ATS 2009: Flu Vaccination May Triple Risk for Flu-Related Hospitalization in Children With Asthma

Trivalent inactivated flu vaccine (TIV) was not an effective protection against hospitalization in pediatric populations, particularly in children with asthma; in fact, there was a 3-fold increased risk for hospitalization in asthmatic children who received the TIV, according to a study released here at ATS 2009: the American Thoracic Society International Conference. However, experts agree that this is not a reason to stop vaccinating children with asthma, because the vaccine is still helpful in making protective antibodies.

Dr. Avni Joshi

"The flu shot is a killed vaccine. Inherently, it's a safe vaccine so we tend to give it to everyone, but we don't think about how effective it is — especially in asthmatic children," lead investigator Avni Joshi, MD, fellow, instructor in pediatric medicine, and fellow-in-training in allergy and infectious diseases, Division of Allergic Diseases, Mayo Clinic, Rochester, Minnesota, told Medscape Pulmonary Medicine in an interview after her presentation. "Just because a flu shot has proved to be very safe for kids, especially those with asthma, [doesn't mean we] know how effective it is in preventing hospitalizations in cases of influenza in all children, particularly those with asthma."

Currently, the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices and the American Academy of Pediatrics recommend annual influenza vaccination for all children 6 months to 18 years. The National Asthma Education and Prevention Program (third revision) also recommends annual flu vaccination of asthmatic children older than 6 months.

This was a cohort study that evaluated the efficacy of TIV in all pediatric patients 6 months to 18 years with laboratory-confirmed influenza (263 children) who were seen at the Mayo Clinic during flu seasons from 1999 to 2006. TIV has unknown effects on patients with asthma.

Dr. Joshi and colleagues determined which subjects had received the flu vaccine and which subjects had not. They then looked at asthma status, and determined which subjects required hospitalization and which did not. The record for each subject in which flu vaccination status was noted before illness and hospitalization was reviewed.

The study found an overall trend toward higher rates of hospitalization in subjects who received TIV than in those who did not (odds ratio [OR], 2.97; 95% confidence interval [CI], 1.3 - 6.7). They used the Cochran-Mantel-Haenszel test for asthma-status stratification, and documented a significant association between hospitalization in the asthmatic subjects and TIV (P = .006). The severity of asthma did not determine the risk for hospitalization or length of hospital stay. There was also no association between emergency-department visits and having received TIV. In looking at access to medical care, no association between hospitalizations and healthcare insurance plans was found (OR, 0.3; P = .13).

Dr. Joshi pointed to studies that have looked at whether FluMist (a live intranasal influenza virus vaccine) is more effective when there is a mismatch between the vaccine strain and the circulating strain. "But the safety of live vaccine has been questioned by various studies," she said. "It appears to trigger wheezing episodes, especially in children under 2. This study opens the doors to looking at live vaccines, to which we say no most of the time, especially in asthmatics."

Dr. Joshi emphasized: "We should continue vaccinating all children, but continue our quest to find a more effective influenza vaccine."

Dr. Anthony M. Szema

Anthony M. Szema, MD, assistant professor of medicine and surgery at SUNY Stony Brook School of Medicine in New York, commented on Dr. Joshi's study: "These authors do not address mortality protection or specific [immunoglobulin G] antibody production. Nevertheless, the take-home message is that parents should continue to vaccinate their healthy and asthmatic children, but should not be lulled into a false sense of security that, should their children succumb to the flu, this vaccination will prevent hospitalization."

"The point is, if they have asthma and are unlucky enough to get the flu, they're going to get hospitalized more often if they have asthma; this is not a reason to say, 'I'm not going to vaccinate my kids.' Vaccines are supposed to protect against morbidity and mortality against the flu," said Dr. Szema, who said he agreed with Dr. Joshi that a next-generation vaccine that would be able to protect against hospitalization in the asthmatic population would be ideal. "What we have now is helpful in making protective antibodies, but is not completely protective, especially in asthmatics who already have inflamed airways."

ATS 2009: American Thoracic Society International Conference: Abstract 561. Presented May 19, 2009.

Source : http://www.medscape.com/viewarticle/703235?sssdmh=dm1.476505&src=nldne

Ischemic Symptoms Linked to Increased Cardiovascular Risk in Women

Women with symptoms and signs suggesting ischemia but without findings of obstructive coronary artery disease (CAD) may be at higher cardiovascular risk than asymptomatic community-dwelling women, according to the results of a study reported in the May 11 issue of the Archives of Internal Medicine.

"Women with clinical findings suggestive of ischemia but without findings of obstructive...CAD on angiography represent a frequent clinical problem; predicting prognosis is challenging," write Martha Gulati, MD, MS, from Northwestern University in Chicago, Illinois, and colleagues.

In the Women's Ischemia Syndrome Evaluation (WISE) study, women with ischemic symptoms were referred for clinically indicated coronary angiography. Mean duration of follow-up was 5.2 years. In the St. James Women Take Heart (WTH) Project, asymptomatic, community-dwelling women with no history of heart disease at baseline were observed for 10 years.

The investigators compared rates of cardiovascular events, including myocardial infarction, stroke, hospitalization for heart failure, and mortality in 540 women from WISE who had suspected ischemia but no angiographic evidence of obstructive CAD vs those in a cohort of 1000 women from WTH who were matched for age and race.

Baseline prevalence of obesity, family history of CAD, hypertension, and diabetes mellitus were lower in asymptomatic women from WTH vs the matched sample from WISE (P < .001). After adjustment for risk factors for CAD at baseline, 5-year annualized cardiovascular event rates were 16.0% in women from the WISE study with nonobstructive CAD (defined as stenosis in any coronary artery of 1% to 49%) vs 7.9% in the women from WISE with normal coronary arteries (defined as 0% stenosis in all coronary arteries) and 2.4% in asymptomatic women from WTH (P = .002).

Women with 4 or more cardiac risk factors had the highest rate of cardiovascular events. Five-year annualized cardiovascular event rate was 25.3% in women with nonobstructive CAD, 13.9% in women from WISE with normal coronary arteries, and 6.5% in asymptomatic women (P = .003).

"Women with symptoms and signs suggestive of ischemia but without obstructive CAD are at elevated risk for cardiovascular events compared with asymptomatic community-based women," the study authors write.

"Based on our findings reported herein and the findings of others linking endothelial dysfunction and future cardiovascular events, we recommend that all women with symptoms suggestive of ischemia undergo initial evaluation for obstructive CAD. If there is no evidence of obstructive CAD, such women need further assessment for endothelial dysfunction."

Limitations of this study include the referral pattern of the symptomatic women from WISE, because women were referred for a coronary angiogram only if clinically indicated based on signs and symptoms suggesting myocardial ischemia. Women in this group had access to healthcare and volunteered for exercise stress testing, creating other possible bias in this group. Self-report of cardiovascular events in both cohorts creates the potential for recall bias.

Furthermore, cause of death was confirmed by medical records only for deaths in the WISE cohort, and the WTH cohort was reevaluated for cardiovascular events only at 10 years vs annually, again increasing the risk for recall bias. In both cohorts, women came from different geographic regions with different rates of cardiovascular disease, creating possible confounding. Electrocardiography was not available for the full WISE cohort, preventing adjustment for left ventricular hypertrophy.

"Given that CAD remains the leading cause of death in women in the United States and that this clinical scenario of cardiac symptoms in the absence of obstructive CAD is relatively common, future investigations need to expand on the mechanisms and pathophysiologic processes of vascular dysfunction in symptomatic women," the study authors conclude.

"In addition, future research needs to focus on randomized clinical trials to determine the effectiveness of treatment both for symptoms and for endothelial dysfunction. Nonetheless, symptomatic women with normal coronary arteries or nonobstructive CAD do not have a benign prognosis and, as such, should have cardiac risk factors aggressively treated and possibly should be considered for further testing for endothelial dysfunction."

The National Heart, Lung, and Blood Institute; the Gustavus and Louis Pfeiffer Research Foundation; the Women's Guild of Cedars-Sinai Medical Center; and the Ladies Hospital Aid Society of Western Pennsylvania supported this study. The study authors have disclosed no relevant financial relationships.

Arch Intern Med. 2009;169:843-850.

Clinical Context

Women with angina or other symptoms suggesting cardiac ischemia are sometimes not found to have clinically significant CAD on angiography, and management may be problematic. Although these women were originally thought to have a benign prognosis, recent evidence suggests that they may be increased risk for future cardiac events.

