Top Internal Medicine News of 2009

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).

From MedscapeCME Clinical Briefs

New Test May Detect Early Alzheimer's Disease CMENews Author: Allison Gandey CME Author: Laurie Barclay, MD CME Released: 06/22/2009; Valid for credit through 06/22/2010

Study Highlights

l This cross-sectional study evaluated the performance of a self-administered cognitive screening test ("test your memory" [TYM]) for detection of Alzheimer's disease.

l The TYM was designed for quick administration and suitability for use by general practitioners. l It consists of a series of 10 tasks on a double-sided sheet or card with blanks for the patient to complete. l 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), l Ability to complete the TYM is considered as an additional task. l 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. l 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. l The performance on the TYM of patients with Alzheimer's disease (n = 94) was compared vs age-matched control subjects (n

= 282). l Interrater reliability was excellent, determined by 3 scorers of differing backgrounds marking 100 tests. l The TYM was validated against 2 standard tests, the MMSE and the Addenbrooke's cognitive examination-revised (ACE-R). l Sensitivity and specificity of the TYM in the diagnosis of Alzheimer's disease were calculated. l 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. l Control subjects completed the test in an average time of 5 minutes. l The average TYM score remained constant between the ages of 18 and 70 years and decreased slightly thereafter. l Men and women had similar TYM scores, as did subjects with various geographic backgrounds. l Scores on the TYM score correlated well with scores on the MMSE and ACE-R. l The TYM takes less time to administer than the MMSE and tests a broader range of cognitive domains. l 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. l 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. l 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. l The TYM was more sensitive in the detection of Alzheimer's disease vs the MMSE (sensitivity, 93% vs 52%). l 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%. l 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

l 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.

l 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

This article is a CME certified activity. To earn credit for this activity visit: http://cme.medscape.com/viewarticle/704667

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 www.medscapecme.com. 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

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 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 [email protected]. 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.

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

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 22 000 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:

l Total mortality (relative risk 0.92). l Myocardial infarction (MI; RR 0.90). l Stroke (RR 0.99). l Congestive heart failure (RR 0.88). l Major cardiovascular events (RR 0.94). l 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

From Heartwire CME

No Benefit in Lowering BP Below "Standard" 140/90 mm Hg CMENews Author: Lisa Nainggolan CME Author: Désirée Lie, MD, MSEd CME Released: 07/23/2009; Valid for credit through 07/23/2010

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:CD004349.

2. 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

l 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.

l Included were randomized controlled trials comparing patients vs targets that were standard vs lower than standard. l The following databases were searched: MEDLINE from 1966 to 2008, EMBASE from 1980 to 2008, and CENTRAL to 2008. l Reference lists from review articles were browsed for studies not identified. l 2 independent reviewers determined eligibility, and data were then extracted independently by 2 reviewers for meta-analysis. l Assessment of bias was performed with use of 6 criteria. l 7 randomized trials (22,089 subjects) from 18 publications met the criteria for inclusion, and 6 were excluded. l Primary outcomes were all-cause mortality, total serious adverse events, and CV adverse events. l Secondary outcomes were systolic and diastolic BP, proportion achieving targeted BP, and withdrawals. l Included studies were interventions for BP reduction such as diet modification, angiotensin-converting enzyme inhibitors,

calcium-channel blockers, beta-blockers, and combinations of treatments. l Trials were single randomized, 2 x 2-factorial and 2 x 3-factorial designs. l Duration of trials varied from 19 months to 6.4 years. l In patients randomly assigned to lower targets, the weighted mean systolic BP was 3.9 mm Hg lower (139.3 vs 143.2 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. l These differences were statistically significant. l 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 0.99. l There was no difference in CV or non-CV mortality or major CV outcomes. l Only 1 trial examined CV serious adverse events, and no significant difference was seen.

l For MI, the RR was 0.84, with no significant difference between the 2 targeted BP groups. l In pooled analysis, there was no difference in stroke outcomes. l There was no difference in congestive heart failure rates in pooled analysis. l The outcome of end-stage renal failure defined as requirement for dialysis or kidney transplantation was similar in the 2

groups. l 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. l Information on adverse effects was fragmentary, and in 1 study, cough occurred more frequently in the lower target group

(54.6% vs 47.0%). l However, hypotensive adverse effects were similar in the 2 groups. l 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. l However, because of the heterogeneity of the studies, they also concluded that the health effects of lower BP targets could

not be fully assessed.


l 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.

l 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



Author(s)

Heartwire CME © 2009 MedscapeCME Disclaimer The material presented here does not necessarily reflect the views of MedscapeCME or companies that support educational programming on www.medscapecme.com. 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 [email protected].

Lisa Nainggolan

Lisa Nainggolan is a journalist for theheart.org, part of the WebMD Professional Network. She has been with theheart.org since 2000. 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 1995. She can be reached at [email protected]. Disclosure: Lisa Nainggolan has disclosed no relevant financial relationships.

Editor(s)


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.

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, 2004. 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], 1.57 - 1.98). 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, 1.32 - 2.15), permanent pacemaker insertion (4.7 vs 3.3 events per 1000 person-years; HR, 1.49; 95% CI, 1.12 - 2.00), and hip fracture (22.4 vs 19.8 events per 1000 person-years; HR, 1.18; 95% CI, 1.04 - 1.34).

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;169:867-873.

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

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

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

l 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.

l 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.

l 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.

l The study period lasted from 2002 to 2004. 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.

l 19,803 adults received cholinesterase inhibitors (13,641 received donepezil; 3448, galantamine; and 2714, rivastigmine). These subjects were compared vs 61,499 control subjects.

l 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.

l Subjects receiving cholinesterase inhibitors also experienced significantly higher rates of bradycardia (HR, 1.69) and pacemaker insertion (HR, 1.49).

l 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.

l 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.


l 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.

l 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

This article is a CME/CE certified activity. To earn credit for this activity visit: http://cme.medscape.com/viewarticle/703038

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

Bradycardia and pacemaker placement alone

Bradycardia, syncope, pacemaker placement, and hip fracture

Save and Proceed



Author(s)

Laurie Barclay, MD


Editor(s)



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.

www.medscapecme.com. 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 [email protected].

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 2009-2010 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:

l The guidelines authors elucidate considerations for treatment and chemoprophylaxis in persons vaccinated with the 2009 H1N1 and seasonal influenza vaccines.

l 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.

l For children younger than 1 year, additional oseltamivir dosing instructions are given. l 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


CDC Issues Guidelines for Early Empiric Antiviral Treatment in Persons With Suspected Influenza CME/CENews Author: Laurie Barclay, MD CME Author: Laurie Barclay, MD CME/CE Released: 10/29/2009; Valid for credit through 10/29/2010

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 2009-2010 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, 2009.

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:

l Expanded considerations for treatment and chemoprophylaxis in persons vaccinated with the 2009 H1N1 and seasonal influenza vaccines.

l 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.

l Additional oseltamivir dosing instructions for children younger than 1 year. l A review of adverse events and contraindications associated with use of oseltamivir and zanamivir.

Study Highlights

l 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.

¡ 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.

l Oseltamivir and zanamivir are generally well tolerated. l 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%). l In children, 14% of those treated with oseltamivir had vomiting vs 8.5% of placebo recipients. l Sorbitol contained in oseltamivir suspension may cause diarrhea and abdominal pain in fructose-intolerant patients. l Zanamivir is an inhaled formulation that may induce bronchospasm, and it is therefore not recommended in patients with

underlying pulmonary disease. l Zanamivir should be used only as directed, with use of the Diskhaler device provided with the drug product. l 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.

l Both oseltamivir and zanamivir have been associated with allergic reactions (rash, face or tongue swelling, or anaphylaxis). l 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. l However, influenza itself may cause neurologic and behavioral symptoms, so any causal role of the neuraminidase inhibitors

in these symptoms is unclear. l Retrospective analyses to date have not shown an increased risk for neuropsychiatric events after oseltamivir use. l The FDA recommends that persons receiving neuraminidase inhibitors be monitored for abnormal behavior until additional

data are available. l Healthcare professionals should promptly report all serious adverse events seen after use of antiviral medication to

MedWatch.


l 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.

l 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


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 www.medscapecme.com. 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 [email protected].



