer)


How Should You Approach a Geriatric Insomniac?

September 2, 2009

sleepGilda Boroumand, MS4

Faculty Peer Reviewed

Chronic insomnia, defined as difficulty with the initiation, maintenance, duration, and quality of sleep for at least one month, is a common complaint with significant impact on an individual’s daytime functioning and quality of life. It is particularly prevalent in the elderly, affecting between 23% to 34% of individuals over the age of 64.[1] This same group is also more likely to experience adverse effects from various treatment regimens, thus leaving physicians with the task of weighing possible benefits against the risk of side effects. This is a difficult task, for the assessment of treatment efficacy is complicated by insomnia’s overlap with medical and psychiatric conditions, lack of consistency in diagnostic criteria, variation in methods used to assess treatments, and paucity of long-term follow-up in clinical trials.

Patients often turn to nonprescription antihistamines marketed as sleep aids for initial treatment of insomnia. Physicians, too, commonly prescribe such medications for their sedative-hypnotic effects. The 2005 NIH State of the Science Conference cautioned, however, that there is no systematic evidence for their efficacy despite their widespread use.[2,3] A randomized, controlled trial of the histamine-1 antagonist diphenhydramine demonstrated modest improvement of subjective sleep, but its conclusions are limited by a small number of subjects and short duration of treatment (fourteen days).[4] Moreover, the risks of antihistamine use are numerous and significant. A prospective cohort study of over 1600 elderly subjects with 10-year follow-up showed that extended use of diphenhydramine was associated with impairment on the Mini Mental Status Examination (individuals with dementia were excluded from analysis).[5] Indeed, expert consensus reports have advised against the use of diphenhydramine in the elderly due to its significant anticholinergic side effects, daytime sedation, and cognitive impairment noted in multiple clinical trials.[6,7]

Other frequently used medications include FDA-approved benzodiazepines and the newer nonbenzodiazepines, also known as benzodiazepine receptor agonists: zaleplon (Sonata), zolpidem (Ambien), and eszopiclone (Lunesta). The use of benzodiazepines for insomnia in the elderly is controversial given the uncertainty regarding their risk-to-benefit ratio. The efficacy of benzodiazepines in improving sleep latency, sleep maintenance, and total sleep duration was initially demonstrated by a meta-analysis performed in 1997, but more recent work by Holbrook et al. supports only a benefit in sleep duration (by approximately 60 minutes), with no difference in outcome when compared with antihistamines.[8,9] This benefit is countered by a number of adverse effects, including memory, cognitive function, psychomotor impairment, daytime drowsiness, and an increased risk of falling.[4] Additionally, benzodiazepines are only approved for short-term treatment of insomnia and the vast majority of studies evaluating their efficacy provide only two-week follow-up. Certainly their benefits cannot be expected to persist long after discontinuation.

The general consensus among researchers thus appears to favor nonbenzodiazepine agents for their relatively brief half-life and superior side-effect profile, though these, too, are riddled with problems. As compared to the benzodiazepines, longer clinical trials have been performed with the nonbenzodiazepines, with improved subjective sleep demonstrated after six months of treatment with zolpidem and eszopiclone.[10,11] Nonetheless, a 2005 meta-analysis of sedative hypnotics in elderly patients challenges the prevalent belief that nonbenzodiazepines have fewer adverse effects. A review of six studies comparing the two drug classes reported little difference in the number of adverse events and, specifically, no significant difference in cognitive or psychomotor adverse events.[12] Furthermore, the number needed to treat for improved sleep quality was 13 whereas the number needed to harm for any adverse event was 6. Though only a rough indicator, this ratio suggests that sedative medications may not benefit the elderly to the same degree as other adults. The common occurrence of adverse events in the elderly may not justify the subjectively improved sleep quality and increase of approximately 25 minutes in total sleep duration.

The armamentarium of pharmacologic treatments for insomnia includes one agent that does not appear to be associated with hypnotic side effects – but is of rather limited value. Ramelteon (Rozarem), a recently-approved melatonin receptor agonist, is said to provide its greatest benefit to patients with sleep-onset insomnia. One of the first randomized trials to test its efficacy demonstrated a subjective decrease of 10 to 15 minutes in sleep latency and increase of 10 to 15 minutes in total sleep time. [13] Similar results have been reported in studies of elderly patients.[14] Ramelteon is much better tolerated than hypnotic medications, with its side effects of headache, somnolence, and sore throat occurring in less than 1% of patients. Though safe, its gain of a mere 10 to 15 minutes of sleep can hardly be considered ground-breaking.

