PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
JAMA. Author manuscript; available in PMC Oct 13, 2011.
Published in final edited form as:
PMCID: PMC2981606
NIHMSID: NIHMS249646
Managing medications in clinically complex elders: “There’s got to be a happy medium”
Michael A. Steinman, MD and Joseph T. Hanlon, PharmD, MS
Division of Geriatrics, University of California, San Francisco and the San Francisco VA Medical Center (Dr. Steinman); the Division of Geriatric Medicine, Department of Medicine; Department of Epidemiology, and Department of Pharmacy and Therapeutics, University of Pittsburgh, Pittsburgh, PA; the Geriatric Research Education and Clinical Center (GRECC) and Center for Health Equity Research and Promotion (CHERP), Veterans Affairs Pittsburgh Healthcare System (VAPHS), Pittsburgh, PA (Dr. Hanlon)
Corresponding author: Michael Steinman, MD, 4150 Clement St, Box 181G, San Francisco VA Medical Center, San Francisco, CA 94121, mike.steinman/at/ucsf.edu, (tel) 415.221.4810 x3677, (fax) 415.750.6641, Dr Hanlon’s ; jth14/at/pitt.edu
Multiple medication use is common in older adults and may ameliorate symptoms, improve and extend quality of life, and occasionally cure disease. Unfortunately, multiple medication use is also a major risk factor for prescribing and adherence problems, adverse drug events, and other adverse health outcomes. This article describes a typical case of an older patient taking multiple medications and summarizes the evidence-based literature about improving medication use and withdrawing specific drugs and drug classes. It also describes a systematic approach for how health professionals can assess and improve medication regimens. The application of these approaches should be of benefit to patients, caregivers and family, and to health professionals themselves.
Mr L is an 84-year-old man with dementia first seen by Dr S in November 2008. His past medical history was significant for atrial fibrillation, diabetes mellitus, hypertension, hyperlipidemia, chronic kidney disease (estimated creatinine clearance of 42ml/min), and gastritis and gastroesophageal reflux disease. His past surgeries included a transurethral bladder resection for bladder cancer with subsequent urinary incontinence and a lumbar decompression for spinal stenosis in 2008.
Mr L lives with his wife, Mrs L, who cares for him. He is a retired writer and editor in the music business, and a lifelong tennis player. On first presentation, his initial complaints were forgetfulness, difficulty walking, and falling. His wife reported that he was “doing almost nothing,” maintaining a sedentary lifestyle at home and following her around. He needed considerable help with bathing and dressing and some assistance with toileting and transfers, and was dependent in most instrumental activities of daily living including shopping, housekeeping, and preparing meals. His wife hired a home health aide for several hours a day to help alleviate her substantial caregiving burden.
At his initial visit, blood pressure was approximately 135/60 mmHg, and heart rate was in the 50s. He scored 13 of 29 points on a Folstein Mini Mental Status Exam (MMSE) performed shortly before the visit, consistent with Dr S’s clinical impression of moderately severe cognitive impairment. His medications were glyburide 2.5 mg orally daily, memantine 10 mg orally twice daily, metoprolol 25 mg orally twice daily, digoxin 0.125 mg orally daily, warfarin (varying dose) daily, multivitamin, iron, etodolac 200 mg 2 tablets orally in the AM, gabapentin 300 mg orally twice daily, docusate sodium 100 mg orally daily, essential fatty acids orally 3 times daily, acetaminophen 650 mg orally every 6 hours as needed, and lactulose as needed, for a total of 13 medications at 16 scheduled doses per day.
Mr L’s hemoglobin A1c was 5.9% so Dr S stopped the glyburide. Dr S referred him to physical therapy and social services to discuss options regarding caregiving, social engagement, and long-term care plans. His warfarin dose was managed by nurse practitioners in a nearby hospital’s Anticoagulation Clinic, and his INRs were maintained in the desired range between 2.0 to 3.0.
Mr L had been maintained on etodolac and gabapentin after his 2008 lumbar laminectomy, despite no longer having pain complaints. Dr S sequentially tapered off both medications, watching for increased complaints of pain. He did fine, his walking improved, and he had no further falls. Dr S also tapered off the digoxin. She first cut the dose in half for 1 week. His heart rate remained in the 50-70 range, so she stopped it entirely. He began going to yoga with his wife and then to the gym twice weekly.
His initial labs had shown a normal Hgb of 13 g/dL, and his physician decided to stop the iron; his Hgb subsequently remained stable. Seven months after his first visit, Dr S discussed with his wife whether the memantine was helping Mr L’s memory (he previously had not tolerated donepezil). His wife was unsure, and together they decided to try tapering him off it. Thereafter, he had greater difficulty with nouns and names, so Dr S referred him to speech therapy for cognitive exercises and resumed the memantine at its full dose. He initially showed some improvement, but within 6 months cognitive decline was again apparent.
His wife continues to pay for his medication under a Medicare Part D plan. She reports that his activities of daily living have been stable. Socially, he is improved.
Mrs L and Dr S were interviewed by a Care of the Aging Patient editor in December 2009.
Ms L: Just looking at [some of his medications] you realized that you could keep taking it, but you don’t really have to…. It’s better to pull it out.
Use of multiple medications is a common source of concern for patients and clinicians. Nearly 20% of community-dwelling adults age 65 and older take 10 or more medications, a figure which can easily be reached by following practice guidelines for a handful of coexisting conditions.1-2 Multiple medication use is associated with greater use of inappropriate medications and non-adherence, and imposes substantial cost burdens on older patients even when they have prescription drug insurance.3-5 In addition, the frequency of adverse drug events rises in proportion to the number of medications used, including drug-specific phenomena as well as non-specific syndromes including weight loss, falls, and decline in functional and cognitive status.6-10 Such adverse drug events affect an estimated 5-35% of older patients living in the community per year, and are responsible for approximately 10% of hospital admissions in older adults.11-15
Despite legitimate concerns over multiple medication use, believing that Mr L is on “too many” medicines does not help the clinician know which ones to stop. Moreover, such labels can distract from addressing underuse of potentially beneficial medications, which is as prevalent in older adults taking many drugs as in those taking relatively few.16-17 The task for Dr S is not to determine if her patient is on too many or too few medications, but if he is on the right medications tailored to his individual circumstances, including his constellation of comorbidities, goals of care, and preferences and ability to adhere to medications.