Author(s)

Laurie Barclay, MD

Freelance writer and reviewer, MedscapeCME Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

Editor(s)



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.

June 8, 2009 — One of the first large studies to look at the safety of different nonsteroidal anti-inflammatory drugs (NSAIDs) specifically in patients with heart disease has found that naproxen appears to have better cardiovascular safety than diclofenac, ibuprofen, and higher doses of rofecoxib (Vioxx, Merck) and celecoxib (Celebrex, Pfizer) [1].

The study, published in the May 2009 issue of Circulation: Cardiovascular Quality and Outcomes, was conducted by a group led by Dr Wayne Ray (Vanderbilt University School of Medicine, Nashville, TN).

They explain that the cardiovascular safety of NSAIDs is highly controversial, with several studies suggesting increased cardiovascular risk associated with the new COX-2 inhibitors and also some older traditional NSAIDs, and that this issue is particularly important for patients with existing serious coronary heart disease, whose baseline risk of adverse cardiovascular events is increased. In addition, many of these patients take low-dose aspirin, which may interact with the NSAID.

But they note that data on the cardiovascular safety of these drugs in heart-disease patients is limited. They therefore conducted the current retrospective cohort study in which they examined the cardiovascular safety of individual NSAIDs in 48,566 patients with a hospitalization for myocardial infarction (MI), revascularization, or unstable angina that had been recorded in one of three large databases--Tennessee's expanded Medicaid program, Saskatchewan Health databases in Canada, and the United Kingdom's General Practice Research Database--between 1999 and 2004. Medications given outside the hospital were identified from pharmacy and physician records. The primary study end point was serious coronary heart disease, defined as MI or out-of-hospital death from CHD [coronary heart disease]. A secondary end point was the composite of serious cardiovascular disease (MI or stroke) and death from any cause. Preplanned analyses were conducted for the most frequently prescribed NSAIDs, which were naproxen, ibuprofen diclofenac, celecoxib, and rofecoxib.

Results showed that cardiovascular safety was best for naproxen, which had a lower incidence rate ratio (IRR) for serious cardiovascular disease than non-NSAID users. In contrast, there was evidence that cardiovascular risk was increased for users of the other study NSAIDs.

Incidence Rate Ratios (IRRs) for Serious CV Disease or Serious CV Disease and Death for Users of Various NSAIDS vs Non-NSAID Users

Other results showed that individuals who took diclofenac had a 50% increased risk of MI, stroke, or death from any cause compared with naproxen users. The authors point out that diclofenac is widely used outside the US and has been the reference drug in several COX-2-inhibitor outcome trials, and this excess risk was present for low and moderate doses (< 150 mg/day) as well as higher doses. Ibuprofen users had a 25% increased risk for the MI, stroke, or death end point compared with naproxen users. In a comparison with high-dose naproxen use, users of higher doses of celecoxib (> 200 mg/day) and rofecoxib (> 25 mg/day) had increased risk of serious coronary heart disease.

Relative to NSAID nonusers, serious coronary heart disease risk increased with short-term (less than 90 days) use for ibuprofen, diclofenac, celecoxib, and rofecoxib, but not for naproxen. The authors note that this is in contrast to a widely publicized post hoc analysis of the APPROVE trial data, interpreted by some as suggesting no risk for use of less than 18 months. But they point out that observational studies of rofecoxib have reported increased risk within the first month of therapy, and in the VICTOR trial, rofecoxib patients had increased risk after a mean duration of 7.4 months. "Thus, our findings add to the evidence that at least one of the mechanisms for increased cardiovascular risk is acute," they say.

They comment that their current findings are generally consistent with previous studies, most of which were not restricted to patients

Drug IRR (serious CV disease) IRR (serious CV disease/death)

Naproxen 0.88 0.91

Ibuprofen 1.18 1.14

Diclofenac 1.27 1.38

Celecoxib 1.03 0.99

Rofecoxib 1.19 1.07

From Heartwire CME

Naproxen Best NSAID for Heart-Disease Patients CMENews Author: Sue Hughes CME Author: Charles P. Vega, MD, FAAFP CME Released: 06/08/2009; Valid for credit through 06/08/2010

with serious coronary heart disease. They caution that the follow-up in this study began 45 days after the qualifying hospitalization admission for coronary heart disease, so these results do not apply to the early postdischarge period, during which NSAID use may be particularly hazardous.

Breaking New Ground

In an accompanying editorial [2], Dr Daniel Solomon (Brigham and Women's Hospital, Boston, MA) says that this study breaks new ground in focusing on patients with known cardiovascular disease. As arthritis and cardiovascular disease commonly coexist, studying the cardiovascular safety of NSAIDs in this subgroup is of great public-health value, he comments.

Noting that the relative risks for rofecoxib were consistently lower when death from any cause was also included in the end point, Solomon suggests that this raises the possibility that death from gastrointestinal bleeds may have been reduced in persons using rofecoxib. He says this leads to questions about how to measure the overall safety of a drug. "Cardiovascular safety in patients with known cardiovascular disease is tremendously important, but clinicians and patients should focus on 'net' safety," he writes. But he adds that this is difficult concept to understand and even harder to measure.

Solomon continues that the use of NSAIDs in patients with cardiovascular disease is concerning because of the cardiovascular and gastrointestinal toxicities associated with these agents, but until newer analgesics are developed, these agents will continue to be used in this patient group.

While more information will come from the PRECISION trial, a large randomized comparison of celecoxib, naproxen, and ibuprofen in patients at moderate cardiovascular risk, these results will not be available until 2011 or later, and thus, until then, doctors will continue to rely on well-done pharmacoepidemiology to help answer questions about the relative safety of various analgesic strategies in important subgroups of patients, Solomon says.

He concludes that the current study "gives us new and useful information from an observational study focusing on an important subgroup with known cardiovascular disease" and that "diclofenac use should be limited in this group and naproxen appears relatively safe, but non-NSAID analgesic strategies might also be considered."

This study was funded by an unrestricted grant from Pfizer. Ray has consulted with plaintiff's attorneys and insurance companies regarding rofecoxib. Two other authors were employees of Pfizer when this research began, and other authors have received research support from Merck, AstraZeneca, Novartis, and Pfizer. Solomon receives salary support for research from Amgen and Abbott. He serves as an unpaid member of the executive committee of the Pfizer-sponsored PRECISION trial, and he serves as an unpaid member of the data safety monitoring board of a Pfizer-sponsored trial investigating a non-NSAID analgesic for osteoarthritis.

References

1. Ray WA, Varas-Lorenzo C, Chung CP, et al. Cardiovascular risks of nonsteroidal antiinflammatory drugs in patients after hospitalization for serious coronary heart disease. Circ Cardiovasc Qual Outcomes 2009; 2:155-163.

2. Solomon D H. Searching for a safe analgesic in patients with cardiovascular disease. Circ Cardiovasc Qual Outcomes 2009; 2:146-147.

Clinical Context

There has been significant attention to the cardiovascular risks associated with NSAIDs and particularly the risk associated with COX-2 inhibitors. In a previous systematic review and meta-analysis by McGettigan and Henry, which was published in the October 4, 2006, issue of the Journal of the American Medical Association, the researchers found that rofecoxib significantly increased the risk for cardiovascular events, and this risk increased with higher doses of rofecoxib. Moreover, the risk for cardiovascular events with rofecoxib was evident in the first month of treatment. However, the researchers also found no significant association between celecoxib and the risk for cardiovascular events.

This systematic review also noted a higher risk for cardiovascular events in patients who received older, nonselective NSAIDs, particularly diclofenac. The current study examines this issue in patients at a high risk for events because of preexisting coronary heart disease.

