Clinical Update on Nursing Home Medicine: 2011

UPDATES FROM THE AMDA MEETING

Clinical Update on Nursing Home Medicine: 2011 Barbara J. Messinger-Rapport, MS, PhD, FACP, CMD, John E. Morley, MB, BCh, David R. Thomas, MD, FACP, AGSF, FGSA, CMD, and Julie K. Gammack, MD

This represents the fifth article in the series on yearly updates of hot topics in long term care (J Am Med Dir Assoc 2011; 12: 615–626)

Keywords: Osteoporosis; Diabetes mellitus; Weight loss; Anticoagulants; Proton pump inhibitors; Delirium; Polypharmacy

PHARMACOLOGICAL OSTEOPOROSIS MANAGEMENT

cer patients. The latter risk of typical femur fracture rises after 5 years of use, but is rare, with an incidence of 2.3 fractures per 10,000 patient-years.13 Although some advocate a ‘‘drug holiday’’ after 5 years of use, evidence for optimal duration of therapy and use of a drug holiday is not available, and the benefit of ‘‘typical’’ femur fracture risk reduction continues past 5 years.14 Denosumab (Prolia) is a recently approved osteoporosis drug which has been shown to reduce the risk of hip fractures in osteoporotic women by 40%15 and vertebral fractures in men with androgen deprivation by 62%.16 A monoclonal antibody, it is a member of the TNF superfamily and binds to the receptor activator of nuclear factor B ligand (RANKL). Cleared by nonrenal mechanisms, it can be administered to persons with CKD, though there is inadequate data on end stage renal failure. It is given subcutaneously twice yearly. Given the potential to suppress immune function, its role in routine osteoporosis treatment in frail elders who may be vulnerable to infection is limited at this time until more postmarketing studies are available. Vitamin D levels are low in the majority of nursing home residents.17–25 Daily Vitamin D, regardless of calcium intake, has been shown to reduce the rate of falls and fracture in older adults26 but the optimal dose and frequency are not known. Very high doses separated by long intervals (for example, 500,000 units yearly) was associated with an increase in falls and fracture in 1 study.27 The value of calcium supplementation above and beyond dietary intake when there is adequate vitamin D supplementation is likely low.26 Additionally, calcium supplements are associated with nephrolithiasis,28 advanced and fatal prostate cancer,29 and can prevent absorption of medications often used in older adults, including floroquinolones, ketoconazole, phenytoin, levo-thyroxine, iron supplements, gabapentin, and others. Recent studies30–32 found an increased cardiovascular risk to supplemental calcium at doses typically used in older adults (600–2000 mg/d). Estrogens and selective estrogen receptor modulator increase bone density and are associated with vertebral fracture

Osteoporosis and hip fractures are extremely common in nursing home residents and are associated with increased disability and mortality.1–10 Despite the plethora of drugs for preventing and treating osteoporosis, there are only 2 drugs which demonstrate an outcome of lowered risk of hip fracture: bisphosphonates, and denosumab. Bisphosphonates reduce the risk of hip fracture by 25–40%, with a NNT of 20–200 depending upon the study and the risk of fracture.11 Bisphosphonates can be administered orally on a daily, weekly, monthly, or quarterly basis, or IV either quarterly (ibandronate) or yearly (zolendronate). Conditions seen in older patients, such as esophageal varices, severe kyphosis, dysphagia, and dementia (impaired oropharyngeal coordination, lack of compliance with upright restrictions, or both) limit the efficacy and safety of the oral versions. The high prevalence of chronic kidney disease (CKD) in the older population limits this drug as well, since it is not approved for use in CKD 4 or 5. Off-label use in those with advanced CKD in the absence of biochemical markers for CKD-associated bone mineral disorders has emerged but long-term and prospective data are absent.12 Potential and emerging adverse effects include osteonecrosis of the jaw and atypical femur fracture. The former risk is seen mainly with IV pamidronate or zolendronic acid in canCleveland Clinic, Section of Geriatric Medicine, Cleveland, OH (B.J.M.-R); Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, MO (J.E.M., D.R.T., J.K.G). This represents the fifth article in the series on yearly updates of hot topics in long-term care. Address correspondence to John E. Morley, MB, BCh, Division of Geriatric Medicine, Saint Louis University School of Medicine, 1402 S. Grand Boulevard, M238, St. Louis, MO 63104. E-mail: [email protected]

Published by Elsevier Inc. on behalf of the American Medical Directors Association, Inc. DOI:10.1016/j.jamda.2011.08.007 UPDATES FROM THE AMDA MEETING

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risk reduction as primary outcomes.11 However, estrogen therapy is associated with an excess risk of stroke despite reduction of hip fracture risk.33 Oral estrogen/progesterone combination treatment is associated with an increased risk of coronary heart disease, breast cancer34 and dementia.35 Fracture risk is based primarily on bone density (the World Health Organization utilizes a cut-off of T #2.5 standard deviations). When the bone density does not reach this low level but there is concern, 1 risk tool to consider is the FRAX.36 A FRAX score of at least 3% for hip and 20% for major osteoporotic fractures suggests benefit to pharmacological intervention. This score incorporates bone density, gender, race, age (up to 90), use of alcohol and tobacco, body mass index, glucocorticoids, personal and family history of fracture, secondary causes of osteoporosis. It expands treatment to persons who might not reach the WHO cutoff, and reassures clinicians that some with osteopenia may not need treatment at the current time. The problem with the FRAX score and other standardized risk models such as the Fracture Risk Calculator (FRC) is that many conditions and medications common to geriatric patients increase the risk of falls, thus increasing the risk of fracture. Examples of conditions that increase the risk of falls include visual impairment, orthostatic hypotension, diabetes (with vision impairment and/or neuropathy and/or recurrent hypoglycemic episodes), Parkinson’s disease, and dementia. These conditions are not included in current risk calculators. Older diabetics may have neuropathy, which increases the risk of falls, or may have overt or subclinical hypoglycemia due to medications, increasing the risk of confusion and falls. Movement disorders of all types, particularly Parkinson’s disease and parkinsonian conditions, increase the risk of fall and fracture. The reduced attention span and judgment found in dementia lead to falls. The relatively sedentary lifestyles of these patients may increase the rate of decline of bone density faster than the risk calculators account for as well. In summary, fracture prevention in frail elders, particularly those with dementia and those in long-term care, is based primarily on adequate calcium intake (up to 1000 mg/d), adequate vitamin D intake (800–1000 units daily), maintenance of mobility and balance, appropriate treatment of diseases that predispose to falls, and medication parsimony to reduce falls and limit the decline in bone density. Oral bisphosphonates in frail elders requires judicious monitoring if the patient has severe kyphosis, dysphagia, or is unreliable in taking it in the upright position. Yearly IV infusion of zolendronate may be helpful in mobile but frail elders who may be at risk with the oral route of bisphosphonates. Denosumab is too new to be considered for routine use in mobile, frail elders who may be vulnerable to an as yet unclear immunosuppressive effect.

