Clinical Update on Nursing Home Medicine: 2008

UPDATES FROM THE AMDA MEETING

Clinical Update on Nursing Home Medicine: 2008 Barbara J. Messinger-Rapport, MD, PhD, FACP, CMD, David R. Thomas, MD, FACP, AGSF, GSAF, CMD, Julie K. Gammack, MD, and John E. Morley, MB, BCh In 2007 we provided an overview of clinical advances in the nursing home based on a series of presentations at the American Medical Directors Association.1 This will now be a regular yearly series. Topics covered this year are nutrition, exercise, diabetes mellitus, lipids,

hypertension, pressure ulcers, COPD, and osteoporosis. (J Am Med Dir Assoc 2008; 9: 460 – 475)

NUTRITION

Assessment (MNA) should be used to further define the cause of weight loss.20 Persons losing weight have been shown to have poor function.18 Depression is the major cause of weight loss in older persons.21–23 Tube feeding appears to be overutilized in older malnourished persons.24 Sarcopenia is the physiological loss of muscle mass with aging.25 It has multiple causes including anorexia, decreased physical activity, decreased anabolic hormones, vitamin D deficiency, decreased insulin growth factor-I and mechanogrowth factor, decreased motor unit function, cytokine excess, decreased protein intake, insulin resistance, mitochondrial abnormalities, and atherosclerosis. There are now solid data demonstrating that both creatine intake and increased essential amino acid intake enhances muscle function in older persons.26,27 Older persons need at least 1 to 2 g/kg protein to maintain muscle mass. There is increasing evidence that testosterone may not only improve strength but also physical performance in older men and perhaps also women.28 –31 Selective androgen receptor molecules (SARMs), such as ostarine, are being developed to be available to treat sarcopenia and frailty. Antibodies to myostatin, a muscle growth inhibitor, are also being developed. Yeh et al32,33 reviewed the potential treatments for sarcopenia and stressed the important role of cytokine excess in muscle loss (Table 3). The need to increase the awareness of dehydration has been recently reviewed in the Journal.34,35 The need to recognize the existence of intracellular dehydration, which presents with hyponatremia, an increased blood urea nitrogen to creatinine and metabolic alkalosis, is a key to not missing hypo-osmolar dehydration. This needs to be distinguished from syndrome of inappropriate antidiuretic hormone, which is extremely common in nursing home residents.36 The use of subcutaneous infusion with recombinant hyaluronidase is an important tool for treating dehydration in the nursing home.

It is now recognized that weight loss is the major poor prognostic sign.2– 4 Not only can weight loss be a sign of disease-induced cachexia,5,6 but it also is a hallmark of the frailty syndrome.7,8 Frailty consists of the following components: fatigue, decline in strength (power), decline in aerobic function (walking speed/distance), increased number of diseases, and loss of weight.9 –13 A number of nutrient factors have been identified in the pathogenesis of frailty. These include a low daily energy intake (⬍21 kcal/dL), low protein and vitamin D intake, and low levels of vitamin E.14,15 The European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk study found an estimated 14-year improvement in physiological age could be obtained by not smoking, being physically active, having a moderate alcohol intake (1 to 14/week), and having 5 servings per day of fruits and vegetables.16 There are multiple causes of weight loss: anorexia, cachexia, sarcopenia, dehydration, malabsorption, hypermetabolism, and rheumatoid cachexia.17 Many of the causes of weight loss are treatable as illustrated by the “MEALS-ONWHEELS” mnemonic (Table 1).18 Anorexia is an independent predictor of mortality.19 For this reason, the Simplified Nutrition Assessment Questionnaire (SNAQ) has been developed to recognize persons at risk for weight loss early (Table 2).19 If the SNAQ is positive, the Mini-Nutritional

Cleveland Clinic, Section of Geriatric Medicine, Cleveland, OH (B.J.M.-R.); Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, MO (D.R.T., J.K.G., J.E.M.); GRECC, St. Louis VAMC, St. Louis, MO (J.E.M.). Address correspondence to John E. Morley, MB, BCh, Division of Geriatric Medicine, Saint Louis University School of Medicine, 1402 S. Grand Blvd., M238, St. Louis, MO 63104. E-mail: [email protected]

Copyright ©2008 American Medical Directors Association DOI: 10.1016/j.jamda.2008.07.006 460 Messinger-Rapport et al

Keywords: Nutrition; exercise; diabetes mellitus; lipids; hypertension; pressure ulcers; COPD; osteoporosis

JAMDA – September 2008

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

Table 3. Potential Treatments for Cachexia and Sarcopenia Drug

Mechanism of Action

Megestrol acetate

Inhibits cytokines Enhances appetite Increases fat ⬎ muscle Lowers testosterone in healthy men Glucocorticoid effect Increased food intake by activating cannabinoid receptor Increases muscle function enzyme inhibitors Increase muscle protein anabolism Decrease catabolism Increase satellite cells Inhibit adipogenesis Increase satellite muscle cell cycling Inhibit protein catabolism Increase food intake and increase growth hormone Increase phosphocreatine and energy availability Enhance availability of building blocks for muscle anabolism

Dronabinol Angiotensin-converting Testosterone/Selective androgen receptor modulators (SARMs) Myostatin antibodies

Omega-3 fatty acids are anti-inflammatory.37 There are 3 major omega-3 fatty acids: alpha-linolenic acid, eicosapentanoic acid, and docosahexanoic acid. Alpha-linolenic acid is derived from plants and can be converted into the other 2 omega-3 fatty acids that are derived from fish. Omega-3 fatty acids have a number of positive effects including decreasing triglycerides, a small reduction in blood pressure, a reduction in tumor necrosis factor and interleukin-1, inhibition of platelet adhesion, increased fibrinolysis, decreased arrythmogenic induction, improved plaque stability, enhanced endothelial relaxation, and a possible reduction in adhesion molecules. In

Table 2. Appetite Questionnaire to Predict Weight Loss in Older Persons—SNAQ (Simplified Nutritional Appetite Questionnaire) 1. My appetite is A. very poor B. poor C. average D. good E. very good 2. When I eat A. I feel full after eating only a few mouthfuls B. I feel full after eating about a third of a meal C. I feel full after eating over half a meal D. I feel full after eating most of the meal E. I hardly ever feel full 3. Food tastes A. very bad B. bad C. average D. good E. very good 4. Normally I eat A. less than one meal a day B. one meal a day C. two meals a day D. three meals a day E. more than 3 meals a day Instructions: Complete the questionnaire by circling the correct answers and then tally the results based upon the following numerical scale: A ⫽ 1, B ⫽ 2, C ⫽ 3, D ⫽ 4, E ⫽ 5. Scoring: If the mini-SNAQ is less than 14, there is a significant risk of weight loss. UPDATES FROM THE AMDA MEETING

Ghrelin agonists Creatine supplementation Caloric and protein supplementation

epidemiological studies, fish consumption has been associated with decreased myocardial infarction stroke and mortality.38 – 42 Omega-3 fatty acids reduced mortality in Japanese women who already had a high fish intake.43 Randomized controlled trials have shown decreased mortality in persons with coronary artery disease receiving fish oil derivatives.44 – 46 Fish oil may enhance memory in persons with amnestic mild cognitive impairment.47 Based on these data it would seem that fish oil would be a better treatment than statins for nursing home residents. Delirium is considered the sixth vital sign.48 It is a common problem in long-term care.49,50 Multiple vitamin deficiencies are associated with cognitive dysfunction.51 Thus, in persons with unresolved delirium, administration of a multivitamin preparation is reasonable. EXERCISE With increasing awareness that medication for cognitive deterioration has minimal clinical utility, it is important that other approaches to treating dementia are explored.52–55 A number of studies have suggested that exercise improves cognitive function and delays the onset of dementia.56 –58 Rolland et al59 have shown that two, 1-hour a week exercise programs for demented nursing home residents for 1 year markedly slows deterioration in activities of daily living. Other studies have shown a similar improvement in cognition.60 Exercise also improves mood in persons with dementia.61 Continuous activity programming decreases adverse behavioral symptoms.62 Exercise has to be a key in the management of residents in the nursing home. Messinger-Rapport et al 461

DIABETES MELLITUS

DPP-IV Inhibitors

Diabetes mellitus was shown to be present in 24.6% of 11,939 nursing home residents.63 Most older diabetic patients have a moderate degree of insulin secretory failure as well as insulin resistance.64 Most older diabetic patients are not overweight.65,66 The reasons for treating older diabetic patients, other than preventing hyperglycemic comas and long-term complications, are reduction of pain,67 reduction of infections,68 prevention of trace mineral deficiency,69 reduction of nocturia,70 improvement of incontinence,71 prevention of injurious falls,72 and limitation of cognitive impairment.73 Besides lowering glucose, new treatments for peripheral neuropathy are now available. Alpha-lipoic acid has been shown to reverse nerve damage.74 –76 Topiramate appears to cause regeneration of nerves and enhanced touch, prickling, and vibration thresholds.77 Fragility fractures are increased in persons with Type 2 diabetes.78 – 81 Falls appear to be more common when the HbA1C level is below 7%.82 Hyperglycemia is also associated with an increase in pressure ulcers.63,83– 85 Dysphoria is a major predictor of poor outcomes in persons with diabetes mellitus.86 Surprisingly, studies in nursing home residents have shown that most have HbA1C levels below 7% and very few have levels greater than 8%.87–90 Blood pressure control appears equally good. Aspirin is only used in 42%, as is a yearly eye exam. Foot examinations are done monthly in 87%. The management of diabetes in older persons in nursing homes involves medical nutrition therapy, exercise, oral medications, and insulin.91–93 Exercise has been shown to be an excellent therapy for older diabetic patients.94 As in other older persons, weight loss in diabetic patients is associated with increased mortality.95 There is no evidence to support the use of therapeutic diets in nursing home residents.96,97 The available insulins are shown in Figure 1. Glargine can be used once a day and can be given in the morning in nursing homes when qualified nursing staff are in more abundance. It has no higher degree of hypoglycemia than does continuous

Available insulin

Rapid-acting: lispro, aspart, glulisine Regular NPH, Detemir

Glargine

5

10

15

20

Time in hours Fig. 1. Characteristics of available insulin. (Available insulins referred to above). 462 Messinger-Rapport et al

Glucagon-like peptide Alpha-glucosidase Inhibitors Acarbose Miglitol Metformin

Sulfonylureas Meglintinides

Thiazolidinediones

Fig. 2. Oral agents used to treat diabetes.