We conducted several systematic literature reviews. Our main review evaluated the impact of interventions to improve suboptimal prescribing across the medication regimen (i.e., without focus on a single drug class or disease) for elders in ambulatory settings who were taking multiple medications. Searching PubMed and International Pharmaceutical Abstracts (IPA) from 1975 through March 2010, the search used a combination of the terms polypharmacy, multiple medications, polymedicine, suboptimal prescribing, medication misuse, inappropriate prescribing, elderly, geriatric, and aged, and was restricted to randomized clinical trials published in English that involved patients age 65 years and over and reported both process measures about improvement in prescribing and clinical outcomes measures. We also reviewed studies of the effects of discontinuing specific types of medications taken by Mr L. Details of search strategies are available in an e-appendix.
Before optimizing Mr L’s medication regimen, Dr S needs to assess what drugs Mr L thinks he should be taking, what he is actually taking, and the benefits and harms he is experiencing from his drugs.
Medication review
A good medication review is essential because discrepancies are common between what patients think they should be taking and what doctors record on their medication lists.18-19 There is little direct evidence to support 1 specific method of medication review over another in ambulatory settings.20 However, a “brown bag” review in which patients are asked to bring in all of their medicines (including all prescription and over-the-counter medicines, vitamins, supplements, and herbal preparations) can provide a useful snapshot of the patient’s current medication use. The clinician can review each medication brought in the “brown bag” one at a time and inquire about how the patient takes it (e.g., by asking “tell me how you take this medication”).
Brown bag reviews often present an opportune time to review the effectiveness of medications (e.g., control of pain, constipation, or depressed mood) as well as their adverse effects. Patients often do not report drug-related symptoms to their physicians, in part due to limited physician efforts to solicit this information.21-22 In one major study, such communication gaps were responsible for 37% of remediable adverse drug events.23 The question “In the past XX months, have you noticed any side effects, unwanted reactions, or other problems with medications you have taken?” has been validated as an effective way to inquire about adverse drug events.15 Directed questions about common or high-risk symptoms may also be necessary – for example, inquiring about postural symptoms in a patient taking antihypertensive medications.
Assessing adherence
Ms L: I opened his 7-day pill container on a Monday and it was wet. It turned out that he had been taking them out and moving them around and had spilled water in there somehow.
Mr L has several red flags for adherence problems, including his dementia, complex medication regimen, and previous drug adverse drug events.5, 24 Approximately half of older patients have problems with adherence to at least one medication, being evenly split between occasional, frequent, and near-universal omissions of drug doses, although patients non-adherent to one of their medications are commonly adherent to their others. 24-25
Patients are often reluctant to admit to non-adherence, so a multifaceted approach to evaluating adherence is necessary.24, 26 During medication review, clues about adherence can be deduced from observing medication organization, pill counts, and refill history (using information on the refill date and quantity dispensed printed on the label). Asking patients and their caregivers about their understanding of why they take each medication can also be useful. Although older adults understand the purpose of up to 88% of their medications and age itself does not predict adherence, lack of understanding increases risk of non-adherence and provides a ready target for intervention.5, 27 More generally, non-adherence can be elicited by non-judgmental questions such as ““I know it must be difficult to take all your medications regularly. How often do you miss taking them?”24 If non-adherence is identified, the patient should be asked why, with prompting as necessary for common reasons such as those listed in Table 2.5, 24 Interventions to improve medication use and adherence are most likely to succeed when they address the underlying reasons behind these problems.
Table 2
Table 2
Selected barriers to medication adherence and targeted solutions
For many physicians, ideal medication reviews and adherence assessments are a far-off reality given the time pressures of office-based practice. 28 In this setting, focusing on the highest-risk and highest-benefit drugs can yield good return on a limited time investment. Better yet is sharing these responsibilities with other health care providers. Contacting community pharmacists with concerns about patients can help engage their expertise in identifying and crafting solutions to problems with the medication regimen or adherence. Where health systems permit, nurses and clinic-based pharmacists should share medication management responsibilities as articulated in the patient-centered medical home model of care.29 Finally, some medication management programs are available through pharmacy benefit management plans serving Medicare Part D patients (see Resources). Eligibility criteria and scope of these programs are often limited, although more widespread benefits are mandated for implementation by 2013.30
Ms L: The family is all guilt-ridden and they tell themselves that they have to keep dear old dad alive …. My stake is that he himself has a decent day-to-day life as much as he can.
Like many older patients in the final chapter of their lives, Mr L and his caregivers face choices about using medications that may increase his longevity but negatively affect his quality of life.31 When getting to know Mr L, one of Dr S’s first tasks was to learn what he and his family are trying to achieve through medication use, including extension of longevity, reduction in symptoms, and minimization of pill burden, medication side effects, and costs.32 Many patients would like to achieve all these goals, but often they come into conflict. The physician’s role is thus to clarify the relative prioritization of these values, which usually emerges from multiple conversations about specific medication decisions and general goals of care discussions.
Understanding the life expectancy of patients through application of prognostic tools and clinical judgment can help inform goal-driven decisions about prescribing (see Resources).33 A short life expectancy affords patients limited opportunity to be helped by medications that take several years to start accruing benefits, such as drugs to improve glycemic control in diabetes.31-32, 34 In addition, for patients with advanced dementia and/or poor prognosis, consensus panels have failed to recommend (and in some cases advocated against) medications such as HMG-coA reductase inhibitors (statins), bisphosphonates, and cholinesterase inhibitors, although these positions are not universally endorsed.35-37
Given Mr L’s complex medication regimen and multiple comorbidities, he seems to be a good candidate for structured medication review and management. The evidence base to guide such approaches is limited. Among 6 studies of medication management that met inclusion criteria in our literature review (as described in the methods section), 3 tested the effect of a clinical pharmacist, 2 examined a comprehensive interdisciplinary medication review in a geriatric clinic, and 1 examined the impact of expert clinician recommendations through computer-based feedback (Table 1).38-44 Overall, these programs improved markers of pharmaceutical care quality such as reducing medication burden, correcting underuse of medications, and improving a multicomponent score of medication appropriateness. Less evidence is available about the impact of these interventions on clinical outcomes. In the largest study of its type, Schmader et al. reduced the rate of serious adverse drug events from 0.6 to 0.4 events per 1000 person-days (P=.02).43 A similar degree of reduction in all adverse drug reactions was observed in a study of veterans age 65 and older by Hanlon et al, with adverse events in 30% of patients receiving medication management vs. 40% in patients receiving usual care, although the finding was not significant (P=0.19).38 There is little conclusive evidence about the impact of comprehensive medication management on other clinical outcomes, including quality of life, health services utilization, and major clinical events, as in general these studies were underpowered for these outcomes.
