"Longer scales are used in specialist settings," Dr. Nicholl notes, "but the test is not designed to replace these."

Transcription

1 From MedscapeCME Clinical Briefs New Test May Detect Early Alzheimer's Disease CME News Author: Allison Gandey CME Author: Laurie Barclay, MD CME Released: 06/22/2009; Valid for credit through 06/22/2010 June 22, 2009 Researchers have developed a new cognitive test that is quick to use, examines 10 skills, and reportedly detects 93% of cases of Alzheimer's disease. Published online June 10 in BMJ, investigators suggest the new self-administered test is a powerful and valid screening tool. "If a patient completes the test while in the waiting area supervised by the receptionist, it can be scored and analyzed by the doctor in 2 minutes," explain the researchers, led by Jeremy Brown, MD, from Addenbrooke's Hospital, in Cambridge, the United Kingdom. "If there is time during the consultation to observe the patients filling in the test, this can also be a useful aid to diagnosis." Dr. Brown is a neurologist, but his team found that with 10 minutes' training and a scoring sheet, a nurse without experience working in memory clinics was able to evaluate the test as accurately as a specialist. In an accompanying editorial, Claire Nicholl, MD, also at Addenbrooke s Hospital, pointed out that the study showed that the new test was more sensitive than the Mini-Mental State Examination (MMSE) in this patient population (93% vs 52%). More Sensitive Than Mini-Mental State Examination "Longer scales are used in specialist settings," Dr. Nicholl notes, "but the test is not designed to replace these." In this cross-sectional study, investigators evaluated subjects from 3 hospitals including a memory clinic. They looked at 540 control participants and 139 patients with dementia or amnesic mild cognitive impairment. In the diagnosis of early Alzheimer's disease with a cut-off point of <42/50, the test had good sensitivity (93%), specificity (86%), and interrater reliability. The test requires participants to write 10 answers on a double-sided card. The requested tasks evaluate a range of areas, including the patient's semantic knowledge, ability to calculate and name objects, and recall. "If the memory test is to be adopted more widely, it must be validated in a range of settings and different populations," Dr. Nicholl writes. "Until then, the most important message is that clinicians should identify a test that suits their clinical setting, use it to screen or case find as appropriate, and develop experience in its use to improve the identification of patients with early dementia." Must Be Validated Dr. Nicholl points out that the authors do not comment on the ethnicity of the study participants, but the local population is mainly white and some of the items on the test likely show some cultural bias. Elizabeth Gould, director of quality care programs at the Alzheimer's Association, echoed similar concerns to Medscape Neurology. Speaking during a recent interview, she emphasized the importance of taking cultural differences into account as much as possible. She also stressed the importance of early detection. A Web site is being developed for clinicians to download the new test, scoring sheets, and further instructions. The researchers and editorialist have disclosed no relevant financial relationships. BMJ. 2009;338:b2030 Abstract, b1176. Abstract Clinical Context Worldwide, approximately 24 million people have dementia, and it is estimated that the prevalence will double every 20 years. The prevalence of mild cognitive impairment is even greater. Cognitive tests are useful to diagnose dementia and to evaluate functional ability, and a quick, sensitive test will be even more important once there are effective treatments of Alzheimer's disease. Currently available cognitive tests do not satisfy criteria for widespread use by nonspecialists (minimal operator time to administer, testing of a broad variety of cognitive functions, and sensitivity to mild Alzheimer's disease).