No previous prospective studies have evaluated the prognosis of women who have chest pain without obstructive CAD vs the prognosis in symptomatic women. Even in the absence of obstructive CAD, chest pain and similar symptoms may have important functional ramifications for affected women and economic repercussions for society.

Study Highlights

• The goal of this prospective study was to determine the prognostic implications of cardiac symptoms in women with nonobstructive CAD vs community-dwelling women without cardiac symptoms.
• Women with ischemic symptoms who were referred for clinically indicated coronary angiography in the WISE study (n = 540) were compared with an age-matched and race-matched cohort from the WTH Project.
• The WTH comparison group consisted of 1000 asymptomatic, community-dwelling women free of known CAD at baseline.
• Mean duration of follow-up was 5.2 years in WISE and 10 years in WTH.
• In both cohorts, the cardiovascular endpoint included myocardial infarction, hospitalization for heart failure, stroke, cardiac mortality, and all-cause mortality.
• The primary composite endpoint was cardiovascular events, defined as myocardial infarction, hospitalization for heart failure, stroke, or cardiac death.
• The secondary composite endpoint was myocardial infarction, hospitalization for heart failure, stroke, or all-cause mortality.
• Compared with the matched sample from WISE, the asymptomatic women from WTH had lower prevalence of obesity, family history of CAD, hypertension, and diabetes mellitus (P < .001).
• Nonobstructive CAD was defined as stenosis in any coronary artery of 1% to 49%, and normal coronary arteries were defined as 0% stenosis in all coronary arteries.
• 5-year annualized cardiovascular event rates were 16.0% in women from WISE with nonobstructive CAD, 7.9% in women from WISE with normal coronary arteries, and 2.4% in asymptomatic women from WTH, after adjustment for risk factors for CAD at baseline (P ≤ .002),
• The highest 5-year annualized cardiovascular event rates occurred in women with ≥ 4 cardiac risk factors at baseline: 25.3% in women with nonobstructive CAD, 13.9% in women from WISE with normal coronary arteries, and 6.5% in asymptomatic women (P = .003).
• The investigators concluded that women without obstructive CAD but with symptoms and signs suggesting ischemia are at higher risk for cardiovascular events vs asymptomatic, community-based women.
• Therefore, the investigators recommend that all women with symptoms suggesting ischemia be evaluated for obstructive CAD, with further workup for endothelial dysfunction if results of workup for obstructive CAD are negative.
• Limitations of the study include potential referral bias, volunteer bias, and recall bias, as well as possible confounding.
• Cause of death was confirmed by medical records only for deaths in the WISE cohort, but electrocardiography was not available for the full WISE cohort, preventing adjustment for left ventricular hypertrophy.

Clinical Implications

• Community-dwelling women with symptoms suggesting myocardial ischemia but without findings of obstructive CAD are at greater risk for future cardiovascular events than asymptomatic women. Five-year risk for cardiovascular events in symptomatic women with nonobstructive CAD is almost twice that in symptomatic women with normal coronary arteries.
• The highest 5-year annualized cardiovascular event rates occurred in women with 4 or more cardiac risk factors at baseline: 25.3% in women with nonobstructive CAD, 13.9% in women from WISE with normal coronary arteries, and 6.5% in asymptomatic women.

Source : http://cme.medscape.com/viewarticle/703147?sssdmh=dm1.476505&src=nldne

Give Blood Pressure Drugs to All

Blood-pressure-lowering drugs should be offered to everyone, regardless of their blood pressure level, as a safeguard against coronary heart disease and stroke, researchers who conducted a meta-analysis of 147 randomized trials (comprising 958 000 people) conclude in the May 19 issue of BMJ [1].

“Guidelines on the use of blood-pressure-lowering drugs can be simplified so that drugs are offered to people with all levels of blood pressure,” write Drs Malcolm R Law and Nicholas Wald (Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine, Queen Mary University of London, UK). “Our results indicate the importance of lowering blood pressure in everyone over a certain age, rather than measuring it in everyone and treating it in some.”

“Whatever your blood pressure, you benefit from lowering it further,” Law told heartwire . “Everyone benefits from taking blood-pressure-lowering drugs. There is no one who does not benefit because their blood pressure is so-called normal.”

Six years ago, Law and Wald advocated the use of a polypill--containing a statin, three blood-pressure-lowering drugs (each at half the standard dose), folic acid, and aspirin--which they maintained could prevent heart attacks and stroke if taken by everyone 55 years and older and by everyone with existing cardiovascular disease [2].

In the current meta-analysis, which included people aged 60 to 69, they singled out blood-pressure-lowering drugs to determine the quantitative efficacy of different classes of antihypertensive agents in preventing coronary heart disease (CHD) and stroke. They also sought to determine who should receive treatment.

All Antihypertensives Prevent CHD and Stroke

Overall, the results of the meta-analysis showed that in people aged 60 to 69 with a diastolic blood pressure before treatment of 90 mm Hg or a systolic blood pressure of 150 mm Hg, three drugs at half standard dose in combination (as in the polypill) reduced the risk of CHD by approximately 46% and of stroke by 62%. However, when used individually, a single antihypertensive agent at standard dose had about half this effect.

The five main classes of blood-pressure-lowering drugs--thiazides, beta blockers, angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers, and calcium-channel blockers--were similarly effective in preventing CHD events and strokes, with the exception of calcium-channel blockers, which had a greater preventive effect on stroke than the other four agents (relative risk, 0.92; 95% confidence interval, 0.85 to 0.98).

People with and without cardiovascular disease derived equal benefit, with similar percentage reductions in CHD events and stroke, and regardless of what their blood pressure was before treatment. Even patients with blood pressures considered to be low--110 mm Hg systolic and 70 mm Hg diastolic--showed fewer CHD events and a reduced incidence of stroke when taking an antihypertensive.

Law and Wald also report that calcium-channel blockers reduced the incidence of heart failure by 19%, and that the other antihypertensive agents reduced heart failure by 24%.

In an accompanying editorial [3], Dr Richard McManus (University of Birmingham, UK) and Dr Jonathan Mant (University of Cambridge, UK) write that the findings of Law and Wald will contribute to debate on the management of hypertension in several areas. “Taken at face value, these findings provide tacit support for the use of a ‘polypill’ to lower the risk of cardiovascular disease in people likely to be at high risk (such as all people over the age of 55) without first checking their blood pressure.”

In a comment to heartwire , McManus added that he believes that the findings reinforce the view that treatment to lower blood pressure should be offered on the basis of risk, regardless of blood pressure.

Throwing the Baby Out With the Bath Water

On the other side of the Atlantic, hypertension experts were not so sanguine in their opinion of Law and Wald’s conclusions.

Commenting on this study for heartwire , Dr James Elliott (Rush Medical College, Chicago, IL) said he took issue with the authors’ suggestion that the measuring of blood pressure was unnecessary.

“Professors Wald and Law made the revolutionary comment some years ago that we should abandon blood pressure and simply treat everyone at high CVD risk with their magic polypill, which they claimed reduced heart disease and stroke by 90%.This meta-analysis is an unusual compilation of data that supports that hypothesis.”

Abandoning blood pressure measuring is like throwing the baby out with the bath water, Elliott said.

Elliott also took issue with the meta-analysis, which he called “old-fashioned.”

“I think Wald and Law have become the ultimate lumpers. They have included the 37 studies where beta blockers were used against placebo in people with heart attacks, and they have lumped those in with all the other kinds of therapies that we use to lower blood pressure and prevent other events. Nobody, as far as I can remember, has ever included that set of 37 trials in with the other antihypertensive trials because it represents such a different population. They have done the old-fashioned, simple meta-analysis. But there are better ways to understand the data.”

A Meta-Analysis Is Like a Sausage

Adding his opinion, Dr Franz Messerli (St Luke’s-Roosevelt Hospital Center, New York City) said that by including 147 trials in their meta-analysis, the authors had to make numerous assumptions, “some possibly valid, others clearly not.”

Because the “blood pressure fall was not reported in patients with a history of coronary heart disease, they estimated this fall from a meta-analysis of blood pressure trials. This is clearly inappropriate since the fall in blood pressure depends on the pretreatment level, and patients with coronary heart disease who often are hypotensive (particularly post MI) will not respond the same way as do patients with hypertension,” he told heartwire.

It is little surprise that beta blockers now, all of a sudden, look better than in any other review ever done, Messerli added. “Numerous meta-analyses have clearly demonstrated that beta blockers do not reduce the risk of coronary heart disease in hypertension, despite the fact that they lower blood pressure. Thus, despite its appearance of being bigger and better, this study is yet another example of my dictum: A meta-analysis is like a sausage, only God and the butcher know what goes in it and neither would ever eat any.”