Table 1
Table 1
Randomized controlled studies designed to improve pharmaceutical care quality in ambulatory older adults using multiple medications
Of note, most studies on improving medication prescribing for elders with multiple medication use evaluated an external intervention, such as pharmacist review or referral to a geriatric evaluation and management clinic. Few studies have evaluated clinicians’ own attempts to integrate medication management principles into their practice.45 However, limited data suggest that physicians provided structured assessment tools for medication review are able to identify and correct medication problems in a large percent of their patients, although time limitations impede widespread implementation of such reviews. 45-47
Matching the medication regimen to the patient’s conditions and goals of care
Although limited data is available about the impact of structured medication management on patient health and well-being, such approaches are endorsed by experts, in part due to clear evidence of beneficial effects on markers of prescribing quality.48 A simple and effective approach to systematically identify prescribing problems is to match each of the patient’s conditions with their medications (Table 3). Areas of mismatch can highlight drugs that are being overused (i.e., used with no indication), underused (i.e., conditions that may benefit from drug therapy that is not currently being offered), and misused (i.e., drugs given for an appropriate indication that could be improved by changing the dose, frequency, or substituting another drug with a better profile of benefits, harms, and costs).49
Table 3
Table 3
Matching Mr L’s conditions and medications *
Of note, the proper “match” between clinical conditions and medications is defined not only by guideline recommendations and best practices, but by how medication treatment for a given condition will help the patient attain their goals of care. Thus, the optimized medication regimen for a patient desiring a palliative approach that minimizes medication burden may look quite different than the regimen for an identical patient whose overriding goal is maximizing longevity.
Should medications be discontinued or substituted? Which ones?
Dr S: A lot of the pain complaints that he used to have had disappeared after he had a lumbar surgery in 2008. [His wife] didn’t know if he still needed the pain medication, but was too worried to stop them.
Without knowing anything else about Mr L, the fact that he was taking 13 medications when he first met Dr S suggests a high probability that 1 or more of his medications can or should be stopped.16, 50 Studies of community-based older patients have documented an average of 1 unnecessary drug per patient, including drugs with no identifiable indication or which provide little benefit for the indication for which they are prescribed.51-52 Perpetuation of unnecessary medications is particularly acute in older adults with multiple prescribers or transitions of care (e.g., recent hospital visits). 53-56 In the hospital setting, a large study found that 44% of hospitalized frail older patients were discharged on at least 1 unnecessary medication; common culprits include proton-pump inhibitors, central nervous system medications, and vitamin and mineral supplements.54, 57-58
In addition, drugs given for a useful clinical purpose are often mis-prescribed. For example, highly anticholinergic antihistamines, tricyclic antidepressants, and other high-risk drugs described in “drugs-to-avoid” lists for older patients are used by approximately 20-30% of adults over age 65, whereas in many cases drugs with better safety and/or efficacy would be a more appropriate choice for the target condition.59-63 Other common problems with mis-prescribing include use of inappropriately high or low doses, drug-drug and drug-disease interactions, incorrect directions, and choice of expensive drugs where less expensive alternatives would provide similar benefit at lower cost.49
As shown in Table 3, matching Mr L’s medications with his conditions shows several drugs without a clear current indication, including his etodolac, gabapentin, acetaminophen, multivitamins, and iron. These should be among the first drugs considered for discontinuation. Next are drugs which have a current indication but may provide limited or no benefit for the patient’s condition, for example memantine for Mr L’s dementia, glyburide for his diabetes, and digoxin for rate control of his atrial fibrillation. Finally, certain drugs may have benefits but an unfavorable risk profile and should be substituted for others with a more favorable ratio of benefits to harms.
Troublesome symptoms obviously caused by a drug provide a clear signal to consider discontinuation. However, the adverse effects of many drugs are non-specific and can mimic underlying disease processes, such as Mr L’s generalized functional decline. Often, the only way to know whether or not a symptom is a drug side effect is to temporarily stop the drug(s) and see whether the symptoms improve.64 While these are individualized clinical decisions, it can be useful to remember the adage that “any symptom in an older patient should be considered a drug side effect until proven otherwise.”65
With limited exceptions, there are very few studies about the benefits and harms of discontinuing specific types of medications.64, 66 In the case of Mr L, we could not identify any controlled studies that evaluated outcomes of withdrawing digoxin for rate control in atrial fibrillation, discontinuing hypoglycemic medications in diabetes, or withdrawing memantine in dementia (although we identified 1 randomized trial and 2 poorly-controlled trials about withdrawal of cholinesterase inhibitors, which suggested worsening of cognition after stopping the drug).67-69
In the absence of high-quality trial data on discontinuing medications, discontinuation decisions should be guided by the epidemiology of prescribing problems and by common sense. In assessing harms, particular attention should be paid to drugs that carry a high risk of serious adverse effects, including warfarin, hypoglycemic medications, and digoxin (see Table 4). These three account for one-third of all emergency room visits in older patients due to adverse drug events.70 In the case of Mr L, this provides extra reason to critically evaluate Mr L’s diabetes regimen and digoxin. Mr L likely does not need medications for his diabetes, on the basis of guidelines and evidence that suggest that tight glycemic control in the setting of advanced age or multiple comorbidities can result in greater harms than benefits.34, 71 Even if Mr L did require medication for glycemic control, glyburide would be a poor choice, as this agent is relatively contraindicated for patients with creatinine clearance under 50ml/min and carries a higher risk of severe hypoglycemia than other sulfonylureas.72-74 Nonetheless, the presence of a high-risk drug should not automatically mandate a medication change without further exploration of context.51 For example, tricyclic antidepressants are often problematic in elders due to a high frequency of anticholinergic adverse effects. However, if an older patient is already taking a tricyclic antidepressant for a valid indication and reports excellent symptom control, has no anticholinergic symptoms, and is reluctant to switch medications, it may be reasonable to continue the medication while educating the patient to be vigilant for potential future adverse effects.