fecal incontinence.38–44 Diabetics also have a higher rate of falls, fractures, renal failure, depression and mobility impairment.45–48 For all of these reasons there is a need to focus on appropriate diabetic care.49,50 Diabetics tend to have better outcomes when systolic blood pressure is reduced below 160 mm Hg compared to nondiabetics.51 Most available data suggests that controlling the blood pressure around 145 mm Hg is optimal with no evidence to support going below 130 mm Hg.52 Orthostatic hypertension and postprandial hypotension need to be assessed in all persons with diabetes mellitus.53,54 Persons with postprandial hypotension can be treated with alpha-lglucosidase inhibitors such as miglitol or acarbose.55 Acarbose also decreases the occurrence of hypoglycemia.56 The 25(OH) vitamin D levels are often low in diabetics.57 Replacement of vitamin D may improve diabetic control, reduce hypertension, decrease falls and fractures and increase muscle strength.58 Depression is common is persons with diabetes and needs to be vigorously treated.46 Both alphalipoic acid and topiramate have been shown to be efficacious in treating painful peripheral neuropathy.59,60 Studies in general have found that in the United States persons with diabetes have HbA1C levels \7 in 67–89% of residents.61–63 This becomes disturbing when it is recognized that the 3 recent major diabetes trials (ACCORD, ADVANCE and the Veterans Administration Diabetes Trial) found no effect on cardiovascular disease or total mortality when HbA1C was controlled to below 7.0.64–66 Currie et al,67 using a United Kingdom database in a general population, found that in persons on 2 antidiabetic medicines, optimal survival occurred at a HbA1C of 7.5 and in persons on insulin at an HbA1C of 7.9. Falls in older diabetics increase markedly when the HbA1C falls below 7.68 Thus, it would seem that in the nursing home diabetic control should be aimed at maintaining the HbA1C at levels between 7 and 8. Weight loss has been shown to be associated with increased mortality in older persons with diabetes.69 Therapeutic diets have failed to be shown to be of benefit in diabetics in nursing homes.70,71 For this reason, the American Diabetic Association diets in long-term care have been retired in favor of liberalized diets which may be individualized.72 Numerous studies support the concept of both aerobic and resistance exercise to improve diabetic control.73,74 In addition, exercise programs in nursing homes have been shown to improve function, decrease injurious falls, decrease depression, improve cognition and decrease agitated behavior.75–77 Postprandial walking has been found to have better effects on glucose control than walking before meals.78 In older diabetics, every 1-MET increase in exercise activity resulted in a 16% lower mortality.79

MANAGEMENT OF DIABETES MELLITUS

Oral drugs have been the mainstay of modern treatment for type 2 diabetes mellitus.80 Of these only metformin has been shown to decrease mortality and myocardial infarction.81 It needs to be recognized that its effects on atherosclerotic disease may be independent from its glucose lowering effects and related to its ability to increase metric oxide synthase and

Based on national surveys the prevalence of diabetes mellitus in nursing homes has increased to 26.4% in men and 22.2% in females.37 Diabetics in nursing homes tend to have a greater disease burden, are more likely to be frail and have cognitive decline, and have an increase in aspiration pneumonia and 616 Messinger-Rapport et al

Choice of Hypoglycemic Agent in Older Adults

JAMDA – November 2011

thus alter blood flow.82 Metformin produces anorexia and weight loss and when severe, may need to be discontinued.83 While there is a fear of lactic acidosis, metformin can be used in persons over 80 years old provided they do not have chronic kidney disease. Thiazolidinediones appeared to be potentially excellent drugs to manage diabetes in older persons. Unfortunately, it is possible the rosiglitazone has a negative effect on cardiovascular disease.84 In addition, thiazolidinediones decrease osteoblast function, increase bone loss and increase differentiation of mesenchymal stem cells towards adipocytes rather than osteoblasts through increased PPARg activation.85,86 In the ADOPT trial thiozolidendiones increased fracture risk in women.87 Rosiglitazone decreases bone mineral density and markers of bone formation in humans.1 This effect of thiazolidinediones on increasing osteoporosis makes these drugs inappropriate for use in older nursing home residents. Glucagon-like peptide I (GLP-I) is an incretin that stimulates insulin and decreases glucagon, It also inhibits hepatic glucose production and produces anorexia and delayed gastric emptying. Glucagon-like peptide 7 levels are decreased in type 2 diabetics. Analogs of GLP-I, originally derived from the gila monster, have been developed to treat obese type 2 diabetics. As they cause major weight loss they should be avoided in the nursing home. Interestingly alpha-1glucosidase inhibitors (i.e., acarbose and miglitol) both increase GLP-I.88,89 More recently dipeptydyl IV inhibitors have been developed.90 These drugs increase GLP-I levels by blocking their breakdown. Both sitagleptin and vildagleptin lower HbA1C by 0.65–0.8%. Side effects include tremor and rarely a severe skin rash. Unlike the alpha-1glucosidase inhibitors, they do not reduce weight. Saxagliptin is metabolized by the CYP system and has a high risk of drug– drug interaction.91 Sulfonylureas are the oldest of the antidiabetic drugs. They all produce hypoglycemia.91 They act by increasing insulin. The evidence suggests that in the long-term they may have negative effects on the cardiovascular system. As such, they are no longer first line drugs for older persons. In the nursing home insulin should be substituted for oral agents when the HbA1C cannot be maintained below 8.92 The choice of insulin depends more upon affordability and adverse effect than efficacy. Studies which compare NPH with the 2 newer, more expensive, but more truly ‘‘basal’’ insulins, detemir and glargine, suggest that all 3 are similarly efficacious in lowering HbA1C.93–95 However, there is less hypoglycemia, particularly nocturnal hypoglycemia, with the newer agents, detemir and glargine. In frail elders predisposed to cognitive impairment and falls, preventing hypoglycemia is essential. Some frail elders on NPH with or without Regular humulin may be better served on detemir or glargine. Additionally, transitioning persons with NPH plus a ‘‘sliding scale’’ of regular humulin to a basal regimen may reduce hypoglycemia as well as facilitate a simpler but as efficacious diabetic treatment regimen. Glargine may be the easiest basal insulin to utilize in a long-term care setting due to its pharmacodynamics. Caution should be taken UPDATES FROM THE AMDA MEETING