Law and Wald disclosed that they hold patents (granted and pending) on the formulation of a combined pill to simultaneously reduce four cardiovascular risk factors, including blood pressure. McManus disclosed that he has a financial relationship with Sanofi-Aventis, Pfizer, A.Menarini Pharma, and Merck Sharp & Dohme. Elliott and Messerli have disclosed no relevant financial conflicts of interest.

Source : http://www.medscape.com/viewarticle/703216?sssdmh=dm1.476505&src=nldne

New Risk Index Predicts Dementia in Elderly

A new 15-point index that includes both conventional and newly identified dementia risk factors was 81% accurate at identifying older adults who would subsequently develop dementia — a finding that may improve patient selection for future intervention studies.

Deborah E. Barnes, PhD, from the University of California, San Francisco, and colleagues describe the late-life dementia risk index in a study published online May 13 in Neurology.

The researchers tested the new scale in 3375 participants (mean age, 76 years) in the Cardiovascular Health Cognition Study. Fifty-nine percent were women and 15% were African American. None had dementia at baseline.

The index items include older age, poor cognitive test performance, body-mass index, 1 or more apolipoprotein E4 alleles, white-matter disease on cerebral magnetic resonance imaging (MRI), ventricular enlargement on cerebral MRI, internal carotid artery thickening on ultrasound, history of bypass surgery, slow physical performance, and lack of alcohol consumption.

Fourteen percent of the patients (n = 480) developed dementia within 6 years of baseline. This included 56% of subjects with high scores (8 or more points), 23% of subjects with moderate scores (4 to 7 points), and 4% of subjects with low scores (0 to 3 points).

Dr. Barnes told Medscape Psychiatry that the index needs to be validated in different study populations but that most of the risk factors had been identified in previous dementia studies, so there were no true surprises.

"We had hypothesized that the index would include a combination of cardiovascular risk factors, such as hypertension and diabetes, but these turned out to not be as predictive as variables such as brain MRI findings or low cognitive test scores, which are likely to be markers that directly reflect the impact of dementia on the brain," Dr. Barnes said.

Too Expensive for Routine Use?

Constantine Lyketsos, MD, from Johns Hopkins Bayview Medical Center, in Baltimore, Maryland, told Medscape Psychiatry that the index is likely to be very helpful for researchers. "If validated, this will enable us to use dementia risk as a research variable in clinical trials," he said.

Dr. Lyketsos, who is also codirector of the division of geriatric psychiatry and neuropsychiatry and director of the Memory and Alzheimer's Treatment Center, noted that to be clinically useful, an index must include variables that are widely available and not too expensive.

He added that several measures included in the index, such as the Modified Mini-Mental State Exam measure of global cognitive function, the Digit Symbol Substitution Test, carotid Doppler ultrasound to measure intima medial thickness, and the particular type of MRI quantification used, are not routine tests.

"This would be an expensive package of tests for the average person, amounting to thousands of dollars," Dr. Lyketsos said, "particularly as we do not yet have an intervention that we would use for someone with a high-risk score."

Dr. Lyketsos called clinicians' attention to 1 interesting finding — that lack of alcohol consumption is a risk factor for dementia. "People think of alcohol as damaging to cognition, but most data show that low to moderate alcohol consumption actually helps you," he said.

Inclusion of African Americans a Strength

Sharon A. Brangman, MD, who heads the geriatrics division at State University of New York (SUNY) Upstate Medical University, in Syracuse, noted that 1 strong point of this study is that 15% of the subjects were African American.

"Given the increasing racial/cultural diversity of the geriatric population and the higher rates of Alzheimer's disease that are documented in African American and Latino populations (maybe due to the high rates of diabetes and hypertension in these groups), we need to have data that includes these groups and others. I think 15% African American inclusion in this paper is better than most studies," Dr. Brangman said.

Clinically, Dr. Brangman said that this index might help families with long-term planning and physicians in starting therapy early.

"But I am always torn when faced with the dilemma of identifying a terminal condition for which there is no cure," Dr. Brangman said. "Do we increase the emotional burden when we predict a terminal illness that may or may not occur? What are the ethical considerations when using the risk index in the clinical setting if we cannot offer a cure?

"I do think it is important that we are thinking in terms of a risk index, since increasing our understanding of the disease process, especially in its early stages, can only help in better understanding the disease and the eventual identification of beneficial therapies."

Jerson Laks, MD, director of the Alzheimer Center at the Instituto de Psiquiatria in Rio de Janeiro, Brazil, said that the index would potentially be useful in both research and clinical settings. "However, it should prove to have a high sensitivity/specificity, so that the outcome of dementia may be predicted with a low chance of mistake," he warned.

The researchers are currently seeking funding to develop a shorter index that might have greater clinical utility.

The study was supported by the National Heart, Lung and Blood Institute; the National Institute on Aging; the National Institute of Neurological Disorders and Stroke; and the National Institutes of Health. The researchers have disclosed no relevant financial relationships.

Source : http://www.medscape.com/viewarticle/703255?sssdmh=dm1.476505&src=nldne

Intensive Glucose Control Reduces MI and CHD-Event Risk, New Meta-Analysis Shows

A new meta-analysis suggests that intensively controlling blood glucose levels significantly reduces the risk of MI and coronary heart disease (CHD) events and has no effect on all-cause mortality [1]. The findings, which include five of the pivotal diabetes studies that have caused a stir regarding glucose control, support continued therapy that lowers elevated glycated hemoglobin A_1c (HbA_1c) to less than 7.0%, say researchers.

"There has been a huge amount of controversy and concern that the treatments we had been advocating because we believed they were important, even though there wasn't as much evidence as in other areas like cholesterol and blood pressure, might actually be flawed," lead investigator Dr Kausik Ray (University of Cambridge, UK) told heartwire . "The danger is that our patients and physicians start to slip up in control of sugars because they're not actually sure that it's beneficial and might actually be harmful."

Those concerns stemmed particularly from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Action in Diabetes and Vascular Disease (ADVANCE) studies. While ADVANCE showed a reduction in the progression of albuminuria with intensive glucose control, there was no effect on cardiovascular-event rates. ACCORD, on the other hand, was stopped early because of an increased risk of death in patients who underwent intensive blood glucose lowering.

The meta-analysis, however, should help clinicians feel more comfortable adhering to the clinical guideline target of HbA_1c.

"We do need more information about who shouldn't get to aggressive targets, and that we'll only get with further research," added Ray. "What this study does do is help those individuals out there with diabetes and their caregivers and lets them know that what they've been doing is likely safe and is justified."

In an editorial appearing in the May 23, 2009 issue of Lancet alongside the study by Ray and colleagues, Dr Thomas Mazzone (University of Illinois, Chicago) also stresses that clinicians should not undervalue the potential benefits of managing hyperglycemia, especially given the effects on microvascular disease, the observational data linking indices of glycemia control to cardiovascular risk, and pathophysiological studies in type 1 diabetics showing reduced cardiovascular events with tight glycemic control [2].

"A glycosylated hemoglobin of 7% for most patients seems reasonable and safe," writes Mazzone.

Intensive Glucose Control Questioned

In addition to ACCORD and ADVANCE, the Veterans Affairs Diabetes Trial (VADT), a long-term study of US veterans with type 2 diabetes receiving intensive blood glucose control, recently showed that intensive blood glucose lowering in patients had no significant effect on the rates of cardiovascular events, death, or microvascular complications. Long-term follow-up of the United Kingdom Prospective Diabetes Study (UKPDS), however, did show that a strategy of early intensive glucose lowering, either with a sulfonylurea or metformin, had lasting, significant effects not only on major diabetes end points but also on risk of MI or all-cause mortality.

Against this backdrop of differing results, Ray and colleagues performed a meta-analysis of randomized clinical trials, including UKPDS, ADVANCE, VADT, ACCORD, and the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROACTIVE). The five trials enrolled 33 040 patients, and all compared the effects of an intensive glucose-lowering regimen on death and cardiovascular outcomes with standard treatment.

Compared with standard therapy, mean HbA_1c levels were 0.9% lower among those treated with intensive treatment.

During follow-up of approximately 163 000 person-years, which included 1497 MIs, 2318 CHD events, and 2892 all-cause deaths, investigators report that intensive glycemic control resulted in a 17% reduction in MI and a 15% reduction in the risk of CHD events. There was no effect on stroke and no effect on all-cause mortality.