Table 4
Table 4
Selected high-risk drugs
Underuse of potentially beneficial medications
While use of ineffective or harmful medications is common in older adults, the same patients often are not prescribed potentially beneficial medications, for example warfarin for atrial fibrillation,, antidepressants for major depression, pain medications, and laxatives.16, 49, 75 Mr L has several conditions that may benefit from additional drug therapy above what he is currently receiving (see Table 3). In patients in their final years of life, preference usually should be given to ensuring that troublesome symptoms such as pain and depressed mood are adequately treated. However, some forms of primary prevention can be appropriate if consistent with goals of care. For example, Vitamin D deficiency is common in older patients and has been implicated in falls, and fracture risk (along with an emerging variety of other conditions), and repletion can reduce risk of these outcomes.76-77 Thus, Vitamin D supplementation (at a dose of at least 800 IU per day) should be considered for Mr L, particularly if his serum 25-hydroxy Vitamin D level is low.77 For many conditions, the relative paucity of drug trials that include adults in the upper reaches of age or with extensive comorbid burden limits the evidence basis for treating patients such as Mr L. However, in many cases it appears likely that the relative risk reduction observed in middle-aged and “young-old” adults is not radically different in the old-old.78
Stopping medications
Dr S: I very rarely stop things cold – especially something such as a pain medicine, which could very well be helping the patient; that might be the reason he’s not complaining of pain.
When starting drugs in older adults, geriatricians often begin drugs one at a time and follow the dosing mantra of “start low and go slow.” Limited evidence is available about the best ways to stop medications in this group, although in clinical practice many follow a similarly sequential, step-wise approach to discontinuing drugs.64 In certain circumstances, an “all-at-once” approach may be warranted when dangerous signs or symptoms are thought likely to be due to drugs but the exact culprit cannot be identified, or when tendencies toward clinical inertia in a patient or practice environment suggest that future opportunities for medication modification will be limited.
Medications can typically be effectively withdrawn once the decision has been made to do so, although unwanted reactions in the period after withdrawal are common.79-80 In 1 of the only broad-based studies of the topic in ambulatory older patients, 26% of drug discontinuations were accompanied by worsening of the underlying disease (eg, recurrence of angina or high blood pressure) and 4% were accompanied by physiologic withdrawal reactions (mostly to beta blockers and benzodiazepines).81 For many drugs, risk of adverse withdrawal events can be minimized by slow, careful tapering of drug dose. This is particularly true for drugs to which the body adapts over time, for example through up- or down-regulation of end-organ receptors, producing a physiologic withdrawal reaction if the drug is withdrawn abruptly.64 While the scientific basis for how to withdraw specific drugs is scant, a rule of thumb is that drugs can usually be tapered down at the same rate at which they are titrated up at the initiation of drug therapy. Common drugs that require tapering include opioids, beta blockers, clonidine, gabapentin, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants.64 Regardless of the speed of the taper, patients should be monitored for adverse withdrawal events, including educating and activating patients to recognize and report concerning symptoms.13, 29
Sometimes drugs are stopped on a trial basis to determine if potential adverse drug effects resolve or symptoms of the underlying disease worsen. Such assessments can be complicated by fluctuations of symptoms and biomarkers in an individual patient; for example, it may be difficult to ascertain whether improvement in symptoms after withdrawing a drug was the result of stopping the drug or natural fluctuations in the disease course. In this case, a formal rechallenge with the drug (i.e., as part of an N-of-1 trial) may help to establish causality.82
IMPROVING ADHERENCE TO THE NEW REGIMEN
Mrs S: We looked and saw how confused he was so I told him I was going to take over all of his medicines.
The benefits of changing the medication regimen are contingent on the patient adhering to the revised plan of care. Improving adherence requires diagnosing barriers to proper medication use and devising strategies to overcome those barriers (Table 2).
Randomized controlled trials of strategies to improve adherence to chronic medications have yielded mixed results, and often have studied multifaceted interventions in a manner that makes it difficult to unpack the contribution of each component to improving adherence.83-85 However, several lessons emerge from the data. First, education through oral counseling or written instructions is important, but often insufficient unto itself. Most randomized trials of intensive educational interventions have yielded minimal to moderate impacts on adherence and little effect on clinical outcomes.83-84 Nonetheless, common sense suggests it is useful to briefly discuss and write out instructions for how to take a medication that is being newly prescribed or modified. A “teach-back” approach, in which the patient or caregiver is asked to describe the purpose of the drug, instructions for its use, and adverse effects to be aware of can help to ensure comprehension.
In contrast to a focus on education, a potent intervention to improve adherence is simplifying medication dosing schedules. Observational studies have found that adherence drops steeply with increasing number of doses per day, with average adherence falling from roughly 80% in patients taking once-daily regimens to 50% in those taking four-times-per-day regimens.86 Randomized controlled trials have found large differences in adherence in patients randomized to medications requiring different numbers doses per day, although effects on downstream clinical outcomes were mixed.83 Thus, where possible clinicians should minimize dosing frequency by prescribing longer-acting medications and dosing different drugs at the same time. In addition, pill burden can be reduced by using medications that can treat two or three conditions simultaneously (for example, beta blockers in a patient with hypertension, heart failure, and atrial fibrillation with rapid ventricular response). Attempts to reduce dosing frequency may be particularly potent for patients with cognitive difficulties, but are also helpful for cognitively intact patients or caregivers (such as Mr L’s wife). Such persons can also frequently forget to take or administer medicines and may resist the pill burden and lifestyle impacts that come with multiple dosings.24
Other approaches can help address common barriers to adherence, including behavioral interventions (e.g., cues, medication organizers, packaging), involvement of family and friends (e.g., support, monitoring, and administering medications, as was done for Mr L), and by having patients demonstrate ability to self-medicate in a controlled environment (e.g., in hospital or long term care facility) before discharged to home without support.83-85 In addition, addressing medication costs – for example, by prescribing lower-cost generic alternatives instead of brand-name drugs – can reduce cost-related non-adherence as well as negative impacts on other aspects of patient’s financial well-being.87 Many patients will need a combination of approaches and pharmacists can be helpful partners in devising and following strategies to improve adherence.