2 Study Highlights This cross-sectional study evaluated the performance of a self-administered cognitive screening test ("test your memory" [TYM]) for detection of Alzheimer's disease. The TYM was designed for quick administration and suitability for use by general practitioners. It consists of a series of 10 tasks on a double-sided sheet or card with blanks for the patient to complete. The tasks include orientation (10 points), ability to copy a sentence (2 points), semantic knowledge (3 points), calculation (4 points), verbal fluency (4 points), similarities (4 points), naming (5 points), and visuospatial abilities (2 tasks, total 7 points), Ability to complete the TYM is considered as an additional task. At the outpatient departments of 3 hospitals, 139 patients seen at a memory clinic for dementia or amnestic mild cognitive impairment and 540 control participants aged 18 to 95 years were tested with the TYM. Of the 139 patients with dementia or amnestic mild cognitive impairment, 108 had Alzheimer's disease or amnestic mild cognitive impairment, and 31 had non-alzheimer's degenerative dementias. The performance on the TYM of patients with Alzheimer's disease (n = 94) was compared vs age-matched control subjects (n = 282). Interrater reliability was excellent, determined by 3 scorers of differing backgrounds marking 100 tests. The TYM was validated against 2 standard tests, the MMSE and the Addenbrooke's cognitive examination-revised (ACE-R). Sensitivity and specificity of the TYM in the diagnosis of Alzheimer's disease were calculated. Average TYM score was 33 of 50 for patients with Alzheimer's disease vs 39 of 50 in 31 patients with non-alzheimer's dementias, 45 of 50 for patients with mild cognitive impairment, and 47 of 50 for control subjects. Control subjects completed the test in an average time of 5 minutes. The average TYM score remained constant between the ages of 18 and 70 years and decreased slightly thereafter. Men and women had similar TYM scores, as did subjects with various geographic backgrounds. Scores on the TYM score correlated well with scores on the MMSE and ACE-R. The TYM takes less time to administer than the MMSE and tests a broader range of cognitive domains. Although the ACE-R tests a similar number of cognitive domains to the TYM and is sensitive to mild Alzheimer's disease, it takes 20 minutes to administer and score. Both the TYM and the ACE-R require specially printed sheets, but a Web site is being developed to address this limitation of the TYM. Using a cutoff score of less than or equal to 42 of 50, the TYM was 93% sensitive and 86% specific in the diagnosis of Alzheimer's disease. The TYM was more sensitive in the detection of Alzheimer's disease vs the MMSE (sensitivity, 93% vs 52%). Assuming a prevalence of Alzheimer's disease of 10%, the negative predictive value of the TYM (with a cutoff point of 42) was 99%, and the positive predictive value was 42%. The investigators concluded that the TYM can be completed quickly and accurately by healthy control subjects and that it is a powerful and valid screening test for the detection of Alzheimer's disease. Clinical Implications The TYM, which tests a broad range of cognitive domains, was designed for quick administration (approximately 5 minutes for control subjects to complete) and suitability for use by nonspecialists. Interrater reliability was excellent. Score on the TYM score correlated well with score on the MMSE and ACE-R. With use of a cutoff score of less than or equal to 42 of 50, the TYM was 93% sensitive and 86% specific in the diagnosis of Alzheimer's disease. The investigators concluded that the TYM is a powerful and valid screening test for the detection of Alzheimer's disease. CME Test According to the study by Brown and colleagues, which of the following statements about test characteristics of the TYM, MMSE, and ACE-R is correct? Score on the TYM score correlated well with score on the MMSE but not on the ACE-R The TYM takes more operator time to administer than the MMSE The range of cognitive domains tested by the TYM is less than the ACE-R

3 The TYM was designed for quick administration and suitability for use by nonspecialists According to the study by Brown and colleagues, which of the following statements about the diagnostic usefulness of the TYM in the detection of Alzheimer's disease is not correct? With use of a cutoff score of less than or equal to 42 of 50, the TYM was 93% sensitive in the diagnosis of Alzheimer's disease With use of a cutoff score of less than or equal to 42 of 50, the TYM was 86% specific in the diagnosis of Alzheimer's disease Assuming a prevalence of Alzheimer's disease of 10%, the negative predictive value of the TYM (with a cutoff point of 42) was 99% Interrater reliability is poor Save and Proceed Authors and Disclosures This article is a CME certified activity. To earn credit for this activity visit: As an organization accredited by the ACCME, MedscapeCME requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines "relevant financial relationships" as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest. MedscapeCME encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content. Author(s) Allison Gandey Allison Gandey is a journalist for Medscape. She is the former science affairs analyst for the Canadian Medical Association Journal. Allison, who has a master of journalism specializing in science from Carleton University, has edited a variety of medical association publications and has worked in radio and television. She can be contacted at agandey@webmd.net. Disclosure: Allison Gandey has disclosed no relevant financial relationships. Editor(s) Brande Nicole Martin Brande Nicole Martin is the News CME editor for Medscape Medical News. Disclosure: Brande Nicole Martin has disclosed no relevant financial information. CME Author(s) Laurie Barclay, MD Laurie Barclay, MD, is a freelance writer and reviewer for Medscape. Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships. MedscapeCME Clinical Briefs 2009 MedscapeCME Disclaimer The material presented here does not necessarily reflect the views of MedscapeCME or companies that support educational programming on These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers

4 should verify all information and data before treating patients or employing any therapies described in this educational activity. Send press releases and comments to