Surprisingly (or perhaps predictably), behavioral therapies may provide the best results for the treatment of insomnia. Cognitive behavioral therapy (CBT) has been shown to be the most effective. It combines multiple behavioral approaches, usually incorporating stimulus control (which reestablishes the bed as the space where sleep occurs), sleep restriction (which works to increase sleep time by inducing temporary sleep deprivation by reducing time in bed), relaxation therapies (predicated on the idea that insomnia is associated with hyperarousal), and a cognitive component that educates the patient about sleep needs and corrects unrealistic expectations.[15] Several trials have demonstrated the efficacy of CBT in older adults. [16]Moreover, a randomized, controlled trial of elderly patients showed that CBT provided greater benefit than a benzodiazepine, with a sustained therapeutic effect at two-year follow-up.[17] Combined CBT and pharmacotherapy were most efficacious in this study, but this result is challenged by a subsequent trial in which combined therapy provided no advantage over CBT alone, with benzodiazepines producing only moderate benefits during drug administration, with return to baseline after their discontinuation.[18] Researchers in this study concluded that perhaps patients are less committed to learning and practicing CBT if they know they can “control” their insomnia with medications. Of note, although CBT has been administered by psychologists in most studies, successful results have also been reported when therapy was delivered by primary care physicians who received brief training.[19] Perhaps the widespread use of CBT is a possibility for future therapy.

Despite modest treatment efficacy and significant risks of adverse effects, particularly in the elderly population, pharmacotherapy remains the most frequently recommended intervention for insomnia. Long-term use of medications is contraindicated, as remarkably little is known about the effects on sleep, daytime functioning, and quality of life beyond two-week follow-up, but drugs continue to be overused. Behavioral therapies currently hold the greatest promise for the treatment of insomnia, but these techniques have yet to be adopted by primary care physicians. Large-scale, long-term comparative studies of over-the-counter medications, hypnotics, behavioral therapy, and other remedies would be valuable in gaining a clearer understanding of the treatment of insomnia in elderly adults.

Ms. Boroumand is a 4th year medical student at NYU School of Medicine.

Peer reviewed and commentary by Dr. David Sutin, Associate Professor, NYU Division of General Internal Medicine

I strongly agree with trying behavioral therapy before medications and avoiding anti-histamines. Psychiatric and medical conditions, medications, and primary sleep disorders all need to be evaluated and their contribution to the sleep problem assessed. In the elderly person, any presenting symptom often has many etiologies, and the more that are identified and addressed, the better the outcome. The patient with coexisting depression might well benefit from a sedating antidepressant such as trazodone or mirtazapine. Sleep apnea is found in 24-40% of elderly people; interestingly, less oxygen desaturation occurs with the apneic episodes. The presence of sleep apnea is obviously a contraindication to use of many sedatives.

References:

1. Foley DJ, Monjan AA, Brown SL, Simonsick EM, Wallace RB, Blazer DG. Sleep complaints among elderly persons: an epidemiologic study of three communities. Sleep. 1995;18:425-432.
2. National Institutes of Health State of the Science Conference Statement on Manifestations and Management of Chronic Insomnia in Adults. Sleep. 2005;28:1049-1057
3. Bloom HG, Ahmed I, Alessi CA, et al. Evidence-based recommendations for the assessment and management of sleep disorders in older persons. J Am Geriatr Soc. 2009;57:761-789.
4. Morin CM, Koetter U, Bastien C, Ware JC, Wooten V. Valerian-hops combination and diphenhydramine for treating insomnia: a randomized placebo-controlled clinical trial. Sleep 2005;28:1465-1471.
5. Basu R, Dodge H, Stoehr GP, Ganguli M. Sedative-hypnotic use of diphenhydramine in a rural, older adult, community-based cohort: effects on cognition. Am J Geriatr Psychiatry. 2003;11:205-213.
6. Beers, MH. Explicit criteria for determining potentially inappropriate medication use by the elderly: an update. Arch Intern Med. 1997;157:1531-1536.
7. Wolkove N, Elkholy O, Baltzan M, Palayew M. Sleep and aging: 2. Management of sleep disorders in older people. CMAJ. 2007;176:1449-1454.
8. Nowell PD, Mazumdar S, Buysse DJ, Dew MA, Reynolds CF 3rd, Kupfer DJ. Benzodiazepines and zolpidem for chronic insomnia: a meta-analysis of treatment efficacy. JAMA. 1997;278:2170-2177.
9. Holbrook AM, Crowther R, Lotter A, Cheng C, King D. Meta-analysis of benzodiazepine use in the treatment of insomnia. CMAJ. 2000;162:225-233.
10. Walsh JK, Krystal AD, Amato DA, et al. Nightly treatment of primary insomnia with eszopiclone for six months: effect on sleep, quality of life, and work limitations. Sleep. 2007; 30:959-968.
11. Krystal AD, Erman M, Zammit GK, Soubrane C, Roth T; ZOLONG Study Group. Long-term efficacy and safety of zolpidem extended-release 12.5 mg, administered 3 to 7 nights per week for 24 weeks, in patients with chronic primary insomnia: a 6-month, randomized, double-blind, placebo-controlled, parallel-group, multicenter study. Sleep. 2008;31:79-90.
12. Glass J, Lanctot KL, Herrmann N, Sproule BA, Busto UE. Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. BMJ. 2005;331:1169.
13. Erman M, Seiden D, Zammit G, Sainati S, Zhang J. An efficacy, safety, and dose-response study of Ramelteon in patients with chronic primary insomnia. Sleep Med. 2006;7:17-24.
14. Mini LJ, Wang-Weigand S, Zhang J. Self-reported efficacy and tolerability of ramelteon 8 mg in older adults experiencing severe sleep-onset difficulty. Am J Geriatr Pharmacother. 2007;5:177-184.
15. Silber, MH. Clinical practice. Chronic insomnia. N Engl J Med. 2005;353:803-810.
16. Morin CM, Bootzin PR, Buysse DJ, Edinger JD, Espie CA, Lichstein KL. Psychological and behavioral treatment of insomnia: update of the recent evidence (1998-2004). Sleep. 2006;29:1398-1414.
17. Morin CM, Colecchi C, Stone J, Sood R, Brink D. Behavioral and pharmacological therapies for late-life insomnia: a randomized controlled trial. JAMA. 1999;281:991-999.
18. Jacobs GD, Pace-Schott EF, Stickgold R, Otto MW. Cognitive behavior therapy and pharmacotherapy for insomnia: a randomized controlled trial and direct comparison. Arch Intern Med. 2004;164:1888-1896.
19. Baillargeon L, Demers M, Ladouceur R. Stimulus-control: nonpharmacologic treatment for insomnia. Can Fam Physician. 1998;44:73-79.

Frailty- an emerging syndrome

August 21, 2008

Commentary by David Sutin MD, NYU Section 0f Geriatric Medicine

The Annual American Geriatric Society meeting, held May 2008, in Washington DC, was as usual fascinating. The meeting highlights included a lively discussion of the treatment of hypertension in the very elderly, and a talk on the emerging syndrome of frailty. Frailty was the selected subject for the Henderson State-of-the Art lecture, delivered by Dr Linda Fried, which I will summarize below.

The Syndrome of Frailty is characterized by at least 3 of the following 5 criteria-weakness, low energy and exhaustion, slow walking speed, low physical activity and weight loss. In the Cardiovascular Health study 7.3% of women over age 65, and 4.9% of men over 65 years of age were frail, with frailty being especially common in those over 80 years of age. Subjects who were frail had a Hazard Ratio, over 3 years, of 1.98 for worsening ADL disability and 2.24 for death. (Fried LP, Tangen CM, Walston J. et al. Frailty in older adults: evidence for a phenotype, Journal of Gerontology Series A-Biological Sciences and Medical Sciences. 2001, 56(3):M146-56.)

Dysregulation and deficits of multiple systems are associated with frailty including sarcopenia, inflammation, decreased heart rate variability, altered clotting, altered insulin resistance, anemia, higher levels IL-6, CRP, cortisol and lower levels DHEA-S and the presence of micronutrient deficiency.

It is felt that there are 3 major courses of death in adults.  In 20% there is a fatal illness, with a rapid decline prior to death (median age 65 years). In 25% there is a slow decline in physical capacities that is punctuated by serious exacerbations of different pathologies such as congestive heart failure or COPD (median age 75 years). In 40% there is a long term decline of function, requiring many years of assistance due to progressive fraility and cognitive impairment with death generally occuring after a physiological challenge, (median age 85 years).