Study Highlights

l Researchers used 3 large patient databases in Canada, the United States, and the United Kingdom to examine disease and prescription data in adults between the ages of 40 and 89 years who had been hospitalized for acute MI, coronary heart revascularization, or unstable angina pectoris.

l All participants were enrolled in a health plan, which provided full medication information to the study database, and all subjects had at least 1 prescription or outpatient visit record. Patients with a history of other potentially life-threatening illness were excluded from study analysis.

l The primary outcome of the study was the relationship between the use of NSAIDs and incident MI or cardiac death. Participants were analyzed from day 45 after their initial cardiovascular event for this outcome, and researchers accounted for participants' comorbid conditions in the study analysis.

l 48,566 adults had data for analysis. The mean age was 65 years, and 58% of the cohort consisted of men. The qualifying hospitalization was for acute MI in 40% of subjects, and coronary revascularization and unstable angina pectoris accounted as reasons for the qualifying hospitalization in another 40% and 20% of subjects, respectively.

l The baseline cardiovascular risk score was similar in adults who did and did not use NSAIDs. l There were 111,162 person-years of follow-up and 3600 coronary heart disease events during this period. l Compared with adults who did not use NSAIDs, the use of naproxen was associated with nonsignificant reductions in the

rates of serious coronary heart disease events and cardiovascular disease/death. l Conversely, users of diclofenac experienced significantly higher rates of serious coronary heart disease events (IRR, 1.44)

and cardiovascular disease/death (IRR, 1.52) vs adults who received naproxen. l Compared with the use of naproxen, the use of ibuprofen also increased the risk for cardiovascular disease/death (IRR,

1.25). l Even high-dose naproxen was not associated with a higher risk for cardiovascular disease. However, users of higher dose of

high-dose celecoxib and rofecoxib had a higher risk for serious coronary heart disease vs subjects who received high-dose naproxen (IRR, 1.61 and 2.29, respectively).

l The NSAIDs noted were associated with a higher risk for coronary heart disease events when the duration of use was less than 90 days but not with longer periods of use.

l Subgroup analysis failed to alter the main outcome of the study.


l In a previous meta-analysis, rofecoxib was found to increase the risk for cardiovascular events in a dose-dependent fashion, and this risk was apparent within 1 month of the initiation of therapy. However, celecoxib was not associated with a significantly increased risk for cardiovascular events.

l In the current study, the use of naproxen was not associated with a higher risk for coronary heart disease events or cardiac death in patients with a history of coronary heart disease. However, ibuprofen; high-dose celecoxib; high-dose rofecoxib; and, most significantly, diclofenac, did increase this risk.

CME Test

All of the following statements were findings of the previous meta-analysis of NSAIDs and the risk for cardiovascular events by McGettigan and Henry except:

Diclofenac increased the risk for cardiovascular events

Higher doses of rofecoxib were associated with higher rates of cardiovascular events

Celecoxib increased the risk for cardiovascular events

Rofecoxib was associated with a higher rate of cardiovascular events within 1 month of the initiation of therapy

Which of the following NSAIDs was least associated with an increased risk for serious cardiovascular events in the current study by Ray and colleagues?

Naproxen

Ibuprofen

Diclofenac

High-dose celecoxib

Save and Proceed





Author(s)

Sue Hughes

Sue Hughes is a journalist for Medscape. She joined theheart.org, part of the WebMD Professional Network, in 2000. She was previously science editor of Scrip World Pharmaceutical News. Graduating in pharmacy from Manchester University, UK, she started her career as a hospital pharmacist before moving as a journalist to a UK pharmacy trade publication. She can be reached at [email protected]. Disclosure: Sue Hughes has disclosed no relevant financial relationships.

Editor(s)



CME Author(s)

Charles P. Vega, MD, FAAFP

Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine Disclosure: Charles P. Vega, MD, FAAFP, has disclosed no relevant financial relationships.

July 8, 2009 — The American College of Sports Medicine has issued a position stand providing an overview of issues critical to understanding the importance of exercise and physical activity in older adult populations. The review and guidelines are published in the July issue of Medicine & Science in Sports & Exercise.

"The 2008 Physical Activity Guidelines for Americans affirms that regular physical activity reduces the risk of many adverse health outcomes," write Wojtek J. Chodzko-Zajko, PhD, and colleagues from the American College of Sports Medicine. "The guidelines state that all adults should avoid inactivity, that some physical activity is better than none, and that adults who participate in any amount of physical activity gain some health benefits. However, the guidelines emphasize that for most health outcomes, additional benefits occur as the amount of physical activity increases through higher intensity, greater frequency, and/or longer duration."

The 3 sections of the position stand review the structural and functional changes accompanying normal human aging, the degree to which exercise and physical activity can affect the aging process, and the benefits of both long-term exercise and physical activity and shorter-duration exercise programs on health and functional capacity.

The reviewers conclude that no amount of physical activity can stop biological aging but that evidence to date affirms that by limiting the development and progression of chronic disease and disabling conditions, regular exercise can reduce the physiologic harms of an otherwise sedentary lifestyle and improve active life expectancy. Older adults who engage in regular exercise may also experience significant psychological and cognitive benefits.

The position stand recommends that all older adults participate in regular physical activity and avoid an inactive lifestyle and that exercise prescription for older adults include aerobic, muscle-strengthening, and flexibility exercises. Overall, the recommendations and underlying evidence are consistent with the 2008 Physical Activity Guidelines for Americans and with earlier American College of Sports Medicine statements regarding types and amounts of physical exercise suggested for older adults.

Benefits of Physical Activity and Exercise

The following are some specific evidence statements regarding the benefits of physical activity and exercise, and their accompanying level of evidence rating (see "Note" at end of article for explanation of the ratings):

l Vigorous, long-term participation in aerobic exercise training (AET) improves cardiovascular reserve and skeletal muscle adaptations, allowing trained older persons to sustain a submaximal exercise load with less cardiovascular stress and muscular fatigue than their untrained peers. Prolonged AET may also reduce age-related accumulation of central body fat, thereby protecting the heart (level of evidence, B).

l Prolonged participation in resistance exercise training (RET) increases muscle and bone mass and strength to a greater extent vs AET (level of evidence, B).

l In healthy middle-aged and older adults, AET programs of sufficiently intense (≥ 60% of pretraining VO2max), frequency, and length (≥ 3 days/week for ≥ 16 weeks) may significantly improve VO2max (level of evidence, A).

l In healthy middle-aged and older adults, 3 months or more of moderate-intensity AET are associated with cardiovascular adaptations which are apparent both at rest and in response to acute dynamic exercise (level of evidence, A/B).

l Moderate-intensity AET has been shown to reduce total body fat, but not fat-free mass, in overweight middle-aged and older adults (level of evidence, A/B).

l Beneficial metabolic changes associated with AET include improved glycemic control and clearance of postprandial lipids, as well as preferential utilization of fat during submaximal exercise (level of evidence, B).

l In postmenopausal women, AET may counteract age-related decreases in bone mineral density (level of evidence, B). l RET may markedly increase strength and muscular power in older adults (level of evidence, A). l Older and younger adults have similar age-related increases in muscle quality, and these increases do not appear to be sex

specific (level of evidence, B). l Improvements in muscular endurance have been reported after RET using moderate- to higher-intensity protocols, but not

lower-intensity RET, and may improve muscular endurance (level of evidence, C). l Although the effect of exercise on physical function is poorly understood and may not be linear, RET may improve walking,

chair stand, and balance activities (level of evidence, C/D). l Older adults who regularly take part in moderate- or high-intensity RET may have increased fat-free mass, decreased total

body fat mass, and other beneficial changes in body composition (level of evidence, B/C). l Compared with sedentary control subjects, adults who participate in high-intensity RET have maintained or improved bone

mineral density, with a direct relationship between muscle and bone adaptations (level of evidence, B).


Importance of Exercise and Physical Activity in Older Adults Reviewed CME/CENews Author: Laurie Barclay, MD CME Author: Désirée Lie, MD, MSEd CME/CE Released: 07/08/2009; Valid for credit through 07/08/2010

l Evidence is mixed regarding the effect of RET on metabolic variables (level of evidence, B/C). l In populations at increased risk of falling, multimodal exercise, including strength and balance exercises, and tai chi may

decrease the risk for noninjurious and sometimes injurious falls (level of evidence, C). l Few controlled studies have evaluated the effect of flexibility exercise on range of motion in older adults (level of evidence,

D). l Regular exercise and physical activity are linked to significant improvements in overall psychological well-being, possibly via

effects on self-concept and self-esteem. Physical fitness and AET are linked to a lower risk for clinical depression or anxiety (level of evidence, A/B).

l Cardiovascular fitness and higher levels of physical activity lower the risk for cognitive decline and dementia, based on epidemiologic studies. In experimental studies, AET and RET, alone or especially combined, improve some measures of cognitive functioning, especially those requiring executive control, in previously sedentary older adults (level of evidence, A/B).

l Physical activity appears to be linked to some aspects of quality of life, but the precise nature of the relationship is unclear (level of evidence, D).

l High-intensity RET is effective for treating clinical depression. Additional research should address the optimal intensity and frequency of RET needed to elicit specific improvements in other measures of psychological health and well-being (level of evidence, A/B).