with frail elders, however, since if a person becomes hypoglycemic, the episode can be prolonged.96 The approach to residents in the nursing home should be to use generic metformin, when it is safe to use. The second choice would be between a generic sulfonylurea (glipizide, glyburide, or glimipride) or the much more expensive DPPIV inhibitors. If the resident has postprandial hypotension, acarbose or miglitol should be used. When the resident is on 2 oral agents and the HbA1C is greater than 8, insulin glargine should be started and the oral antidiabetic drugs stopped. Utilizing more than 2 antidiabetic drugs leads to polypharmacy and multiple studies have demonstrated the dangers of polypharmacy in the nursing home.97–100 A number of new drugs are under development to treat diabetes. Among those closest to clinical use is the antianginal sodium channel modulator101 and Depaglifozin, a SGLT-2 antagonist, that inhibits glucose reabsorption in the kidney tubules.102 Finally, all nursing homes should have a policy for glucose monitoring and regularly undertake a quality improvement program on diabetes.103 Identifying and Reaching the Glycemic Target in a Facility The spectrum of diabetes in LTC includes newly diagnosed disease in robust individuals undergoing rehabilitation as well as advanced disease in frail elders. The target intensity of glycemic control varies depending upon the comorbidities, medical goals, and overall personal goals. Additionally, the ability to monitor and deliver the care needed to accomplish the desired glycemic control requires accommodating the facility, and engaging the team of clinicians, pharmacy consultants, emergency contingency kit, nursing aides, nurses, patients, families, and information technology consultants, where appropriate. The glycemic goal of 6.5% or less in type 2 Diabetes is not supported by interventional trials in older adults.66,104,105 except, possibly, in the subset of those with shorter duration of disease and less total burden of calcium.106 Older adults with early disease and active lifestyles might be able to maintain this target safely. For most elders, a HbA1C goal of 7– 7.5% is appropriate. Higher HbA1C targets (less than 8%, or even \ 9%) would be appropriate for those persons with a shorter life expectancy, where the goals of care are to reduce symptoms from geriatric syndromes and limit hospitalization. When the HbA1C is approximately 6%–9%, postprandial glucose is a better measure of control than fasting glucose,107 and can be incorporated into periodic monitoring. Fasting blood glucose contributes a greater predictive value as glycemic control worsens. Early type 2 diabetics managed with ‘‘diet’’ or sensitizers (glitazones or metformin) do not need any scheduled fasting capillary blood glucose (CBG) testing; it is very unlikely that they will become iatrogenically hypoglycemic. A postprandial CBG periodically (weekly is reasonable) reflects HbA1C when the patient has reasonable glycemic control.89 The postprandial CBG is typically 30–50 mg/dL higher than the preprandial value, but will vary depending upon the meal and the timing of the postprandial test. Combined with Messinger-Rapport et al 617

a premeal blood glucose, the difference offers insight into both mealtime carbohydrate intake and overall glycemic control. Once a pattern of postprandial CBG is established, it can be used as a therapeutic target to reduce or liberalize the HbA1C. Longstanding type 2 diabetes—glycemic control is more difficult than in early diabetes, requiring 1 or 2 oral medications or a basal insulin injection plus or minus a sensitizer daily. These persons typically have been diagnosed with diabetes for several years (their actual disease duration may be unknown). A regimen for a fairly stable patient on 1 or 2 hypoglycemic agents might consist of a fasting CBG Monday, Wednesday, and Friday to identify a pattern of iatrogenic hypoglycemia, and a postprandial CBG Tuesday and Thursday to monitor efficacy and diet. Patient/staff can check additional blood glucose as symptoms indicate. Additionally, the older regimen of a sliding scale of regular humulin should be discouraged, since it treats elevated blood glucose reactively, rather than proactively.92,108 Because of the relatively long half-life of regular humulin, the person may become hypoglycemic prior to the next meal. The patient and nursing staff may need guidance that an elevated postprandial CBG does not, in general, require action to immediately lower the level. Notification of the clinician is performed to review the recent pattern of CBG and to adjust the basal dose, which will lower the CBG over the next 1–2 weeks. Type 1 diabetes is frequently seen in those receiving rehabilitation at a facility. They usually need 1–2 daily doses of a basal insulin and plus prandial doses of rapid-acting insulin in order to maintain glycemic control. Adjusting preprandial or postprandial rapid-acting insulin dosing to intake and preprandial glucose measurements makes the management more complicated but may be required for this individual. Episodic postprandial CBG can be helpful to verify mealtime carbohydrate intake and overall glycemic control. Advanced or ‘‘end-stage’’ type 2 diabetes with blood glucose that is difficult to control may needed to be treated as if they were a type 1 diabetic, with 1–2 daily doses of a basal insulin plus prandial doses of rapid-acting insulin according to consumption and possibly adjusted to CBG. These persons have had diabetes, diagnosed or not, for many years. Many have gastroparesis, resulting in wild glucose swings. Addition of metoclopramide or, outside of the United States, domperidone, may be helpful. End of life: A patient with longstanding type 2 diabetes close to the end of life may still require hypoglycemic drugs and monitoring in order to stay comfortable. Uncontrolled diabetes may impair comfort if it leads to thirst, dehydration, infections, urinary incontinence, and falls. A sample palliative treatment plan might include 1 hypoglycemic agent daily (whether oral or injectable insulin) with a capillary blood glucose (CBG) a few times weekly, perhaps alternating a fasting measurement (to verify lack of iatrogenically induced hypoglycemia) with a measurement 2 hours after the largest meal (to verify efficacy). Verification of control with a serum HbA1C would not be necessary if the goal is symptom management. Hypoglycemic agents could be adjusted to keep 618 Messinger-Rapport et al

the fasting BG greater than 100 and the postprandial BG less than 350. Many patients, nurses, and physicians are accustomed to a ‘‘sliding scale’’ prior to mealtime and bedtime for the diabetic patient. In fact, facilities may have very few persons requiring complicated administration and glycemic monitoring regimens once the target HbA1C and postprandial CBG are explicitly identified. Those needing an intense level of monitoring are typically the type 1 diabetics (particularly in the postacute unit receiving skilled services until they return home) and the ‘‘end stage’’ type 2 diabetics with wildly (and often dangerously) fluctuating blood glucose. Most elders with diabetes have type 2 diabetes in an early or middle stage. These persons can be managed with diet, or a sensitizer, or with 1–2 oral agents, or 1 daily dose of basal insulin, with monitoring needed 1–7 times per week. Understanding facility limitations will help staff design safe environments for glycemic control, particularly for those few persons judged to require a complex administration and monitoring regimen. The inability to administer injectibles in the dining room may limit the ability to provide rapidacting insulin safely. A patient receiving rapid-acting insulin at an interval greater than the package insert lists for proximity to a meal may be at risk for harm or, ineffectiveness. Additionally, the facility may risk citation. The accuracy of the aide in assessing meal consumption is limited and is a barrier to fine-tuning rapid-acting insulin administration. Aides vary by ability and estimated meal consumption is typically higher than actual.109 On the other hand, registered nurses are taught carbohydrate counting (as grams or servings) as part of their training and facilities can incorporate carbohydrate counting when appropriate for adjusting rapid-acting insulin dosing for type 1 or brittle type 2 diabetics. The facility dietician plays a key role in educating aides and nurses in appropriate estimates of consumption. In summary, intensity of glycemic control is established by the attending physician, with input from patients, family, and facility staff. Target of the HbA1C and complexity of CBG management follow from the goals of care. Most older diabetics can be managed with a liberal diet and an oral hypoglycemic or simple basal regimen. The few patients in a facility requiring more complicated management need a team approach to their diabetic care. Non– physician providers can educate the patient, nurses, and families regarding goals and management and the engaged team works together to implement a comprehensive and individualized glycemic administration and monitoring regimen. WEIGHT LOSS Weight loss is extremely common in persons following hospitalization and in the nursing home for rehabilitation.110 It is now generally recognized that weight loss in old frail individuals is strongly related with increased mortality.111–113 Weight loss also leads to increased institutionalization114 hip fracture,115 pressure ulcers, infections, poor cognition, JAMDA – November 2011