subcutaneous insulin infusion.98 When used together with oral agents, it has less hypoglycemia than premixed 70/30 insulin.99 Levemir insulin is more an intermediate insulin. It has slightly lower risk of hypoglycemia than neutral protamine hagedorn (NPH) insulin.100 The oral agents available for the management of diabetes mellitus are shown in Figure 2. Metformin works less well as persons age.101 It produces anorexia,102 most probably by modulating nitric oxide levels in the central nervous system.103 It should not be used in the nursing home when the creatinine is greater than 1.2 mg/dL, or the creatinine clearance is below 50 mg/mL. It should also be avoided in persons with severe heart failure. Thiazolidinediones are associated with increased edema. Rosiglitazone has been associated with an increase in myocardial infarction, congestive heart failure, and increased mortality.104,105 This has not been shown for proglitazone. Both thiazolidinediones increase the risk of fracture in diabetic patients.106 This appears to be due to inhibition of osteoblast function.107 Alpha-1-glucosidase inhibitors (acarbose and miglitol) both slow carbohydrate absorption and increase the incretin glucagon-like peptide I (GLP-I).108,109 These drugs produce a variety of gastrointestinal side effects and weight loss.109 Postprandial hypotension is common in older persons and is associated with falls, syncope, stroke, and myocardial infarction.110,111 In nursing homes, persons with postprandial hypotension have increased mortality.112 Postprandial hypotension is due to the release of the vasodilatory peptide, calcitonin gene–related peptide.113 Both acarbose and miglitol can be used to prevent postprandial hypotension.114 –116 Sitagliptin is a dipeptidyl peptidase IV inhibitor that is orally active.117 It increases GLP-I. It reduces HbA1C by about 0.65% to 0.8%. It can be used by itself or in combination with other drugs. Numerous new drugs are available to treat diabetes in older persons. In nursing home residents an HbA1C beJAMDA – September 2008

tween 6.5% and 7.5% should be aimed for as a reasonable level of control. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study suggested that lower levels of HbA1C may have an increased mortality but this has not been confirmed by the Steno Diabetes Center in Denmark (STENO) or the Action in Diabetes and Vascular Disease (ADVANCE) studies.118 –120 Occasionally spuriously elevated HbA1C levels are seen in nursing home residents and if the HbA1C does not match glucose levels, a fructosamine should be obtained.121 Use of insulin, particularly glargine, should be instituted early. LIPID THERAPY IN FRAIL ELDERS: WHAT DO WE KNOW? The current concept of hyperlipidemia is primarily based on vascular risk and levels of low-density lipoprotein (LDL). The Adult Treatment Panel (ATP) III recommends that persons with vascular conditions such as diabetes, peripheral vascular disease, stroke, or known coronary disease be treated to reach an LDL less than 100.122 High-risk individuals may be treated more aggressively to an LDL target of less than 70 mg/dL.123,124 Although guidelines do not exclude older adults, there are actually very limited data to support the same targets for those 65 and older, and specifically in the old-old (80 years and older). What do we know about lipids in older adults, specifically (1) lowering LDL to reduce vascular risk, (2) the relative benefits to elders of medications currently available for hyperlipidemia, and (3) the potential of new medications to treat hyperlipidemia? Studies of statins to lower LDL in adults 65 years and older consistently demonstrate a lower risk of important clinical outcomes such as cardiovascular events and stroke.125 There is evidence for benefit in other clinical vascular outcomes important in the older population such as reduced risk of atrial fibrillation126 and heart failure127; studies are evaluating the role of statins on the progression of early aortic stenosis. However, only one interventional statin study enrolled adults over the age of 80, and that study, the Prosper study, capped the age limit at 82.128 Nevertheless, clinical outcomes of statin treatment in the middle aged, young-old, and the oldold appear comparable, despite limited data in the oldold.125,129 Although there are multiple case reports of myopathy, ataxia, diminished muscle function, impaired diastolic function, and cognitive impairment from statin use in elders, large clinical trials do not support these outcomes and find only elevated liver function tests as a consistent but infrequent adverse effect.130,131 The target LDL of 70 versus 100 mg/dL derives from the Treating to New Target study.132 In this study of adults 75 years and younger, the intervention group with atorvastatin of 80 mg attained an average LDL of 77 mg/dL; the control group treated with 10 mg attained an LDL of 101 mg/dL. The intervention group had a relative risk reduction (RRR) of 22% in the first cardiovascular event, compared with the control group. Additionally, there was a RRR of 25% in stroke in the intervention group. There was no increase in hemorrhagic stroke with more intensive treatment.133 UPDATES FROM THE AMDA MEETING

Two additional issues to consider with statin treatment are the time to benefit from therapy, and the use of C-reactive protein (CRP) as a co-target with LDL. Scrutiny of statin intervention trials reveals that the time to impact clinically important outcomes such as cardiovascular events is less than 2 years.128,134-136 The statin-based PROVE-IT TIMI trial136 demonstrated that intensive lowering of LDL to 70 mg/dL provided the most benefit only when the CRP was also lowered to less than 2 mg/L, and that meeting these 2 targets (lower LDL and lower CRP) was more important than choosing one statin over another. The proven clinical outcome achieved by lowering LDL, the ability to lower CRP to less than 2 with a further benefit to clinical outcome, and the potential benefit within a 2-year period differentiate the statins from other anti-lipid drugs currently available. For example, ezetimibe (EZT) lowers LDL effectively and rapidly, has few adverse effects, and fewer drug interactions. However, EZT does not lower CRP when used alone. Additionally, no study has ever demonstrated a benefit to an important clinical outcome such as cardiovascular event or stroke, or even a surrogate outcome such as carotid intimal thickness.137 Other drugs are currently available to treat hyperlipidemia, including niacin, fibrates, bile acid sequestrants, and fish oil. Niacin raises high-density lipoprotein (HDL) and lowers both triglycerides (TG) and LDL. The drug has been available for decades, both in prescription and over-the-counter formulations. It is not a first-line treatment in most older adults because of significant adverse effects including flushing, abnormal liver function tests, peptic ulcer disease, arrhythmia such as atrial fibrillation, and insulin resistance. There are no data on whether it lowers CRP, and no recent clinical outcomes data on older adults other than surrogate data on carotid intima. In the well-known Coronary Drug Project, there was a clear long-term mortality benefit of niacin in subjects with post-myocardial infarction (all men under the age of 65), but the time to separation of the treatment from the control outcomes was 6 to 8 years.138 Adding niacin to a statin also increases the risk for muscle and liver toxicity. The risk-benefit ratio regarding important vascular outcomes may not be established until the completion of the AIM-HIGH trial NCT00120289. There are several fibrates on the market. They lower LDL variably depending on the choice of fibrate, but consistently raise HDL and lower TG. Their effect on CRP is variable. Adverse effects include muscle and liver toxicity, with an increased risk when given with a statin. The FIELD trial139 did not demonstrate a reduction in the primary outcome of coronary events with fenofibrate in diabetic patients, but the study was “contaminated” by off-trial statin use. The ACCORD trial using a statin ⫾ fenofibrate may clarify the benefit to this drug in diabetic patients when it is completed.140 Bile acid sequestrants are not considered first- or secondline drugs, mainly because of gastrointestinal intolerability and drug interactions. There are no recent clinical data on cholestyramine or other bile acid sequestrants regarding clinical outcomes in elders or time to effect. Adding colesevalam, Messinger-Rapport et al 463

464 Messinger-Rapport et al

Reduction in risk of nonfatal coronary events with 1.8 gm fish oil added to a statin. 4 g fish oil lowers TG 45%. Intense treatment goals may require LDL⬍70 mg/dL and CRP ⬍ 2 mg/L Comments

LDL, low density lipoprotein; HDL, high-density lipoprotein; TG, triglycerides; CRP, c-reactive protein.

Second line drug. Awaiting clinical outcomes of trials of older adults. Second line drug in diabetic patients. Awaiting outcome of ACCORD trial. Reduction in risk of coronary events. No recent drug trials. Reduction in risk of coronary None events, stroke, heart determined failure, atrial fibrillation.

Unclear Unclear N/A 6–24 months

Time to benefit Benefit

2LDL, 2CRP 2LDL, 2CRP Target

2LDL. ↔ CRP

1HDL. 1TG. Variable effect on LDL and CRP (Fenofibrate lowers both) Unclear

May be ⬎ 5 years

2TG. May raise LDL. Effect on CRP unknown.

Decreased platelet aggregation (clinical effect on bleeding risk unknown). Fishy burp

Flushing, insulin resistance, arrhythmia (atrial fibrillation), peptic ulcer disease, thrombocytopenia, abnormal LFT. 2LDL, 1HDL, 2TG. Effect on CRP unknown 1risk myopathy, abnormal LFT with statins. Cholecystitis. Multiple drug interactions. Constipation. None Abnormal LFT; myopathy. Adverse effects

Fish Oil Niacin Fibrates Bile Acid Sequestrants Ezetimibe Statins

Table 4. Treatment of Hyperlipidemia to Reduce Vascular Risk

a bile acid sequestrant, to a statin does lower both CRP and LDL more than a statin alone.141 Fish oil is now available in prescription form and has few side effects other than nausea, gastrointestinal upset, and a fishy burp. It impairs platelet aggregation, although the clinical impact on bleeding risk is unknown. A dose of 4 g daily reduces triglycerides by 45%. Fish oil may modestly increase LDL when used in doses higher than 1 g per day, and its effect on CRP is unknown. Although a Cochrane review in 2004 did not demonstrate a benefit in clinical outcomes, 2 recent meta-analyses and 1 large prospective study demonstrated significant reduction in important clinical outcomes.142–145 A variety of new drugs are in the pipeline, but it is unclear when or if any will appear on the market. Early trials of inhibitors of cholesteryl ester transfer proteins demonstrate that these drugs lower LDL and increase HDL. One of them, torcetrapib, raises blood pressure. A sister drug, anacetrapib, appears to have short-term safety and efficacy outcomes.146 Other drugs under evaluation include a Chinese herb berberine, which is an LDL preceptor protein, ETC-216 (an apolipoprotein A-1 Milano-phospholipid complex), mixed peroxisome proliferator–activated receptor agonists, and others. Additional risk reduction may be obtained by considering lipid components other than LDL. Targeting triglycerides, HDL, Lp(a), and others factors along with LDL and CRP may reduce vascular risk. Other potential future targets are interleukin-6, vascular monocyte chemotactic protein-1, plasminogen activator inhibitor-1, and matrix metalloproteinase activity. In summary (Table 4), the data currently favor statins as the drug of choice in lowering vascular risk. Drugs in this class lower LDL and CRP both, and demonstrate a benefit to important clinical outcomes in fewer than 2 years for most outcomes and populations. A meta-analysis of 51,351 persons between 60 and 80 years receiving statins found a 15% reduction in mortality and decreases in the rates of myocardial infarction and stroke.147 Although EZT lowers LDL, it may not reduce vascular risk. The role of fibrates as adjunctive therapy in diabetic patients may be clarified soon as the ACCORD study is completed. Niacin and bile acid sequestrants have not been subjected to recent trials with older adults using important clinical outcomes. A significant limitation to niacin would be its side effect profile (dose-related) and the potential time to benefit (much longer than with statins). The frequently asked question of whether to treat hyperlipidemia at all and how aggressively to do so in an older adult, particularly one over 80 years old, has not been answered by the literature and is likely not to be addressed in the near future. Estimation of vascular risk of older adults without a diagnosed vascular condition is elusive, since vascular risk calculators do not utilize age older than 75 years. Additionally, in the oldest old, even though the specific cause of death is usually vascular (coronary disease or stroke), vascular diagnoses are not strong predictors of death compared with physical disability and cognitive impairment.148 This predicament leaves the decision of how intensely (if at all) to treat hyperlipidemia on the shoulders of the clinician, since he or she