"A combination of AET and RET activities seems to be more effective than either form of training alone in counteracting the detrimental effects of a sedentary lifestyle on the health and functioning of the cardiovascular system and skeletal muscles," the authors of the position stand conclude. "Although there are clear fitness, metabolic, and performance benefits associated with higher-intensity exercise training programs in healthy older adults, it is now evident that such programs do not need to be of high intensity to reduce the risks of developing chronic cardiovascular and metabolic disease. However, the outcome of treatment of some established diseases and geriatric syndromes is more effective with higher-intensity exercise (e.g., type 2 diabetes, clinical depression, osteopenia, sarcopenia, muscle weakness)."

Med Sci Sports Exerc. 2009;41:1510-1530.

(Note: Level A evidence — Overwhelming substantial evidence from randomized controlled trials (RCTs) and observational studies; Level B evidence — Strong, somewhat inconsistent evidence from RCTs and observational studies; Level C evidence — Generally positive evidence from observational and uncontrolled or nonrandomized trials; and Level D — Insufficient evidence).

Clinical Context

The American College of Sports Medicine and the American Heart Association published physical activity and public health recommendations for older adults in 2007. The College now has best practice guidelines that recommend at least 150 minutes of moderate-intensity aerobic activity per week for older adults.

This is a position stand to provide an overview of the structural and physiologic bases of the recommendations, the extent to which exercise influences aging, and the benefits of long-term and short-duration exercise.

Study Highlights

l Studies of long-term physical activity in athletes suggest the following benefits: more favorable body composition with less abdominal and total body fat, greater lean muscle mass and higher bone mineral density, higher oxygen-carrying capacity, and less cardiometabolic stress with reduced coronary risk profile.

l In older people, these benefits translate into lower waist circumference, better lipid profile, better endothelial function, and slower development of disability.

l Sedentary people in the United States typically gain 8 to 9 kg of body weight, mainly fat, between the ages of 18 and 55 years followed by 1 to 2 kg in the next decade.

l Prolonged aerobic exercise slows the age-related accumulation of central body fat and is cardioprotective. l In previously sedentary individuals, 3 or more months of moderate-intensity AET in middle-aged and older adults produces a

lower heart rate; smaller increases in systolic, diastolic, and mean blood pressure; improvements in oxygen uptake capacity; and numerous cardioprotective effects.

l Moderate-intensity AET can reduce the fat gain in overweight adults independent of dietary changes. l Bone health in postmenopausal women and men has been shown to improve with low-intensity weight-bearing activities

such as walking, with a lower rate of bone loss and reduced hip fracture risk.

l AET can also enhance glycemic control at rest, promote clearing of atherogenic lipids, and increase preference for fat as fuel.

l RET with isometric, isokinetic repetitions in older adults is associated with an increase in muscle strength, muscle power, and muscle quality in older adults.

l Moderate- to high-intensity regimens are associated with marked improvements in muscle endurance. l Muscle quality improvements may be greater in younger vs older women. l Significant improvements in bone mineral density at most sites have been noted in both premenopausal and

postmenopausal women. l Multimodal exercise, including strength and balance exercises and tai chi, have been shown to reduce the risk for falls in

those prone to falls. l Both AET and RET have been shown to reduce clinical depression and anxiety and improve cognitive function including

tasks requiring complex executive control. l The American College of Sports Medicine and the American Heart Association recommend that older adults engage in

endurance exercise with moderate intensity of 30 to 60 minutes per day in at least 10-minute bouts to at least 150 to 300 minutes per week.

l Vigorous-intensity activities are recommended at 20 to 30 minutes per day for a total of 75 to 150 minutes per week. l RET is recommended at least 2 days per week at moderate to vigorous intensity. l Balance exercises are recommended for those at risk for falls or for those with mobility problems. l There is no specific recommendation for frequency and duration of balance exercises because of insufficient evidence. l The following guidelines are recommended: progressively difficult postures that gradually reduce the base of support,

dynamic activities that perturb the center of gravity (eg, tandem walks, circle turns), stressing postural muscle groups, and reducing sensory input (eg, shutting the eyes while standing).

l For older adults who are highly deconditioned, have chronic diseases, or who are functionally limited, intensity and duration should be low and graded gradually.

l Older adults should perform physical activity as tolerated to avoid being sedentary.


l The benefits of AET and RET in older adults include cardiovascular and metabolic protection, reduced body fat, improved bone health, reduced depression and anxiety, and improved cognition.

l AET at moderate intensity is recommended at 150 to 300 minutes per week, RET at 2 days a week, and balance exercises for those at risk for falls.

CME/CE Test


Which of the following best describes the benefits of RET in older adults?

Improves muscle strength but not muscle quality Reduces clinical depression

Improves muscle quality in women but not in men

Only high-intensity regimens improve muscle endurance

Which of the following best describes the American College of Sports Medicine and American Heart Association recommendations for balance exercises in older adults at risk of falling?

At least 75 minutes per week

Should be at moderate to high intensity

At least 20 minutes per session

No specific recommendation

Save and Proceed

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.


Author(s)

Laurie Barclay, MD


Editor(s)



Nurse Planner

Laurie Scudder, MS, NP


CME Author(s)



June 05, 2009 — Despite being a key cause of heart disease, obesity appears to be protective in a range of cardiovascular problems, a new review concludes [1]. But that doesn't mean people shouldn't try to lose weight, lead author on the paper, Dr Carl J Lavie (Ochsner Medical Center, New Orleans, LA), told heartwire . Indeed, patients who fare the best seem to be obese patients who manage to lose some weight, he said.

"First, obesity is a very strong risk factor and increases all types of heart disease, but second, once you get heart disease, the obese patients do better, so their prognosis is not doomsday," Lavie explained. "In fact, if you have obese patients with congestive heart failure or coronary heart disease or other heart disorders, those patients actually have a pretty good prognosis if they are treated well. But third, the ones who lose weight do even better."

According to Lavie, there is solid evidence to suggest that being overweight or obese may improve survival, not just in heart failure, but also in diseases like hypertension, coronary artery disease, and peripheral artery disease.

"There are a large number of cardiologists who don't even recognize that this is the case, and they are confused about it, too. It is honestly a confusing topic because if obesity is so bad, and it contributes to all cardiovascular risk factors and markedly increases the prevalence of developing heart disease of almost every type, then why, once they get it, do obese patients do better?"

The new review appears in the May 26, 2009 issue of the Journal of the American College of Cardiology (JACC) [1].

Obesity Likely Protects Through Various Mechanisms

The protective effects of excess weight have been best documented in heart-failure patients, where patients with higher body weight or percent body fat have demonstrated better event-free survival. In this setting, says Lavie, extra weight may function much the same way it does with cancer and other chronic diseases, by providing the body with additional fuel to help fight the disease.

Less well known is the relationship between obesity and hypertension, Lavie et al note. While people who are obese do have more hypertension, five papers spanning almost 20 years also point to the fact that obese people with hypertension seem to have lower mortality and/or lower stroke risk, despite less effective blood-pressure control, than do normal-weight people. In this setting, obese patients "may have a better prognosis in part because of having lower systemic vascular resistance and plasma renin activity compared with more lean hypertensive patients," Lavie et al write.

Also incompletely understood is the paradoxical relationship of obesity and coronary and peripheral artery diseases. Obesity is believed to play a causal role in the development of a number of major risk factors for arterial disease, among them hypertension, dyslipidemia, and diabetes, and is believed to be, in and of itself, a risk factor for atherosclerosis. But according to the JACC authors, there is also literature to suggest that overweight and obese coronary heart disease patients have a lower risk for mortality compared with under- and normal-weight coronary heart disease patients who have undergone revascularization procedures. A similar contradictory relationship has been seen in patients with peripheral artery disease.