anemia, muscle weakness, fatigue and edema.116 Weight loss was recognized by the IAGG as a major area for further research in the nursing home.117 Older persons develop a physiological anorexia of aging.118 This has multiple causes including loss of taste and smell,119 alterations in fundal compliance,120,121 increased cholecystokinin levels and activity122 and in males low testosterone leading to elevated leptin levels.123 These appear to interact within the central nervous system with a decline in the opioid feeding system.124,125 Anorexia has been shown to independently predict mortality.126 There are major causes of weight loss viz., anorexia, cachexia, malabsorption, hypermetabolism, dehydration and sarcopenia.127 Anorexia can be detected early by using the Simplified Nutrition Assessment Questionnaire (SNAQ).128 This has been validated in a nursing population. The MiniNutritional Assessment is an excellent screening test for malnutrition.129–132 It also tends to recognize persons with frailty.133,134 Serum proteins such as albumin, prealbumin and transthyretin are poor indicators of nutritional status as these levels are markedly decreased in the presence of cytokine excess.135 In the nursing home depression is the most common cause of anorexia and weight loss.136–138 Almost a third of nursing home residents who lose weight are depressed. A simple list of the causes of reversible weight loss is the MEALS-ONWHEELS mnemonic (Table 1). Cachexia is generally due to proinflammatory cytokine excess and results in a loss of both muscle and adipose tissue.139–143 The increase in cytokines is usually related to underlying disease processes such as congestive heart failure, chronic obstructive pulmonary disease, kidney disease or cancer.144,145 Sarcopenia is muscle loss associated with aging.146,147 Newer definitions have stressed that for it to be considered a geriatric syndrome it should be associated with loss of strength, power and/or mobility.148–150 Sarcopenia is not always associated with weight loss as muscle loss may be replaced by fat – the obese sarcopenic or ‘‘fat frail’’ syndrome.151,152 Dehydration is a not uncommon cause of weight loss that is often forgotten.153,154 An algorhythm for the management of weight loss in the nursing home has been published.155 A key to preventing weight loss in nursing homes is having an attractive dining ambience.156 Ice cream parlors and snack carts can also help to maintain resident weight.157 A meta-analysis has shown that protein and energy supplementation in elderly malnourished persons decreases mortality and length of hospitalization.158 Oral liquid supplements need to be given between meals to be optimally effective.159 The Intercom Trial showed that an early nutritional intervention in COPD continued for 24 months improved weight, fat free mass, muscle strength and 6 minute walking distance and decreased hospitalization.160 Neelemaat et al161 showed that a 3-month nutritional intervention, including an energy and protein enriched diet, resulted in improved function 3 months after discharge from hospital. A leucine enriched essential amino acid UPDATES FROM THE AMDA MEETING

Table 1. MEALS-ON-WHEELS Mnemonic for Treatable Causes of Weight Loss in Older Persons Medications (e.g., digoxin, theophylline, cimetidine) Emotional (e.g., depression) Alcoholism, elder abuse, anorexia tardive Late life paranoia Swallowing problems Oral factors Nosocomial infections (e.g., tuberculosis) Wandering and other dementia related factors Hyperthyroidism, Hypercalcemia, Hypoadrenalism Enteral problems (e.g., gluten enteropathy) Eating problems Low salt, low cholesterol and other therapeutic diets Stones (cholecystitis)

supplementation is considered the supplement most likely to enhance muscle strength.162 Megestrol acetate is the drug most effective at producing weight gain.113,163 It also decreases cytokine activity.164 It tends to increase predominantly adipose tissue. There is no evidence that it improves function or mortality. As megestrol acetate is poorly absorbed in the fasting state, a megestrol acetate nanocrystal disperson oral suspension has been developed and has much improved absorption in the fasting state.165 Thus, in persons with low food intake, the megace ES form should be used for the first month. Dronabinol is a tetrahydrocannabinoid that increases food intake.166,167 It produces minimal weight gain. It is an excellent drug for palliative care. Testosterone levels decline markedly with age.168 Recently studies have found that testosterone replacement may increase muscle mass and walking speed and decrease hospitalizations in persons with frailty and heart failure.169–173 The major side effect is increased edema. A number of new drugs are under development to enhance food intake and improve weight gain. These include selective androgen receptor molecules, ghrelin agonists and a novel peptide–nucleic acid compound.174–176 It would appear that tube feeding, especially G-tubes, are grossly overused in demented elderly persons.177,178 Ethical thought processes fail to support the use of G-tubes in most demented older persons. CLINICAL USE OF ANTICOAGULANTS The use of anticoagulants is a major problem in nursing homes.179–181 In part, this is related to drug interactions, many of which, such as the acetaminophen–warfarin interaction, are underappreciated.182 New data and new drugs drive a reevaluation of use of anticoagulation in clinical practice. An overview of several frequent clinical questions follows. Is Warfarin Superior to Antiplatelet Agents in Patients With Atrial Fibrillation? Most guidelines recommend warfarin therapy for nonvalvular atrial fibrillation in persons at high risk for stroke, and antiplatelet agents (chiefly aspirin) for persons considered Messinger-Rapport et al 619

to either be at low risk of stroke or for those persons who cannot safely receive warfarin therapy. From the standpoint of long-term care physicians, most older persons are judged to be a high risk, but also judged to be more likely not to be able to safely take adjusted dose warfarin therapy. There are several risk stratification schemes to predict future stroke risk, but the cut points and specificity are somewhat controversial. A meta-analysis of 8 trials comparing adjusted dose warfarin to antiplatelet therapy in persons with nonvalvular atrial fibrillation and no prior history of stroke or transient ischemic attack demonstrates that warfarin is superior to antiplatelet agents for the prevention of all stroke, ischemic stroke, and systemic emboli, but is not different for fatal stroke, myocardial infarction, vascular death, or all cause death. The incidence of an intracranial bleed is higher with warfarin compared to aspirin.183 In relative terms warfarin reduces the risk of stroke by about 30% and aspirin reduces the risk by about 20%. However, the incidence of stroke in the studied populations is relatively small. Thus, the absolute risk reduction is estimated to be about 1%; that is, 100 persons would be treated for 1 year to prevent 1 additional stroke. In persons who have a history of prior stroke or transient ischemic attack, warfarin is clearly superior to antiplatelet agents alone for the secondary prevention of recurrent stroke.184 A useful risk assessment tool for secondary prevention is the CHADS2 score.185 With a history of prior stroke or transient ischemic attack and age over 75 years, the CHADS2 score would be 3 (without any additional risk factors), and the relative risk for stroke would be 6% per 100 patient-years. The addition of congestive heart failure, hypertension, and diabetes further increases the risk to about 18 per 100 patient-years. A new direct thrombin inhibitor is available for treatment. In direct comparisons, noninferiority has been demonstrated for the prevention of stroke or systemic embolization compared to warfarin (1.1% versus 1.5%), and no difference in total mortality was observed. Hemorrhagic stroke occurred less often in the dabigitran group (0.1% versus 0.4%), and fewer bleeding complications were observed in the dabigitran group compared to warfarin (2.7% versus 3.4%).186 Dabigitran offers the advantage of not requiring venous blood sampling or dose adjustment, but also has the disadvantage of being highly dependent on renal function and does not have a rapid antidote in the presence of bleeding. One of the chief reasons cited for avoiding anticoagulation in older persons is the fear of intra cranial bleeding or other bleeding injury from falling. Elderly persons who fall have a mean of 1.8 falls per year. At this rate, decision analysis techniques suggest that the risk of subdural hematoma must be 535-fold or greater for the risks of warfarin therapy to outweigh the benefits. Persons taking warfarin must fall about 295 times in 1 year for warfarin to not be the optimal therapy.187 In terms of quality-adjusted life-years (QUALYs) per patient in persons with average risks of stroke and falling, warfarin therapy was associated with 12.90 QALYs, aspirin therapy with 11.17 QUALYs, and no antithrombotic therapy with 10.15 QUALYs. 620 Messinger-Rapport et al