JAMDA – September 2008

balances the need for disease management with the art of limiting polypharmacy and improving quality of life. HYPERTENSION THERAPY IN FRAIL ELDERS: WHAT DO WE KNOW? The current concept of hypertension (HTN) is primarily based on vascular risk and levels of systolic and diastolic pressure. The Joint National Commission (JNC) VII recommends reducing blood pressure (BP) to less than 140/90 to reduce the risk of vascular conditions such as stroke and coronary heart disease.149 High-risk individuals with diabetes or renal disease should be treated until BP is less than 130/ 80.150 There is evidence to support treatment of HTN in all adults, even in the old-old. What do we know about (1) lowering BP to reduce vascular risk in older adults, (2) the relative benefits to elders of medications currently available for hypertension, and (3) the potential of new medications to treat hypertension? Two large trials of antihypertensive treatment proved that treating systolic hypertension, the most common form of HTN in older adults, reduced the risk of stroke and major cardiac events. These 2 trials were the Systolic Hypertension in the Elderly Program (SHEP),151 using the diuretic chlorthalidone, and the Systolic Hypertension in Europe (Syst-Eur) trial, using the dihydropyridine calcium channel blocker nitrendipine.152 Neither of these trials limited the upper age of enrollment. However, the inclusion and exclusion criteria were such that the average subject age was just under 72 years, and few were enrolled at the age of 80 and above in either trial. Only the Hypertension in the Very Elderly Trial (HYVET) enrolled adults 80 years old.153,154 The data safety monitoring board terminated the study early when review of data found that the risks of stroke, fatal stroke, heart failure, and total mortality were reduced in the intervention group receiving indapamide (a diuretic).155 In all 3 of these major studies, the benefit in stroke reduction was demonstrated within the first year of the trial. None of these trials lowered systolic blood pressure below 160 mm Hg. In addition to reducing the risks of stroke and major cardiovascular events, antihypertensive treatment reduced the risk of other vascular outcomes important to older adults. The intervention in the SHEP study (a thiazide diuretic) demonstrated lower risks of heart failure and microalbuminuria. The intervention group in the Syst-Eur study (a dihydropine calcium channel blocker) demonstrated a 50% reduction in the risk of the incidence of dementia.156 Separate studies demonstrate that subjects taking antihypertensive drugs and who have controlled BP have a reduced risk of severe white matter hyperintensities,157,158 which are associated with substantial neurologic, psychiatric, and medical morbidity.159,160 In another study called the Perindopril Protection against Recurrent Stroke Study (PROGRESS), those in the intervention group (taking an ace inhibitor) who had a recurrent stroke during the study, demonstrated a significant reduction in the risk of poststroke dementia or cognitive decline.161 Perindopril in adults with mean age 78.6 years also increased the distance walked in 6 minutes compared with placebo.162 There were limits to the benefits of antihypertensives. UPDATES FROM THE AMDA MEETING

Those with nonsustained hypertension (elevated in the office but having normal average ambulatory pressures) did not as a group appear to attain a vascular risk reduction from antihypertensives in the SHEP study.163 Antihypertensives decreased stroke risk only when the diastolic pressure (dBP) maintained at least 60 mm Hg in the SHEP study.164 Similarly, in the Syst-Eur trial, active treatment reduction of dBP below 55 mm Hg and below 70 mmHg in those with preexisting heart disease was associated with increased cardiovascular risk.165 Quality-of-life surveys suggested slightly lower quality of life in the intervention group in the Syst-Eur study compared with the placebo.166 Concerns about potential adverse outcomes of orthostasis such as falls and fractures were addressed in the HYVET study but results are not yet available.153 Persons with severe orthostasis were excluded from the trial. Different classes of antihypertensives may exert different outcomes. In ALLHAT, which enrolled adults over the age of 55 years (mean age 67 years), the alpha-blocker arm was terminated because of excessive stroke, combined cardiovascular disease rate, and heart failure compared with chlorthalidone.167 There was no difference in the primary outcome of fatal or nonfatal coronary heart disease in the 3 remaining antihypertensives: diuretic (chlorthalidone), calcium channel blocker (amlodipine), and angiotensin-converting enzyme (ACE) inhibitor (lisinopril).168 However, subjects assigned the ACE inhibitor had a higher 6-year rate of combined cardiovascular disease. Subjects assigned the calcium channel blocker had a higher rate of heart failure, and subjects assigned the diuretic had a higher risk of diabetes compared with those receiving the ACE inhibitor.168 Meta-analysis of prospective clinical trials of older hypertensives as first-line antihypertensive therapy demonstrate clear benefits in all vascular outcomes with diuretics, and lack of benefit with beta blockers as first-line therapy in the outcomes of stroke mortality, coronary heart disease, cardiovascular mortality, and all-cause mortality.169 There are some new antihypertensive drugs on the horizon. One has emerged recently, the renin inhibitor aliskiren. Calcium channel blockers with different subtypes of blockade are under evaluation. For example, amlodipine is an L-type calcium channel blocker already on the market. Mibefradil and efonidipine block L channels but also T-type channels, possibly decreasing renin production. Clinidipine blocks both L and N type of calcium channels and may possibly exert a sympatholytic and renal protective effect.150 There are new beta blockers emerging, as well as a variety of combination therapy drugs. Statins, approved for hyperlipidemia, may actually lower systolic and diastolic blood pressure approximately 2 mm Hg.170 In summary (see Table 5), there is evidence that treating hypertension in the older adult, even in those older than 80, to a systolic blood pressure below 160 mmHg, results in clinically important vascular benefits. Risk of stroke and cardiovascular events are reduced. There is no evidence of increased mortality, and in fact the study enrolling the oldest adults, the HYVET study, demonstrated a reduced risk of overall mortality with treating hypertension. Additional vasMessinger-Rapport et al 465

Table 5. Primary Treatment of Systolic Hypertension to Reduce Vascular Risk Thiazide-type Diuretics Adverse effects

Target

Time to benefit Benefit

Beta Blockers

ACE/ARB

Dihydropyridine CCB

Alpha-blocker

Other

Clonidine: Urinary impaired incontinence in cognition. women. Excessive Hydralazine: stroke, combined orthostasis, cardiovascualar lupus effect. disease rate, and heart failure compared with thiazide. Studies enrolled adults with systolic blood pressure ⬎160 mm Hg, with goal of lowering sBP to ⬍ 140. Diastolic BP should be ⱖ70 mm Hg for pre-existing vascular disease, and ⱖ55 mm Hg otherwise. Consider deferring treatment when ambulatory BP is normal, or when standing sBP ⬍ 140 mm Hg. Although the goal for diabetic patients or those with chronic kidney disease is ⬍ 130/80, the data did not derive from adults 75⫹ years. 6–24 months N/A Unclear 6–24 months Unclear Unclear

Bradycardia Electrolyte abnormalities and glucose intolerance at high doses. 1risk diabetes.

Cough, Edema, urinary angioedema. incontinence, increased risk heart failure.

2risk of stroke. 2risk of stroke, Third or fourth line Large trials 2risk of stroke, Meta-analyses in cardiovascular choice of with clinical cardiovascular older adults events. May antihypertensive. outcomes in events, heart suggest limited increase risk of elders not failure. benefit as a heart failure. available. primary antihypertensive agent May also reduce risk Comments May also Beta Blockers are May increase of dementia. 6-minute reduce risk of important walking dementia. treatments for distance. May decrease atrial fibrillation, May also mortality. systolic heart reduce risk of failure, and post-stroke myocardial dementia. infarctions. BP, blood pressure; sBP, systolic blood pressure; CCB, calcium channel blocker; ACE/ARB, ace-inhibitor; ace receptor blocker.

cular risks important to older adults such as heart failure and poststroke dementia may be reduced. Beta blockers used as first-line therapy for hypertension do not perform as well as diuretics in reducing vascular risk.169 Despite all the evidence described above regarding hypertension and lipid management in older adults, it has never been shown that multifactorial intervention to prevent recurrent cardiovascular events in community-dwelling old-old provide a clinical benefit.171 Thus, the decision of how intensely to treat hypertension, as well as hyperlipidemia, is still on the shoulders of the clinician, who balances the need for disease management with the art of limiting polypharmacy and improving quality of life. Quality indicators in older persons should recognize the difference between frail and healthy elderly, as done in the Glidepaths172 and should not advocate for extremely tight control of BP or lipids in older persons.173,174 It is recognized that others have a more aggressive approach to the treatment of these conditions in nursing homes.175–180 There is a need for controlled trials in nursing home residents to settle these differing viewpoints.

clude proposed changes to the staging system for pressure ulcers, a change in the regulatory environment, new insights into prevention, support surfaces, local wound treatment strategies, and studies in nutrition and outcomes.

PRESSURE ULCERS: PREVENTION AND MANAGEMENT

The regulatory environment for pressure ulcers has undergone extensive revision with the publication of surveyor guidelines effective in 2004. These guidelines update current thinking about prevention and management of pressure ul-

Over the past several years, several areas of pressure ulcer prevention and management have progressed.181 These in466 Messinger-Rapport et al

Staging System The current staging system for pressure ulcers is more commonly recognized as inadequate for clinical practice. Several authors have suggested that stage 1 and 2 pressure ulcers may be fundamentally and etiologically different from stage 2 to 4 lesions.182 The etiology of higher stage pressure ulcers may begin with injury to muscle and fat (deep tissue) as opposed to skin only (superficial tissue). Thus, a clinician may suspect deep tissue injury and rapid evolution into a higher stage wound even in the absence of superficial skin changes. A hypothesized “suspected deep tissue injury” may be added to the typical stage 1 to 4 classification.183,184 Ultrasonography may be a mechanism for diagnosing this injury, but has not been linked to prediction of pressure ulcer development.185 Regulatory Environment

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cers. Clinicians who work in long-term care environments should review the changes and the evidence supporting them.186 In general, the new guidelines follow a much more evidence-based pattern. Despite improvements in adherence to prevention and treatment interventions, there appears to be a floor effect in the prevention of pressure ulcers.187 Although improvements were made in documentation and prevention interventions, the incidence of pressure ulcers in long-term care facilities was not impacted by an educational and wound care team intervention.188 Insights into Prevention A systematic review of prevention strategies for pressure ulcer prevention examined 59 published trials.189 Of these randomized, controlled trials, 51 addressed immobility and positioning, 5 addressed nutritional interventions, and 3 addressed impaired skin. In trials of turning and positioning, insufficient evidence was found to recommend any specific turning regimens for patients with impaired mobility. One of 5 trials suggested that a general nutritional supplement may decrease the incidence of pressure ulcers,190 while the other 4 did not show a measurable effect. Trials of impaired skin treatment found no incremental benefit of specific topical agents over simple moisturizers in patients with impaired skin. The Braden scale is the most commonly used risk assessment instrument used in the United States; however, in the long-term care setting, the positive predictive value is only 54%. Using a cutoff value of less than 17, 44% of residents in 11 long-term care facilities were at risk of developing a pressure ulcer.191 However, only 20% of these at-risk subjects went on to develop a pressure ulcer. In those screened as not-at-risk, 15% of subjects developed a pressure ulcer. Since the Braden scale appears too insensitive to the development of a pressure ulcer, different strategies have been evaluated for timing of prevention interventions. In 1617 subjects in institutional settings, one group was randomized to receive prevention interventions when the Braden score was less than 17. The other group was examined daily and prevention interventions were started when there was evidence of nonblanchable erythema of the skin (a stage 1 pressure ulcer). Based on the criteria, 32% of subjects were at-risk by Braden scale and received interventions, while 16% of subjects developed a stage 1 pressure ulcer and were started on prevention interventions. The incidence of a stage 2 or higher pressure ulcer was the same in both groups (6.7% versus 6.8%).192 This study also demonstrated that 17% of subjects in the control group went on to develop a stage 2 or higher pressure ulcer despite prevention interventions started when identified as being at risk by the Braden scale. The Braden scale cut point for being at risk is very sensitive. When a cut point of less than 18 is applied, 61% of subjects would need prevention interventions. The cost of prevention intervention based on the Braden scale was much higher because of application on such a broad population. UPDATES FROM THE AMDA MEETING