5 From Heartwire CME No Benefit in Lowering BP Below "Standard" 140/90 mm Hg CME News Author: Lisa Nainggolan CME Author: Désirée Lie, MD, MSEd CME Released: 07/23/2009; Valid for credit through 07/23/2010 July 23, 2009 A new review has found that lowering blood pressure below the "standard" target of 140/90 mm Hg is not beneficial in terms of reducing mortality or morbidity [1]. Dr Jose Agustin Arguedas (Universidad de Costa Rica, San Pedro de Montes de Oca) and colleagues report their findings online July 8, 2009 in the Cochrane Database of Systematic Reviews. They explain that over the past five years, a trend toward lower targets has been recommended by hypertension experts who set treatment guidelines, "based on the assumption that the use of drugs to bring the BP lower than 140/90 mm Hg will reduce heart attack and stroke." But this approach "is not proven," they point out. Arguedas told heartwire that they reviewed seven trials with more than subjects comparing lower or standard diastolic BP targets, but they were unable to identify any studies comparing different systolic BP targets. "We found there is no evidence that reaching a target of below 90 mm Hg diastolic BP will provide additional clinical benefit, but we can't say whether lowering systolic BP below 140 mm Hg will be beneficial or not; there are no data." Dr Franz Messerli (St Luke Roosevelt Hospital, New York, NY), who was not involved with this review, told heartwire that there is no question that the 140/90-mm-Hg BP limit is "absolutely arbitrary, and the benefits of antihypertensive medications are most obvious in patients with the highest BP. The closer we get to 'normotension,' the more difficult it becomes to show benefits of BP lowering. "The Lewington meta-analysis of one million patients has convincingly shown that people fare better ie, have fewer strokes and heart attacks when their 'usual' BP is 115/70 mm Hg compared with those with a 'usual' BP of 130/80," Messerli adds. "However there are no data and probably never will be that lowering BP from 130/80 mm Hg to 115/70 mm Hg confers any benefits," he says. Further Review Required in at-risk Patients Attempting to achieve lower BP targets has several consequences, the researchers note; "the most obvious is the need for large doses and increased number of antihypertensive drugs. This has inconvenience and economic costs to patients. More drugs and higher doses will also increase adverse drug effects, which if serious could negate any potential benefit associated with lower BP." There is also the potential that lowering BP too much may cause adverse cardiovascular (CV) events, the so-called "J-curve" phenomenon, they observe. In their review, they included: the Modification of Diet in Renal Disease (MDRD) trial; the Hypertension Optimal Treatment (HOT) study; the BP Control in Diabetes (ABCD) trials H and N; the African American Study of Kidney Disease and Hypertension (AASK), and the Renoprotection in Patients With Nondiabetic Chronic Renal Disease (REIN-2) study. They found that, despite a 4/3-mm-Hg-greater achieved reduction in systolic/diastolic BP (p < 0.001), attempting to achieve "lower targets" instead of "standard targets" did not change: Total mortality (relative risk 0.92). Myocardial infarction (MI; RR 0.90). Stroke (RR 0.99). Congestive heart failure (RR 0.88). Major cardiovascular events (RR 0.94). End-stage renal disease (RR 1.01). "This strategy did not prolong survival or reduce stroke, heart attack, heart failure, or kidney failure," they note. "More trials are needed, but at present there is no evidence to support aiming for a blood-pressure target lower than 140/90 mm Hg in any hypertensive patient." The researchers say they were unable to fully assess the net health effect of lower targets due to lack of information regarding all total serious adverse events and withdrawals due to adverse effects in six of seven trials. Trials Needed to Compare Lower With Standard Systolic Targets Arguedas and his colleagues note that a lower BP target of 130/80 mm Hg is currently recommended for at-risk patients, and they did perform a sensitivity analysis in diabetic and kidney-disease patients, which did not show significant benefits for treating to

6 targets of lower than 135/85 mm Hg. "However, in these two populations, the evidence for a lack of benefit is less robust," they note. Arguedas told heartwire that properly conducted randomized controlled trials are needed comparing lower systolic BP targets with standard ones in the general population and also in specific subgroups of at-risk patients. One such study is the ongoing Action to Control Cardiovascular Disease in Diabetes (ACCORD) blood-pressure trial an unmasked, open-label, randomized trial with participants randomized to one of two groups with different treatment goals: systolic blood pressure < 120 mm Hg for the more intensive goal, and systolic blood pressure < 140 mm Hg for the less intensive goal [2]. The primary outcome measure is the first occurrence of a major CVD event, specifically nonfatal MI or stroke, or cardiovascular death during a follow-up period ranging from four to eight years. The results should provide some of the first definitive clinical-trial data on the possible benefit of treating to a more aggressive systolic blood-pressure goal. In the meantime, says Arguedas, "We are doing another separate systematic review specifically in patients with diabetes and chronic kidney disease to see whether targets lower than 130/80 mm Hg change morbidity or mortality as compared with standard targets." References 1. Arguedas JA, Perez MI, Wright JM. Treatment blood pressure targets for hypertension. Cochrane Database Syst Rev 2009; 3:CD Cushman WC, Grimm RH Jr, Cutler JA, et al. Rationale and design for the blood pressure intervention of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Am J Cardiol 2007; 99(12A):44i-55i. Clinical Context There is a continuous adverse relationship between BP and CV events, but despite practice guidelines recommending control of BP with a threshold of 140/90 mm Hg, it is unclear if lower thresholds are associated with improved outcomes. In recent practice guidelines, lower thresholds have been recommended for patients with comorbidities such as diabetes or renal disease, but data for patients without these comorbidities are scarce. This is a systematic review to examine if lower targeted BP is achieved in trials with lower vs higher targets and if lower targets are associated with improved clinical outcomes. Study Highlights Lower targets were defined as BP targets of 135/85 mm Hg or lower and standard targets as 140 or lower to 160/90 to 100 mm Hg. Included were randomized controlled trials comparing patients vs targets that were standard vs lower than standard. The following databases were searched: MEDLINE from 1966 to 2008, EMBASE from 1980 to 2008, and CENTRAL to Reference lists from review articles were browsed for studies not identified. 2 independent reviewers determined eligibility, and data were then extracted independently by 2 reviewers for meta-analysis. Assessment of bias was performed with use of 6 criteria. 7 randomized trials (22,089 subjects) from 18 publications met the criteria for inclusion, and 6 were excluded. Primary outcomes were all-cause mortality, total serious adverse events, and CV adverse events. Secondary outcomes were systolic and diastolic BP, proportion achieving targeted BP, and withdrawals. Included studies were interventions for BP reduction such as diet modification, angiotensin-converting enzyme inhibitors, calcium-channel blockers, beta-blockers, and combinations of treatments. Trials were single randomized, 2 x 2-factorial and 2 x 3-factorial designs. Duration of trials varied from 19 months to 6.4 years. In patients randomly assigned to lower targets, the weighted mean systolic BP was 3.9 mm Hg lower (139.3 vs mm Hg), and the weighted mean diastolic BP was 3.4 mm Hg lower (81.7 vs 85.1 mm Hg) than the standard target group. These differences were statistically significant. 6 of 7 trials assessed total mortality rate, and the meta-analysis showed no significant difference in the 2 target BP groups, with an RR of There was no difference in CV or non-cv mortality or major CV outcomes. Only 1 trial examined CV serious adverse events, and no significant difference was seen.