Speaking with heartwire , Lavie emphasized that the protective effects of excess weight and excess fat likely function in different ways in different diseases. "We know that fat cells do a lot of bad things, but it's certainly conceivable that in advanced disease, the fat cell could have some beneficial effects. There's still a lot that needs to be known about this process."

Weight Loss Still Key

A key new piece of the puzzle that emerged in Lavie et al's review, however, is that weight loss, often touted as a way to reduce cardiovascular risk, appears to be a good thing in spite of the protective effects of extra weight.

"For people who follow this field, these kinds of findings have led them to question whether weight loss is good for heart-disease patients. . . . We found that the patients who do the best are the obese patients who lose weight."

This additional contradiction may be explained in part by the theory that heart disease in obese patients is likely "a different disease" than heart disease in lean people, in whom genetic factors are probably more important. "It may be that the obese person wouldn't have even gotten blocked arteries if [he] hadn't gained 70 pounds over a 30-year period," Lavie said. "The thin person who gets blocked arteries or congestive heart failure or high blood pressure is probably different from the obese patient who got the disease from becoming obese."

From Heartwire CME

Obesity Paradox Probed in New Review CMENews Author: Shelley Wood CME Author: Laurie Barclay, MD CME Released: 06/05/2009; Valid for credit through 06/05/2010

For now, he says, it's important particularly for the general public to appreciate that the "protective" effects of obesity in no way provide a rationale for weight gain. "Very clearly," he said, "if no one in our country became overweight or obese, heart-disease rates would go down dramatically."

For physicians, the data today are sufficiently comprehensive for them to encourage their overweight and obese patients to stay motivated to reduce their risk factors. That wasn't always the case, he added. "When people were finding this in their data, five and six years ago, they probably had some trouble getting their papers published, because it didn't make any sense."

The authors do not list any disclosures.

References

1. Lavie CJ, Milani RV, Ventura HO. Obesity and cardiovascular disease. Risk factor, paradox, and impact of weight loss. J Am Coll Cardiol 2009; 53:1925–1932.

Clinical Context

The prevalence of obesity in US adults increased by nearly 50% during the 1980s and 1990s, resulting in nearly 70% of adults being classified as overweight or obese vs fewer than 25% 4 decades ago. Compared with the increase in the proportion of the population with overweight and mild obesity, the proportion with morbid obesity has increased by an even greater extent.

The morbidity attributable to obesity is even greater vs smoking, alcoholism, and poverty. Based on current projections, obesity may soon become the leading cause of preventable death in the United States (which is now cigarette abuse).

Study Highlights

l Overweight in adults is defined as body mass index of 25 to 29.9 kg/m2 and obesity as body mass index of 30 kg/m2 or more. l Indices of obesity that may have more predictive power vs body mass index include body fatness, waist circumference,

waist-to-hip ratio, and weight-to-height ratio. l In both adults and children, obesity has reached global epidemic proportions, which may result in an end to the steady

increase in life expectancy. l Many comorbid conditions have been linked to obesity, including hypertension, type 2 diabetes mellitus, and dyslipidemia. l In addition to type 2 diabetes, obesity may contribute to other increases in insulin resistance such as glucose intolerance and

metabolic syndrome. l Dyslipidemias linked with obesity include elevated total cholesterol; triglycerides; low-density lipoprotein cholesterol; non-

high-density lipoprotein cholesterol; apolipoprotein-B; and small, dense low-density lipoprotein cholesterol particles; and decreased high-density lipoprotein cholesterol and apolipoprotein A-1 levels.

l Obesity increases the risk for cardiovascular abnormalities, including left ventricular concentric remodeling or hypertrophy, endothelial dysfunction, increased systemic inflammation and prothrombotic state, and systolic and diastolic dysfunction.

l Obesity is linked to increased prevalence and severity of cardiovascular diseases including heart failure, coronary heart disease, sudden cardiac death, and atrial fibrillation.

l Noncardiovascular diseases associated with obesity include obstructive sleep apnea, sleep-disordered breathing, albuminuria, osteoarthritis, and specific cancers.

l The importance of obesity in the pathogenesis and progression of cardiovascular disease is confirmed by overwhelming evidence.

l Overall survival duration is decreased in obese patients. l The obesity paradox refers to the unexpectedly better short- and long-term prognosis, confirmed by evidence from clinical

cohorts of patients with established cardiovascular diseases (eg, hypertension, heart failure, coronary heart disease, and peripheral arterial disease) of overweight and obese vs nonoverweight/nonobese people with these diseases.

l Reasons for the obesity paradox are unclear. l Obese patients with hypertension may have a better prognosis vs those who are lean, possibly because of lower systemic

vascular resistance and plasma renin activity. l Excess body weight may offer some protection against heart failure mortality, perhaps because of more metabolic reserve

and protective cytokines and neuroendocrine profiles. l The review also describes current understanding of the role of weight reduction in preventing and treating cardiovascular

disease. l Despite the obesity paradox, the bulk of evidence still supports voluntary weight loss for prevention and treatment of

cardiovascular disease. l Lifestyle interventions (exercise training and energy restriction resulting in mild weight loss) may reduce risk for type 2

diabetes by nearly 60%. l Patients with hypertension who lose weight have significant decreases in arterial pressure. l In heart failure, weight loss may be associated with improvements in left ventricular mass and in systolic and diastolic

ventricular function. l Bariatric surgery in obese patients is associated with short- and long-term reductions in major morbidity and all-cause

mortality, particularly related to cancer, diabetes, cardiovascular disease, and long-term lowering of cardiovascular risk. l More research is needed in the metabolic consequences of obesity, the pathophysiologic effects of obesity on cardiovascular

risk factors and disease, and the potential risks and benefits of purposeful weight loss.


l Many comorbid conditions have been linked to obesity, including cardiovascular risk factors such as hypertension, type 2 diabetes, and dyslipidemia. Cardiovascular abnormalities associated with obesity include left ventricular concentric remodeling or hypertrophy, endothelial dysfunction, increased systemic inflammation and prothrombotic state, and systolic and diastolic dysfunction.

l Reasons for the obesity paradox, or the unexpectedly better prognosis of obese vs nonobese patients with established cardiovascular diseases, are unclear. Despite the obesity paradox, the bulk of evidence still supports voluntary weight loss for prevention and treatment of cardiovascular diseases.

CME Test


According to the review by Lavie and colleagues, which of the following statements about cardiovascular risk factors and diseases associated with obesity is not correct?

Cardiovascular risk factors associated with obesity include hypertension, dyslipidemia, and type 2 diabetes

Prothrombotic state has not been linked to obesity

Risk for sudden cardiac death is increased in obese patients Obesity increases the risk for left ventricular concentric remodeling or hypertrophy

According to the review by Lavie and colleagues, which of the following statements about the role of weight reduction in the prevention and treatment of cardiovascular diseases in obese patients is correct?

For patients with established cardiovascular diseases, those who are lean have a better prognosis vs those who are obese

The obesity paradox is well understood

Bariatric surgery is too risky in obese patients

Despite the obesity paradox, the bulk of evidence still supports voluntary weight loss for prevention and treatment of cardiovascular diseases

Save and Proceed



Author(s)


Shelley Wood

Shelley Wood is a journalist for theheart.org, part of the WebMD Professional Network. She has been with theheart.org since 2000, and specializes in interventional cardiology. She studied literature at McGill University and the University of Cape Town and received her graduate degree in journalism from the University of British Columbia, specializing in health reporting. She can be reached at [email protected]. Disclosure: Shelley Wood has disclosed no relevant financial relationships.

Editor(s)



CME Author(s)

Laurie Barclay, MD


October 26, 2009 — The International Diabetes Federation (IDF) announced the release of several new guidelines related to diabetes management here at the IDF 20th World Diabetes Congress. These include the first-ever international guidelines on the management of diabetes in pregnancy and guidelines on the use of self-monitoring of blood glucose (SMBG) among type 2 diabetic patients not being treated with insulin.