Overall Odds Ratios for Clinical End Points in Meta-Analysis

End point	Odds ratio (95% CI)
Nonfatal MI	0.83 (0.75–0.93)
Coronary heart disease events	0.85 (0.77–0.93)
Stroke	0.93 (0.81–1.06)
All-cause mortality	1.02 (0.87–1.19)

To heartwire , Ray said the meta-analysis shows the importance of large numbers when assessing risk and benefit. He suspects that these earlier studies, such as ADVANCE and VADT, were underpowered and didn't have sufficient follow-up to show an impact on cardiovascular events. The study also showed that glucose control is slightly less effective than blood-pressure and cholesterol reductions for preventing cardiovascular events and that clinicians should first target hypertension and elevated LDL cholesterol and then go after elevated HbA_1c levels, he said.

"Diabetics, as we know, die mostly of vascular disease, and they die about seven years earlier than their nondiabetic counterparts, even though we've made strides in terms of improving outcomes with better blood-pressure control and the use of statins for LDL reduction," said Ray. "There is still residual risk, and this is a further method to reduce that residual risk. If you do all these things together, we know that this is beneficial."

In terms of adverse effects, patients treated with intensive glucose lowering gained more weight, 5.5 pounds, on average, and had almost twice as many severe hypoglycemic events, compared with conventional treatment.

For clinicians, Ray said the study reinforces the recommendations of the American Diabetes Association, American Heart Association, and American College of Cardiology, which state that clinicians should aim to get HbA_1c levels to less than 7.0%. Like these organizations, Ray stressed that treatment should be individualized, however, and agents that avoid weight gain and hypoglycemia should be used.

In his editorial, Mazzone echoed a similar sentiment, noting that the 7% target can be adjusted for patients with lower risks associated with hypoglycemia, such as younger patients with no CHD, and those with higher risks, such as elderly patients with heart disease. Like Ray, Mazzone noted that blood-pressure control and LDL-cholesterol reductions will provide greater benefit toward cardiovascular-disease risk, but it is "premature to conclude that glucose control has no part to play."

Source : http://www.medscape.com/viewarticle/703217?sssdmh=dm1.476505&src=nldne

Recent developments in Alzheimer's disease therapeutics

Abstract

Alzheimer's disease is a devastating neurological disorder that affects more than 37 million people worldwide. The economic burden of Alzheimer's disease is massive; in the United States alone, the estimated direct and indirect annual cost of patient care is at least $100 billion. Current FDA-approved drugs for Alzheimer's disease do not prevent or reverse the disease, and provide only modest symptomatic benefits. Driven by the clear unmet medical need and a growing understanding of the molecular pathophysiology of Alzheimer's disease, the number of agents in development has increased dramatically in recent years. Truly *disease-modifying' therapies that target the underlying mechanisms of Alzheimer's disease have now reached late stages of human clinical trials. Primary targets include beta-amyloid, whose presence and accumulation in the brain is thought to contribute to the development of Alzheimer's disease, and tau protein which, when hyperphosphorylated, results in the self-assembly of tangles of paired helical filaments also believed to be involved in the pathogenesis of Alzheimer's disease. In this review, we briefly discuss the current status of Alzheimer's disease therapies under study, as well the scientific context in which they have been developed.

Review

Synaptotoxic β-amyloid (Aβ) peptide and the plaques composed of aggregated Aβ, as well as the neurofibrillary tangles composed of hyperphosphorylated tau protein, are believed to be central to the pathogenesis of Alzheimer's disease (AD). Although both the amyloid and tangle pathways present multiple opportunities to create disease-modifying therapies for AD, most of the biotech and pharmaceutical industry efforts have focused on the *amyloid hypothesis'; this focus is supported by strong genetic evidence implicating the primacy of the amyloid pathway [1].

Therapeutic strategies aimed at preventing Aβ formation, blocking its aggregation into plaques, lowering its soluble levels in the brain, and disassembling existing amyloid plaques are among the main strategies employed to slow the progression of AD. Recently, a few therapeutic programs have aimed at reducing tau phosphorylation and/or aggregation. Beyond plaque- and tangle-related targets, other aspects of AD pathophysiology, including mitochondrial dysfunction, failure of molecular transport mechanisms, oxidative damage, inflammation, and cell-cycle dysregulation, may also provide therapeutic opportunities. In this review, we will discuss drugs under study that are thought to slow the progression of AD by each of the above-mentioned mechanisms. Key development programs are listed in Table 1.

Table 1. Selected Alzheimer's disease drug development programs

Decreasing Aβ formation through direct binding or altered trafficking

Direct interaction with Aβ may reduce aggregation and accumulation, thereby limiting amyloid-mediated synaptic dysfunction and neurotoxicity.

Tramiprosate

The first anti-amyloid drug to reach a pivotal clinical trial was tramiprosate. Tramiprosate is a glycosaminoglycan mimetic that binds to monomeric Aβ, thereby reducing aggregation and neurotoxicity while promoting clearance from brain [2]. A Phase II trial demonstrated that the drug reduces Aβ42 in the cerebrospinal fluid of patients with AD [3]. The North American Phase III study included 1052 patients with mild to moderate AD, randomly assigned to receive placebo or 100 mg or 150 mg twice daily of tramiprosate. Though treatment was well tolerated, the study failed to demonstrate a beneficial effect on the primary outcomes, change in cognition and clinical stage. Unexplained variance in the planned statistical model may have contributed to these disappointing results. There are currently no additional trials planned utilizing this mechanism of action.

Abeta42 vaccines, monoclonal Aβ antibodies, polyclonal antibodies

Immunotherapy targeting the amyloid peptide is a leading approach to disease-modifying treatment [4]. Mechanistically, molecules that bind Aβ peptide in the blood could *draw' the peptide from the brain through the blood-brain barrier, possibly by a receptor-mediated process. Heparin, gelsolin, and other molecules are thought to *sink' or trap Aβ peptide in the blood and, at least in animal models, reduce Aβ accumulation in the brain [5]. Alternatively, such antibodies, which generally penetrate into the brain to a small but definite extent, may promote microglial phagocytosis and clearance of amyloid.

A Phase II trial of the first-generation amyloid vaccine AN-1792 (Elan/Wyeth), using aggregated amyloid peptide as the immunogen, suggested a positive efficacy trend: patients with AD who developed an antibody response improved over a 12-month period in some neuropsychological tests [6]. However, owing to the development of aseptic meningoencephalitis in 6% of the patients the AN-1792 program was discontinued. A second-generation vaccine, ACC-001 (Elan/Wyeth), which was engineered to have an improved safety profile (with a short Aβ sequence as the immunogen, presumably preventing the induction of a toxic cellular immune response), is now in a Phase II clinical trial. Similar active vaccination programs from Novartis and Merck are also in clinical testing.

Compared with active immunization, passive immunization would incorporate regular intravenous administration of anti-Aβ antibodies which, although cumbersome, could offer more control over safety and efficacy. A number of monoclonal antibodies against various domains of Aβ are currently in development to capitalize on this notion. The furthest along in clinical testing is bapineuzumab (Elan/Wyeth), now being investigated in a series of Phase III trials; a Phase II study of this antibody yielded some encouraging results, particularly in the subgroup of patients not carrying the apolipoprotein ε4 allele. A small Phase II trial of pooled human immunoglobulin (IgIV) which contains naturally occurring anti-amyloid antibodies showed evidence of cognitive and clinical benefits, and a Phase III trial has just been launched.

RAGE Inhibitor

Amyloid is also known to bind to receptors for advanced glycated endproducts (RAGE) on the surface of cells and at the blood-brain barrier; this binding may contribute to inflammation and neuronal death [7]. In laboratory studies, blocking amyloid-RAGE binding can reduce amyloid accumulation and neurotoxicity. PF-04494700 (formerly TTP488) is an orally bioavailable small molecule antagonist of RAGE. It is now being investigated in a Phase II clinical study to determine its potential in AD therapy.

Decreasing Aβ production – gamma-secretase inhibitors

Another approach to lowering the level of Aβ in the brain is to decrease its production. Gamma-secretase is a transmembrane enzyme complex that cleaves the amyloid precursor protein at one end of the Aβ sequence; its activity is required for Aβ generation in brain.

Tarenflurbil

Tarenflurbil, the enantiomer of the non-steroidal anti-inflammatory drug flurbiprofen, modulates the activity of gamma-secretase, thereby reducing Aβ [8]. In a Phase II trial in patients with mild-to-moderate AD, tarenflurbil was safe and well tolerated, but the primary analyses did not show a beneficial effect on cognition or function; post-hoc analyses suggested possible benefit of treatment of mildly affected patients with the highest dose tested [9]. A large 18-month Phase III trial showed no benefit of treatment, and the development program has been discontinued. A plausible explanation for the failure of tarenflurbil is that oral administration produced insufficient brain concentrations to reduce Aβ to a meaningful extent.