What About Primary Prevention in Patients With Normal Sinus Rhythm? Primary and secondary prevention in persons with atrial fibrillation is clearly beneficial. Primary prevention in persons without atrial fibrillation (normal sinus rhythm) is much more problematic. Two studies examined the benefit of several prevention strategies with the outcome of death, nonfatal myocardial infarction, and stroke. There were no differences in groups treated with aspirin, warfarin, or no treatment in the first trial,188 or between aspirin, warfarin, or clopidrogel in the second trial.189 In a trial of patients at high risk for a cardiovascular event, clopidrogel plus low-dose aspirin (75–162 mg) was compared to placebo plus low-dose aspirin. At 28 months, the incidence of myocardial infarction, stroke, or cardiovascular death was not different between groups.190 In a subset analysis of this trial, no difference in stroke or stroke and transient ischemic attack was observed between groups.191 This data suggest that clinicians should not add clopidogrel to standard long-term aspirin therapy for preventing cardiovascular or neurological events in people at high risk of cardiovascular disease and in those with established cardiovascular disease.192 How Long Should Antiplatelet Therapy Be Continued in Patients With Stents? Stent thrombosis most commonly occurs in the first month after stent implantation, classified as ‘‘subacute stent thrombosis.’’ However, numerous cases of ‘‘late’’ stent thrombosis, particularly in patients who have been treated with drug eluting stents, have been described as occurring months or even years after stent implantation. In the majority of cases, stent thrombosis is a catastrophic event, resulting in life-threatening complications.193 In a trial which followed subjects with stent placement for 12 months, current use of clopidrogrel at either 6 or 12 months was associated with a reduction in stent thrombois in drug-eluting stents, but demonstrated no difference in persons receiving bare metal stents. Therefore, suggested recommendations for treatment include clopidogrel 75 mg and aspirin 325 mg at a minimum of 1 month after bare-metal stent implantation; 3 months after sirolimus drug eluting stent (DES) implantation; 6 months after paclitaxel DES implantation; and ideally, up to 12 months if the patient is not at high risk for bleeding.193 In patients with acute non–ST elevation myocardial infarction (NSTEMI), there is evidence of benefit outweighing harms caused by major bleeding with aspirin plus clopridrogel. Subjects were randomized to clopidogrel (loading dose, 300 mg orally, followed by 75 mg/day or to placebo plus aspirin (75–325 mg/day). For every 1000 persons treated for 9 months, 23 cardiovascular events were prevented and 10 major bleeds were caused in the clopridogrel group.194 It has been hypothesized that certain groups of patients with high platelet reactivity might be at higher risk for DES stent occlusion, and thus higher loading doses of clopridogrel may be more effective. Subjects with high in vitro platelet reactivity at 24 hours after DES placement were randomized to JAMDA – November 2011

a 600 mg loading dose of clopridogrel followed by 150 mg daily plus aspirin 75–162 mg daily or to placebo loading dose of clopridogrel followed by 75 mg daily plus aspirin 75–162 mg daily. At months of followup, both groups experienced the same rate of cardiovascular death, nonfatal myocardial infarction, or stent thrombosis (2.3%).195 In summary, warfarin is superior to aspirin for the prevention of stroke and systemic emboli in persons with atrial fibrillation. Withholding warfarin for patients who have a falling history is overdone, particularly in persons with a high CHADS2 score. However, therapy can be individualized, since the absolute risk reduction for primary prevention of stroke is small. Darbigitran is equivalent to warfarin for primary prevention in atrial fibrillation. There is no advantage of aspirin or other anticoagulants over no therapy for primary prevention of cardiovascular events in patients who are in normal sinus rhythm. There is no benefit for the addition of clopidogrel to aspirin for the primary prevention of stroke or transient ischemic attack. The addition of clopidogrel to aspirin therapy provides benefit in patients with NSTEMI. The duration of therapy with clopidogrel and aspirin varies with the type of stent, but when possible, should be continued for 12 months after drug-eluting stent placement. DEADLY PROPHYLACTIC PROTON PUMP INHIBITORS? The development of proton pump inhibitors has been a boon to the treatment of gastrointestinal diseases. Proton pump inhibitors (PPIs) are superior to placebo or to histamine-2 receptor antagosists (H2RAs) in healing peptic ulcers. PPIs reduce rebleeding following endoscopic therapy for bleeding ulcers by 54% and reduce the need for surgical intervention by 41%. Symptoms in gastroesophageal reflux disease are improved in 65–75% of patients by 8 weeks, and healing of erosive gastritis has been demonstrated in 85– 95% of patients by 8 weeks. However, symptomatic relief in nonerosive esophagitis is lower, around 37% at 4 weeks. PPIs are superior to double-dose H2RAs or placebo controls in reducing nonsteroidal anti-inflammatory drug induced gastritis, leading to widespread prophylactic use.196 Another widespread area of prophylactic use has been in Table 2.

the prevention of stress-induced ulcers in critically ill patients. Clinically important bleeding occurs in 1.5% of critically ill patients, but differs considerably by patient risk factors. Bleeding occurs in 3.7% of patients with respiratory failure (odds ratio 15.6) and coagulopathy (odds ratio 4.3), but in only 0.1% of patients without these risk factors.197 This low incidence may explain nonsignificant differences in prophylaxsis clinical trials comparing PPIs, H2RAs, and sucalafrate to placebo.198 No difference in the incidence of ventilator acquired pneumonia has been observed comparing patients treated with PPI, H2R, or sucalafrate to control subjects.199 No difference in incidence of pneumonia or mortality has been observed in patients treated for stress ulcer prophylaxsis comparing a PPI versus a H2R.200 The widespread use of PPIs in critical care settings has led some authors to conclude that prophylactic use is frequently inappropriate. Classification of appropriate use is shown in Table 2. Using these definitions, 71% of subjects receiving intravenous PPIs in a teaching hospital did not meet appropriate use criteria. Once started, PPIs are continued, mostly by intravenous route, in about 50% of subjects after being discharged to nonintensive care settings.201 The data suggest that PPIs should only be continued until the patient either begins an oral diet or until discharge from the critical care setting.202 The risk of clinically important bleeding outside of the critical care setting is considered too low to justify continued prophylaxsis.203 Outside of the acute setting PPIs are often used for years at a time. Indeed, estimates suggest that 40% of the US population receives a PPI chronically.204 Recent concerns about interactions of PPI with drugs and with geriatric diseases are relevant to long-term care physicians. Omeprazole and Clopidrogel Interaction? An potential interaction with omeprazole and clopidrogel was suggested by the observation that men taking both drugs after an acute myocardial infarction had a higher recurrence rate 90 days after hospital discharge compared to men not taking omeprazole.205 In another trial, using a unique

Appropriate and Nonappropriate use of PPIs

Appropriate Use in UGIB

Appropriate Use in UGIB

Inappropriate Use

After endoscopic hemostasis of gastrointestinal bleeding

Stress ulcer prophylaxes in NPO patients with either mechanical ventilation or coagulopathy Severe dysmotility or illeus