Pregnancy and Diabetes Guidelines Call for Universal Screening

Lois Jovanovič, MD, CEO and chief scientific officer of Sansum Diabetes Research Institute in Santa Barbara, California, and clinical professor of medicine at the University of Southern California-Los Angeles Medical Center, is one of the authors of the IDF Global Guideline on Pregnancy and Diabetes. "The guidelines were created with evidence-based medicine. Then we asked an international group [of experts] to give us their opinion," she told Medscape Diabetes & Endocrinology.

"There was no international standard [for the diagnosis and management of gestational diabetes], said Dr. Jovanovič. "There was no consensus, there was a lot of confusion, women were suffering, and their pregnancy outcome was affected by having no standard by which to judge whether their diabetes was worth treating or not. This is the first time there is a worldwide consensus."

A key message of the new guidelines, according to Dr. Jovanovič, is the importance of universal screening. "Look for hyperglycemia in pregnancy," she said. "Preconceptional counseling [also] has to be universal. . . . For a [primary care] physician who has a [patient] in child-bearing years, the first question should be: Are you interested in getting pregnant again?"

Self-Monitoring of Blood Glucose in Noninsulin-Treated Type 2 Diabetes

The IDF Guideline on Self-Monitoring of Blood Glucose in Non-Insulin Treated Type 2 Diabetes was developed in a manner similar to the IDF pregnancy guidelines. Their highlights include the following:

l SMBG should be considered at the time of diagnosis but should only be used when patients, their caregivers, and/or their healthcare providers have the knowledge and willingness to incorporate findings into the diabetes management plan.

l SMBG should be considered a part of ongoing diabetes self-management education. l SMBG protocols should be individualized. l Patients and their healthcare providers should agree on how to use SMBG data. l Tools used to measure SMBG must be easy to use and accurate.

Unique Features of Guidelines

Both sets of guidelines have key features that differentiate them from guidelines on the same topics put out by other diabetes associations, such as the American Diabetes Association (ADA), said Dr. Jovanovič.

"The ADA hopefully will change soon, but right now they don't subscribe to the philosophy of universal screening [in pregnancy]. They talk about selective screening. Our guidelines not only talk about universal screening but almost assume that every woman has diabetes [and] doing the testing is to reassure her that she doesn't. So, it's a paradigm shift. The second major difference is the [IDF] recommendation that it be a 1-step [oral glucose tolerance] test, not a 2-step test [as currently recommended by the ADA]. The ADA also have the criteria for diagnosis [of gestational diabetes] very high to minimize the number of women identified. The strategies in the [IDF] guidelines actually increase the number of women that would be identified and therefore offer treatment worldwide with 1 standard of care."

According to a coauthor of the SMBG guidelines, David Owens, MD, from the Cardiff University Diabetes Research Unit in the United Kingdom, a unique feature of the IDF SMBG guidelines is that they clarify the role of SMBG in diabetic patients who are not receiving insulin therapy. "For the noninsulin-treated individuals, [other guidelines] say that it's a good idea to incorporate SMBG, . . . but there is no real clarity as to what to do about it. That's where we've tried to extend the story more toward what the patient can do about it in their circumstances. . . . There are [other] guidelines that suggest that maybe there's no reason to monitor blood glucose in the noninsulin-treated, and they say that . . . you need to look at the current evidence and see its limitations. Many of those publications are really not designed to ask [that] question."

Dr. Jovanovič has disclosed no relevant financial relationships. Dr. Owens reports being paid for lecturing by Roche Diagnostics, Sanofi-Aventis, Novo Nordisk, Merck Sharpe & Dohme, LifeScan, and Pfizer; being on advisory boards for Roche Diagnostics,


IDF Releases New Guidelines on Diabetes Management CMENews Author: Alison Palkhivala CME Author: Désirée Lie, MD, MSEd CME Released: 10/26/2009; Valid for credit through 10/26/2010

Sanofi-Aventis, Novo Nordisk, Merck Sharpe & Dohme, LifeScan, and Pfizer; and receiving research funding from Sanofi-Aventis and Novo Nordisk.

International Diabetes Federation (IDF) 20th World Diabetes Congress: Abstracts 0498 and 0499. Presented October 22, 2009.

Study Highlights

l Pregnancy and diabetes ¡ A 1-stage oral glucose tolerance test at 26 to 28 weeks' gestation is recommended to screen all pregnant women for

gestational diabetes vs the ADA recommendation for selective screening in at-risk women only. ¡ For women at high risk for diabetes because of previous gestational diabetes, screening should be performed as soon

as practical and should be repeated at 26 to 28 weeks' gestation. ¡ For women with preexisting diabetes, glycemic control should be optimized before planned pregnancy. ¡ Angiotensin-converting enzyme inhibitors and angiotensin-II receptor blockers should be stopped and substituted with

appropriate medications in pregnant women. ¡ Statins, fibrates, and niacin should be stopped in pregnancy. ¡ In women with existing diabetes or gestational diabetes, risks for glucose-lowering agents should be discussed, and

use of insulin and the type of insulin should be assessed and discussed. ¡ A hemoglobin A1c target of 6.0% or lower is desired in pregnant women with diabetes. ¡ If possible, SMBG should be done frequently in pregnant women with diabetes. ¡ Doses of glucose-lowering agents should be adjusted according to self-monitoring results, hemoglobin A1c level, and

experience of hypoglycemia. ¡ Eyes should be examined at the first prenatal visit and at each trimester. ¡ Breast-feeding should be encouraged.

l SMBG ¡ SMBG should be performed to attain agreed-on treatment goals, and results should be acted on. ¡ Protocols (intensity and frequency) for SMBG should be individualized to specific behavioral and clinical requirements

and meet the needs of therapeutic decision making. ¡ SMBG should be performed in patients with type 2 diabetes in conjunction with self-management and education of

patients. ¡ An easy procedure should be available to patients who perform SMBG to monitor the performance and accuracy of

their glucose meter.


l The IDF recommends screening all pregnant women for diabetes using a 1-stage testing process. l SMBG should be performed to attain specific treatment goals.

CME Test

Which of the following best describes the recommendation of the IDF for screening of pregnant women for diabetes?

Women with abnormal weight gain should be screened

Only women with previous gestational diabetes should be screened

Both A and B All pregnant women should be screened

Which of the following best describes the IDF recommendation for SMBG in patients with type 2 diabetes?

SMBG should be performed in all patients with type 2 diabetes

SMBG should be performed when diabetes is out of control

SMBG should be individualized for therapy goals



SMBG should be performed when hemoglobin A1c level is more than 6.0%

Save and Proceed



Author(s)

Alison Palkhivala

Alison Palkhivala is a freelance writer for Medscape. Disclosure: Alison Palkhivala has disclosed no relevant financial information.

Editor(s)



CME Author(s)



CME Reviewer(s)

Sarah Fleischman

CME Program Manager, MedscapeCME Disclosure: Sarah Fleischman has disclosed that she has no relevant financial relationships.

May 11, 2009 — A consensus statement of the American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association (ADA) issues clinical recommendations on the proper treatment of hospitalized patients with high blood glucose levels.

The new guidelines, which target healthcare professionals, supporting staff, hospital administrators, and others involved in improved management of hyperglycemia in inpatient settings, are published in the May/June issue of Endocrine Practice and in the May issue of Diabetes Care.

"Although the costs of illness-related stress hyperglycemia are not known, they are likely to be considerable in light of the poor prognosis of such patients," write Etie S. Moghissi, MD, FACP, FACE, from the University of California in Los Angeles, and colleagues. "There is substantial observational evidence linking hyperglycemia in hospitalized patients (with or without diabetes) to poor outcomes. Cohort studies as well as a few early randomized controlled trials (RCTs) suggested that intensive treatment of hyperglycemia improved hospital outcomes."

In 2004, the American College of Endocrinology (ACE) and the AACE, in collaboration with the ADA and other medical organizations, developed recommendations for treatment of inpatient hyperglycemia. These guidelines generally endorsed tight glycemic control in critical care units. In 2005, the ADA annual Standards of Medical Care included recommendations for treatment of inpatient hyperglycemia. In 2006, the ACE and ADA collaborated on a joint "Call to Action" for inpatient glycemic control, highlighting several barriers to systematic implementation in hospitals.