MONITORING AND FOLLOW-UP
Ongoing monitoring for the toxicity and effectiveness of drug therapy is critical to providing quality care and improving outcomes, but current practices often fall short.88-89 Approximately one-third to two-thirds of patients on ACE inhibitors, digoxin, carbamazepine, and other drugs that require laboratory-based safety monitoring fail to receive minimum standards for monitoring.48, 90-91 If suboptimal monitoring or frequent deviations from target levels have been present, barriers to monitoring and safe drug dosing should be assessed. If such barriers cannot readily be remediated, one should consider discontinuing the drug.
Finally, systematic review of a patient’s medication list (for example, using the framework suggested in this article) is a form of monitoring that should be done periodically. While the frequency of such reviews should be tailored to patient circumstances, a good starting point is recommendations by the National Committee for Quality Assurance and the ACOVE program, which consider medication review at least once per year to be an important measure of care quality in older adults.92-93 Declines in function and the onset or worsening of geriatric syndromes such as cognitive decline or falls may represent adverse drug effects or signal a change in goals of care and should also precipitate medication review.
CONCLUSIONS
Prescribing for older patients is an extraordinarily complex endeavor. However, as illustrated by Dr S and Mr L, a thoughtful, systematic approach to addressing the medication regimen can bring order to complexity and make a meaningful difference in patient outcomes. The success of Dr S’s care of Mr L was not in knowing the “right” answer for her patient from the beginning, but rather from employing a careful, step-wise process that merged key principles of pharmacologic care with the clinical reality, social situation, and goals of her patient.
Acknowledgments
The authors thank Lars Osterberg, MD, Rabbi Dorothy Richman, and the physician, patient, and caregiver who provided the case example for this paper.
Funding/Support.
Dr Steinman was supported by the National Institute on Aging and the American Federation for Aging Research (K23 AG030999) and by the Department of Veterans Affairs (IIR 06-080). Dr Hanlon was supported by National Institute of Aging grants (R01AG027017, P30AG024827, T32 AG021885, K07AG033174, R01AG034056), a National Institute of Mental Health grant (R34 MH082682), a National Institute of Nursing Research grant (R01 NR010135), Agency for Healthcare Research and Quality grants (HS017695 and HS018721 and a VA Health Services Research grant (IIR-06-062).
The Care of the Aging Patient series is made possible by funding from The SCAN Foundation.
Editorial control
Editors from the Care of the Aging Patient series provided suggestions on the structure and content of this manuscript. Otherwise, the funders of this work had no input on the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
Appendix: Resources for clinicians
Table 5
ADHERENCE, MEDICATION MANAGEMENT, REDUCING DRUG COSTS
Tools to improve adherence
Medication management programs
Assistance with payment for medications
IDENTIFYING AND AVOIDING COMMON PRESCRIBING PROBLEMS
Identifying potentially inappropriate medications
Identifying underuse
Renal dosing for common drugs
Identifying clinically significant drug-disease interactions
Identifying clinically significant drug-drug interactions
Footnotes
Disclosure
Dr Steinman and Hanlon report no outside support other than the grants listed below.
1. Boyd CM, Darer J, Boult C, Fried LP, Boult L, Wu AW. Clinical practice guidelines and quality of care for older patients with multiple comorbid diseases: implications for pay for performance. JAMA. 2005 Aug 10;294(6):716–724. [PubMed]
2. Slone Epidemiololgy Center at Boston University Patterns of medication use in the United States 2006: A report from the Slone survey. [Accessed 2 June 2010]. http://www.bu.edu/slone/SloneSurvey/AnnualRpt/SloneSurveyWebReport2006.pdf.
3. Madden JM, Graves AJ, Zhang F, et al. Cost-related medication nonadherence and spending on basic needs following implementation of Medicare Part D. JAMA. 2008 Apr 23;299(16):1922–1928. [PubMed]
4. Steinman MA, Landefeld CS, Rosenthal GE, Berthenthal D, Sen S, Kaboli PJ. Polypharmacy and prescribing quality in older people. J Am Geriatr Soc. 2006 Oct;54(10):1516–1523. [PubMed]
5. Vik SA, Maxwell CJ, Hogan DB. Measurement, correlates, and health outcomes of medication adherence among seniors. Ann Pharmacother. 2004 Feb;38(2):303–312. [PubMed]
6. Chrischilles E, Rubenstein L, Van Gilder R, Voelker M, Wright K, Wallace R. Risk factors for adverse drug events in older adults with mobility limitations in the community setting. J Am Geriatr Soc. 2007 Jan;55(1):29–34. [PubMed]
7. Field TS, Gurwitz JH, Harrold LR, et al. Risk factors for adverse drug events among older adults in the ambulatory setting. J Am Geriatr Soc. 2004 Aug;52(8):1349–1354. [PubMed]
8. Agostini JV, Han L, Tinetti ME. The relationship between number of medications and weight loss or impaired balance in older adults. J Am Geriatr Soc. 2004 Oct;52(10):1719–1723. [PubMed]
9. Magaziner J, Cadigan D, Fedder D. Medication use and functional decline among community dwelling older women. J Aging Health. 1989;1:470–484.