7 For MI, the RR was 0.84, with no significant difference between the 2 targeted BP groups. In pooled analysis, there was no difference in stroke outcomes. There was no difference in congestive heart failure rates in pooled analysis. The outcome of end-stage renal failure defined as requirement for dialysis or kidney transplantation was similar in the 2 groups. A sensitivity analysis in diabetic patients and in those with chronic renal disease did not show a reduction in mortality and morbidity rates with lower vs standard targets. Information on adverse effects was fragmentary, and in 1 study, cough occurred more frequently in the lower target group (54.6% vs 47.0%). However, hypotensive adverse effects were similar in the 2 groups. The authors concluded that although a lower targeted BP is associated with lower systolic and diastolic BPs in patients with hypertension, there was no significant difference in outcomes of mortality, CV, stroke, and other outcomes. However, because of the heterogeneity of the studies, they also concluded that the health effects of lower BP targets could not be fully assessed. Clinical Implications Interventions targeting lower BP goals in patients with hypertension are associated with a reduction of 3.9 and 3.4 mm Hg in systolic BP and diastolic BP, respectively. Lower targeted goals of BP control are not associated with improved mortality and morbidity outcomes in patients with hypertension. CME Test Which of the following best describes the BP lowering for systolic and diastolic BP associated with lower target BP vs standard target BP in patients with hypertension? 5.6/4.8 mm Hg 3.9/3.4 mm Hg 7.8/4.5 mm Hg 1.0/2.5 mm Hg Which of the following outcomes is most likely to be improved with lower target BP vs standard target BP goals in patients with hypertension? All-cause mortality Congestive heart failure Stroke None of the above Save and Proceed Authors and Disclosures This article is a CME certified activity. To earn credit for this activity visit: As an organization accredited by the ACCME, MedscapeCME requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines "relevant financial relationships" as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest. MedscapeCME encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content. Author(s)

8 Lisa Nainggolan Lisa Nainggolan is a journalist for theheart.org, part of the WebMD Professional Network. She has been with theheart.org since Previously, she was science editor of Scrip World Pharmaceutical News, covering news about research and development in the pharmaceutical industry, and a consultant editor of Scrip Magazine. Graduating in physiology from Sheffield University, UK, she began her career as a poisons information specialist at Guy's Hospital before becoming a medical journalist in She can be reached at LNainggolan@webmd.net. Disclosure: Lisa Nainggolan has disclosed no relevant financial relationships. Editor(s) Brande Nicole Martin is the News CME editor for Medscape Medical News. Disclosure: Brande Nicole Martin has disclosed no relevant financial information. CME Author(s) Désirée Lie, MD, MSEd Clinical Professor, Family Medicine, University of California, Orange; Director, Division of Faculty Development, UCI Medical Center, Orange, California Disclosure: Désirée Lie, MD, MSEd, has disclosed no relevant financial relationships. Heartwire CME 2009 MedscapeCME Disclaimer The material presented here does not necessarily reflect the views of MedscapeCME or companies that support educational programming on These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity. Send press releases and comments to news@medscape.net.