Turning and Positioning and Support Surfaces The appropriate interval for turning and positioning a patient at risk for development of a pressure ulcer remains controversial. Four differing strategies were examined in a group of 868 subjects in an institutionalized setting who were at risk (Braden scale less than 17). On a “standard” hospital mattress, turning every 2 or every 3 hours did not result in a different incidence of a stage 1 (48% versus 45%), or incidence of a stage 2 or higher pressure ulcer (14% versus 24%). No difference in incidence of a stage 1 pressure ulcer was observed when the subject was turned every 6 hours on a pressure-reducing mattress or when no strict turning interval was applied (46% versus 43%). No difference in stage 2 or higher pressure ulcers was observed in these groups (16% versus 20%). No difference in development of a stage 1 pressure ulcer was seen in the group that was turned every 4 hours on a pressure-reducing mattress. However, in the group turned every 4 hours on a pressure-reducing mattress, a reduction in the development of a stage 2 or higher pressure ulcer was observed (3%).193 Various combinations of positioning have been examined. Compared to turning 4 hours in a semi-Fowler’s position, 2 hours in a lateral position, and 2 hours up in a chair, extending the time in the semi-Fowler’s position to 4 hours did not result in a higher incidence of stage 2 or higher pressure ulcer.194 These data emphasize the lack of a knowledge base on the effectiveness of turning and repositioning to prevent pressure ulcers. The data suggest than turning every 4 hours on a pressure-reducing device is the most effective strategy. Positioning by traditional methods does not appear to be effective. It is disconcerting to note that 19% of subjects in these turning studies developed a stage 2 or higher pressure ulcer despite rigorous compliance with the protocol. This suggests that frequent turning and positioning is relatively ineffective for the prevention of pressure ulcers. A paradigm for progressive use of pressure-reducing devices has been suggested.195 Pressure-reducing mattress overlays or low-air-loss devices should be tried for prevention of pressure ulcers. Dynamic support devices (eg, alternating-air mattresses) should be considered for patients who cannot self position. Air-fluidized beds should be considered for patients who do not otherwise respond to treatment or who have more severe ulcers. Heel devices should completely eliminate pressure on the heels (eg, L’Nard or Multi-Podus Splints). Local Wound Treatment A systematic review of randomized, controlled trials of local wound treatments identified 21 published studies.196 Pooled assessment of trials comparing traditional saline dressings to a hydrocolloid dressing found a higher rate of healing with the hydrocolloid dressing. Three of 4 studies comparing saline to other dressings (polyurethane, dexametor) found a higher rate of healing with the advanced dressing. A trial of hydrogel compared to saline was equivalent. Eight trials comparing one advanced dressing to another advanced dressing found no differences in complete healing. These data suggest that adMessinger-Rapport et al 467

vanced dressings, and in particular hydrocolloid dressings, are more effective for healing pressure ulcers compared to traditional dressings. The choice of a specific advanced dressing should be targeted to the specific characteristics of the wound, such as exudate amount, deadspace or tunneling, and need for debridement. No new trials in vacuum-assisted therapy have been published subsequent to 3 previous trials showing no superiority in healing pressure ulcers.181 Outcome Studies A retrospective analysis of treatment outcome measures in outpatient wound care clinics, home health settings, and a long-term care setting again confirms the poor effect of certain intervention measures.197 Pressure ulcers were less likely to heal when subjects were turned every 2 hours, received a pressure-reducing mattress, or a nutritional supplement. This is likely due to selection bias, but one would like to see some effect of these commonly recommended interventions.198 Compared to dry or conventional local wound dressings, a hydrocolloid dressing improved healing (6% versus 27%), but use of an antibiotic, antiseptic, wound cleanser, a silver dressing, or a topical growth factor was not associated with improved healing. Subjects in long-term care facilities were much more likely to be given an antibiotic for a pressure ulcer, but there was no difference in healing rate. MANAGEMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE Management of chronic obstructive lung disease is evolving as new data accumulate. A step care approach includes assessing and monitoring disease progression, reducing risk factors, managing stable disease, and managing acute exacerbations. Assessing and Monitoring Disease COPD must be distinguished from other respiratory symptom complexes. While there is about a 10% overlap between asthma and COPD, the 2 conditions are clinically distinct and increasingly are managed differently. COPD is recognized as an abnormal inflammatory response to inhaled particles.199 Smoking is strongly associated with COPD, but only 15% of smokers develop the inflammatory reaction leading to COPD, and 5% to 10% of persons with COPD have never smoked.200 This variation presents attractively because it could explain why only a fraction of smokers of the same age and sex who have smoked equivalent amounts develop COPD.201 The criteria for diagnosis of COPD include symptoms of cough, sputum production, or dyspnea and/or a history of exposure to risk factors for the disease. The diagnosis is confirmed by spirometry with a postbronchodilator forced expiratory volume in 1 second (FEV1) less than 80% of predicted value in combination with a forced expiratory volume in 1 second ratio to forced vital capacity (FVC) of less than 70% and an airflow limitation that is not fully reversible. 468 Messinger-Rapport et al

Reduce Risk Factors Despite a low association for an interaction between particulate matter from tobacco smoke and inflammatory host factors necessary for the development of COPD, smoking cessation is the hallmark of treatment. In fact, smoking cessation is the only treatment that produces a decrease in the progressive decline in FEV1. In persons with COPD who quit smoking, the decline in FEV1 was 27 mL/min per year compared to a 60 mL/min decline in persons who continue to smoke.202 Nevertheless, a progressive decline in FEV1 occurs despite smoking cessation, indicating the inflammatory nature of the disease. Vaccination against influenza and pneumococcal infections are effective in reducing infection rates in persons with COPD. Managing Stable Disease There is no cure for COPD. Data demonstrate a progressive decline in lung function despite treatment interventions. Therefore, the aim of clinical therapy is to modulate the symptoms and improve the functional status of the patient. Stage 1 disease is characterized by an FEV1/FVC ratio less than 70%. An FEV1 greater than 80% of predicted is usually, but not always, associated with chronic cough and sputum production. The treatment strategy should be begun with an as-needed inhaled short-acting beta agonist. Several preparations are available and all are equally effective. Levoalbuterol has fewer side effects and can be used in persons who cannot tolerate albuterol, at an increased cost. Stage 2 disease is characterized by an FEV1 30% to 80% of predicted with shortness of breath on exertion, and a tendency toward symptom exacerbations. Inhaled anticholinergics should be added at this stage. Two forms are available: ipratropium and tiotropium. Compared to placebo, ipratropium, and salmeterol, tiotropium has been shown to decrease exacerbations and hospitalizations.203 Both tiotropium and a long-acting beta agonist (salmeterol) are superior to placebo in reducing exacerbations, but tiotropium appears to have an advantage.204 Comparison of a long-acting beta agonist, tiotropium, inhaled steroids, or inhaled steroids combined with a long-acting beta agonist has shown effectiveness in reducing exacerbations with no superiority over any strategy. A long-acting beta agonist reduces the number of exacerbations compared to short-acting beta agonists, improves perceived quality of life, but does not improve the rate of decline in FEV1 or reduce overall mortality.205 Pulmonary rehabilitation programs are effective in reducing exacerbations and should be considered at this stage. Stage 3 disease is characterized by severe airflow limitation (FEV1 less than 30% predicted), or the presence of respiratory failure, or clinical signs of right heart failure. Supplemental oxygen clearly improves survival when the PaO2 saturation is less than 60 torr, but has no effect when levels are consistently above this threshold.187 Lung reduction surgery may have a beneficial effect in some patients. JAMDA – September 2008

Managing Exacerbations An exacerbation of COPD is confirmed by increased breathlessness, sputum volume or sputum purulence (Type 1), or the presence of 2 of these symptoms (Type 2), or presence of 1 symptom plus 1 of the following: an upper respiratory tract infection in the past 5 days, or fever without other cause, or increased wheezing or cough, or an increase in heart rate or respiratory rate by 20% (Type 3). Although the mortality rate for an acute exacerbation has been reduced, 23% of patients died in a 2003 study.206 Sixty percent of acute exacerbations are caused by an infection, while an additional 10% are attributed to environmental factors. The rest are unexplained. Among infectious causes, the largest category is due to viruses (30%) or unknown causes (23%). The remainder are distributed among other organisms including Haemophilus influenza, Streptococcus pneumoniae, Moraxhella catarrhalis, Haemophilus parainfluenza, and others.207 Sputum cultures have little correlation to proven infectious causes.208 There is no advantage to inhaled beta agonists delivered by nebulization or metered dose inhaler, although some individuals report subjective improvement during an acute exacerbation with nebulized therapy.209 Some older persons may not be able to manually administer a metered dose inhaler because of a functional or cognitive impairment. Studies of various interventions have been shown to reduce the annual exacerbation rate to around 20% to 26% with no apparent advantage of a single strategy. The interventions include inhaled steroids, tiotropium, combinations of shortacting beta agonists and anticholinergics, N-acetylcystine, and pulmonary rehabilitation programs. The only exception is a failure to demonstrate a reduction in exacerbations with inhaled budesonide. Combination of inhaled fluticasone and salmeterol improves FEV1 by about 100 mL/min at 1 year.210 In longer trials of inhaled corticosteroids, an improvement in FEV1 of about 75 to 100 mL/min occurs after initiation of therapy, but the improvement in FEV1 converges with placebo therapy at 30 months.211 Overall, chronic inhaled steroids in COPD improve the patient’s perception of quality of life but have little disease-modifying effect.212 Corticosteroids have multiple adverse effects including dysphonia, oropharyngeal candidiasis, skin bruising, reduction in bone mineral density, increased fracture risk, cataracts, and glaucoma. The prolonged use of corticosteroids in persons with osteopenia should be treated with calcium and vitamin D, or a bisphosphonate. Summary COPD is increasingly recognized as a systemic inflammatory reaction to inhaled particulate matter. Smoking cessation is the only intervention that has been shown to reduce the progressive decline in lung function. Other treatment modalities have shown little effect in disease modulation, but improve symptoms, reduce the number of exacerbations, and improve patient-reported quality of life. The treatment plan should be directed to a step care approach based on pulmonary function and symptom score. Reduction in exacerbation UPDATES FROM THE AMDA MEETING