Questions to Be Considered

The main objectives of the AACE and ADA in preparing this updated consensus statement were to identify reasonable, achievable, and safe glycemic targets and to describe the protocols, procedures, and system improvements needed to facilitate their implementation. After extensive review of the most current literature, members of the consensus panel considered the following questions:

1. Does improving glycemic control for inpatients with hyperglycemia improve clinical outcomes?

2. What glycemic targets should be recommended for different patient populations?

3. In specific clinical situations, which available treatment options can safely and effectively achieve optimal glycemic targets?

4. What safety issues are associated with inpatient management of hyperglycemia?

5. What systems need to be in place to implement these recommendations?

6. Is it cost-effective to treat hyperglycemia in hospitalized patients?

7. What are the best strategies to shift management of hyperglycemia to outpatient care?

8. What additional research is needed?

Recommendations for Critically Ill Patients

Specific clinical recommendations for critically ill patients are as follows:

• For treatment of persistent hyperglycemia, beginning at a threshold of no greater than 180 mg/dL (10.0 mmol/L), insulin therapy should be started.

• For most critically ill patients, a glucose range of 140 to 180 mg/dL (7.8 - 10.0 mmol/L) is recommended once insulin therapy has been started.

• To achieve and maintain glycemic control in critically ill patients, the preferred method is intravenous insulin infusions.

• Validated insulin infusion protocols that are shown to be safe and effective and to have low rates of hypoglycemia are

From Medscape Medical News

New Guidelines Address Treatment of Hospitalized Patients With High Blood Glucose Levels CME/CE

News Author: Laurie Barclay, MD CME Author: Charles Vega, MD, FAAFP CME/CE Released: 05/11/2009; Valid for credit through 05/11/2010

recommended.

• To reduce hypoglycemia and to achieve optimal glucose control, frequent glucose monitoring is essential in patients receiving intravenous insulin.

Recommendations for Patients Who Are Not Critically Ill

Specific clinical recommendations for noncritically ill patients are as follows:

• For most noncritically ill patients receiving insulin therapy, the premeal blood glucose target should generally be less than 140 mg/dL (< 7.8 mmol/L), and random blood glucose levels should be less than 180 mg/dL (< 10.0 mmol/L), provided these targets can be safely achieved.

• In stable patients in whom tight glycemic control was previously achieved, more rigorous targets may be appropriate.

• In terminally ill patients or in those with severe comorbidities, less stringent targets may be appropriate.

• For achieving and maintaining glucose control, the preferred method is scheduled subcutaneous administration of insulin, with basal, nutritional, and correction components.

• Prolonged treatment with sliding-scale insulin as the only therapeutic agent is discouraged.

• For most hospitalized patients who require treatment of hyperglycemia, noninsulin antihyperglycemic agents are not appropriate.

• Day-to-day decisions concerning treatment of hyperglycemia must be based on clinical judgment and ongoing evaluation of clinical status.

Safety Recommendations

Specific recommendations geared toward improving safety in management of inpatient hyperglycemia are as follows:

• Major safety issues include overtreatment and undertreatment of hyperglycemia.

• Hospital staff must be educated to engage the support of those involved in the care of inpatients with hyperglycemia.

• In patients with anemia, polycythemia, hypoperfusion, or use of some medications, caution is needed when interpreting results of point-of-care glucose meters.

• To promote a rational systems approach to inpatient glycemic management, buy-in and financial support from hospital administration are required.

The guidelines also propose a selected number of research questions and topics to guide the management of inpatient hyperglycemia in different hospital settings.

"Appropriate inpatient management of hyperglycemia is cost-effective," the guidelines authors conclude. "Preparation for transition to the outpatient setting should begin at the time of hospital admission. Discharge planning, patient education, and clear communication with outpatient providers are critical for ensuring a safe and successful transition to outpatient glycemic management."

Some of the guidelines authors have disclosed various financial relationships with sanofi-aventis U.S. LLC; Amylin Pharmaceuticals, Inc;Takeda Pharmaceuticals North America, Inc; AstraZeneca; GlaxoSmithKline; Johnson & Johnson Services, Inc; Eli Lilly & Co; Medtronic, Inc; Novo Nordisk A/S; Halozyme Therapeutics; MannKind Corporation; Abbott Laboratories; F. Hoffman La Roche Ltd. (Roche); and/or Merck & Co.

Endocr Pract. 2009;15:1-15.

Diabetes Care. Published online May 8, 2009.

Clinical Context

Hyperglycemia is common in the inpatient setting, and reducing high blood glucose levels is associated with better patient outcomes. However, a study by Finfer and colleagues, which was published in the March 26, 2009, issue of The New England

Journal of Medicine, found that more intense glucose treatment could actually result in higher mortality rates in critically ill patients.

Compared with a cohort of patients randomly assigned to a target blood glucose level of 180 mg/dL or less, participants randomly selected to target glucose levels of 81 to 108 mg/dL experienced a 14% increase in the risk for death. Rates of hypoglycemia were much higher in the intensive vs standard-control group, and intensive therapy did not significantly alter the duration of hospital stay, the need for renal replacement therapy, or the number of days of mechanical ventilation.

The current review examines the sum of evidence for the management of hyperglycemia in inpatient settings and makes treatment recommendations.

Study Highlights

l Treatment of hyperglycemia is associated with reduced rates of wound infection after cardiothoracic surgery, lower rates of infection and lower poor neurologic outcomes in patients with traumatic brain injury, and reduced rates of congestive heart failure after acute myocardial infarction.

l The current recommendations state that hyperglycemia be treated at a threshold of 180 mg/dL in critically ill patients. The target glucose level should be between 140 and 180 mg/dL.

l Intravenous insulin infusion is the preferred means of treatment of hyperglycemia in critically ill patients. l There is less clinical evidence regarding the treatment of hyperglycemia in hospitalized patients who are not critically ill, so the

current recommendations regarding this subject are based on clinical experience and judgment. The authors suggest that premeal glucose targets should be less than 140 mg/dL, and random blood glucose values should be less than 180 mg/dL.

l Less stringent treatment criteria may be appropriate for terminally ill patients and those with severe comorbidities. l To avoid hypoglycemia in patients without critical illness, clinicians should consider altering the insulin regimen if blood

glucose levels decline below 100 mg/dL. l The ideal treatment of hyperglycemia in noncritically ill hospitalized patients should involve basal, nutritional, and correction

insulin delivered subcutaneously. l Treatment with sliding-scale insulin therapy alone is discouraged, and noninsulin antihyperglycemic agents do not have a

significant role among inpatients. l Hyperglycemia develops in many patients receiving corticosteroids. These patients should receive at least 48 hours of blood

glucose monitoring and treatment as appropriate. l In patients receiving continuous enteral or parenteral nutrition, blood glucose monitoring should be performed every 4 to 6

hours. Glucose testing should be performed every 30 minutes to 2 hours in patients receiving intravenous insulin infusions. l Appropriate inpatient management of hyperglycemia is cost-effective. l Multidisciplinary teams can establish and enforce local hospital recommendations regarding inpatient treatment of

hyperglycemia, and preprinted order sets and computerized ordering systems can improve guideline adherence.


l A recent study found a higher risk for death associated with more intensive treatment of hyperglycemia in critically ill patients. l The current recommendations suggest that antihyperglycemic treatment should begin when the blood glucose level reaches

180 mg/dL among critically ill inpatients, and blood glucose levels should be maintained between 140 and 180 mg/dL in these patients. Blood glucose levels should be maintained below 140 mg/dL before meals and below 180 mg/dL at random times among other inpatients.

CME/CE Test

Which of the following outcomes was significantly different in comparing the intensive glucose control group vs the standard glucose control group in the previous study by Finfer and colleagues?

Overall mortality rate

Duration of mechanical ventilation

Duration of hospital stay

Need for renal replacement therapy


The current guidelines by Moghissi and colleagues recommend all of the following interventions for the treatment of hyperglycemia except:

Initiation of treatment when the glucose level is at a threshold of no higher than 180 mg/dL in critically ill patients

A target blood glucose level between 140 and 180 mg/dL in all critically ill patients A blood glucose level below 100 mg/dL before meals among inpatients without critical illness

A random blood glucose level less than 180 mg/dL among inpatients without critical illness

Save and Proceed



Author(s)

Laurie Barclay, MD


Editor(s)



Nurse Planner

Laurie Scudder, MS, NP


CME Author(s)

Charles P. Vega, MD

Charles P. Vega, MD, FAAFP, is an associate professor and residency director in the Department of Family Medicine at the University of California, Irvine. Disclosure: Charles Vega, MD, FAAFP, has disclosed no relevant financial relationships.