Other gamma-secretase inhibitors

A large Phase III study examining treatment with semagacestat (LY450139) [10], a gamma-secretase inhibitor, is currently underway. Earlier studies of this drug demonstrated significant reduction of amyloid peptide generation in blood and cerebrospinal fluid of patients with AD treated with tolerable doses; this is notable in view of concerns that gamma-secretase inhibition may cause serious toxicity mediated by inhibition of Notch cleavage [11].

A number of other candidate anti-amyloid compounds are entering clinical trials. These include inhibitors of beta-secretase (the second endopeptidase involved in Aβ cleavage from its precursor protein), considered by some to be the most promising target of all because it may be an essential component of the amyloid cascade yet its inhibition may be free of serious toxicity [12]. Additional anti-aggregation agents such as scyllo-inositol [13] and compounds that interfere with the interaction of amyloid peptides with metals [14] have also shown some promise.

Targeting tau

Consensus is growing that a truly effective, disease-modifying therapy will have to reduce both amyloid and tau-related pathology. Tau is a microtubule-associated protein, abundant in neurons, which promotes and stabilizes tubulin assembly into microtubules. Hyperphosphorylation of tau interferes with its function and can result in self-assembly into paired helical filaments that form intraneuronal tangles. In the neurobiology underlying the development of AD, there is a progression of hyperphosphorylated tau-bearing tangles appearing initially in the entorhinal cortex and hippocampus, then progressing to neocortex of the temporal, frontal, and parietal cortices. An optimal disease-modifying strategy should interfere with this cascade either by interfering with an upstream causal event (thought by many to be generation of Aβ) or targeting tangle formation directly.

Methylene blue

Methylene blue, a widely used histology dye, has been shown to interfere with tau aggregation [15]. This compound is now being investigated (under the trade name Rember) as a potential treatment for AD. A Phase II study has been completed; some analyses suggested a drug benefit in subsets of participants [16]. Pivotal Phase III trials are planned, with the aim of providing definitive evidence of the efficacy and safety of this approach.

NAP

A small peptide called NAP (AL-108), derived from a natural neurotrophic protein, can be delivered to the central nervous system via intranasal administration [17]. Animal studies indicate that intranasal NAP markedly reduces tau phosphorylation [18], and preliminary human studies have been encouraging.

Neuroprotection

The term neuroprotection refers to mechanisms that protect neurons from degeneration, for example following ischemic injury or as a result of chronic neurodegenerative diseases. AD and other neurodegenerative disorders are associated with oxidative and inflammatory stress and mitochondrial dysfunction. While trials of antioxidants and anti-inflammatory treatments have provided modest or no beneficial effects, efforts to develop effective neuroprotectants continue.

Dimebon

Dimebon is a 25-year-old antihistamine that was studied in Russia as a treatment for AD on the basis of in vitro evidence of cholinesterase inhibition and NMDA receptor antagonism; in fact, the efficacy of Dimebon in AD appears to be unrelated to these activities, but relates rather to a unique mechanism of action involving stabilization of mitochondria. In a 6-month trial of Dimebon (20 mg three times a day) in 183 patients with mild to moderate AD conducted in Russia, the drug showed significant improvement in all cognitive, behavioral and global outcome measures [19]. Further, the benefits of drug treatment were greater after a blinded extension period of 6 months, suggesting the possibility of a disease-modifying effect. The sponsor, Medivation, is now conducting a confirmatory Phase III trial.

Conclusion

Currently, the anti-amyloid strategies are proceeding with the greatest number of candidate drugs. Numerous candidate disease-modifying therapies that target the underlying pathogenic mechanisms of AD are currently in clinical trials. While it is not possible to predict the success of any individual program, one or more are likely to prove effective. Indeed, it seems reasonable to predict that in the not-too-distant future, a synergistic combination of agents will have the capacity to alter the neurodegenerative cascade and reduce the global impact of this devastating disease.

Competing interests

MSR has nothing to disclose. PSA is the recipient of grants from Pfizer and Baxter, and is a consultant to Elan, Wyeth, Eisai, Novartis, Neurochem, Schering-Plough, Bristol Myers Squibb, Lilly, Medivation, Neurophage, Merck and Roche.

Authors' contributions

MSR and PSA each participated in writing and editing of this minireview. Both authors have read and approved the final manuscript.

Acknowledgements

This work has been supported by a grant (U01-AG10483) from the National Institute on Aging.

References

1. Hardy J, Selkoe DJ: The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics.

   Science 2002, 297:353-356. PubMed Abstract | Publisher Full Text

   Return to text

2. Gervais F: GAG mimetics: potential to modify underlying disease process in AD.

   Neurobiol Aging 2004, 25:S11-12.

   Return to text

3. Aisen PS, Saumier D, Briand R, Laurin J, Gervais F, Tremblay P, Garceau D: A Phase II study targeting amyloid-beta with 3APS in mild-to-moderate Alzheimer disease.

   Neurology 2006, 67:1757-1763. PubMed Abstract | Publisher Full Text

   Return to text

4. Relkin NR: Current state of immunotherapy for Alzheimer's disease.

   CNS Spectr 2008, 13(Suppl 16):39-41. PubMed Abstract

   Return to text

5. DeMattos RB, Bales KR, Cummins DJ, Paul SM, Holtzman DM: Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer's disease.

   Science 2002, 295:2264-2267. PubMed Abstract | Publisher Full Text

   Return to text

6. Gilman S, Koller M, Black RS, Jenkins L, Griffith SG, Fox NC, Eisner L, Kirby L, Rovira MB, Forette F, Orgogozo JM: Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial.

   Neurology 2005, 64:1553-1562. PubMed Abstract | Publisher Full Text

   Return to text

7. Chen X, Walker DG, Schmidt AM, Arancio O, Lue LF, Yan SD: RAGE: a potential target for Abeta-mediated cellular perturbation in Alzheimer's disease.

   Curr Mol Med 2007, 7:735-742. PubMed Abstract | Publisher Full Text

   Return to text

8. Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, McLendon DC, Ozols VV, Jessing KW, Zavitz KH, Koo EH, Golde TE: NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo.

   J Clin Invest 2003, 112:440-449. PubMed Abstract | Publisher Full Text | PubMed Central Full Text

   Return to text

9. Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA: Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II trial.

   Lancet Neurol 2008, 7:483-493. PubMed Abstract | Publisher Full Text

   Return to text

10. Fleisher AS, Raman R, Siemers ER, Becerra L, Clark CM, Dean RA, Farlow MR, Galvin JE, Peskind ER, Quinn JF, Sherzai A, Sowell BB, Aisen PS, Thal LJl: Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease.

    Arch Neurol 2008, 65:1031-1038. PubMed Abstract | Publisher Full Text

    Return to text

11. Wolfe MS: Inhibition and modulation of gamma-secretase for Alzheimer's disease.

    Neurotherapeutics 2008, 5:391-398. PubMed Abstract | Publisher Full Text

    Return to text

12. Ghosh AK, Gemma S, Tang J: beta-Secretase as a therapeutic target for Alzheimer's disease.

    Neurotherapeutics 2008, 5:399-408. PubMed Abstract | Publisher Full Text

    Return to text

13. McLaurin J, Golomb R, Jurewicz A, Antel JP, Fraser PE: Inositol stereoisomers stabilize an oligomeric aggregate of Alzheimer amyloid beta peptide and inhibit abeta-induced toxicity.

    J Biol Chem 2000, 275:18495-18502. PubMed Abstract | Publisher Full Text

    Return to text

14. Lannfelt L, Blennow K, Zetterberg H, Batsman S, Ames D, Harrison J, Masters CL, Targum S, Bush AI, Murdoch R, Wilson J, Ritchie CW: Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial.

    Lancet Neurol 2008, 7:779-786. PubMed Abstract | Publisher Full Text

    Return to text

15. Wischik CM, Edwards PC, Lai RY, Roth M, Harrington CR: Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines.

    Proc Natl Acad Sci USA 1996, 93:11213-11218. PubMed Abstract | Publisher Full Text | PubMed Central Full Text

    Return to text

16. Gura T: Hope in Alzheimer's fight emerges from unexpected places.

    Nat Med 2008, 14:894. PubMed Abstract | Publisher Full Text

    Return to text

17. Gozes I, Morimoto BH, Tiong J, Fox A, Sutherland K, Dangoor D, Holser-Cochav M, Vered K, Newton P, Aisen PS, Matsuoka Y, van Dyck CH, Thal L: NAP: research and development of a peptide derived from activity-dependent neuroprotective protein (ADNP).