of symptoms and the need for hospitalization is achievable. Vaccination is a critical component of the therapeutic plan. UPDATE ON OSTEOPOROSIS TREATMENT Osteoporosis causes significant morbidity and mortality to both men and women. Although fractures are the most serious consequence, this disease causes many individuals chronic pain, skeletal deformity, and impaired mobility. Over half of women older than 50 will have a fracture in their lifetime. One quarter of individuals who sustain a hip fracture will die within 1 year of this event. Osteoporosis is undertreated by physicians.213,214 A number of recent articles in the Journal of the American Medical Directors Association have highlighted the importance of osteoporosis.215–219 In treating osteoporosis, it is not sufficient to simply improve bone mineral density; medications must demonstrate reduction in fracture rates to receive a Food and Drug Administration (FDA) treatment indication. Many medication classes are known to improve bone mineral density and reduce fracture risk, however not all agents reduce fractures equally at the 2 most important fracture sites: the spine and the hip. To quantify the benefit of osteoporosis treatments, MacLean et al220 performed a systematic review of randomized placebocontrolled trials (RCTs) measuring fracture as the primary outcome. Seventy-seven studies including 24 meta-analyses reviewed bisphosphonates, selective estrogen receptor antagonists (SERMs), calcitonin, estrogen, teriparatide, calcium, and vitamin D. Most published studies were of bisphosphonates (n ⫽ 36). Only 2 studies looked at individual agents head-to-head; one of these showed no difference between 2 bisphosphonates, and was not powered to detect fracture outcomes between agents. The authors of this meta-analysis found good or fair evidence that bisphosphonates (alendronate, etidronate, ibandronate, risidronate, and zoledronic acid), estrogen, and teriperitide (PTH) reduce fractures at both vertebral and nonvertebral sites. Calcitonin and raloxifene demonstrated fracture reduction only in the spine. There was weak or no evidence that calcium alone and vitamin D alone reduce fracture rates. Only 9 studies of these included men with osteoporosis. Three demonstrated fracture reduction: risedronate for hip fracture (relative risk [RR] 0.25; 0.08–0.78), calcitonin at the spine (RR 0.09; 0.01–0.96), and parathyroid hormone (PTH) for total fractures (RR 0.16; 0.04–0.65). A separate systematic review of men with osteoporosis performed by other researchers221 found only 2 studies (total n ⫽ 375) of sufficient quality for analysis. These authors found evidence of reduced fracture rates at the spine (odds ratio [OR] 0.36; 0.17– 0.77) with alendronate but no fracture reduction at nonvertebral sites (OR 0.73; 0.32–1.67). Of interest, Greenspan et al222 studied men (n ⫽ 112) on androgen deprivation for prostate cancer treatment with and without alendronate for the outcome of change in bone mineral density (BMD). Ninety-one percent of these men met BMD criteria for osteopenia or osteoporosis at study onset. After 1 year, men randomized to alendronate had a 3.7% improvement in BMD (95% confidence interval [CI] 2.8%– 4.6%, P ⬍ .001) at the spine and 1.6% (95% CI Messinger-Rapport et al 469

0.4 –2.8%, P ⫽ .008) improvement at the femoral neck. Men in the placebo group lost bone density at both sites. Although not powered to demonstrate fracture risk reduction, this study begins to address the need for treating men with osteoporosis or at high risk for developing osteoporosis who are receiving androgen-deprivation therapy. One of the newest agents to receive FDA approval for osteoporosis treatment is zoledronic acid, an intravenous bisphosphonate administered yearly. Two large (total N ⫽ 9892) RCTs of this treatment have demonstrated reduction in fractures at both vertebral and nonvertebral sites over 3 years.223,224 In the study of postmenopausal women with osteoporosis,223 vertebral fractures occurred in 10.9% of placebo versus 3.3% of treated women (RR 0.3; 0.24 – 0.38; P ⬍ .001). Hip fractures occurred in 2.5% of untreated versus 1.4% of treated women (RR 0.59; 0.42– 0.83; P ⫽ .002). In the study of both women and men treated after sustaining a hip fracture,224 new vertebral fractures were reduced in treated individuals versus placebo (1.7% versus 3.8%, P ⫽ .02) but new hip fracture rates were not significantly reduced in the treated group (2.0% versus 3.5%, P ⫽ .18). Significant adverse events in the treatment group for both studies included a transient increase in creatinine clearance (ⱖ 0.5 mg/dL), posttreatment flu-like symptoms, and serious atrial fibrillation. Two cases of osteonecrosis of the jaw were reported (one each in the treatment and placebo groups). Another new class of medication for osteoporosis treatment is teriparatide or parathyroid hormone (PTH). Two recent studies have evaluated the use of this medication in osteoporosis treatment.225,226 Although these studies primarily evaluated change in bone mineral density, some fracture data were presented also. In the meta-analysis226 of PTH studies (n ⫽ 2074), treatment reduced nonvertebral fracture rates compared with placebo (RR 0.62, 0.46 – 0.82, P ⬍ .01). PTH treatment also reduced vertebral fracture rates (n ⫽ 4155) compared with placebo (RR 0.37, 0.28 – 0.48, P ⬍ .01). In an 18-month RCT,225 428 men and women with osteoporosis (mean age 57 years, 80% female) who were receiving glucocorticoid treatment for at least 3 months, and thus were at high risk of fracture, were treated with either alendronate or PTH. BMD improved significantly at the spine (7.2% versus 3.4%, P ⬍ .001) and at the hip (3.8% versus 2.4%, P ⫽ .005) in the PTH group compared to the alendronate group. Ten vertebral fractures occurred in the alendronate group compared with 1 in the PTH group (P ⫽ .004). There were no differences in nonvertebral fractures between the groups (8 versus 12, P ⫽ .36). Significantly more subjects withdrew from the PTH arm (11.7%) compared with alendronate (6.1%) due to adverse events p ⫽ 0.04. In most recent studies of osteoporosis treatment, both calcium and vitamin D were administered to treatment and placebo groups; however, this was not consistently performed in older studies. Until recently, data have been mixed on the importance of co-administration of calcium and vitamin D compared with calcium or vitamin D monotherapy. Two recent studies have clarified the need for providing calcium 470 Messinger-Rapport et al

and vitamin D together in order to reduce fracture risk in osteoporosis.227,228 In 2 meta-analyses (each with over 50,000 subjects), fracture outcomes were compared in the group receiving monotherapy (calcium or vitamin D alone) versus combination therapy (calcium plus vitamin D). In both studies there was no reduction in fracture rates with monotherapy. For vitamin D alone, the relative risk of fracture was 1.10 (95% CI 0.89 –1.36; P ⫽ .38) and for calcium alone the relative risk was 0.90 (95% CI 0.80 –1.00). In both studies, fractures rates were reduced when combination therapy was provided: RR 0.082 (95% CI 0.71– 0.94; P ⫽ .0005)228 and RR 0.88 (95% CI 0.83– 0.95; P ⫽ .0004).227 REFERENCES 1. Messinger-Rapport BJ, Morley JE, Thomas DR, Gammack JK. Intensive Session: New approaches to medical issues in long-term care. J Am Med Dir Assoc 2007;8:421– 433. 2. Morley JE. Weight loss in the nursing home. J Am Med Dir Assoc 2007;8:201–204. 3. Aoyama L, Weintraub N, Reuben DB. Is weight loss in the nursing home a reversible problem? J Am Med Dir Assoc 2006;7:S66 –S72. 4. Kalantar-Zadeh K, Horich TB, Oreopoulos A, et al. Risk factor paradox in wasting diseases. Curr Opin Nutr Metab Care 2007;10:433– 442. 5. Morley JE, Thomas DR, Wilson MM. Cachexia: Pathophysiology and clinical relevance. Am J Clin Nutr 2006;83:735–743. 6. Morley JE, Thomas DR. Cachexia: New advances in the management of wasting diseases. J Am Med Dir Assoc 2008;9:205–210. 7. Morley JE, Perry HM 3rd, Miller DK. Editorial: Something about frailty. J Gerontol A Biol Sci Med Sci 2002;57:M698 –M704. 8. Bergman H, Ferrucci L, Guralnik J, et al. Frailty: An emerging research and clinical paradigm-issues and controversies. J Gerontol A Biol Sci Med Sci 2007;62:731–737. 9. Abellan van Kan G, Rolland YM, Morley JE, Vellas B. Frailty: Toward a clinical definition. J Am Med Dir Assoc 2008;9:71–72. 10. Fried LP, Ferrucci L, Darer J, et al. Untangling the concepts of disability, frailty, and comorbidity: Implications for improved targeting and care. J Gerontol A Biol Sci Med Sci 2004;59:255–263. 11. Rockwood K, Abeysundera MJ, Mitnitski A. How should we grade frailty in nursing home patients? J Am Med Dir Assoc 2007;8:595– 603. 12. Aggellan van Kan G, Rolland Y, Bergman H, et al. The I.A.N.A. Task Force on frailty assessment of older people in clinical practice. J Nutr Health Aging 2008;12:29 –37. 13. Morley JE, Kim MJ, Haren MT, et al. Frailty and the aging male. Aging Male 2005;8:135–140. 14. Bartali B, Frongillo EA, Bandinelli S, et al. Low nutrient intake is an essential component of frailty in older persons. J Gerontol A Biol Sci Med Sci 2006;61:589 –593. 15. Semba RD, Bartali B, Zhou J, et al. Low serum micronutrient concentrations predict frailty among older women living in the community. J Gerontol A Biol Sci Med Sci 2006;61:594 –599. 16. Khaw KT, Wareham N, Bingham S, et al. Combined impact of health behaviours and mortality in men and women: The EPIC-Norfolk prospective population study. PLoS Med 2008;5:e12. 17. Morley JE. Weight loss in older persons: New therapeutic approaches. Curr Pharm Des 2007;13:3637–3647. 18. Morley JE, Silver AJ. Nutritional issues in nursing home care. Ann Intern Med 1995;123:850 – 859. 19. Wilson MM, Thomas DR, Rubenstein LZ, et al. Appetite assessment: Simple appetite questionnaire predicts weight loss in communitydwelling adults and nursing home residents. Am J Clin Nutr 2005;82: 1074 –1081. 20. Vellas B, Villars H, Abellan G, et al. Overview of the MNA—Its history and challenges. J Nutr Health Aging 2006;10:456 – 463. 21. Thakur M, Blazer DG. Depression in long-term care. J Am Med Dir Assoc 2008;9:82– 87. JAMDA – September 2008