9 From Medscape Medical News Cholinesterase Inhibitors Linked to Serious Adverse Events in Older Adults With Dementia CME/CE News Author: Laurie Barclay, MD CME Author: Charles Vega, MD, FAAFP CME/CE Released: 05/20/2009; Valid for credit through 05/20/2010 May 20, 2009 Cholinesterase inhibitors are associated with previously underrecognized serious adverse events in older adults with dementia, which must be carefully balanced against the generally modest benefits of these drugs, according to the results of a population-based cohort study reported in the May 11 issue of the Archives of Internal Medicine. "Cholinesterase inhibitors are commonly prescribed to treat dementia, but their adverse effect profile has received little attention," write Sudeep S. Gill, MD, MSc, from the Institute for Clinical Evaluative Sciences in Toronto, Ontario, Canada, and colleagues. "These drugs can provoke symptomatic bradycardia and syncope, which may lead to permanent pacemaker insertion. Drug-induced syncope may also precipitate fall-related injuries, including hip fracture." To evaluate the association between use of cholinesterase inhibitors and syncope-related outcomes, the investigators used healthcare databases from Ontario, Canada, with enrollment from April 1, 2002, to March 31, The study cohort consisted of 19,803 community-dwelling older adults with dementia who were prescribed cholinesterase inhibitors and 61,499 control subjects who were not using these medications. Compared with control subjects, patients who were prescribed cholinesterase inhibitors had more frequent hospital visits for syncope (31.5 vs 18.6 events per 1000 person-years; adjusted hazard ratio [HR], 1.76; 95% confidence interval [CI], ). Participants receiving cholinesterase inhibitors also had a higher frequency of other syncope-related events vs control subjects. These events included hospital visits for bradycardia (6.9 vs 4.4 events per 1000 person-years; HR, 1.69; 95% CI, ), permanent pacemaker insertion (4.7 vs 3.3 events per 1000 person-years; HR, 1.49; 95% CI, ), and hip fracture (22.4 vs 19.8 events per 1000 person-years; HR, 1.18; 95% CI, ). Additional analyses in which participants were matched either on their baseline comorbidity status or use of propensity scores yielded similar findings. "Use of cholinesterase inhibitors is associated with increased rates of syncope, bradycardia, pacemaker insertion, and hip fracture in older adults with dementia," the study authors write. "The risk of these previously underrecognized serious adverse events must be weighed carefully against the drugs' generally modest benefits." Limitations of this study include retrospective, observational design; additional risk factors for syncope in many patients; possible residual confounding and hidden bias; failure to compare individual cholinesterase inhibitors or to examine dose-response relationships; lack of evaluation of fall-related injuries other than hip fracture; and exclusion of patients with a recent history of syncope. "Older adults with dementia are vulnerable to adverse drug effects, and future RCTs [randomized controlled trials] evaluating treatments targeted to this population should therefore provide comprehensive documentation of common and serious outcomes such as falls (syncopal or otherwise) and injuries," the study authors conclude. The Clinical Teachers Association of Queen's Endowment Fund and a Chronic Disease New Emerging Team program grant from the Canadian Institutes of Health Research (CIHR) supported this study. The New Emerging Team program receives joint sponsorship from the Canadian Diabetes Association; the Kidney Foundation of Canada; the Heart and Stroke Foundation of Canada; and the CIHR Institutes of Nutrition, Metabolism and Diabetes, and Circulatory and Respiratory Health. Some of the study authors have disclosed various financial relationships with Bayer Canada, the Ontario Ministry of Health, the University of Toronto, and the CIHR. Arch Intern Med. 2009;169: Clinical Context Cholinesterase inhibitors are widely used to treat Alzheimer's disease and other forms of dementia, although previous trials have questioned their efficacy in relationship to their cost. In a randomized trial by Courtney and colleagues, which was published in the June 26, 2004, issue of the Lancet, use of donepezil was associated with modest improvements in cognition and function scores vs placebo during the first 2 years of treatment. However, rates of institutionalization and progression of

10 disability were similar between donepezil and placebo at 3 years, and the 2 treatment groups also experienced similar rates of behavioral and psychological symptoms. Donepezil was not associated with a higher rate of adverse events in the study by Courtney and colleagues, but this might have been the result of a small sample size. The current study uses a large patient cohort to examine the potential for serious adverse events associated with treatment with cholinesterase inhibitors. Study Highlights Researchers used public health databases from Ontario, Canada, which capture nearly all health-related events. They focused on residents 66 years or older with a previous diagnosis of dementia. The study authors compared community-dwelling subjects who had received cholinesterase inhibitors vs patients who had not (control group). Control subjects needed to have recent contact with their clinician, and patients with a history of syncope in the last year were excluded from analysis. Hospital and emergency department records were reviewed for the diagnoses of syncope, bradycardia, complete atrioventricular block, and hip fracture unrelated to a traumatic injury or cancer. The study period lasted from 2002 to Researchers examined the relationship between the use of cholinesterase inhibitors and the above diagnoses. They adjusted for multiple covariates that could act as confounders, including demographic, disease, and pharmaceutic variables. 19,803 adults received cholinesterase inhibitors (13,641 received donepezil; 3448, galantamine; and 2714, rivastigmine). These subjects were compared vs 61,499 control subjects. The average number of hospital visits for syncope in subjects receiving cholinesterase inhibitors and in control subjects was 31.5 and 18.6 per 1000 person-years, respectively. The adjusted HR of 1.76 for this outcome was significant. Subjects receiving cholinesterase inhibitors also experienced significantly higher rates of bradycardia (HR, 1.69) and pacemaker insertion (HR, 1.49). The average rates of hip fracture in subjects receiving cholinesterase inhibitors and in control subjects were 22.4 and 19.8 per 1000 person-years, respectively. The adjusted HR of 1.18 for this outcome was also significant. Additional analyses with a scale of all potential comorbidities failed to alter the main outcome of the study. Researchers also examined the relationship between 2 outcomes thought to be completely unrelated to the use of cholinesterase inhibitors (pulmonary embolism and cataract extraction) as a means to demonstrate that their positive findings were valid. Cholinesterase inhibitors had no association with pulmonary embolism or cataract extraction. Clinical Implications In a previous randomized study, use of donepezil for the treatment of Alzheimer's disease was associated with modest improvements in cognition and function scores but did not reduce rates of institutionalization, progression of disability, or behavioral symptoms vs placebo. In the current cohort study, the use of cholinesterase inhibitors in older adults with dementia was associated with higher rates of syncope, bradycardia, pacemaker placement, and hip fracture. CME/CE Test Which of the following outcomes was most improved with use of donepezil for the treatment of Alzheimer's disease vs placebo in the previous study by Courtney and colleagues? Rate of institutionalization Cognition score Progression of disability Behavioral symptoms Cholinesterase inhibitors were associated with higher rates of which of the following outcomes in the current study by Gill and colleagues? Bradycardia alone Bradycardia and syncope alone