10. Larson EB, Kukull WA, Buchner D, Reifler BV. Adverse drug reactions associated with global cognitive impairment in elderly persons. Ann Intern Med. 1987 Aug;107(2):169–173. [PubMed]
11. Kongkaew C, Noyce PR, Ashcroft DM. Hospital admissions associated with adverse drug reactions: a systematic review of prospective observational studies. Ann Pharmacother. 2008 Jul;42(7):1017–1025. [PubMed]
12. Hanlon JT, Pieper CF, Hajjar ER, et al. Incidence and predictors of all and preventable adverse drug reactions in frail elderly persons after hospital stay. J Gerontol A Biol Sci Med Sci. 2006 May;61(5):511–515. [PubMed]
13. Gurwitz JH, Field TS, Harrold LR, et al. Incidence and preventability of adverse drug events among older persons in the ambulatory setting. JAMA. 2003 Mar 5;289(9):1107–1116. [PubMed]
14. Hanlon JT, Schmader KE, Koronkowski MJ, et al. Adverse drug events in high risk older outpatients. J Am Geriatr Soc. 1997 Aug;45(8):945–948. [PubMed]
15. Chrischilles EA, Segar ET, Wallace RB. Self-reported adverse drug reactions and related resource use. A study of community-dwelling persons 65 years of age and older. Ann Intern Med. 1992 Oct 15;117(8):634–640. [PubMed]
16. Steinman MA. Polypharmacy and the balance of medication benefits and risks. Am J Geriatr Pharmacother. 2007 Dec;5(4):314–316. [PubMed]
17. Gurwitz JH. Polypharmacy: a new paradigm for quality drug therapy in the elderly? Arch Intern Med. 2004 Oct 11;164(18):1957–1959. [PubMed]
18. Kaboli PJ, McClimon BJ, Hoth AB, Barnett MJ. Assessing the accuracy of computerized medication histories. Am J Manag Care. 2004 Nov;10(11 Pt 2):872–877. [PubMed]
19. Bedell SE, Jabbour S, Goldberg R, et al. Discrepancies in the use of medications: their extent and predictors in an outpatient practice. Arch Intern Med. 2000 Jul 24;160(14):2129–2134. [PubMed]
20. Bayoumi I, Howard M, Holbrook AM, Schabort I. Interventions to improve medication reconciliation in primary care. Ann Pharmacother. 2009 Oct;43(10):1667–1675. [PubMed]
21. Weingart SN, Gandhi TK, Seger AC, et al. Patient-reported medication symptoms in primary care. Arch Intern Med. 2005 Jan 24;165(2):234–240. [PubMed]
22. Richard C, Lussier MT. Nature and frequency of exchanges on medications during primary care encounters. Patient Educ Couns. 2006 Dec;64(1-3):207–216. [PubMed]
23. Gandhi TK, Weingart SN, Borus J, et al. Adverse drug events in ambulatory care. N Engl J Med. 2003 Apr 17;348(16):1556–1564. [PubMed]
24. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005 Aug 4;353(5):487–497. [PubMed]
25. Gray SL, Mahoney JE, Blough DK. Medication adherence in elderly patients receiving home health services following hospital discharge. Ann Pharmacother. 2001 May;35(5):539–545. [PubMed]
26. Morisky DE, Green LW, Levine DM. Concurrent and predictive validity of a self-reported measure of medication adherence. Med Care. 1986 Jan;24(1):67–74. [PubMed]
27. Wallsten SM, Sullivan RJ, Jr., Hanlon JT, Blazer DG, Tyrey MJ, Westlund R. Medication taking behaviors in the high- and low-functioning elderly: MacArthur field studies of successful aging. Ann Pharmacother. 1995 Apr;29(4):359–364. [PubMed]
28. Cutler DM, Everett W. Thinking outside the pillbox--medication adherence as a priority for health care reform. N Engl J Med. Apr 29;362(17):1553–1555. [PubMed]
29. Feldstein AC, Smith DH, Perrin N, et al. Improved therapeutic monitoring with several interventions: a randomized trial. Arch Intern Med. 2006 Sep 25;166(17):1848–1854. [PubMed]
30. Thompson CA. New health care laws will bring changes for pharmacists. Am J Health Syst Pharm. May 1;67(9):690–695. [PubMed]
31. Walter LC, Covinsky KE. Cancer screening in elderly patients: a framework for individualized decision making. Jama. 2001 Jun 6;285(21):2750–2756. [PubMed]
32. Holmes HM, Hayley DC, Alexander GC, Sachs GA. Reconsidering medication appropriateness for patients late in life. Arch Intern Med. 2006 Mar 27;166(6):605–609. [PubMed]
33. Reuben DB. Medical care for the final years of life: “When you’re 83, it’s not going to be 20 years” JAMA. 2009 Dec 23;302(24):2686–2694. [PMC free article] [PubMed]
34. Brown AF, Mangione CM, Saliba D, Sarkisian CA. Guidelines for improving the care of the older person with diabetes mellitus. J Am Geriatr Soc. 2003 May;51(5 Suppl):S265–280. Guidelines. [PubMed]
35. Holmes HM, Sachs GA, Shega JW, Hougham GW, Cox Hayley D, Dale W. Integrating palliative medicine into the care of persons with advanced dementia: identifying appropriate medication use. J Am Geriatr Soc. 2008 Jul;56(7):1306–1311. [PubMed]
36. Parsons C, Hughes CM, Passmore AP, Lapane KL. Withholding, discontinuing and withdrawing medications in dementia patients at the end of life: a neglected problem in the disadvantaged dying? Drugs Aging. 2010 Jun 1;27(6):435–449. [PubMed]
37. Wenger NS, Solomon DH, Amin A, et al. Application of assessing care of vulnerable elders-3 quality indicators to patients with advanced dementia and poor prognosis. J Am Geriatr Soc. 2007 Oct;55(Suppl 2):S457–463. [PubMed]
38. Hanlon JT, Weinberger M, Samsa GP, et al. A randomized, controlled trial of a clinical pharmacist intervention to improve inappropriate prescribing in elderly outpatients with polypharmacy. Am J Med. 1996 Apr;100(4):428–437. [PubMed]
39. Cowper PA, Weinberger M, Hanlon JT, et al. The cost-effectiveness of a clinical pharmacist intervention among elderly outpatients. Pharmacotherapy. 1998 Mar-Apr;18(2):327–332. [PubMed]
40. Krska J, Cromarty JA, Arris F, et al. Pharmacist-led medication review in patients over 65: a randomized, controlled trial in primary care. Age Ageing. 2001 May;30(3):205–211. [PubMed]