22. Cabrera MA, Mesas AE, Garcia AR, de Andrade SM. Malnutrition and depression among community-dwelling elderly people. J Am Med Dir Assoc 2007;8:582–584. 23. Morley JE, Kraenzle D. Causes of weight loss in a community nursing home. J Am Geriatr Soc 1994;42:583–585. 24. Finucane TE, Christmas C, Leff BA. Tube feeding in dementia: How incentives undermine health care quality and patient safety. J Am Med Dir Assoc 2007;8:205–208. 25. Morley JE, Baumgartner RN, Roubenoff R, et al. Sarcopenia. J Lab Clin Med 2001;137:231–243. 26. Morley JE. Anorexia, sarcopenia and aging. Nutrition 2001;17:660 – 663. 27. Candow DG, Chilibeck PD. Effect of creatine supplementation during resistance training on muscle accretion in the elderly. J Nutr Health Aging 2007;11:185–188. 28. Nieschlag E, Swerdloff R, Behre HM, et al. Investigation, treatment and monitoring of late-onset hypogonadism in males. Aging Male 2005;8: 56 –58. 29. Wittert GA, Chapman IM, Haren MT, et al. Oral testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low-normal gonadal status. J Gerontol A BIol Sci Med Sci 2003;58:618 – 625. 30. Morley JE. Androgens and aging. Maturitas 2001;38:61–71. 31. Matsumoto AM. Andropause: Clinical implications of the decline in serum testosterone levels with aging in men. J Gerontol A Biol Sci Med Sci 2002;57:M76 –M99. 32. Yeh SS, Lovitt S, Schuster MW. Pharmacological treatment of geriatric cachexia: Evidence and safety in perspective. J Am Med Dir Assoc 2007;8:363–377. 33. Yeh SS, Blackwood K, Schuster MW. The cytokine basis of cachexia and its treatment: Are they ready for prime time? J Am Med Dir Assoc 2008;9:219 –236. 34. Thomas DR, Cote TR, Lawhorne L, et al. Understanding clinical dehydration and its treatments. J Am Med Dir Assoc 2008;9:292–301. 35. Crecelius C. Dehydration: Myth and reality. J Am Med Dir Assoc 2008;9:287–288. 36. Miller M, Morley JE, Rubenstein LZ. Hyponatremia in a nursing home population. J Am Geriatr Soc 1995;43:1410 –1413. 37. Kakor P, Watson T, Lip GYH. New approaches to therapy with omega-3 fatty acids. Curr Atherosclerosis Reports 2008;10:79 – 87. 38. Kromhout D, Bosschieter EB, de Lezenne Coulander C. The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med 2985;312:1205–1209. 39. Kromhout D, Feskens EJ, Bowles CH. The protective effect of a small amount of fish on coronary heart disease mortality in an elderly population. Int J Epidemiol 1995;24:341–345. 40. Simon JA, Fong J, Bernert JT Jr, Browner WS. Serum fatty acids and the risk of stroke. Stroke 1995;26:778 –782. 41. Zhang J, Sasaki S, Amano K, Kestleloot H. Fish consumption and mortality from all causes, ischemic heart disease, and stroke: An ecological study. Prev Med 1999;28:520 –529. 42. Hu FB, Bronner L, Willett WC, et al. Fish and omega-3 fatty acid intake and risk of coronary heart disease in women. JAMA 2002;287: 1815–1821. 43. Yokoyama M, Origasa H, JELIS Investigators. Effects of eicosapentaenoic acid on cardiovascular events in Japanese patients with hypercholesterolemia: rationale, design, and baseline characteristics of the Japan EPA Lipid Intervention Study (JELIS). Am Heart J 2003;146: 613– 620. 44. Marchioli R, Barzi F, Bomba E, et al. GISSI-Prevenzione Investigators: Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: Time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione. Circulation 2002;105:1897–1903. 45. Barr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: Diet and reinfarction Trial (DART). Lancet 1989;2:757–761. UPDATES FROM THE AMDA MEETING

46. Singh RB, Niaz MA, Sharma JP, et al. Randomized double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: The Indian experiment of infarct survival-4. Cardiovasc Drugs Ther 1997;11:485– 491. 47. Freund-Levi Y, Eriksdotter-Jonhagen M, Cederholm T, et al. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegaAD study: A randomized double-blind trial. Arch Neurol 2006;63:1402–1408. 48. Flaherty JH, Rudolph J, Shay K, et al. Delirium is a serious and under-recognized problem: why assessment of mental status should be the sixth vital sign. J Am Med Dir Assoc 2007;8:273–275. 49. Eeles E, Rockwood K. Delirium in the long-term care setting: Clinical and research challenges. J Am Med Dir Assoc 2008;9:157–161. 50. Lyons WL. Delirium in postacute and long-term care. J Am Med Dir Assoc 2006;7:254 –261. 51. Espino DV, Jules-Bradley AC, Johnston CL, Mouton CP. Diagnostic approach to the confused elderly patient. Am Fam Physician 1998;57: 1358 –1366. 52. Lee J, Monette J, Sourial N, et al. The use of a cholinesterase inhibitor review committee in long-term care. J Am Med Dir Assoc 2007;8:243– 247. 53. Morley JE. Managing persons with dementia in the nursing home: High touch trumps high tech. J Am Med Dir Assoc 2008;9:139 –146. 54. Banks WA, Morley JE. Memories are made of this: Recent advances in understanding cognitive impairments and dementia. J Gerontol A Biol Sci Med Sci 2003;58:314 –321. 55. Belgeri M, Morley JE. A step back in time: Is there a place for older drugs in the treatment of dementia? J Gerontol A Biol Sci Med Sci 2004;59:1025–1028. 56. Hui EK, Rubenstein LZ. Promoting physical activity and exercise in older adults. J Am Med Dir Assoc 2006;7:310 –314. 57. Andel R, Crowe M, Pedersen NL, et al. Physical exercise at midlife and risk of dementia three decades later: A population-based study of Swedish twins. J Gerontol A Biol Sci Med Sci 2008;63:62– 66. 58. Raina P, Santaguida P, Ismaila A, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: Evidence review for a clinical practice guideline. Ann Intern Med 2008;148:379 –397. 59. Rolland Y, Pillard F, Klapouszczak A, et al. Exercise program for nursing home residents with Alzheimer’s disease: A 1-year randomized, controlled trial. J Am Geriatr Soc 2007;55:158 –165. 60. Heyn PC, Johnson KE, Kramer AF. Endurance and strength training outcomes on cognitively impaired and cognitively intact older adults: a meta-analysis. J Nutr Health Aging 2008;12:401– 409. 61. Williams CL, Tappen RM. Exercise training for depressed older adults with Alzheimer’s disease. Aging Ment Health 2008;12:72– 80. 62. Volicer L, Simard J, Pupa JH, et al. Effects of continuous activity programming on behavioral symptoms of dementia. J Am Med Dir Assoc 2006;7:426 – 431. 63. Resnick HE, Heineman J, Stone R, Shorr RI. Diabetes in U.S. Nursing homes, 2004. Diabetes Care 2008;31:287–288. 64. Morley JE. Diabetes mellitus: a major disease of older persons. J Gerontol A Biol Sci Med Sci 2000;55:M255–M256. 65. Rodriguez-Saldana J, Morley JE, Reynoso MT, et al. Diabetes mellitus in a subgroup of older Mexicans: Prevalence, association with cardiovascular risk factors, functional and cognitive impairment, and mortality. J Am Geriatr Soc 2002;50:111–116. 66. Miller DK, Lui LY, Perry HM 3rd, et al. Reported and measured physical functioning in older inner-city diabetic African Americans. J Gerontol A Biol Sci Med Sci 1999;54:M230 –M236. 67. Morley GK, Mooradian AD, Levine AS, Morley JE. Mechanism of pain in diabetic peripheral neuropathy. Effect of glucose on pain perception in humans. Am J Med 1984;77:79 – 82. 68. Kim MJ, Rolland Y, Cepeda O, et al. Diabetes mellitus in older men. Aging Male 2006;9:139 –147. 69. Mooradian AD, Morley JE. Micronutrient status in diabetes mellitus. Am J Clin Nutr 1987;45:877– 895. 70. Morley JE. An overview of diabetes mellitus in older persons. Clin Geriatr Med 1999;15:211–224. Messinger-Rapport et al 471

71. Morley JE. The elderly Type 2 diabetic patient: Special considerations. Diabet Med 1998;15:S41–S46. 72. Morley JE. Falls—where do we stand? Mo Med 2007;104:63– 67. 73. Grodstein F, Chen J, Wilson RS, Manson JE. Nurses’ Health Study. Type 2 diabetes and cognitive function in community-dwelling elderly women. Diabetes Care 2001;24:1060 –1065. 74. Ziegler D. Treatment of diabetic neuropathy and neuropathic pain: How far have we come? Diabetes Care 2008;31:S255–S261. 75. Ziegler D, Hanefeld M, Ruhnau KJ, et al. Treatment of symptomatic diabetic peripheral neuropathy with the antioxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia 1994;38:1425–1433. 76. Jin HY, Joung SJ, Park JH, et al. The effect of alpha-lipoic acid on symptoms and skin blood flow in diabetic neuropathy. Diabet Med 2007;24:1034 –1038. 77. Donofrio PD, Raskin P, Rosenthal NR, et al. Safety and effectiveness of topiramate for the management of painful diabetic peripheral neuropathy in an open-label extension study. Clin Ther 2005;27:1420 –1431. 78. Mascitelli L, Pezzetta F. Diabetes and osteoporotic fractures. CMAJ 2007;177:1391–1392. 79. Strotmeyer ES, Cauley JA. Diabetes mellitus, bone mineral density, and fracture risk. Curr Opin Endocrinol Diabetes Obes 2007;14:429 – 435. 80. Patel S, Hyer S, Tweed K, et al. Risk factors and falls in older women with type 2 diabetes mellitus. Calcif Tissue Int 2008;82:87–91. 81. Epstein S, Leroith D. Diabetes and fragility fractures—a burgeoning epidemic? Bone 2008;43:3– 6. 82. Nelson JM, Dufraux K, Cook PF. The relationship between glycemic control and falls in older adults. J Am Geriatr Soc 2007;55:2041–2044. 83. Berlowitz DR, Brandeis GH, Morris JN, et al. Deriving a risk-adjustment model for pressure ulcer development using the Minimum Data Set. J Am Geriatr Soc 2001;49:866 – 871. 84. Brandeis GH, Ooi WL, Hossain M, et al. A longitudinal study of risk factors associated with the formation of pressure ulcers in nursing homes. J Am Geriatr Soc 1994;42:388 –393. 85. Spector WD. Correlates of pressure sores in nursing homes: Evidence from the National Medical Expenditure Survey. J Invest Dermatol 1994;102:42S– 45S. 86. Rosenthal MJ, Fajardo M, Gilmore S, et al. Hospitalization and mortality of diabetes in older adults. A 3-year prospective study. Diabetes Care 1998;21:231–235. 87. Meyers RM, Broton JC, Woo-Rippe KW, et al. Variability in glycosylated hemoglobin values in diabetic patients living in long-term care facilities. J Am Med Dir Assoc 2007;8:511–514. 88. Joseph J, Koka M, Aronow WS. Prevalence of hemoglobin A1C less than 7.0%, of a blood pressure less than 130/80 mm Hg, and of a serum low-density lipoprotein cholesterol less than 100 mg/dL in older patients with diabetes mellitus in an academic nursing home. J Am Med Dir Assoc 2008;9:51–54. 89. Rizvi AA. Management of diabetes in older adults. Am J Med Sci 2007;333:35– 47. 90. Holt RM, Schwartz FL, Fhubrook JH. Diabetes care in extended-care facilities: Appropriate intensity of care? Diabetes Care 1007;30:1454 – 1458. 91. Haas LB. Optimizing insulin use in type 2 diabetes: Role of basal and prandial insulin in long-term care facilities. J Am Med Dir Assoc 2007;8:502–510. 92. Mazza AD, Morley JE. Update on diabetes in the elderly and the application of current therapeutics. J Am Med Dir Assoc 2007;8:489 – 492. 93. Zarowitz BJ, Tangalos EG, Hollenack K, O’Shea T. The application of evidence-based principles of care in older persons (issue 3): Management of diabetes mellitus. J Am Med Dir Assoc 2006;7:234 –240. 94. Colberg SR, Somma CT, Sechrist SR. Physical activity participation may offset some of the negative impact of diabetes on cognitive function. J Am Med Dir Assoc 2008;9:434 – 438. 95. Wedick NM, Barrett-Connor E, Knoke JD, Wingard DL. The relationship between weight loss and all-cause mortality in older men and women with and without diabetes mellitus: The Rancho Bernardo study. J Am Geriatr Soc 2002;50:1810 –1815. 472 Messinger-Rapport et al