Stress ulcer prophylaxes in patients not meeting criteria

Suspected UGIB 12 hours prior to endoscopy Confirmed endoscopic UGIB for 72 hours High risk for UGIB for 72 hours

Zollinger-Ellison syndrome History of esophagitis in NPO patient

Nausea or vomiting Suspected esophageal varices bleed Probable gastritis Lower gastrointestinal bleed History of peptic ulcer disease Esophagitis, not NPO No indication, not NPO Standard prophylaxes in ICU

UGIB 5 upper gastrointestinal bleeding; NPO 5 nothing by mouth. Adapted from: Hoover JG, et al. Use of intravenous proton-pump inhibitors in a teaching hospital practice. Dig Dis Sci 2009;54:1947–1952.219

UPDATES FROM THE AMDA MEETING

Messinger-Rapport et al 621

preparation of omeprazole, the study was halted before completion. However, no difference in cardiovascular events were observed.206 Although controversial, there is a clear invitro effect of omeprazole on platelet function, and no association has been reported for other PPIs such as pantoprazole. PPIs and Community-Acquired Pneumonia? The second line of the body’s defense against bacteria is high acidity in the stomach, which is active against most organisms. This has led to speculation that low gastric acidity may allow overgrowth of bacteria in stomach contents. Several observational studies seem to bear this out. Newly diagnosed community-acquired pneumonia was associated with current use of proton pump inhibitors (odds ratio1.16, 95% confidence intervals (CI) 1.03–1.31), but not with use of H2RAs (odds ratio 0.98, CI 0.80–1.20).207 Acid-suppressive drug users had a higher incidence rate compared with non acid suppressive drug users (OR 1.73, 95% CI 1.33–2.25). The risk for community acquired pneumonia was also higher among PPI users compared with those who stopped use of a PPI (OR 1.89 (95% CI 1.36–2.62).208,209 PPIs and Skeletal Fractures? The use of PPIs has also been associated with an increase in skeletal fractures. Persons who used a PPI within the last year had an overall increase in risk of fracture (OR 5 1.18, 95% CI 1.12–1.43), an increased risk of hip fracture (OR 5 1.45, 95% CI 1.28–1.65), and an increased risk of spine fracture (OR 5 1.60, 95% CI 1.25–2.04).210 In this same population, the use of an H2RA was associated with a lower risk of fracture. A higher risk of osteoporotic fractures has also been observed among users of PPIs, which is time-dependent. Exposure of 7 or more years was associated with increased risk of all osteoporotic fractures (OR 1.92, 95% CI 1.16–3.18). An increased risk of hip fracture began after 5 or more years of exposure (OR 1.62, 95% CI 1.02–2.58), and increased after 7 or more years of exposure (OR 4.55, 95% CI 1.68–12.29).211 PPIs and Clostridium difficile Infection? Although antibiotic use is associated with risk of Clostridium difficile infection, over half of persons admitted to acute care settings have no antibiotic exposure within the past 45 days. However, the current use of a PPI was associated with a higher risk of infection (relative risk 1.6, 95% CI 1.3–2.0).212 In a hospital outbreak, only the use of a PPI or the use of a cephalosporin was a risk factor for Clostridium difficile infection. Other risk factors, including use of an H2RA, a fluroquinalone, an antipsychotic, or the presence of chronic obstructive pulmonary disease, were not associated with infection.213 A systematic review of twelve studies analyzing the use of PPIs and enteric infection confirmed an increased risk of Clostridium difficile infection (OR 1.94, 95% CI 1.37–2.75).214 The risk was also higher for Salmonella, Campylobacter, and other enteric infections in studies. In a long-term care setting, 60% of persons with a Clostridium difficile infection had used a PPI, compared to 32% of controls.215 622 Messinger-Rapport et al

PPIs and Drug Interactions? Because of the low to absent gastric acidity in persons taking a PPI, the absorption of drugs requiring an acid medium may be impaired. A large number of drugs may be either poorly absorbed (cefuroxime and other antibiotics) or more actively absorbed (digoxin). The frequency of drug interactions require that new drugs added to a person’s regimen be screened for compatibility with a PPI. Other nutrients may be affected by interaction with PPIs. There is some evidence that PPI therapy lowers intragastric concentrations of vitamin C, and may affect serum vitamin C levels.216 Absorption of vitamin B12 may potentially be affected, but the clinical evidence is weak. PPIs reduced the absorption of nonheme iron from a test meal by approximately 50%.217 Thus, in persons with iron deficiency anemia, replacement of iron may be limited by concurrent use of a PPI.218,219 In summary, the availability of PPIs have revolutionized the treatment of hyperacidity gastrointestinal diseases. However, prophylactic use and long durations of therapy have raised concerns about unintended consequences. The large number of potential drug interactions require diligence in careful prescribing. Duration of exposure to PPI should be limited to the shortest possible times consistent with therapeutic goals. For those patients who require long-term maintenance therapy, the use of H2RA has not been associated with the major long-term adverse effects of PPI use. DELIRIUM Delirium is a dangerous diagnosis for older adults in the hospital or long-term care setting. It is associated with a loss of functional ability, increased hospital length of stay, and higher likelihood of long-term care placement. Delirium is an independent risk factor for posthospital institutionalization and rehospitalization.220 Wilcox and colleagues found that delirium carries a 1-year institutionalization rate of 33.4% compared to a baseline rate of 10.7% (odds ratio 2.41; 95% CI 1.77–3.29).221 At 2 years posthospitalization, the mortality rate for individuals having had a diagnosis of delirium was 38% versus 28% in the nondelirious population (HR 1.95; 95% CI 1.51–2.52). Individuals with both dementia and delirium were at greatest risk for institutionalization, with 62.5% being placed in longterm care over 4 years, compared with 8.1% in a nondemented population (OR 12.52; 95% CI 1.86–84.21). In another study, those admitted to postacute rehabilitation with clinical instability or delirium were 15 times more likely to be readmitted to the hospital (30.1% versus 2%, p \ .001) and more than twice as likely to have poor functional recovery (86% versus 38%, p 5 .033).222 Poor functional recovery may be a result of impaired motor functioning in the delirious state. Italian researchers have demonstrated that individuals entering postacute rehabilitation with delirium or dementia have significantly more dysfunction with trunk control and with gait and balance compared with individuals without these diagnoses.223 Those with delirium often demonstrated JAMDA – November 2011

Table 3.

Table 4.