41. Lenaghan E, Holland R, Brooks A. Home-based medication review in a high risk elderly population in primary care--the POLYMED randomised controlled trial. Age Ageing. 2007 May;36(3):292–297. [PubMed]
42. Williams ME, Pulliam CC, Hunter R, et al. The short-term effect of interdisciplinary medication review on function and cost in ambulatory elderly people. J Am Geriatr Soc. 2004 Jan;52(1):93–98. [PubMed]
43. Schmader KE, Hanlon JT, Pieper CF, et al. Effects of geriatric evaluation and management on adverse drug reactions and suboptimal prescribing in the frail elderly. Am J Med. 2004 Mar 15;116(6):394–401. [PubMed]
44. Weber V, White A, McIlvried R. An electronic medical record (EMR)-based intervention to reduce polypharmacy and falls in an ambulatory rural elderly population. J Gen Intern Med. 2008 Apr;23(4):399–404. [PMC free article] [PubMed]
45. Pit SW, Byles JE, Cockburn J. Medication review: patient selection and general practitioner’s report of drug-related problems and actions taken in elderly Australians. J Am Geriatr Soc. 2007 Jun;55(6):927–934. [PubMed]
46. Krska J, Gill D, Hansford D. Pharmacist-supported medication review training for general practitioners: feasibility and acceptability. Med Educ. 2006 Dec;40(12):1217–1225. [PubMed]
47. Drenth-van Maanen AC, van Marum RJ, Knol W, van der Linden CM, Jansen PA. Prescribing optimization method for improving prescribing in elderly patients receiving polypharmacy: results of application to case histories by general practitioners. Drugs Aging. 2009;26(8):687–701. [PubMed]
48. Higashi T, Shekelle PG, Solomon DH, et al. The quality of pharmacologic care for vulnerable older patients. Ann Intern Med. 2004 May 4;140(9):714–720. [PubMed]
49. Hanlon JT, Schmader KE, Ruby CM, Weinberger M. Suboptimal prescribing in older inpatients and outpatients. J Am Geriatr Soc. 2001;49(2):200–209. [PubMed]
50. Goulding MR. Inappropriate medication prescribing for elderly ambulatory care patients. Arch Intern Med. 2004 Feb 9;164(3):305–312. [PubMed]
51. Steinman MA, Rosenthal GE, Landefeld CS, Bertenthal D, Kaboli PJ. Agreement between drugs-to-avoid criteria and expert assessments of problematic prescribing. Arch Intern Med. 2009 Jul 27;169(14):1326–1332. [PMC free article] [PubMed]
52. Doucette WR, McDonough RP, Klepser D, McCarthy R. Comprehensive medication therapy management: identifying and resolving drug-related issues in a community pharmacy. Clin Ther. 2005 Jul;27(7):1104–1111. [PubMed]
53. Boockvar KS, Liu S, Goldstein N, Nebeker J, Siu A, Fried T. Prescribing discrepancies likely to cause adverse drug events after patient transfer. Qual Saf Health Care. 2009 Feb;18(1):32–36. [PMC free article] [PubMed]
54. Hajjar ER, Hanlon JT, Sloane RJ, et al. Unnecessary drug use in frail older people at hospital discharge. J Am Geriatr Soc. 2005 Sep;53(9):1518–1523. [PubMed]
55. Hajjar ER, Hanlon JT, Artz MB, et al. Adverse drug reaction risk factors in older outpatients. Am J Geriatr Pharmacother. 2003 Dec;1(2):82–89. [PubMed]
56. Green JL, Hawley JN, Rask KJ. Is the number of prescribing physicians an independent risk factor for adverse drug events in an elderly outpatient population? Am J Geriatr Pharmacother. 2007 Mar;5(1):31–39. [PubMed]
57. Grant K, Al-Adhami N, Tordoff J, Livesey J, Barbezat G, Reith D. Continuation of proton pump inhibitors from hospital to community. Pharm World Sci. 2006 Aug;28(4):189–193. [PubMed]
58. Thomas L, Culley EJ, Gladowski P, Goff V, Fong J, Marche SM. Longitudinal analysis of the costs associated with inpatient initiation and subsequent outpatient continuation of proton pump inhibitor therapy for stress ulcer prophylaxis in a large managed care organization. J Manag Care Pharm. Mar;16(2):122–129. [PubMed]
59. Simon SR, Chan KA, Soumerai SB, et al. Potentially inappropriate medication use by elderly persons in U.S. Health Maintenance Organizations, 2000-2001. J Am Geriatr Soc. 2005 Feb;53(2):227–232. [PubMed]
60. Pugh MJ, Hanlon JT, Zeber JE, Bierman A, Cornell J, Berlowitz DR. Assessing potentially inappropriate prescribing in the elderly Veterans Affairs population using the HEDIS 2006 quality measure. J Manag Care Pharm. 2006 Sep;12(7):537–545. [PubMed]
61. Zhan C, Sangl J, Bierman AS, et al. Potentially inappropriate medication use in the community-dwelling elderly: findings from the 1996 Medical Expenditure Panel Survey. JAMA. 2001 Dec 12;286(22):2823–2829. [PubMed]
62. Fick DM, Cooper JW, Wade WE, Waller JL, Maclean JR, Beers MH. Updating the Beers criteria for potentially inappropriate medication use in older adults: results of a US consensus panel of experts. Arch Intern Med. 2003 Dec 8-22;163(22):2716–2724. [PubMed]
63. Ryan C, O’Mahony D, Kennedy J, Weedle P, Byrne S. Potentially inappropriate prescribing in an Irish elderly population in primary care. Br J Clin Pharmacol. 2009 Dec;68(6):936–947. [PubMed]
64. Bain KT, Holmes HM, Beers MH, Maio V, Handler SM, Pauker SG. Discontinuing medications: a novel approach for revising the prescribing stage of the medication-use process. J Am Geriatr Soc. 2008 Oct;56(10):1946–1952. [PMC free article] [PubMed]
65. Rochon PA, Gurwitz JH. Optimising drug treatment for elderly people: the prescribing cascade. BMJ. 1997 Oct 25;315(7115):1096–1099. [PMC free article] [PubMed]
66. Iyer S, Naganathan V, McLachlan AJ, Le Couteur DG. Medication withdrawal trials in people aged 65 years and older: a systematic review. Drugs Aging. 2008;25(12):1021–1031. [PubMed]