96. Tariq SH, Karcic E, Thomas DR, et al. The use of a no-concentratedsweets diet in the management of type 2 diabetes in nursing homes. J Am Diet Assoc 2001;101:1463–1466. 97. Coulston AM, Mandelbaum D, Reaven GM. Dietary management of nursing home residents with non-insulin-dependent diabetes mellitus. Am J Clin Nutr 1990;51:67–71. 98. Parkner T, Laursen T, Vestergaard ET, et al. Insulin and glucose profiles during continuous subcutaneous insulin infusion compared with injection of a long-acting insulin in Type 2 diabetes. Diabet Med 2008;25: 585–591. 99. Schiel R, Muller UA. Efficacy and treatment satisfaction of once-daily insulin glargine plus one or two oral antidiabetic agents versus continuing premixed human insulin in patients with type 2 diabetes previously on long-term conventional insulin therapy: The Switch pilot study. Exp Clin Endocrinol Diabetes 2007;115:627– 633. 100. Fulcher GR, Gilbert RE, Yue DK. Glargine is superior to neutral protamine Hagedorn for improving glycated haemoglobin and fasting blood glucose levels during intensive insulin therapy. Intern Med J 2005;35:536 –542. 101. Diabetes Prevention Program Research Group, Crandall J, Schade D, et al. The influence of age on the effects of lifestyle modification and metformin in prevention of diabetes. J Gerontol A Biol Sci Med Sci 2006;61:1075–1081. 102. Lee A, Morley JE. Metformin decreases food consumption and induces weight loss in subjects with obesity with type II non-insulin-dependent diabetes. Obes Res 1998;6:47–53. 103. Kumar VB, Bernardo AE, Vyas K, et al. Effect of metformin on nitric oxide synthase in genetically obese (ob/ob) mice. Life Sci 2001;69: 2789 –2799. 104. Lipscombe LL, Gomes T, Levesque LE, et al. Thiazolidinediones and cardiovascular outcomes in older patients with diabetes. JAMA 2007; 298:2634 –2643. 105. Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: A meta-analysis. JAMA 2007;298:1189 –1195. 106. Meier C, Kraenzlin ME, Bodmer M, et al. Use of thiazolidinediones and fracture risk. Arch Intern Med 2008;168:820 – 825. 107. Benvenuti S, Cellai I, Luciani P, et al. Rosiglitazone stimulates adipogenesis and decreases osteoblastogenesis in human mesenchymal stem cells. J Endocrinol Invest 2007;30:RC26 –30. 108. Lee A, Patrick P, Wishart J, et al. The effects of miglitol on glucagonlike peptide-1 secretion and appetite sensations in obese type 2 diabetics. Diabetes Obes Metab 2002;4:329 –335. 109. van de Laar FA, Lucassen PL, Akkermans RP, et al. Alpha-glucosidase inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev 2005;18:CD003639. 110. Morley JE. Postprandial hypotension—the ultimate Big Mac attack. J Gerontol A Biol Sci Med Sci 2001;56:M744 –M748. 111. Morley JE. The aging gut: Physiology. Clin Geriatr Med 2007;23:757– 767. 112. Fisher AA, Davis MW, Srikusalanukul W, Budge MM. Postprandial hypotension predicts all-cause mortality in older, low-level care residents. J Am Geriatr Soc 2005;53:1313–1320. 113. Edwards BJ, Perry HM 3rd, Kaiser FE, et al. Relationship of age and calcitonin gene-related peptide to postprandial hypotension. Mech Ageing Dev 1996;87:61–73. 114. Shibao C, Gamboa A, Diedrich A, et al. Acarbose, an alpha-glucosidase inhibitor, attenuates postprandial hypotension in autonomic failure. Hypertension 2007;50:54 – 61. 115. Gentilcore D, Bryant B, Wishart JM, et al. Acarbose attenuates the hypotensive response to sucrose and slows gastric emptying in the elderly. Am J Med 2005;118:1289. 116. Sasaki E, Goda K, Nagata K, et al. Acarbose improved severe postprandial hypotension in a patient with diabetes mellitus. J Diabetes Complications 2001;15:158 –161. 117. Pham DQ, Nogid A, Plakogiannis R. Sitagliptin: A novel agent for the management of type 2 diabetes mellitus. Am J Health Syst Pharm 2008;65:521–531. JAMDA – September 2008

118. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008;358:580 –591. 119. American Diabetes Association. Statement from the American Diabetes Association related to the ADVANCE Study Announcement. Available at: http://www.diabetes.org/for-media/pr-statement-advancestudy-021308.jsp. Accessed May 21, 2008. 120. American Diabetes Association. Statement from the American Diabetes Association related to the ACCORD Trial Announcement. Available at: http://www.diabetes.org/for-media/pr-ada-statement-related-toaccord-trail-announcement-020608.jsp. Accessed May 21, 2008. 121. Negoro H, Morley JE, Rosenthal MJ. Utility of serum fructosamine as a measure of glycemia in young and old diabetic and non-diabetic subjects. Am J Med 1988;85:360 –364. 122. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285(19):2486 –2497. 123. Grundy SM, Cleeman JI, Merz CNB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004;110(2):227–239. 124. American Diabetes Association. Standards of medical care in diabetes— 2008. Diabetes Care 2008;31:S12–54. 125. Afilalo J, Duque G, Steele R, et al. Statins for secondary prevention in elderly patients. J Am Coll Cardiol 2008;51:37– 45. 126. Young-Xu Y, Jabbour S, Goldberg R, et al. Usefulness of statin drugs in protecting against atrial fibrillation in patients with coronary artery disease. Am J Cardiol 2003;92:1379 –1383. 127. Kjekshus J, Pedersen T, Olsson A, et al. The effects of simvastatin on the incidence of heart failure in patients with coronary heart disease. J Card Fail 1997;3:249 –254. 128. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): A randomised controlled trial. Lancet 2002;360:1623–1630. 129. Allen Maycock CA, Muhlestein JB, Horne BD, et al. Statin therapy is associated with reduced mortality across all age groups of individuals with significant coronary disease, including very elderly patients. J Am Coll Cardiol 2002;40(10):1777–1785. 130. Kashani A, Phillips CO, Foody JM, et al. Risks associated with statin therapy: A systematic overview of randomized clinical trials. Circulation 2006;114(25):2788 –2797. 131. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: Prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267– 1278. 132. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425–1435. 133. Waters DD, LaRosa JC, Barter P, et al. Effects of high-dose atorvastatin on cerebrovascular events in patients with stable coronary disease in the TNT (treating to new targets) study. J Am Coll Cardiol 2006;48:1793– 1799. 134. Serruys PWJC, de Feyter P, Macaya C, et al. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: A randomized controlled trial. JAMA 2002;287:3215–3222. 135. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383– 1389. 136. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005;352:20 –28. 137. Kastelein JJP, Akdim F, Stroes ESG, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358: 1431–1443. 138. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: Long-term benefit with niacin. J Am Coll Cardiol 1986;8:1245–1255. UPDATES FROM THE AMDA MEETING

139. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): Randomised controlled trial. Lancet 2005; 366:1849 –1861. 140. Ginsberg H, Bonds D, Lovato L, et al. Evolution of the Lipid Trial Protocol of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial. Am J Cardiol 2007;99:S56 –S67. 141. Bays H. Effects of colesevelam hydrochloride on low-density lipoprotein cholesterol and high-sensitivity C-reactive protein when added to statins in patients with hypercholesterolemia. Am J Cardiol 2006;97: 1198 –1205. 142. Mozaffarian D, Rimm EB. Fish intake, contaminants, and human health: Evaluating the risks and the benefits. JAMA 2006;296:1885– 1899. 143. Wang C, Harris WS, Chung M, et al. n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: A systematic review. Am J Clin Nutr 2006;84:5–17. 144. Hooper L, Thompson RL, Harrison RA, et al. Omega 3 fatty acids for prevention and treatment of cardiovascular disease. Cochrane Database Syst Rev 2004;(4):CD003177. 145. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): A randomised open-label, blinded endpoint analysis. Lancet 2007;369:1090 –1098. 146. Krishna R, Anderson MS, Bergman AJ, et al. Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: Two double-blind, randomised placebo-controlled phase I studies. Lancet 2007;370:1907–1914. 147. Roberts CG, Guallar E, Rodriguez A. Efficacy and safety of statin monotherapy in older adults: A meta-analysis. J Gerontol A Biol Sci Med Sci 2007;62:879 – 887. 148. Nybo H, Petersen HC, Gaist D, et al. Predictors of mortality in 2,249 nonagenarians—the Danish 1905-Cohort Survey. J Am Geriatr Soc 2003;51:1365–1373. 149. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report. JAMA 2003; 289:2560 –2571. 150. Lip GY, Lip PL, Zarifis J, et al. Fibrin D-dimer and beta-thromboglobulin as markers of thrombogenesis and platelet activation in atrial fibrillation. Effects of introducing ultra-low-dose warfarin and aspirin [see comments]. Circulation 1996;94:425– 431. 151. Anonymous. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA 1991;265:3255–3264. 152. Staessen JA, Fagard R, Thijs L, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 1997;350:757–764. 153. Bulpitt C, Fletcher A, Beckett N, et al. Hypertension in the Very Elderly Trial (HYVET): Protocol for the main trial. Drugs Aging 2001;18:151–164. 154. Bulpitt CJ, Beckett NS, Cooke J, et al. Results of the pilot study for the Hypertension in the Very Elderly Trial. J Hypertens 2003;21:2409 – 2417. 155. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008;358:1887– 1898. 156. Forette F, Seux ML, Staessen JA, et al. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet 1998;352:1347–1351. 157. van Dijk EJ, Breteler MM, Schmidt R, et al. The association between blood pressure, hypertension, and cerebral white matter lesions: Cardiovascular determinants of dementia study. Hypertension 2004;44: 625– 630. Messinger-Rapport et al 473