    CNS Drug Rev 2005, 11:353-368. PubMed Abstract

    Return to text

18. Matsuoka Y, Jouroukhin Y, Gray AJ, Ma L, Hirata-Fukae C, Li HF, Feng L, Lecanu L, Walker BR, Planel E, Arancio O, Gozes I, Aisen PS: A neuronal microtubule-interacting agent, NAPVSIPQ, reduces tau pathology and enhances cognitive function in a mouse model of Alzheimer's disease.

    J Pharmacol Exp Ther 2008, 325:146-153. PubMed Abstract | Publisher Full Text

    Return to text

19. Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, Seely L, Hung D: Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study.

    Lancet 2008, 372:207-215. PubMed Abstract | Publisher Full Text

Source : http://www.biomedcentral.com/1741-7015/7/7

Actual or Simulated Acupuncture Therapy May Be Effective for Chronic Low Back Pain

May 20, 2009 — Actual or simulated acupuncture therapy appears to be more effective than usual care for chronic low back pain, according to the results of a randomized controlled trial reported in the May 11 issue of the Archives of Internal Medicine.

"Acupuncture is a popular complementary and alternative treatment for chronic back pain," write Daniel C. Cherkin, PhD, from the Center for Health Studies in Seattle, Washington, and colleagues. "Recent European trials suggest similar short-term benefits from real and sham acupuncture needling. This trial addresses the importance of needle placement and skin penetration in eliciting acupuncture effects for patients with chronic low back pain."

In this study, 638 adults with chronic mechanical low back pain were assigned to receive individualized acupuncture, standardized acupuncture, simulated acupuncture, or usual care. All acupuncture groups received 10 treatments administered by experienced acupuncturists during a 7-week period. The main endpoints of the study were back-related dysfunction measured with the Roland-Morris Disability Questionnaire (scored 0 - 23) and symptom bothersomeness (scored 0 - 10), evaluated at baseline and after 8, 26, and 52 weeks.

At 8 weeks, improvements in mean dysfunction scores were 2.1 points for those receiving usual care, 4.4 points for individualized acupuncture, 4.5 points for standardized acupuncture, and 4.4 points for simulated acupuncture (P < .001). Compared with participants receiving usual care, those receiving real or simulated acupuncture were more likely to achieve clinically meaningful improvements on the dysfunction scale (60% vs 39%; P < .001).

In the usual-care group, symptoms improved by 0.7 points vs 1.6 to 1.9 points in the treatment groups (P < .001). Clinically meaningful improvements in dysfunction persisted in the treatment groups vs the usual-care group after 1 year (59% - 65% vs 50%, respectively; P = .02), but symptom improvements were not significantly different among groups (P > .05).

"Although acupuncture was found effective for chronic low back pain, tailoring needling sites to each patient and penetration of the skin appear to be unimportant in eliciting therapeutic benefits," the study authors write. "These findings raise questions about acupuncture's purported mechanisms of action. It remains unclear whether acupuncture or our simulated method of acupuncture provide[s] physiologically important stimulation or represent[s] placebo or nonspecific effects."

Limitations of this study include restricting treatment to only the needling component of traditional Chinese acupuncture, predetermined number and duration of treatments, limited conversation between the acupuncturists and the patients, and lack of a medical care comparison group.

"The reduction in long-term exposure to the potential adverse effects of medications is an important benefit that may enhance the safety of conventional medical care," the study authors write. "The number of patients who would need to be treated with insertive or superficial acupuncture stimulation to result in 1 person achieving meaningful improvement in function ranges from 5 (for short-term benefits) to 8 (for persisting benefits)."

A National Institutes of Health Cooperative Agreement with the National Center for Complementary and Alternative Medicine funded this study. Lhasa OMS, Inc, Weymouth, Massachusetts, donated the Seirin acupuncture needles used in this study. The study authors have disclosed no relevant financial relationships.

Arch Intern Med. 2009;169:858-866.

Clinical Context

Back pain is the leading reason for visits to licensed acupuncturists. Recent studies suggest that sham and actual acupuncture are similarly effective in patients with low back pain and superior to usual care and wait-list control.

This is a 4-group randomized controlled trial of patients with chronic low back pain at 2 integrated health delivery systems in the United States to compare the effectiveness of the procedures vs one another and vs usual care.

Study Highlights

• Included were patients aged 18 to 70 years receiving care for low back pain from an integrated health delivery system in Washington state and California.
• Electronic records were used to identify patients with uncomplicated low back pain for the past 3 to 12 months.
• Participants had to have a rating of at least 3 of 10 on the back pain bothersomeness scale.
• Excluded were those with specific causes of low back pain, complicated back problems, contraindications for acupuncture, less than 3 months of back pain, and conditions that might confound results of acupuncture treatment.
• 638 participants were allocated to 1 of 4 groups: individualized acupuncture (n = 157), standard acupuncture (n = 158), simulated acupuncture (n = 162), or usual care (n = 161).
• The individualized group was evaluated by diagnosticians with 7 to 18 years' experience with acupuncture who prescribed individualized Chinese medical treatments, which were then delivered by therapists.
• Therapists delivered the treatments using 18-gauge needles retained for 18 minutes and 74 potential distinct points.
• The standardized group received treatment at 8 points on the lower back and lower leg and were needled for 20 minutes to achieve "de qi"; the needles were twirled for 10 minutes before withdrawal.
• The simulated group received a simulated insertion with a needle guide tube containing a toothpick to imitate the process of inserting the needle to a proper depth.
• 10 treatments per person were offered.
• The usual-care group received no study-related care.
• All participants received a self-care book.
• Primary outcome were back-related symptoms and symptom bothersomeness by the modified Roland-Morris Disability Questionnaire and the bothersomeness scale (0 - 10).
• Secondary outcomes were 26- and 52-week outcomes, physical and mental health components of the Medical Outcomes Study Short-Form 36 Health Survey quality-of-life scale, number of days in bed, number of days lost from work or school, medication use for low back pain, and health service use.
• Mean age was 47 years, 62% were women, 68% were white, and 53% were college graduates.
• Low back pain was moderately bothersome, and two thirds reported at least 1 year of pain and current medication use for pain.
• Participants were moderately optimistic that acupuncture would help (6.7 on a 0 - 10 scale).
• Adherence, defined as completion of 8 or more treatments, was 84% to 90% in the 3 acupuncture groups.
• All groups showed improved function at 8 weeks with an improvement of 4.4 to 4.5 points on the Roland-Morris Disability Questionnaire for all acupuncture vs 2.1 points for the usual-care group.
• The 3 acupuncture groups did not differ in effectiveness for function.
• Superior functional outcomes for the 3 acupuncture groups vs usual care were maintained at 26 weeks (P = .01) and 52 weeks (P = .02).
• By 52 weeks, differences for bothersomeness in the 4 groups were no longer significant.
• Use of medications was lower in the 3 acupuncture groups (47%) vs the usual-care group (59%).
• There were small differences in the Medical Outcomes Study Short-Form 36 Health Survey for both physical and mental components, with the acupuncture groups being superior, but these disappeared by 52 weeks.
• More participants in the usual-care group took days off work or school in the previous month.
• The usual-care group was more likely to report clinician or physical therapist visits (21% vs 11%; P = .001) or visits to a complementary and alternative medicine provider (18% vs 8%; P < .001).
• There were no differences among the 3 acupuncture groups.
• No cost savings were associated with acupuncture.

Clinical Implications

• Use of any of 3 types of acupuncture treatment is associated with superior outcomes of bothersomeness and improved function vs usual care during 8 weeks.
• Individualized, standard, and simulated acupuncture are similarly associated with superior outcomes of medication use, function, and use of health services vs usual care.

Source : http://cme.medscape.com/viewarticle/703032?src=mpnews&spon=34&uac=133298AG

Comprehensive Treatment Effective for Refractory Chronic Daily Headache

NEW YORK (Reuters Health) May 18 - Comprehensive inpatient treatment is effective in the majority of patients with refractory chronic daily headache, according to findings published in the April issue of Headache.

"An evidence-based assessment (2004) concluded that many intractable headache patients benefit from inpatient treatment, and underscored the need for more research, including identification of outcome predictors," Dr. Alvin E. Lake III, and colleagues from Michigan Head-Pain and Neurological Institute, Ann Arbor, write.