Diagnostic Features of Delirium

Risk Factors for Delirium

1. Inattention AND 2. Disorganized thinking PLUS At least 2 of the following:  Reduced level of consciousness  Perceptual disturbances  Disturbance of sleep-wake cycle  Increased or decreased psychomotor activity  Disorientation  Memory impairment  Abrupt onset and fluctuating course

D E L

a significant decline in motor function before clinical improvement was made. Delirium is a common diagnosis, yet underrecognized by health care providers. Studies consistently demonstrate that delirium is present in up to one third of individuals at the time of hospital admission or during hospitalization.224–227 Delirium is present in 50–75% of postoperative elders. Despite the prevalence of the condition, delirium is missed in one-third to two-thirds of hospitalized patients. A Veterans Affairs committee has suggested that a method for systematically and objectively measuring mental status is needed, and that ‘‘Mental Status’’ should represent the sixth vital sign.228

This cohort study found that those with the allele were more likely to develop delirium (OR 1.7; 95% CI 1.1–2.6) after correcting for age, cognitive status or functional abilities.232 A meta-analysis combining 4 large studies (n51100) of this genetic factor did not find a similar positive relationship.232 Individuals who were homozygous for a known dopamine transporter gene, were found to have a lower likelihood of developing delirium (OR 0.4; 95% CI 0.2–0.6, p\ .001). A second gene for the dopamine receptor provided no protective or beneficial effect for delirium.233

I R I U M S

Diagnostic Criteria for Delirium Delirium has a clear definition based on the Diagnostic and Statistical Manual of Mental Disorders version IV (DSM-IV; see Table 3).229 The DSM-IV diagnostic criteria have been utilized in the development of several delirium screening tools for clinicians. The most widely recognized of these tools is the Confusion Assessment Method (CAM).230 In order to meet screening criteria, the CAM requires the presence of (1) acute change in mental status with fluctuating course, plus (2) inattention and the presence of either, (3) disorganized thinking, or (4) altered level of consciousness. This screening tool has a sensitivity of .94% and specificity of .90%.230 Delirium Risk Factors The risk factors for delirium are many, and include underlying or new medical conditions, medications, and metabolic abnormalities. A mnemonic can assist in recalling potential risk factors and high risk medications (Table 4, and Table 5).231 In addition to these factors, there is growing interest in genetic risks that may predispose individuals to the development of delirium. In 1 study, researchers looked at the presence of the apolipoprotein E-4 allele as a risk for delirium.

Delirium Screening Tools In order to better identify and categorize delirium, several new screening tools have been developed. The Nursing Home CAM (NH-CAM) uses data from the Minimum Data Set (MDS) to retrospectively identify delirium based on presence of diagnostic features recorded through this database. The CAM criteria were identified using the MDS (version 2.0) sections B (question 5a–e) and E (questions 3 and 5). Using this method, a Swiss study of nearly 12,000 nursing home residents identified delirium in 6.5% of the population and subsyndromal delirium (SSD) in 39.7%.234 SSD is defined as meeting 2, but not all, of the delirium criteria and may represent a precursor state to the development of full criterion-based delirium. In another long-term care study, nearly half of residents with dementia with change in mental status were found to meet criteria for SSD.235 The NH-CAM has also been used to measure delirium outcomes of 90-day mortality and rehospitalization. Using a Medicare sample of nearly 38,000 nursing home admissions, patients with delirium had a 57% survival rate at 90 days compared with 83% without delirium. Rehospitalization occurred in 69% without and 62% with delirium. The presence of even 1 or 2 criteria for delirium increased the 90-day risk of death or rehospitalization.236 In a cohort of 457 delirious nursing home patients, mortality was highest in the hypoactive group compared with normal patients (HR 1.6; 94% CI 1.09–2.34)

Table 5.

Drug Categories That Can Cause Acute Change in Mental Status (MS)

A C U T E

anti-Parkinson corticosteroids urinary incontinence theophylline emptying drugs

UPDATES FROM THE AMDA MEETING

C H A N G E

Drugs Eyes-Ears (vision or hearing impairment) Low oxygen states (acute coronary syndrome, stroke, pulmonary embolism) Infection Retention (urine or stool) Ictal state Underhydration / Undernutrition Metabolic causes Subdural hematoma

cardiovascular H2 blockers antibiotics narcotics gero-psychiatry ear-nose-throat

I N

insomnia NSAIDS

M S

muscle relaxants seizure

Messinger-Rapport et al 623

after controlling for age, gender, comorbidity, dementia, and delirium severity.237

Delirium Prevention and Treatment Prevention of delirium is classically based on reduction of risk factors. Recent studies have looked at the use of medications to prevent or treat delirium. One hypothesis is that delirium may result from cholinergic neurotransmission imbalance and therefore, treatment with cholinesterase inhibitors may be helpful in delirium. Four placebo-controlled studies have recently investigated the use of cholinesterase inhibitors (3 rivastigmine, 1 donepezil) in hospitalized elders to prevent or treat delirium.238–241 Two of these studies focused on prevention and 2 focused on treatment.238,241 Outcomes included incidence of delirium, delirium duration, and hospital length of stay. No study showed any benefit in the treated group compared with placebo. One study was halted early as the treatment group showed a higher mortality rate (22%) compared with the placebo group (5%) and delirium duration was longer in the treated group.240 There are also several recent studies exploring the use of antipsychotics to treat or prevent delirium. These drugs must be used with caution given the associated increased risk of death with antipsychotics (OR 1.5, p 5 .02).242 A small study (n 5 42) of quetiapine versus placebo for treatment of delirium showed a more rapid recovery for the treatment group.243 A larger (n 5 400) prevention trial in postoperative elders showed a reduction in incident delirium with olanzapine, but also a concerning increase in severity of delirium in the treated group.244 A meta-analysis found that for the treatment group, haloperidol and atypical antipsychotics were beneficial in reducing the intensity and duration of delirium symptoms.245 Given this conflicting data and awareness of the risks associated with antipsychotics, routine use of antipsychotics for delirium would not be advised. Until further data clarifies the benefit, use of antipsychotics for delirium treatment should be limited to the most severe cases after exhausting nonpharmacological options. Nonpharmacological strategies and risk factor modification remain the standard of care for delirium treatment and prevention. Multifactorial hospital-based interventions have demonstrated benefit in reducing incidence and severity of delirium. In a study of 199 postoperative hospitalized patients age . 70, a program of medical management, rehabilitation and comprehensive geriatric assessment reduced incident delirium from 75–55% (p 5 .003). The duration of delirium was also reduced (5.0 versus 10.2 day; p 5 .009) and length of hospitalization declined from 28 versus 38 days (p 5 .028).246 In summary, for screening and managing delirium in hospitalized and institutionalized older adults, the following points should be kept in mind:  Delirium carries a high risk of functional decline, rehospitalization, institutionalization, and mortality  Delirium is frequently underrecognized by health care professionals 624 Messinger-Rapport et al

 New screening tools may assist in classifying disease severity and disease course  Subsyndromal delirium may precede the full diagnosis of delirium  Cholinesterase inhibitors are not effective in preventing or treating delirium  Evidence is mixed on the benefit of antipsychotics for prevention and treatment of delirium

POLYPHARMACY Polypharmacy is more than just ‘‘too many’’ medications. Although traditionally defined as the use of multiple medications or more medications than are clinically indicated, polypharmacy also includes the use of: Inappropriate classes/ agents, inappropriate dosing, failure to stop treatment, failure to start treatment, and medication with high risk for drug– drug/drug–disease interactions. Polypharmacy can lead to adverse drug reactions or events, increased cost, reduced patient compliance, and a higher likelihood of administration errors. Adverse Drug Events Adverse drug events (ADEs) are defined as any harm that results from the use of a medication (Figure 1). These include adverse drug reactions (harmful effects from the drug at normal doses and during normal use) and preventable events such as overdoses, inappropriate prescribing and medication errors. Fortunately, most medication errors and inappropriate prescribing do not result in an adverse drug event. Some do not result in any appreciable harm and others are caught as a ‘‘near miss’’ before harm occurs. The evidence is clear that, in older adult populations, as the number of medications increases, the risk for adverse drug events increases. Falls are a classic example of such a relationship. Chen and colleagues studied the rate of falls and fall-related events in elders using 7 or more medications. Compared to those using fewer medications, those taking