11 Bradycardia and pacemaker placement alone Bradycardia, syncope, pacemaker placement, and hip fracture Save and Proceed This article is a CME/CE certified activity. To earn credit for this activity visit: Authors and Disclosures As an organization accredited by the ACCME, MedscapeCME requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines "relevant financial relationships" as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest. MedscapeCME encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content. Author(s) Laurie Barclay, MD Laurie Barclay, MD, is a freelance writer and reviewer for Medscape. Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships. Editor(s) Brande Nicole Martin is the News CME editor for Medscape Medical News. Disclosure: Brande Nicole Martin has disclosed no relevant financial information. Nurse Planner Laurie E. Scudder, MS, NP Accreditation Coordinator, Continuing Professional Education Department, MedscapeCME; Clinical Assistant Professor, School of Nursing and Allied Health, George Washington University, Washington, DC; Nurse Practitioner, School-Based Health Centers, Baltimore City Public Schools, Baltimore, Maryland Disclosure: Laurie E. Scudder, MS, NP, has disclosed that she has no relevant financial relationships. CME Author(s) Charles P. Vega, MD Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine Disclosure: Charles Vega, MD, FAAFP, has disclosed an advisor/consultant relationship to Novartis, Inc. Medscape Medical News 2009 MedscapeCME Disclaimer The material presented here does not necessarily reflect the views of MedscapeCME or companies that support educational programming on

12 These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity. Send press releases and comments to news@medscape.net.

13 From MedscapeCME Clinical Briefs CDC Issues Guidelines for Early Empiric Antiviral Treatment in Persons With Suspected Influenza CME/CE News Author: Laurie Barclay, MD CME Author: Laurie Barclay, MD CME/CE Released: 10/29/2009; Valid for credit through 10/29/2010 October 29, 2009 On October 16, the US Centers for Disease Control and Prevention (CDC) issued interim guidelines for chemoprophylaxis and early empiric antiviral treatment in persons with suspected influenza, including 2009 H1N1 influenza infection and seasonal influenza. The new interim recommendations, which update those from September 22, 2009, aim to assist clinicians during the influenza season in prioritizing use of antiviral medications for hospitalized patients and those at higher risk for complications from influenza. The CDC notes that the recommendations can be modified as indicated by local epidemiologic data, patterns of antiviral susceptibility, antiviral supply considerations, or observed changes in the clinical presentation or antiviral susceptibility of 2009 H1N1 influenza. These guidelines should be considered interim recommendations and will be updated as needed. "As of October 3, 2009, 99% of circulating influenza viruses in the United States were 2009 H1N1 influenza (previously referred to as novel influenza A [H1N1])," the guidelines authors write. "Among people who become infected with 2009 H1N1, certain groups appear to be at increased risk of complications and may benefit most from early treatment with antiviral medications. Based on currently available data, approximately 70% of persons hospitalized with 2009 H1N1 influenza have had a recognized high risk condition." High-risk groups include children younger than 2 years, adults 65 years or older, and pregnant women and those up to 2 weeks after delivery or miscarriage. In addition, persons at high-risk include those with immunosuppression; disorders compromising respiratory tract function or handling of respiratory secretions or increasing risk for aspiration; or chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, hematologic (including sickle cell disease), or metabolic diseases (including diabetes mellitus). Updated Guidelines Updates since the September 22, 2009, guidelines include the following: The guidelines authors elucidate considerations for treatment and chemoprophylaxis in persons vaccinated with the 2009 H1N1 and seasonal influenza vaccines. In addition to pregnant women, those up to 2 weeks postpartum or after a miscarriage are now included as being at increased risk for complications from 2009 H1N1 influenza. For children younger than 1 year, additional oseltamivir dosing instructions are given. Adverse events and contraindications associated with use of oseltamivir and zanamivir are reviewed. The guidelines note that antiviral medications can decrease the severity and duration of influenza illness and can lower the risk for severe illness, mortality, and other complications. Treatment or prophylaxis with antiviral medications is not necessary for most healthy individuals with an illness consistent with uncomplicated influenza or for those who appear to be recovering from influenza. Severe symptoms, including evidence of lower respiratory tract infection or clinical deterioration, in persons of any age or previous health status presenting with suspected influenza should mandate prompt empiric antiviral therapy. All persons hospitalized for suspected or confirmed influenza should be treated with oseltamivir or zanamivir. Persons with suspected or confirmed influenza who are at higher risk for complications should be considered for early empiric treatment with oseltamivir or zanamivir. Compared with older children and adults, children aged 2 to 4 years are more likely to need hospitalization or urgent medical evaluation for influenza. However, the risk is still much lower vs children younger than 2 years, and antiviral treatment is not necessarily needed for children aged 2 to 4 years with mild illness and without high-risk conditions. When antiviral treatment is indicated, it should be started as soon as possible because maximal benefits ensue when patients begin treatment within the first 2 days of illness, although some studies of patients hospitalized for seasonal and 2009 H1N1 influenza have shown possible benefit of antiviral therapy started later than 48 hours after symptom onset. Measures to minimize delays in starting treatment may include educating individuals who are at higher risk for influenza complications of the signs and symptoms of influenza and the need for early treatment as soon as possible after onset of influenza symptoms such as fever or respiratory tract symptoms. In addition, these patients and those who report severe illness should have