The program included intravenous and oral medication programs, withdrawal from overused medications, cognitive behavioral therapy and psychoeducational groups. When needed, patients also received interventional anesthesiology, physical and occupational therapy, and consultation for comorbid conditions. The mean length of stay in the inpatient program was 13 days. Outcome measures included patient-reported pain levels and consensus of medical staff.

A total of 267 patients (212 women and 55 men) from 43 states and Canada completed the program. The mean age of the subjects was 40.3 years. The modal primary diagnosis was intractable chronic daily headache, predominantly migraine (n = 226).

Overall, 158 patients met the criteria for medication overuse headache, primarily involving opioids (n = 127), followed by triptans (n = 39) and ergots (n = 4), and butalbital compounds (n = 28). A total of 115 subjects had both a mood and anxiety disorder. Personality disorders were observed in 70 patients.

Overall, 78% of completers had moderate to significant pain reduction. These patients had comparable improvement in mood, function, and behavior.

The authors report that 84% of patients with medication overuse headache attained moderate to significant improvements in headache control, compared to 69% of non-overusers (p <>

"Comparisons involving the presence or absence of a personality disorder diagnosis found that patients with personality disorders were more often opioid-dependent (62.3% versus 37.7%, p <>Source : http://www.medscape.com/viewarticle/703005?src=mpnews&spon=34&uac=133298AG

Metoclopramide Plus Diphenhydramine Helpful for Severe Nausea, Vomiting During Pregnancy

May 18, 2009 — A protocol including metoclopramide plus diphenhydramine may be helpful for hyperemesis gravidarum (HG), the most severe form of nausea and vomiting during pregnancy, according to the results of a retrospective cohort study reported in the May issue of the European Journal of Obstetrics & Gynecology and Reproductive Biology.

"[HG] is the second most common reason for hospitalisation during pregnancy," write Anaïs Lacasse, BSc, from the University of Montreal in Quebec, Canada, and colleagues. "Since 2002, a new HG treatment protocol consisting of metoclopramide plus diphenhydramine was put in place at CHU Sainte-Justine, affiliated to University of Montreal, Quebec, Canada.

The objectives of this study were to evaluate the effectiveness of this new HG protocol regarding length of hospitalisation for HG, rate of rehospitalisation, evolution of nausea and vomiting symptoms, and rate of adverse events."

From 2002 to 2006, 130 pregnant women diagnosed with HG were treated at CHU Sainte-Justine with the new protocol, consisting of intravenous (IV) metoclopramide 1.2 to 1.8 mg/hour plus diphenhydramine 50 mg every 6 hours. Outcomes in these women were compared with those in a historical control group of 99 women with HG who were treated in the same institution between 1998 and 2001 with IV droperidol 0.5 to 1 mg/hour plus diphenhydramine 25 to 50 mg every 6 hours.

Compared with the old protocol including droperidol, the new protocol was associated with greater improvement in vomiting symptoms (36% vs 21%; P = .0397), with fewer adverse events. Both protocols were associated with similar rates of reduction in nausea symptoms, length of hospitalization (3.7 days vs 3.1 days), and rate of rehospitalisation for HG (19.23% vs 24.44%).

"The new protocol consisting of the combination of metoclopramide and diphenhydramine appears to be a good option in the management of hyperemesis gravidarum," the study authors write. "The combination metoclopramide and diphenhydramine was associated with a higher improvement of vomiting symptoms, and fewer adverse events."

Limitations of this study include that the baseline HG status at first hospitalization was different between the 2 study groups (but the severity of vomiting symptoms on day 1 of the first hospitalization was not different between groups). Other limitations include a lack of data for hematocrit, liver function, blood urea, or creatinine; and a small sample size, limiting conclusions on the safety of metoclopramide plus diphenhydramine during pregnancy.

"The new HG protocol was not better than the droperidol and diphenhydramine combination when looking at improvement of nausea symptoms, length of hospitalisation, and rehospitalisations for HG," the study authors conclude." However, its use is justified given safety concerns regarding the use of droperidol."

The study authors have disclosed no relevant financial relationships.

Eur J Obstet Gynecol Reprod Biol. 2009:143:43-49.

Clinical Context

HG, the most severe form of nausea and vomiting of pregnancy, is intractable vomiting associated with weight loss of at least 5% of prepregnancy weight, dehydration, ketonuria, and hypokalemia. Second only to preterm labor, HG is a leading cause of hospitalization during pregnancy.

There is no gold standard for HG treatment, but droperidol and diphenhydramine have been used since 1998. Warnings about the cardiovascular toxicity of injectable droperidol, including QT prolongations, serious arrhythmia, and sudden death, were issued by the US Food and Drug Administration in December 2001 and subsequently by Health Canada. A new HG protocol replacing droperidol with metoclopramide has been used since June 2002 but has not previously been evaluated.

Study Highlights

• The goals of this retrospective cohort study were to compare a new HG protocol with an old HG protocol in terms of nausea and vomiting symptoms, length of hospitalization for HG, rate of rehospitalization, and rate of adverse events.
• The new protocol consisted of IV metoclopramide 1.2 to 1.8 mg/hour plus diphenhydramine 50 mg every 6 hours.
• The old protocol consisted of IV droperidol 0.5 to 1 mg/hour plus diphenhydramine 25 to 50 mg every 6 hours.
• From 2002 to 2006, 130 pregnant women diagnosed with HG were treated at CHU Sainte-Justine with the new protocol; their outcomes were compared with those in 99 women with HG treated in the same institution between 1998 and 2001 using the old protocol.
• Compared with the old protocol, the new protocol was associated with greater improvement in vomiting symptoms (36% vs 21%; P = .0397).
• The new protocol group had slightly lower improvement in nausea symptoms (50% vs 58%; P = .0398), but this was not thought to be clinically relevant.
• The new HG protocol was associated with significantly fewer adverse events than the old protocol, with dystonia in 0.88% vs 9.2% of the patients (P = .0065), tachycardia in 3.5% vs 14.3% of the patients (P = .0053), and anxiety/nervousness in 3.5% vs 14.3% of the patients (P = .0053).
• Length of hospitalization was similar for both protocols (3.7 days vs 3.1 days).
• Rate of rehospitalization for HG was similar for both protocols (19.23% vs 24.44%).
• The only predictor of rehospitalization for HG in women treated with the new protocol was race (black women were more likely to be rehospitalized for HG than white women).
• The investigators concluded that the new protocol is a good therapeutic option for HG, with greater improvement in vomiting symptoms and fewer adverse events than the old protocol.
• Limitations of this study include different baseline HG status at first hospitalization in the 2 groups, lack of laboratory data, and small sample size limiting conclusions on the safety of metoclopramide plus diphenhydramine during pregnancy.

Clinical Implications

• For treatment of HG, a new protocol consisting of IV metoclopramide 1.2 to 1.8 mg/hour plus diphenhydramine 50 mg every 6 hours appears to be a good therapeutic option for HG, with greater improvement in vomiting symptoms than achieved with the old protocol consisting of IV droperidol 0.5 to 1 mg/hour plus diphenhydramine 25 to 50 mg every 6 hours.
• The new HG protocol was associated with significantly fewer adverse events than the old protocol, with lower rates of dystonia, tachycardia, and anxiety/nervousness. Length of hospitalization and rate of rehospitalization for HG were similar for both protocols.

Source : http://cme.medscape.com/viewarticle/702960?src=mpnews&spon=34&uac=133298AG

World Health Organization Issues Guidelines on Hand Hygiene in Healthcare

May 6, 2009 — The World Health Organization (WHO) has issued Guidelines on Hand Hygiene in Health Care, offering a thorough review of evidence on hand hygiene in healthcare and specific recommendations to improve hygiene practices and reduce transmission of pathogenic microorganisms to patients and healthcare workers (HCWs).

The guidelines target hospital administrators and public health officials as well as HCWs, and they are designed to be used in any setting in which healthcare is delivered either to a patient or to a specific group, including all settings where healthcare is permanently or occasionally performed, such as home care by birth attendants. Individual adaptation of the recommendations is encouraged, based on local regulations, settings, needs, and resources.

Hand Hygiene Indications

Indications for hand hygiene are as follows:

• Wash hands with soap and water when visibly dirty, when soiled with blood or other body fluids, or after using the toilet.

• Handwashing with soap and water is preferred when exposure to potential spore-forming pathogens, such as Clostridium difficile, is strongly suspected or proven.

• In all other clinical situations, use an alcohol-based handrub as the preferred means for routine hand antisepsis, if hands are not visibly soiled. Wash hands with soap and water if alcohol-based handrub is not available.