158. Dufouil C, Chalmers J, Coskun O, et al. Effects of blood pressure lowering on cerebral white matter hyperintensities in patients with stroke: The PROGRESS (Perindopril Protection Against Recurrent Stroke Study) Magnetic Resonance Imaging Substudy. Circulation 2005;112:1644 –1650. 159. Soderlund H, Nilsson LG, Berger K, et al. Cerebral changes on MRI and cognitive function: The CASCADE study. Neurobiol Aging 2006;27: 16 –23. 160. Steffens DC, Potter GG, McQuoid DR, et al. Longitudinal magnetic resonance imaging vascular changes, apolipoprotein E genotype, and development of dementia in the neurocognitive outcomes of depression in the elderly study. Am J Geriatr Psychiatry 2007;15:839 – 849. 161. Tzourio C. Vascular factors and cognition: Toward a prevention of dementia? J Hypertens Supplement 2003;21:S15–19. 162. Sumukadas D, Witham MD, Struthers AD, McMurdo ME. Effect of perindopril on physical function in elderly people with functional impairment: A randomized controlled trial. CMAJ 2007;177:867– 874. 163. Fagard RH, Staessen JA, Thijs L, et al. Response to antihypertensive therapy in older patients with sustained and nonsustained systolic hypertension. Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Circulation 2000;102:1139 –1144. 164. Somes G, Pahor M, Shorr R, et al. The role of diastolic blood pressure when treating isolated systolic hypertension. Arch of Intern Med 1999; 159:2004 –2009. 165. Fagard RH, Staessen JA, Thijs L, et al. On-treatment diastolic blood pressure and prognosis in systolic hypertension. Arch Intern Med 2007; 167:1884 –1891. 166. Fletcher AE, Bulpitt CJ, Thijs L, et al. Quality of life on randomized treatment for isolated systolic hypertension: Results from the Syst-Eur Trial. J Hypertens 2002;20:2069 –2079. 167. ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2000;283:1967–1975. 168. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981–2997. 169. Messerli FH, Grossman E, Goldbourt U. Are beta-blockers efficacious as first-line therapy for hypertension in the elderly? A systematic review. JAMA 1998;279:1903–1907. 170. Golomb BA, Dimsdale JE, White HL, et al. Reduction in blood pressure with statins: Results from the UCSD Statin Study, a randomized trial. Arch Intern Med 2008;168:721–727. 171. Strandberg TE, Pitkala KH, Berglind S, et al. Multifactorial intervention to prevent recurrent cardiovascular events in patients 75 years or older: The Drugs and Evidence-Based Medicine in the Elderly (DEBATE) study: A randomized, controlled trial. Am Heart J 2006; 152:585–592. 172. Flaherty JH, Morley JE, Murphy DJ, Wasserman MR. The development of outpatient Clinical Glidepaths. J Am Geriatr Soc 2002;50:1886 – 1901. 173. Morley JE. Caring for the vulnerable elderly: Are available quality indicators appropriate. J Am Med Dir Assoc 2008;9:1–3. 174. Levenson SA, Morley JE. Evidence rocks in long-term care, but does it roll? J Am Med Dir Assoc 2007;8:493–501. 175. Koka M, Joseph J, Aronow WS. Adequacy of control of hypertension in an academic nursing home. J Am Med Dir Assoc 2007;8:538 –540. 176. Aronow WS. Drug therapy of older persons with hypertension. J Am Med Dir Assoc 2006;7:193–196. 177. Joseph J, Koka M, Aronow WS. Prevalence of use of antiplatelet drugs, beta blockers, statins, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in older patients with coronary artery disease in an academic nursing home. J Am Med Dir Assoc 2008;9: 124 –127. 474 Messinger-Rapport et al

178. Joseph J, Koka M, Aronow WS. Prevalence of a hemoglobin A1C less than 7.0%, of a blood pressure less than 130/80 mm Hg, and of a serum low-density lipoprotein cholesterol less than 10 mg/dL in older patients with diabetes mellitus in an academic nursing home. J Am Med Dir Assoc 2008;9:51–54. 179. Koka M, Joseph J, Aronow WS. Prevalence of adequate and of optimal control of serum low-density lipoprotein cholesterol in an academic nursing home. J Am Med Dir Assoc 2007;8:604 – 606. 180. Roberts CG, Guallar E, Rodriquez A. Efficacy and safety of statin monotherapy in older adults: a meta-analysis. J Gerontol A Biol Sci Med Sci 2007;62:879 – 887. 181. Thomas DR. Management of pressure ulcers. J Am Med Dir Assoc 2006;7:46 –59. 182. Lynn J, West J, Hausmann S, et al. Collaborative clinical quality improvement for pressure ulcers in nursing homes. J Am Geriatr Soc 2007;55:1663–1669. 183. Berlowitz DR, Brienza DM. Are all pressure ulcers the result of deep tissue injury? A review of the literature. Ostomy Wound Manage 2007;53:34 –38. 184. Black J, Baharestani M, Cuddigan J, et al. National Pressure Ulcer Advisory Panel’s updated pressure ulcer staging system. Dermatol Nurs 2007;19:343–349. 185. Quintavalle PR, Lyder CH, Mertz PJ, et al. Use of high-resolution, high-frequency diagnostic ultrasound to investigate the pathogenesis of pressure ulcer development. Adv Skin Wound Care 2006;19:498 –505. 186. Thomas DR. The new F-tag 314: Prevention and management of pressure ulcers. J Am Med Dir Assoc 2006;7:523–531. 187. Thomas DR, Osterweil D. Is a pressure ulcer a marker for quality of care? J Am Med Dir Assoc 2005;6:228 –229. 188. Abel RL, Warren K, Bean G, et al. Quality improvement in nursing homes in Texas: Results from a pressure ulcer prevention project. J Am Med Dir Assoc 2005;6:181–188. 189. Reddy M, Gill SS, Rochon PA. Preventing pressure ulcers: A systematic review. JAMA 2006;296:974 –984. 190. Bourdel-Marchasson I, Barateau M, Rondeau V, et al. A multi-center trial of the effects of oral nutritional supplementation in critically ill older inpatients. GAGE Group. Groupe Aquitain Geriatrique d’Evaluation. Nutrition 2000;16(1):1–5. 191. Defloor T, Grypdonck MF. Validation of pressure ulcer risk assessment scales: A critique. J Adv Nurs 2004;48:613– 621. 192. Vanderwee K, Grypdonck M, Defloor T, et al. Non-blanchable erythema as an indicator for the need for pressure ulcer prevention: a randomized-controlled trial. J Clin Nurs 2007;16:325–335. 193. DeFloor T, De Bacquer D, Grypdonck MH, et al. The effect of various combinations of turning and pressure reducing devices on the incidence of pressure ulcers. Int J Nurs Stud 2005;42:37– 46. 194. Vanderwee K, Grypdonck MH, De Bacquer D, Defloor T, et al. Effectiveness of turning with unequal time intervals on the incidence of pressure ulcer lesions. J Adv Nurs 2006;57:59 – 68. 195. Thomas DR. Physicians Information Education Resource, American College of Physicians. Available at: www.acponline.org/clinical_ information/journals_publications/acp_internist/jul-aug07/special.htm. Accessed August 4, 2008. 196. Bouza C, Saz Z, Munoz A, Amate J. Efficacy of advanced dressings in the treatment of pressure ulcers: A systematic review. J Wound Care 2005;14:193. 197. Jones KR, Fennie K. Factors influencing pressure ulcer healing in adults over 50: An exploratory study. J Am Med Dir Assoc 2007;8:378 –387. 198. Thomas DR. Managing pressure ulcers: Learning to give up cherished dogma. J Am Med Dir Assoc 2007;8:347–348. 199. Petty TL. COPD in perspective. Chest 2002;121:116S–120S. 200. Barnes PJ. New therapies for chronic obstructive pulmonary disease. Thorax 1998;53:137–147. 201. Vestbo J, Hogg JC. Convergence of the epidemiology and pathology of COPD. Thorax 2006;61:86 – 88. 202. Anthonisen NR, Connett JE, Murray RP. Smoking and lung function of Lung Health Study participants after 11 years. Am J Respir Crit Care Med 2002;166:675– 679. JAMDA – September 2008

203. Barr RG, Bourbeau J, Camargo CA, Ram FS. Inhaled tiotropium for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2005;(2):CD002876. 204. Brusasco V, Hodder R, Miravitlles M, et al. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax 2003;58:399 – 404. 205. Sin DD, McAlister FA, Man SF, Anthonisen NR. Contemporary management of chronic obstructive pulmonary disease: Scientific review. JAMA 2003;290:2301–2312. 206. Groenewegen KH, Schols AM, Wouters EF. Mortality and mortalityrelated factors after hospitalization for acute exacerbation of COPD. Chest 2003;124:459 – 467. 207. Sapey E, Stockley RA. COPD exacerbations. 2: Aetiology. Thorax 2006;61:250 –258. 208. Murphy TF, Brauer AL, Schiffmacher AT, Sethi S. Persistent colonization by Haemophilus influenzae in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;170:266 –272. 209. O’Driscoll BR, Kay EA, Taylor RJ, et al. A long-term prospective assessment of home nebulizer treatment. Respir Med 1992;86: 317–325. 210. Calverley P, Pauwels R, Vestbo J, et al. Trial of inhaled steroids and long-acting beta2 agonists study group. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: A randomised controlled trial. Lancet 2003;361:449 – 456. 211. Burge PS, Calverley PM, Jones PW, et al. Prednisolone response in patients with chronic obstructive pulmonary disease: Results from the ISOLDE study. Thorax 2003;58:654 – 658. 212. Decramer M, Gosselink R, Bartsch P, et al. Effect of treatments on the progression of COPD: Report of a workshop held in Leuven, 11–12 March 2004. Thorax 2005;60:343– 649. 213. Kamel HK, Hussain MS, Tariq S, et al. Failure to diagnose and treat osteoporosis in elderly patients hospitalized with hip fracture. Am J Med 2000;109:326 –328. 214. Gloth FM, Simonson W. Osteoporosis is underdiagnosed in skilled nursing facilities: A large-scale heel BMD screening study. J Am Med Dir Assoc 2008;9:190 –193. 215. Zylstra RG, Porter LL, Shapiro JL, Prater CD. Prevalence of osteoporosis in community-dwelling individuals with intellectual and/or developmental disabilities. J Am Med Dir Assoc 2008;9:109 –113. 216. Wright RM. Use of osteoporosis medications in older nursing facility residents. J Am Med Dir Assoc 2007;8:453– 457.

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217. Kamel HK. Update on osteoporosis management in long-term care: Focus on bisphosphonates. J Am Med Dir Assoc 2007;8:434 – 440. 218. Duque G. To treat or not to treat, that is the question: Proceedings of the Quebec Symposium for the Treatment of Osteoporosis in LongTerm Care Institutions, Saint-Hyacinthe, Quebec, November 5, 2004. J Am Med Dir Assoc 2007;8:e67– e73. 219. Zarowitz BJ, Stefanacci R, Hollenack K, O’Shea T. The application of evidence-based principles of care in older persons (issue 1): Management of osteoporosis. J Am Med Dir Assoc 2007;8:e51– e57. 220. MacLean C, Newberry S, Maglione M, et al. Systematic review: Comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis. Ann Intern Med 2008; 148:197–213. 221. Sawka AM, Papaioannou A, Adachi JD, et al. Does alendronate reduce the risk of fracture in men? A meta-analysis incorporating prior knowledge of anti-fracture efficacy in women. BMC Musculoskelet Disord 2005;6:39. 222. Greenspan SL, Nelson JB, Trump DL, Resnick NM. Effect of onceweekly oral alendronate on bone loss in men receiving androgen deprivation therapy for prostate cancer: A randomized trial. Ann Intern Med 2007;146:416 – 424. 223. Black DM, Delmas PD, Eastell R, et al. HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis.N Engl J Med 2007;356:1809 –1822. 224. Lyles KW, Colon-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007; 357:1799 – 809. 225. Saag KG, Shane E, Boonen S, et al. Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N Engl J Med 2007;357:2028–2039. 226. Vestergaard P, Jorgensen NR, Mosekilde L, Schwarz P. Effects of parathyroid hormone alone or in combination with antiresorptive therapy on bone mineral density and fracture risk—a meta-analysis. Osteoporos Int 2007;18:45–57. 227. Tang BM, Eslick GD, Nowson C, et al. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: A meta-analysis. Lancet 2007;370:657– 666. 228. Boonen S, Lips P, Bouillon R, et al. Need for additional calcium to reduce the risk of hip fracture with vitamin D supplementation: Evidence from a comparative metaanalysis of randomized controlled trials. J Clin Endocrinol Metab 2007;92:1415–1423.

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