14 rapid access to telephone consultation and clinical evaluation. Empiric treatment based on telephone contact may be considered for patients at higher risk for influenza complications, if hospitalization is not needed, and if this will result in markedly less delay before treatment is started. Because a negative rapid test result for influenza does not rule out influenza, treatment should not be delayed pending laboratory confirmation of influenza. Sensitivity of rapid tests ranges from 10% to 70% for detection of 2009 H1N1. In accordance with guidelines from local and state health departments, real-time reverse transcriptase-polymerase chain reaction testing for 2009 H1N1 influenza infection should be prioritized for individuals with suspected or confirmed influenza requiring hospitalization. Consideration for antiviral chemoprophylaxis should usually be limited to individuals at greater risk for influenza-related complications who have been exposed to someone likely to have been infected with influenza. After a suspected exposure, however, early treatment may be an option preferred vs chemoprophylaxis. Those persons at high risk who are household or close contacts of confirmed or suspected influenza cases can be educated regarding the early signs and symptoms, and if these develop, they can be instructed to contact their healthcare provider immediately for evaluation and possible early treatment. When vaccinated persons have a suspected exposure, early recognition of illness and treatment when indicated are preferred vs chemoprophylaxis. Circulating Viruses In the influenza season, the most common influenza viruses among those circulating are likely to be 2009 H1N1 influenza viruses, especially in younger age groups, but circulation of seasonal influenza viruses is also anticipated. These predictions are based on global experience to date, but the timing and intensity of seasonal influenza virus vs 2009 H1N1 circulation may not be accurately predicted in advance. The 2009 H1N1 viruses now circulating are susceptible to oseltamivir and zanamivir but are resistant to amantadine and rimantadine. Based on new antiviral resistance or viral surveillance data, however, recommended antiviral treatment regimens may change accordingly. The updated guidelines contain information on the dose and dosing schedule for oseltamivir and zanamivir. The emergency use of oseltamivir in children younger than 1 year is reviewed in an April 2009 Emergency Use Authorization. The guidelines are available online on the CDC's H1N1 Web site. Published online October 19, Clinical Context The CDC guidelines issued October 16, which update those from September 22, 2009, aim to help clinicians prioritize use of antiviral medications for hospitalized patients and those at higher risk for influenza complications during the 2009 to 2010 season. As of October 3, a total of 99% of circulating influenza viruses in the United States were 2009 H1N1 influenza. Updates since the September 22, 2009, guidelines include the following: Expanded considerations for treatment and chemoprophylaxis in persons vaccinated with the 2009 H1N1 and seasonal influenza vaccines. A new recommendation that women up to 2 weeks postpartum or after a miscarriage should be considered to be at increased risk for complications from 2009 H1N1 influenza. Additional oseltamivir dosing instructions for children younger than 1 year. A review of adverse events and contraindications associated with use of oseltamivir and zanamivir. Study Highlights Dosing recommendations for antiviral treatment or chemoprophylaxis with oseltamivir for children younger than 1 year are as follows: Recommended treatment dose for infants younger than 3 months is 12 mg twice daily for 5 days. Because of limited data on use of oseltamivir in infants younger than 3 months, prophylaxis is not recommended unless the situation is judged to be critical. For infants aged 3 to 5 months, recommended treatment dose is 20 mg twice daily for 5 days, and recommended prophylaxis dose is 20 mg once daily for 10 days.