Fig. 1. Unwanted medication effects. JAMDA – November 2011

more than 7 medications had 1.3 times the risk of sustaining a fall-related fracture (HR 1.3; 1.04–1.62, p 5 .02).247 Exactly how many is too many medications? Studies clearly demonstrate that the more medications taken, the higher the risk of ADEs. A study of 335 nursing home residents found that the rate of ADEs was 1.2 per person/year for those taking 9 or more medications, compared with 0.53 per person/year in those taking fewer than 9 medications.248 Research in a Veterans Affairs population also showed that 9 medications was a cutoff for adverse events. Compared to those receiving regular care, a group of men receiving a targeted medication reduction program had a decrease in number of medications from 13.1 to 8.2 and a 30% reduction in hospitalizations (p \ .0002).249 As the number of medications increases, compliance with appropriate use declines. A study of patients who were randomized to a tight pharmacological disease-based control had an increase of 1.1 medications per person (compared with 0.6 medications in the control group) but a significant decline in compliance with suggested medication usage (OR 0.84; 95% CI 0.78–0.91, p \ .001).250 In the past 20 years, much work had been done to define and identify inappropriate medication use in older adults. In 1991, Mark Beers and 12 experts used the Delphi method to create a list containing 19 medications/classes which were potentially inappropriate for use in older adults in the nursing home setting. The ‘‘Beers List’’ as it is called was a stepping stone from which other groups created and modified ‘‘inappropriate’’ medication lists for older adults in a variety of clinical settings.251 The Beers List The Beers List underwent its first revision in 1997 to include 28 different medications or classes of medications considered to be high risk for use in older adults. A third iteration, including 48 medications/classes, was introduced in 2003. In this version, medications were classified as inappropriate ‘‘independent of diagnosis or condition’’ and potentially inappropriate when ‘‘considering diagnosis or condition’’ that could result in adverse drug-disease events.252,253 Clinicians and researchers have used various versions of the Beers List, applied to different care settings, to measure outcomes and trends in medication prescribing. Stuart et al measured the impact of the Beers List in community dwelling elders between 1995 and 1999. 7600 medication profiles were reviewed. A statistically significant drop in use of Beers List medications was seen over time (25% versus 21%, p \ .05).254A larger database analysis of ambulatory elders found similar results with 21% having filled a high risk Beers medication in the preceding year.255 A later study in 2003 of assisted living residents found that 16% were taking at least 1 medication on the Beers List and nearly all subjects were on 5 or more medications.256 Due to concerns about the generalizability of the Beers List outside of long-term care, Zhan and colleagues convened a panel of experts with the purpose of identifying drugs that should be avoided in the community-dwelling elderly population and which could be used to monitor medication usage in UPDATES FROM THE AMDA MEETING

Table 6.

Medication Appropriateness Index

Criterion

Weighted Score

Are there significant drug-drug interactions? Are there significant drug-disease interactions? Is there an indication for the drug? Is the drug effective for the indication? Is there unnecessary duplication with other drugs? Is the duration of therapy acceptable Is the dosage correct? Are the directions correct? Are the directions practical? Is the drug the least expensive alternative?

2 2 3 3 1 1 2 2 1 1

U.S. Medicare beneficiaries. This group identified 33 medications which were classified as always inappropriate, rarely appropriate, or having some indications. Data collected from a 1996 survey using Zhan criteria found 21% of communitydwelling elders were using 1 of 33 potentially risky medications.257 Despite the wide popularity of the Beers List, expert panel guidelines are known to possess significant methodological limitations. There have been concerns about nursing home surveyors using this list as a regulatory tool in the long-term care setting, a purpose for which it was not designed. AMDA thus developed a position statement regarding the use of the Beers List criteria when applied to the long-term care setting.258 This statement indicates that, ‘‘The Beers list is a helpful general guide regarding potentially inappropriate medication use of medications for older adults, but it must be use in conjunction with a patient-centered care process.Ultimately, decisions about medication prescribing must be clinically based and consider the patient’s total clinical picture, including the entire medication regimen, history of medication use, comorbidities, functional status, and prognosis. Checklist approaches should not substitute for the necessary steps in the care process for appropirate prescribing.’’

New Measures of Polypharmacy In the past 10 years, several new methods have been developed for measuring and classifying inappropriate medication. These methods are frequently compared with the Beers List, often by measuring the ability to predict the occurrence of adverse drug events. The Medication Appropriateness Index (MAI) is a 10question weighted scale that assigns an individual patient risk score based on a medication profile (Table 6). Using the MAI and the Beers Criteria as risk measures, an elderly Veteran cohort was assessed for ADEs. 14% of 238 patients had an ADE during the study period. 49% were taking a Beers List medication and 99% met at least 1 MAI criterion. The authors concluded that the MAI was a better scale for predicting the potential risk of ADEs than was the Beers List.259 Messinger-Rapport et al 625

In the United Kingdom, the START (Screening Tool to Alert doctors to Right Treatments) and STOPP (Screening Tool of Older People’s potentially inappropriate Prescriptions) tools have been developed to guide clinicians in medication management of older adults. These tools are quite extensive and include over 75 organ system-based medication recommendations.260 A study of over 1000 Irish elders did not find that the START or STOPP tools identified potential medication problems any better than did the Beers List.260 Reducing Polypharmacy Reducing polypharmacy requires not only an awareness of potentially inappropriate medications (by whatever criterion used) but a process by which a patient’s medication list can be reviewed, discussed, and modified as appropriate. This is best accomplished in a collaborative partnership that may include the patient, pharmacist, physician, family, and nurse. Education is crucial as many members of this care team may be unaware of the potential risks of certain medications in older adults. Education and team based approaches can reduce the use of high risk medication. When a consultant pharmacist advised physicians of high-risk prescribing patterns, the use of inappropriate medication dropped.257,261,262 A team-based geriatric inpatient unit that focused on medication management was able to reduce the number of medications and the use of high-risk medications.263 An electronic medical record

626 Messinger-Rapport et al

which flags high risk medication and provides warnings for drug–drug interactions has significantly reduced inappropriate prescribing in older adults.264–266 Engaging the patient in discussions of medication risk and in appropriate use can have profound potential benefits. When the physician and patient partnered in completing a Medication Risk Assessment Form and a Medication Review Checklist in the ambulatory setting, 88% of patient medication profiles were found to have at least 1 medication problem. The clinician acted to modify the medication profile in 88% of these cases.267 In summary, polypharmacy remains a significant finding in older adults throughout the healthcare system. Despite over 2 decades of using the Beers List, over 20% of elders continue to use medications which may be potentially inappropriate. New screening tools for identifying high risk medications have been recently developed. Tools such as the MAI, STOPP, START, and Zahn Criteria may be better suited in some cases to identify potential medication problems and risk of adverse drug events. Despite the criterion posed in these screening tools, appropriate prescribing must account for patient disease, needs and wishes. It is clear that educational and team-based interventions to reduce polypharmacy are effective in a variety of clinical settings. REFERENCES References available at www.jamda.com with your JAMDA login.

JAMDA – November 2011

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