Preventing frailty is obviously a major focus of geriatrics and includes the treatment of sarcopenia, which is modifiable. Data have shown that in frail nursing home patients resistance exercise increased muscle mass by 180% and strength by 100%. Nutritional supplementation may also be helpful. Further research on all aspects of frailty is needed. Among several comprehensive reviews of frailty, we suggest the following:
Ahmed N, Mandel R, Fain MJ, Frailty: An emerging Geriatric Syndrome, The American Journal of Medicine. 2007, Vol 120, pg 748-753

Old age and frailty: Biology and Socio-cultural Constructs

August 21, 2008

41_01_52-elderly-people_web.jpgCommentary by Antonella Surbone MD PhD FACP, Department of Medicine, New York University Medical School, Clinical Correlations Ethics Section Editor

According to the Institute of Medicine (IOM) report of April 14th, 2008, the elderly comprise 12% of the U.S. population, and their number is projected to almost double between 2005 and 2030, from 37 million to 70 million. The elderly currently account for more than one third of all hospital stays and of prescriptions, and more than a fourth of all office visits to physicians in the U.S. The average 75 year old American has three or more comorbidities and takes at least four medications. [1] Thus, delivering optimal geriatric care has become a medical and ethical priority in our aging society.
In western countries, old age tends to be represented mostly in terms of decreased productivity, functional impairment, co-morbidity, cognitive limitations and the burden of care placed on the family and the health care system. Healthcare providers thus tend to view the older population through a skewed “ageist” prism, acting on assumptions of uniform frailty and cognitive impairment. This distorted appraisal continues to limit the appropriateness of care and the adequacy of research and education in geriatrics. The older adult population, however, is physiologically, psychologically, socially and culturally heterogeneous. [2]

Aging involves a progressive decline in the functional reserve of multiple organs and systems that modulate the person’s adaptation to stress. [3] The word “frailty” has been often used improperly to refer to elderly patients’ increased vulnerability, when compared to younger adults. As reported by Dr. Sutin, research has lead to a precise conceptualization of frailty as the result of the interplay of physical, psychological, cognitive, functional, social and environmental factors [4,5]. Comorbidity, disability and frailty may occur in elderly patients as separate or concomitant entities, and their multidimensional assessment should guide clinical decision making in geriatrics.

In geriatric oncology, for example, the patient’s frailty often limits the safety of administration of standard and experimental treatments. Frailty, however, may result from the patient’s underlying cancer, and it can be improved or even reversed by active oncologic treatment. [6,7] Studies show that the frequent under-treatment of elderly cancer patients and their under-representation in clinical trials frequently stems from misconceptions about an inevitable correlation between aging, vulnerability and frailty. By contrast, available data suggest that age itself, in the absence of severe concomitant illnesses or psychological, cognitive or functional impairment, is not an independent risk factor for either increased toxicity or lack of cancer treatment efficacy. [8]

The distorted cultural perception of age that dominates most western societies, known as ageism, has a major influence on our attitudes toward, and practices of, providing health care to elderly patients, who often suffer from social isolation due to the loss of their past former productive roles. Poverty is especially common in the elderly, and socioeconomic, combined with cultural, factors in ethnic minorities in western countries limit their access to medical care and research. [2] Frailty is worsened by lack of social support and elderly patients are at risk for diminished quality of life and increased psychological stress.

In conclusion, when offering specific treatments to elderly patients, we must take into consideration different medical, psychological, functional and social factors. Understanding the determinants of frailty and learning how to recognize and measure it in the clinic is essential to achieve the objective of basing our clinical judgments on sound evidence, rather than on cultural myths, biases, or prejudices that rather endanger quality and effectiveness of geriatric care.

1. Institute of Medicine. Retooling for an aging America: Building the health care workforce. Committee on the Healthcare Workforce for older Americans- Washington, D.C.: The National Academies Press, 2008.

2. Lipsitz LA. Physiological complexity, aging, and the path to frailty. Sci Aging Knowl Envir 2004; p. pe16.

3. Fried LP, Ferrucci L, Darer J, Williamson JD, Anderson G. Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care. J Gerontol 2004; 59: 255-263.

4. Balducci L. Aging, frailty and chemotherapy. Cancer Control 2007; 14: 7-14.

5. Monfardini S, Basso U. Oncological causes of frailty in older cancer patients. Eur J Cancer 2007; 43:1230-1231.

6. Surbone A, Kagawa-Singer M, Terret C, Baider L. The illness trajectory of elderly cancer patients age across cultures: SIOG position paper. Ann Oncol 2006; 18:633-638.

7. Surbone A. Ethical considerations in conducting clinical trials for elderly cancer patients. Aging Health 2008; 4: 253-260.

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