Medscape Medical News © 2009 MedscapeCME The material presented here does not necessarily reflect the views of Medscape or companies that support educational programming on www.medscapecme.com. 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 [email protected].

November 16, 2009 — A new study has shown that walking speed over 6 m in older people is predictive of cardiovascular mortality, with those in the slowest tertile three times more likely to suffer CV death over five years than those who walked faster [1]. Dr Julien Dumurgier (INSERM, Paris, France) and colleagues say this kind of walking test could be part of a general clinical assessment of those aged over 65; they report their findings online November 10, 2009 in BMJ.

"We found that old persons who walk slowly have an increased risk of death, in particular cardiovascular death; it's an easy message," second author, epidemiologist Dr Alexis Elbaz (INSERM), told heartwire . "This shows us the very important role of trying to maintain good fitness in older persons," he added.

Geriatricians Drs Rowan H Harwood (Queen's Medical Center, Nottingham, UK) and Simon P Conroy (Leicester Royal Infirmary, Leicester, UK) are the authors of an editorial accompanying the study [2]. Harwood told heartwire that the study was "technically well done," if not new information.

Nevertheless, he says, what the French group has done, "nicely, is that they show a strong relationship" between slow walking speed and cardiovascular death. "People have looked at vascular events before and they have looked at vascular mortality, but they haven't put it in the context of all the other sorts of mortality, and they haven't pulled mortality apart in the way that this group did."

No Association Between Walking Speed and Cancer Mortality

In their linked prospective cohort study, Dumurgier and colleagues recruited 3208 men and women living in the community in Dijon between 1999 and 2001 aged 65 or older who were participating in the Three-City study. They were followed for an average of 5.1 years.

The main outcome measures were mortality overall and according to the main cause of death, by tertiles of baseline walking speed, adjusted for several potential confounders.

Elbaz explained that walking speed was measured by asking participants to walk at their usual speed and then asking them to walk, over 6 m down a corridor, at their maximum pace without running. Although chronometers were used in this study, this measure could also be simply performed in a doctor's office using a watch or timer, to obtain walking speed in meters per second, he noted.

During follow-up, 209 participants died (99 from cancer, 59 from cardiovascular disease, 51 from other causes); those in the lowest third of baseline walking speed had a 44% increased risk of death (hazard ratio 1.44), compared with the upper tertiles.

Analyses for specific causes of death showed that those with a low walking speed had about a threefold increased risk of cardiovascular death (HR 2.92) compared with participants who walked faster. There was no association between walking speed and cancer mortality (HR 1.03), however.

Walking Speed: An Objective Measure of Physical Fitness

Elbaz said that assessment of walking speed is simple and can be performed easily in a routine clinical setting, "in fact, some geriatricians already do this kind of thing, following the measure over time, seeing if it remains stable, etc," he noted.

However, he cautioned that walking speed should not be used in isolation to identify people at high risk of cardiovascular death but rather "in the context of a global assessment." And he noted that the participants studied by his group were community-dwelling, well-functioning older people in fairly good health who were able to come by themselves to the study center. Assessment of older, frailer individuals "is more complicated," he admitted.

Harwood said: "I would like to caution against being too simplistic. One of the things this study is telling us is how fit someone is, which is a reflection of how much exercise they do, and we know exercise is good for us." And he says that in an observational study, "you can never completely adjust for all confounders, so residual confounding is always a problem."

But he agrees that measuring walking speed in this way is, at least, "an objective measure of physical performance, and it's far more accurate than asking a person how much regular exercise they do. It's a bit like the difference between asking a person how much they eat and weighing them."

References

From Heartwire CME

Walking Speed Predicts CV Mortality in Older People CMENews Author: Lisa Nainggolan CME Author: Charles P. Vega, MD CME Released: 11/16/2009; Valid for credit through 11/16/2010

1. Dumurgier J, Elbaz A, Ducimetiere P, et al. Slow walking speed and cardiovascular death in well functioning older adults: prospective cohort study. BMJ 2009; DOI: 10.1136/bmj.b4460. Available at: http://www.bmj.com.

2. Harwood RH and Conroy SP. Slow walking speed in elderly people. BMJ 2009; DOI:10.1136/bmj.b4236. Available at: http://www.bmj.com.

Clinical Context

Walking is one of the favorite activity pastimes of older adults, but few of them might consider that increasing their speed and agility may prevent hospitalization or disability. However, a study by Cesari and colleagues, which was published in the October 2005 issue of the Journal of the American Geriatric Society, demonstrated that walking speed translates into important clinical outcomes. Among 3047 older adults, those with a walking speed of less than 1 meter per second were more likely to have a hospitalization or lower extremity disability vs older adults with a faster walking speed.

The Cesari study also suggested that participants with a slower walking speed also experienced an increased risk for death. The current study further investigates this issue.

Study Highlights

l Study researchers recruited community-dwelling adults between the ages of 65 and 85 years from 3 cities in France. l Participants provided demographic and medical information at baseline. They also underwent an assessment of

cardiovascular risk factors. l Participants also performed a 6-meter walk test at their regular pace and maximal velocity. l Researchers reevaluated participants approximately every 2 years for a mean of 5.1 years. The main outcome of the study

was the rate of overall mortality. Researchers also examined the rates of cardiovascular and cancer mortality. All of these outcomes were adjusted to account for baseline risk factors for mortality. In addition, researchers accounted for covariates, such as baseline physical activity, which might affect walking velocity.

l 3208 participants provided data for analysis. The mean age was 73.2 years, and 65% of subjects were women. l There were 209 deaths during a total of 16,414 person-years. Participants who died were more likely to be men and have

more cardiovascular risks. l Participants in the lowest third of walking speed were older, smaller, had a higher body mass index, and had lower physical

activity levels and higher depression scores. Slower participants were also more likely to have hypertension or diabetes. l There was no difference in any mortality outcome in comparing the middle vs upper tertiles of walking speed. l Compared with the upper tertile of walking speed, those in the lowest tertile experienced a significant HR of 1.44 for all-cause

mortality. l The risk for cardiovascular death was nearly 3 times as high in comparing the lowest vs the highest tertile of walking speed. l Walking speed had no significant effect on the risk for cancer mortality. l Slow walking speed was associated with a higher risk for death in subgroup analyses based on sex, median age, median

body mass index, the presence of coronary artery disease, and baseline level of physical activity.


l A previous study found that slower walking speed among older adults predicted higher risks for lower extremity disability and hospitalization.

l In the current study, slower walking speed was associated with higher risks for overall and cardiovascular mortality, but walking speed had no independent effect on the risk for cancer mortality.

CME Test

Slower walking speed was associated with which of the following outcomes in the previous study by Cesari and colleagues?

Lower extremity disability only

A higher risk for hospitalization only


Higher risks for lower extremity disability and hospitalization

Neither lower extremity disability nor hospitalization

Slow walking speed increased the risks for which of the following mortality outcomes in the current study by Dumurgier and colleagues?

Overall mortality and cardiovascular mortality

Overall mortality and cancer mortality

Cancer mortality and cardiovascular mortality

Cardiovascular mortality only

Save and Proceed



Author(s)

Lisa Nainggolan

Lisa Nainggolan is a journalist for theheart.org, part of the WebMD Professional Network. She has been with theheart.org since 2000. 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 1995. She can be reached at [email protected]. Disclosure: Lisa Nainggolan has disclosed no relevant financial information.

Editor(s)



CME Author(s)

Charles P. Vega, MD

CME Reviewer(s)

Associate Professor and Residency Director, Department of Family Medicine, University of California-Irvine, Irvine California Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.

Disclaimer The material presented here does not necessarily reflect the views of MedscapeCME or companies that support educational programming on www.medscapecme.com. 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 [email protected].

Heartwire CME © 2009 MedscapeCME

Sarah Fleischman

CME Program Manager, MedscapeCME Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.

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