• Hand hygiene is needed before and after touching the patient; before touching an invasive device used for patient care, whether gloves are used; after contact with body fluids or excretions, mucous membranes, nonintact skin, or wound dressings; if moving from a contaminated body site to another body site on the same patient; after touching inanimate surfaces and objects in the immediate vicinity; and after removing gloves.

• Hand hygiene is needed before handling medication or preparing food using an alcohol-based handrub or handwashing with water and either plain or antimicrobial soap.

• Soap and alcohol-based handrub should not be used together.

Hand Hygiene Techniques

Specific recommendations for hand hygiene technique are as follows:

• Rub a palmful of alcohol-based handrub over all hand surfaces until dry.

• When washing hands, wet hands with water and apply enough soap to cover all surfaces; rinse hands with water and dry thoroughly with a single-use towel. Whenever possible, use clean, running water. Avoid hot water, which may increase the risk for dermatitis.

• Use the towel to turn off the tap or faucet, and do not reuse the towel.

• Liquid, bar, leaf, or powdered soap is acceptable; bars should be small and placed in racks that allow drainage.

Surgical Hand Preparation

Specific recommendations for surgical hand preparation are as follows:

• Before beginning surgical hand preparation, remove jewelry. Artificial nails are prohibited.

• Sinks should be designed to reduce the risk for splashes.

• Visibly soiled hands should be washed with plain soap before surgical hand preparation, and a nail cleaner should be used to remove debris from underneath the fingernails, preferably under running water.

• Brushes are not recommended.

• Before donning sterile gloves, surgical hand antisepsis should be performed with a suitable antimicrobial soap or alcohol-based handrub, preferably one that ensures sustained activity. Alcohol-based handrub should be used when quality of water is not assured.

• When using an antimicrobial soap, scrub hands and forearms for the length of time recommended by the maker, usually 2 to 5 minutes.

• When using an alcohol-based surgical handrub, follow the maker's instructions; apply to dry hands only; do not combine with alcohol-based products sequentially; use enough product to keep hands and forearms wet throughout surgical hand preparation; and allow hands and forearms to dry thoroughly before donning sterile gloves.

Selecting Hand Hygiene Agents

Some specific recommendations for selection and handling of hand hygiene agents are as follows:

• Provide effective hand hygiene products with low potential to cause irritation.

• Ask for HCW input regarding skin tolerance, feel, and fragrance of any products being considered.

• Determine any known interaction between products used for cleaning hands, skin care products, and gloves used in the institution.

• Provide appropriate, accessible, well-functioning, clean dispensers at the point of care, and do not add soap or alcohol-based formulations to a partially empty dispenser.

Skin Care Recommendations

Some specific recommendations for skin care are as follows:

• Educate HCWs about hand-care practices designed to reduce the risk for irritant contact dermatitis and other skin damage.

• Provide alternative hand hygiene products for HCWs with confirmed allergies to standard products.

• Provide HCWs with hand lotions or creams to reduce the risk for irritant contact dermatitis.

• Use of antimicrobial soap is not recommended when alcohol-based handrub is available. Soap and alcohol-based handrub should not be used together.

Recommendations for Glove Use

Some specific recommendations for use of gloves are as follows:

• Glove use does not replace the need for hand hygiene.

• Gloves are recommended in situations in which contact with blood or other potentially infectious materials is likely.

• Remove gloves after caring for a patient, and do not reuse.

• Change or remove gloves if moving from a contaminated body site to either another body site within the same patient or the environment.

"In hand hygiene promotion programmes for HCWs, focus specifically on factors currently found to have a significant influence on behaviour, and not solely on the type of hand hygiene products," the guidelines authors write. "The strategy should be multifaceted and multimodal and include education and senior executive support for implementation. Educate HCWs about the type of patient-care activities that can result in hand contamination and about the advantages and disadvantages of various methods used to clean their hands."

Four of the guidelines authors have disclosed various financial relationships with GOJO, Clorox, and GlaxoSmithKline, and other companies and institutions. A complete description of their disclosures is available in the original article. The other guidelines authors have disclosed no relevant financial relationships.

WHO Guidelines on Hand Hygiene in Health Care. May 2009.

Clinical Context

In 2004, WHO convened a group of international experts in infection control to prepare guidelines for hand hygiene in healthcare. In 2002, the Centers for Disease Control and Prevention Guideline for Hand Hygiene in Health-Care Settings was adopted. Following a systematic review of the literature and task force meetings, the Advanced Draft of the WHO Guidelines on Hand Hygiene in Health Care was published in 2006. An Executive Summary of the Advanced Draft of the Guidelines is available separately (http://www.who.int/gpsc/tools/en/). Pilot testing of the advanced draft occurred, with subsequent updating and finalization of the guidelines.

The WHO Guidelines on Hand Hygiene in Health Care includes a review of scientific data, consensus recommendations, process and outcome measurements, proposals for large scale promotion of hand hygiene, patient participation in promotion of hand hygiene, and a review of national and subnational guidelines. The recommendations are expected to be valid until 2011 and will be updated every 2 to 3 years.

Study Highlights

• Indications for washing hands with soap and water include visibly dirty hands, hands visibly soiled with body fluids, or after using the toilet.
• Handwashing with soap and water is preferred after exposure to potential spore-forming pathogens, including Clostridium difficile outbreaks.
• Alcohol-based handrub is preferred in the following situations if hands are not visibly soiled: before and after touching a patient; before handling an invasive device for patient care; after contact with body fluids or excretions, mucous membranes, nonintact skin, or wound dressings; between contact with a contaminated body site to another site on the same patient; after contact with inanimate surfaces and objects; and after removing sterile or nonsterile gloves.
• Handwashing with soap and water is recommended when alcohol-based handrub is unavailable.
• Alcohol-based handrub or soap and water can be used before handling medication or preparing food.
• Concomitant alcohol-based handrub and soap use is not recommended.
• Soap and water hand-washing technique includes using a towel to turn off the faucet, thorough drying of hands, and single towel use.
• Acceptable forms of soap are liquid, bar, leaf, or powdered.
• Bar soap racks should allow drainage to ensure that the soap dries.
• Alcohol-based handrub technique includes applying palmful amount of handrub, covering all surfaces, and rubbing hands until dry.
• Surgical hand hygiene recommendations include removal of jewelry, no brushes, and use of either antimicrobial soap or alcohol-based handrub according to the maker's recommendations.
• Selection of hand hygiene agents should consider input from HCWs, interaction with other products or gloves, risk for contamination, accessibility and proper functioning of dispensers, approval of dispensers for flammable materials, and cost comparisons.
• Soap or alcohol-based handrub should not be added to partially empty soap dispensers.
• Skin care irritation in HCWs can be avoided by providing educational programs, alternative hand hygiene products for those with allergies or adverse reactions to standard products, and hand moisturizers to reduce irritant contact dermatitis.
• Glove use does not replace the need for handrub or handwashing.
• Gloves should be used if contact with potentially infectious body fluids, mucous membranes, or nonintact skin is anticipated.
• Gloves should be removed or changed after each patient or after contact with a contaminated body site.
• Artificial nails or extenders should not be used, and the length of natural nail tips should be less than 0.5 cm.
• Educational and motivational programs for HCWs should focus on behavior; be multimodal; include senior executive support; educate about the advantages and disadvantages of various hand hygiene methods; monitor adherence and provide performance feedback; and encourage partnership between patients, families, and HCWs.
• Healthcare administrators should provide and monitor safe, continuous water supply; provide alcohol-based handrub at the point of patient care; prioritize compliance; provide leadership, administrative support, and financial resources; ensure training; implement a multidisciplinary, multifaceted, and multimodal program to improve adherence; and adhere to national safety guidelines and local legal requirements.
• National governments should prioritize adherence; consider funded, coordinated implementation and monitoring; support strengthening of infection control in healthcare settings; promote community hand hygiene; and encourage use of hand hygiene as a quality indicator in healthcare settings.

Clinical Implications

• The WHO guidelines recommend handwashing with soap and water for visibly dirty hands, hands visibly soiled with body fluids, after toilet use, exposure to potential spore-forming pathogens, and if alcohol-based handrub is not available in other situations.
• The WHO guidelines recommend alcohol-based handrub before and after touching patients; before handling invasive devices; after contact with body fluids or excretions, mucous membranes, nonintact skin, or wound dressings; between touching contaminated body site and another body site; after contact with inanimate surfaces and objects; and after removing gloves.

Source : http://cme.medscape.com/viewarticle/702403?src=cmenews