67. Holmes C, Wilkinson D, Dean C, et al. The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease. Neurology. 2004 Jul 27;63(2):214–219. [PubMed]
68. Minett TS, Thomas A, Wilkinson LM, et al. What happens when donepezil is suddenly withdrawn? An open label trial in dementia with Lewy bodies and Parkinson’s disease with dementia. Int J Geriatr Psychiatry. 2003 Nov;18(11):988–993. [PubMed]
69. Farlow M, Potkin S, Koumaras B, Veach J, Mirski D. Analysis of outcome in retrieved dropout patients in a rivastigmine vs placebo, 26-week, Alzheimer disease trial. Arch Neurol. 2003 Jun;60(6):843–848. [PubMed]
70. Budnitz DS, Shehab N, Kegler SR, Richards CL. Medication use leading to emergency department visits for adverse drug events in older adults. Ann Intern Med. 2007 Dec 4;147(11):755–765. [PubMed]
71. Greenfield S, Billimek J, Pellegrini F, et al. Comorbidity affects the relationship between glycemic control and cardiovascular outcomes in diabetes: a cohort study. Ann Intern Med. 2009 Dec 15;151(12):854–860. [PubMed]
72. Shorr RI, Ray WA, Daugherty JR, Griffin MR. Incidence and risk factors for serious hypoglycemia in older persons using insulin or sulfonylureas. Arch Intern Med. 1997 Aug 11-25;157(15):1681–1686. [PubMed]
73. Charpentier G, Riveline JP, Varroud-Vial M. Management of drugs affecting blood glucose in diabetic patients with renal failure. Diabetes Metab. 2000 Jul;26(Suppl 4):73–85. [PubMed]
74. Gangji AS, Cukierman T, Gerstein HC, Goldsmith CH, Clase CM. A systematic review and meta-analysis of hypoglycemia and cardiovascular events: a comparison of glyburide with other secretagogues and with insulin. Diabetes Care. 2007 Feb;30(2):389–394. [PubMed]
75. Lipton HL, Bero LA, Bird JA, McPhee SJ. The impact of clinical pharmacists’ consultations on physicians’ geriatric drug prescribing. A randomized controlled trial. Medical Care. 1992;30(7):646–658. [PubMed]
76. Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, et al. Effect of Vitamin D on falls: a meta-analysis. JAMA. 2004 Apr 28;291(16):1999–2006. [PubMed]
77. Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch Intern Med. 2009 Mar 23;169(6):551–561. [PubMed]
78. Scott IA, Guyatt GH. Cautionary tales in the interpretation of clinical studies involving older persons. Arch Intern Med. 2010 Apr 12;170(7):587–595. [PubMed]
79. Gerety MB, Cornell JE, Plichta DT, Eimer M. Adverse events related to drugs and drug withdrawal in nursing home residents. J Am Geriatr Soc. 1993 Dec;41(12):1326–1332. [PubMed]
80. Garfinkel D, Zur-Gil S, Ben-Israel J. The war against polypharmacy: a new cost-effective geriatric-palliative approach for improving drug therapy in disabled elderly people. Isr Med Assoc J. 2007 Jun;9(6):430–434. [PubMed]
81. Graves T, Hanlon JT, Schmader KE, et al. Adverse events after discontinuing medications in elderly outpatients. Arch Intern Med. 1997 Oct 27;157(19):2205–2210. [PubMed]
82. Scuffham PA, Nikles J, Mitchell GK, et al. Using N-of-1 Trials to Improve Patient Management and Save Costs. J Gen Intern Med. 2010 Apr 13; [PMC free article] [PubMed]
83. Kripalani S, Yao X, Haynes RB. Interventions to enhance medication adherence in chronic medical conditions: a systematic review. Arch Intern Med. 2007 Mar 26;167(6):540–550. [PubMed]
84. Conn VS, Hafdahl AR, Cooper PS, Ruppar TM, Mehr DR, Russell CL. Interventions to improve medication adherence among older adults: meta-analysis of adherence outcomes among randomized controlled trials. Gerontologist. 2009 Aug;49(4):447–462. [PubMed]
85. Russell CL, Conn VS, Jantarakupt P. Older adult medication compliance: integrated review of randomized controlled trials. Am J Health Behav. 2006 Nov-Dec;30(6):636–650. [PubMed]
86. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther. Aug. 2001;23(8):1296–1310. [PubMed]
87. Hsu J, Fung V, Price M, et al. Medicare beneficiaries’ knowledge of Part D prescription drug program benefits and responses to drug costs. JAMA. 2008 Apr 23;299(16):1929–1936. [PubMed]
88. Budnitz DS, Pollock DA, Weidenbach KN, Mendelsohn AB, Schroeder TJ, Annest JL. National surveillance of emergency department visits for outpatient adverse drug events. JAMA. 2006 Oct 18;296(15):1858–1866. [PubMed]
89. Raebel MA, Ross C, Xu S, et al. Diabetes and drug-associated hyperkalemia: effect of potassium monitoring. J Gen Intern Med. Apr;25(4):326–333. [PMC free article] [PubMed]
90. Hurley JS, Roberts M, Solberg LI, et al. Laboratory safety monitoring of chronic medications in ambulatory care settings. J Gen Intern Med. 2005 Apr;20(4):331–333. [PMC free article] [PubMed]
91. Raebel MA, McClure DL, Simon SR, et al. Laboratory monitoring of potassium and creatinine in ambulatory patients receiving angiotensin converting enzyme inhibitors and angiotensin receptor blockers. Pharmacoepidemiol Drug Saf. 2007 Jan;16(1):55–64. [PubMed]
92. National Committee for Quality Assurance HEDIS 2010. [Accessed May 4, 2010]. 2010. http://www.ncqa.org/tabid/1044/Default.aspx.
93. Shrank WH, Polinski JM, Avorn J. Quality indicators for medication use in vulnerable elders. J Am Geriatr Soc. 2007 Oct;55(Suppl 2):S373–382. [PubMed]
94. Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2545–2559. [PubMed]
95. Mant J, Hobbs FD, Fletcher K, et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet. 2007 Aug 11;370(9586):493–503. [PubMed]
96. Woolcott JC, Richardson KJ, Wiens MO, et al. Meta-analysis of the impact of 9 medication classes on falls in elderly persons. Arch Intern Med. 2009 Nov 23;169(21):1952–1960. [PubMed]
97. Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA. 2005 Oct 19;294(15):1934–1943. [PubMed]