15 At ages 6 to 11 months, recommended treatment dose is 25 mg twice daily for 5 days, and recommended prophylaxis dose is 25 mg once daily for 10 days. Prescribers should specify the concentration (eg, oral suspension 12 mg/ml) if prescribing in milliliters or teaspoons, or to prescribe the dose in milligrams. Oseltamivir and zanamivir are generally well tolerated. Compared with placebo, oseltamivir is more often associated with reports of nausea and vomiting in adults (nausea without vomiting, approximately 10% vs 6%; vomiting, approximately 9% vs 3%). In children, 14% of those treated with oseltamivir had vomiting vs 8.5% of placebo recipients. Sorbitol contained in oseltamivir suspension may cause diarrhea and abdominal pain in fructose-intolerant patients. Zanamivir is an inhaled formulation that may induce bronchospasm, and it is therefore not recommended in patients with underlying pulmonary disease. Zanamivir should be used only as directed, with use of the Diskhaler device provided with the drug product. Commercially available zanamivir (Relenza Inhalation Powder; GlaxoSmithKline) uses a lactose drug carrier and should not be used in any nebulizer or mechanical ventilator because the lactose sugar may obstruct proper functioning of mechanical ventilator equipment. Both oseltamivir and zanamivir have been associated with allergic reactions (rash, face or tongue swelling, or anaphylaxis). Transient neuropsychiatric events (self-injury or delirium) with oseltamivir and zanamivir have rarely been reported in postmarketing surveillance, mostly in children and adolescents living in Japan. However, influenza itself may cause neurologic and behavioral symptoms, so any causal role of the neuraminidase inhibitors in these symptoms is unclear. Retrospective analyses to date have not shown an increased risk for neuropsychiatric events after oseltamivir use. The FDA recommends that persons receiving neuraminidase inhibitors be monitored for abnormal behavior until additional data are available. Healthcare professionals should promptly report all serious adverse events seen after use of antiviral medication to MedWatch. Clinical Implications The new CDC guidelines contain dosing recommendations for antiviral treatment (for 5 days) or chemoprophylaxis (for 10 days) with oseltamivir for children younger than 1 year. Because of limited data on use of oseltamivir in infants younger than 3 months, prophylaxis is not recommended in this age group unless the situation is judged to be critical. Oseltamivir and zanamivir are generally well tolerated. Oseltamivir use may be associated with nausea and vomiting. Zanamivir is an inhaled formulation that may induce bronchospasm, and it is not recommended in patients with underlying pulmonary disease. Both drugs have been associated with allergic reactions. CME/CE Test According to the October 16 update of the CDC guidelines for chemoprophylaxis and early empiric antiviral treatment in persons with suspected influenza, which of the following statements about additional oseltamivir dosing instructions for children younger than 1 year is correct? Recommended treatment dose for infants younger than 3 months is 12 mg twice daily for 5 days Recommended prophylaxis dose for infants younger than 3 months is 12 mg twice daily for 5 days For infants aged 3 to 5 months, recommended treatment dose is 20 mg once daily for 5 days At ages 6 to 11 months, recommended prophylaxis dose is 15 mg once daily for 10 days According to the October 16 update of the CDC guidelines for chemoprophylaxis and early empiric antiviral treatment in persons with suspected influenza, which of the following is not an adverse event associated with use of oseltamivir and zanamivir? Diarrhea and abdominal pain in fructose-intolerant patients given oseltamivir Bronchospasm with zanamivir Nausea and vomiting with zanamivir Allergic reactions with either drug Save and Proceed

16 This article is a CME/CE certified activity. To earn credit for this activity visit: Authors and Disclosures As an organization accredited by the ACCME, MedscapeCME requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines "relevant financial relationships" as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest. MedscapeCME encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content. Author(s) Laurie Barclay, MD Freelance writer and reviewer, MedscapeCME Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships. Editor(s) Brande Nicole Martin is the News CME editor for Medscape Medical News. Disclosure: Brande Nicole Martin has disclosed no relevant financial information. CME Author(s) Laurie Barclay, MD Freelance writer and reviewer, MedscapeCME Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships. Nurse Planner and CME Reviewer Laurie E. Scudder, MS, NP Accreditation Coordinator, Continuing Professional Education Department, MedscapeCME; Clinical Assistant Professor, School of Nursing and Allied Health, George Washington University, Washington, DC; Nurse Practitioner, School-Based Health Centers, Baltimore City Public Schools, Baltimore, Maryland Disclosure: Laurie E. Scudder, MS, NP, has disclosed no relevant financial relationships. MedscapeCME Clinical Briefs 2009 MedscapeCME Disclaimer The material presented here does not necessarily reflect the views of MedscapeCME or companies that support educational programming on These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity. Send press releases and comments to news@medscape.net.